U.S. patent application number 14/730843 was filed with the patent office on 2016-01-21 for crystallization method and bioavailability.
This patent application is currently assigned to THAR PHARMACEUTICALS, INC.. The applicant listed for this patent is THAR PHARMACEUTICALS, INC.. Invention is credited to Miranda L. CHENEY, Mazen HANNA, Raymond HOUCK, Ning SHAN, David R. WEYNA.
Application Number | 20160016982 14/730843 |
Document ID | / |
Family ID | 55074000 |
Filed Date | 2016-01-21 |
United States Patent
Application |
20160016982 |
Kind Code |
A1 |
HANNA; Mazen ; et
al. |
January 21, 2016 |
CRYSTALLIZATION METHOD AND BIOAVAILABILITY
Abstract
Preparation and in vitro and in vivo characterization of novel
forms of active pharmaceutical ingredients, suitable for
pharmaceutical compositions in drug delivery systems for
humans.
Inventors: |
HANNA; Mazen; (Lutz, FL)
; SHAN; Ning; (Tampa, FL) ; CHENEY; Miranda
L.; (Bishops Quay, IE) ; WEYNA; David R.;
(Lutz, FL) ; HOUCK; Raymond; (Oakmont,
PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
THAR PHARMACEUTICALS, INC. |
Pittisburgh |
PA |
US |
|
|
Assignee: |
THAR PHARMACEUTICALS, INC.
Pittsburgh
PA
|
Family ID: |
55074000 |
Appl. No.: |
14/730843 |
Filed: |
June 4, 2015 |
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Application
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13567827 |
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9169279 |
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14730843 |
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8399023 |
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12847568 |
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PCT/US10/43892 |
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PCT/US10/43916 |
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61230222 |
Jul 31, 2009 |
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61288036 |
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61302110 |
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61312879 |
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61318503 |
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61359544 |
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61230234 |
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61302110 |
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61333041 |
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61333028 |
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61379814 |
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61455778 |
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61312879 |
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61318503 |
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61359544 |
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61522116 |
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Current U.S.
Class: |
544/277 ;
546/316; 548/112 |
Current CPC
Class: |
C07C 229/08 20130101;
A61K 31/675 20130101; C07F 9/6506 20130101; C07B 2200/13 20130101;
C07C 229/26 20130101; C07D 213/82 20130101; C07D 473/34
20130101 |
International
Class: |
C07F 9/6506 20060101
C07F009/6506; A61K 31/675 20060101 A61K031/675; C07C 229/26
20060101 C07C229/26; C07C 229/08 20060101 C07C229/08; C07D 213/82
20060101 C07D213/82; C07D 473/34 20060101 C07D473/34 |
Claims
1. A composition comprising at least one API and at least one
coformer: wherein said at least one coformer is a molecular complex
coformer and/or an additional coformer; and wherein said API and
said molecular complex coformer form a molecular complex.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 USC 120 as a
Continuation of U.S. patent application Ser. No. 13/567,827, filed
Aug. 6, 2012, which is a continuation-in-Part of U.S. patent
application Ser. No. 12/847,568, filed Jul. 30, 2010, which issued
as U.S. Pat. No. 8,399,023 on Mar. 19, 2013, and which claims the
benefit of U.S. Provisional Application Nos. 61/230,222 filed Jul.
31, 2009, 61/288,036 filed Dec. 18, 2009, 61/302,110 filed Feb. 6,
2010, 61/312,879 filed Mar. 11, 2010, 61/318,503 filed Mar. 29,
2010, and 61/359,544 filed Jun. 29, 2010; U.S. patent application
Ser. No. 13/567,827 is also a Continuation-in-Part of U.S. patent
application Ser. No. 13/387,490, filed Apr. 13, 2012, which issued
as U.S. Pat. No. 8,980,868 on Mar. 17, 2015, and is the National
Stage under 35 USC 371 of PCT International Application No.
PCT/US2010/043916 filed Jul. 30, 2010, which claims benefit of U.S.
Provisional Application No. 61/230,234 filed Jul. 31, 2009; U.S.
patent application Ser. No. 13/567,827 is also a
Continuation-in-Part of PCT International Application No.
PCT/US2011/023427 filed Feb. 2, 2011, which claims the benefit of
U.S. Provisional Application Nos. 61/302,110 filed Feb. 6, 2010,
61/333,041 filed May 10, 2010, 61/333,028 filed May 10, 2010,
61/379,814 filed Sep. 3, 2010, 61/455,778 filed Oct. 26, 2010,
61/312,879 filed Mar. 11, 2010, 61/318,503 filed Mar. 29, 2010, and
61/359,544 filed Jun. 29, 2010, and which is a Continuation-in-Part
of U.S. patent application Ser. No. 12/847,568, filed Jul. 30,
2010, which issued as U.S. Pat. No. 8,399,023 on Mar. 19, 2013, a
Continuation-in-Part of PCT International Application No.
PCT/US10/43916 filed Jul. 30, 2010, and a Continuation-in-Part of
PCT International Application No. PCT/US10/43892 filed Jul. 30,
2010; and U.S. patent application Ser. No. 13/567,827 also claims
priority under 35 USC .sctn.119 to U.S. Provisional Application No.
61/522,116 filed Aug. 10, 2011. The disclosures of each are
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This disclosure pertains to improvement of the aqueous
solubility and permeability of poorly permeable and sparingly water
soluble drug compounds through generating novel crystalline forms
of such drugs. The novel forms include but are not limited to
cocrystals, salts, hydrates, solvates, solvates of salts, and
mixtures thereof. Methods for the preparation and pharmaceutical
compositions suitable for drug delivery systems that include one or
more of these new forms are disclosed.
BACKGROUND OF THE INVENTION
[0003] Many Biopharmaceutics Classification System (BCS) class III
or IV drugs suffer from the lack of gastrointestinal (GI) tract
membrane permeability leading to poor oral bioavailability.
Different strategies have been implemented to improve the
permeability and subsequently the oral bioavailability of such
drugs. For example, the U.S. patent application 20060068010
describes a formulation method for improving the permeability of
drugs and subsequently increasing their bioavailability by
granulation of the physical solid mixture of the drug with one or
more amino acids, at least one inter-granular hydrophilic polymer,
and an additional immediate release excipient. Another application
WO 200602009 A1 disclosed an increase in the oral bioavailability
of poorly permeable bisphosphonate drugs; risedronate, an exemplary
bisphosphonate, was mixed with a chelating agent such as
ethylenediaminetetraacetic acid (EDTA) and other excipients to make
an oral dosage form with enhanced bioavailability. In another
application, WO 2007093226 describes a method for improving the
bioavailability of ibandronate by generating a physical mixture of
the drug together with a modified amino acid (acylation or
sulphonation of the amino group with phenyl or cyclohexyl) and
other excipients. Another application, WO 2003007916 A1, reports a
gastric retention system to improve the bioavailability of a poorly
permeable drug, alendronate, which was orally formulated with
vitamin D and released an hour after the immediate release of
vitamin D. WO 2006080780 discloses yet another method to improve
the permeability and bioavailability of alendronate by mixing it
with a biocompatible cationic polymer (i.e. water soluble chitosan)
with up to a 10:1 weight ratio of the chitosan to the drug, while
the resulting mixture can be formulated into a solid or liquid oral
dosage form. An additional method of improving permeability of drug
materials was discussed in the U.S. patent application 2007/014319
A1, where an oral dosage form was formulated by a powder mixture of
a bisphosphonic acid (e.g. zoledronic acid) together with an
inactive ingredient (either an ester of a medium chain fatty acid
or a lipophilic polyethylene glycol ester). A similar approach was
disclosed in the US application 2007/0238707 A1 where a medium
chain length fatty acid or its derivative (6-20 carbon atom fatty
acid chain) was physically mixed with a poorly permeable drug (e.g.
zoledronic acid) in a capsule that was enterically coated.
[0004] Zoledronic acid, known as
(1-hydroxy-2-imidazol-1-yl-1-phosphono-ethyl)phosphonic acid, is
depicted by the following chemical structure:
##STR00001##
[0005] Zoledronic acid is a third generation bisphosphonate which
far exceeds the previous generations in terms of efficacy and is
used predominately for indications of osteoporosis, Paget's
disease, hypercalcemia, and inhibition of bone metastasis. It was
originally developed by Novartis and marketed as the monohydrate
under the brand names Zometa.RTM. and Reclast.RTM.. Zoledronic acid
was first approved in 2000 for the treatment of hypercalcemia in
Canada. It was later approved for use in the US for hypercalcemia
in 2001, for multiple myeloma and bone metastases from solid tumors
in 2002, and for osteoporosis and Paget's disease in 2007. Clinical
trials have also been conducted and are on-going to explore the use
of zoledronic acid in neoadjuvant or adjuvant cancer therapy,
Coleman, et al., British J Cancer 2010; 102(7):1099-1105, Gnant, et
al., New England J Medicine. 2009, 360 (17):679-691 and Davies, et
al. J Clinical Oncology, 2010, 28(7s): Abstract 8021. Zoledronic
acid is administered as an intravenous (IV) dose of 4 mg over 15
minutes for hypercalcemia of malignancy, multiple myeloma, and bone
metastases from solid tumors, while an IV dose of 5 mg over 15
minutes is used for osteoporosis and Paget's disease.
[0006] Zoledronic acid is sparingly soluble in water and 0.1 N HCl
solution but is freely soluble in 0.1 N NaOH. Zoledronic acid is
practically insoluble in various organic solvents. Much effort has
been taken to generate novel oral formulations of zoledronic acid
through crystallization and metal salt formation to improve its
aqueous solubility, permeability, and subsequent oral
bioavailability. A crystalline trihydrate was disclosed in the U.S.
Patent application 2006/0178439 A1 and world patent application
WO2007/032808. Seven hydrated forms, an amorphous form, three
monosodium salts, and eleven disodium salts with varying degrees of
hydration of zoledronic acid were also disclosed in the patent
application WO2005/005447 A2. Zoledronate metal salts including
Na.sup.+, Mg.sup.2+, Zn.sup.2+ were reported in the journal of
Drugs of the Future (Sorbera et al, Drugs of the Future, 2000,
25(3): 259-268). Zoledronate, zoledronic, or zoledronic salt
represents the ionic form of zoledronic acid. Patent application
WO2008/064849 A1 from Novartis disclosed additional metal salts
including two Ca.sup.2+ salts, two Zn.sup.2+ salts, one Mg.sup.2+
salt, as well as a monohydrate, a trihydrate, an amorphous form,
and an anhydrous form.
[0007] According to the US Food and Drug Administration (FDA)
Summary Basis of Approval (SBA) for zoledronic acid, the poor oral
bioavailability (approximately 1%), is partially due to its poor
permeability in the GI tract. It was also noted that insoluble
metal complexes were formed in the upper intestines, most commonly
with calcium. Zoledronic acid has also been shown to cause severe
gastric and intestinal irritations.
[0008] All of the above attempts to improve the oral
bioavailability of zoledronic acid were either focused on improving
the aqueous solubility by generating novel solid forms; or by
mixing the drug with an inactive ingredient that has enhanced GI
tract permeability. The improvement of aqueous solubility failed to
improve the bioavailability of zoledronic acid, since the formation
of insoluble zoledronate calcium complexes is unlikely to be
prevented. On the other hand, powder mixtures of the poorly
permeable drug with inactive permeability enhancers improved the
bioavailability of the drug. This approach of mixing different
materials with different particle sizes and size distributions
could result in poor blend/physical mixture uniformity.
Constituents of the mixture could also segregate during
transportation or with shaking and vibration. Additionally, the
powder blends require rigorous batch-to-batch consistency to ensure
the uniformity of the blend batches.
[0009] The upward trend in the use of oral drugs continues
especially in light of the goal to decrease the overall cost of
healthcare. Orally administered drugs are becoming more preferred
in various therapeutic areas including oncology. Clearly, there is
an opportunity to create oral dosage forms of drugs with poor
aqueous solubility and/or poor permeability. One such example is
zoledronic acid which is only approved for intravenous
administration due to its low oral bioavailability, resulting from
poor permeability. By using pharmaceutically acceptable and/or
approved coformers to hydrogen or ionically bond with an API, novel
molecular complexes (e.g. cocrystals, salts, solvates, and mixtures
thereof) with improved solubility and/or permeability can be
created. These novel molecular complexes could be used in the
development of novel oral dosage forms of BCS Class III and IV
drugs.
SUMMARY OF THE INVENTION
[0010] The present invention addresses the issue of low oral
bioavailability using two approaches. The first approach represents
a deliberate molecular design in the form of a molecular complex
comprising drug and certain excipient(s) (coformer(s)) in a single
crystalline structure. The benefit of such a design can reduce
batch to batch blend uniformity and particle segregation problems
that powder blends often suffer from. In addition, this invention
simplifies the manufacturing of a solid dosage form (comprised of
drug and excipient) such that the final solid dosage form is, in
one embodiment, a particulate or powder of the molecular complex.
Additionally, the resulting molecular complexes possess very
different physicochemical properties compared to the parent drug or
coformer or the physical mixture thereof. These properties include
but are not limited to melting point, thermal and electrical
conductivity, aqueous solubility, rate of dissolution and
permeability across the GI tract membrane. The second approach
targets the issue of low permeability of BCS class III and IV
drugs. The approach involves combining a low permeability drug with
an amino acid which can increase permeability and subsequent oral
bioavailability.
[0011] The present disclosure is directed towards generating new
forms of APIs, e.g., zoledronic acid, with improved physicochemical
properties, such as improved aqueous solubility, rate of
dissolution, and, particularly, improved permeability resulting in
enhanced bioavailability.
[0012] One aspect of the present invention includes novel molecular
complexes of APIs (e.g., zoledronic acid) in the form of
cocrystals, salts, cocrystals of salts and solvates (including
hydrates and mixed solvates) thereof. In addition, the disclosure
further includes processes of making and methods for using the
molecular complexes. The present invention is further directed to
compositions comprising a molecular complex and additional or
excess coformer, including processes of making and methods of using
the same.
[0013] The present invention is still further directed to
compositions comprising BCS Class III and IV drugs and an
`additional` or `excess` coformer. In this aspect the role of the
coformer is as a functional excipient. The additional coformer of
the invention is particularly an amino acid, more particularly
lysine or glycine, and more particularly lysine, wherein the
coformer, particularly lysine or glycine, more particularly lysine,
increases the oral bioavailability of BCS Class III and IV
drugs.
[0014] In another aspect the present invention provides for a
composition comprising a molecular complex, wherein the molecular
complex comprises an API and at least one coformer. In one
embodiment the molecular complex is a salt. In one embodiment the
salt is a crystal. In another embodiment the molecular complex is a
cocrystal. In another embodiment the molecular complex is a
cocrystal of a salt. In another embodiment the molecular complex is
a crystalline two-component molecular complex between the API and a
single coformer. In another embodiment the molecular complex is a
crystalline three-component molecular complex comprising the API
and the at least one coformer. In a further embodiment the
crystalline three-component molecular complex consists of the API,
a first coformer and a second (different) coformer. In a further
embodiment the crystalline three-component molecular complex
consists of the API, a coformer and a solvent. In a further
embodiment the solvent is water.
[0015] In one aspect the molar ratio of coformer to API is about
1:1. In another aspect the coformer is in molar excess to the API.
In one embodiment the molar ratio of coformer to API is between
about 2:1 and 10:1. In one embodiment the molar ratio of coformer
to API is between about 1:1 and 4:1. In one embodiment the molar
ratio of coformer to API is between about 1:1 and 3:1. In one
embodiment the molar ratio of coformer to API is between about 1:1
and 2:1. In another embodiment the ratio is between about 2:1 and
about 5:1. In another embodiment the ratio is about 1.5:1. In
another embodiment the ratio is about 2:1. In another embodiment
the ratio is about 3:1. In another embodiment the ratio is about
4:1. In another embodiment the ratio is about 5:1
[0016] In one aspect the API is in molar excess to the coformer. In
one embodiment the molar ration of API to coformer is between about
2:1 and about 10:1. In one embodiment the molar ratio of coformer
to API is between about 1:1 and 4:1. In one embodiment the molar
ratio of coformer to API is between about 1:1 and 3:1. In one
embodiment the molar ratio of coformer to API is between about 1:1
and 2:1. In another embodiment the molar ratio is between about 2:1
and about 5:1. In another embodiment the ratio is about 1.5:1. In
another embodiment the molar ratio is about 2:1. In another
embodiment the molar ratio is about 3:1. In another embodiment the
molar ratio is about 4:1. In another embodiment the molar ratio is
about 5:1.
[0017] In another aspect the composition of the present invention
further comprises `additional coformer` that is not in the form of
a molecular complex with the API. In one embodiment the additional
coformer and the coformer that forms a molecular complex with the
API (i.e., the `molecular complex coformer`) are the same. In
another embodiment the additional coformer and the molecular
complex coformer are different. In another embodiment the
additional coformer is crystalline. In another embodiment the
additional coformer is amorphous. In one embodiment the amount of
additional coformer in the composition is greater than the amount
of molecular complex coformer. In another embodiment the mass ratio
of the additional coformer to the molecular complex coformer is
between about 2:1 to about 5000:1. In another embodiment the ratio
is between about 1000:1 to about 5000:1. In another embodiment the
ratio is between about 1000:1 to about 4000:1. In another
embodiment the ratio is between about 2000:1 to about 4000:1. In
another embodiment the ratio is between about 1000:1 to about
2000:1. In another embodiment the ratio is between about 100:1 to
about 2000:1. In another embodiment the ratio is between about
100:1 to about 1000:1. In another embodiment the ratio is between
about 100:1 to about 750:1. In another embodiment the ratio is
between about 100:1 to about 500:1. In another embodiment the ratio
is between about 100:1 to about 275:1. In another embodiment the
ratio is between about 200:1 to about 275:1. In another embodiment
the ratio is between about 175:1 to about 275:1. In another
embodiment the ratio is between about 150:1 to about 250:1. In
another embodiment the ratio is between about 100:1 to about 250:1.
In another embodiment the ratio is between about 100:1 to about
200:1. In another embodiment the ratio is between about 50:1 to
about 200:1. In another embodiment the ratio is between about 50:1
to about 150:1. In another embodiment the ratio is between about
50:1 to about 100:1. In another embodiment the ratio is between
about 2:1 to about 100:1. In another embodiment the ratio is
between about 5:1 to about 100:1. In another embodiment the ratio
is between about 10:1 to about 100:1. In another embodiment the
ratio is between about 11:1 to about 100:1. In another embodiment
the ratio is between about 25:1 to about 100:1. In another
embodiment the ratio is between about 50:1 to about 100:1. In
another embodiment the ratio is between about 75:1 to about 100:1.
In another embodiment the ratio is between about 2:1 to about 50:1.
In another embodiment the ratio is between about 2:1 to about 25:1.
In another embodiment the ratio is between about 2:1 to about 20:1.
In another embodiment the ratio is between about 2:1 to about 15:1.
In another embodiment the ratio is between about 2:1 to about 10:1.
In another embodiment the ratio is between about 2:1 to about 5:1.
In another embodiment the ratio is between about 5:1 to about 50:1.
In another embodiment the ratio is between about 5:1 to about 25:1.
In another embodiment the ratio is between about 5:1 to about 20:1.
In another embodiment the ratio is between about 5:1 to about 15:1.
In another embodiment the ratio is between about 5:1 to about 10:1.
In another embodiment the ratio is between about 10:1 to about
50:1. In another embodiment the ratio is between about 10:1 to
about 25:1. In another embodiment the ratio is between about 10:1
to about 20:1. In another embodiment the ratio is between about
10:1 to about 15:1. In another embodiment the ratio is between
about 11:1 to about 50:1. In another embodiment the ratio is
between about 12:1 to about 50:1. In another embodiment the ratio
is between about 13:1 to about 50:1. In another embodiment the
ratio is between about 14:1 to about 50:1. In another embodiment
the ratio is between about 15:1 to about 50:1. In another
embodiment the ratio is between about 25:1 to about 50:1. In
another embodiment the ratio is between about 35:1 to about 50:1.
In another embodiment the ratio is at least 2:1. In another
embodiment the ratio is at least 5:1. In another embodiment the
ratio is at least 7.5:1. In another embodiment the ratio is at
least 9:1. In another embodiment the ratio is at least 10:1. In
another embodiment the ratio is at least 11:1. In another
embodiment the ratio is at least 12:1. In another embodiment the
ratio is at least 13:1. In another embodiment the ratio is at least
14:1. In another embodiment the ratio is at least 15:1. In another
embodiment the ratio is at least 25:1. In another embodiment the
ratio is at least 35:1. In another embodiment the ratio is at least
50:1. In another embodiment the ratio is at least 65:1. In another
embodiment the ratio is at least 75:1. In another embodiment the
ratio is at least 85:1. In another embodiment the ratio is at least
100:1. In another embodiment the ratio is at least 125:1. In
another embodiment the ratio is at least 150:1. In another
embodiment the ratio is at least 175:1. In another embodiment the
ratio is at least 200:1. In another embodiment the ratio is at
least 225:1. In another embodiment the ratio is at least 250:1. In
another embodiment the ratio is at least 275:1. In another
embodiment the ratio is at least 500:1. In another embodiment the
ratio is at least 750:1. In another embodiment the ratio is at
least 100:1. In another embodiment the ratio is at least 2000:1. In
another embodiment the ratio is at least 3000:1. In another
embodiment the ratio is at least 4000:1.
[0018] In another aspect the invention provides for a composition
comprising an API and additional coformer, wherein the API is
present in its free form, as a free acid or free base, or present
as a salt or cocrystal with one or more coformers that are
different from the additional coformer. In one embodiment the
amount of additional coformer present in the composition is in
excess to the amount of API present in the composition. In another
embodiment the mass ratio of the additional coformer to API is
between about 2:1 to about 5000:1. In another embodiment the ratio
is between about 1000:1 to about 5000:1. In another embodiment the
ratio is between about 1000:1 to about 4000:1. In another
embodiment the ratio is between about 2000:1 to about 4000:1. In
another embodiment the ratio is between about 1000:1 to about
2000:1. In another embodiment the ratio is between about 100:1 to
about 2000:1. In another embodiment the ratio is between about
100:1 to about 1000:1. In another embodiment the ratio is between
about 100:1 to about 750:1. In another embodiment the ratio is
between about 100:1 to about 500:1. In another embodiment the ratio
is between about 100:1 to about 275:1. In another embodiment the
ratio is between about 200:1 to about 275:1. In another embodiment
the ratio is between about 175:1 to about 275:1. In another
embodiment the ratio is between about 150:1 to about 250:1. In
another embodiment the ratio is between about 100:1 to about 250:1.
In another embodiment the ratio is between about 100:1 to about
200:1. In another embodiment the ratio is between about 50:1 to
about 200:1. In another embodiment the ratio is between about 50:1
to about 150:1. In another embodiment the ratio is between about
50:1 to about 100:1. In another embodiment the ratio is between
about 2:1 to about 100:1. In another embodiment the ratio is
between about 5:1 to about 100:1. In another embodiment the ratio
is between about 10:1 to about 100:1. In another embodiment the
ratio is between about 11:1 to about 100:1. In another embodiment
the ratio is between about 11:1 to about 100:1. In another
embodiment the ratio is between about 12:1 to about 100:1. In
another embodiment the ratio is between about 13:1 to about 100:1.
In another embodiment the ratio is between about 14:1 to about
100:1. In another embodiment the ratio is between about 15:1 to
about 100:1. In another embodiment the ratio is between about 25:1
to about 100:1. In another embodiment the ratio is between about
50:1 to about 100:1. In another embodiment the ratio is between
about 75:1 to about 100:1. In another embodiment the ratio is
between about 2:1 to about 50:1. In another embodiment the ratio is
between about 2:1 to about 25:1. In another embodiment the ratio is
between about 2:1 to about 20:1. In another embodiment the ratio is
between about 2:1 to about 15:1. In another embodiment the ratio is
between about 2:1 to about 10:1. In another embodiment the ratio is
between about 2:1 to about 5:1. In another embodiment the ratio is
between about 5:1 to about 50:1. In another embodiment the ratio is
between about 5:1 to about 25:1. In another embodiment the ratio is
between about 5:1 to about 20:1. In another embodiment the ratio is
between about 5:1 to about 15:1. In another embodiment the ratio is
between about 5:1 to about 10:1. In another embodiment the ratio is
between about 10:1 to about 50:1. In another embodiment the ratio
is between about 10:1 to about 25:1. In another embodiment the
ratio is between about 10:1 to about 20:1. In another embodiment
the ratio is between about 10:1 to about 15:1. In another
embodiment the ratio is between about 11:1 to about 50:1. In
another embodiment the ratio is between about 12:1 to about 50:1.
In another embodiment the ratio is between about 13:1 to about
50:1. In another embodiment the ratio is between about 14:1 to
about 50:1. In another embodiment the ratio is between about 15:1
to about 50:1. In another embodiment the ratio is between about
25:1 to about 50:1. In another embodiment the ratio is between
about 35:1 to about 50:1. In another embodiment the ratio is at
least 2:1. In another embodiment the ratio is at least 5:1. In
another embodiment the ratio is at least 7.5:1. In another
embodiment the ratio is at least 9:1. In another embodiment the
ratio is at least 10:1. In another embodiment the ratio is at least
11:1. In another embodiment the ratio is at least 12:1. In another
embodiment the ratio is at least 13:1. In another embodiment the
ratio is at least 14:1. In another embodiment the ratio is at least
15:1. In another embodiment the ratio is at least 17.5:1. In
another embodiment the ratio is at least 20:1. In another
embodiment the ratio is at least 25:1. In another embodiment the
ratio is at least 30:1. In another embodiment the ratio is at least
35:1. In another embodiment the ratio is at least 40:1. In another
embodiment the ratio is at least 50:1. In another embodiment the
ratio is at least 65:1. In another embodiment the ratio is at least
75:1. In another embodiment the ratio is at least 85:1. In another
embodiment the ratio is at least 100:1. In another embodiment the
ratio is at least 125:1. In another embodiment the ratio is at
least 150:1. In another embodiment the ratio is at least 175:1. In
another embodiment the ratio is at least 200:1. In another
embodiment the ratio is at least 225:1. In another embodiment the
ratio is at least 250:1. In another embodiment the ratio is at
least 275:1. In another embodiment the ratio is at least 500:1. In
another embodiment the ratio is at least 750:1. In another
embodiment the ratio is at least 1000:1. In another embodiment the
ratio is at least 2000:1. In another embodiment the ratio is at
least 3000:1. In another embodiment the ratio is at least
4000:1.
[0019] In particular embodiments the invention provides for a
composition of Tables 11-15.
[0020] In another aspect the coformer of the present invention
increases the oral bioavailability of the API. In one embodiment
the coformer increases oral bioavailability of the API by at least
10%. In one embodiment the coformer increases oral bioavailability
of the API by at least 25%. In one embodiment the coformer
increases oral bioavailability of the API by at least 75%. In one
embodiment the coformer increases oral bioavailability of the API
by at least two fold. In one embodiment the coformer increases oral
bioavailability of the API by at least three fold. In one
embodiment the coformer increases oral bioavailability of the API
by at least five fold.
[0021] In another aspect the coformer increases the C.sub.max of
the API. In one embodiment the coformer increases C.sub.max of the
API by at least 10%. In one embodiment the coformer increases
C.sub.max of the API by at least 25%. In one embodiment the
coformer increases C.sub.max of the API by at least 75%. In one
embodiment the coformer increases C.sub.max of the API by at least
two fold. In one embodiment the coformer increases C.sub.max of the
API by at least three fold. In one embodiment the coformer
increases C.sub.max of the API by at least five fold.
[0022] In another aspect the coformer reduces the time to the
T.sub.max of the API. In one embodiment the coformer reduces the
time to the T.sub.max of the API by at least 10%. In one embodiment
the coformer reduces the time to the T.sub.max of the API by at
least 25%. In one embodiment the coformer reduces the time to the
T.sub.max of the API by at least 75%. In one embodiment the
coformer reduces the time to the T.sub.max of the API by at least
two fold. In one embodiment the coformer reduces the time to the
T.sub.max of the API by at least three fold. In one embodiment the
coformer reduces the time to the T.sub.max of the API by at least
five fold.
[0023] In another aspect the coformer increases the permeability of
the API in the small intestine. In one embodiment the coformer
increases the permeability of the API by at least 10%. In one
embodiment the coformer increases the permeability of the API by at
least 25%. In one embodiment the coformer increases the
permeability of the API by at least 75%. In one embodiment the
coformer increases the permeability of the API by at least two
fold. In one embodiment the coformer increases the permeability of
the API by at least three fold. In one embodiment the coformer
increases the permeability of the API by at least five fold.
[0024] Another aspect of the present invention provides for a
method of enhancing the permeability of an API comprising the step
of contacting the API with a coformer to form the molecular complex
of the present invention.
[0025] Another aspect of the present invention provides for a
method of enhancing the oral bioavailability of an API comprising
the step of contacting the API with a coformer to form the
molecular complex of the present invention.
[0026] Another aspect of the present invention provides for a
method of enhancing the permeability of an API comprising the step
of combining the API with a coformer to form a pharmaceutical
composition of the present invention.
[0027] Another aspect of the present invention provides for a
method of enhancing the oral bioavailability of an API comprising
the step of combining the API with a coformer to form a
pharmaceutical composition of the present invention.
[0028] In particular embodiments of the present invention, the API
is abacavir, acarbose, acetazolamide, acyclovir, albuterol
(salbutamol), allopurinol, amiloride, amisulpride, amlodipine,
amoxicillin, amphetamine, atenolol, atropine, azathioprine,
benserazide, benznidazole, camostat, captopril, cefdinir, cefotiam
hexetil hydrochloride, cefprozil, cefuroxime axetil,
chloramphenicol, cimetidine, ciprofloxacin, codeine, colchicine,
cyclophosphamide, dapsone, dexamethasone, didanosine,
diethylcarbamazine, methionine, dolasetron, doxifluridine,
doxycycline, ergonovine, erythromycin ethylsuccinate, ethambutol,
ethosuximide, famotidine, fluconazole, folic acid, furosemide,
fursultiamine, gabapentin, glipizide, granisetron, griseofulvin,
hydralazine, hydrochlorothiazide, imidapril, isoniazid, lamivudine,
l-carbocysteine, levetiracetam, levofloxacin, linezolid,
lisinopril, losartan, methotrexate, methyldopa, s-methylmethionine,
metoclopramide, metronidazole, moxifloxacin, nalidixic acid,
nicorandil, nifurtimox, nitrofurantoin, nizatidine, nystatin,
ondansetron, oseltamivir, oxcarbazepine, penicillamine,
perindopril, phenobarbital, phenoxymethylpenicillin, pravastatin
sodium, prednisolone, primaquine, procaterol, propylthiouracil,
pseudoephedrine, pyrazinamide, pyridostigmine bromide, pyridoxine
hydrochloride, ranitidine, ribavirin, riboflavin, rizatriptan,
stavudine, sulfadiazine, sulfamethoxazole, sultamicillin,
sumatriptan, taltirelin, tegafur, tenofovir disoproxil,
theophylline, thiamine, trimetazidine, trimethoprim, voglibose,
zidovudine, zolmitriptan, acetylcarnitine, capecitabine, cefaclor,
cefixime, cefmetazole, cefpodoxime proxetil, cefroxadine,
alfoscerate, cilazapril, cimetropium bromide, diacerein,
erdosteine, famciclovir, gemifloxacin, levosulpiride, nabumetone,
oxiracetam, phendimetrazine, rabeprazole, roxatidine acetate,
tamsulosin, terazosin, thioctic, tosufloxacin, triflusal,
zaltoprofen, etidronic acid, zoledronic acid, clodronic acid,
tiludronic acid, pamidronic acid, alendronic acid, risedronic acid
or ibandronic acid.
[0029] In one aspect of the present invention the conformer is
selected from the group consisting of sodium, ammonium, ammonia,
L-lysine, DL-lysine, nicotinamide, adenine, and glycine.
[0030] In one aspect of the present invention the coformer is an
amino acid. In one embodiment the coformer is L-lysine. In another
embodiment the coformer is DL-lysine. In another embodiment the
coformer is D-lysine. In another embodiment the coformer is
glycine.
[0031] Another aspect of the present invention provides for a
pharmaceutical composition, wherein the pharmaceutical composition
comprises a composition of the present invention. In one aspect the
pharmaceutical composition further comprises at least one
pharmaceutically acceptable excipient. In another aspect the
pharmaceutical composition consists of a molecular complex of the
present invention. In another aspect the pharmaceutical composition
consists of a molecular complex and an additional coformer of the
present invention. In another aspect the pharmaceutical composition
is an oral dosage form. In another aspect the pharmaceutical
composition is a unit dose.
[0032] Another aspect of the present invention provides for a
method of treating or preventing a disease for which the API is
indicated, the method comprising the step of administering to a
patient in need of the API a therapeutically effective amount of a
pharmaceutical composition of the present invention. In one aspect
the method is for treating such a disease. In another aspect the
method is for preventing such as disease.
[0033] Another aspect of the present invention provides for a
medicament comprising a pharmaceutical composition of the present
invention for use in treating or preventing a disease for which the
API is indicated. In one aspect the medicament is for use in
treating such a disease. In another aspect the medicament is for
use in preventing such a disease.
[0034] Obvious variants of the disclosed forms in the disclosure,
including those described by the drawings, tables and examples,
will be readily apparent to the person of ordinary skill in the art
having the present disclosure and such variants are considered to
be a part of the current invention.
[0035] The various aspects and embodiments of the present invention
expressly provide for combinations in any consistent manner since
providing for all such combinations would unduly lengthen the
specification. For example, the ranges provided for the amount of
API or coformer apply to any one of the individual API-coformer
combination and accordingly, each of which should be considered a
specific embodiment of the present invention. To list each such API
or coformer combination for each range would needlessly lengthen
the specification.
[0036] The following detailed description, including Examples,
which proceeds with reference to the accompanying drawings and
tables are meant to be illustrative, not limiting, of the
invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0037] FIG. 1 shows PXRD diffractograms of: (A=zoledronic acid,
sodium zoledronic salt and water complex), (B=NaCl), (Z1=Zoledronic
acid monohydrate), (Z3=Zoledronic acid trihydrate).
[0038] FIG. 2 is an FTIR spectrum of a complex comprising
zoledronic acid, sodium zoledronic salt, and water.
[0039] FIG. 3 shows PXRD diffractograms of: (C=ammonium zoledronic
salt and water complex), (Z1=Zoledronic acid monohydrate), and
(Z3=Zoledronic acid trihydrate).
[0040] FIG. 4 is an FTIR spectrum of ammonium zoledronic salt and
water complex.
[0041] FIG. 5 shows PXRD diffractograms of: (D=zoledronic,
L-lysine, and water complex), (E=L-lysine), (Z1=Zoledronic acid
monohydrate), and (Z3=Zoledronic acid trihydrate).
[0042] FIG. 6 is an FTIR spectrum of zoledronic, L-lysine, and
water complex.
[0043] FIG. 7 shows PXRD diffractograms of: (F=zoledronic,
DL-lysine, and water complex), (G=DL-lysine), (Z1=Zoledronic acid
monohydrate), and (Z3=Zoledronic acid trihydrate).
[0044] FIG. 8 is an FTIR spectrum of zoledronic, DL-lysine, and
water complex.
[0045] FIG. 9 shows PXRD diffractograms of: (H=zoledronic acid,
zoledronic, DL-lysine, ethanol, and water complex), (G=DL-lysine),
(Z1=Zoledronic acid monohydrate), (Z3=Zoledronic acid
trihydrate).
[0046] FIG. 10 is an FTIR spectrum of zoledronic acid, zoledronic,
DL-lysine, ethanol, and water complex.
[0047] FIG. 11 shows PXRD diffractograms of: (I=zoledronic,
nicotinamide, and water complex), (J=nicotinamide), (Z1=Zoledronic
acid monohydrate), and (Z3=Zoledronic acid trihydrate).
[0048] FIG. 12 is an FTIR spectrum of zoledronic, nicotinamide, and
water complex.
[0049] FIG. 13 shows PXRD diffractograms of: (K=zoledronic,
adenine, and water complex), (L=adenine), (Z1=Zoledronic acid
monohydrate), (Z3=Zoledronic acid trihydrate).
[0050] FIG. 14 is an FTIR spectrum of zoledronic, adenine, and
water complex.
[0051] FIG. 15 shows PXRD diffractograms of: (M=zoledronic and
glycine complex), (N=glycine), (Z1=Zoledronic acid monohydrate),
and (Z3=Zoledronic acid trihydrate).
[0052] FIG. 16 is an FTIR spectrum of zoledronic and glycine
complex.
[0053] FIG. 17 shows PXRD diffractograms of: (0=zoledronic
diammonia water complex), (Z1=Zoledronic acid monohydrate), and
(Z3=Zoledronic acid trihydrate).
[0054] FIG. 18 is an FTIR spectrum of zoledronic diammonia water
complex.
[0055] FIG. 19 shows PXRD diffractograms of: (P=zoledronic,
DL-lysine, and water complex), (G=DL-lysine), (Z1=Zoledronic acid
monohydrate), and (Z3=Zoledronic acid trihydrate).
[0056] FIG. 20 is an FTIR spectrum of zoledronic, DL-lysine, and
water complex.
[0057] FIG. 21 shows PXRD diffractograms of: (R=zoledronic,
DL-lysine, and water complex), (G=DL-lysine), (Z1=Zoledronic acid
monohydrate), and (Z3=Zoledronic acid trihydrate).
[0058] FIG. 22 is an FTIR spectrum of zoledronic, DL-lysine, and
water complex.
[0059] FIG. 23 shows PXRD diffractograms of: (R=zoledronic,
DL-lysine, and water complex), (G=DL-lysine), (Z1=Zoledronic acid
monohydrate), and (Z3=Zoledronic acid trihydrate).
[0060] FIG. 24 is an FTIR spectrum of zoledronic, DL-lysine, and
water complex.
[0061] FIG. 25 shows PXRD diffractograms of: (Q=zoledronic,
L-lysine, and water complex), (E=L-lysine), (Z1=Zoledronic acid
monohydrate), and (Z3=Zoledronic acid trihydrate).
[0062] FIG. 26 is an FTIR spectrum of zoledronic, L-lysine, and
water complex.
[0063] FIG. 27 shows the 24 hr rat plasma PK profile of parent
zoledronic acid and zoledronic acid complexes delivered via IV,
oral, and intraduodenal (ID) routes.
[0064] FIG. 28 shows the 4 hr rat plasma PK profile of parent
zoledronic acid and zoledronic acid complexes delivered orally.
[0065] FIG. 29 shows the 4 hr rat plasma PK profile of parent
zoledronic acid and zoledronic acid complexes delivered ID.
[0066] FIG. 30 shows the 24 hr rat plasma PK profile of parent
zoledronic acid and zoledronic acid complexes delivered by oral
gavage.
[0067] FIG. 31 shows the 4 hr rat plasma PK profile of parent
zoledronic acid and zoledronic acid complexes delivered orally.
[0068] FIG. 32 shows the 4 hr rat plasma PK profile of parent
zoledronic acid and selected zoledronic acid complexes delivered
orally.
[0069] FIG. 33 shows the dog serum PK profile of parent zoledronic
acid and zoledronic acid complexes delivered IV and orally.
[0070] FIG. 34 shows the 4 hr dog serum PK profile of parent
zoledronic acid and zoledronic acid complexes delivered IV and
orally.
[0071] FIG. 35 shows the dog serum PK profile of parent zoledronic
acid and zoledronic acid complexes delivered IV and orally, using
enteric and non-enteric coated capsules.
[0072] FIG. 36 shows the 6 hr dog serum PK profile of parent
zoledronic acid and zoledronic acid complexes delivered IV and
orally, using enteric and non-enteric coated capsules.
[0073] FIG. 37 shows the dog serum PK data for the enteric and
non-enteric coated hard gelatin capsules.
[0074] FIG. 38 shows the 24 hr dog serum PK profile of zoledronic
acid complexes delivered IV and orally.
[0075] FIG. 39 shows the 4 hr dog serum PK profile of zoledronic
acid complexes delivered IV and orally.
[0076] FIG. 40 shows the 4 hr dog serum PK profile of zoledronic
acid complexes delivered orally.
[0077] FIG. 41 shows the 24 hr dog serum PK profile of zoledronic
acid complexes delivered orally.
[0078] FIG. 42 shows the 4 hr dog serum PK profile of zoledronic
acid complex delivered orally.
[0079] FIG. 43 shows the 24 hr dog serum PK profile of zoledronic
acid complex delivered orally.
[0080] FIG. 44 shows the 4 hr dog serum PK profile of zoledronic
acid complex with excess coformer delivered orally.
[0081] FIG. 45 shows the 24 hr dog serum PK profile of zoledronic
acid complex with excess coformer delivered orally.
[0082] FIG. 46 shows PXRD diffractograms of: (P=zoledronic,
DL-lysine, and water complex), (G=DL-lysine), (Z1=Zoledronic acid
monohydrate), and (Z3=Zoledronic acid trihydrate).
[0083] FIG. 47 is an FTIR spectrum of zoledronic, DL-lysine, and
water complex.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0084] Novel API forms and formulations provide an opportunity to
improve the performance characteristics of a pharmaceutical
product. The present disclosure is directed to new forms of active
pharmaceutical ingredients (APIs) with improved physicochemical
properties, such as improved aqueous solubility, rate of
dissolution, and, particularly, increased permeability and
bioavailability.
[0085] The term `active pharmaceutical ingredient(s)` or `API(s)`
refers to the substance in a pharmaceutical drug that is
biologically active.
[0086] As used herein, the terms `treat`, `treating` or `treatment`
means to alleviate, reduce or abrogate one or more symptoms or
characteristics of a disease and may be curative, palliative,
prophylactic or slow the progression of the disease. The term
`therapeutically effective amount` is intended to mean that amount
of drug that will elicit a desired biological or pharmacological
response, i.e., an amount sufficient to treat said disease.
[0087] The term `patient` includes mammals, especially humans. In
one embodiment the patient is a human. In another embodiment the
patient is a human male. In another embodiment the patient is a
human female.
[0088] The term `excipient` refers to a pharmaceutically
acceptable, inactive substance used as a carrier for the
pharmaceutically active ingredient(s) and includes antiadherents,
binders, coatings, disintegrants, fillers, diluents, flavors,
bulkants, colours, glidants, dispersing agents, wetting agents,
lubricants, preservatives, sorbents and sweeteners. The choice of
excipient(s) will depend on factors such as the particular mode of
administration and the nature of the dosage form. The term
`functional excipient` refers to an excipient that improves the
oral bioavailability of a drug, e.g., by increasing absorption,
e.g., increasing paracellular and/or transcellular permeability, or
increasing aqueous solubility.
[0089] The term `oral bioavailability` is defined as AUC.sub.oral
dose.sub.i.v./AUC.sub.i.v.dose.sub.oral100%.
[0090] The term `significant` or `significantly` is determined by
t-test at 0.05 level of significance.
[0091] The term `molecular complex` refers to a material comprised
of two or more unique molecules (in the case of a cocrystal) or
ions (in the case of a salt) that are bonded together, and wherein
one of the molecule/ions is an API and another of the molecule/ions
is a coformer. The API and coformer are bonded either through ionic
bonds (in the case of a salt) or hydrogen bonds (in the case of a
cocrystal), or a combination of both ionic and hydrogen bonds in
the case of a cocrystal of a salt. Other modes of molecular
recognition may also be present including, pi-stacking, guest-host
complexation and van der Waals interactions. The term also includes
solvates, including hydrates, thereof.
[0092] The term `cocrystal` refers to a crystalline material
comprised of two or more unique molecules that are solids at room
temperature, wherein one of the molecules is an API and one of the
molecules is a coformer, wherein the API and coformer are both
solids at room temperature and are bonded together by hydrogen
bonds. Other modes of molecular recognition may also be present
including, pi-stacking, guest-host complexation and van der Waals
interactions. The term includes solvates of cocrystals, i.e., a
solvated cocrystal, including hydrates of the same.
[0093] The term `salt` refers to an ionic compound resulting from
the neutralization reaction of an acid and a base, and in the case
of a composition of the present invention, whereby one of the ions
is an API and one of the ions, of an opposite charge, is a
coformer, whereby the product is neutral (without a net
charge).
[0094] The term `coformer` refers to either (or both) a `molecular
complex coformer` or an `additional coformer` (`excess coformer`).
The term `molecular complex coformer` refers to a coformer that is
a component of a molecular complex with an API. The terms
`additional coformer` or `excess coformer` refers to a coformer of
the present invention that is not bound to the API as part of a
molecular complex, i.e., wherein the coformer is a `functional
excipient`. An `additional coformer` or `excess coformer` may be
present in addition to a `molecular complex coformer` or may be
present in the absence of a `molecular complex coformer` (e.g.,
when an API is a free acid or free base).
[0095] The term `unit dose` refers to the amount of API
administered to a patient in a single dose.
[0096] The present invention is directed in part to pharmaceutical
compositions with increased permeability. In one aspect increased
permeability is achieved through the addition of a coformer to a
pharmaceutical composition comprising an API, wherein the coformer
is an amino acid.
[0097] In one aspect the API is in the form of a molecular complex
with the amino acid or other coformer. In another aspect a portion
of the amino acid is in the form of a molecular complex with the
API (as a molecular complex coformer) and a portion is not bound to
the API (as an additional coformer). In one embodiment the
API-amino acid molecular complex is a cocrystal. In another
embodiment the API and amino acid molecular complex is a salt. In
one embodiment the salt is crystalline. In another embodiment the
amino acid not bound to the API is crystalline (as an additional
coformer only).
[0098] In another aspect the invention provides for a
pharmaceutical composition comprising an amino acid and an API,
wherein the API is a BCS Class III or IV drug. In one embodiment
the API is abacavir. In another embodiment the API is acarbose. In
another embodiment the API is acetazolamide. In another embodiment
the API is acyclovir. In another embodiment the API is albuterol
(salbutamol). In another embodiment the API is allopurinol. In
another embodiment the API is amiloride. In another embodiment the
API is amisulpride. In another embodiment the API is amlodipine. In
another embodiment the API is amoxicillin. In another embodiment
the API is amphetamine. In another embodiment the API is atenolol.
In another embodiment the API is atropine. In another embodiment
the API is azathioprine. In another embodiment the API is
benserazide. In another embodiment the API is benznidazole. In
another embodiment the API is camostat. In another embodiment the
API is captopril. In another embodiment the API is cefdinir. In
another embodiment the API is cefotiam hexetil hydrochloride. In
another embodiment the API is cefprozil. In another embodiment the
API is cefuroxime axetil. In another embodiment the API is
chloramphenicol. In another embodiment the API is cimetidine. In
another embodiment the API is ciprofloxacin. In another embodiment
the API is codeine. In another embodiment the API is colchicine. In
another embodiment the API is cyclophosphamide. In another
embodiment the API is dapsone. In another embodiment the API is
dexamethasone. In another embodiment the API is didanosine. In
another embodiment the API is diethylcarbamazine. In another
embodiment the API is methionine. In another embodiment the API is
dolasetron. In another embodiment the API is doxifluridine. In
another embodiment the API is doxycycline. In another embodiment
the API is ergonovine. In another embodiment the API is
erythromycin ethylsuccinate. In another embodiment the API is
ethambutol. In another embodiment the API is ethosuximide. In
another embodiment the API is famotidine. In another embodiment the
API is fluconazole. In another embodiment the API is folic acid. In
another embodiment the API is furosemide. In another embodiment the
API is fursultiamine. In another embodiment the API is gabapentin.
In another embodiment the API is glipizide. In another embodiment
the API is granisetron. In another embodiment the API is
griseofulvin. In another embodiment the API is hydralazine. In
another embodiment the API is hydrochlorothiazide. In another
embodiment the API is imidapril. In another embodiment the API is
isoniazid. In another embodiment the API is lamivudine. In another
embodiment the API is 1-carbocysteine. In another embodiment the
API is levetiracetam. In another embodiment the API is
levofloxacin. In another embodiment the API is linezolid. In
another embodiment the API is lisinopril. In another embodiment the
API is losartan. In another embodiment the API is methotrexate. In
another embodiment the API is methyldopa. In another embodiment the
API is s-methylmethionine. In another embodiment the API is
metoclopramide. In another embodiment the API is metronidazole. In
another embodiment the API is moxifloxacin. In another embodiment
the API is nalidixic acid. In another embodiment the API is
nicorandil. In another embodiment the API is nifurtimox. In another
embodiment the API is nitrofurantoin. In another embodiment the API
is nizatidine. In another embodiment the API is nystatin. In
another embodiment the API is ondansetron. In another embodiment
the API is oseltamivir. In another embodiment the API is
oxcarbazepine. In another embodiment the API is penicillamine. In
another embodiment the API is perindopril. In another embodiment
the API is phenobarbital. In another embodiment the API is
phenoxymethylpenicillin. In another embodiment the API is
pravastatin sodium. In another embodiment the API is prednisolone.
In another embodiment the API is primaquine. In another embodiment
the API is procaterol. In another embodiment the API is
propylthiouracil. In another embodiment the API is pseudoephedrine.
In another embodiment the API is pyrazinamide. In another
embodiment the API is pyridostigmine bromide. In another embodiment
the API is pyridoxine hydrochloride. In another embodiment the API
is ranitidine. In another embodiment the API is ribavirin. In
another embodiment the API is riboflavin. In another embodiment the
API is rizatriptan. In another embodiment the API is stavudine. In
another embodiment the API is sulfadiazine. In another embodiment
the API is sulfamethoxazole. In another embodiment the API is
sultamicillin. In another embodiment the API is sumatriptan. In
another embodiment the API is taltirelin. In another embodiment the
API is tegafur. In another embodiment the API is tenofovir
disoproxil. In another embodiment the API is theophylline. In
another embodiment the API is thiamine. In another embodiment the
API is trimetazidine. In another embodiment the API is
trimethoprim. In another embodiment the API is voglibose. In
another embodiment the API is zidovudine. In another embodiment the
API is zolmitriptan. In another embodiment the API is
acetylcarnitine. In another embodiment the API is capecitabine. In
another embodiment the API is cefaclor. In another embodiment the
API is cefixime. In another embodiment the API is cefmetazole. In
another embodiment the API is cefpodoxime proxetil. In another
embodiment the API is cefroxadine. In another embodiment the API is
alfoscerate. In another embodiment the API is cilazapril. In
another embodiment the API is cimetropium bromide. In another
embodiment the API is diacerein. In another embodiment the API is
erdosteine. In another embodiment the API is famciclovir. In
another embodiment the API is gemifloxacin. In another embodiment
the API is levosulpiride. In another embodiment the API is
nabumetone. In another embodiment the API is oxiracetam. In another
embodiment the API is phendimetrazine. In another embodiment the
API is rabeprazole. In another embodiment the API is roxatidine
acetate. In another embodiment the API is tamsulosin. In another
embodiment the API is terazosin. In another embodiment the API is
thioctic. In another embodiment the API is tosufloxacin. In another
embodiment the API is triflusal. In another embodiment the API is
zaltoprofen. In another embodiment the API is etidronic acid. In
another embodiment the API is zoledronic acid. In another
embodiment the API is clodronic acid. In another embodiment the API
is tiludronic acid. In another embodiment the API is pamidronic
acid. In another embodiment the API is alendronic acid. In another
embodiment the API is risedronic acid. In another embodiment the
API is ibandronic acid. For each of the above APIs the name
includes the free form as well as salts, cocrystals, and/or
solvates where consistent with the invention.
[0099] In one aspect the amino acid is a standard amino acid. In
particular embodiments the amino acid is isoleucine, alanine,
leucine, asparagine, lysine, aspartic acid, methionine, cysteine,
phenylalanine, glutamic acid, threonine, glutamine, tryptophan,
glycine, valine, proline, serine, tyrosine arginine or histidine.
In another embodiment the amino acid is selenocysteine, ornithine
or taurine. In further particular embodiments the amino acid is the
L-form (e.g., L-lysine). In other particular embodiments the amino
acid is the D-form (e.g., D-lysine). In other particular
embodiments the amino acid is the DL-form (e.g., DL-lysine).
[0100] In one embodiment the API is a BCS Class III or IV drug and
the amino acid is lysine or glycine. In another embodiment the API
is a BCS Class III or IV drug and the amino acid is L-lysine. In
further particular embodiments the L-lysine is an L-lysine hydrate.
In further particular embodiments the L-lysine is an L-lysine salt.
In further particular embodiments the L-lysine salt is an L-lysine
HCl salt. In another embodiment the API is a BCS Class III or IV
drug and the amino acid is D-lysine. In further particular
embodiments the D-lysine is a D-lysine hydrate. In further
particular embodiments the D-lysine is a D-lysine salt. In further
particular embodiments the D-lysine salt is a D-lysine HCl salt. In
another embodiment the API is a BCS Class III or IV drug and the
amino acid is DL-lysine. In further particular embodiments the
DL-lysine is a DL-lysine hydrate. In further particular embodiments
the DL-lysine is a DL-lysine monohydrate. In further particular
embodiments the DL-lysine is a DL-lysine salt. In further
particular embodiments the DL-lysine salt is a DL-lysine HCl salt.
In other particular embodiments the composition is a composition of
Tables 11-15.
[0101] In one aspect, compositions of the present invention
comprising an amino acid have increased permeability of the API
(compared to the corresponding composition without the amino acid).
In one embodiment the compositions comprising an amino acid have
increased paracellular transport of the API. In another embodiment
the compositions comprising an amino acid have increased
transcellular transport of the API. The increase in permeability
results in an increase in bioavailability of the API. Thus the
compositions of the present invention are particularly advantageous
for oral dosage forms.
[0102] In one aspect the pharmaceutical compositions of the present
invention comprising an amino acid have increased the oral
bioavailability of the API (compared to the corresponding
composition without the amino acid). In one embodiment the increase
in oral bioavailability is at least 10%. In another embodiment the
increase in oral bioavailability is at least 25%. In another
embodiment the increase in oral bioavailability is at least 50%. In
another embodiment the increase in oral bioavailability is at least
75%. In another embodiment the increase in oral bioavailability is
at least two fold. In another embodiment the increase in oral
bioavailability is at least three fold.
[0103] In one aspect the majority of the increase in oral
bioavailability is due to the presence of the amino acid. In one
embodiment the amino acid as a molecular complex coformer and/or as
an additional coformer is the only component of a pharmaceutical
composition that significantly increases the oral bioavailability
of the API. In one embodiment the increase in oral bioavailability
is achieved without the need of additional excipients, e.g., an
intra-granular hydrophilic polymer.
[0104] Another aspect of the present invention provides for a
method of enhancing the permeability of an API comprising the step
of combining the API with an amino acid to form a pharmaceutical
composition of the present invention. In another aspect the API is
a BCS Class III or IV drug. In one embodiment the API is a BCS
Class III or IV drug and the amino acid is L-lysine. In a further
particular embodiments the L-lysine is a L-lysine salt or hydrate,
including L-lysine HCl. In another embodiment the API is a BCS
Class III or IV drug and the amino acid is DL-lysine. In a further
particular embodiments the DL-lysine is a DL-lysine salt or
hydrate, including DL-lysine monohydrate. In another embodiment the
API is a BCS Class III or IV drug and the amino acid is D-lysine.
In another embodiment the API is a BCS Class III or IV drug and the
amino acid is glycine.
[0105] In one aspect the pharmaceutical composition consists of or
consists essentially of an API and an amino acid. In one embodiment
the pharmaceutical composition consists of or consists essentially
of a BCS Class III or IV drug and one or more amino acids. In one
embodiment the pharmaceutical composition consists of or consists
essentially of a BCS Class III or IV drug and L-lysine. In another
embodiment the pharmaceutical composition consists of or consists
essentially of a BCS Class III or IV drug and DL-lysine. In a
further aspect the pharmaceutical composition consists of or
consists essentially of a BCS Class III or IV drug and D-lysine. In
one embodiment of the present invention the coformer is glycine. In
another embodiment the pharmaceutical composition further includes
at least one pharmaceutically acceptable excipient.
[0106] In one aspect the pharmaceutical composition is an oral
dosage form. In one embodiment the oral dosage form is a solid oral
dosage form. In one embodiment the oral dosage form is a liquid
oral dosage form. In one embodiment the liquid oral dosage form is
a solution. In another embodiment the liquid oral dosage form is a
suspension. In one embodiment the oral dosage form is a semi-solid
oral dosage form.
[0107] In another aspect the pharmaceutical composition is a unit
dose. In one embodiment the unit dose comprises at least 100 mg of
amino acid. In another embodiment the unit dose comprises at least
250 mg of amino acid. In another embodiment the unit dose comprises
at least 500 mg of amino acid. In another embodiment the unit dose
comprises at least 750 mg of amino acid. In another embodiment the
unit dose comprises at least 800 mg of amino acid. In another
embodiment the unit dose comprises at least 900 mg of amino acid.
In another embodiment the unit dose comprises at least 1000 mg of
amino acid. In another embodiment the unit dose comprises at least
1100 mg of amino acid. In another embodiment the unit dose
comprises at least 1250 mg of amino acid. In another embodiment the
unit dose comprises at least 1750 mg of amino acid. In another
embodiment the unit dose comprises at least 2000 mg of amino acid.
In another embodiment the unit dose comprises at least 2250 mg of
amino acid. In another embodiment the unit dose comprises at least
2500 mg of amino acid. In another embodiment the unit dose
comprises at least 2750 mg of amino acid. In another embodiment the
unit dose comprises at least 3000 mg of amino acid. In another
embodiment the unit dose comprises at least 3250 mg of amino acid.
In another embodiment the unit dose comprises at least 3500 mg of
amino acid. In another embodiment the unit dose comprises at least
4000 mg of amino acid. In another embodiment the unit dose
comprises at least 4500 mg of amino acid. In another embodiment the
unit dose comprises at least 5000 mg of amino acid. In another
embodiment the unit dose comprises at least 6000 mg of amino acid.
In another embodiment the unit dose comprises at least 7000 mg of
amino acid. In another embodiment the unit dose comprises at least
8000 mg of amino acid. In another embodiment the unit dose
comprises at least 9000 mg of amino acid. In another embodiment the
unit dose comprises at least 10 g of amino acid. In another
embodiment the unit dose comprises at least 11 g of amino acid. In
another embodiment the unit dose comprises at least 12 g of amino
acid. In another embodiment the unit dose comprises at least 13 g
of amino acid. In another embodiment the unit dose comprises at
least 14 g of amino acid. In another embodiment the unit dose
comprises at least 15 g of amino acid. In another embodiment the
unit dose comprises at least 16 g of amino acid. In another
embodiment the unit dose comprises at least 17 g of amino acid. In
another embodiment the unit dose comprises at least 18 g of amino
acid. In another embodiment the unit dose comprises at least 19 g
of amino acid. In another embodiment the unit dose comprises at
least 20 g of amino acid. In another embodiment the unit dose
comprises between about 50 to about 5000 mg of amino acid. In
another embodiment the unit dose comprises between about 100 to
about 1000 mg of amino acid. In another embodiment the unit dose
comprises between about 500 to about 1000 mg of amino acid. In
another embodiment the unit dose comprises between about 750 to
about 1000 mg of amino acid. In another embodiment the unit dose
comprises between about 500 to about 1500 mg of amino acid. In
another embodiment the unit dose comprises between about 500 to
about 1250 mg of amino acid. In another embodiment the unit dose
comprises between about 750 to about 1500 mg of amino acid. In
another embodiment the unit dose comprises between about 750 to
about 1250 mg of amino acid. In another embodiment the unit dose
comprises between about 1000 to about 5000 mg of amino acid. In
another embodiment the unit dose comprises between about 1000 to
about 4500 mg of amino acid. In another embodiment the unit dose
comprises between about 1000 to about 4000 mg of amino acid. In
another embodiment the unit dose comprises between about 1000 to
about 3500 mg of amino acid. In another embodiment the unit dose
comprises between about 1000 to about 3000 mg of amino acid. In
another embodiment the unit dose comprises between about 1000 to
about 2500 mg of amino acid. In another embodiment the unit dose
comprises between about 1000 to about 2000 mg of amino acid. In
another embodiment the unit dose comprises between about 1000 to
about 1500 mg of amino acid. In another embodiment the unit dose
comprises between about 1250 to about 5000 mg of amino acid. In
another embodiment the unit dose comprises between about 1250 to
about 4500 mg of amino acid. In another embodiment the unit dose
comprises between about 1250 to about 4000 mg of amino acid. In
another embodiment the unit dose comprises between about 1250 to
about 3500 mg of amino acid. In another embodiment the unit dose
comprises between about 1250 to about 3000 mg of amino acid. In
another embodiment the unit dose comprises between about 1250 to
about 2500 mg of amino acid. In another embodiment the unit dose
comprises between about 1250 to about 2000 mg of amino acid. In
another embodiment the unit dose comprises between about 1250 to
about 1750 mg of amino acid. In another embodiment the unit dose
comprises between about 2000 to about 5000 mg of amino acid. In
another embodiment the unit dose comprises between about 2000 to
about 4500 mg of amino acid. In another embodiment the unit dose
comprises between about 2000 to about 4000 mg of amino acid. In
another embodiment the unit dose comprises between about 2000 to
about 3500 mg of amino acid. In another embodiment the unit dose
comprises between about 2000 to about 3000 mg of amino acid. In
another embodiment the unit dose comprises between about 2000 to
about 2500 mg of amino acid. In another embodiment the unit
dose'comprises between about 3000 to about 5000 mg of amino acid.
In another embodiment the unit dose comprises between about 3000 to
about 4500 mg of amino acid. In another embodiment the unit dose
comprises between about 3000 to about 4000 mg of amino acid. In
another embodiment the unit dose comprises between about 3000 to
about 3500 mg of amino acid. In another embodiment the unit dose
comprises between about 1 g to about 20 g of amino acid. In another
embodiment the unit dose comprises between about 1250 mg to about
20 g of amino acid. In another embodiment the unit dose comprises
between about 1500 mg to about 20 g of amino acid. In another
embodiment the unit dose comprises between about 1 g to about 10 g
of amino acid. In another embodiment the unit dose comprises
between about 1250 mg to about 10 g of amino acid. In another
embodiment the unit dose comprises between about 1500 mg to about
10 g of amino acid. In another embodiment the unit dose comprises
between about 1 g to about 5 g of amino acid. In another embodiment
the unit dose comprises between about 1250 mg to about 5 g of amino
acid. In another embodiment the unit dose comprises between about
1500 mg to about 5 g of amino acid. In another embodiment the unit
dose comprises between about 5 g to about 15 g of amino acid. In
another embodiment the unit dose comprises between about 5 g to
about 10 g of amino acid. In another embodiment the unit dose
comprises between about 7 g to about 10 g of amino acid. In another
embodiment the unit dose comprises between about 10 g to about 20 g
of amino acid. In another embodiment the unit dose comprises
between about 10 g to about 15 g of amino acid. In another
embodiment the unit dose comprises between about 10 g to about 12.5
g of amino acid. In another embodiment the unit dose comprises
between about 12.5 g to about 20 g of amino acid. In another
embodiment the unit dose comprises between about 12.5 g to about
17.5 g of amino acid. In another embodiment the unit dose comprises
between about 15 g to about 20 g of amino acid. In another
embodiment the unit dose comprises between about 17.5 g to about 20
g of amino acid. In another embodiment the unit dose comprises
between about 1 g to about 2 g of amino acid. In another embodiment
the lysine is a lysine salt. In another embodiment the lysine is a
lysine hydrate. In another embodiment the lysine salt is a lysine
HCl salt. In another embodiment the lysine HCl salt is a lysine
monohydrochloride salt. In another embodiment the lysine HCl salt
is a lysine dihydrochloride salt. In another embodiment the lysine
hydrate is a lysine monohydrate. In another embodiment the amino
acid is L-lysine. In another embodiment the L-lysine is a L-lysine
salt. In another embodiment the L-lysine is a L-lysine hydrate. In
another embodiment the L-lysine salt is a L-lysine HCl salt. In
another embodiment the L-lysine HCl salt is a L-lysine
monohydrochloride salt. In another embodiment the L-lysine HCl salt
is a L-lysine dihydrochloride salt. In another embodiment the
L-lysine hydrate is a L-lysine monohydrate. In another embodiment
the amino acid is DL-lysine. In another embodiment the DL-lysine is
a DL-lysine salt. In another embodiment the DL-lysine is a
DL-lysine hydrate. In another embodiment the DL-lysine salt is a
DL-lysine HCl salt. In another embodiment the DL-lysine HCl salt is
a DL-lysine monohydrochloride salt. In another embodiment the
DL-lysine HCl salt is a DL-lysine dihydrochloride salt. In another
embodiment the DL-lysine hydrate is a DL-lysine monohydrate. In
another embodiment the amino acid is D-lysine. In another
embodiment the D-lysine is a D-lysine salt. In another embodiment
the D-lysine is a D-lysine hydrate. In another embodiment the
D-lysine salt is a D-lysine HCl salt. In another embodiment the
D-lysine HCl salt is a D-lysine monohydrochloride salt. In another
embodiment the D-lysine HCl salt is a D-lysine dihydrochloride
salt. In another embodiment the D-lysine hydrate is a D-lysine
monohydrate. In another embodiment the amino acid is glycine. In
another embodiment the API is a BCS Class III or IV drug. In one
embodiment the drug is a BCS Class III or IV drug and the amino
acid is lysine or glycine. In one embodiment the drug is a BCS
Class III or IV drug and the amino acid is L-lysine. In one
embodiment the drug is a BCS Class III or IV drug and the amino
acid is DL-lysine. In one embodiment the drug is a BCS Class III or
IV drug and the amino acid is D-lysine. In one embodiment the drug
is a BCS Class III or IV drug and the amino acid is glycine. In
certain individual embodiments the BCS Class III or IV drug is
abacavir, acarbose, acetazolamide, acyclovir, albuterol
(salbutamol), allopurinol, amiloride, amisulpride, amlodipine,
amoxicillin, amphetamine, atenolol, atropine, azathioprine,
benserazide, benznidazole, camostat, captopril, cefdinir, cefotiam
hexetil hydrochloride, cefprozil, cefuroxime axetil,
chloramphenicol, cimetidine; ciprofloxacin, codeine, colchicine,
cyclophosphamide, dapsone, dexamethasone, didanosine,
diethylcarbamazine, methionine, dolasetron, doxifluridine,
doxycycline, ergonovine, erythromycin ethylsuccinate, ethambutol,
ethosuximide, famotidine, fluconazole, folic acid, furosemide,
fursultiamine, gabapentin, glipizide, granisetron, griseofulvin,
hydralazine, hydrochlorothiazide, imidapril, isoniazid, lamivudine,
l-carbocysteine, levetiracetam, levofloxacin, linezolid,
lisinopril, losartan, methotrexate, methyldopa, s-methylmethionine,
metoclopramide, metronidazole, moxifloxacin, nalidixic acid,
nicorandil, nifurtimox, nitrofurantoin, nizatidine, nystatin,
ondansetron, oseltamivir, oxcarbazepine, penicillamine,
perindopril, phenobarbital, phenoxymethylpenicillin, pravastatin
sodium, prednisolone, primaquine, procaterol, propylthiouracil,
pseudoephedrine, pyrazinamide, pyridostigmine bromide, pyridoxine
hydrochloride, ranitidine, ribavirin, riboflavin, rizatriptan,
stavudine, sulfadiazine, sulfamethoxazole, sultamicillin,
sumatriptan, taltirelin, tegafur, tenofovir disoproxil,
theophylline, thiamine, trimetazidine, trimethoprim, voglibose,
zidovudine, zolmitriptan, acetylcarnitine, capecitabine, cefaclor,
cefixime, cefmetazole, cefpodoxime proxetil, cefroxadine,
alfoscerate, cilazapril, cimetropium bromide, diacerein,
erdosteine, famciclovir, gemifloxacin, levosulpiride, nabumetone,
oxiracetam, phendimetrazine, rabeprazole, roxatidine acetate,
tamsulosin, terazosin, thioctic, tosufloxacin, triflusal,
zaltoprofen, etidronic acid, zoledronic acid, clodronic acid,
tiludronic acid, pamidronic acid, alendronic acid, risedronic acid
or ibandronic acid.
[0108] Another aspect of the present invention provides for a
method of treating or preventing a disease for which an API is
indicated, the method comprising the step of administering to a
patient in need of the API a therapeutically effective amount of a
pharmaceutical composition of the present invention comprising the
API. In one embodiment the method is for treating such a disease.
In another embodiment the method is for preventing such as disease.
Another aspect of the present invention provides for as medicament
comprising a pharmaceutical composition of the present invention
for use in treating or preventing a disease for which the API is
indicated. In one embodiment the medicament is for use in treating
such a disease. In another embodiment the medicament is for use in
preventing such a disease.
Bisphosphonic Acids
[0109] One aspect of the present invention relates to new
crystalline forms and compositions of bisphosphonic acids.
Bisphosphonic acids of the present invention include but are not
limited to zoledronic acid, clodronic acid, tiludronic acid,
pamidronic acid, alendronic acid, risedronic acid or ibandronic
acid. In one aspect the invention relates to zoledronic acid. In
another aspect the invention relates to clodronic acid. In another
aspect the invention relates to tiludronic acid. In another aspect
the invention relates to pamidronic acid. In another aspect the
invention relates to alendronic acid. In another aspect the
invention relates to risedronic acid. In another aspect the
invention relates to ibandronic acid.
[0110] For example, a number of novel zoledronic acid forms and
compositions with improved properties have been synthesized,
characterized, and disclosed herein. Of particular interest are
novel crystalline forms of zoledronic acid and compositions
comprising zoledronic acid and a standard amino acid with enhanced
permeability.
[0111] The results with bisphosphonic acids, e.g., zoledronic acid,
are both surprising and unexpected. For example, it is known that
bisphosphonic acids form insoluble complexes with metal ions such
as Ca.sup.2+. Two means of depleting Ca.sup.2+ in the small
intestine would be to either chelate the metal ion or cause its
absorption before it could bind the bisphosphonic acid. Lysine and
glycine however, are unable to form a coordinate covalent bond with
Ca.sup.2+ based on their structure. At the physiological pH of the
small intestine, which is about 6-6.5 in the duodenum and about 7.5
in the jejunum and ileum, lysine has a net positive charge. Even at
a pH of .gtoreq.10.5, it will carry only a net negative charge of
-1. Similarly, glycine can at most have a net negative charge of
-1, occurring at about pH of .gtoreq.9.7, and thus, cannot form a
coordinate covalent bond with Ca.sup.2+. At physiological pH,
glycine is neutral. Alternatively, if lysine or glycine were acting
to increase absorption of Ca.sup.2+ in the intestine, one would
expect that the amino acid would have to be released into the small
intestine long before the bisphosphonic acid in order provide
enough time for the small intestine to absorb the Ca.sup.2+ present
in the GI tract. PCT publication WO 03/007916 teaches that a
Ca.sup.2+ absorption activator needs to be released into the small
intestine at least one hour before the bisphosphonic acid. The
compositions of the present invention, on the other hand, do not
have additional formulation requirements. The compositions do not
require the bisphosphonic acid to be formulated as a delayed
release. Further the compositions do not have particular
granulation requirements. For example, the compositions do not have
to be granulated with a hydrophilic polymer as do the compositions
of PCT publication WO 06/039499.
[0112] Further unexpected and surprising is the extent to which the
compositions of the present invention improve the oral
bioavailability of bisphosphonic acids. For example, an oral
bioavailability of greater than 8% has been achieved with
zoledronic acid (see Leg 37). The data predicts an oral
bioavailability well over this with increasing amounts of amino
acid. The ability to achieve such high levels of oral
bioavailability has the distinct advantage of being able to lower
the dose of the drug, thereby increasing safety to the patient. In
the case of bisphosphonic acids, side effects center on severe
esophageal and GI irritation and ulceration that are worse when
stringent dosing guidelines are not followed. A lower dose of
bisphosphonic acid should result in reduced esophageal and GI
irritation or ulceration and thus, increased safety to the patient.
Accordingly, one aspect of the invention is an oral dosage form of
a pharmaceutical composition of the present invention comprising a
bisphosphonic acid, wherein said pharmaceutical composition has an
improved safety profile over the corresponding marketed
formulation: in the case of alendronate sodium, marketed as
FOSAMAX; etidronate disodium, marketed as DIDRONEL; ibandronate
sodium, marketed as BONIVA; pamidronate disodium, marketed as
AREDIA; risedronate sodium, marketed as ACTONEL; tiludronate
disodium, marketed as SKELID; zoledronic acid, marketed as ZOMETA
as a 4 mg dose for hypercalcemia of malignancy, metastatic bone
disease, osteoporosis, and Paget's disease and marketed as RECLAST
as a 5 mg annual dose for postmenopausal osteoporosis. Another
aspect of the invention is an oral dosage form of a pharmaceutical
composition of the present invention comprising a bisphosphonic
acid, wherein said pharmaceutical composition has reduced
esophageal and GI irritation or ulceration over the corresponding
bisphosphonic acid or marketed formulation. Another aspect of the
invention is an oral dosage form of a pharmaceutical composition of
the present invention comprising a bisphosphonic acid, wherein the
permeability of said pharmaceutical composition is less affected by
food, i.e., wherein said pharmaceutical composition has a reduced
food effect, compared to that of the corresponding marketed oral
formulation.
[0113] In one aspect the pharmaceutical composition comprises a
bisphosphonic acid and an amino acid. In one embodiment the
pharmaceutical composition comprises zoledronic acid and an amino
acid. In one embodiment the amino acid is lysine or glycine. In
another embodiment the lysine is a lysine salt. In another
embodiment the lysine is a lysine hydrate. In another embodiment
the lysine salt is a lysine HCl salt. In another embodiment the
lysine HCl salt is a lysine monohydrochloride salt. In another
embodiment the lysine HCl salt is a lysine dihydrochloride salt. In
another embodiment the lysine hydrate is a lysine monohydrate. In
another embodiment the amino acid is L-lysine. In another
embodiment the L-lysine is a L-lysine salt. In another embodiment
the L-lysine is a L-lysine hydrate. In another embodiment the
L-lysine salt is a L-lysine HCl salt. In another embodiment the
L-lysine HCl salt is a L-lysine monohydrochloride salt. In another
embodiment the L-lysine HCl salt is a L-lysine dihydrochloride
salt. In another embodiment the L-lysine hydrate is a L-lysine
monohydrate. In another embodiment the amino acid is DL-lysine. In
another embodiment the DL-lysine is a DL-lysine salt. In another
embodiment the DL-lysine is a DL-lysine hydrate. In another
embodiment the DL-lysine salt is a DL-lysine HCl salt. In another
embodiment the DL-lysine HCl salt is a DL-lysine monohydrochloride
salt. In another embodiment the DL-lysine HCl salt is a DL-lysine
dihydrochloride salt. In another embodiment the DL-lysine hydrate
is a DL-lysine monohydrate. In another embodiment the amino acid is
D-lysine. In another embodiment the D-lysine is a D-lysine salt. In
another embodiment the D-lysine is a D-lysine hydrate. In another
embodiment the D-lysine salt is a D-lysine HCl salt. In another
embodiment the D-lysine HCl salt is a D-lysine monohydrochloride
salt. In another embodiment the D-lysine HCl salt is a D-lysine
dihydrochloride salt. In another embodiment the D-lysine hydrate is
a D-lysine monohydrate. In one embodiment the bisphosphonic acid is
zoledronic acid. In another embodiment the bisphosphonic acid is
clodronic acid. In another embodiment the bisphosphonic acid is
tiludronic acid. In another embodiment the bisphosphonic acid is
pamidronic acid. In another embodiment the bisphosphonic acid is
alendronic acid. In another embodiment the bisphosphonic acid is
risedronic acid. In another embodiment the bisphosphonic acid is
ibandronic acid.
[0114] One aspect provides for pharmaceutical composition
comprising zoledronic acid and an amino acid. In one embodiment the
amino acid is lysine or glycine. In another embodiment the lysine
is a lysine salt. In another embodiment the lysine is a lysine
hydrate. In another embodiment the lysine salt is a lysine HCl
salt. In another embodiment the lysine HCl salt is a lysine
monohydrochloride salt. In another embodiment the lysine HCl salt
is a lysine dihydrochloride salt. In another embodiment the lysine
hydrate is a lysine monohydrate. In another embodiment the amino
acid is L-lysine. In another embodiment the L-lysine is a L-lysine
salt. In another embodiment the L-lysine is a L-lysine hydrate. In
another embodiment the L-lysine salt is a L-lysine HCl salt. In
another embodiment the L-lysine HCl salt is a L-lysine
monohydrochloride salt. In another embodiment the L-lysine HCl salt
is a L-lysine dihydrochloride salt. In another embodiment the
L-lysine hydrate is a L-lysine monohydrate. In another embodiment
the amino acid is DL-lysine. In another embodiment the DL-lysine is
a DL-lysine salt. In another embodiment the DL-lysine is a
DL-lysine hydrate. In another embodiment the DL-lysine salt is a
DL-lysine HCl salt. In another embodiment the DL-lysine HCl salt is
a DL-lysine monohydrochloride salt. In another embodiment the
DL-lysine HCl salt is a DL-lysine dihydrochloride salt. In another
embodiment the DL-lysine hydrate is a DL-lysine monohydrate. In
another embodiment the amino acid is D-lysine. In another
embodiment the D-lysine is a D-lysine salt. In another embodiment
the D-lysine is a D-lysine hydrate. In another embodiment the
D-lysine salt is a D-lysine HCl salt. In another embodiment the
D-lysine HCl salt is a D-lysine monohydrochloride salt. In another
embodiment the D-lysine HCl salt is a D-lysine dihydrochloride
salt. In another embodiment the D-lysine hydrate is a D-lysine
monohydrate. In another embodiment the amino acid is glycine. In
another embodiment the pharmaceutical composition has an improved
safety profile over the marketed form. In another embodiment the
pharmaceutical composition has reduced esophageal and GI irritation
or ulceration over the marketed form. In another embodiment the
pharmaceutical composition has reduced food effect over the
marketed form. In another embodiment the pharmaceutical composition
has reduced esophageal and GI irritation or ulceration over the
same pharmaceutical composition except without the amino acid. In
another embodiment the pharmaceutical composition has reduced food
effect over the same pharmaceutical composition except without the
amino acid.
[0115] Schematic diagrams for zoledronic acid:amino acid complexes
(a zoledronic acid:lysine complex and a zoledronic acid:glycine
complex, two embodiments of the invention) are shown below. The
diagrams show a molecular structure of the complex and possible
interactions between the constituents of the complex which is
different from the physical mix of the constituents.
[0116] Zoledronic Acid: Lysine Complex
##STR00002##
[0117] Zoledronic Acid: Glycine Complex
##STR00003##
[0118] These represent one of the arrangements in which the
molecules of the drug and the standard amino acids coformers could
interact to form a stable complex that, even when stressed
thermally in an elevated relative humidity (RH) environment, have
not displayed any signs of deterioration or disintegration to its
original constituents. Such stability can be attributed to the
hydrogen bonding (dashed line in the box) or ionic interactions in
these molecular complexes. When packing in a crystal structure
these complexes exhibit a very different spatial arrangement in
comparison to that of its constituents or their physical mix as
indicated by their powder X-ray diffraction (PXRD) patterns and
therefore would possess different, unpredictable physicochemical
properties.
[0119] The present invention includes new forms and formulations of
bisphosphonic acids including zoledronic acid, with improved
physicochemical properties, such as improved, safety, stability,
aqueous solubility, rate of dissolution, permeability, and/or
enhanced bioavailability.
[0120] One aspect of the present invention includes novel molecular
complexes of bisphosphonic acids (e.g., zoledronic acid) in the
form of cocrystals, salts, mixed cocrystal-salts and solvates (e.g.
hydrates), as well as combinations of such materials. In addition,
the disclosure further includes methods for the preparation of such
molecular complexes.
[0121] In another aspect the present invention provides for a
composition comprising a molecular complex, wherein the molecular
complex comprises a bisphosphonic acid or salt thereof and at least
one coformer. In one embodiment the molecular complex is a salt. In
another embodiment the salt is crystalline. In another embodiment
the molecular complex is a cocrystal. In another embodiment the
molecular complex is a crystalline two-component molecular complex
between the bisphosphonic acid and a single coformer. In another
embodiment the molecular complex is a crystalline three-component
molecular complex comprising the bisphosphonic acid and at least
one coformer. In a further embodiment the crystalline
three-component molecular complex consists of the bisphosphonic
acid, a first coformer and a second (different) coformer. In a
further embodiment the crystalline three-component molecular
complex consists of the bisphosphonic acid, a coformer and a
solvent. In a further embodiment the solvent is water. In one
embodiment the bisphosphonic acid is zoledronic acid. In another
embodiment the bisphosphonic acid is clodronic acid. In another
embodiment the bisphosphonic acid is tiludronic acid. In another
embodiment the bisphosphonic acid is pamidronic acid. In another
embodiment the bisphosphonic acid is alendronic acid. In another
embodiment the bisphosphonic acid is risedronic acid. In another
embodiment the bisphosphonic acid is ibandronic acid.
[0122] In one aspect the molar ratio of coformer to bisphosphonic
acid in the molecular complex is about 1:1. In another aspect the
coformer is in molar excess to the bisphosphonic acid. In one
embodiment the molar ratio of coformer to bisphosphonic acid is
between about 1:1 and about 5:1. In one embodiment the molar ratio
of coformer to bisphosphonic acid is between about 1:1 and about
4:1. In one embodiment the molar ratio of coformer to bisphosphonic
acid is between about 1:1 and about 3:1. In one embodiment the
molar ratio of coformer to bisphosphonic acid is between about 1:1
and about 2:1. In one embodiment the molar ratio of coformer to
bisphosphonic acid is between about 2:1 and about 3:1. In one
embodiment the molar ratio of coformer to bisphosphonic acid is
between about 2:1 and about 10:1. In a further embodiment the molar
ratio is between about 2:1 and about 5:1. In a further embodiment
the molar ratio is about 2:1. In another embodiment the molar ratio
is about 3:1. In another embodiment the molar ratio is about 4:1.
In another embodiment the molar ratio is about 5:1. In another
aspect the bisphosphonic acid is in molar excess to the coformer.
In one embodiment the molar ratio is between about 1:1 and about
5:1. In one embodiment the molar ratio is between about 1:1 and
about 4:1. In one embodiment the molar ratio is between about 1:1
and about 3:1. In one embodiment the molar ratio is between about
1:1 and about 2:1. In one embodiment the molar ratio is between
about 2:1 and about 3:1. In one embodiment the molar ratio is
between about 2:1 and about 10:1. In another embodiment the molar
ratio is between about 2:1 and about 5:1. In another embodiment the
molar ratio is about 2:1. In another embodiment the molar ratio is
about 3:1. In another embodiment the molar ratio is about 4:1. In
another embodiment the molar ratio is about 5:1. In one embodiment
the bisphosphonic acid is zoledronic acid. In another embodiment
the bisphosphonic acid is clodronic acid. In another embodiment the
bisphosphonic acid is tiludronic acid. In another embodiment the
bisphosphonic acid is pamidronic acid. In another embodiment the
bisphosphonic acid is alendronic acid. In another embodiment the
bisphosphonic acid is risedronic acid. In another embodiment the
bisphosphonic acid is ibandronic acid.
[0123] In one aspect the composition of the present invention
further comprises additional coformer. In one embodiment the
additional coformer and the coformer that forms a molecular complex
with the bisphosphonic acid, i.e., the molecular complex coformer,
are the same. In another embodiment the additional coformer and the
molecular complex coformer are different. In another embodiment the
additional coformer is crystalline. In another embodiment the
additional coformer is amorphous. In another embodiment the amount
of additional coformer is in excess to the amount of molecular
complex coformer. In another embodiment the mass ratio of the
additional coformer to the molecular complex coformer is between
about 2:1 to about 5000:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
1000:1 to about 5000:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
1000:1 to about 4000:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
2000:1 to about 4000:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
1000:1 to about 2000:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
100:1 to about 2000:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
100:1 to about 1000:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
100:1 to about 750:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
100:1 to about 500:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
100:1 to about 275:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
200:1 to about 275:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
175:1 to about 275:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
150:1 to about 250:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
100:1 to about 250:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
100:1 to about 200:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
50:1 to about 200:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
50:1 to about 150:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
50:1 to about 100:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
2:1 to about 100:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
5:1 to about 100:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
10:1 to about 100:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
11:1 to about 100:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
25:1 to about 100:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
50:1 to about 100:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
75:1 to about 100:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
2:1 to about 50:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
2:1 to about 25:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
2:1 to about 20:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
2:1 to about 15:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
2:1 to about 10:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
2:1 to about 5:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
5:1 to about 50:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
5:1 to about 25:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
5:1 to about 20:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
5:1 to about 15:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
5:1 to about 10:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
10:1 to about 50:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
10:1 to about 25:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
10:1 to about 20:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
10:1 to about 15:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
11:1 to about 50:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
15:1 to about 50:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
25:1 to about 50:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is between about
35:1 to about 50:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is at least 2:1.
In another embodiment the mass ratio of additional coformer to
molecular complex coformer is at least 5:1. In another embodiment
the mass ratio of additional coformer to molecular complex coformer
is at least 7.5:1. In another embodiment the ratio is at least 9:1.
In another embodiment the mass ratio of additional coformer to
molecular complex coformer is at least 10:1. In another embodiment
the mass ratio of additional coformer to molecular complex coformer
is at least 11:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is at least 15:1.
In another embodiment the mass ratio of additional coformer to
molecular complex coformer is at least 25:1. In another embodiment
the mass ratio of additional coformer to molecular complex coformer
is at least 35:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is at least 50:1.
In another embodiment the mass ratio of additional coformer to
molecular complex coformer is at least 65:1. In another embodiment
the mass ratio of additional coformer to molecular complex coformer
is at least 75:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is at least 85:1.
In another embodiment the mass ratio of additional coformer to
molecular complex coformer is at least 100:1. In another embodiment
the mass ratio of additional coformer to molecular complex coformer
is at least 125:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is at least
150:1. In another embodiment the mass ratio of additional coformer
to molecular complex coformer is at least 175:1. In another
embodiment the mass ratio of additional coformer to molecular
complex coformer is at least 200:1. In another embodiment the mass
ratio of additional coformer to molecular complex coformer is at
least 225:1. In another embodiment the mass ratio of additional
coformer to molecular complex coformer is at least 250:1. In
another embodiment the mass ratio of additional coformer to
molecular complex coformer is at least 275:1. In another embodiment
the mass ratio of additional coformer to molecular complex coformer
is at least 500:1. In another embodiment the mass ratio of
additional coformer to molecular complex coformer is at least
750:1. In another embodiment the mass ratio of additional coformer
to molecular complex coformer is at least 1000:1. In another
embodiment the mass ratio of additional coformer to molecular
complex coformer is at least 2000:1. In another embodiment the mass
ratio of additional coformer to molecular complex coformer is at
least 3000:1. In another embodiment the mass ratio of additional
coformer to molecular complex coformer is at least 4000:1.
[0124] Another aspect of the invention provides for a composition
comprising a bisphosphonic acid and a coformer, wherein the
bisphosphonic acid and coformer are not associated in a molecular
complex, i.e., a composition comprising additional conformer but
not a molecular complex coformer. In one embodiment the amount of
additional coformer present in the composition is in excess to the
amount of bisphosphonic acid present in the composition. In another
embodiment the mass ratio of the additional coformer to
bisphosphonic acid is between about 2:1 to about 5000:1. In another
embodiment the mass ratio of additional coformer to bisphosphonic
acid is between about 1000:1 to about 5000:1. In another embodiment
the mass ratio of additional coformer to bisphosphonic acid is
between about 1000:1 to about 4000:1. In another embodiment the
mass ratio of additional coformer to bisphosphonic acid is between
about 2000:1 to about 4000:1. In another embodiment the mass ratio
of additional coformer to bisphosphonic acid is between about
1000:1 to about 2000:1. In another embodiment the mass ratio of
additional coformer to bisphosphonic acid is between about 100:1 to
about 2000:1. In another embodiment the mass ratio of additional
coformer to bisphosphonic acid is between about 100:1 to about
1000:1. In another embodiment the mass ratio of additional coformer
to bisphosphonic acid is between about 100:1 to about 750:1. In
another embodiment the mass ratio of additional coformer to
bisphosphonic acid is between about 100:1 to about 500:1. In
another embodiment the mass ratio of additional coformer to
bisphosphonic acid is between about 100:1 to about 275:1. In
another embodiment the mass ratio of additional coformer to
bisphosphonic acid is between about 200:1 to about 275:1. In
another embodiment the mass ratio of additional coformer to
bisphosphonic acid is between about 175:1 to about 275:1. In
another embodiment the mass ratio of additional coformer to
bisphosphonic acid is between about 150:1 to about 250:1. In
another embodiment the mass ratio of additional coformer to
bisphosphonic acid is between about 100:1 to about 250:1. In
another embodiment the mass ratio of additional coformer to
bisphosphonic acid is between about 100:1 to about 200:1. In
another embodiment the mass ratio of additional coformer to
bisphosphonic acid is between about 50:1 to about 200:1. In another
embodiment the mass ratio of additional coformer to bisphosphonic
acid is between about 50:1 to about 150:1. In another embodiment
the mass ratio of additional coformer to bisphosphonic acid is
between about 50:1 to about 100:1. In another embodiment the mass
ratio of additional coformer to bisphosphonic acid is between about
2:1 to about 100:1. In another embodiment the mass ratio of
additional coformer to bisphosphonic acid is between about 5:1 to
about 100:1. In another embodiment the mass ratio of additional
coformer to bisphosphonic acid is between about 10:1 to about
100:1. In another embodiment the mass ratio of additional coformer
to bisphosphonic acid is between about 11:1 to about 100:1. In
another embodiment the mass ratio of additional coformer to
bisphosphonic acid is between about 25:1 to about 100:1. In another
embodiment the mass ratio of additional coformer to bisphosphonic
acid is between about 50:1 to about 100:1. In another embodiment
the mass ratio of additional coformer to bisphosphonic acid is
between about 75:1 to about 100:1. In another embodiment the mass
ratio of additional coformer to bisphosphonic acid is between about
2:1 to about 50:1. In another embodiment the mass ratio of
additional coformer to bisphosphonic acid is between about 2:1 to
about 25:1. In another embodiment the mass ratio of additional
coformer to bisphosphonic acid is between about 2:1 to about 20:1.
In another embodiment the mass ratio of additional coformer to
bisphosphonic acid is between about 2:1 to about 15:1. In another
embodiment the mass ratio of additional coformer to bisphosphonic
acid is between about 2:1 to about 10:1. In another embodiment the
mass ratio of additional coformer to bisphosphonic acid is between
about 2:1 to about 5:1. In another embodiment the mass ratio of
additional coformer to bisphosphonic acid is between about 5:1 to
about 50:1. In another embodiment the mass ratio of additional
coformer to bisphosphonic acid is between about 5:1 to about 25:1.
In another embodiment the mass ratio of additional coformer to
bisphosphonic acid is between about 5:1 to about 20:1. In another
embodiment the mass ratio of additional coformer to bisphosphonic
acid is between about 5:1 to about 15:1. In another embodiment the
mass ratio of additional coformer to bisphosphonic acid is between
about 5:1 to about 10:1. In another embodiment the mass ratio of
additional coformer to bisphosphonic acid is between about 10:1 to
about 50:1. In another embodiment the mass ratio of additional
coformer to bisphosphonic acid is between about 10:1 to about 25:1.
In another embodiment the mass ratio of additional coformer to
bisphosphonic acid is between about 10:1 to about 20:1. In another
embodiment the mass ratio of additional coformer to bisphosphonic
acid is between about 10:1 to about 15:1. In another embodiment the
mass ratio of additional coformer to bisphosphonic acid is between
about 11:1 to about 50:1. In another embodiment the mass ratio of
additional coformer to bisphosphonic acid is between about 15:1 to
about 50:1. In another embodiment the mass ratio of additional
coformer to bisphosphonic acid is between about 25:1 to about 50:1.
In another embodiment the mass ratio of additional coformer to
bisphosphonic acid is between about 35:1 to about 50:1. In another
embodiment the mass ratio of additional coformer to bisphosphonic
acid is at least 2:1. In another embodiment the mass ratio of
additional coformer to bisphosphonic acid is at least 5:1. In
another embodiment the mass ratio of additional coformer to
bisphosphonic acid is at least 7.5:1. In another embodiment the
mass ratio of additional coformer to bisphosphonic acid is at least
9:1. In another embodiment the mass ratio of additional coformer to
bisphosphonic acid is at least 10:1. In another embodiment the mass
ratio of additional coformer to bisphosphonic acid is at least
11:1. In another embodiment the mass ratio of additional coformer
to bisphosphonic acid is at least 15:1. In another embodiment the
mass ratio of additional coformer to bisphosphonic acid is at least
25:1. In another embodiment the mass ratio of additional coformer
to bisphosphonic acid is at least 35:1. In another embodiment the
mass ratio of additional coformer to bisphosphonic acid is at least
50:1. In another embodiment the mass ratio of additional coformer
to bisphosphonic acid is at least 65:1. In another embodiment the
mass ratio of additional coformer to bisphosphonic acid is at least
75:1. In another embodiment the mass ratio of additional coformer
to bisphosphonic acid is at least 85:1. In another embodiment the
mass ratio of additional coformer to bisphosphonic acid is at least
100:1. In another embodiment the mass ratio of additional coformer
to bisphosphonic acid is at least 125:1. In another embodiment the
mass ratio of additional coformer to bisphosphonic acid is at least
150:1. In another embodiment the mass ratio of additional coformer
to bisphosphonic acid is at least 175:1. In another embodiment the
mass ratio of additional coformer to bisphosphonic acid is at least
200:1. In another embodiment the mass ratio of additional coformer
to bisphosphonic acid is at least 225:1. In another embodiment the
mass ratio of additional coformer to bisphosphonic acid is at least
250:1. In another embodiment the mass ratio of additional coformer
to bisphosphonic acid is at least 275:1. In another embodiment the
mass ratio of additional coformer to bisphosphonic acid is at least
500:1. In another embodiment the mass ratio of additional coformer
to bisphosphonic acid is at least 750:1. In another embodiment the
mass ratio of additional coformer to bisphosphonic acid is at least
1000:1. In another embodiment the mass ratio of additional coformer
to bisphosphonic acid is at least 2000:1. In another embodiment the
mass ratio of additional coformer to bisphosphonic acid is at least
3000:1. In another embodiment the mass ratio of additional coformer
to bisphosphonic acid is at least 4000:1. In one embodiment the
bisphosphonic acid is zoledronic acid. In another embodiment the
bisphosphonic acid is clodronic acid. In another embodiment the
bisphosphonic acid is tiludronic acid. In another embodiment the
bisphosphonic acid is pamidronic acid. In another embodiment the
bisphosphonic acid is alendronic acid. In another embodiment the
bisphosphonic acid is risedronic acid. In another embodiment the
bisphosphonic acid is ibandronic acid.
[0125] In particular embodiments the invention provides for a
composition of Table 12
[0126] In other particular embodiments the invention provides for a
composition of Table 13.
[0127] In other particular embodiments the invention provides for a
composition of Table 14.
[0128] In other particular embodiments the invention provides for a
composition of Table 15.
[0129] Another aspect of the invention provides for a method of
increasing aqueous solubility of a bisphosphonic acid (e.g.,
zoledronic acid), compared with the free acid, comprising the step
of combining a bisphosphonic acid with a coformer and forming a
composition of the present invention. In one embodiment the method
comprises the step of forming a molecular complex of the present
invention. In another embodiment the method comprises the step of
combining a bisphosphonic acid (including salts, cocrystals,
solvates and prodrugs) with an amino acid. In one embodiment the
bisphosphonic acid is zoledronic acid. In another embodiment the
bisphosphonic acid is clodronic acid. In another embodiment the
bisphosphonic acid is tiludronic acid. In another embodiment the
bisphosphonic acid is pamidronic acid. In another embodiment the
bisphosphonic acid is alendronic acid. In another embodiment the
bisphosphonic acid is risedronic acid. In another embodiment the
bisphosphonic acid is ibandronic acid. In another embodiment the
bisphosphonic acid is zoledronic acid and the amino acid is lysine
or glycine. In another embodiment the bisphosphonic acid is
zoledronic acid and the amino acid is L-lysine. In another
embodiment the bisphosphonic acid is zoledronic acid and the
L-lysine is an L-lysine salt. In another embodiment the
bisphosphonic acid is zoledronic acid and the L-lysine is an
L-lysine hydrate. In another embodiment the bisphosphonic acid is
zoledronic acid and the L-lysine salt is an L-lysine HCl salt. In
another embodiment the bisphosphonic acid is zoledronic acid and
the L-lysine hydrate is an L-lysine monohydrate. In another
embodiment the bisphosphonic acid is zoledronic acid and the amino
acid is DL-lysine. In another embodiment the bisphosphonic acid is
zoledronic acid and the DL-lysine is a DL-lysine salt. In another
embodiment the bisphosphonic acid is zoledronic acid and the
DL-lysine is a DL-lysine hydrate. In another embodiment the
bisphosphonic acid is zoledronic acid and the DL-lysine salt is a
DL-lysine HCl salt. In another embodiment the bisphosphonic acid is
zoledronic acid and the DL-lysine hydrate is a DL-lysine
monohydrate. In another embodiment the bisphosphonic acid is
zoledronic acid and the amino acid is D-lysine. In another
embodiment the bisphosphonic acid is zoledronic acid and the
D-lysine is a D-lysine salt. In another embodiment the
bisphosphonic acid is zoledronic acid and the D-lysine is a
D-lysine hydrate. In another embodiment the bisphosphonic acid is
zoledronic acid and the D-lysine salt is a D-lysine HCl salt. In
another embodiment the bisphosphonic acid is zoledronic acid and
the D-lysine hydrate is a D-lysine monohydrate. In another
embodiment the aqueous solubility of the composition comprising
zoledronic acid is at least 5 mg/ml. In another embodiment the
aqueous solubility of the composition comprising zoledronic acid is
at least 10 mg/ml. In another embodiment the aqueous solubility of
the composition comprising zoledronic acid is at least 13
mg/ml.
[0130] In another aspect the coformer of the present invention
significantly increases the oral bioavailability of the
bisphosphonic acid, as compared to the corresponding marketed form
or the corresponding composition without the coformer. In one
embodiment the bisphosphonic acid is zoledronic acid. In another
embodiment the bisphosphonic acid is clodronic acid. In another
embodiment the bisphosphonic acid is tiludronic acid. In another
embodiment the bisphosphonic acid is pamidronic acid. In another
embodiment the bisphosphonic acid is alendronic acid. In another
embodiment the bisphosphonic acid is risedronic acid. In another
embodiment the bisphosphonic acid is ibandronic acid. In one
embodiment the oral bioavailability of the bisphosphonic acid in a
pharmaceutical composition of the present invention is at least 3%.
In another embodiment the oral bioavailability of the bisphosphonic
acid is at least 4%. In another embodiment the oral bioavailability
of the bisphosphonic acid is at least 5%. In another embodiment the
oral bioavailability of the bisphosphonic acid is at least 6%. In
another embodiment the oral bioavailability of the bisphosphonic
acid is at least 7%. In another embodiment the oral bioavailability
of the bisphosphonic acid is at least 8%. In another embodiment the
oral bioavailability of the bisphosphonic acid is at least 9%. In
another embodiment the oral bioavailability of the bisphosphonic
acid is at least 10%.
[0131] In another aspect the coformer significantly increases the
C.sub.max of the bisphosphonic acid as compared to the
corresponding marketed form or the corresponding composition
without the coformer. In one embodiment the bisphosphonic acid is
zoledronic acid. In another embodiment the bisphosphonic acid is
clodronic acid. In another embodiment the bisphosphonic acid is
tiludronic acid. In another embodiment the bisphosphonic acid is
pamidronic acid. In another embodiment the bisphosphonic acid is
alendronic acid. In another embodiment the bisphosphonic acid is
risedronic acid. In another embodiment the bisphosphonic acid is
ibandronic acid.
[0132] In another aspect the coformer significantly increases the
gastrointestinal permeability of the bisphosphonic acid, as
compared to the corresponding marketed formulation or the
corresponding composition without the coformer. In one embodiment
the coformer significantly increases the paracellular transport of
the bisphosphonic acid across the intestinal epithelium. In another
embodiment the coformer significantly increases the transcellular
transport of the bisphosphonic acid through the intestinal
epithelium. In one embodiment the bisphosphonic acid is zoledronic
acid. In another embodiment the bisphosphonic acid is clodronic
acid. In another embodiment the bisphosphonic acid is tiludronic
acid. In another embodiment the bisphosphonic acid is pamidronic
acid. In another embodiment the bisphosphonic acid is alendronic
acid. In another embodiment the bisphosphonic acid is risedronic
acid. In another embodiment the bisphosphonic acid is ibandronic
acid.
[0133] Another aspect of the present invention provides for a
method of significantly enhancing the bioavailabilty or
permeability of a bisphosphonic acid comprising the step of
combining the bisphosphonic acid with a coformer to form a
pharmaceutical composition of the present invention. In one
embodiment the method comprises the step of contacting the
bisphosphonic acid with a coformer to form a molecular complex of
the present invention. In one embodiment the bisphosphonic acid is
zoledronic acid. In another embodiment the bisphosphonic acid is
clodronic acid. In another embodiment the bisphosphonic acid is
tiludronic acid. In another embodiment the bisphosphonic acid is
pamidronic acid. In another embodiment the bisphosphonic acid is
alendronic acid. In another embodiment the bisphosphonic acid is
risedronic acid. In another embodiment the bisphosphonic acid is
ibandronic acid.
[0134] In one aspect the coformer is an amino acid. In one
embodiment the coformer is an amino acid and the bisphosphonic acid
is zoledronic acid. In another embodiment the coformer is an amino
acid and the bisphosphonic acid is clodronic acid. In another
embodiment the coformer is an amino acid and the bisphosphonic acid
is tiludronic acid. In another embodiment the coformer is an amino
acid and the bisphosphonic acid is pamidronic acid. In another
embodiment the coformer is an amino acid and the bisphosphonic acid
is alendronic acid. In another embodiment the coformer is an amino
acid and the bisphosphonic acid is risedronic acid. In another
embodiment the coformer is an amino acid and the bisphosphonic acid
is ibandronic acid. In particular embodiments the amino acid is
isoleucine, alanine, leucine, asparagine, lysine, aspartic acid,
methionine, cysteine, phenylalanine, glutamic acid, threonine,
glutamine, tryptophan, glycine, valine, proline, serine, tyrosine
arginine, histidine, selenocysteine, ornithine or taurine. In
another embodiment of the present invention the coformer is
selected from the group consisting of sodium, ammonium, ammonia,
L-lysine, DL-lysine, nicotinamide, adenine, and glycine. In one
embodiment the coformer is L-lysine. In another embodiment the
coformer is DL-lysine. In another embodiment the coformer is
D-lysine. In another embodiment the coformer is glycine. In one
particular embodiment of the present invention the bisphosphonic
acid is zoledronic acid and the coformer is lysine. In another
particular embodiment the molecular complex of the present
invention consists of zoledronic acid, lysine and water. In another
particular embodiment the molecular complex of the present
invention consists of zoledronic acid and lysine. In another
particular embodiment the molecular complex of the present
invention consists of zoledronic acid and L-lysine. In another
particular embodiment the molecular complex of the present
invention consists of zoledronic acid and DL-lysine. In another
particular embodiment the molecular complex of the present
invention consists of zoledronic acid and D-lysine. In another
particular embodiment the molecular complex of the present
invention consists of zoledronic acid, water and L-lysine. In
another particular embodiment the molecular complex of the present
invention consists of zoledronic acid, water and DL-lysine. In
another particular embodiment the molecular complex of the present
invention consists of zoledronic acid, water and D-lysine.
[0135] One aspect of the invention provides for a molecular complex
comprising a bisphosphonic acid and lysine. In one embodiment the
bisphosphonic acid is zoledronic acid. In another embodiment the
bisphosphonic acid is clodronic acid. In another embodiment the
bisphosphonic acid is tiludronic acid. In another embodiment the
bisphosphonic acid is pamidronic acid. In another embodiment the
bisphosphonic acid is alendronic acid. In another embodiment the
bisphosphonic acid is risedronic acid. In another embodiment the
bisphosphonic acid is ibandronic acid. In one embodiment the
molecular complex comprising the bisphosphonic acid and lysine is
crystalline.
[0136] Another aspect provides for molecular complexes that are
crystalline forms of a bisphosphonic acid comprising a
bisphosphonic acid, water, and a compound selected from L-lysine;
DL-lysine, nicotinamide, adenine or glycine. In one embodiment the
compound is L-lysine. In another embodiment the compound is
DL-lysine. In another embodiment the compound is D-lysine. In
another embodiment the compound is glycine. In one embodiment the
bisphosphonic acid is zoledronic acid. In another embodiment the
bisphosphonic acid is clodronic acid. In another embodiment the
bisphosphonic acid is tiludronic acid. In another embodiment the
bisphosphonic acid is pamidronic acid. In another embodiment the
bisphosphonic acid is alendronic acid. In another embodiment the
bisphosphonic acid is risedronic acid. In another embodiment the
bisphosphonic acid is ibandronic acid.
[0137] In one embodiment the molecular complex is a crystalline
zoledronic acid, sodium zoledronate and water complex characterized
by an X-ray powder diffraction pattern having peaks at about 8.1,
13.3, 21.5, 24.6, and 25.6.+-.0.2 degrees two-theta.
[0138] In another embodiment the molecular complex is a crystalline
ammonium zoledronic acid salt and water complex characterized by an
X-ray powder diffraction pattern having strong peaks at about 11.0,
14.6, 15.4, 19.9, and 29.4.+-.0.2 degrees two-theta.
[0139] In another embodiment the molecular complex is a zoledronic
acid diammonia water complex characterized by an X-ray powder
diffraction pattern having strong peaks at about 12.2, 13.0, 14.1,
17.1, and 19.3.+-.0.2 degrees two-theta.
[0140] In another embodiment the molecular complex is a crystalline
zoledronic acid, L-lysine, and water complex characterized by an
X-ray powder diffraction pattern having peaks at about 9.0, 14.4,
18.1, 26.0, and 29.6.+-.0.2 degrees two-theta.
[0141] In another embodiment the molecular complex is a crystalline
zoledronic acid, L-lysine, and water complex characterized by an
X-ray powder diffraction pattern comprising peaks at about 9.6,
10.7, 14.3, 21.4, 23.5.+-.0.2 degrees two theta.
[0142] In another embodiment the molecular complex is a crystalline
zoledronic acid, DL-lysine and water complex characterized by an
X-ray powder diffraction pattern comprising peaks at about 8.3,
11.8, 12.3, 15.8, and 20.8.+-.0.2 degrees two-theta.
[0143] In another embodiment the molecular complex is a crystalline
zoledronic acid, DL-lysine, and water complex characterized by an
X-ray powder diffraction pattern comprising peaks at about 9.1,
14.7, 18.0, 21.2, and 26.0.+-.0.2 degrees two-theta.
[0144] In another embodiment the molecular complex is a crystalline
zoledronic acid, DL-lysine, and water complex characterized by an
X-ray powder diffraction pattern comprising peaks at about 9.7,
10.8, 14.4, 18.9, 21.4.+-.0.2 degrees two theta.
[0145] In another embodiment the molecular complex is a crystalline
zoledronic acid, DL-lysine, ethanol, and water complex
characterized by an X-ray powder diffraction pattern comprising
peaks at about 8.8, 9.7, 17.6, 23.1, and 26.5.+-.0.2 degrees
two-theta.
[0146] In another embodiment the molecular complex is a crystalline
zoledronic acid, adenine, and water complex characterized by an
X-ray powder diffraction pattern comprising peaks at about 13.6,
15.9, 19.7, 27.9, and 29.5.+-.0.2 degrees two-theta.
[0147] In another embodiment the molecular complex is a crystalline
zoledronic acid, nicotinamide, and water complex characterized by
an X-ray powder diffraction pattern comprising peaks at about 13.1,
15.2, 21.0, 23.9, and 26.5.+-.0.2 degrees two-theta.
[0148] Another embodiment provides for a molecular complex
comprising zoledronic acid and glycine. In one embodiment the
molecular complex is crystalline. In another particular embodiment
the zoledronic and glycine crystalline form is characterized by an
X-ray powder diffraction pattern comprising peaks at about 10.2,
17.8, 19.9, 22.9, and 28.1.+-.0.2 degrees two-theta.
[0149] Another aspect provides for a molecular complex comprising
zoledronic acid; water; a compound selected from L-lysine,
D,L-lysine, nicotinamide, adenine or glycine; and optionally
further comprising a zoledronic acid salt. In one embodiment the
molecular complex is a zoledronic acid, sodium zoledronate and
water complex. In another embodiment the molecular complex is an
ammonium zoledronic acid salt and water complex. In another
embodiment the molecular complex is a zoledronic diammonia water
complex. In another embodiment the molecular complex is a
zoledronic acid, L-lysine, and water complex. In another embodiment
the molecular complex is a zoledronic acid DL-lysine and water
complex. In another embodiment the molecular complex is a
zoledronic acid, zoledronic, DL-lysine, ethanol, and water complex.
In another embodiment the molecular complex is a zoledronic acid,
adenine, and water complex. In another embodiment the molecular
complex is a zoledronic acid, nicotinamide, and water complex. In
another embodiment the molecular complex is a zoledronic acid
glycine complex.
[0150] In another aspect the composition of the present invention
comprising a bisphosphonic acid and coformer is a pharmaceutical
composition. In one embodiment the bisphosphonic acid is zoledronic
acid. In another embodiment the bisphosphonic acid is clodronic
acid. In another embodiment the bisphosphonic acid is tiludronic
acid. In another embodiment the bisphosphonic acid is pamidronic
acid. In another embodiment the bisphosphonic acid is alendronic
acid. In another embodiment the bisphosphonic acid is risedronic
acid. In another embodiment the bisphosphonic acid is ibandronic
acid. In one embodiment the pharmaceutical composition comprises a
molecular complex. In another embodiment the pharmaceutical
composition comprises a molecular complex and an additional
coformer. In another embodiment the pharmaceutical composition
comprises an additional coformer. In another embodiment the
pharmaceutical composition consists of or consists essentially of a
molecular complex. In another embodiment the pharmaceutical
composition consists of or consists essentially of a molecular
complex and an additional coformer. In another embodiment the
pharmaceutical composition consists of or consists essentially of
an additional coformer. In another embodiment the pharmaceutical
composition is a solid dosage form. In another embodiment the
pharmaceutical composition is a liquid dosage form. In another
embodiment the pharmaceutical composition further includes at least
one pharmaceutically acceptable excipient. In another embodiment
the pharmaceutical composition is an oral dosage form. In another
embodiment the oral dosage form is a tablet which can be
manufactured in any shape such as a caplet (an oval shaped
medicinal tablet in the shape of a capsule). In another embodiment
the oral dosage form is an enteric coated tablet or caplet. In
another embodiment the oral dosage form is a capsule. In another
embodiment the oral dosage form is an enteric coated capsule. In
another embodiment the pharmaceutical composition is a unit dose.
In another embodiment the unit dose is a single tablet, caplet or
capsule. In another embodiment the unit dose is two tablets or
capsules. In another embodiment the unit dose is in the form of a
particulate material, e.g., a granulated particulate material or
powder. In another embodiment the unit dose is enclosed in a
sachet, a disposable one time use package. In another embodiment
the unit dose is in the form of a solution. In another embodiment
the unit dose is in the form of a suspension. In another embodiment
the unit dose is an effervescent formulation. In one aspect of an
oral dosage form comprising a bisphosphonic acid and an additional
coformer, both the bisphosphonic acid and the additional coformer
are formulated to have the same release profile. In another
embodiment both the bisphosphonic acid and the additional coformer
are formulated to have an enteric release profile. In another
embodiment the bisphosphonic acid is formulated to have an enteric
release profile. In another embodiment both the bisphosphonic acid
and the additional coformer are formulated to have a sustained
release profile. In another embodiment the bisphosphonic acid is
formulated to have a sustained release profile. In another
embodiment both the additional coformer is formulated to have a
sustained release profile. In another embodiment both the
bisphosphonic acid and the additional coformer are formulated to
have a delayed+sustained release profile. In another embodiment the
bisphosphonic acid is formulated to have a delayed+sustained
release profile. In another embodiment the additional coformer is
formulated to have a delayed+sustained release profile. In one
embodiment, the sustained release is a first-order release. In
another embodiment the sustained release is a zero-order release.
In another embodiment the bisphosphonic acid and the additional
coformer are formulated a biphasic release. In one embodiment the
T.sub.max of the bisphosphonic acid is reached within one hour of
the T.sub.max of the coformer. In another embodiment the T.sub.max
of the bisphosphonic acid is reached within 45 minutes of the
T.sub.max of the coformer. In another embodiment the T.sub.max of
the bisphosphonic acid is reached within 30 minutes of the
T.sub.max of the coformer. In another embodiment the C.sub.max of
the bisphosphonic acid is reached within one hour of the C.sub.max
of the coformer. In another embodiment the C.sub.max of the
bisphosphonic acid is reached within 45 minutes of the C.sub.max of
the coformer. In another embodiment the C.sub.max of the
bisphosphonic acid is reached within 30 minutes of the C.sub.max of
the coformer. In another embodiment the C.sub.max and T.sub.max for
the coformer occurs less than one hour before the C.sub.max and
T.sub.max of the bisphosphonic acid. In another embodiment, the
C.sub.max and T.sub.max for the coformer occur less than 45 minutes
before the C.sub.max and T.sub.max of the bisphosphonic acid. In
another embodiment, the C.sub.max and T.sub.max for the coformer
occur less than 30 minutes before the C.sub.max and T.sub.max of
the bisphosphonic acid. In another embodiment, the C.sub.max and
T.sub.max for the bisphosphonic acid occurs before the C.sub.max
and T.sub.max of the coformer.
[0151] The pharmaceutical compositions generally contain about 1%
to about 99% by weight of at least one novel molecular complex of a
bisphosphonic acid (e.g., zoledronic acid) of the invention with
the remaining 99% to 1% by weight of a comprising one or more
coformers and, optionally, one or more suitable pharmaceutical
excipients. Pharmaceutical compositions comprising excess coformer
generally comprise excess coformer in the range from 0.001 to
99.999%, particularly, 0.01 to 99.99% more particularly 0.1 to
99.9% by weight of the coformer to the bisphosphonic acid (e.g.,
zoledronic acid). In one embodiment the pharmaceutical composition
comprises about 50% to about 99% coformer. In another embodiment
the pharmaceutical composition comprises about 60% to about 98%
coformer. In another embodiment the pharmaceutical composition
comprises about 70% to about 95% coformer. In another embodiment
the pharmaceutical composition comprises about 80% to about 95%
coformer. In another embodiment the pharmaceutical composition
comprises about 85% to about 95% coformer. In another embodiment
the pharmaceutical composition comprises about 90% to about 98%
coformer. In another embodiment the pharmaceutical composition
comprises about 90% to about 95% coformer.
In one aspect the pharmaceutical composition of the present
invention is a unit dose comprising a bisphosphonic acid and an
amino acid. In one embodiment the bisphosphonic acid is zoledronic
acid. In another embodiment the bisphosphonic acid is clodronic
acid. In another embodiment the bisphosphonic acid is tiludronic
acid. In another embodiment the bisphosphonic acid is pamidronic
acid. In another embodiment the bisphosphonic acid is alendronic
acid. In another embodiment the bisphosphonic acid is risedronic
acid. In another embodiment the bisphosphonic acid is ibandronic
acid. In one embodiment the amino acid is selected from isoleucine,
alanine, leucine, asparagine, lysine, aspartic acid, methionine,
cysteine, phenylalanine, glutamic acid, threonine, glutamine,
tryptophan, glycine, valine, proline, serine, tyrosine arginine,
histidine, selenocysteine, ornithine or taurine. In one embodiment
the unit dose of bisphosphonic acid comprises at least 100 mg of an
amino acid. In one embodiment the amino acid is present as a
component of a molecular complex with the bisphosphonic acid. In
another embodiment the amino acid is present both as a component of
a molecular complex with the bisphosphonic acid and as an
additional coformer. In another embodiment the amino acid is
present only as an additional coformer. In one embodiment the unit
dose comprises between about 50 to about 5000 mg of amino acid. In
another embodiment the unit dose comprises between about 100 to
about 1000 mg of amino acid. In another embodiment the unit dose
comprises between about 500 to about 1000 mg of amino acid. In
another embodiment the unit dose comprises between about 750 to
about 1000 mg of amino acid. In another embodiment the unit dose
comprises between about 500 to about 1500 mg of amino acid. In
another embodiment the unit dose comprises between about 500 to
about 1250 mg of amino acid. In another embodiment the unit dose
comprises between about 750 to about 1500 mg of amino acid. In
another embodiment the unit dose comprises between about 750 to
about 1250 mg of amino acid. In another embodiment the unit dose
comprises between about 1000 to about 5000 mg of amino acid. In
another embodiment the unit dose comprises between about 1000 to
about 4500 mg of amino acid. In another embodiment the unit dose
comprises between about 1000 to about 4000 mg of amino acid. In
another embodiment the unit dose comprises between about 1000 to
about 3500 mg of amino acid. In another embodiment the unit dose
comprises between about 1000 to about 3000 mg of amino acid. In
another embodiment the unit dose comprises between about 1000 to
about 2500 mg of amino acid. In another embodiment the unit dose
comprises between about 1000 to about 2000 mg of amino acid. In
another embodiment the unit dose comprises between about 1000 to
about 1500 mg of amino acid. In another embodiment the unit dose
comprises between about 1250 to about 5000 mg of amino acid. In
another embodiment the unit dose comprises between about 1250 to
about 4500 mg of amino acid. In another embodiment the unit dose
comprises between about 1250 to about 4000 mg of amino acid. In
another embodiment the unit dose comprises between about 1250 to
about 3500 mg of amino acid. In another embodiment the unit dose
comprises between about 1250 to about 3000 mg of amino acid. In
another embodiment the unit dose comprises between about 1250 to
about 2500 mg of amino acid. In another embodiment the unit dose
comprises between about 1250 to about 2000 mg of amino acid. In
another embodiment the unit dose comprises between about 1250 to
about 1750 mg of amino acid. In another embodiment the unit dose
comprises between about 1500 to about 5000 mg of amino acid. In
another embodiment the unit dose comprises between about 2000 to
about 5000 mg of amino acid. In another embodiment the unit dose
comprises between about 2000 to about 4500 mg of amino acid. In
another embodiment the unit dose comprises between about 2000 to
about 4000 mg of amino acid. In another embodiment the unit dose
comprises between about 2000 to about 3500 mg of amino acid. In
another embodiment the unit dose comprises between about 2000 to
about 3000 mg of amino acid. In another embodiment the unit dose
comprises between about 2000 to about 2500 mg of amino acid. In
another embodiment the unit dose comprises between about 3000 to
about 5000 mg of amino acid. In another embodiment the unit dose
comprises between about 3000 to about 4500 mg of amino acid. In
another embodiment the unit dose comprises between about 3000 to
about 4000 mg of amino acid. In another embodiment the unit dose
comprises between about 3000 to about 3500 mg of amino acid. In
another embodiment the unit dose comprises between about 1 g to
about 20 g of amino acid. In another embodiment the unit dose
comprises between about 5 g to about 20 g of amino acid. In another
embodiment the unit dose comprises between about 10 g to about 20 g
of amino acid. In another embodiment the unit dose comprises
between about 1 g to about 10 g of amino acid. In another
embodiment the unit dose comprises between about 5 g to about 10 g
of amino acid. In another embodiment the unit dose comprises
between about 7.5 g to about 10 g of amino acid. In another
embodiment the unit dose comprises between about 5 g to about 15 g
of amino acid. In another embodiment the unit dose comprises
between about 10 g to about 15 g of amino acid. In another
embodiment the unit dose comprises between about 10 g to about 12.5
g of amino acid. In another embodiment the unit dose comprises
between about 12.5 g to about 20 g of amino acid. In another
embodiment the unit dose comprises between about 12.5 g to about
17.5 g of amino acid. In another embodiment the unit dose comprises
between about 15 g to about 20 g of amino acid. In another
embodiment the unit dose comprises between about 17.5 g to about 20
g of amino acid. In another embodiment the unit dose comprises at
least 250 mg of an amino acid. In another embodiment the unit dose
comprises at least 500 mg of an amino acid. In another embodiment
the unit dose comprises at least 600 mg of an amino acid. In
another embodiment the unit dose comprises at least 700 mg of an
amino acid. In another embodiment the unit dose comprises at least
750 mg of an amino acid. In another embodiment the unit dose
comprises at least 800 mg of an amino acid. In another embodiment
the unit dose comprises at least 900 mg of an amino acid. In
another embodiment the unit dose comprises at least 1000 mg of an
amino acid. In another embodiment the unit dose comprises at least
1100 mg of an amino acid. In another embodiment the unit dose
comprises at least 1200 mg of an amino acid. In another embodiment
the unit dose comprises at least 1250 mg of an amino acid. In
another embodiment the unit dose comprises at least 1500 mg of an
amino acid. In another embodiment the unit dose comprises at least
1750 mg of an amino acid. In another embodiment the unit dose
comprises at least 1900 mg of an amino acid. In another embodiment
the unit dose comprises at least 2000 mg of an amino acid. In
another embodiment the unit dose comprises at least 2500 mg of an
amino acid. In another embodiment the unit dose comprises at least
3000 mg of an amino acid. In another embodiment the unit dose
comprises at least 3500 mg of an amino acid. In another embodiment
the unit dose comprises at least 4000 mg of an amino acid. In
another embodiment the unit dose comprises at least 4500 mg of an
amino acid. In another embodiment the unit dose comprises at least
5000 mg of an amino acid. In another embodiment the unit dose
comprises at least 6000 mg of amino acid. In another embodiment the
unit dose comprises at least 7000 mg of amino acid. In another
embodiment the unit dose comprises at least 8000 mg of amino acid.
In another embodiment the unit dose comprises at least 9000 mg of
amino acid. In another embodiment the unit dose comprises at least
10 g of amino acid. In another embodiment the unit dose comprises
at least 11 g of amino acid. In another embodiment the unit dose
comprises at least 12 g of amino acid. In another embodiment the
unit dose comprises at least 13 g of amino acid. In another
embodiment the unit dose comprises at least 14 g of amino acid. In
another embodiment the unit dose comprises at least 15 g of amino
acid. In another embodiment the unit dose comprises at least 16 g
of amino acid. In another embodiment the unit dose comprises at
least 17 g of amino acid. In another embodiment the unit dose
comprises at least 18 g of amino acid. In another embodiment the
unit dose comprises at least 19 g of amino acid. In another
embodiment the unit dose comprises at least 20 g of amino acid. In
one embodiment the bisphosphonic acid is zoledronic acid. In one
embodiment the amino acid is lysine or glycine. In one embodiment
the unit dose of zoledronic acid comprises between about 50 to
about 5000 mg of lysine. In another embodiment the unit dose of
zoledronic acid comprises between about 100 to about 1000 mg of
lysine. In another embodiment the unit dose of zoledronic acid
comprises between about 500 to about 1000 mg of lysine. In another
embodiment the unit dose of zoledronic acid comprises between about
750 to about 1000 mg of lysine. In another embodiment the unit dose
of zoledronic acid comprises between about 500 to about 1500 mg of
lysine. In another embodiment the unit dose of zoledronic acid
comprises between about 500 to about 1250 mg of lysine. In another
embodiment the unit dose of zoledronic acid comprises between about
750 to about 1500 mg of lysine. In another embodiment the unit dose
of zoledronic acid comprises between about 750 to about 1250 mg of
lysine. In another embodiment the unit dose of zoledronic acid
comprises between about 1000 to about 5000 mg of lysine. In another
embodiment the unit dose of zoledronic acid comprises between about
1000 to about 4500 mg of lysine. In another embodiment the unit
dose of zoledronic acid comprises between about 1000 to about 4000
mg of lysine. In another embodiment the unit dose of zoledronic
acid comprises between about 1000 to about 3500 mg of lysine. In
another embodiment the unit dose of zoledronic acid comprises
between about 1000 to about 3000 mg of lysine. In another
embodiment the unit dose of zoledronic acid comprises between about
1000 to about 2500 mg of lysine. In another embodiment the unit
dose of zoledronic acid comprises between about 1000 to about 2000
mg of lysine. In another embodiment the unit dose of zoledronic
acid comprises between about 1000 to about 1500 mg of lysine. In
another embodiment the unit dose of zoledronic acid comprises
between about 1250 to about 5000 mg of lysine. In another
embodiment the unit dose of zoledronic acid comprises between about
1250 to about 4500 mg of lysine. In another embodiment the unit
dose of zoledronic acid comprises between about 1250 to about 4000
mg of lysine. In another embodiment the unit dose of zoledronic
acid comprises between about 1250 to about 3500 mg of lysine. In
another embodiment the unit dose of zoledronic acid comprises
between about 1250 to about 3000 mg of lysine. In another
embodiment the unit dose of zoledronic acid comprises between about
1250 to about 2500 mg of lysine. In another embodiment the unit
dose of zoledronic acid comprises between about 1250 to about 2000
mg of lysine. In another embodiment the unit dose of zoledronic
acid comprises between about 1250 to about 1750 mg of lysine. In
another embodiment the unit dose of zoledronic acid comprises
between about 1500 to about 2500 mg of lysine. In another
embodiment the unit dose of zoledronic acid comprises between about
1500 to about 2000 mg of lysine. In another embodiment the unit
dose of zoledronic acid comprises between about 1500 to about 5000
mg of lysine. In another embodiment the unit dose of zoledronic
acid comprises between about 2000 to about 5000 mg of lysine. In
another embodiment the unit dose of zoledronic acid comprises
between about 2000 to about 4500 mg of lysine. In another
embodiment the unit dose of zoledronic acid comprises between about
2000 to about 4000 mg of lysine. In another embodiment the unit
dose of zoledronic acid comprises between about 2000 to about 3500
mg of lysine. In another embodiment the unit dose of zoledronic
acid comprises between about 2000 to about 3000 mg of lysine. In
another embodiment the unit dose of zoledronic acid comprises
between about 2000 to about 2500 mg of lysine. In another
embodiment the unit dose of zoledronic acid comprises between about
3000 to about 5000 mg of lysine. In another embodiment the unit
dose of zoledronic acid comprises between about 3000 to about 4500
mg of lysine. In another embodiment the unit dose of zoledronic
acid comprises between about 3000 to about 4000 mg of lysine. In
another embodiment the unit dose of zoledronic acid comprises
between about 3000 to about 3500 mg of lysine. In another
embodiment the unit dose of zoledronic acid comprises between about
1 g to about 20 g of lysine. In another embodiment the unit dose of
zoledronic acid comprises between about 5 g to about 20 g of
lysine. In another embodiment the unit dose of zoledronic acid
comprises between about 10 g to about 20 g of lysine. In another
embodiment the unit dose of zoledronic acid comprises between about
15 g to about 20 g of lysine. In another embodiment the unit dose
of zoledronic acid comprises between about 17.5 g to about 20 g of
lysine. In another embodiment the unit dose of zoledronic acid
comprises between about 1 g to about 10 g of lysine. In another
embodiment the unit dose of zoledronic acid comprises between about
2.5 g to about 10 g of lysine. In another embodiment the unit dose
of zoledronic acid comprises between about 5 g to about 10 g of
lysine. In another embodiment the unit dose of zoledronic acid
comprises between about 7 g to about 10 g of lysine. In another
embodiment the unit dose of zoledronic acid comprises between about
7.5 g to about 10 g of lysine. In another embodiment the unit dose
of zoledronic acid comprises between about 7.5 g to about 15 g of
lysine. In another embodiment the unit dose of zoledronic acid
comprises between about 10 g to about 15 g of lysine. In another
embodiment the unit dose of zoledronic acid comprises between about
12.5 g to about 15 g of lysine. In another embodiment the unit dose
of zoledronic acid comprises between about 10 g to about 12.5 g of
lysine. In another embodiment the unit dose of zoledronic acid
comprises between about 12.5 g to about 20 g of lysine. In another
embodiment the unit dose of zoledronic acid comprises between about
12.5 g to about 17.5 g of lysine. In another embodiment a unit dose
of a zoledronic acid pharmaceutical composition comprises at least
100 mg of lysine. In another embodiment the unit dose of zoledronic
acid comprises at least 250 mg of lysine. In another embodiment the
unit dose of zoledronic acid comprises at least 500 mg of lysine.
In another embodiment the unit dose of zoledronic acid comprises at
least 600 mg of lysine. In another embodiment the unit dose of
zoledronic acid comprises at least 700 mg of lysine. In another
embodiment the unit dose of zoledronic acid comprises at least 750
mg of lysine. In another embodiment the unit dose of zoledronic
acid comprises at least 800 mg of lysine. In another embodiment the
unit dose of zoledronic acid comprises at least 900 mg of lysine.
In another embodiment the unit dose of zoledronic acid comprises at
least 1000 mg of lysine. In another embodiment the unit dose of
zoledronic acid comprises at least 1100 mg of lysine. In another
embodiment the unit dose of zoledronic acid comprises at least 1200
mg of lysine. In another embodiment the unit dose of zoledronic
acid comprises at least 1250 mg of lysine. In another embodiment
the unit dose of zoledronic acid comprises at least 1500 mg of
lysine. In another embodiment the unit dose of zoledronic acid
comprises at least 1750 mg of lysine. In another embodiment the
unit dose of zoledronic acid comprises at least 1900 mg of lysine.
In another embodiment the unit dose of zoledronic acid comprises at
least 2000 mg of lysine. In another embodiment the unit dose of
zoledronic acid comprises at least 2500 mg of lysine. In another
embodiment the unit dose of zoledronic acid comprises at least 3000
mg of lysine. In another embodiment the unit dose of zoledronic
acid comprises at least 3500 mg of lysine. In another embodiment
the unit dose of zoledronic acid comprises at least 4000 mg of
lysine. In another embodiment the unit dose of zoledronic acid
comprises at least 4500 mg of lysine. In another embodiment the
unit dose of zoledronic acid comprises at least 5000 mg of lysine.
In another embodiment the unit dose of zoledronic acid comprises at
least 6000 mg of lysine. In another embodiment the unit dose of
zoledronic acid comprises at least 7000 mg of lysine. In another
embodiment the unit dose of zoledronic acid comprises at least 8000
mg of lysine. In another embodiment the unit dose of zoledronic
acid comprises at least 9000 mg of lysine. In another embodiment
the unit dose of zoledronic acid comprises at least 10 g of lysine.
In another embodiment the unit dose of zoledronic acid comprises at
least 11 g of lysine. In another embodiment the unit dose of
zoledronic acid comprises at least 12 g of lysine. In another
embodiment the unit dose of zoledronic acid comprises at least 13 g
of lysine. In another embodiment the unit dose of zoledronic acid
comprises at least 14 g of lysine. In another embodiment the unit
dose of zoledronic acid comprises at least 15 g of lysine. In
another embodiment the unit dose of
zoledronic acid comprises at least 16 g of lysine. In another
embodiment the unit dose of zoledronic acid comprises at least 17 g
of lysine. In another embodiment the unit dose of zoledronic acid
comprises at least 18 g of lysine. In another embodiment the unit
dose of zoledronic acid comprises at least 19 g of lysine. In
another embodiment the unit dose of zoledronic acid comprises at
least 20 g of lysine. In one embodiment the lysine in the unit dose
of zoledronic acid is L-lysine. In one embodiment the L-lysine in
the unit dose of zoledronic acid comprises an L-lysine salt. In one
embodiment the L-lysine in the unit dose of zoledronic acid
comprises an L-lysine hydrate. In one embodiment the L-lysine salt
in the unit dose of zoledronic acid comprises an L-lysine HCl salt.
In one embodiment the L-lysine hydrate in the unit dose of
zoledronic acid comprises a L-lysine monohydrate. In another
embodiment the lysine in the unit dose of zoledronic acid is
DL-lysine. In one embodiment the DL-lysine in the unit dose of
zoledronic acid comprises a DL-lysine salt. In one embodiment the
DL-lysine salt in the unit dose of zoledronic acid comprises a
DL-lysine HCl salt. In one embodiment the DL-lysine in the unit
dose of zoledronic acid comprises a DL-lysine hydrate. In one
embodiment the DL-lysine hydrate in the unit dose of zoledronic
acid comprises a DL-lysine monohydrate. In another embodiment the
lysine in the unit dose of zoledronic kid is D-lysine. In one
embodiment the D-lysine in the unit dose of zoledronic acid
comprises a D-lysine salt. In one embodiment the D-lysine salt in
the unit dose of zoledronic acid comprises a D-lysine HCl salt. In
one embodiment the D-lysine in the unit dose of zoledronic acid
comprises a D-lysine hydrate. In one embodiment the D-lysine
hydrate in the unit dose of zoledronic acid comprises D-lysine
monohydrate. In one embodiment a unit dose of a zoledronic acid
pharmaceutical composition comprises at least 100 mg of glycine. In
another embodiment the unit dose of zoledronic acid comprises at
least 250 mg of glycine. In another embodiment the unit dose of
zoledronic acid comprises at least 500 mg of glycine. In another
embodiment the unit dose of zoledronic acid comprises at least 750
mg of glycine. In another embodiment the unit dose of zoledronic
acid comprises at least 1000 mg of glycine. In another embodiment
the unit dose of zoledronic acid comprises at least 1100 mg of
glycine. In another embodiment the unit dose of zoledronic acid
comprises at least 1200 mg of glycine. In another embodiment the
unit dose of zoledronic acid comprises at least 1250 mg of glycine.
In another embodiment the unit dose of zoledronic acid comprises at
least 1500 mg of glycine. In another embodiment the unit dose of
zoledronic acid comprises at least 1750 mg of glycine. In another
embodiment the unit dose of zoledronic acid comprises at least 1900
mg of glycine. In another embodiment the unit dose of zoledronic
acid comprises at least 2000 mg of glycine. In another embodiment
the unit dose of zoledronic acid comprises at least 2500 mg of
glycine. In another embodiment the unit dose of zoledronic acid
comprises at least 3000 mg of glycine. In another embodiment the
unit dose of zoledronic acid comprises at least 3500 mg of glycine.
In another embodiment the unit dose of zoledronic acid comprises at
least 4000 mg of glycine. In another embodiment the unit dose of
zoledronic acid comprises at least 4500 mg of glycine. In another
embodiment the unit dose of zoledronic acid comprises at least 5000
mg of glycine. In another embodiment the unit dose of zoledronic
acid comprises at least 6000 mg of glycine. In another embodiment
the unit dose of zoledronic acid comprises at least 7000 mg of
glycine. In another embodiment the unit dose of zoledronic acid
comprises at least 8000 mg of glycine. In another embodiment the
unit dose of zoledronic acid comprises at least 9000 mg of glycine.
In another embodiment the unit dose of zoledronic acid comprises at
least 10 g of glycine. In another embodiment the unit dose of
zoledronic acid comprises at least 11 g of glycine. In another
embodiment the unit dose of zoledronic acid comprises at least 12 g
of glycine. In another embodiment the unit dose of zoledronic acid
comprises at least 13 g of glycine. In another embodiment the unit
dose of zoledronic acid comprises at least 14 g of glycine. In
another embodiment the unit dose of zoledronic acid comprises at
least 15 g of glycine. In another embodiment the unit dose of
zoledronic acid comprises at least 16 g of glycine. In another
embodiment the unit dose of zoledronic acid comprises at least 17 g
of glycine. In another embodiment the unit dose of zoledronic acid
comprises at least 18 g of glycine. In another embodiment the unit
dose of zoledronic acid comprises at least 19 g of glycine. In
another embodiment the unit dose of zoledronic acid comprises at
least 20 g of glycine. In another embodiment the unit dose of
zoledronic acid comprises between about 50 to about 5000 mg of
glycine. In another embodiment the unit dose of zoledronic acid
comprises between about 100 to about 1000 mg of glycine. In another
embodiment the unit dose of zoledronic acid comprises between about
1250 to about 5000 mg of glycine. In another embodiment the unit
dose of zoledronic acid comprises between about 2000 to about 5000
mg of glycine. In another embodiment the unit dose of zoledronic
acid comprises between about 3000 to about 5000 mg of glycine. In
another embodiment the unit dose of zoledronic acid comprises
between about 1250 to about 3000 mg of glycine. In another
embodiment the unit dose of zoledronic acid comprises between about
1250 to about 2500 mg of glycine. In another embodiment the unit
dose of zoledronic acid comprises between about 1 g to about 20 g
of glycine. In another embodiment the unit dose of zoledronic acid
comprises between about 1250 mg to about 20 g of glycine. In
another embodiment the unit dose of zoledronic acid comprises
between about 1500 mg to about 20 g of glycine. In another
embodiment the unit dose of zoledronic acid comprises between about
1 g to about 10 g of glycine. In another embodiment the unit dose
of zoledronic acid comprises between about 1250 mg to about 10 g of
glycine. In another embodiment the unit dose of zoledronic acid
comprises between about 1500 mg to about 10 g of glycine. In
another embodiment the unit dose of zoledronic acid comprises
between about 1 g to about 5 g of glycine. In another embodiment
the unit dose of zoledronic acid comprises between about 1250 mg to
about 5 g of glycine. In another embodiment the unit dose of
zoledronic acid comprises between about 1500 mg to about 5 g of
glycine. In another embodiment the unit dose of zoledronic acid
comprises between about 5 g to about 15 g of glycine. In another
embodiment the unit dose of zoledronic acid comprises between about
5 g to about 10 g of glycine. In another embodiment the unit dose
of zoledronic acid comprises between about 7 g to about 10 g of
glycine. In another embodiment the unit dose of zoledronic acid
comprises between about 10 g to about 20 g of glycine. In another
embodiment the unit dose of zoledronic acid comprises between about
10 g to about 15 g of glycine. In another embodiment the unit dose
of zoledronic acid comprises between about 10 g to about 12.5 g of
glycine. In another embodiment the unit dose of zoledronic acid
comprises between about 12.5 g to about 20 g of glycine. In another
embodiment the unit dose of zoledronic acid comprises between about
12.5 g to about 17.5 g of glycine. In another embodiment the unit
dose of zoledronic acid comprises between about 15 g to about 20 g
of glycine. In another embodiment the unit dose of zoledronic acid
comprises between about 17.5 g to about 20 g of glycine. In another
embodiment the unit dose of zoledronic acid comprises between about
1 g to about 2 g of glycine.
[0153] In one aspect a unit dose of a zoledronic acid
pharmaceutical composition comprising zoledronic acid and an amino
acid has an oral bioavailability of at least 3%. In another
embodiment the composition has an oral bioavailability of at least
5%. In another embodiment the composition has an oral
bioavailability of at least 8%. In one embodiment the amino acid is
L-lysine and the oral bioavailability is at least 3%. In one
embodiment the amino acid is L-lysine and the oral bioavailability
is at least 5%. In one embodiment the amino acid is L-lysine and
the oral bioavailability is at least 8%. In one embodiment the
amino acid is DL-lysine and the oral bioavailability is at least
3%. In one embodiment the amino acid is DL-lysine and the oral
bioavailability is at least 5%. In one embodiment the amino acid is
DL-lysine and the oral bioavailability is at least 8%. In one
embodiment the amino acid is D-lysine and the oral bioavailability
is at least 3%. In one embodiment the amino acid is D-lysine and
the oral bioavailability is at least 5%. In one embodiment the
amino acid is D-lysine and the oral bioavailability is at least 8%.
In one embodiment the amino acid is glycine and the oral
bioavailability is at least 3%. In one embodiment the amino acid is
glycine and the oral bioavailability is at least 5%. In one
embodiment the amino acid is glycine and the oral bioavailability
is at least 8%.
[0154] In one aspect the majority of the increase in oral
bioavailability is due to the presence of the coformer, whether as
part of a molecular complex or as additional coformer. In one
embodiment the coformer is the only component of a pharmaceutical
composition comprising a bisphosphonic acid-coformer molecular
complex that significantly increases the oral bioavailability of
the molecular complex. In one embodiment the amino acid added as an
excipient is the only component of a pharmaceutical composition
comprising a bisphosphonic acid that increases the oral
bioavailability of the molecular complex. In one embodiment the
increase in oral bioavailability is achieved without the need of
additional excipients, e.g., an intra-granular hydrophilic
polymer.
In one aspect a unit oral dose of a zoledronic acid pharmaceutical
composition comprising zoledronic acid and an amino acid is no more
than 4.1 mg/kg (mass zoledronic acid/mass patient) and is at least
equivalent in efficacy to a 4 mg unit dose of the marketed form
ZOMETA (or its equivalent) administered intravenously. In one
embodiment a unit oral dose of a zoledronic acid pharmaceutical
composition comprising zoledronic acid and an amino acid is no more
than 2.5 mg/kg and is at least equivalent in efficacy to a 4 mg
unit dose of the marketed form ZOMETA (or its equivalent)
administered intravenously. In one embodiment a unit oral dose of a
zoledronic acid pharmaceutical composition comprising zoledronic
acid and an amino acid is no more than 2.25 mg/kg and is at least
equivalent in efficacy to a 4 mg unit dose of the marketed form
ZOMETA (or its equivalent) administered intravenously. In one
embodiment a unit oral dose of a zoledronic acid pharmaceutical
composition comprising zoledronic acid and an amino acid is no more
than 2.0 mg/kg and is at least equivalent in efficacy to a 4 mg
unit dose of the marketed form ZOMETA (or its equivalent)
administered intravenously. In one embodiment a unit oral dose of a
zoledronic acid pharmaceutical composition comprising zoledronic
acid and an amino acid is no more than 1.75 mg/kg and is at least
equivalent in efficacy to a 4 mg unit dose of the marketed form
ZOMETA (or its equivalent) administered intravenously. In another
embodiment a unit oral dose of a zoledronic acid pharmaceutical
composition comprising zoledronic acid and an amino acid is no more
than 1.5 mg/kg and is at least equivalent in efficacy to a 4 mg
unit dose of the marketed form ZOMETA (or its equivalent)
administered intravenously. In one embodiment a unit oral dose of a
zoledronic acid pharmaceutical composition comprising zoledronic
acid and an amino acid is no more than 1.25 mg/kg and is at least
equivalent in efficacy to a 4 mg unit dose of the marketed form
ZOMETA (or its equivalent) administered intravenously. In another
embodiment a unit oral dose of a zoledronic acid pharmaceutical
composition comprising zoledronic acid and an amino acid is no more
than 1 mg/kg and is at least equivalent in efficacy to a 4 mg unit
dose of the marketed form ZOMETA (or its equivalent) administered
intravenously. In another embodiment a unit oral dose of a
zoledronic acid pharmaceutical composition comprising zoledronic
acid and an amino acid is no more than 0.75 mg/kg and is at least
equivalent in efficacy to a 4 mg unit dose of the marketed form
ZOMETA (or its equivalent) administered intravenously. In another
embodiment a unit oral dose of a zoledronic acid pharmaceutical
composition comprising zoledronic acid and an amino acid is no more
than 0.5 mg/kg and is at least equivalent in efficacy to a 4 mg
unit dose of the marketed form ZOMETA (or its equivalent)
administered intravenously. In another embodiment a unit oral dose
of a zoledronic acid pharmaceutical composition comprising
zoledronic acid and an amino acid is no more than 0.3 mg/kg and is
at least equivalent in efficacy to a 4 mg unit dose of the marketed
form ZOMETA (or its equivalent) administered intravenously. In one
embodiment a unit oral dose of a zoledronic acid pharmaceutical
composition comprising zoledronic acid and lysine is no more than
4.1 mg/kg and is at least equivalent in efficacy to a 4 mg unit
dose of the marketed form ZOMETA (or its equivalent) administered
intravenously. In one embodiment a unit oral dose of a zoledronic
acid pharmaceutical composition comprising zoledronic acid and
lysine is no more than 2.25 mg/kg and is at least equivalent in
efficacy to a 4 mg unit dose of the marketed form ZOMETA (or its
equivalent) administered intravenously. In one embodiment a unit
oral dose of a zoledronic acid pharmaceutical composition
comprising zoledronic acid and lysine is no more than 2.0 mg/kg and
is at least equivalent in efficacy to a 4 mg unit dose of the
marketed form ZOMETA (or its equivalent) administered
intravenously. In one embodiment a unit oral dose of a zoledronic
acid pharmaceutical composition comprising zoledronic acid and
lysine is no more than 1.75 mg/kg and is at least equivalent in
efficacy to a 4 mg unit dose of the marketed form ZOMETA (or its
equivalent) administered intravenously. In another embodiment a
unit oral dose of a zoledronic acid pharmaceutical composition
comprising zoledronic acid and lysine is no more than 1.5 mg/kg and
is at least equivalent in efficacy to a 4 mg unit dose of the
marketed form ZOMETA (or its equivalent) administered
intravenously. In one embodiment a unit oral dose of a zoledronic
acid pharmaceutical composition comprising zoledronic acid and
lysine is no more than 1.25 mg/kg and is at least equivalent in
efficacy to a 4 mg unit dose of the marketed form ZOMETA (or its
equivalent) administered intravenously. In another embodiment a
unit oral dose of a zoledronic acid pharmaceutical composition
comprising zoledronic acid and lysine is no more than 1 mg/kg and
is at least equivalent in efficacy to a 4 mg unit dose of the
marketed form ZOMETA (or its equivalent) administered
intravenously. In another embodiment a unit oral dose of a
zoledronic acid pharmaceutical composition comprising zoledronic
acid and lysine is no more than 0.75 mg/kg and is at least
equivalent in efficacy to a 4 mg unit dose of the marketed form
ZOMETA (or its equivalent) administered intravenously. In another
embodiment a unit oral dose of a zoledronic acid pharmaceutical
composition comprising zoledronic acid and lysine is no more than
0.5 mg/kg and is at least equivalent in efficacy to a 4 mg unit
dose of the marketed form ZOMETA (or its equivalent) administered
intravenously. In another embodiment a unit oral dose of a
zoledronic acid pharmaceutical composition comprising zoledronic
acid and lysine is no more than 0.3 mg/kg and is at least
equivalent in efficacy to a 4 mg unit dose of the marketed form
ZOMETA (or its equivalent) administered intravenously. In further
particular embodiments the unit dose consists of or consists
essentially of zoledronic acid and lysine. In one embodiment a unit
oral dose of a zoledronic acid pharmaceutical composition
comprising zoledronic acid and L-lysine is no more than 4.1 mg/kg
and is at least equivalent in efficacy to a 4 mg unit dose of the
marketed form ZOMETA (or its equivalent) administered
intravenously. In one embodiment a unit oral dose of a zoledronic
acid pharmaceutical composition comprising zoledronic acid and
L-lysine is no more than 2.5 mg/kg and is at least equivalent in
efficacy to a 4 mg unit dose of the marketed form ZOMETA (or its
equivalent) administered intravenously. In one embodiment a unit
oral dose of a zoledronic acid pharmaceutical composition
comprising zoledronic acid and L-lysine is no more than 2.25 mg/kg
and is at least equivalent in efficacy to a 4 mg unit dose of the
marketed form ZOMETA (or its equivalent) administered
intravenously. In one embodiment a unit oral dose of a zoledronic
acid pharmaceutical composition comprising zoledronic acid and
L-lysine is no more than 2.0 mg/kg and is at least equivalent in
efficacy to a 4 mg unit dose of the marketed form ZOMETA (or its
equivalent) administered intravenously. In one embodiment a unit
oral dose of a zoledronic acid pharmaceutical composition
comprising zoledronic acid and L-lysine is no more than 1.75 mg/kg
and is at least equivalent in efficacy to a 4 mg unit dose of the
marketed form ZOMETA (or its equivalent) administered
intravenously. In another embodiment a unit oral dose of a
zoledronic acid pharmaceutical composition comprising zoledronic
acid and L-lysine is no more than 1.5 mg/kg and is at least
equivalent in efficacy to a 4 mg unit dose of the marketed form
ZOMETA (or its equivalent) administered intravenously. In one
embodiment a unit oral dose of a zoledronic acid pharmaceutical
composition comprising zoledronic acid and L-lysine is no more than
1.25 mg/kg and is at least equivalent in efficacy to a 4 mg unit
dose of the marketed form ZOMETA (or its equivalent) administered
intravenously. In another embodiment a unit oral dose of a
zoledronic acid pharmaceutical composition comprising zoledronic
acid and L-lysine is no more than 1 mg/kg and is at least
equivalent in efficacy to a 4 mg unit dose of the marketed form
ZOMETA (or its equivalent) administered intravenously. In another
embodiment a unit oral dose of a zoledronic acid pharmaceutical
composition comprising zoledronic acid and L-lysine is no more than
0.75 mg/kg and is at least equivalent in efficacy to a 4 mg unit
dose of the marketed form ZOMETA (or its equivalent) administered
intravenously. In another embodiment a unit oral dose of a
zoledronic acid pharmaceutical composition comprising zoledronic
acid and L-lysine is no more than 0.5 mg/kg and is at least
equivalent in efficacy to a 4 mg unit dose of the marketed form
ZOMETA (or its equivalent) administered intravenously. In another
embodiment a unit oral dose of a zoledronic acid pharmaceutical
composition comprising zoledronic acid and L-lysine is no more than
0.3 mg/kg and is at least equivalent in efficacy to a 4 mg unit
dose of the marketed form ZOMETA (or its equivalent) administered
intravenously. In further particular embodiments the unit dose
consists of or consists essentially of zoledronic acid and
L-lysine. In one embodiment a unit oral dose of a zoledronic acid
pharmaceutical composition comprising zoledronic acid and DL-lysine
is no more than 4.1 mg/kg and is at least equivalent in efficacy to
a 4 mg unit dose of the marketed form ZOMETA (or its equivalent)
administered intravenously. In one embodiment a unit oral dose of a
zoledronic acid pharmaceutical composition comprising zoledronic
acid and DL-lysine is no more than 2.5 mg/kg and is at least
equivalent in efficacy to a 4 mg unit dose of the marketed form
ZOMETA (or its equivalent) administered intravenously. In one
embodiment a unit oral dose of a zoledronic acid pharmaceutical
composition comprising zoledronic acid and DL-lysine is no more
than 2.25 mg/kg and is at least equivalent in efficacy to a 4 mg
unit dose of the marketed form ZOMETA (or its equivalent)
administered intravenously. In one embodiment a unit oral dose of a
zoledronic acid pharmaceutical composition comprising zoledronic
acid and DL-lysine is no more than 2.0 mg/kg and is at least
equivalent in efficacy to a 4 mg unit dose of the marketed form
ZOMETA (or its equivalent) administered intravenously. In one
embodiment a unit oral dose of a zoledronic acid pharmaceutical
composition comprising zoledronic acid and DL-lysine is no more
than 1.75 mg/kg and is at least equivalent in efficacy to a 4 mg
unit dose of the marketed form ZOMETA (or its equivalent)
administered intravenously. In another embodiment a unit oral dose
of a zoledronic acid pharmaceutical composition comprising
zoledronic acid and DL-lysine is no more than 1.5 mg/kg and is at
least equivalent in efficacy to a 4 mg unit dose of the marketed
form ZOMETA (or its equivalent) administered intravenously. In one
embodiment a unit oral dose of a zoledronic acid pharmaceutical
composition comprising zoledronic acid and DL-lysine is no more
than 1.25 mg/kg and is at least equivalent in efficacy to a 4 mg
unit dose of the marketed form ZOMETA (or its equivalent)
administered intravenously. In another embodiment a unit oral dose
of a zoledronic acid pharmaceutical composition comprising
zoledronic acid and DL-lysine is no more than 1 mg/kg and is at
least equivalent in efficacy to a 4 mg unit dose of the marketed
form ZOMETA (or its equivalent) administered intravenously. In
another embodiment a unit oral dose of a zoledronic acid
pharmaceutical composition comprising zoledronic acid and DL-lysine
is no more than 0.75 mg/kg and is at least equivalent in efficacy
to a 4 mg unit dose of the marketed form ZOMETA (or its equivalent)
administered intravenously. In another embodiment a unit oral dose
of a zoledronic acid pharmaceutical composition comprising
zoledronic acid and DL-lysine is no more than 0.5 mg/kg and is at
least equivalent in efficacy to a 4 mg unit dose of the marketed
form ZOMETA (or its equivalent) administered intravenously. In
another embodiment a unit oral dose of a zoledronic acid
pharmaceutical composition comprising zoledronic acid and DL-lysine
is no more than 0.3 mg/kg and is at least equivalent in efficacy to
a 4 mg unit dose of the marketed form ZOMETA (or its equivalent)
administered intravenously. In further particular embodiments the
unit dose consists of or consists essentially of zoledronic acid
and DL-lysine. In one embodiment a unit oral dose of a zoledronic
acid pharmaceutical composition comprising zoledronic acid and
D-lysine is no more than 4.1 mg/kg and is at least equivalent in
efficacy to a 4 mg unit dose of the marketed form ZOMETA (or its
equivalent) administered intravenously. In one embodiment a unit
oral dose of a zoledronic acid pharmaceutical composition
comprising zoledronic acid and D-lysine is no more than 2.5 mg/kg
and is at least equivalent in efficacy to a 4 mg unit dose of the
marketed form ZOMETA (or its equivalent) administered
intravenously. In one embodiment a unit oral dose of a zoledronic
acid pharmaceutical composition comprising zoledronic acid and
D-lysine is no more than 2.25 mg/kg and is at least equivalent in
efficacy to a 4 mg unit dose of the marketed form ZOMETA (or its
equivalent) administered intravenously. In one embodiment a unit
oral dose of a zoledronic acid pharmaceutical composition
comprising zoledronic acid and D-lysine is no more than 2.0 mg/kg
and is at least equivalent in efficacy to a 4 mg unit dose of the
marketed form ZOMETA (or its equivalent) administered
intravenously. In one embodiment a unit oral dose of a zoledronic
acid pharmaceutical composition comprising zoledronic acid and
D-lysine is no more than 1.75 mg/kg and is at least equivalent in
efficacy to a 4 mg unit dose of the marketed form ZOMETA (or its
equivalent) administered intravenously. In another embodiment a
unit oral dose of a zoledronic acid pharmaceutical composition
comprising zoledronic acid and D-lysine is no more than 1.5 mg/kg
and is at least equivalent in efficacy to a 4 mg unit dose of the
marketed form ZOMETA (or its equivalent) administered
intravenously. In one embodiment a unit oral dose of a zoledronic
acid pharmaceutical composition comprising zoledronic acid and
D-lysine is no more than 1.25 mg/kg and is at least equivalent in
efficacy to a 4 mg unit dose of the marketed form ZOMETA (or its
equivalent) administered intravenously. In another embodiment a
unit oral dose of a zoledronic acid pharmaceutical composition
comprising zoledronic acid and D-lysine is no more than 1 mg/kg and
is at least equivalent in efficacy to a 4 mg unit dose of the
marketed form ZOMETA (or its equivalent) administered
intravenously. In another embodiment a unit oral dose of a
zoledronic acid pharmaceutical composition comprising zoledronic
acid and D-lysine is no more than 0.75 mg/kg and is at least
equivalent in efficacy to a 4 mg unit dose of the marketed form
ZOMETA (or its equivalent) administered intravenously. In another
embodiment a unit oral dose of a zoledronic acid pharmaceutical
composition comprising zoledronic acid and D-lysine is no more than
0.5 mg/kg and is at least equivalent in efficacy to a 4 mg unit
dose of the marketed form ZOMETA (or its equivalent) administered
intravenously. In another embodiment a unit oral dose of a
zoledronic acid pharmaceutical composition comprising zoledronic
acid and D-lysine is no more than 0.3 mg/kg and is at least
equivalent in efficacy to a 4 mg unit dose of the marketed form
ZOMETA (or its equivalent) administered intravenously. In further
particular embodiments the unit dose consists of or consists
essentially of zoledronic acid and D-lysine. In one embodiment a
unit oral dose of a zoledronic acid pharmaceutical composition
comprising zoledronic acid and glycine is no more than 4.1 mg/kg
and is at least equivalent in efficacy to a 4 mg unit dose of the
marketed form ZOMETA (or its equivalent) administered
intravenously. In one embodiment a unit oral dose of a zoledronic
acid pharmaceutical composition comprising zoledronic acid and
glycine is no more than 2.5 mg/kg and is at least equivalent in
efficacy to a 4 mg unit dose of the marketed form ZOMETA (or its
equivalent) administered intravenously. In another embodiment a
unit oral dose of a zoledronic acid pharmaceutical composition
comprising zoledronic acid and glycine is no more than 1.5 mg/kg
and is at least equivalent in efficacy to a 4 mg unit dose of the
marketed form ZOMETA (or its equivalent) administered
intravenously. In another embodiment a unit oral dose of a
zoledronic acid pharmaceutical composition comprising zoledronic
acid and glycine is no more than 1 mg/kg and is at least equivalent
in efficacy to a 4 mg unit dose of the marketed form ZOMETA (or its
equivalent) administered intravenously. In another embodiment a
unit oral dose of a zoledronic acid pharmaceutical composition
comprising zoledronic acid and glycine is no more than 0.75 mg/kg
and is at least equivalent in efficacy to a 4 mg unit dose of the
marketed form ZOMETA (or its equivalent) administered
intravenously. In another embodiment a unit oral dose of a
zoledronic acid pharmaceutical composition comprising zoledronic
acid and glycine is no more than 0.5 mg/kg and is at least
equivalent in efficacy to a 4 mg unit dose of the marketed form
ZOMETA (or its equivalent) administered intravenously. In another
embodiment a unit oral dose of a zoledronic acid pharmaceutical
composition comprising zoledronic acid and
glycine is no more than 0.3 mg/kg and is at least equivalent in
efficacy to a 4 mg unit dose of the marketed form ZOMETA (or its
equivalent) administered intravenously. In further particular
embodiments the unit dose consists of or consists essentially of
zoledronic acid and glycine.
[0156] Another aspect of the present invention provides for a
method of treating or preventing a disease for which a
bisphosphonic acid is indicated, the method comprising the step of
administering to a patient in need of the bisphosphonic acid a
therapeutically effective amount of a pharmaceutical composition of
the present invention. In one embodiment the bisphosphonic acid is
zoledronic acid. In another embodiment the bisphosphonic acid is
clodronic acid. In another embodiment the bisphosphonic acid is
tiludronic acid. In another embodiment the bisphosphonic acid is
pamidronic acid. In another embodiment the bisphosphonic acid is
alendronic acid. In another embodiment the bisphosphonic acid is
risedronic acid. In another embodiment the bisphosphonic acid is
ibandronic acid. In one embodiment the disease is selected from
osteoporosis, hypercalcemia, cancer induced bone metastasis,
Paget's disease, adjuvant cancer therapy or neoadjuvant cancer
therapy. In one particular embodiment the method is for treating
such a disease. In another particular embodiment the method is for
preventing such as disease.
[0157] Another aspect of the present invention provides for a
medicament comprising a pharmaceutical composition of the present
invention for use in treating or preventing a disease for which a
bisphosphonic acid is indicated. In one embodiment the
bisphosphonic acid is zoledronic acid. In another embodiment the
bisphosphonic acid is clodronic acid. In another embodiment the
bisphosphonic acid is tiludronic acid. In another embodiment the
bisphosphonic acid is pamidronic acid. In another embodiment the
bisphosphonic acid is alendronic acid. In another embodiment the
bisphosphonic acid is risedronic acid. In another embodiment the
bisphosphonic acid is ibandronic acid. In one embodiment the
disease is selected from osteoporosis, hypercalcemia, cancer
induced bone metastasis, Paget's disease, adjuvant cancer therapy
or neoadjuvant cancer therapy. In one embodiment the medicament is
for use in treating such a disease. In another embodiment the
medicament is for use in preventing such a disease.
[0158] In one aspect, the present invention includes complexes of a
bisphosphonic acid (e.g., zoledronic acid) with sodium, ammonium,
ammonia, L-lysine, DL-lysine, nicotinamide, adenine and glycine
which are capable of complexing in the solid-state, for example,
through dry or solvent-drop grinding (liquid assisted grinding),
heating or solvent evaporation of their solution in single or mixed
solvent systems, slurry suspension, supercritical fluids or other
techniques known to a person skilled in the art.
[0159] In one embodiment the invention provides for a zoledronic
and nicotinamide complex to be made by dissolving both compounds in
a water:ethylacetate (1:1 v/v) mixture and allowing the solvent to
evaporate to form crystalline material.
[0160] In another embodiment the invention provides for a
zoledronic and glycine solid complex made by dissolving both
compounds in water, and allowing the solvent to evaporate to form
crystalline material.
[0161] In one aspect the invention provides for a molecular complex
of zoledronic acid and a coformer selected from sodium, ammonium,
ammonia, L-lysine, DL-lysine, nicotinamide, adenine or glycine,
suitable for a pharmaceutical formulation than can be delivered
orally to the human body. In one aspect of the pharmaceutical
composition of the present invention comprises a therapeutically
effective amount of at least one of the novel molecular complexes
according to the invention and may further include at least one
additional coformer and at least one pharmaceutically acceptable
excipient. The novel molecular complexes of zoledronic acid are
therapeutically useful for the treatment and/or prevention of
disease states for which a bisphosphonic acid is indicated, for
example, disease states associated with osteoporosis, hypercalcemia
(TIH), cancer induced bone metastasis, Paget's disease or adjuvant
or neoadjuvant therapies.
Pharmaceutical Compositions
[0162] A pharmaceutical composition of the invention may be in any
pharmaceutical form, for example, a tablet, capsule, particulate
material, e.g., granulated particulate material or a powder, oral
liquid suspension, oral liquid solution, an injectable solution, a
lyophilized material for reconstitution, suppository, topical, or
transdermal.
[0163] In one aspect the invention provides for a composition
comprising a micronized molecular complex of the present invention.
In one embodiment the micronized molecular complex is zoledronic,
DL-lysine and water molecular complex. In other embodiment the
composition further comprises excess micronized cocrystal former
(e.g., DL-lysine).
[0164] Another embodiment of the invention provides micronized
novel zoledronic acid complex (zoledronic, DL-lysine and water)
where the particle mean size diameter is 5 microns by volume.
[0165] Another aspect of the invention provides micronized excess
coformer (e.g, DL-lysine) where the mean particle size diameter is
5 microns by volume.
[0166] Generally, the oral dosage forms of the present invention
will contain from about 1 mg to about 500 mg of an API (e.g,
bisphosphonic acid) on an anhydrous weight basis, depending on the
particular API administered. In one aspect the oral dosage form is
a unit dose of bisphosphonic acid. In one embodiment the
bisphosphonic acid is zoledronic acid. In one embodiment the unit
dose is between about 10 mg to about 500 mg. In one embodiment the
unit dose is between about 10 mg to about 400 mg. In one embodiment
the unit dose is between about 10 mg to about 300 mg. In one
embodiment the unit dose is between about 10 mg to about 200 mg. In
another embodiment the unit dose is between about 10 mg to about
100 mg. In another embodiment the unit dose is between about 10 mg
to about 90 mg. In another embodiment the unit dose is between
about 10 mg to about 80 mg. In another embodiment the unit dose is
between about 10 mg to about 70 mg. In another embodiment the unit
dose is between about 10 mg to about 60 mg. In another embodiment
the unit dose is between about 10 mg to about 50 mg. In another
embodiment the unit dose is between about 100 mg to about 500 mg.
In another embodiment the unit dose is between about 100 mg to
about 400 mg. In another embodiment the unit dose is between about
100 mg to about 300 mg. In another embodiment the unit dose is
between about 100 mg to about 200 mg. In another embodiment the
unit dose is between about 50 mg to about 250 mg. In another
embodiment the unit dose is between about 50 mg to about 150 mg. In
another embodiment the unit dose is between about 50 mg to about
100 mg. In another embodiment the unit dose is between about 40 mg
to about 120 mg. In another embodiment the unit dose is between
about 50 mg to about 100 mg. In another embodiment the unit dose is
between about 40 mg to about 50 mg. In another embodiment the unit
dose is between about 50 mg to about 60 mg. In another embodiment
the unit dose is between about 60 mg to about 70 mg. In another
embodiment the unit dose is between about 70 mg to about 80 mg. In
another embodiment the unit dose is between about 80 mg to about 90
mg. In another embodiment the unit dose is between about 90 mg to
about 100 mg. In another embodiment the unit dose is between about
100 mg to about 110 mg. In another embodiment the unit dose is
between about 110 mg to about 120 mg. In another embodiment the
unit dose is between about 100 mg to about 200 mg. In another
embodiment the unit dose is between about 150 mg to about 250 mg.
In another embodiment the unit dose is between about 200 mg to
about 300 mg. In another embodiment the unit dose is between about
250 mg to about 350 mg. In another embodiment the unit dose is
between about 300 mg to about 400 mg. In another embodiment the
unit dose is between about 350 mg to about 450 mg. In another
embodiment the unit dose is between about 400 mg to about 500 mg.
In another embodiment the unit dose is about 40 mg. In another
embodiment the unit dose is about 50 mg. In another embodiment the
unit dose is about 60 mg. In another embodiment the unit dose is
about 70 mg. In another embodiment the unit dose is about 80 mg. In
another embodiment the unit dose is about 90 mg. In another
embodiment the unit dose is about 100 mg. In another embodiment the
unit dose is about 110 mg. In another embodiment the unit dose is
about 120 mg. In another embodiment the unit dose is about 130 mg.
In another embodiment the unit dose is about 140 mg. In another
embodiment the unit dose is about 150 mg. In another embodiment the
unit dose is about 160 mg. In another embodiment the unit dose is
about 170 mg. In another embodiment the unit dose is about 180 mg.
In another embodiment the unit dose is about 190 mg. In another
embodiment the unit dose is about 200 mg. In another embodiment the
unit dose is between about 1 mg to about 10 mg. In one embodiment
the bisphosphonic acid is dosed on a daily basis. In another
embodiment the bisphosphonic acid is dosed twice weekly. In one
embodiment the bisphosphonic acid is dosed on a weekly basis. In
one embodiment the time between doses is ten days. In another
embodiment the time between doses is two weeks. In another
embodiment the time between doses is three weeks. In another
embodiment the time between doses is four weeks. In another
embodiment the time between doses is one month. In another
embodiment the time between doses is six weeks. In another
embodiment the time between doses is eight weeks. In another
embodiment the time between doses is two months. In one embodiment
the bisphosphonic acid is dosed no more frequent than once in a
three month period. In one embodiment the bisphosphonic acid is
dosed no more frequent than once in a six month period. In one
embodiment the bisphosphonic acid is dosed no more frequent than
once in a year. In one embodiment a course of treatment is between
one month and one year. In another embodiment a course of treatment
is between one month and six months. In one embodiment a course of
treatment is between one month and three months. In one embodiment
a course of treatment is between three months and six months. In
one embodiment a course of treatment is one month. In another
embodiment a course of treatment is two months. In another
embodiment a course of treatment is three months.
[0167] The API (whether in the form of a molecular complex or as a
free acid or base) and additional coformer combinations of the
present invention (e.g., a zoledronic acid, L-lysine, and water
complex and excess lysine) may be administered together or
sequentially in single or multiple doses.
[0168] In one aspect the API and excess coformer are administered
as a fixed dose combination product (e.g., a tablet containing both
the molecular complex and excess coformer). In one embodiment the
fixed dose combination product is a tablet or a capsule. In another
embodiment the fixed dose combination product is a liquid solution
or suspension. In another embodiment the fixed dose combination
product is a particulate material, e.g., powder. In another
embodiment the fixed dose combination product is a particulate
material and is enclosed in a sachet. In another embodiment the
fixed dose combination product is administered in single doses as
part of a therapeutic treatment program or regimen. In another
embodiment the fixed dose combination product is administered in
multiple doses as part of a therapeutic treatment program or
regimen.
[0169] In another aspect the API and excess coformer are
administered as separate unit doses (e.g., two different tablets)
but as part of the same therapeutic treatment program or regimen.
In one embodiment, the API and excess coformer are administered
simultaneously. In another embodiment the API and excess coformer
are administered sequentially. In another embodiment the excess
coformer is administered before the API. In another embodiment the
API and excess coformer are administered in a single dose as part
of the same therapeutic treatment program or regimen. In another
embodiment the API and/or excess coformer is administered in
multiple doses as part of the same therapeutic treatment program or
regimen.
[0170] The compositions and dosage forms described herein can be
administered via any conventional route of administration. In one
embodiment the route of administration is oral.
[0171] Examples of suitable oral compositions of the present
invention include tablets, capsules, troches, lozenges,
suspensions, solutions, dispersible powders or granules, emulsions,
syrups and elixirs.
[0172] Examples of fillers and diluents of the present invention
include, for example, sodium carbonate, lactose, sodium phosphate
and plant cellulose (pure plant filler). A range of vegetable fats
and oils may be used in soft gelatin capsules. Other examples of
fillers of the present invention include sucrose, glucose,
mannitol, sorbitol, and magnesium stearate.
[0173] Examples of granulating and disintegrants of the present
invention include corn starch and alginic acid, crosslinked
polyvinyl pyrrolidone, sodium starch glycolate or crosslinked
sodium carboxymethyl cellulose (crosscarmellose).
[0174] Examples of binding agents of the present invention include
starch, gelatin, acacia, cellulose, cellulose derivatives, such as
methyl cellulose, microcrystalline cellulose and hydroxypropyl
cellulose, polyvinylpyrrolidone, sucrose, polyethylene glycol,
lactose, or sugar alcohols like xylitol, sorbitol and maltitol.
[0175] Examples of lubricants of the present invention include
magnesium stearate, stearic acid and talc.
[0176] Tablets or capsules of the present invention and/or the drug
containing particles therein may be uncoated or coated by known
techniques. Such coatings may delay disintegration and thus,
absorption in the gastrointestinal tract and/or may provide a
sustained action over a longer period.
[0177] Coatings, e.g., enteric coating, may be applied using an
appropriate aqueous solvent or organic solvent. Examples of enteric
coatings include polymethacrylates, such as methacrylic acid/ethyl
acrylate; cellulose esters, such as cellulose acetate phthalate
(CAP), cellulose acetate trimellitate (CAT), and
hydroxypropylmethylcellulose acetate succinate (HPMCAS); and
polyvinyl derivatives, such as polyvinyl acetate phthalate (PVAP).
In one embodiment the tablet/capsule or particles/granules
comprising a pharmaceutical composition of the present invention is
enteric coated using an organic solvent coating.
[0178] The pharmaceutical compositions of the present invention
comprising an API and excess coformer may be formulated such that
the API and excess coformer have the same release profile or
different release profiles. In one aspect the API and excess
coformer have the same release profile. In one embodiment a
pharmaceutical composition comprising zoledronic acid and an amino
acid (e.g., lysine) are formulated such that the zoledronic acid
and amino acid have the same release profile. In another embodiment
the zoledronic acid is released within one hour of the amino acid.
In another embodiment the zoledronic acid is released within 30
minutes of the amino acid. In another embodiment the zoledronic
acid is released within 15 minutes of the amino acid. In another
embodiment the zoledronic acid is released before the amino acid.
In another aspect the API is released before the excess coformer.
In another aspect the excess coformer is released before the API.
In another aspect the amino acid is released before the API.
[0179] The pharmaceutical compositions of the present invention may
be formulated as a sustained release formulation such that the API
or excess coformer is released over a longer period of time that it
would be if formulated as an immediate release formulation. In one
embodiment the excess coformer is formulated as a sustained release
formulation. In another embodiment the API is formulated as a
sustained release formulation. In another embodiment both the API
and the excess coformer are formulated as a sustained release
formulation.
[0180] The pharmaceutical compositions of the present invention may
also be formulated as an immediate release formulation. In one
embodiment the excess coformer is formulated as an immediate
release formulation. In another embodiment the API is formulated as
an immediate release formulation. In another embodiment both the
API and the excess coformer are formulated as an immediate release
formulation.
[0181] The pharmaceutical compositions of the present invention may
further be formulated as a `delayed+sustained release` formulation,
a formulation intended to delay release of a drug until the dosage
form has passed through the stomach, followed by sustained release
of the drug in the small intestine. Such a release profile can be
achieved, e.g., through coating of multiparticulates or hydrophilic
matrix tablets with pH-dependent coating polymers, or coating with
combinations of pH dependent coating polymers and extended release
barrier membrane systems. In one embodiment the excess coformer is
formulated as a delayed+sustained release formulation. In another
embodiment the API is formulated as a delayed+sustained release
formulation.
[0182] The pharmaceutical compositions of the present invention may
further be formulated as an "enteric release" formulation, a
formulation intended to delay release of a drug until the dosage
form has passed through the stomach, followed by rapid release of
the drug in the proximal small intestine. Such a release profile
can be achieved through coating of particles or granules within a
tablet or capsule or coating of the tablet, caplet or capsule with
a pH-dependent polymeric coating system. In one embodiment the
excess coformer is formulated as an enteric release formulation. In
another embodiment the API is formulated as an enteric release
formulation. In another embodiment the pharmaceutical composition
is an enterically coated dosage form. In one embodiment enterically
coated dosage form is an enterically coated hard gelatin capsule.
In another embodiment enterically coated dosage form is an
enterically coated soft or hard gelatin capsule. In another
embodiment the enterically coated dosage form is an enterically
coated tablet.
[0183] The term "modified enteric release" refers to a formulation
that allows for a small portion of a drug dose to be released into
the stomach, with the remainder of release occurring rapidly upon
passage of the dosage form into the small intestine. Such a release
profile can be achieved through the use of hydrophilic pore formers
in pH dependent enteric coatings. In one embodiment the excess
coformer is formulated as a modified enteric release formulation.
In another embodiment the API is formulated as a modified enteric
release formulation. In another embodiment both the excess coformer
and the API are formulated as a modified enteric release
formulation.
[0184] The term "biphasic release" refers to a formulation whereby
a drug is released in a biphasic manner rather than a single phase.
It also refers to a formulation where two different components,
e.g., the excess coformer and API of the present invention, are
released in a biphasic manner rather than a single phase. For
example, a first dose may be released as an immediate release dose
fraction, while a second dose is released as an extended release
phase. Examples of such systems can be found as bilayer tablets,
drug layered matrices, or multiparticulate combinations with
different release profiles. In one embodiment the excess coformer
is formulated as a biphasic release formulation. In another
embodiment the molecular complex is formulated as a biphasic
release formulation.
[0185] In another embodiment the excess coformer and molecular
complex are formulated as a biphasic formulation, wherein said
excess coformer and said API are formulated to be released in
different phases thereby forming a biphasic release profile. In
another embodiment the excess coformer and API are formulated as a
biphasic release formulation, wherein said excess coformer is
formulated to be released as a first phase and said API is
formulated to be released as a second phase. In another embodiment
the pharmaceutical composition of the present invention is
formulated as a bilayer tablet comprising a first layer and a
second layer, wherein said first layer comprises an excess coformer
and an excipient, and wherein said second layer comprises an API
and an excipient.
[0186] In another embodiment the pharmaceutical composition of the
present invention is formulated as a multiparticulate formulation,
i.e., a formulation comprising multiple particles. In one
embodiment the API and excess coformer are in the same
particle.
[0187] In another embodiment the pharmaceutical composition of the
present invention is formulated as a tablet or capsule comprising a
multiparticulate combination, said multiparticulate combination
comprising a first multiparticulate formulation and a second
multiparticulate formulation, wherein said first multiparticulate
formulation comprises an excess coformer and, optionally, one or
more excipient, and wherein said second multiparticulate
formulation comprises a API and, optionally, one or more
excipient.
[0188] In one embodiment the particles comprising the API, excess
coformer or both API and excess coformer have a mean size diameter
by volume of between about 1 and about 1000 microns. In one
embodiment the particles have a mean size of between about 1 and
about 100 microns. In one embodiment the particles have a mean size
of between about 1 and about 10 microns. In one embodiment the
particles have a mean size of between about 1 and about 5 microns.
In one embodiment the particles have a mean size of between about
100 and about 1000 microns. In one embodiment the particles have a
mean size of between about 100 and about 500 microns. In one
embodiment the particles have a mean size of between about 200 and
about 400 microns. In one embodiment the particles have a mean size
of between about 300 and about 500 microns.
[0189] The term "C.sub.max" refers to the maximum plasma
concentration of a drug after administration.
[0190] In one embodiment, the excess coformer and API are
formulated as a biphasic release formulation, wherein said excess
coformer is formulated to be released as a first phase and said API
is formulated to be released as a second phase, and wherein a
C.sub.max of said excess coformer occurs less than 60 minutes
before a C.sub.max of said API. In another embodiment, the
C.sub.max for said excess coformer occurs less than 45 minutes
before the C.sub.max of said API. In another embodiment, the
C.sub.max for said excess coformer occurs less than 30 minutes
before the C.sub.max of said API. In another embodiment, the
C.sub.max for said excess coformer occurs before the C.sub.max of
said API. In another embodiment, the C.sub.max for said API occurs
before the C.sub.max of said excess coformer. In a particular
embodiment wherein the pharmaceutical composition comprises a
bisphosphonic acid, e.g., zoledronic acid and an amino acid, e.g.,
lysine, the C.sub.max for said amino acid occurs less than 60
minutes before the C.sub.max of said bisphosphonic acid. In another
embodiment, the C.sub.max for the amino acid occurs less than 45
minutes before the C.sub.max of the bisphosphonic acid. In another
embodiment, the C.sub.max for the amino acid occurs less than 30
minutes before the C.sub.max of the bisphosphonic acid. In another
embodiment, the C.sub.max for the bisphosphonic acid occurs before
the C.sub.max of the amino acid. In one embodiment, the excess
coformer and API are formulated as a biphasic release formulation,
wherein said excess coformer is formulated to be released as a
first phase and said API is formulated to be released as a second
phase, and wherein a T.sub.max of said excess coformer occurs less
than 60 minutes before a T.sub.max of said API. In another
embodiment, the T.sub.max for said excess coformer occurs less than
45 minutes before the T.sub.max of said API. In another embodiment,
the T.sub.max for said excess coformer occurs less than 30 minutes
before the T.sub.max of said API. In another embodiment, the
T.sub.max for said excess coformer occurs before the T.sub.max of
said API. In another embodiment, the T.sub.max for said API occurs
before the T.sub.max of said excess coformer. In a particular
embodiment wherein the pharmaceutical composition comprises a
bisphosphonic acid, e.g., zoledronic acid and an amino acid, e.g.,
lysine, the T.sub.max for said amino acid occurs less than 60
minutes before the T.sub.max of said bisphosphonic acid. In another
embodiment, the T.sub.max for the amino acid occurs less than 45
minutes before the T.sub.max of the bisphosphonic acid. In another
embodiment, the T.sub.max for the amino acid occurs less than 30
minutes before the T.sub.max of the bisphosphonic acid. In another
embodiment, the T.sub.max for the bisphosphonic acid occurs before
the T.sub.max of the amino acid.
[0191] In one embodiment, the excess coformer and API are
formulated as a biphasic release formulation, wherein said excess
coformer is formulated to be released as a first phase and said API
is formulated to be released as a second phase, and wherein a
C.sub.max and T.sub.max of said excess coformer occurs less than 60
minutes before a C.sub.max and T.sub.max of said API. In another
embodiment, the C.sub.max and T.sub.max for said excess coformer
occurs less than 45 minutes before the C.sub.max and T.sub.max of
said API. In another embodiment, the C.sub.max and T.sub.max for
said excess coformer occurs less than 30 minutes before the
C.sub.max and T.sub.max of said API. In another embodiment, the
C.sub.max and T.sub.max for said excess coformer occurs before the
C.sub.max and T.sub.max of said API. In another embodiment, the
C.sub.max and T.sub.max for said API occurs before the C.sub.max
and T.sub.max of said excess coformer. In a particular embodiment
wherein the pharmaceutical composition comprises a bisphosphonic
acid, e.g., zoledronic acid and an amino acid, e.g., lysine, the
C.sub.max and T.sub.max for said amino acid occurs less than 60
minutes before the C.sub.max and T.sub.max of said bisphosphonic
acid. In another embodiment, the C.sub.max and T.sub.max for the
amino acid occur less than 45 minutes before the C.sub.max and
T.sub.max of the bisphosphonic acid. In another embodiment, the
C.sub.max and T.sub.max for the amino acid occur less than 30
minutes before the C.sub.max and T.sub.max of the bisphosphonic
acid. In another embodiment, the C.sub.max and T.sub.max for the
bisphosphonic acid occur before the C.sub.max and T.sub.max of the
amino acid.
[0192] In one embodiment the excess coformer and API are formulated
as a biphasic release formulation in a fixed dose combination
product (e.g., in a single tablet). In one embodiment the excess
coformer and API are each formulated as a multi-particulate
formulation and combined to form a fixed dose combination product.
In one embodiment the dosage form is a capsule comprising a first
multiparticulate formulation of said excess coformer and a second
multiparticulate formulation of said API as a fixed dose
combination product. In another embodiment the fixed dose
combination product is a bilayer tablet comprising a first layer
and a second layer, wherein said first layer comprises an excess
coformer and said second layer comprises an API.
[0193] In another embodiment, the API and excess coformer are
formulated into a bilayer, whereby the API and matrix-forming
material are combined and compressed to form a sustained release
layer, and the excess coformer is blended with one or more agents
and forms a second layer. In one embodiment the excess coformer
layer is an immediate release formulation. In another embodiment
the bilayer dosage form is enteric coated. In another embodiment
the excess coformer layer and/or the API layer, is an enteric
release formulation
[0194] The term "first-order release" refers to where the rate of
elimination of drug from plasma is proportional to the plasma
concentration of the drug. In one embodiment the excess coformer is
released from the pharmaceutical composition as a first-order
release. In one embodiment the API is released from the
pharmaceutical composition as a first-order release. In one
embodiment both the excess coformer and API are released from the
pharmaceutical composition as a first-order release.
[0195] The term "zero order release" refers to the ability to
deliver a drug at a rate which is independent of time and
concentration of the drug within a pharmaceutical dosage form. Zero
order mechanism ensures that a steady amount of drug is released
over time, minimizing potential peak/trough fluctuations and side
effects, while maximizing the amount of time the drug
concentrations remain within the therapeutic window (efficacy).
Osmotic tablet formulations, coated tablet matrices, and the use of
polymer combinations in hydrophilic matrices, for example, can be
utilized to provide zero order drug release profiles. In one
embodiment the excess coformer is released from the pharmaceutical
composition as a zero-order release. In one embodiment the API is
released from the pharmaceutical composition as a zero-order
release. In one embodiment both the excess coformer and API are
released from the pharmaceutical composition as a zero-order
release.
[0196] Compounds useful for modifying a release profile of a drug
are well known in the art. For example, a time delay material such
as glyceryl monostearate or glyceryl distearate may be employed.
The dosage form may also be coated, by the techniques (e.g., those
described in the U.S. Pat. Nos. 4,256,108; 4,166,452 and 4,265,874,
each incorporated by reference in their entireties) to form osmotic
therapeutic tablets for controlled release. Other controlled
release technologies are also available and are included herein.
Typical ingredients that are useful to slow the release of the drug
in sustained release tablets include various cellulosic compounds,
such as methylcellulose, ethylcellulose, propylcellulose,
hydroxypropylcellulose, hydroxyethylcellulose,
hydroxypropylmethylcellulose, microcrystalline cellulose, starch
and the like. Various natural and synthetic materials are also of
use in sustained release formulations. Examples include alginic
acid and various alginates, polyvinyl pyrrolidone, tragacanth,
locust bean gum, guar gum, gelatin, various long chain alcohols,
such as cetyl alcohol and beeswax.
[0197] One embodiment of the invention includes a sustained release
tablet that comprises the API in combination with one or more of
the cellulosic compounds noted above, compressed into a sustained
release tablet to form a polymer matrix. In another embodiment, the
API and matrix-forming material are combined and compressed to form
a sustained release core, and the excess coformer is blended with
one or more coating agents and coated onto the outer surface of the
core.
[0198] In one embodiment, the excess coformer is provided as a
combined first immediate release dose and a second sustained
release dose. The sustained release dose can be, for example,
zero-order or first order. In certain embodiments the second dose
has a lag time wherein the drug is released from the second dose at
about 30 minutes, in another embodiment 1 hour, in another
embodiment 1.5 hours, in another embodiment 2 hours, in another
embodiment 2.5 hours, in another embodiment 3 hours, in another
embodiment 3.5 hours and in another embodiment 4 hours after
administration. The initial dose may be the same or different
amount from the second dose.
[0199] In one aspect, the API is provided as a combined first
immediate release dose and a second sustained release dose. The
sustained release dose can be, for example, zero-order or first
order. In certain embodiments the second dose has a lag time where
drug is released from the second dose at about 30 minutes, in
another embodiment 1 hour, in another embodiment 1.5 hours, in
another embodiment 2 hours, in another embodiment 2.5 hours, in
another embodiment 3 hours, in another embodiment 3.5 hours and in
another embodiment 4 hours after administration. The initial dose
may be the same or different from the second dose.
[0200] In one aspect, the excess coformer and API is provided in a
combined single unit dose whereby the excess coformer is provided
as an immediate release dose and API as a sustained release dose.
The API sustained release dose can be, for example, zero-order or
first order. In one embodiment the API second dose has a lag time
where drug is released at about 30 minutes, in another embodiment 1
hour, in another embodiment 1.5 hours, in another embodiment 2
hours, in another embodiment 2.5 hours, in another embodiment 3
hours, in another embodiment 3.5 hours and in another embodiment 4
hours after administration.
[0201] Typical release time frames for sustained release tablets in
accordance with the present invention range from about 1 to as long
as about 48 hours, preferably about 4 to about 24 hours, and more
preferably about 8 to about 16 hours.
[0202] Hard gelatin capsules constitute another solid dosage form
for oral use. Such capsules similarly include the active
ingredients mixed with carrier materials as described above. Soft
gelatin capsules include the active ingredients mixed with
water-miscible solvents such as propylene glycol, PEG and ethanol,
or an oil such as peanut oil, liquid paraffin or olive oil. Aqueous
suspensions are also contemplated as containing the active material
in admixture with excipients suitable for the manufacture of
aqueous suspensions. Such excipients include suspending agents, for
example sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, tragacanth and acacia; dispersing or wetting
agents, e.g., lecithin; preservatives, e.g., ethyl, or n-propyl
para-hydroxybenzoate, colorants, flavors, sweeteners and the
like.
[0203] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredients in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Aqueous solutions, suspensions, syrups and
elixirs may also be formulated.
[0204] The techniques and approaches set forth in the present
disclosure can further be used by the person of ordinary skill in
the art to, prepare variants thereof, said variants are considered
to be part of the inventive disclosure.
EXAMPLES
[0205] The following examples illustrate the invention without
intending to limit the scope of the invention.
[0206] Molecular complexes of zoledronic acid and sodium, ammonium,
ammonia, L-lysine, DL-lysine, nicotinamide, adenine, and glycine
have been made and are characterized by their PXRD patterns and
FTIR spectra disclosed herein. Further, in vivo data in rats
concerning the oral bioavailability of zoledronic acid delivered
orally, intravenously, and intraduodenally have been generated as
well as PK profiles of the parent compound.
[0207] Zoledronic acid as a starting material used in all
experiments in this disclosure was supplied by Farmkemi Limited
(Wuhan Pharma Chemical Co.), China with purity of ca. 98% and was
purified further via recrystallization from water. All other pure
chemicals (Analytical Grade) were supplied by Sigma-Aldrich and
used without further purification.
[0208] Enteric coating of gelatin capsules was contracted out to
AzoPharma, Hollywood, Fla., USA. A 10% w/w coating solution of
Eudragit L100-55, and triethyl citrate, 9.09 and 0.91 w/w %
respectively, in purified water and acetone was used in the Vector
LDCS pan coater to achieve a uniform coating layer on the capsules.
The coating uniformity and functionality for duodenal delivery was
tested by 2 hr dissolution in simulated gastric fluid stirred at 75
rpm and 37.degree. C. All capsules remained closed for the duration
of this test.
[0209] Micronization was carried out at the Jet Pulverizer Company
(NJ, USA) using a three inch diameter mill.
Solid Phase Characterization
[0210] Analytical techniques used to observe the crystalline forms
include powder X-ray diffraction (PXRD) and Fourier transform
infrared spectroscopy (FTIR). The particular methodology used in
such analytical techniques should be viewed as illustrative, and
not limiting in the context of data collection. For example, the
particular instrumentation used to collect data may vary; routine
operator error or calibration standards may vary; sample
preparation method may vary (for example, the use of the KBr disk
or Nujol mull technique for FTIR analysis).
[0211] Fourier Transform FTIR Spectroscopy (FTIR): FTIR analysis
was performed on a Perkin Elmer Spectrum 100 FTIR spectrometer
equipped with a solid-state ATR accessory. Powder X-Ray Diffraction
(PXRD): All zoledronic acid molecular complex products were
observed by a D-8 Bruker X-ray Powder Diffractometer using Cu
K.alpha. (.lamda.=1.540562 .ANG.), 40 kV, 40 mA. The data were
collected over an angular range of 3.degree. to 40.degree. 2.theta.
in continuous scan mode at room temperature using a step size of
0.05.degree. 2.theta. and a scan speed of 6.17.degree./min.
[0212] Laser scattering particle size analysis: All micronized
samples were tested using the Horiba LA950 laser scattering
particle size analyzer, dry method using air at pressure of 0.3 MPA
to fluidize the micronized samples before flowing in the path of a
laser beam. The micronized samples were further tested using light
microscopy to verify the Horiba results.
Example 1
Preparation of Zoledronic Acid, Sodium Zoledronic Salt, and Water
Complex
[0213] 200 mg of zoledronic acid was slurried with 180 mg of sodium
chloride in 1 mL of 1:1 ethanol:water overnight. The material was
filtered and rinsed. The particulate material was gathered and
stored in a screw cap vial for subsequent analysis. The material
was characterized by PXRD and FTIR corresponding to FIG. 1 and FIG.
2, respectively.
Example 2
Preparation of Ammonium Zoledronic Salt and Water Complex
[0214] 300 mg of zoledronic acid was slurried in 7N ammonia in
methanol overnight. The material was filtered and rinsed. The
particulate material was dissolved in water and left to evaporate
at ambient conditions to obtain colorless plates after 1 week. The
material was characterized by PXRD and FTIR corresponding to FIG. 3
and FIG. 4, respectively.
Example 3
Preparation of Zoledronic, L-Lysine, and Water Complex
[0215] 200 mg of zoledronic acid and 54 mg of L-lysine were
slurried in 2 mL of tetrahydrofuran and 200 .mu.l of water
overnight. The solids gathered after filtration were dried and
stored in a screw cap vials for subsequent analysis. The material
was characterized by PXRD and FTIR corresponding to FIG. 5 and FIG.
6, respectively.
Example 4
Preparation of Zoledronic, DL-Lysine, and Water Complex
[0216] 204 mg of zoledronic acid and 59 mg of DL-lysine were
slurried in 2 mL of tetrahydrofuran and 200 .mu.l of water
overnight. The solids gathered after filtration were dried and
stored in a screw cap vials for subsequent analysis. The material
was characterized by PXRD and FTIR corresponding to FIG. 7 and FIG.
8 respectively.
Example 5
Preparation of Zoledronic Acid, Zoledronic, DL-Lysine, Ethanol, and
Water Complex
[0217] 103 mg of zoledronic acid and 54 mg of DL-lysine were
dissolved in 400 .mu.l of water, capped and stirred overnight. The
next day 0.25 mL of ethanol was added drop wise. The vial was
capped with a screw cap vial and after 1 day crystals appeared and
were filtered off. The material was stored for subsequent analysis.
The material was characterized by PXRD and FTIR corresponding to
FIG. 9 and FIG. 10 respectively.
Example 6
Preparation of Zoledronic, Nicotinamide, and Water Complex by
Solvent-Drop Grinding
[0218] 99 mg of zoledronic acid was ground with 44 mg of
nicotinamide and 40 .mu.l of water was added to the solid mixture.
The solids gathered after grinding were stored in screw cap vials
for subsequent analysis. The material was characterized by PXRD and
FTIR corresponding to FIG. 11 and FIG. 12, respectively.
Example 7
Preparation of Zoledronic, Nicotinamide, and Water Complex from
Solution Crystallization
[0219] 25 mg of zoledronic acid and 138 mg of nicotinamide were
dissolved in 2 mL of a water:ethylacetate mix (1:1 v/v). The
solution was then allowed to stand for several hours to effect the
slow evaporation of solvent. The solids gathered were characterized
and produced very similar PXRD and FTIR patterns to that of Example
6 product.
Example 8
Preparation of Zoledronic, Adenine, and Water Complex by
Solvent-Drop Grinding
[0220] 96 mg of zoledronic acid was ground with 65 mg of adenine
and 60 .mu.L of water was added to the solid mixture. The solids
gathered after grinding were stored in screw cap vials for
subsequent analysis. The material was characterized by PXRD and
FTIR corresponding to FIG. 13 and FIG. 14, respectively.
Example 9
Preparation of Zoledronic, Adenine, and Water Complex from Solution
Slurry
[0221] 99 mg of zoledronic acid and 54 mg of adenine were slurried
in 2 mL of a water:ethanol mix (1:1 v/v) overnight. The solids
gathered after filtration were dried, characterized and produced
very similar PXRD and FTIR patterns to that of Example 8
product.
Example 10
Preparation of Zoledronic and Glycine Complex
[0222] 178 mg of zoledronic acid and 45 mg of glycine were slurried
in 2 mL of water overnight. The solids gathered after filtration
were dried and stored in a screw cap vials for subsequent analysis.
The material was characterized by PXRD and FTIR corresponding to
FIG. 15 and FIG. 16, respectively.
Example 11
Preparation of Zoledronic Diammonia Water Complex
[0223] 1.5 g of zoledronic acid was slurried in 7N ammonia in
methanol overnight. The material was filtered and rinsed. The
particulate material was dissolved in water with medium heat and
left to evaporate at ambient conditions to obtain colorless blocks
after 1 day. The material was characterized by PXRD and FTIR
corresponding to FIG. 17 and FIG. 18, respectively.
Example 12
Preparation of Zoledronic, DL-Lysine, and Water Complex
[0224] 200 mg of zoledronic acid and 102 mg of DL-lysine were
slurried in 2 mL of tetrahydrofuran and 400 .mu.l of water
overnight. The solids gathered after filtration were dried and
stored in a screw cap vials for subsequent analysis. The material
was characterized by PXRD and FTIR corresponding to FIG. 19 and
FIG. 20 respectively.
Example 13
Preparation of Zoledronic, DL-Lysine, and Water Complex
[0225] 1 g of zoledronic acid and 283 mg of DL-lysine were slurried
in 80 mL of tetrahydrofuran and 8 mL of water overnight. The solids
gathered after filtration were dried and stored in a screw cap
vials for subsequent analysis. The material was characterized by
PXRD and FTIR corresponding to FIG. 21 and FIG. 22
respectively.
Example 14
Preparation of Zoledronic, DL-Lysine, and Water Complex by
Antisolvent Method
[0226] This complex can also be prepared by the antisolvent method
by dissolving 1 g of zoledronic acid and 283 mg of DL-lysine in 5
mL of hot water and adding 40 mL of ethanol as an antisolvent
stirred overnight. Similar PXRD and FTIR profiles were obtained as
shown in FIG. 23 and FIG. 24 respectively.
Example 15
Preparation of Zoledronic, L-Lysine, and Water Complex
[0227] 1 g of zoledronic acid and 255 mg of L-lysine were dissolved
in 60 mL of hot water. 100 mL of ethanol was then added as an
antisolvent. The solids gathered after filtration were dried and
stored in a screw cap vials for subsequent analysis. The material
was characterized by PXRD and FTIR corresponding to FIG. 25 and
FIG. 26 respectively.
Example 16
The Animal PK Studies
[0228] These studies were conducted on rats and dogs as they are
suitable animal models for zoledronic acid. This can be attributed
to the fact that both animals have historically been used in the
safety evaluation and PK screening studies and are recommended by
appropriate regulatory agencies. In addition, rats and dogs have
also been established as appropriate species for assessing the
absorption of bisphosphonate drugs including zoledronic acid. Pure
zoledronic acid and zoledronic acid complexes prepared by the
methods in this invention were delivered to the rats and dogs
through IV or oral routes. Additional tests included ID
administration in rats and administration of enteric coated
capsules in dogs. All compounds delivered were well tolerated by
the animals with no adverse events or physical abnormalities
noticed.
[0229] Test Subjects:
[0230] 8-week male Sprague-Dawley Rats (217-259 grams) were
obtained from Hilltop Lab Animals, Scottdale, Pa. USA. Some animals
have surgical catheters (jugular vein and intraduodenum) were
implanted to the animals prior to the studies. Beagle dogs from
Marshall Farms, N.Y., USA, weighing from (9-12 kg) were used in the
studies presented herein. Surgical catheters (jugular vein) were
implanted prior to the studies.
[0231] Housing:
[0232] Rats were individually housed in stainless steel cages to
prevent catheter exteriorization. Acclimation (Pre-dose Phase) was
for 1 day. Dogs were already in the test facility (Absorption
Systems Inc., USA) and did not need acclimation.
[0233] Environment:
[0234] Environmental controls for the animal room were set to
maintain 18 to 26.degree. C., a relative humidity of 30 to 70%, a
minimum of 10 air changes/hour, and a 12-hour light/12-hour dark
cycle. The light/dark cycle could be interrupted for study-related
activities.
[0235] Diet:
[0236] For rats, water and certified Rodent Diet #8728C (Harlan
Teklad) were provided. For dogs, water and the standard dog chow
diet were given twice daily (every 12 hours).
[0237] Fasting:
[0238] All test animals were fasted overnight before IV, oral, or
ID administration of zoledronic acid or zoledronic acid
complexes.
[0239] Routes of Rat Dosing:
[0240] Zoledronic acid and its complex formulations were
administered through IV, oral and ID. The doses administered to all
rats in these studies were measured as zoledronic acid, not as the
complex form contained in the suspension: [0241] i. IV
Administration: the dose of zoledronic acid for IV administration
was 0.5 mg/kg. The dose of each rat was calculated on a per rat
basis (not on an average weight of all the rats in the lot). [0242]
ii. Oral gavage administration: solid suspensions were
administered. The dose of each rat was calculated on a per rat
basis (not on an average weight of all the rats in the lot). For
solid suspensions, animals were administered 5 mg/kg of zoledronic
acid or 5 mg/kg of zoledronic acid in zoledronic acid complexes
contained in a suspension of PEG 400. [0243] iii. Duodenal cannula
administration: solid suspensions were administered. The dose of
each rat was calculated on a per rat basis (not on an average
weight of all the rats in the lot). For solid suspensions, animals
were administered 5 mg/kg of zoledronic acid or 5 mg/kg of
zoledronic acid in zoledronic acid complexes contained in a
suspension of PEG 400.
[0244] Routes of Dog Dosing:
[0245] Zoledronic acid and its complex formulations were
administered IV and orally. The doses administered to all dogs in
these studies were measured as zoledronic acid in each complex, not
as the complex form contained in the powder in the gelatin capsule
or in solution for IV: [0246] i. IV Administration: The dose volume
of each dog was adjusted based upon the average weight of the dog.
[0247] ii. Oral administration: zoledronic acid and its equivalent
of zoledronic acid complex formulations were administered through
size 0 or 00 gelatin capsules based on the average weight of the
dogs. [0248] iii. Oral administration with enteric coated capsules:
zoledronic acid and its equivalent of zoledronic acid complex
formulations were administered through size 0 enteric coated
gelatin capsules based on the average weight of the dogs. [0249]
iv. Oral administration of the molecular complexes with additional
coformers: physical mixtures of zoledronic acid complexes with
additional coformers were administered through size 0 or 00 or 000
or 13 gelatin capsules based on the average weight of the dogs.
[0250] Groups:
[0251] Two major groups of animals were selected for the study.
[0252] Group 1 consists of rat studies. The rat studies were
divided into four subgroups (I-IV) where the results of each data
point on the PK profile was the average drug concentration in the
plasma of 3 rats. [0253] Group 2 consists of dog studies. The dog
studies were divided into five groups with subgroups (A, B, C, D,
E, F, G, H, J, K, L, M) where the results of each data point on the
PK profile was the average drug concentration in the serum of
mainly 5 dogs. The PK profile for subgroup N was the average
profile of 4 dogs.
Details of Group 1 Rat Dosing
[0254] Group I (IV administration). Group members, designated IV
doses are listed below
TABLE-US-00001 Group # I Designation # of rats Dose* Dose volume G1
Zoledronic Acid 3 0.5 mg/kg 1 mL
IV comparator group, was conducted to calculate MAT (mean
absorption time) and ka (absorption rate constant) for the oral
groups.
[0255] Group II (oral gavage): Group designations and oral doses
are listed below:
TABLE-US-00002 Dose Group # of volume # II Designation Rats Dose*
mL/kg Compound G2 Zoledronic 3 5 mg/kg 1 mL Zoledronic acid Acid in
PEG400 G3 Solid 3 5 mg/kg 1 mL Zoledronic and suspension equivalent
glycine complex in PEG400 G4 Solid 3 5 mg/kg 1 mL Zoledronic,
suspension equivalent nicotinamide, in PEG400 and water complex G5
Solid 3 5 mg/kg 1 mL Zoledronic acid, suspension equivalent sodium
zoledronic in PEG400 salt, and water complex G6 Solid 3 5 mg/kg 1
mL Zoledronic, suspension equivalent L-lysine, and in PEG400 water
complex G7 Solid 3 5 mg/kg 1 mL Zoledronic, suspension equivalent
DL-lysine, and in PEG400 water complex
[0256] Group III (ID administration): Group designations and oral
doses are listed below:
TABLE-US-00003 Dose Group # of volume # III Designation rats Dose*
mL/kg Compound G8 Zoledronic 3 5 mg/kg 1 mL Zoledronic acid Acid in
PEG400 G9 Solid 3 5 mg/kg 1 mL Zoledronic and suspension equivalent
glycine complex in PEG400 G10 Solid 3 5 mg/kg 1 mL Zoledronic,
suspension equivalent nicotinamide, in PEG400 and water complex G11
Solid 3 5 mg/kg 1 mL Zoledronic acid, suspension equivalent sodium
zoledronic in PEG400 salt, and water complex G12 Solid 3 5 mg/kg 1
mL Zoledronic, suspension equivalent L-lysine, and in PEG400 water
complex G13 Solid 3 5 mg/kg 1 mL Zoledronic, suspension equivalent
DL-lysine, and in PEG400 water complex
[0257] Group IV (oral gavage): Group designations and oral doses
are listed below:
TABLE-US-00004 Excess coformer Group # of Dose Excess amount # IV
Compound rats Dose volume/kg coformer mg/kg G14 Zoledronic and 3 5
mg/kg 1 mL Glycine 45 glycine complex, equivalent solid suspension
in PEG400 G15 Zoledronic and 3 5 mg/kg 1 mL Glycine 25 glycine
complex, equivalent solid suspension in PEG400 G16 Zoledronic and 3
5 mg/kg 1 mL Glycine 5 glycine complex, equivalent solid suspension
in PEG400 G17 Zoledronic, DL- 3 5 mg/kg 1 mL DL-lysine 39.32
lysine, and water equivalent monohydrate complex, solid suspension
in PEG400 G18 Zoledronic, DL- 3 5 mg/kg 1 mL DL-lysine 28.08
lysine, and water equivalent monohydrate complex, solid suspension
in PEG400 G19 Zoledronic, DL- 3 5 mg/kg 1 mL DL-lysine 5.62 lysine,
and water equivalent monohydrate complex, solid suspension in
PEG400 G20 Zoledronic, DL- 3 5 mg/kg 1 mL n/a n/a lysine, and water
equivalent complex, solid suspension in PEG400
Rat Blood Sample Collection, Handling and Analysis:
[0258] Blood (approx. 300 .mu.L per sample) samples were withdrawn
from each of 3 animals in Group I (IV administration) at eight (8)
time points: 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 8 hr, and 24
hrs, after initial' administration of zoledronic acid or its
complexes, into EDTA plasma tubes. Plasma was collected after
centrifugation at 13,000 rpm for 5 min at 4.degree. C. and
immediately frozen and stored at -60 to -80.degree. C. until
analysis.
Samples were thawed on the day of analysis and the amount of
zoledronic acid in the samples was quantified by analyzed by
LC/MS/MS method.
Details of Group 2 Dog Dosing:
[0259] Prior to dosing, all dogs received a 20 mL dose of citric
acid (24 mg/mL in water) to lower the pH of their stomach. After
dosing capsules or IV, all dogs received additional 6.25 mL citric
acid solution (24 mg/mL in water) as a rinse.
[0260] Group A, (IV administration). Group members, designated IV
doses are listed below:
TABLE-US-00005 # of Dose Group # A Designation fasted Dogs Dose*
volume Leg 1 Zoledronic Acid 5 0.05 mg/kg 1 mL/kg
IV comparator group, was conducted to calculate MAT (mean
absorption time) and ka (absorption rate constant) for the oral
groups.
[0261] Group B (oral administration): Group designations and oral
doses are listed below:
TABLE-US-00006 Dose of Dosing compound in # of fasted Solution
Group Dosing the gelatin Dogs Conc. # B Compound Route capsules
(9-12 kg) mg/mL Leg 2 Zoledronic oral 5 mg/kg 5 n/a acid equivalent
Leg 3 Zoledronic oral 5 mg/kg 5 n/a and glycine equivalent complex
Leg 4 Zoledronic, oral 5 mg/kg 5 n/a DL-lysine, equivalent and
water complex Leg 5 Zoledronic, oral 5 mg/kg 5 n/a L-lysine,
equivalent and water complex Leg 6 Zoledronic, oral 5 mg/kg 5 n/a
DL-lysine, equivalent and water complex
[0262] Group C (oral administration): Group designations and oral
doses are listed below:
TABLE-US-00007 Dose of # of compound in Excess Group fasted Dosing
the gelatin Excess coformer # C Compound Dogs (9-12 kg) Route
capsules coformer amount Leg 7 Zoledronic acid 5 oral 56.0 mg; n/a
n/a monohydrate enterically coated capsules Leg 8 Zoledronic and 5
oral 67.0 mg; n/a n/a glycine complex enterically coated capsules
Leg 9 Zoledronic, DL- 5 oral 87.7 mg DL-lysine 294.8 mg lysine, and
monohydrate water complex Leg 10 Zoledronic, DL- 5 oral 87.7 mg;
DL-lysine 294.8 mg lysine, and enterically monohydrate water
complex coated capsules Leg 11 Zoledronic, DL- 5 oral 84.2 mg
DL-lysine 294.8 mg lysine, and monohydrate water complex Leg 12
Zoledronic, DL- 5 oral 87.7 mg; n/a n/a lysine, and enterically
water complex coated capsules
[0263] Group D, (15 min IV infusion): Group members, designated IV
doses are listed below:
TABLE-US-00008 # of fasted Dogs Dosing solution Group # D
Designation (9-12 kg) Dose* concentration Leg 13 Zoledronic 5 0.183
mg/kg IV 0.1 mg/mL Acid
[0264] Group E, (oral administration): Group members, designated IV
doses are listed below:
TABLE-US-00009 # of Dose of Excess Group fasted Dosing compound in
the Excess coformer # E Compound Dogs (9-12 kg) Route gelatin
capsules coformer amount Leg 14 Zoledronic, DL- 5 oral 35.4 mg
DL-lysine 123.8 mg lysine, and monohydrate water complex Leg 15
Zoledronic and 5 oral 67.0 mg DL-lysine 294.8 mg glycine complex
monohydrate Leg 16 Zoledronic, L- 5 oral 87.7 mg DL-lysine 294.8 mg
lysine, and monohydrate water complex Leg 17 Zoledronic, DL- 5 oral
35.4 mg DL-lysine 294.8 mg lysine, and monohydrate water
complex
[0265] Group F, (15 min IV infusion): Group members, designated IV
doses are listed below:
TABLE-US-00010 Group # of fasted Dosing solution # F Designation
Dogs (9-12 kg) Dose* concentration Leg 18 Zoledronic 5 0.12 mg/kg
IV 0.1 mg/mL Acid infusion
[0266] Group G (oral administration): Group designations and oral
doses are listed below:
TABLE-US-00011 Dose of # of compound fasted in the Excess Group
Dogs Dosing gelatin Excess coformer # G Compound (10-13 kg) Route
capsules coformer amount Leg 19 Zoledronic acid 5 PO 61.3 mg
DL-lysine 322.9 mg monohydrate Leg 20 Zoledronic, L- 5 PO 76.8 mg
L-lysine HCl 359.2 mg lysine, and water complex
[0267] Group H (oral administration): Group designations and oral
doses are listed below:
TABLE-US-00012 Dose of compound # of in the Excess Group fasted
Dosing gelatin Excess coformer # H Compound Dogs (9-12 kg) Route
capsules coformer amount Leg 21 Zoledronic, DL- 5 PO 84.2 mg
L-lysine HCl 328.0 mg lysine, and water complex Leg 22 Zoledronic,
DL- 5 PO 69.0 mg DL-lysine 241.8 mg lysine, and monohydrate water
complex Leg 23 Zoledronic, L- 5 PO 70.1 mg DL-lysine 294.9 mg
lysine, and monohydrate water complex
[0268] Group J (oral administration): Group designations and oral
doses are listed below:
TABLE-US-00013 Dose of # of compound fasted in the Excess Group
Dogs Dosing gelatin Excess coformer # J Compound (10.5-13.5 kg)
Route capsules coformer amount Leg 24 Zoledronic acid 5 PO 64.0 mg
L-lysine HCl 374.8 mg Leg 25 Zoledronic, L- 5 PO 80.1 mg N/A N/A
lysine, and water complex Leg 26 Zoledronic and 5 PO 76.5 mg
L-lysine HCl 374.8 mg glycine complex
[0269] Group K (oral administration): Group designations and oral
doses are listed below:
TABLE-US-00014 # of Dose of Excess Group fasted Dosing compound in
the Excess coformer # K Compound Dogs (8-11 kg) Route gelatin
capsules coformer amount Leg 27 Zoledronic, DL- 5 PO 32.0 mg
DL-lysine 266.8 mg lysine, and monohydrate water complex Leg 28
Zoledronic, DL- 5 PO 76.2 mg DL-lysine 266.8 mg lysine, and
monohydrate water complex
[0270] Group L (oral administration): Group designations and oral
doses are listed below:
TABLE-US-00015 # of Dose of fasted compound in Excess Group Dogs
Dosing the gelatin Excess coformer # L Compound (8.3-11.3 kg) Route
capsules coformer amount Leg 29 Zoledronic, DL- 5 PO 64.4 mg
DL-lysine 275.2 mg lysine, and monohydrate water complex Leg 30
Micronized 5 PO 64.4 mg Micronized 275.2 mg Zoledronic, DL-
DL-lysine lysine, and monohydrate water complex
[0271] Group M (oral administration): Group designations and oral
doses are listed below:
TABLE-US-00016 # of fasted Dose of Excess Group Dogs Dosing
compound in the Excess coformer # M Compound (8.4-11.4 kg) Route
gelatin capsules coformer amount Leg 31 Zoledronic, DL- 4 PO 50.8
mg DL-lysine 278.0 mg lysine, and monohydrate water complex Leg 32
Micronized 5 PO 50.8 mg Micronized 278.0 mg Zoledronic, DL-
DL-lysine lysine, and monohydrate water complex
[0272] Group N (oral administration): Group designations and oral
doses are listed below:
TABLE-US-00017 # of Excess Group fasted Dosing Dose of Excess
coformer # N Compound Dogs Route compound coformer amount Leg 33
Zoledronic, DL- 4 (7.5-10.5 kg) PO 59.2 mg in the DL-lysine 112.3
mg lysine, and gelatin capsules monohydrate water complex Leg 34
Zoledronic, DL- 4 (8.1-11.1 kg) PO 63.1 mg in the DL-lysine 280.8
mg lysine, and gelatin capsules monohydrate water complex Leg 35
Zoledronic, DL- 4 (10.1-13.1 kg) PO 76.3 mg in the DL-lysine 561.6
mg lysine, and gelatin capsules monohydrate water Complex Leg 36
Zoledronic, DL- 4 (7.5-10.5 kg) PO 59.2 mg in the DL-lysine 1123.3
mg lysine, and gelatin capsules monohydrate water complex Leg 37
Zoledronic, DL- 4 (8.1-11.1 kg) PO 63.1 mg in the DL-lysine 1965.7
mg lysine, and gelatin capsules monohydrate water complex Leg 38
Zoledronic acid 4 (10.1-13.1 kg) IV 0.12 mg/kg, 15 min N/A N/A IV
infusion
[0273] After initial administration of zoledronic acid or its
complexes, blood (approx. 2.5 mL per sample) was withdrawn from
each of 5 animals in Group A (IV administration) at 15 time points:
Pre-dose (0), 2, 5, 10, 15, 30, 45 min, 1, 1.5, 2, 4, 6, 8, 24 and
48 hrs and at 13 time points for Group B (oral administration):
Pre-dose (0), 5, 10, 15, 30, 45 min, 1, 1.5, 2, 4, 6, 8, and 24
hrs. Blood samples were placed without the use of an anticoagulant
and allowed to sit at room temperature for approximately 30
minutes. Samples were then centrifuged at a temperature of
4.degree. C., at a speed of 13,000 rpm, for 5 minutes. Serum was
collected and split into two aliquots and stored frozen
(-80.degree. C.) until analysis. Samples were thawed on the day of
analysis and processed using analytical procedures for zoledronic
acid containing an LC/MS/MS analysis method.
Animal PK Studies Results
[0274] Rat Study:
[0275] The results of the first rat study are summarized in Table
1; the concentrations (ng/mL) of zoledronic acid in the plasma
samples are the average values of the analytical results of 3 rats.
In addition, the PK profiles of the IV, oral and ID groups are
shown in FIG. 27. The profiles of oral and ID groups are shown in
FIGS. 28 and 29. It suggests that some zoledronic acid complexes
have improved oral bioavailability compared with that of the parent
zoledronic acid. The complexes with improved bioavailability were
further tested in a second rat PK study in which excess coformers
were added to the zoledronic acid complexes and then administered
to rats by oral gavage. The results of this second study are
summarized in Table 2 and their PK profiles are shown in FIGS. 30,
31 and 32. These figures show improved bioavailabilities of several
zoledronic acid complexes with excess coformers. The effect of
excess coformers with zoledronic acid complexes in improving
bioavailability is not fully understood.
[0276] Dog Study:
[0277] The results of the first dog study (Legs 1-6) are summarized
in Table 3. The concentrations (ng/mL) of zoledronic acid are the
average values of the analytical results of 5 dogs. The PK profiles
of the IV and oral groups are shown in FIGS. 33 and 34 which
represent the first four hours of the 48 hr PK profile. These
results and FIG. 34 suggest that most if not all zoledronic acid
complexes have achieved improved oral bioavailability compared to
that of the parent zoledronic acid delivered orally.
[0278] The results of another dog study (Legs 7-13) are summarized
in Table 4; the concentrations (ng/mL) of zoledronic acid shown are
the average values of the analytical results of 5 dogs. The PK
profiles of the IV and oral groups are shown in FIGS. 35 and 36.
FIG. 36 represents the first 6 hours of the 24 hour PK profile.
These results and FIG. 35 suggest that most if not all zoledronic
acid complexes have achieved improved oral bioavailability compared
with that of the parent zoledronic acid delivered orally.
Specifically, there was a significant improvement in zoledronic
acid bioavailability for the novel zoledronic acid complexes with
excess amino acid coformer (Leg 11, FIG. 37) compared to that of
the parent drug. The results have also shown that there was
improvement in the bioavailability of the enterically coated
capsules compared with the non-enterically coated capsules (FIG.
37, Legs 7 and 2, Legs 8 and 3, Legs 12 and 4), but surprisingly
the bioavailability was significantly altered when excess amino
acid coformer was added to form a physical mixture inside the
enterically coated capsules (FIG. 37, Legs 9 and 10). The reason
behind it is not fully understood.
[0279] The results have shown that there is a slight increase in
the oral bioavailability of zoledronic acid from the enteric coated
capsules filled with neat (i.e. with no excess coformer) zoledronic
acid amino acid complex. Therefore, it is expected that the excess
coformer with the novel zoledronic acid complexes would also lead
to increased bioavailability when delivered in enterically coated
capsules. Surprisingly, when excess coformer was added to the
zoledronic acid, the bioavailability of the enterically coated
capsules was lower than that of the non-enterically coated
capsules. This suggests that a physical powder mixture of the
molecular complex and excess coformer might decrease the
bioavailability when delivered to the duodenum. The mechanism
behind this surprising finding is not yet understood.
[0280] The analytical results of yet another dog study (Legs 14-18)
are shown in Table 5, which contains averaged data from five dogs.
The PK profiles of the IV and oral groups are shown in FIGS. 38 and
39. FIG. 39 represents the first 4 hours of the 24 hour PK
profile.
[0281] The analytical results of another dog study (Legs 19-26) are
shown in Table 6, which contains averaged data from five dogs. The
PK profiles of the IV and oral groups are shown in FIGS. 40 and 41.
FIG. 40 represents the first 4 hours of the 24 hour PK profile.
[0282] The analytical results of another dog study (Legs 27-32) are
shown in Table 7, which contains the average data from 5 dogs with
the exception of Leg 31 which is the average of 4 dogs. In this
study, micronized materials (zoledronic:DL-lysine:water complex and
pure DL-lysine) with size mean diameter of 5 micron by volume were
used in some legs. Micronized materials were employed in our study
to examine the possibility of increasing the C.sub.max of the drug
through increasing the surface area and subsequently improving its
rate of dissolution that should lead to higher concentration of the
drug available for absorption through the GI tract. The results are
summarized in Leg 30 and 32 in Table 7. The results of the
micronized materials in both legs have shown a slight increase in
the bioavailability of the drug. The PK profiles of the oral groups
are shown in FIGS. 42 and 43. FIG. 42 represents the first 4 hours
of the 24 hour PK profile.
[0283] The analytical results of yet another dog study (Legs 33-38)
are shown in Tables 8 and 9 which contains the average data from 4
dogs. In this study, capsules of particulate materials
(zoledronic:DL-lysine:water complex and excess pure DL-lysine).
Prior to dosing, all dogs received a 20 ml dose of citric acid (24
mg/mL in water) to lower the pH of the stomach. After dosing
capsules or IV, all dogs received additional 6.25 mL citric acid
solution (24 mg/mL in water) as a rinse.
[0284] During the study, both serum and urine samples were
collected from the animals. Urine samples were collected (N=4) over
five intervals, 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours and
24-96 hours. Bioanalysis for urine excretion samples after dosing
was performed. Samples were assayed for zoledronic acid using a
validated LC/MS/MS method.
[0285] The results of Legs 33-38 are summarized in Table 8 (serum)
and Table 9 (urine). The results show a significant increase in
bioavailability of the bisphosphonic acid, particularly with high
levels of lysine. The PK profiles are shown in FIGS. 44 and 45.
FIG. 44 represents the first 4 hours of the 24 hour PK profile.
Example 17
Preparation of Zoledronic, DL-Lysine, and Water Complex
[0286] In a scaled-up version of Example 12, 1.0 g of zoledronic
acid and 0.56 g of DL-Lysine were slurried in 20 mL of
tetrahydrofuran. 2 mL of water was then added drop wise. The
solution was covered and left to stir overnight. The resulting
precipitates were collected by filtration, dried, and stored in a
screw cap vial for subsequent analysis. The solids gathered were
characterized by PXRD and FTIR corresponding to FIG. 46 and FIG. 47
respectively.
TABLE-US-00018 TABLE 1 Rat plasma concentrations of zoledronic acid
from pure zoledronic acid and zoledronic acid complexes delivered
via different routes. Average plasma concentration Dosing Time of 3
rats Group # Complex Route Vehicle (hour) (ng/mL) G1 Zoledronic
acid IV Water 0.083333 3254.05 0.25 1950.62 0.5 1128.75 1 404.28 2
112.68 4 30.46 8 10.66 24 2.98 G2 Zoledronic acid PO PEG 0.25
330.06 400 0.5 267.45 1 138.91 2 47.72 4 11.78 8 2.00 24 0.00 G3
Zoledronic and glycine PO PEG 0.25 648.01 complex 400 0.5 435.38 1
200.88 4 12.78 8 1.46 24 0.00 G4 Zoledronic, nicotinamide, PO PEG
400 0.25 434.61 and water complex 0.5 304.94 1 122.35 4 7.68 8 1.82
24 0.00 G5 Zoledronic acid, sodium PO PEG 400 0.25 278.47
zoledronic salt, and water 0.5 280.20 complex 1 171.59 4 13.42 8
1.78 24 0.00 G6 Zoledronic, L-lysine, PO PEG 0.25 258.43 and water
complex 400 0.5 249.82 1 184.95 4 28.70 8 3.27 24 0.00 G7
Zoledronic, DL-lysine, PO PEG 0.25 494.31 and water complex 400 0.5
379.27 1 213.48 4 14.57 8 3.42 24 0.00 G8 Zoledronic acid ID PEG
0.25 145.67 400 0.5 109.92 1 47.36 2 12.94 4 3.85 8 0.97 24 0.00 G9
Zoledronic and glycine ID PEG 0.25 86.51 complex 400 1 33.93 4 1.75
8 1.55 24 0.00 G10 Zoledronic, nicotinamide, ID PEG 0.25 69.71 and
water complex 400 1 21.03 4 0.86 8 0.00 24 0.00 G11 Zoledronic
acid, sodium ID PEG 0.25 39.99 zoledronic salt, and water 400 1
18.50 complex 4 0.71 8 0.00 24 0.00 G12 Zoledronic, L-lysine, and
ID PEG 0.25 91.21 water complex 400 1 26.53 4 0.74 8 0.00 24 0.00
G13 Zoledronic, DL-lysine, ID PEG 0.25 98.25 and water complex 400
1 34.61 4 2.65 8 1.02 24 0.80
TABLE-US-00019 TABLE 2 Rat plasma concentrations of zoledronic acid
from zoledronic acid complexes with excess coformers, delivered by
oral gavage Average plasma concentration Dosing of 3 rats Group #
Complex Route Vehicle Time (hour) (ng/mL) G14 Zoledronic and
glycine PO PEG 0.0333333 14.61 complex and 45 mg/kg 400 0.0833333
206.26 glycine 0.1666667 340.19 0.25 375.99 0.5 321.36 1 197.01 4
17.35 24 0.00 G15 Zoledronic and glycine PO PEG 0.0333333 24.48
complex and 25 mg/kg 400 0.0833333 281.08 glycine 0.1666667 502.20
0.25 516.58 0.5 430.10 1 203.48 2 73.27 4 14.70 24 0.00 G16
Zoledronic and glycine PO PEG 0.0333333 60.03 complex and 5 mg/kg
400 0.0833333 365.23 glycine 0.1666667 563.83 0.25 625.05 0.5
464.34 1 209.65 2 74.28 4 12.17 24 0.00 G17 Zoledronic, DL-lysine,
PO PEG 0.0333333 168.19 and water complex and 400 0.0833333 263.28
39.32 mg/kg DL-lysine 0.1666667 440.26 monohydrate 0.25 456.18 0.5
385.57 1 209.26 2 85.65 4 14.58 24 0.71 G18 Zoledronic, DL-lysine,
PO PEG 0.0333333 219.95 and water complex and 400 0.0833333 427.02
28.08 mg/kg DL-lysine 0.1666667 729.65 monohydrate 0.25 777.54 0.5
632.07 1 300.86 2 100.59 4 21.14 24 0.00 G19 Zoledronic, DL-lysine,
PO PEG 0.0333333 53.78 and water complex and 400 0.0833333 394.73
5.62 mg/kg DL-lysine 0.1666667 649.52 monohydrate 0.25 669.20 0.5
530.00 1 265.20 2 73.31 4 15.41 24 0.00 G20 Zoledronic, DL-lysine,
PO PEG 0.0333333 103.13 and water complex 400 0.0833333 352.18
0.1666667 475.33 0.25 505.48 0.5 431.41 1 224.56 2 69.95 4 14.96 24
0.00
TABLE-US-00020 TABLE 3 Dog serum concentrations of zoledronic acid
from pure zoledronic acid and zoledronic acid complexes delivered
via different routes. Average serum concentration Dosing Time of 5
dogs Leg # Complex Route Vehicle (hour) (ng/mL) 1 0.05 mg/kg IV
Saline 0 0.00 Zoledronic acid solution 0.0333 413.44 0.0833 311.68
0.1667 228.97 0.25 178.63 0.5 111.11 0.75 75.91 1 56.07 1.5 30.35 2
17.61 4 4.29 8 1.13 24 0.00 48 0.00 2 56.0 mg PO n/a 0 0.00
Zoledronic acid 0.0833 0.00 monohydrate 0.1667 0.00 capsule 0.25
0.31 0.5 110.73 0.75 97.98 1 103.60 1.5 80.57 2 75.16 4 17.86 8
2.71 24 0.56 3 67.0 mg Zoledronic PO n/a 0 0.00 and glycine 0.0833
2.45 complex capsule 0.1667 12.75 0.25 37.07 0.5 149.20 0.75 206.14
1 254.20 1.5 176.11 2 109.25 4 20.43 8 3.96 24 0.97 4 87.7 mg PO
n/a 0 0.00 Zoledronic, DL- 0.0833 3.11 lysine, and water 0.1667
6.49 complex capsule 0.25 22.55 0.5 68.28 0.75 162.72 1 206.14 1.5
149.92 2 105.81 4 25.51 8 4.22 24 0.56 5 87.7 mg PO n/a 0 0.00
Zoledronic, L- 0.0833 0.00 lysine, and water 0.1667 3.13 complex
capsule 0.25 10.06 0.5 188.52 0.75 345.28 1 318.97 1.5 180.77 2
109.23 4 23.11 8 9.73 24 1.93 6 84.2 mg PO n/a 0 0.00 Zoledronic,
DL- 0.0833 0.00 lysine, and water 0.1667 0.20 complex capsule 0.25
1.92 0.5 106.47 0.75 120.13 1 108.13 1.5 90.45 2 54.48 4 18.14 8
4.35 24 1.06
TABLE-US-00021 TABLE 4 Dog serum concentrations of zoledronic acid
from pure zoledronic acid and zoledronic acid complexes delivered
via different routes, using enteric or non-enteric coated gelatin
capsules. Average serum concentration Dosing Time of 5 dogs Leg #
Complex Route Vehicle (hour) (ng/mL) 7 56.0 mg Zoledronic PO n/a 0
0.00 acid monohydrate 0.1667 0.00 enteric coated 0.25 0.00 capsule
0.5 0.00 0.75 0.00 1 9.84 1.5 86.13 2 109.37 4 107.64 6 14.15 8
4.57 24 0.50 8 67.0 mg Zoledronic PO n/a 0 0.00 and glycine 0.1667
0.00 complex enteric 0.25 0.00 coated capsule 0.5 0.00 0.75 0.00 1
4.42 1.5 208.97 2 274.53 4 101.20 6 16.71 8 7.14 24 2.17 9 87.7 mg
PO n/a 0 0.00 Zoledronic, DL- 0.0833 13.31 lysine, and water 0.1667
39.76 complex with 294.8 0.25 120.41 mg DL-lysine 0.5 364.68
monohydrate 0.75 487.59 capsule 1 499.60 1.5 362.16 2 254.72 4
52.22 6 16.61 8 8.93 24 2.92 10 87.7 mg PO n/a 0 0.00 Zoledronic,
DL- 0.1667 0.00 lysine, and water 0.25 0.00 complex with 0.5 0.00
294.8 mg DL-lysine 0.75 3.71 monohydrate enteric 1 51.32 coated
capsule 1.5 403.15 2 309.08 4 44.83 6 13.15 8 7.09 24 2.66 11 84.2
mg PO n/a 0 0.22 Zoledronic, DL- 0.1667 167.03 lysine, and 0.25
533.96 water complex with 0.5 878.63 294.8 mg DL-lysine 0.75 838.82
monohydrate 1 633.50 capsule 1.5 326.63 2 185.44 4 46.86 6 20.26 8
11.49 24 5.95 12 87.7 mg PO n/a 0 0.57 Zoledronic, DL- 0.1667 0.60
lysine, and water 0.25 0.59 complex enteric 0.5 0.61 coated capsule
0.75 0.40 1 132.15 1.5 566.18 2 402.12 4 65.35 6 21.02 8 12.18 24
4.33 13 0.183 mg/kg IV Saline 0 0.64 Zoledronic acid solution
0.0833 476.79 0.1667 755.68 0.25 1057.75 0.3333 745.67 0.4167
629.22 0.5 522.78 0.75 342.58 1 245.36 1.25 182.59 1.5 139.77 2
80.87 4 23.40 8 8.78 24 3.84
TABLE-US-00022 TABLE 5 Dog serum concentrations of zoledronic acid
from pure zoledronic acid and zoledronic acid complexes delivered
via different routes. Average serum concentration Dosing of 5 dogs
Leg # Complex Route Vehicle Time (hour) (ng/mL) 14 35.4 mg
Zoledronic, DL- PO n/a 0 0.00 lysine, and water 0.0833 0.00
complex, with 123.8 mg 0.1667 0.72 DL-lysine monohydrate 0.25 11.40
gelatin capsule 0.5 78.95 0.75 126.46 1 137.38 1.5 64.73 2 33.38 4
6.14 8 0.89 24 0.00 15 67.0 mg Zoledronic and PO n/a 0 0.00 glycine
complex, with 0.0833 2.58 294.8 mg DL-lysine 0.1667 26.13
monohydrate gelatin capsule 0.25 55.58 0.5 225.41 0.75 234.95 1
221.91 1.5 204.90 2 117.22 4 17.79 8 3.34 24 0.77 16 87.7 mg
Zoledronic, L- PO n/a 0 0.00 lysine, and water 0.0833 3.26 complex,
with 294.8 mg 0.1667 17.21 DL-lysine monohydrate 0.25 213.77
gelatin capsule 0.5 504.17 0.75 436.00 1 325.21 1.5 171.42 2 100.81
4 23.38 8 4.65 24 1.48 17 35.4 mg Zoledronic, DL- PO n/a 0 0.00
lysine, and water 0.0833 0.00 complex, with 294.8 mg 0.1667 13.47
DL-lysine monohydrate 0.25 50.04 gelatin capsule 0.5 146.68 0.75
137.24 1 116.38 1.5 66.70 2 44.94 4 8.87 8 1.58 24 0.21 18 0.12
mg/kg Zoledronic IV Saline 0 0.00 acid solution 0.0833 309.13
0.1667 524.58 0.25 717.15 0.3333 501.70 0.4167 392.35 0.5 322.84
0.75 201.78 1 132.86 1.25 93.22 1.5 69.06 2 38.38 4 9.14 8 3.24 24
1.21
TABLE-US-00023 TABLE 6 Dog serum concentrations of zoledronic acid
from pure zoledronic acid and zoledronic acid complexes delivered
orally. Average serum concentration Dosing of 5 dogs Leg # Complex
Route Vehicle Time (hour) (ng/mL) 19 61.3 mg Zoledronic acid, PO
n/a 0 0.00 with 322.9 mg DL-lysine 0.0833 34.10 monohydrate gelatin
0.1667 42.74 capsule 0.25 219.76 0.5 659.25 0.75 478.77 1 383.80
1.5 209.87 2 135.97 4 34.22 8 8.53 24 2.07 20 76.8 mg Zoledronic,
L- PO n/a 0 0.20 lysine, and water 0.0833 0.21 complex, with 359.2
mg 0.1667 4.10 L-lysine HCl gelatin capsule 0.25 12.03 0.5 156.89
0.75 263.80 1 265.48 1.5 178.89 2 118.73 4 36.12 8 12.32 24 2.56 21
84.2 mg Zoledronic, DL- PO n/a 0 0.00 lysine, and water 0.0833 0.20
complex, with 328.0 mg 0.1667 5.77 L-lysine HCl gelatin 0.25 32.62
capsule 0.5 273.09 0.75 373.00 1 314.46 1.5 214.18 2 128.08 4 30.87
8 6.80 24 2.12 22 69.0 mg Zoledronic, DL- PO n/a 0 0.00 lysine, and
water 0.0833 7.35 complex, with 241.8 mg 0.1667 48.84 DL-lysine
monohydrate 0.25 204.61 gelatin capsule 0.5 398.98 0.75 465.56 1
406.10 1.5 265.75 2 161.63 4 36.68 8 9.66 24 3.45 23 70.1 mg
Zoledronic, L- PO n/a 0 0.52 lysine, and water 0.0833 1.99 complex,
with 294.9 mg 0.1667 31.45 DL-lysine monohydrate 0.25 135.92
gelatin capsule 0.5 449.28 0.75 474.97 1 442.86 1.5 290.01 2 162.59
4 42.25 8 10.77 24 3.28 24 64.0 mg Zoledronic acid, PO n/a 0 0.00
with 374.8 mg L-lysine 0.0833 0.00 HCl gelatin capsule 0.1667 1.20
0.25 14.11 0.5 171.59 0.75 340.09 1 283.01 1.5 162.59 2 99.96 4
26.27 8 4.56 24 0.89 25 80.1 mg Zoledronic, L- PO n/a 0 0.00
lysine, and water complex 0.0833 0.00 gelatin capsule 0.1667 0.32
0.25 2.16 0.5 47.70 0.75 181.00 1 224.61 1.5 142.02 2 95.10 4 23.06
8 3.97 24 1.20 26 76.5 mg Zoledronic and PO n/a 0 0.00 glycine
complex, with 0.0833 0.00 374.8 mg L-lysine HCl 0.1667 0.85 gelatin
capsule 0.25 3.18 0.5 169.29 0.75 397.95 1 352.39 1.5 200.22 2
109.96 4 25.15 8 4.34 24 1.66
TABLE-US-00024 TABLE 7 Dog serum concentrations of zoledronic acid
from pure zoledronic acid and zoledronic acid complexes delivered
orally. Average serum concentration Dosing of 5 dogs Leg # Complex
Route Vehicle Time (hour) (ng/mL) 27 32.0 mg Zoledronic, DL- PO n/a
0 0.00 lysine, and water 0.0833 0.00 complex, with 266.8 mg 0.1667
0.52 DL-lysine monohydrate 0.25 4.25 gelatin capsule 0.5 43.64 0.75
91.85 1 148.71 1.5 71.25 2 46.68 4 8.83 8 1.02 24 0.00 28 76.2 mg
Zoledronic, DL- PO n/a 0 0.00 lysine, and water 0.0833 0.37
complex, with 266.8 mg 0.1667 3.48 DL-lysine monohydrate 0.25 12.59
gelatin capsule 0.5 162.37 0.75 244.28 1 295.79 1.5 202.36 2 110.16
4 21.43 8 3.16 24 0.81 29 64.4 mg Zoledronic, DL- PO n/a 0 0.00
lysine, and water 0.0833 0.00 complex, with 275.2 mg 0.1667 2.10
DL-lysine monohydrate 0.25 23.08 gelatin capsule 0.5 197.71 0.75
361.80 1 264.70 1.5 173.72 2 93.35 4 15.54 8 2.97 24 0.71 30 64.4
mg micronized PO n/a 0 0.00 Zoledronic, DL-lysine, 0.0833 2.95 and
water complex, with 0.1667 13.08 275.2 mg micronized DL- 0.25 61.19
lysine monohydrate 0.5 383.13 gelatin capsule 0.75 377.27 1 305.30
1.5 172.67 2 86.54 4 13.56 8 3.52 24 0.87 31 50.8 mg Zoledronic,
DL- PO n/a 0 0.00 lysine, and water 0.0833 0.00 complex, with 278.0
mg 0.1667 0.00 DL-lysine monohydrate 0.25 1.50 gelatin capsule 0.5
116.12 0.75 105.85 1 214.29 1.5 193.10 2 103.50 4 18.42 8 2.57 24
0.31 32 50.8 mg micronized PO n/a 0 0.00 Zoledronic, DL-lysine,
0.0833 2.42 and water complex, with 0.1667 33.98 278.0 mg
micronized DL-lysine 0.25 121.95 monohydrat gelatin capsulee 0.5
212.75 0.75 242.80 1 221.71 1.5 212.75 2 126.93 4 23.77 8 3.64 24
0.80
TABLE-US-00025 TABLE 8 Dog serum concentrations of zoledronic acid
from pure zoledronic acid and zoledronic acid complexes delivered
via different routes. Average serum concentration Dosing of 4 dogs
Leg # Complex Route Vehicle Time (hour) (ng/mL) 33 59.2 mg
Zoledronic, DL- PO n/a 0 0.00 lysine, and water 0.0833 0.00
complex, with 112.3 mg 0.1667 0.00 DL-lysine monohydrate 0.25 0.00
gelatin capsule 0.5 66.80 0.75 139.37 1 161.23 1.5 124.08 2 72.53 4
16.99 8 2.30 24 0.00 34 63.1 mg Zoledronic, DL- PO n/a 0 0.00
lysine, and water 0.0833 0.00 complex, with 280.8 mg 0.1667 0.00
DL-lysine monohydrate 0.25 0.00 gelatin capsule 0.5 206.30 0.75
577.25 1 449.00 1.5 226.50 2 125.33 4 23.45 8 6.00 24 1.37 35 76.3
mg Zoledronic, DL- PO n/a 0 0.00 lysine, and water 0.0833 0.00
complex, with 561.6 mg 0.1667 24.88 DL-lysine monohydrate 0.25
38.21 gelatin capsule 0.5 338.33 0.75 429.38 1 456.23 1.5 304.78 2
186.70 4 41.48 8 11.11 24 2.35 36 59.2 mg Zoledronic, DL- PO n/a 0
0.00 lysine, and water 0.0833 0.00 complex, with 1123.3 mg 0.1667
0.31 DL-lysine monohydrate 0.25 29.50 gelatin capsule 0.5 192.57
0.75 517.75 1 688.50 1.5 451.50 2 259.75 4 37.05 8 6.95 24 2.62 37
63.1 mg Zoledronic, DL- PO n/a 0 0.00 lysine, and water 0.0833 0.00
complex, with 1965.7 mg 0.1667 0.00 DL-lysine monohydrate 0.25 5.55
gelatin capsule 0.5 200.00 0.75 504.73 1 683.50 1.5 606.00 2 488.03
4 81.28 8 12.34 24 4.07 38 0.12 mg/kg Zoledronic acid IV Saline
solution 0 0.00 0.0833 287.75 0.1667 541.50 0.25 710.75 0.3333
528.75 0.4167 405.50 0.5 358.25 0.75 239.50 1 174.00 1.25 121.38
1.5 90.58 2 55.68 4 15.13 8 5.74 24 2.49
TABLE-US-00026 TABLE 9 Quantity of zoledronic acid in dog urine
from zoledronic acid, DL-lysine and water complex and excess
coformer delivered via different routes at different doses. During
the study, urine samples were collected from the animals (N = 4)
over five intervals, 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours
and 24-96 hours. Bioanalysis for urine excretion samples after
dosing has been performed. Samples were assayed for zoledronic acid
using a validated LC/MS/MS method. Average quantity of zoledronic
acid Dosing Time interval in urine excretion Leg # Complex Route
Vehicle (hour) of 4 dogs (ng) 33 59.2 mg Zoledronic, DL- PO n/a 0-4
43251 lysine, and water 4-8 548 complex, with 112.3 mg 8-12 102750
DL-lysine monohydrate 12-24 147710 gelatin capsule 24-96 20571 34
63.1 mg Zoledronic, DL- PO n/a 0-4 121045 lysine, and water 4-8
1393 complex, with 280.8 mg 8-12 228375 DL-lysine monohydrate 12-24
204485 gelatin capsule 24-96 98205 35 76.3 mg Zoledronic, DL- PO
n/a 0-4 440062 lysine, and water 4-8 16970 complex, with 561.6 mg
8-12 285490 DL-lysine monohydrate 12-24 287863 gelatin capsule
24-96 97306 36 59.2 mg Zoledronic, DL- PO n/a 0-4 311764 lysine,
and water 4-8 24 complex, with 1123.3 mg 8-12 385625 DL-lysine
monohydrate 12-24 456538 gelatin capsule 24-96 105767 37 63.1 mg
Zoledronic, DL- PO n/a 0-4 234333 lysine, and water 4-8 178950
complex, with 1965.7 mg 8-12 888750 DL-lysine monohydrate 12-24
117100 gelatin capsule 24-96 186090 38 0.12 mg/kg Zoledronic IV
Saline 0-4 242050 acid solution 4-8 21165 8-12 10925 12-24 43700
24-96 263151
TABLE-US-00027 TABLE 10 Aqueous solubility of zoledronic acid (ZA)
and novel zoledronic acid complexes at room temperature. Compound
Conc. mg/mL mMol/L (complex) ZA monohydrate 1.57 5.41 ZA: Glycine
11.89 34.25 ZA: L-Lysine dihydrate 8.22 18.09 ZA: DL-Lysine
dihydrate 6.85 15.08 ZA: DL-Lysine monohydrate 13.9 31.86
TABLE-US-00028 TABLE 11 Particular embodiments of unit dose
pharmaceutical compositions of the present invention. As indicated
in the columns 1-3 and 4-6 above, the compositions comprise an API
and coformer, wherein the coformer is either present as a molecular
complex coformer, an additional coformer or both a molecular
complex coformer and additional coformer, with the total amount of
coformer present in the unit dose indicated. Each three cell
combination of API, coformer and amount of coformer represent an
individual embodiment of the present invention. Amount Amount of
Amino of Amino Acid per Acid per Unit Amino Unit Dose Amino Dose of
API Acid of API API Acid API abacavir lysine .gtoreq.100 mg
abacavir lysine .gtoreq.3 g acarbose lysine .gtoreq.100 mg acarbose
lysine .gtoreq.3 g acetazolamide lysine .gtoreq.100 mg
acetazolamide lysine .gtoreq.3 g acyclovir lysine .gtoreq.100 mg
acyclovir lysine .gtoreq.3 g albuterol (salbutamol) lysine
.gtoreq.100 mg albuterol (salbutamol) lysine .gtoreq.3 g
allopurinol lysine .gtoreq.100 mg allopurinol lysine .gtoreq.3 g
amiloride lysine .gtoreq.100 mg amiloride lysine .gtoreq.3 g
amisulpride lysine .gtoreq.100 mg amisulpride lysine .gtoreq.3 g
amlodipine lysine .gtoreq.100 mg amlodipine lysine .gtoreq.3 g
amoxicillin lysine .gtoreq.100 mg amoxicillin lysine .gtoreq.3 g
amphetamine lysine .gtoreq.100 mg amphetamine lysine .gtoreq.3 g
atenolol lysine .gtoreq.100 mg atenolol lysine .gtoreq.3 g atropine
lysine .gtoreq.100 mg atropine lysine .gtoreq.3 g azathioprine
lysine .gtoreq.100 mg azathioprine lysine .gtoreq.3 g benserazide
lysine .gtoreq.100 mg benserazide lysine .gtoreq.3 g benznidazole
lysine .gtoreq.100 mg benznidazole lysine .gtoreq.3 g camostat
lysine .gtoreq.100 mg camostat lysine .gtoreq.3 g captopril lysine
.gtoreq.100 mg captopril lysine .gtoreq.3 g cefdinir lysine
.gtoreq.100 mg cefdinir lysine .gtoreq.3 g cefotiam hexetil lysine
.gtoreq.100 mg cefotiam hexetil lysine .gtoreq.3 g hydrochloride
hydrochloride cefprozil lysine .gtoreq.100 mg cefprozil lysine
.gtoreq.3 g cefuroxime axetil lysine .gtoreq.100 mg cefuroxime
axetil lysine .gtoreq.3 g chloramphenicol lysine .gtoreq.100 mg
chloramphenicol lysine .gtoreq.3 g cimetidine lysine .gtoreq.100 mg
cimetidine lysine .gtoreq.3 g ciprofloxacin lysine .gtoreq.100 mg
ciprofloxacin lysine .gtoreq.3 g codeine lysine .gtoreq.100 mg
codeine lysine .gtoreq.3 g colchicine lysine .gtoreq.100 mg
colchicine lysine .gtoreq.3 g cyclophosphamide lysine .gtoreq.100
mg cyclophosphamide lysine .gtoreq.3 g dapsone lysine .gtoreq.100
mg dapsone lysine .gtoreq.3 g dexamethasone lysine .gtoreq.100 mg
dexamethasone lysine .gtoreq.3 g didanosine lysine .gtoreq.100 mg
didanosine lysine .gtoreq.3 g diethylcarbamazine lysine .gtoreq.100
mg diethylcarbamazine lysine .gtoreq.3 g methionine lysine
.gtoreq.100 mg methionine lysine .gtoreq.3 g dolasetron lysine
.gtoreq.100 mg dolasetron lysine .gtoreq.3 g doxifluridine lysine
.gtoreq.100 mg doxifluridine lysine .gtoreq.3 g doxycycline lysine
.gtoreq.100 mg doxycycline lysine .gtoreq.3 g ergonovine lysine
.gtoreq.100 mg ergonovine lysine .gtoreq.3 g erythromycin lysine
.gtoreq.100 mg erythromycin lysine .gtoreq.3 g ethylsuccinate
ethylsuccinate ethambutol lysine .gtoreq.100 mg ethambutol lysine
.gtoreq.3 g ethosuximide lysine .gtoreq.100 mg ethosuximide lysine
.gtoreq.3 g famotidine lysine .gtoreq.100 mg famotidine lysine
.gtoreq.3 g fluconazole lysine .gtoreq.100 mg fluconazole lysine
.gtoreq.3 g folic acid lysine .gtoreq.100 mg folic acid lysine
.gtoreq.3 g furosemide lysine .gtoreq.100 mg furosemide lysine
.gtoreq.3 g fursultiamine lysine .gtoreq.100 mg fursultiamine
lysine .gtoreq.3 g gabapentin lysine .gtoreq.100 mg gabapentin
lysine .gtoreq.3 g glipizide lysine .gtoreq.100 mg glipizide lysine
.gtoreq.3 g granisetron lysine .gtoreq.100 mg granisetron lysine
.gtoreq.3 g griseofulvin lysine .gtoreq.100 mg griseofulvin lysine
.gtoreq.3 g hydralazine lysine .gtoreq.100 mg hydralazine lysine
.gtoreq.3 g hydrochlorothiazide lysine .gtoreq.100 mg
hydrochlorothiazide lysine .gtoreq.3 g imidapril lysine .gtoreq.100
mg imidapril lysine .gtoreq.3 g isoniazid lysine .gtoreq.100 mg
isoniazid lysine .gtoreq.3 g lamivudine lysine .gtoreq.100 mg
lamivudine lysine .gtoreq.3 g l-carbocysteine lysine .gtoreq.100 mg
l-carbocysteine lysine .gtoreq.3 g levetiracetam lysine .gtoreq.100
mg levetiracetam lysine .gtoreq.3 g levofloxacin lysine .gtoreq.100
mg levofloxacin lysine .gtoreq.3 g linezolid lysine .gtoreq.100 mg
linezolid lysine .gtoreq.3 g lisinopril lysine .gtoreq.100 mg
lisinopril lysine .gtoreq.3 g losartan lysine .gtoreq.100 mg
losartan lysine .gtoreq.3 g methotrexate lysine .gtoreq.100 mg
methotrexate lysine .gtoreq.3 g methyldopa lysine .gtoreq.100 mg
methyldopa lysine .gtoreq.3 g s-methylmethionine lysine .gtoreq.100
mg s-methylmethionine lysine .gtoreq.3 g metoclopramide lysine
.gtoreq.100 mg metoclopramide lysine .gtoreq.3 g metronidazole
lysine .gtoreq.100 mg metronidazole lysine .gtoreq.3 g moxifloxacin
lysine .gtoreq.100 mg moxifloxacin lysine .gtoreq.3 g nalidixic
acid lysine .gtoreq.100 mg nalidixic acid lysine .gtoreq.3 g
nicorandil lysine .gtoreq.100 mg nicorandil lysine .gtoreq.3 g
nifurtimox lysine .gtoreq.100 mg nifurtimox lysine .gtoreq.3 g
nitrofurantoin lysine .gtoreq.100 mg nitrofurantoin lysine
.gtoreq.3 g nizatidine lysine .gtoreq.100 mg nizatidine lysine
.gtoreq.3 g nystatin lysine .gtoreq.100 mg nystatin lysine
.gtoreq.3 g ondansetron lysine .gtoreq.100 mg ondansetron lysine
.gtoreq.3 g oseltamivir lysine .gtoreq.100 mg oseltamivir lysine
.gtoreq.3 g oxcarbazepine lysine .gtoreq.100 mg oxcarbazepine
lysine .gtoreq.3 g penicillamine lysine .gtoreq.100 mg
penicillamine lysine .gtoreq.3 g perindopril lysine .gtoreq.100 mg
perindopril lysine .gtoreq.3 g phenobarbital lysine .gtoreq.100 mg
phenobarbital lysine .gtoreq.3 g phenoxymethylpenicillin lysine
.gtoreq.100 mg phenoxymethylpenicillin lysine .gtoreq.3 g
pravastatin sodium lysine .gtoreq.100 mg pravastatin sodium lysine
.gtoreq.3 g prednisolone lysine .gtoreq.100 mg prednisolone lysine
.gtoreq.3 g primaquine lysine .gtoreq.100 mg primaquine lysine
.gtoreq.3 g procaterol lysine .gtoreq.100 mg procaterol lysine
.gtoreq.3 g propylthiouracil lysine .gtoreq.100 mg propylthiouracil
lysine .gtoreq.3 g pseudoephedrine lysine .gtoreq.100 mg
pseudoephedrine lysine .gtoreq.3 g pyrazinamide lysine .gtoreq.100
mg pyrazinamide lysine .gtoreq.3 g pyridostigmine lysine
.gtoreq.100 mg pyridostigmine lysine .gtoreq.3 g bromide bromide
pyridoxine lysine .gtoreq.100 mg pyridoxine lysine .gtoreq.3 g
hydrochloride hydrochloride ranitidine lysine .gtoreq.100 mg
ranitidine lysine .gtoreq.3 g ribavirin lysine .gtoreq.100 mg
ribavirin lysine .gtoreq.3 g riboflavin lysine .gtoreq.100 mg
riboflavin lysine .gtoreq.3 g rizatriptan lysine .gtoreq.100 mg
rizatriptan lysine .gtoreq.3 g stavudine lysine .gtoreq.100 mg
stavudine lysine .gtoreq.3 g sulfadiazine lysine .gtoreq.100 mg
sulfadiazine lysine .gtoreq.3 g sulfamethoxazole lysine .gtoreq.100
mg sulfamethoxazole lysine .gtoreq.3 g sultamicillin lysine
.gtoreq.100 mg sultamicillin lysine .gtoreq.3 g sumatriptan lysine
.gtoreq.100 mg sumatriptan lysine .gtoreq.3 g taltirelin lysine
.gtoreq.100 mg taltirelin lysine .gtoreq.3 g tegafur lysine
.gtoreq.100 mg tegafur lysine .gtoreq.3 g tenofovir disoproxil
lysine .gtoreq.100 mg tenofovir disoproxil lysine .gtoreq.3 g
theophylline lysine .gtoreq.100 mg theophylline lysine .gtoreq.3 g
thiamine lysine .gtoreq.100 mg thiamine lysine .gtoreq.3 g
trimetazidine lysine .gtoreq.100 mg trimetazidine lysine .gtoreq.3
g trimethoprim lysine .gtoreq.100 mg trimethoprim lysine .gtoreq.3
g voglibose lysine .gtoreq.100 mg voglibose lysine .gtoreq.3 g
zidovudine lysine .gtoreq.100 mg zidovudine lysine .gtoreq.3 g
zolmitriptan lysine .gtoreq.100 mg zolmitriptan lysine .gtoreq.3 g
acetylcarnitine lysine .gtoreq.100 mg acetylcarnitine lysine
.gtoreq.3 g capecitabine lysine .gtoreq.100 mg capecitabine lysine
.gtoreq.3 g cefaclor lysine .gtoreq.100 mg cefaclor lysine
.gtoreq.3 g cefixime lysine .gtoreq.100 mg cefixime lysine
.gtoreq.3 g cefmetazole lysine .gtoreq.100 mg cefmetazole lysine
.gtoreq.3 g cefpodoxime proxetil lysine .gtoreq.100 mg cefpodoxime
proxetil lysine .gtoreq.3 g cefroxadine lysine .gtoreq.100 mg
cefroxadine lysine .gtoreq.3 g alfoscerate lysine .gtoreq.100 mg
alfoscerate lysine .gtoreq.3 g cilazapril lysine .gtoreq.100 mg
cilazapril lysine .gtoreq.3 g cimetropium bromide lysine
.gtoreq.100 mg cimetropium bromide lysine .gtoreq.3 g diacerein
lysine .gtoreq.100 mg diacerein lysine .gtoreq.3 g erdosteine
lysine .gtoreq.100 mg erdosteine lysine .gtoreq.3 g famciclovir
lysine .gtoreq.100 mg famciclovir lysine .gtoreq.3 g gemifloxacin
lysine .gtoreq.100 mg gemifloxacin lysine .gtoreq.3 g levosulpiride
lysine .gtoreq.100 mg levosulpiride lysine .gtoreq.3 g nabumetone
lysine .gtoreq.100 mg nabumetone lysine .gtoreq.3 g oxiracetam
lysine .gtoreq.100 mg oxiracetam lysine .gtoreq.3 g phendimetrazine
lysine .gtoreq.100 mg phendimetrazine lysine .gtoreq.3 g
rabeprazole lysine .gtoreq.100 mg rabeprazole lysine .gtoreq.3 g
roxatidine acetate lysine .gtoreq.100 mg roxatidine acetate lysine
.gtoreq.3 g tamsulosin lysine .gtoreq.100 mg tamsulosin lysine
.gtoreq.3 g terazosin lysine .gtoreq.100 mg terazosin lysine
.gtoreq.3 g thioctic lysine .gtoreq.100 mg Thioctic lysine
.gtoreq.3 g tosufloxacin lysine .gtoreq.100 mg tosufloxacin lysine
.gtoreq.3 g triflusal lysine .gtoreq.100 mg Triflusal lysine
.gtoreq.3 g zaltoprofen lysine .gtoreq.100 mg zaltoprofen lysine
.gtoreq.3 g etidronic acid lysine .gtoreq.100 mg etidronic acid
lysine .gtoreq.3 g zoledronic acid lysine .gtoreq.100 mg zoledronic
acid lysine .gtoreq.3 g clodronic acid lysine .gtoreq.100 mg
clodronic acid lysine .gtoreq.3 g tiludronic acid lysine
.gtoreq.100 mg tiludronic acid lysine .gtoreq.3 g pamidronic acid
lysine .gtoreq.100 mg pamidronic acid lysine .gtoreq.3 g alendronic
acid lysine .gtoreq.100 mg alendronic acid lysine .gtoreq.3 g
risedronic acid lysine .gtoreq.100 mg risedronic acid lysine
.gtoreq.3 g ibandronic acid lysine .gtoreq.100 mg ibandronic acid
lysine .gtoreq.3 g abacavir glycine .gtoreq.100 mg abacavir glycine
.gtoreq.3 g acarbose glycine .gtoreq.100 mg acarbose glycine
.gtoreq.3 g acetazolamide glycine .gtoreq.100 mg acetazolamide
glycine .gtoreq.3 g acyclovir glycine .gtoreq.100 mg acyclovir
glycine .gtoreq.3 g albuterol (salbutamol) glycine .gtoreq.100 mg
albuterol (salbutamol) glycine .gtoreq.3 g allopurinol glycine
.gtoreq.100 mg allopurinol glycine .gtoreq.3 g amiloride glycine
.gtoreq.100 mg amiloride glycine .gtoreq.3 g amisulpride glycine
.gtoreq.100 mg amisulpride glycine .gtoreq.3 g amlodipine glycine
.gtoreq.100 mg amlodipine glycine .gtoreq.3 g amoxicillin glycine
.gtoreq.100 mg amoxicillin glycine .gtoreq.3 g amphetamine glycine
.gtoreq.100 mg amphetamine glycine .gtoreq.3 g atenolol glycine
.gtoreq.100 mg atenolol glycine .gtoreq.3 g atropine glycine
.gtoreq.100 mg Atropine glycine .gtoreq.3 g azathioprine glycine
.gtoreq.100 mg azathioprine glycine .gtoreq.3 g benserazide glycine
.gtoreq.100 mg benserazide glycine .gtoreq.3 g benznidazole glycine
.gtoreq.100 mg benznidazole glycine .gtoreq.3 g camostat glycine
.gtoreq.100 mg camostat glycine .gtoreq.3 g captopril glycine
.gtoreq.100 mg captopril glycine .gtoreq.3 g cefdinir glycine
.gtoreq.100 mg Cefdinir glycine .gtoreq.3 g cefotiam hexetil
glycine .gtoreq.100 mg cefotiam hexetil glycine .gtoreq.3 g
hydrochloride hydrochloride cefprozil glycine .gtoreq.100 mg
cefprozil glycine .gtoreq.3 g cefuroxime axetil glycine .gtoreq.100
mg cefuroxime axetil glycine .gtoreq.3 g chloramphenicol glycine
.gtoreq.100 mg chloramphenicol glycine .gtoreq.3 g cimetidine
glycine .gtoreq.100 mg cimetidine glycine .gtoreq.3 g ciprofloxacin
glycine .gtoreq.100 mg ciprofloxacin glycine .gtoreq.3 g codeine
glycine .gtoreq.100 mg Codeine glycine .gtoreq.3 g colchicine
glycine .gtoreq.100 mg colchicine glycine .gtoreq.3 g
cyclophosphamide glycine .gtoreq.100 mg cyclophosphamide glycine
.gtoreq.3 g dapsone glycine .gtoreq.100 mg Dapsone glycine
.gtoreq.3 g dexamethasone glycine .gtoreq.100 mg dexamethasone
glycine .gtoreq.3 g didanosine glycine .gtoreq.100 mg didanosine
glycine .gtoreq.3 g diethylcarbamazine glycine .gtoreq.100 mg
diethylcarbamazine glycine .gtoreq.3 g methionine glycine
.gtoreq.100 mg methionine glycine .gtoreq.3 g dolasetron glycine
.gtoreq.100 mg dolasetron glycine .gtoreq.3 g doxifluridine glycine
.gtoreq.100 mg doxifluridine glycine .gtoreq.3 g doxycycline
glycine .gtoreq.100 mg doxycycline glycine .gtoreq.3 g ergonovine
glycine .gtoreq.100 mg ergonovine glycine .gtoreq.3 g erythromycin
glycine .gtoreq.100 mg erythromycin glycine .gtoreq.3 g
ethylsuccinate ethylsuccinate ethambutol glycine .gtoreq.100 mg
ethambutol glycine .gtoreq.3 g ethosuximide glycine .gtoreq.100 mg
ethosuximide glycine .gtoreq.3 g famotidine glycine .gtoreq.100 mg
famotidine glycine .gtoreq.3 g fluconazole glycine .gtoreq.100 mg
fluconazole glycine .gtoreq.3 g folic acid glycine .gtoreq.100 mg
folic acid glycine .gtoreq.3 g furosemide glycine .gtoreq.100 mg
furosemide glycine .gtoreq.3 g fursultiamine glycine .gtoreq.100 mg
fursultiamine glycine .gtoreq.3 g gabapentin glycine .gtoreq.100 mg
gabapentin glycine .gtoreq.3 g glipizide glycine .gtoreq.100 mg
Glipizide glycine .gtoreq.3 g granisetron glycine .gtoreq.100 mg
granisetron glycine .gtoreq.3 g griseofulvin glycine .gtoreq.100 mg
griseofulvin glycine .gtoreq.3 g hydralazine glycine .gtoreq.100 mg
hydralazine glycine .gtoreq.3 g hydrochlorothiazide glycine
.gtoreq.100 mg hydrochlorothiazide glycine .gtoreq.3 g imidapril
glycine .gtoreq.100 mg imidapril glycine .gtoreq.3 g isoniazid
glycine .gtoreq.100 mg isoniazid glycine .gtoreq.3 g lamivudine
glycine .gtoreq.100 mg lamivudine glycine .gtoreq.3 g
l-carbocysteine glycine .gtoreq.100 mg l-carbocysteine glycine
.gtoreq.3 g levetiracetam glycine .gtoreq.100 mg levetiracetam
glycine .gtoreq.3 g levofloxacin glycine .gtoreq.100 mg
levofloxacin glycine .gtoreq.3 g linezolid glycine .gtoreq.100 mg
Linezolid glycine .gtoreq.3 g
lisinopril glycine .gtoreq.100 mg lisinopril glycine .gtoreq.3 g
losartan glycine .gtoreq.100 mg Losartan glycine .gtoreq.3 g
methotrexate glycine .gtoreq.100 mg methotrexate glycine .gtoreq.3
g methyldopa glycine .gtoreq.100 mg methyldopa glycine .gtoreq.3 g
s-methylmethionine glycine .gtoreq.100 mg s-methylmethionine
glycine .gtoreq.3 g metoclopramide glycine .gtoreq.100 mg
metoclopramide glycine .gtoreq.3 g metronidazole glycine
.gtoreq.100 mg metronidazole glycine .gtoreq.3 g moxifloxacin
glycine .gtoreq.100 mg moxifloxacin glycine .gtoreq.3 g nalidixic
acid glycine .gtoreq.100 mg nalidixic acid glycine .gtoreq.3 g
nicorandil glycine .gtoreq.100 mg nicorandil glycine .gtoreq.3 g
nifurtimox glycine .gtoreq.100 mg nifurtimox glycine .gtoreq.3 g
nitrofurantoin glycine .gtoreq.100 mg nitrofurantoin glycine
.gtoreq.3 g nizatidine glycine .gtoreq.100 mg nizatidine glycine
.gtoreq.3 g nystatin glycine .gtoreq.100 mg Nystatin glycine
.gtoreq.3 g ondansetron glycine .gtoreq.100 mg ondansetron glycine
.gtoreq.3 g oseltamivir glycine .gtoreq.100 mg oseltamivir glycine
.gtoreq.3 g oxcarbazepine glycine .gtoreq.100 mg oxcarbazepine
glycine .gtoreq.3 g penicillamine glycine .gtoreq.100 mg
penicillamine glycine .gtoreq.3 g perindopril glycine .gtoreq.100
mg perindopril glycine .gtoreq.3 g phenobarbital glycine
.gtoreq.100 mg phenobarbital glycine .gtoreq.3 g
phenoxymethylpenicillin glycine .gtoreq.100 mg
Phenoxymethylpenicillin glycine .gtoreq.3 g pravastatin sodium
glycine .gtoreq.100 mg pravastatin sodium glycine .gtoreq.3 g
prednisolone glycine .gtoreq.100 mg prednisolone glycine .gtoreq.3
g primaquine glycine .gtoreq.100 mg primaquine glycine .gtoreq.3 g
procaterol glycine .gtoreq.100 mg procaterol glycine .gtoreq.3 g
propylthiouracil glycine .gtoreq.100 mg propylthiouracil glycine
.gtoreq.3 g pseudoephedrine glycine .gtoreq.100 mg pseudoephedrine
glycine .gtoreq.3 g pyrazinamide glycine .gtoreq.100 mg
pyrazinamide glycine .gtoreq.3 g pyridostigmine glycine .gtoreq.100
mg pyridostigmine glycine .gtoreq.3 g bromide bromide pyridoxine
glycine .gtoreq.100 mg pyridoxine glycine .gtoreq.3 g hydrochloride
hydrochloride ranitidine glycine .gtoreq.100 mg ranitidine glycine
.gtoreq.3 g ribavirin glycine .gtoreq.100 mg Ribavirin glycine
.gtoreq.3 g riboflavin glycine .gtoreq.100 mg riboflavin glycine
.gtoreq.3 g rizatriptan glycine .gtoreq.100 mg rizatriptan glycine
.gtoreq.3 g stavudine glycine .gtoreq.100 mg stavudine glycine
.gtoreq.3 g sulfadiazine glycine .gtoreq.100 mg sulfadiazine
glycine .gtoreq.3 g sulfamethoxazole glycine .gtoreq.100 mg
sulfamethoxazole glycine .gtoreq.3 g sultamicillin glycine
.gtoreq.100 mg sultamicillin glycine .gtoreq.3 g sumatriptan
glycine .gtoreq.100 mg sumatriptan glycine .gtoreq.3 g taltirelin
glycine .gtoreq.100 mg Taltirelin glycine .gtoreq.3 g tegafur
glycine .gtoreq.100 mg Tegafur glycine .gtoreq.3 g tenofovir
disoproxil glycine .gtoreq.100 mg tenofovir disoproxil glycine
.gtoreq.3 g theophylline glycine .gtoreq.100 mg theophylline
glycine .gtoreq.3 g thiamine glycine .gtoreq.100 mg thiamine
glycine .gtoreq.3 g trimetazidine glycine .gtoreq.100 mg
trimetazidine glycine .gtoreq.3 g trimethoprim glycine .gtoreq.100
mg trimethoprim glycine .gtoreq.3 g voglibose glycine .gtoreq.100
mg voglibose glycine .gtoreq.3 g zidovudine glycine .gtoreq.100 mg
zidovudine glycine .gtoreq.3 g zolmitriptan glycine .gtoreq.100 mg
zolmitriptan glycine .gtoreq.3 g acetylcarnitine glycine
.gtoreq.100 mg acetylcarnitine glycine .gtoreq.3 g capecitabine
glycine .gtoreq.100 mg capecitabine glycine .gtoreq.3 g cefaclor
glycine .gtoreq.100 mg Cefaclor glycine .gtoreq.3 g cefixime
glycine .gtoreq.100 mg cefixime glycine .gtoreq.3 g cefmetazole
glycine .gtoreq.100 mg cefmetazole glycine .gtoreq.3 g cefpodoxime
proxetil glycine .gtoreq.100 mg cefpodoxime proxetil glycine
.gtoreq.3 g cefroxadine glycine .gtoreq.100 mg cefroxadine glycine
.gtoreq.3 g alfoscerate glycine .gtoreq.100 mg alfoscerate glycine
.gtoreq.3 g cilazapril glycine .gtoreq.100 mg cilazapril glycine
.gtoreq.3 g cimetropium bromide glycine .gtoreq.100 mg cimetropium
bromide glycine .gtoreq.3 g diacerein glycine .gtoreq.100 mg
diacerein glycine .gtoreq.3 g erdosteine glycine .gtoreq.100 mg
erdosteine glycine .gtoreq.3 g famciclovir glycine .gtoreq.100 mg
famciclovir glycine .gtoreq.3 g gemifloxacin glycine .gtoreq.100 mg
gemifloxacin glycine .gtoreq.3 g levosulpiride glycine .gtoreq.100
mg levosulpiride glycine .gtoreq.3 g nabumetone glycine .gtoreq.100
mg nabumetone glycine .gtoreq.3 g oxiracetam glycine .gtoreq.100 mg
oxiracetam glycine .gtoreq.3 g phendimetrazine glycine .gtoreq.100
mg phendimetrazine glycine .gtoreq.3 g rabeprazole glycine
.gtoreq.100 mg rabeprazole glycine .gtoreq.3 g roxatidine acetate
glycine .gtoreq.100 mg roxatidine acetate glycine .gtoreq.3 g
tamsulosin glycine .gtoreq.100 mg tamsulosin glycine .gtoreq.3 g
terazosin glycine .gtoreq.100 mg terazosin glycine .gtoreq.3 g
thioctic glycine .gtoreq.100 mg Thioctic glycine .gtoreq.3 g
tosufloxacin glycine .gtoreq.100 mg tosufloxacin glycine .gtoreq.3
g triflusal glycine .gtoreq.100 mg Triflusal glycine .gtoreq.3 g
zaltoprofen glycine .gtoreq.100 mg zaltoprofen glycine .gtoreq.3 g
etidronic acid glycine .gtoreq.100 mg etidronic acid glycine
.gtoreq.3 g zoledronic acid glycine .gtoreq.100 mg zoledronic acid
glycine .gtoreq.3 g clodronic acid glycine .gtoreq.100 mg clodronic
acid glycine .gtoreq.3 g tiludronic acid glycine .gtoreq.100 mg
tiludronic acid glycine .gtoreq.3 g pamidronic acid glycine
.gtoreq.100 mg pamidronic acid glycine .gtoreq.3 g alendronic acid
glycine .gtoreq.100 mg alendronic acid glycine .gtoreq.3 g
risedronic acid glycine .gtoreq.100 mg risedronic acid glycine
.gtoreq.3 g ibandronic acid glycine .gtoreq.100 mg ibandronic acid
glycine .gtoreq.3 g ibandronic acid glycine .gtoreq.100 mg abacavir
lysine .gtoreq.5 g abacavir lysine .gtoreq.500 mg acarbose lysine
.gtoreq.5 g acarbose lysine .gtoreq.500 mg acetazolamide lysine
.gtoreq.5 g acetazolamide lysine .gtoreq.500 mg acyclovir lysine
.gtoreq.5 g acyclovir lysine .gtoreq.500 mg albuterol (salbutamol)
lysine .gtoreq.5 g albuterol (salbutamol) lysine .gtoreq.500 mg
allopurinol lysine .gtoreq.5 g allopurinol lysine .gtoreq.500 mg
amiloride lysine .gtoreq.5 g amiloride lysine .gtoreq.500 mg
amisulpride lysine .gtoreq.5 g amisulpride lysine .gtoreq.500 mg
amlodipine lysine .gtoreq.5 g amlodipine lysine .gtoreq.500 mg
amoxicillin lysine .gtoreq.5 g amoxicillin lysine .gtoreq.500 mg
amphetamine lysine .gtoreq.5 g amphetamine lysine .gtoreq.500 mg
atenolol lysine .gtoreq.5 g atenolol lysine .gtoreq.500 mg Atropine
lysine .gtoreq.5 g atropine lysine .gtoreq.500 mg azathioprine
lysine .gtoreq.5 g azathioprine lysine .gtoreq.500 mg benserazide
lysine .gtoreq.5 g benserazide lysine .gtoreq.500 mg benznidazole
lysine .gtoreq.5 g benznidazole lysine .gtoreq.500 mg camostat
lysine .gtoreq.5 g camostat lysine .gtoreq.500 mg captopril lysine
.gtoreq.5 g captopril lysine .gtoreq.500 mg Cefdinir lysine
.gtoreq.5 g cefdinir lysine .gtoreq.500 mg cefotiam hexetil lysine
.gtoreq.5 g hydrochloride cefotiam hexetil lysine .gtoreq.500 mg
cefprozil lysine .gtoreq.5 g hydrochloride cefprozil lysine
.gtoreq.500 mg cefuroxime axetil lysine .gtoreq.5 g cefuroxime
axetil lysine .gtoreq.500 mg chloramphenicol lysine .gtoreq.5 g
chloramphenicol lysine .gtoreq.500 mg cimetidine lysine .gtoreq.5 g
cimetidine lysine .gtoreq.500 mg ciprofloxacin lysine .gtoreq.5 g
ciprofloxacin lysine .gtoreq.500 mg Codeine lysine .gtoreq.5 g
codeine lysine .gtoreq.500 mg colchicine lysine .gtoreq.5 g
colchicines lysine .gtoreq.500 mg cyclophosphamide lysine .gtoreq.5
g cyclophosphamide lysine .gtoreq.500 mg Dapsone lysine .gtoreq.5 g
dapsone lysine .gtoreq.500 mg dexamethasone lysine .gtoreq.5 g
dexamethasone lysine .gtoreq.500 mg didanosine lysine .gtoreq.5 g
didanosine lysine .gtoreq.500 mg diethylcarbamazine lysine
.gtoreq.5 g diethylcarbamazine lysine .gtoreq.500 mg methionine
lysine .gtoreq.5 g methionine lysine .gtoreq.500 mg dolasetron
lysine .gtoreq.5 g dolasetron lysine .gtoreq.500 mg doxifluridine
lysine .gtoreq.5 g doxifluridine lysine .gtoreq.500 mg doxycycline
lysine .gtoreq.5 g doxycycline lysine .gtoreq.500 mg ergonovine
lysine .gtoreq.5 g ergonovine lysine .gtoreq.500 mg erythromycin
lysine .gtoreq.5 g ethylsuccinate erythromycin lysine .gtoreq.500
mg ethambutol lysine .gtoreq.5 g ethylsuccinate ethambutol lysine
.gtoreq.500 mg ethosuximide lysine .gtoreq.5 g ethosuximide lysine
.gtoreq.500 mg famotidine lysine .gtoreq.5 g famotidine lysine
.gtoreq.500 mg fluconazole lysine .gtoreq.5 g fluconazole lysine
.gtoreq.500 mg folic acid lysine .gtoreq.5 g folic acid lysine
.gtoreq.500 mg furosemide lysine .gtoreq.5 g furosemide lysine
.gtoreq.500 mg fursultiamine lysine .gtoreq.5 g fursultiamine
lysine .gtoreq.500 mg gabapentin lysine .gtoreq.5 g gabapentin
lysine .gtoreq.500 mg Glipizide lysine .gtoreq.5 g glipizide lysine
.gtoreq.500 mg granisetron lysine .gtoreq.5 g granisetron lysine
.gtoreq.500 mg griseofulvin lysine .gtoreq.5 g griseofulvin lysine
.gtoreq.500 mg hydralazine lysine .gtoreq.5 g hydralazine lysine
.gtoreq.500 mg hydrochlorothiazide lysine .gtoreq.5 g
hydrochlorothiazide lysine .gtoreq.500 mg imidapril lysine
.gtoreq.5 g imidapril lysine .gtoreq.500 mg isoniazid lysine
.gtoreq.5 g isoniazid lysine .gtoreq.500 mg lamivudine lysine
.gtoreq.5 g lamivudine lysine .gtoreq.500 mg l-carbocysteine lysine
.gtoreq.5 g l-carbocysteine lysine .gtoreq.500 mg levetiracetam
lysine .gtoreq.5 g levetiracetam lysine .gtoreq.500 mg levofloxacin
lysine .gtoreq.5 g levofloxacin lysine .gtoreq.500 mg Linezolid
lysine .gtoreq.5 g linezolid lysine .gtoreq.500 mg lisinopril
lysine .gtoreq.5 g lisinopril lysine .gtoreq.500 mg Losartan lysine
.gtoreq.5 g losartan lysine .gtoreq.500 mg methotrexate lysine
.gtoreq.5 g methotrexate lysine .gtoreq.500 mg methyldopa lysine
.gtoreq.5 g methyldopa lysine .gtoreq.500 mg s-methylmethionine
lysine .gtoreq.5 g s-methylmethionine lysine .gtoreq.500 mg
metoclopramide lysine .gtoreq.5 g metoclopramide lysine .gtoreq.500
mg metronidazole lysine .gtoreq.5 g metronidazole lysine
.gtoreq.500 mg moxifloxacin lysine .gtoreq.5 g moxifloxacin lysine
.gtoreq.500 mg nalidixic acid lysine .gtoreq.5 g nalidixic acid
lysine .gtoreq.500 mg nicorandil lysine .gtoreq.5 g nicorandil
lysine .gtoreq.500 mg nifurtimox lysine .gtoreq.5 g nifurtimox
lysine .gtoreq.500 mg nitrofurantoin lysine .gtoreq.5 g
nitrofurantoin lysine .gtoreq.500 mg nizatidine lysine .gtoreq.5 g
nizatidine lysine .gtoreq.500 mg Nystatin lysine .gtoreq.5 g
nystatin lysine .gtoreq.500 mg ondansetron lysine .gtoreq.5 g
ondansetron lysine .gtoreq.500 mg oseltamivir lysine .gtoreq.5 g
oseltamivir lysine .gtoreq.500 mg oxcarbazepine lysine .gtoreq.5 g
oxcarbazepine lysine .gtoreq.500 mg penicillamine lysine .gtoreq.5
g penicillamine lysine .gtoreq.500 mg perindopril lysine .gtoreq.5
g perindopril lysine .gtoreq.500 mg phenobarbital lysine .gtoreq.5
g phenobarbital lysine .gtoreq.500 mg Phenoxymethylpenicillin
lysine .gtoreq.5 g phenoxymethylpenicillin lysine .gtoreq.500 mg
pravastatin sodium lysine .gtoreq.5 g pravastatin sodium lysine
.gtoreq.500 mg prednisolone lysine .gtoreq.5 g prednisolone lysine
.gtoreq.500 mg primaquine lysine .gtoreq.5 g primaquine lysine
.gtoreq.500 mg procaterol lysine .gtoreq.5 g procaterol lysine
.gtoreq.500 mg propylthiouracil lysine .gtoreq.5 g propylthiouracil
lysine .gtoreq.500 mg pseudoephedrine lysine .gtoreq.5 g
pseudoephedrine lysine .gtoreq.500 mg pyrazinamide lysine .gtoreq.5
g pyrazinamide lysine .gtoreq.500 mg pyridostigmine lysine
.gtoreq.5 g bromide pyridostigmine lysine .gtoreq.500 mg pyridoxine
lysine .gtoreq.5 g bromide hydrochloride pyridoxine lysine
.gtoreq.500 mg ranitidine lysine .gtoreq.5 g hydrochloride
ranitidine lysine .gtoreq.500 mg Ribavirin lysine .gtoreq.5 g
ribavirin lysine .gtoreq.500 mg riboflavin lysine .gtoreq.5 g
riboflavin lysine .gtoreq.500 mg rizatriptan lysine .gtoreq.5 g
rizatriptan lysine .gtoreq.500 mg stavudine lysine .gtoreq.5 g
stavudine lysine .gtoreq.500 mg sulfadiazine lysine .gtoreq.5 g
sulfadiazine lysine .gtoreq.500 mg sulfamethoxazole lysine
.gtoreq.5 g sulfamethoxazole lysine .gtoreq.500 mg sultamicillin
lysine .gtoreq.5 g sultamicillin lysine .gtoreq.500 mg sumatriptan
lysine .gtoreq.5 g sumatriptan lysine .gtoreq.500 mg Taltirelin
lysine .gtoreq.5 g taltirelin lysine .gtoreq.500 mg Tegafur lysine
.gtoreq.5 g tegafur lysine .gtoreq.500 mg tenofovir disoproxil
lysine .gtoreq.5 g tenofovir disoproxil lysine .gtoreq.500 mg
theophylline lysine .gtoreq.5 g theophylline lysine .gtoreq.500 mg
thiamine lysine .gtoreq.5 g thiamine lysine .gtoreq.500 mg
trimetazidine lysine .gtoreq.5 g trimetazidine lysine .gtoreq.500
mg trimethoprim lysine .gtoreq.5 g trimethoprim lysine .gtoreq.500
mg voglibose lysine .gtoreq.5 g voglibose lysine .gtoreq.500 mg
zidovudine lysine .gtoreq.5 g zidovudine lysine .gtoreq.500 mg
zolmitriptan lysine .gtoreq.5 g zolmitriptan lysine .gtoreq.500 mg
acetylcarnitine lysine .gtoreq.5 g acetylcarnitine lysine
.gtoreq.500 mg capecitabine lysine .gtoreq.5 g capecitabine lysine
.gtoreq.500 mg Cefaclor lysine .gtoreq.5 g cefaclor lysine
.gtoreq.500 mg cefixime lysine .gtoreq.5 g cefixime lysine
.gtoreq.500 mg cefmetazole lysine .gtoreq.5 g cefmetazole lysine
.gtoreq.500 mg cefpodoxime proxetil lysine .gtoreq.5 g cefpodoxime
proxetil lysine .gtoreq.500 mg cefroxadine lysine .gtoreq.5 g
cefroxadine lysine .gtoreq.500 mg alfoscerate lysine .gtoreq.5 g
alfoscerate lysine .gtoreq.500 mg cilazapril lysine .gtoreq.5 g
cilazapril lysine .gtoreq.500 mg cimetropium bromide lysine
.gtoreq.5 g cimetropium bromide lysine .gtoreq.500 mg diacerein
lysine .gtoreq.5 g diacerein lysine .gtoreq.500 mg erdosteine
lysine .gtoreq.5 g erdosteine lysine .gtoreq.500 mg famciclovir
lysine .gtoreq.5 g famciclovir lysine .gtoreq.500 mg gemifloxacin
lysine .gtoreq.5 g gemifloxacin lysine .gtoreq.500 mg levosulpiride
lysine .gtoreq.5 g levosulpiride lysine .gtoreq.500 mg nabumetone
lysine .gtoreq.5 g nabumetone lysine .gtoreq.500 mg oxiracetam
lysine .gtoreq.5 g oxiracetam lysine .gtoreq.500 mg phendimetrazine
lysine .gtoreq.5 g phendimetrazine lysine .gtoreq.500 mg
rabeprazole lysine .gtoreq.5 g rabeprazole lysine .gtoreq.500 mg
roxatidine acetate lysine .gtoreq.5 g roxatidine acetate lysine
.gtoreq.500 mg tamsulosin lysine .gtoreq.5 g tamsulosin lysine
.gtoreq.500 mg terazosin lysine .gtoreq.5 g terazosin lysine
.gtoreq.500 mg Thioctic lysine .gtoreq.5 g thioctic lysine
.gtoreq.500 mg tosufloxacin lysine .gtoreq.5 g tosufloxacin lysine
.gtoreq.500 mg Triflusal lysine .gtoreq.5 g triflusal lysine
.gtoreq.500 mg zaltoprofen lysine .gtoreq.5 g zaltoprofen lysine
.gtoreq.500 mg etidronic acid lysine .gtoreq.5 g etidronic acid
lysine .gtoreq.500 mg zoledronic acid lysine .gtoreq.5 g
zoledronic acid lysine .gtoreq.500 mg clodronic acid lysine
.gtoreq.5 g zoledronic acid lysine .gtoreq.600 mg zoledronic acid
lysine .gtoreq.900 mg zoledronic acid lysine .gtoreq.700 mg
zoledronic acid lysine .gtoreq.1000 mg zoledronic acid lysine
.gtoreq.800 mg zoledronic acid lysine .gtoreq.1100 mg clodronic
acid lysine .gtoreq.500 mg tiludronic acid lysine .gtoreq.5 g
tiludronic acid lysine .gtoreq.500 mg pamidronic acid lysine
.gtoreq.5 g pamidronic acid lysine .gtoreq.500 mg alendronic acid
lysine .gtoreq.5 g alendronic acid lysine .gtoreq.500 mg risedronic
acid lysine .gtoreq.5 g risedronic acid lysine .gtoreq.500 mg
ibandronic acid lysine .gtoreq.5 g ibandronic acid lysine
.gtoreq.500 mg abacavir glycine .gtoreq.5 g abacavir glycine
.gtoreq.500 mg acarbose glycine .gtoreq.5 g acarbose glycine
.gtoreq.500 mg acetazolamide glycine .gtoreq.5 g acetazolamide
glycine .gtoreq.500 mg acyclovir glycine .gtoreq.5 g acyclovir
glycine .gtoreq.500 mg albuterol (salbutamol) glycine .gtoreq.5 g
albuterol (salbutamol) glycine .gtoreq.500 mg allopurinol glycine
.gtoreq.5 g allopurinol glycine .gtoreq.500 mg amiloride glycine
.gtoreq.5 g amiloride glycine .gtoreq.500 mg amisulpride glycine
.gtoreq.5 g amisulpride glycine .gtoreq.500 mg amlodipine glycine
.gtoreq.5 g amlodipine glycine .gtoreq.500 mg amoxicillin glycine
.gtoreq.5 g amoxicillin glycine .gtoreq.500 mg amphetamine glycine
.gtoreq.5 g amphetamine glycine .gtoreq.500 mg atenolol glycine
.gtoreq.5 g atenolol glycine .gtoreq.500 mg Atropine glycine
.gtoreq.5 g atropine glycine .gtoreq.500 mg azathioprine glycine
.gtoreq.5 g azathioprine glycine .gtoreq.500 mg benserazide glycine
.gtoreq.5 g benserazide glycine .gtoreq.500 mg benznidazole glycine
.gtoreq.5 g benznidazole glycine .gtoreq.500 mg camostat glycine
.gtoreq.5 g camostat glycine .gtoreq.500 mg captopril glycine
.gtoreq.5 g captopril glycine .gtoreq.500 mg Cefdinir glycine
.gtoreq.5 g cefdinir glycine .gtoreq.500 mg cefotiam hexetil
glycine .gtoreq.5 g hydrochloride cefotiam hexetil glycine
.gtoreq.500 mg cefprozil glycine .gtoreq.5 g hydrochloride
cefprozil glycine .gtoreq.500 mg cefuroxime axetil glycine
.gtoreq.5 g cefuroxime axetil glycine .gtoreq.500 mg
chloramphenicol glycine .gtoreq.5 g chloramphenicol glycine
.gtoreq.500 mg cimetidine glycine .gtoreq.5 g cimetidine glycine
.gtoreq.500 mg ciprofloxacin glycine .gtoreq.5 g ciprofloxacin
glycine .gtoreq.500 mg Codeine glycine .gtoreq.5 g codeine glycine
.gtoreq.500 mg colchicine glycine .gtoreq.5 g colchicines glycine
.gtoreq.500 mg cyclophosphamide glycine .gtoreq.5 g
cyclophosphamide glycine .gtoreq.500 mg Dapsone glycine .gtoreq.5 g
dapsone glycine .gtoreq.500 mg dexamethasone glycine .gtoreq.5 g
dexamethasone glycine .gtoreq.500 mg didanosine glycine .gtoreq.5 g
didanosine glycine .gtoreq.500 mg diethylcarbamazine glycine
.gtoreq.5 g diethylcarbamazine glycine .gtoreq.500 mg methionine
glycine .gtoreq.5 g methionine glycine .gtoreq.500 mg dolasetron
glycine .gtoreq.5 g dolasetron glycine .gtoreq.500 mg doxifluridine
glycine .gtoreq.5 g doxifluridine glycine .gtoreq.500 mg
doxycycline glycine .gtoreq.5 g doxycycline glycine .gtoreq.500 mg
ergonovine glycine .gtoreq.5 g ergonovine glycine .gtoreq.500 mg
erythromycin glycine .gtoreq.5 g ethylsuccinate erythromycin
glycine .gtoreq.500 mg ethambutol glycine .gtoreq.5 g
ethylsuccinate ethambutol glycine .gtoreq.500 mg ethosuximide
glycine .gtoreq.5 g ethosuximide glycine .gtoreq.500 mg famotidine
glycine .gtoreq.5 g famotidine glycine .gtoreq.500 mg fluconazole
glycine .gtoreq.5 g fluconazole glycine .gtoreq.500 mg folic acid
glycine .gtoreq.5 g folic acid glycine .gtoreq.500 mg furosemide
glycine .gtoreq.5 g furosemide glycine .gtoreq.500 mg fursultiamine
glycine .gtoreq.5 g fursultiamine glycine .gtoreq.500 mg gabapentin
glycine .gtoreq.5 g gabapentin glycine .gtoreq.500 mg glipizide
glycine .gtoreq.5 g glipizide glycine .gtoreq.500 mg granisetron
glycine .gtoreq.5 g granisetron glycine .gtoreq.500 mg griseofulvin
glycine .gtoreq.5 g griseofulvin glycine .gtoreq.500 mg hydralazine
glycine .gtoreq.5 g hydralazine glycine .gtoreq.500 mg
hydrochlorothiazide glycine .gtoreq.5 g hydrochlorothiazide glycine
.gtoreq.500 mg imidapril glycine .gtoreq.5 g imidapril glycine
.gtoreq.500 mg isoniazid glycine .gtoreq.5 g isoniazid glycine
.gtoreq.500 mg lamivudine glycine .gtoreq.5 g lamivudine glycine
.gtoreq.500 mg l-carbocysteine glycine .gtoreq.5 g l-carbocysteine
glycine .gtoreq.500 mg levetiracetam glycine .gtoreq.5 g
levetiracetam glycine .gtoreq.500 mg levofloxacin glycine .gtoreq.5
g levofloxacin glycine .gtoreq.500 mg linezolid glycine .gtoreq.5 g
linezolid glycine .gtoreq.500 mg lisinopril glycine .gtoreq.5 g
lisinopril glycine .gtoreq.500 mg losartan glycine .gtoreq.5 g
losartan glycine .gtoreq.500 mg methotrexate glycine .gtoreq.5 g
methotrexate glycine .gtoreq.500 mg methyldopa glycine .gtoreq.5 g
methyldopa glycine .gtoreq.500 mg s-methylmethionine glycine
.gtoreq.5 g s-methylmethionine glycine .gtoreq.500 mg
metoclopramide glycine .gtoreq.5 g metoclopramide glycine
.gtoreq.500 mg metronidazole glycine .gtoreq.5 g metronidazole
glycine .gtoreq.500 mg moxifloxacin glycine .gtoreq.5 g
moxifloxacin glycine .gtoreq.500 mg nalidixic acid glycine
.gtoreq.5 g nalidixic acid glycine .gtoreq.500 mg nicorandil
glycine .gtoreq.5 g nicorandil glycine .gtoreq.500 mg nifurtimox
glycine .gtoreq.5 g nifurtimox glycine .gtoreq.500 mg
nitrofurantoin glycine .gtoreq.5 g nitrofurantoin glycine
.gtoreq.500 mg nizatidine glycine .gtoreq.5 g nizatidine glycine
.gtoreq.500 mg nystatin glycine .gtoreq.5 g nystatin glycine
.gtoreq.500 mg ondansetron glycine .gtoreq.5 g ondansetron glycine
.gtoreq.500 mg oseltamivir glycine .gtoreq.5 g oseltamivir glycine
.gtoreq.500 mg oxcarbazepine glycine .gtoreq.5 g oxcarbazepine
glycine .gtoreq.500 mg penicillamine glycine .gtoreq.5 g
penicillamine glycine .gtoreq.500 mg perindopril glycine .gtoreq.5
g perindopril glycine .gtoreq.500 mg phenobarbital glycine
.gtoreq.5 g phenobarbital glycine .gtoreq.500 mg
phenoxymethylpenicillin glycine .gtoreq.5 g phenoxymethylpenicillin
glycine .gtoreq.500 mg pravastatin sodium glycine .gtoreq.5 g
pravastatin sodium glycine .gtoreq.500 mg prednisolone glycine
.gtoreq.5 g prednisolone glycine .gtoreq.500 mg primaquine glycine
.gtoreq.5 g primaquine glycine .gtoreq.500 mg procaterol glycine
.gtoreq.5 g procaterol glycine .gtoreq.500 mg propylthiouracil
glycine .gtoreq.5 g propylthiouracil glycine .gtoreq.500 mg
pseudoephedrine glycine .gtoreq.5 g pseudoephedrine glycine
.gtoreq.500 mg pyrazinamide glycine .gtoreq.5 g pyrazinamide
glycine .gtoreq.500 mg pyridostigmine glycine .gtoreq.5 g bromide
pyridostigmine glycine .gtoreq.500 mg pyridoxine glycine .gtoreq.5
g bromide hydrochloride pyridoxine glycine .gtoreq.500 mg
ranitidine glycine .gtoreq.5 g hydrochloride ranitidine glycine
.gtoreq.500 mg ribavirin glycine .gtoreq.5 g ribavirin glycine
.gtoreq.500 mg riboflavin glycine .gtoreq.5 g riboflavin glycine
.gtoreq.500 mg rizatriptan glycine .gtoreq.5 g rizatriptan glycine
.gtoreq.500 mg stavudine glycine .gtoreq.5 g stavudine glycine
.gtoreq.500 mg sulfadiazine glycine .gtoreq.5 g sulfadiazine
glycine .gtoreq.500 mg sulfamethoxazole glycine .gtoreq.5 g
sulfamethoxazole glycine .gtoreq.500 mg sultamicillin glycine
.gtoreq.5 g sultamicillin glycine .gtoreq.500 mg sumatriptan
glycine .gtoreq.5 g sumatriptan glycine .gtoreq.500 mg taltirelin
glycine .gtoreq.5 g taltirelin glycine .gtoreq.500 mg tegafur
glycine .gtoreq.5 g tegafur glycine .gtoreq.500 mg tenofovir
disoproxil glycine .gtoreq.5 g tenofovir disoproxil glycine
.gtoreq.500 mg theophylline glycine .gtoreq.5 g theophylline
glycine .gtoreq.500 mg thiamine glycine .gtoreq.5 g thiamine
glycine .gtoreq.500 mg trimetazidine glycine .gtoreq.5 g
trimetazidine glycine .gtoreq.500 mg trimethoprim glycine .gtoreq.5
g trimethoprim glycine .gtoreq.500 mg voglibose glycine .gtoreq.5 g
voglibose glycine .gtoreq.500 mg zidovudine glycine .gtoreq.5 g
zidovudine glycine .gtoreq.500 mg zolmitriptan glycine .gtoreq.5 g
zolmitriptan glycine .gtoreq.500 mg acetylcarnitine glycine
.gtoreq.5 g acetylcarnitine glycine .gtoreq.500 mg capecitabine
glycine .gtoreq.5 g capecitabine glycine .gtoreq.500 mg cefaclor
glycine .gtoreq.5 g cefaclor glycine .gtoreq.500 mg cefixime
glycine .gtoreq.5 g cefixime glycine .gtoreq.500 mg cefmetazole
glycine .gtoreq.5 g cefmetazole glycine .gtoreq.500 mg cefpodoxime
proxetil glycine .gtoreq.5 g cefpodoxime proxetil glycine
.gtoreq.500 mg cefroxadine glycine .gtoreq.5 g cefroxadine glycine
.gtoreq.500 mg alfoscerate glycine .gtoreq.5 g alfoscerate glycine
.gtoreq.500 mg cilazapril glycine .gtoreq.5 g cilazapril glycine
.gtoreq.500 mg cimetropium bromide glycine .gtoreq.5 g cimetropium
bromide glycine .gtoreq.500 mg diacerein glycine .gtoreq.5 g
diacerein glycine .gtoreq.500 mg erdosteine glycine .gtoreq.5 g
erdosteine glycine .gtoreq.500 mg famciclovir glycine .gtoreq.5 g
famciclovir glycine .gtoreq.500 mg gemifloxacin glycine .gtoreq.5 g
gemifloxacin glycine .gtoreq.500 mg levosulpiride glycine .gtoreq.5
g levosulpiride glycine .gtoreq.500 mg nabumetone glycine .gtoreq.5
g nabumetone glycine .gtoreq.500 mg oxiracetam glycine .gtoreq.5 g
oxiracetam glycine .gtoreq.500 mg phendimetrazine glycine .gtoreq.5
g phendimetrazine glycine .gtoreq.500 mg rabeprazole glycine
.gtoreq.5 g rabeprazole glycine .gtoreq.500 mg roxatidine acetate
glycine .gtoreq.5 g roxatidine acetate glycine .gtoreq.500 mg
tamsulosin glycine .gtoreq.5 g tamsulosin glycine .gtoreq.500 mg
terazosin glycine .gtoreq.5 g terazosin glycine .gtoreq.500 mg
thioctic glycine .gtoreq.5 g thioctic glycine .gtoreq.500 mg
tosufloxacin glycine .gtoreq.5 g tosufloxacin glycine .gtoreq.500
mg triflusal glycine .gtoreq.5 g triflusal glycine .gtoreq.500 mg
zaltoprofen glycine .gtoreq.5 g zaltoprofen glycine .gtoreq.500 mg
etidronic acid glycine .gtoreq.5 g etidronic acid glycine
.gtoreq.500 mg zoledronic acid glycine .gtoreq.5 g zoledronic acid
glycine .gtoreq.500 mg clodronic acid glycine .gtoreq.5 g clodronic
acid glycine .gtoreq.500 mg tiludronic acid glycine .gtoreq.5 g
tiludronic acid glycine .gtoreq.500 mg pamidronic acid glycine
.gtoreq.5 g pamidronic acid glycine .gtoreq.500 mg alendronic acid
glycine .gtoreq.5 g alendronic acid glycine .gtoreq.500 mg
risedronic acid glycine .gtoreq.5 g risedronic acid glycine
.gtoreq.500 mg ibandronic acid glycine .gtoreq.5 g ibandronic acid
glycine .gtoreq.500 mg abacavir lysine .gtoreq.7.5 g ibandronic
acid glycine .gtoreq.500 mg acarbose lysine .gtoreq.7.5 g abacavir
lysine .gtoreq.1.25 g acetazolamide lysine .gtoreq.7.5 g acarbose
lysine .gtoreq.1.25 g acyclovir lysine .gtoreq.7.5 g acetazolamide
lysine .gtoreq.1.25 g albuterol (salbutamol) lysine .gtoreq.7.5 g
acyclovir lysine .gtoreq.1.25 g allopurinol lysine .gtoreq.7.5 g
albuterol (salbutamol) lysine .gtoreq.1.25 g amiloride lysine
.gtoreq.7.5 g allopurinol lysine .gtoreq.1.25 g amisulpride lysine
.gtoreq.7.5 g amiloride lysine .gtoreq.1.25 g amlodipine lysine
.gtoreq.7.5 g amisulpride lysine .gtoreq.1.25 g amoxicillin lysine
.gtoreq.7.5 g amlodipine lysine .gtoreq.1.25 g amphetamine lysine
.gtoreq.7.5 g amoxicillin lysine .gtoreq.1.25 g atenolol lysine
.gtoreq.7.5 g amphetamine lysine .gtoreq.1.25 g atropine lysine
.gtoreq.7.5 g atenolol lysine .gtoreq.1.25 g azathioprine lysine
.gtoreq.7.5 g atropine lysine .gtoreq.1.25 g benserazide lysine
.gtoreq.7.5 g azathioprine lysine .gtoreq.1.25 g benznidazole
lysine .gtoreq.7.5 g benserazide lysine .gtoreq.1.25 g camostat
lysine .gtoreq.7.5 g benznidazole lysine .gtoreq.1.25 g captopril
lysine .gtoreq.7.5 g camostat lysine .gtoreq.1.25 g cefdinir lysine
.gtoreq.7.5 g captopril lysine .gtoreq.1.25 g cefotiam hexetil
lysine .gtoreq.7.5 g hydrochloride cefdinir lysine .gtoreq.1.25 g
cefprozil lysine .gtoreq.7.5 g cefotiam hexetil lysine .gtoreq.1.25
g cefuroxime axetil lysine .gtoreq.7.5 g hydrochloride cefprozil
lysine .gtoreq.1.25 g chloramphenicol lysine .gtoreq.7.5 g
cefuroxime axetil lysine .gtoreq.1.25 g cimetidine lysine
.gtoreq.7.5 g chloramphenicol lysine .gtoreq.1.25 g ciprofloxacin
lysine .gtoreq.7.5 g cimetidine lysine .gtoreq.1.25 g codeine
lysine .gtoreq.7.5 g ciprofloxacin lysine .gtoreq.1.25 g colchicine
lysine .gtoreq.7.5 g codeine lysine .gtoreq.1.25 g cyclophosphamide
lysine .gtoreq.7.5 g colchicine lysine .gtoreq.1.25 g dapsone
lysine .gtoreq.7.5 g cyclophosphamide lysine .gtoreq.1.25 g
dexamethasone lysine .gtoreq.7.5 g dapsone lysine .gtoreq.1.25 g
didanosine lysine .gtoreq.7.5 g dexamethasone lysine .gtoreq.1.25 g
diethylcarbamazine lysine .gtoreq.7.5 g didanosine lysine
.gtoreq.1.25 g methionine lysine .gtoreq.7.5 g diethylcarbamazine
lysine .gtoreq.1.25 g dolasetron lysine .gtoreq.7.5 g methionine
lysine .gtoreq.1.25 g doxifluridine lysine .gtoreq.7.5 g dolasetron
lysine .gtoreq.1.25 g doxycycline lysine .gtoreq.7.5 g
doxifluridine lysine .gtoreq.1.25 g ergonovine lysine .gtoreq.7.5 g
doxycycline lysine .gtoreq.1.25 g erythromycin lysine .gtoreq.7.5 g
ethylsuccinate ergonovine lysine .gtoreq.1.25 g ethambutol lysine
.gtoreq.7.5 g erythromycin lysine .gtoreq.1.25 g ethosuximide
lysine .gtoreq.7.5 g ethylsuccinate ethambutol lysine .gtoreq.1.25
g famotidine lysine .gtoreq.7.5 g ethosuximide lysine .gtoreq.1.25
g fluconazole lysine .gtoreq.7.5 g famotidine lysine .gtoreq.1.25 g
folic acid lysine .gtoreq.7.5 g fluconazole lysine .gtoreq.1.25 g
furosemide lysine .gtoreq.7.5 g folic acid lysine .gtoreq.1.25 g
fursultiamine lysine .gtoreq.7.5 g furosemide lysine .gtoreq.1.25 g
gabapentin lysine .gtoreq.7.5 g fursultiamine lysine .gtoreq.1.25 g
glipizide lysine .gtoreq.7.5 g gabapentin lysine .gtoreq.1.25 g
granisetron lysine .gtoreq.7.5 g glipizide lysine .gtoreq.1.25 g
griseofulvin lysine .gtoreq.7.5 g granisetron lysine .gtoreq.1.25 g
hydralazine lysine .gtoreq.7.5 g griseofulvin lysine .gtoreq.1.25 g
hydrochlorothiazide lysine .gtoreq.7.5 g hydralazine lysine
.gtoreq.1.25 g imidapril lysine .gtoreq.7.5 g hydrochlorothiazide
lysine .gtoreq.1.25 g isoniazid lysine .gtoreq.7.5 g imidapril
lysine .gtoreq.1.25 g lamivudine lysine .gtoreq.7.5 g isoniazid
lysine .gtoreq.1.25 g l-carbocysteine lysine .gtoreq.7.5 g
lamivudine lysine .gtoreq.1.25 g levetiracetam lysine .gtoreq.7.5 g
l-carbocysteine lysine .gtoreq.1.25 g levofloxacin lysine
.gtoreq.7.5 g levetiracetam lysine .gtoreq.1.25 g linezolid lysine
.gtoreq.7.5 g levofloxacin lysine .gtoreq.1.25 g lisinopril lysine
.gtoreq.7.5 g linezolid lysine .gtoreq.1.25 g losartan lysine
.gtoreq.7.5 g lisinopril lysine .gtoreq.1.25 g methotrexate lysine
.gtoreq.7.5 g losartan lysine .gtoreq.1.25 g methyldopa lysine
.gtoreq.7.5 g methotrexate lysine .gtoreq.1.25 g s-methylmethionine
lysine .gtoreq.7.5 g methyldopa lysine .gtoreq.1.25 g
metoclopramide lysine .gtoreq.7.5 g s-methylmethionine lysine
.gtoreq.1.25 g metronidazole lysine .gtoreq.7.5
g metoclopramide lysine .gtoreq.1.25 g moxifloxacin lysine
.gtoreq.7.5 g metronidazole lysine .gtoreq.1.25 g nalidixic acid
lysine .gtoreq.7.5 g moxifloxacin lysine .gtoreq.1.25 g nicorandil
lysine .gtoreq.7.5 g nalidixic acid lysine .gtoreq.1.25 g
nifurtimox lysine .gtoreq.7.5 g nicorandil lysine .gtoreq.1.25 g
nitrofurantoin lysine .gtoreq.7.5 g nifurtimox lysine .gtoreq.1.25
g nizatidine lysine .gtoreq.7.5 g nitrofurantoin lysine
.gtoreq.1.25 g nystatin lysine .gtoreq.7.5 g nizatidine lysine
.gtoreq.1.25 g ondansetron lysine .gtoreq.7.5 g nystatin lysine
.gtoreq.1.25 g oseltamivir lysine .gtoreq.7.5 g ondansetron lysine
.gtoreq.1.25 g oxcarbazepine lysine .gtoreq.7.5 g oseltamivir
lysine .gtoreq.1.25 g penicillamine lysine .gtoreq.7.5 g
oxcarbazepine lysine .gtoreq.1.25 g perindopril lysine .gtoreq.7.5
g penicillamine lysine .gtoreq.1.25 g phenobarbital lysine
.gtoreq.7.5 g perindopril lysine .gtoreq.1.25 g
phenoxymethylpenicillin lysine .gtoreq.7.5 g phenobarbital lysine
.gtoreq.1.25 g pravastatin sodium lysine .gtoreq.7.5 g
phenoxymethylpenicillin lysine .gtoreq.1.25 g prednisolone lysine
.gtoreq.7.5 g pravastatin sodium lysine .gtoreq.1.25 g primaquine
lysine .gtoreq.7.5 g prednisolone lysine .gtoreq.1.25 g procaterol
lysine .gtoreq.7.5 g primaquine lysine .gtoreq.1.25 g
propylthiouracil lysine .gtoreq.7.5 g procaterol lysine
.gtoreq.1.25 g pseudoephedrine lysine .gtoreq.7.5 g
propylthiouracil lysine .gtoreq.1.25 g pyrazinamide lysine
.gtoreq.7.5 g pseudoephedrine lysine .gtoreq.1.25 g pyridostigmine
lysine .gtoreq.7.5 g bromide pyrazinamide lysine .gtoreq.1.25 g
pyridoxine lysine .gtoreq.7.5 g hydrochloride pyridostigmine lysine
.gtoreq.1.25 g ranitidine lysine .gtoreq.7.5 g bromide pyridoxine
lysine .gtoreq.1.25 g ribavirin lysine .gtoreq.7.5 g hydrochloride
ranitidine lysine .gtoreq.1.25 g riboflavin lysine .gtoreq.7.5 g
ribavirin lysine .gtoreq.1.25 g rizatriptan lysine .gtoreq.7.5 g
riboflavin lysine .gtoreq.1.25 g stavudine lysine .gtoreq.7.5 g
rizatriptan lysine .gtoreq.1.25 g sulfadiazine lysine .gtoreq.7.5 g
stavudine lysine .gtoreq.1.25 g sulfamethoxazole lysine .gtoreq.7.5
g sulfadiazine lysine .gtoreq.1.25 g sultamicillin lysine
.gtoreq.7.5 g sulfamethoxazole lysine .gtoreq.1.25 g sumatriptan
lysine .gtoreq.7.5 g sultamicillin lysine .gtoreq.1.25 g taltirelin
lysine .gtoreq.7.5 g sumatriptan lysine .gtoreq.1.25 g tegafur
lysine .gtoreq.7.5 g taltirelin lysine .gtoreq.1.25 g tenofovir
disoproxil lysine .gtoreq.7.5 g tegafur lysine .gtoreq.1.25 g
theophylline lysine .gtoreq.7.5 g tenofovir disoproxil lysine
.gtoreq.1.25 g thiamine lysine .gtoreq.7.5 g theophylline lysine
.gtoreq.1.25 g trimetazidine lysine .gtoreq.7.5 g thiamine lysine
.gtoreq.1.25 g trimethoprim lysine .gtoreq.7.5 g trimetazidine
lysine .gtoreq.1.25 g voglibose lysine .gtoreq.7.5 g trimethoprim
lysine .gtoreq.1.25 g zidovudine lysine .gtoreq.7.5 g voglibose
lysine .gtoreq.1.25 g zolmitriptan lysine .gtoreq.7.5 g zidovudine
lysine .gtoreq.1.25 g acetylcarnitine lysine .gtoreq.7.5 g
zolmitriptan lysine .gtoreq.1.25 g capecitabine lysine .gtoreq.7.5
g acetylcarnitine lysine .gtoreq.1.25 g cefaclor lysine .gtoreq.7.5
g capecitabine lysine .gtoreq.1.25 g cefixime lysine .gtoreq.7.5 g
cefaclor lysine .gtoreq.1.25 g cefmetazole lysine .gtoreq.7.5 g
cefixime lysine .gtoreq.1.25 g cefpodoxime proxetil lysine
.gtoreq.7.5 g cefmetazole lysine .gtoreq.1.25 g cefroxadine lysine
.gtoreq.7.5 g cefpodoxime proxetil lysine .gtoreq.1.25 g
alfoscerate lysine .gtoreq.7.5 g cefroxadine lysine .gtoreq.1.25 g
cilazapril lysine .gtoreq.7.5 g alfoscerate lysine .gtoreq.1.25 g
cimetropium bromide lysine .gtoreq.7.5 g cilazapril lysine
.gtoreq.1.25 g diacerein lysine .gtoreq.7.5 g cimetropium bromide
lysine .gtoreq.1.25 g erdosteine lysine .gtoreq.7.5 g diacerein
lysine .gtoreq.1.25 g famciclovir lysine .gtoreq.7.5 g erdosteine
lysine .gtoreq.1.25 g gemifloxacin lysine .gtoreq.7.5 g famciclovir
lysine .gtoreq.1.25 g levosulpiride lysine .gtoreq.7.5 g
gemifloxacin lysine .gtoreq.1.25 g nabumetone lysine .gtoreq.7.5 g
levosulpiride lysine .gtoreq.1.25 g oxiracetam lysine .gtoreq.7.5 g
nabumetone lysine .gtoreq.1.25 g phendimetrazine lysine .gtoreq.7.5
g oxiracetam lysine .gtoreq.1.25 g rabeprazole lysine .gtoreq.7.5 g
phendimetrazine lysine .gtoreq.1.25 g roxatidine acetate lysine
.gtoreq.7.5 g rabeprazole lysine .gtoreq.1.25 g tamsulosin lysine
.gtoreq.7.5 g roxatidine acetate lysine .gtoreq.1.25 g terazosin
lysine .gtoreq.7.5 g tamsulosin lysine .gtoreq.1.25 g thioctic
lysine .gtoreq.7.5 g terazosin lysine .gtoreq.1.25 g tosufloxacin
lysine .gtoreq.7.5 g thioctic lysine .gtoreq.1.25 g triflusal
lysine .gtoreq.7.5 g tosufloxacin lysine .gtoreq.1.25 g zaltoprofen
lysine .gtoreq.7.5 g triflusal lysine .gtoreq.1.25 g etidronic acid
lysine .gtoreq.7.5 g zaltoprofen lysine .gtoreq.1.25 g zoledronic
acid lysine .gtoreq.7.5 g etidronic acid lysine .gtoreq.1.25 g
clodronic acid lysine .gtoreq.7.5 g zoledronic acid lysine
.gtoreq.1.25 g tiludronic acid lysine .gtoreq.7.5 g zoledronic acid
lysine .gtoreq.1.3 g zoledronic acid lysine .gtoreq.1.6 g
zoledronic acid lysine .gtoreq.1.4 g zoledronic acid lysine
.gtoreq.1.7 g zoledronic acid lysine .gtoreq.1.8 g zoledronic acid
lysine .gtoreq.1.9 g clodronic acid lysine .gtoreq.1.25 g
pamidronic acid lysine .gtoreq.7.5 g tiludronic acid lysine
.gtoreq.1.25 g alendronic acid lysine .gtoreq.7.5 g pamidronic acid
lysine .gtoreq.1.25 g risedronic acid lysine .gtoreq.7.5 g
alendronic acid lysine .gtoreq.1.25 g ibandronic acid lysine
.gtoreq.7.5 g risedronic acid lysine .gtoreq.1.25 g abacavir
glycine .gtoreq.7.5 g ibandronic acid lysine .gtoreq.1.25 g
acarbose glycine .gtoreq.7.5 g abacavir glycine .gtoreq.1.25 g
acetazolamide glycine .gtoreq.7.5 g acarbose glycine .gtoreq.1.25 g
acyclovir glycine .gtoreq.7.5 g acetazolamide glycine .gtoreq.1.25
g albuterol (salbutamol) glycine .gtoreq.7.5 g acyclovir glycine
.gtoreq.1.25 g allopurinol glycine .gtoreq.7.5 g albuterol
(salbutamol) glycine .gtoreq.1.25 g amiloride glycine .gtoreq.7.5 g
allopurinol glycine .gtoreq.1.25 g amisulpride glycine .gtoreq.7.5
g amiloride glycine .gtoreq.1.25 g amlodipine glycine .gtoreq.7.5 g
amisulpride glycine .gtoreq.1.25 g amoxicillin glycine .gtoreq.7.5
g amlodipine glycine .gtoreq.1.25 g amphetamine glycine .gtoreq.7.5
g amoxicillin glycine .gtoreq.1.25 g atenolol glycine .gtoreq.7.5 g
amphetamine glycine .gtoreq.1.25 g atropine glycine .gtoreq.7.5 g
atenolol glycine .gtoreq.1.25 g azathioprine glycine .gtoreq.7.5 g
atropine glycine .gtoreq.1.25 g benserazide glycine .gtoreq.7.5 g
azathioprine glycine .gtoreq.1.25 g benznidazole glycine
.gtoreq.7.5 g benserazide glycine .gtoreq.1.25 g camostat glycine
.gtoreq.7.5 g benznidazole glycine .gtoreq.1.25 g captopril glycine
.gtoreq.7.5 g camostat glycine .gtoreq.1.25 g cefdinir glycine
.gtoreq.7.5 g captopril glycine .gtoreq.1.25 g cefotiam hexetil
glycine .gtoreq.7.5 g hydrochloride cefdinir glycine .gtoreq.1.25 g
cefprozil glycine .gtoreq.7.5 g cefotiam hexetil glycine
.gtoreq.1.25 g cefuroxime axetil glycine .gtoreq.7.5 g
hydrochloride cefprozil glycine .gtoreq.1.25 g chloramphenicol
glycine .gtoreq.7.5 g cefuroxime axetil glycine .gtoreq.1.25 g
cimetidine glycine .gtoreq.7.5 g chloramphenicol glycine
.gtoreq.1.25 g ciprofloxacin glycine .gtoreq.7.5 g cimetidine
glycine .gtoreq.1.25 g codeine glycine .gtoreq.7.5 g ciprofloxacin
glycine .gtoreq.1.25 g colchicine glycine .gtoreq.7.5 g codeine
glycine .gtoreq.1.25 g cyclophosphamide glycine .gtoreq.7.5 g
colchicine glycine .gtoreq.1.25 g dapsone glycine .gtoreq.7.5 g
cyclophosphamide glycine .gtoreq.1.25 g dexamethasone glycine
.gtoreq.7.5 g dapsone glycine .gtoreq.1.25 g didanosine glycine
.gtoreq.7.5 g dexamethasone glycine .gtoreq.1.25 g
diethylcarbamazine glycine .gtoreq.7.5 g didanosine glycine
.gtoreq.1.25 g methionine glycine .gtoreq.7.5 g diethylcarbamazine
glycine .gtoreq.1.25 g dolasetron glycine .gtoreq.7.5 g methionine
glycine .gtoreq.1.25 g doxifluridine glycine .gtoreq.7.5 g
dolasetron glycine .gtoreq.1.25 g doxycycline glycine .gtoreq.7.5 g
doxifluridine glycine .gtoreq.1.25 g ergonovine glycine .gtoreq.7.5
g doxycycline glycine .gtoreq.1.25 g erythromycin glycine
.gtoreq.7.5 g ethylsuccinate ergonovine glycine .gtoreq.1.25 g
ethambutol glycine .gtoreq.7.5 g erythromycin glycine .gtoreq.1.25
g ethosuximide glycine .gtoreq.7.5 g ethylsuccinate ethambutol
glycine .gtoreq.1.25 g famotidine glycine .gtoreq.7.5 g
ethosuximide glycine .gtoreq.1.25 g fluconazole glycine .gtoreq.7.5
g famotidine glycine .gtoreq.1.25 g folic acid glycine .gtoreq.7.5
g fluconazole glycine .gtoreq.1.25 g furosemide glycine .gtoreq.7.5
g folic acid glycine .gtoreq.1.25 g fursultiamine glycine
.gtoreq.7.5 g furosemide glycine .gtoreq.1.25 g gabapentin glycine
.gtoreq.7.5 g fursultiamine glycine .gtoreq.1.25 g glipizide
glycine .gtoreq.7.5 g gabapentin glycine .gtoreq.1.25 g granisetron
glycine .gtoreq.7.5 g glipizide glycine .gtoreq.1.25 g griseofulvin
glycine .gtoreq.7.5 g granisetron glycine .gtoreq.1.25 g
hydralazine glycine .gtoreq.7.5 g griseofulvin glycine .gtoreq.1.25
g hydrochlorothiazide glycine .gtoreq.7.5 g hydralazine glycine
.gtoreq.1.25 g imidapril glycine .gtoreq.7.5 g hydrochlorothiazide
glycine .gtoreq.1.25 g isoniazid glycine .gtoreq.7.5 g imidapril
glycine .gtoreq.1.25 g lamivudine glycine .gtoreq.7.5 g isoniazid
glycine .gtoreq.1.25 g l-carbocysteine glycine .gtoreq.7.5 g
lamivudine glycine .gtoreq.1.25 g levetiracetam glycine .gtoreq.7.5
g l-carbocysteine glycine .gtoreq.1.25 g levofloxacin glycine
.gtoreq.7.5 g levetiracetam glycine .gtoreq.1.25 g linezolid
glycine .gtoreq.7.5 g levofloxacin glycine .gtoreq.1.25 g
lisinopril glycine .gtoreq.7.5 g linezolid glycine .gtoreq.1.25 g
losartan glycine .gtoreq.7.5 g lisinopril glycine .gtoreq.1.25 g
methotrexate glycine .gtoreq.7.5 g losartan glycine .gtoreq.1.25 g
methyldopa glycine .gtoreq.7.5 g methotrexate glycine .gtoreq.1.25
g s-methylmethionine glycine .gtoreq.7.5 g methyldopa glycine
.gtoreq.1.25 g metoclopramide glycine .gtoreq.7.5 g
s-methylmethionine glycine .gtoreq.1.25 g metronidazole glycine
.gtoreq.7.5 g metoclopramide glycine .gtoreq.1.25 g moxifloxacin
glycine .gtoreq.7.5 g metronidazole glycine .gtoreq.1.25 g
nalidixic acid glycine .gtoreq.7.5 g moxifloxacin glycine
.gtoreq.1.25 g nicorandil glycine .gtoreq.7.5 g nalidixic acid
glycine .gtoreq.1.25 g nifurtimox glycine .gtoreq.7.5 g nicorandil
glycine .gtoreq.1.25 g nitrofurantoin glycine .gtoreq.7.5 g
nifurtimox glycine .gtoreq.1.25 g nizatidine glycine .gtoreq.7.5 g
nitrofurantoin glycine .gtoreq.1.25 g nystatin glycine .gtoreq.7.5
g nizatidine glycine .gtoreq.1.25 g ondansetron glycine .gtoreq.7.5
g nystatin glycine .gtoreq.1.25 g oseltamivir glycine .gtoreq.7.5 g
ondansetron glycine .gtoreq.1.25 g oxcarbazepine glycine
.gtoreq.7.5 g oseltamivir glycine .gtoreq.1.25 g penicillamine
glycine .gtoreq.7.5 g oxcarbazepine glycine .gtoreq.1.25 g
perindopril glycine .gtoreq.7.5 g penicillamine glycine
.gtoreq.1.25 g phenobarbital glycine .gtoreq.7.5 g perindopril
glycine .gtoreq.1.25 g phenoxymethylpenicillin glycine .gtoreq.7.5
g phenobarbital glycine .gtoreq.1.25 g pravastatin sodium glycine
.gtoreq.7.5 g phenoxymethylpenicillin glycine .gtoreq.1.25 g
prednisolone glycine .gtoreq.7.5 g pravastatin sodium glycine
.gtoreq.1.25 g primaquine glycine .gtoreq.7.5 g prednisolone
glycine .gtoreq.1.25 g procaterol glycine .gtoreq.7.5 g primaquine
glycine .gtoreq.1.25 g propylthiouracil glycine .gtoreq.7.5 g
procaterol glycine .gtoreq.1.25 g pseudoephedrine glycine
.gtoreq.7.5 g propylthiouracil glycine .gtoreq.1.25 g pyrazinamide
glycine .gtoreq.7.5 g pseudoephedrine glycine .gtoreq.1.25 g
pyridostigmine glycine .gtoreq.7.5 g bromide pyrazinamide glycine
.gtoreq.1.25 g pyridoxine glycine .gtoreq.7.5 g hydrochloride
pyridostigmine glycine .gtoreq.1.25 g ranitidine glycine
.gtoreq.7.5 g bromide pyridoxine glycine .gtoreq.1.25 g ribavirin
glycine .gtoreq.7.5 g hydrochloride ranitidine glycine .gtoreq.1.25
g riboflavin glycine .gtoreq.7.5 g ribavirin glycine .gtoreq.1.25 g
rizatriptan glycine .gtoreq.7.5 g riboflavin glycine .gtoreq.1.25 g
stavudine glycine .gtoreq.7.5 g rizatriptan glycine .gtoreq.1.25 g
sulfadiazine glycine .gtoreq.7.5 g stavudine glycine .gtoreq.1.25 g
sulfamethoxazole glycine .gtoreq.7.5 g sulfadiazine glycine
.gtoreq.1.25 g sultamicillin glycine .gtoreq.7.5 g sulfamethoxazole
glycine .gtoreq.1.25 g sumatriptan glycine .gtoreq.7.5 g
sultamicillin glycine .gtoreq.1.25 g taltirelin glycine .gtoreq.7.5
g sumatriptan glycine .gtoreq.1.25 g tegafur glycine .gtoreq.7.5 g
taltirelin glycine .gtoreq.1.25 g tenofovir disoproxil glycine
.gtoreq.7.5 g tegafur glycine .gtoreq.1.25 g theophylline glycine
.gtoreq.7.5 g tenofovir disoproxil glycine .gtoreq.1.25 g thiamine
glycine .gtoreq.7.5 g theophylline glycine .gtoreq.1.25 g
trimetazidine glycine .gtoreq.7.5 g thiamine glycine .gtoreq.1.25 g
trimethoprim glycine .gtoreq.7.5 g trimetazidine glycine
.gtoreq.1.25 g voglibose glycine .gtoreq.7.5 g trimethoprim glycine
.gtoreq.1.25 g zidovudine glycine .gtoreq.7.5 g voglibose glycine
.gtoreq.1.25 g zolmitriptan glycine .gtoreq.7.5 g zidovudine
glycine .gtoreq.1.25 g acetylcarnitine glycine .gtoreq.7.5 g
zolmitriptan glycine .gtoreq.1.25 g capecitabine glycine
.gtoreq.7.5 g acetylcarnitine glycine .gtoreq.1.25 g cefaclor
glycine .gtoreq.7.5 g capecitabine glycine .gtoreq.1.25 g cefixime
glycine .gtoreq.7.5 g cefaclor glycine .gtoreq.1.25 g cefmetazole
glycine .gtoreq.7.5 g cefixime glycine .gtoreq.1.25 g cefpodoxime
proxetil glycine .gtoreq.7.5 g cefmetazole glycine .gtoreq.1.25 g
cefroxadine glycine .gtoreq.7.5 g cefpodoxime proxetil glycine
.gtoreq.1.25 g alfoscerate glycine .gtoreq.7.5 g cefroxadine
glycine .gtoreq.1.25 g cilazapril glycine .gtoreq.7.5 g alfoscerate
glycine .gtoreq.1.25 g cimetropium bromide glycine .gtoreq.7.5 g
cilazapril glycine .gtoreq.1.25 g diacerein glycine .gtoreq.7.5 g
cimetropium bromide glycine .gtoreq.1.25 g erdosteine glycine
.gtoreq.7.5 g diacerein glycine .gtoreq.1.25 g famciclovir glycine
.gtoreq.7.5 g erdosteine glycine .gtoreq.1.25 g gemifloxacin
glycine .gtoreq.7.5 g famciclovir glycine .gtoreq.1.25 g
levosulpiride glycine .gtoreq.7.5 g gemifloxacin glycine
.gtoreq.1.25 g nabumetone glycine .gtoreq.7.5 g levosulpiride
glycine .gtoreq.1.25 g oxiracetam glycine .gtoreq.7.5 g nabumetone
glycine .gtoreq.1.25 g phendimetrazine glycine .gtoreq.7.5 g
oxiracetam glycine .gtoreq.1.25 g rabeprazole glycine .gtoreq.7.5 g
phendimetrazine glycine .gtoreq.1.25 g roxatidine acetate glycine
.gtoreq.7.5 g rabeprazole glycine .gtoreq.1.25 g tamsulosin glycine
.gtoreq.7.5 g roxatidine acetate glycine .gtoreq.1.25 g terazosin
glycine .gtoreq.7.5 g tamsulosin glycine .gtoreq.1.25 g thioctic
glycine .gtoreq.7.5 g terazosin glycine .gtoreq.1.25 g tosufloxacin
glycine .gtoreq.7.5 g thioctic glycine .gtoreq.1.25 g triflusal
glycine .gtoreq.7.5 g tosufloxacin glycine .gtoreq.1.25 g
zaltoprofen glycine .gtoreq.7.5 g triflusal glycine .gtoreq.1.25 g
etidronic acid glycine .gtoreq.7.5 g zaltoprofen glycine
.gtoreq.1.25 g zoledronic acid glycine .gtoreq.7.5 g etidronic acid
glycine .gtoreq.1.25 g clodronic acid glycine .gtoreq.7.5 g
zoledronic acid glycine .gtoreq.1.25 g tiludronic acid glycine
.gtoreq.7.5 g clodronic acid glycine .gtoreq.1.25 g pamidronic acid
glycine .gtoreq.7.5 g tiludronic acid glycine .gtoreq.1.25 g
alendronic acid glycine .gtoreq.7.5 g pamidronic acid glycine
.gtoreq.1.25 g risedronic acid glycine .gtoreq.7.5 g alendronic
acid glycine .gtoreq.1.25 g ibandronic acid glycine .gtoreq.7.5 g
risedronic acid glycine .gtoreq.1.25 g abacavir lysine .gtoreq.10 g
ibandronic acid glycine .gtoreq.1.25 g acarbose lysine .gtoreq.10 g
abacavir lysine .gtoreq.1.5 g acetazolamide lysine .gtoreq.10 g
acarbose lysine .gtoreq.1.5 g acyclovir lysine .gtoreq.10 g
acetazolamide lysine .gtoreq.1.5 g albuterol (salbutamol) lysine
.gtoreq.10 g acyclovir lysine .gtoreq.1.5 g allopurinol lysine
.gtoreq.10 g albuterol (salbutamol) lysine .gtoreq.1.5 g amiloride
lysine .gtoreq.10 g allopurinol lysine .gtoreq.1.5 g amisulpride
lysine .gtoreq.10 g amiloride lysine .gtoreq.1.5 g amlodipine
lysine .gtoreq.10 g amisulpride lysine .gtoreq.1.5 g amoxicillin
lysine .gtoreq.10 g amlodipine lysine .gtoreq.1.5 g amphetamine
lysine .gtoreq.10 g amoxicillin lysine .gtoreq.1.5 g atenolol
lysine .gtoreq.10 g amphetamine lysine .gtoreq.1.5 g atropine
lysine .gtoreq.10 g atenolol lysine .gtoreq.1.5 g azathioprine
lysine .gtoreq.10 g atropine lysine .gtoreq.1.5 g benserazide
lysine .gtoreq.10 g azathioprine lysine .gtoreq.1.5 g benznidazole
lysine .gtoreq.10 g benserazide lysine .gtoreq.1.5 g camostat
lysine .gtoreq.10 g benznidazole lysine .gtoreq.1.5 g captopril
lysine .gtoreq.10 g camostat lysine .gtoreq.1.5 g cefdinir lysine
.gtoreq.10 g captopril lysine .gtoreq.1.5 g cefotiam hexetil lysine
.gtoreq.10 g hydrochloride cefdinir lysine .gtoreq.1.5 g cefprozil
lysine .gtoreq.10 g cefotiam hexetil lysine .gtoreq.1.5 g
cefuroxime axetil lysine .gtoreq.10 g hydrochloride cefprozil
lysine .gtoreq.1.5 g chloramphenicol lysine .gtoreq.10 g cefuroxime
axetil lysine .gtoreq.1.5 g cimetidine lysine .gtoreq.10 g
chloramphenicol lysine .gtoreq.1.5 g ciprofloxacin lysine
.gtoreq.10 g cimetidine lysine .gtoreq.1.5 g codeine lysine
.gtoreq.10 g ciprofloxacin lysine .gtoreq.1.5 g colchicine lysine
.gtoreq.10 g codeine lysine .gtoreq.1.5 g cyclophosphamide lysine
.gtoreq.10 g colchicine lysine .gtoreq.1.5 g dapsone lysine
.gtoreq.10 g cyclophosphamide lysine .gtoreq.1.5 g dexamethasone
lysine .gtoreq.10 g dapsone lysine .gtoreq.1.5 g didanosine lysine
.gtoreq.10 g dexamethasone lysine .gtoreq.1.5 g diethylcarbamazine
lysine .gtoreq.10 g didanosine lysine .gtoreq.1.5 g methionine
lysine .gtoreq.10 g diethylcarbamazine lysine .gtoreq.1.5 g
dolasetron lysine .gtoreq.10 g methionine lysine .gtoreq.1.5 g
doxifluridine lysine .gtoreq.10 g dolasetron lysine .gtoreq.1.5 g
doxycycline lysine .gtoreq.10 g doxifluridine lysine .gtoreq.1.5 g
ergonovine lysine .gtoreq.10 g doxycycline lysine .gtoreq.1.5 g
erythromycin lysine .gtoreq.10 g ethylsuccinate ergonovine lysine
.gtoreq.1.5 g ethambutol lysine .gtoreq.10 g erythromycin lysine
.gtoreq.1.5 g ethosuximide lysine .gtoreq.10 g ethylsuccinate
ethambutol lysine .gtoreq.1.5 g famotidine lysine .gtoreq.10 g
ethosuximide lysine .gtoreq.1.5 g fluconazole lysine .gtoreq.10 g
famotidine lysine .gtoreq.1.5 g folic acid lysine .gtoreq.10 g
fluconazole lysine .gtoreq.1.5 g furosemide lysine .gtoreq.10 g
folic acid lysine .gtoreq.1.5 g fursultiamine lysine .gtoreq.10 g
furosemide lysine .gtoreq.1.5 g gabapentin lysine .gtoreq.10 g
fursultiamine lysine .gtoreq.1.5 g glipizide lysine .gtoreq.10 g
gabapentin lysine .gtoreq.1.5 g granisetron lysine .gtoreq.10 g
glipizide lysine .gtoreq.1.5 g griseofulvin lysine .gtoreq.10 g
granisetron lysine .gtoreq.1.5 g hydralazine lysine .gtoreq.10 g
griseofulvin lysine .gtoreq.1.5 g hydrochlorothiazide lysine
.gtoreq.10 g hydralazine lysine .gtoreq.1.5 g imidapril lysine
.gtoreq.10 g hydrochlorothiazide lysine .gtoreq.1.5 g isoniazid
lysine .gtoreq.10 g imidapril lysine .gtoreq.1.5 g lamivudine
lysine .gtoreq.10 g isoniazid lysine .gtoreq.1.5 g l-carbocysteine
lysine .gtoreq.10 g lamivudine lysine .gtoreq.1.5 g levetiracetam
lysine .gtoreq.10 g l-carbocysteine lysine .gtoreq.1.5 g
levofloxacin lysine .gtoreq.10 g levetiracetam lysine .gtoreq.1.5 g
linezolid lysine .gtoreq.10 g levofloxacin lysine .gtoreq.1.5 g
lisinopril lysine .gtoreq.10 g linezolid lysine .gtoreq.1.5 g
losartan lysine .gtoreq.10 g lisinopril lysine .gtoreq.1.5 g
methotrexate lysine .gtoreq.10 g losartan lysine .gtoreq.1.5 g
methyldopa lysine .gtoreq.10 g methotrexate lysine .gtoreq.1.5 g
s-methylmethionine lysine .gtoreq.10 g methyldopa lysine
.gtoreq.1.5 g metoclopramide lysine .gtoreq.10 g s-methylmethionine
lysine .gtoreq.1.5 g metronidazole lysine .gtoreq.10 g
metoclopramide lysine .gtoreq.1.5 g moxifloxacin lysine .gtoreq.10
g metronidazole lysine .gtoreq.1.5 g nalidixic acid lysine
.gtoreq.10 g moxifloxacin lysine .gtoreq.1.5 g nicorandil lysine
.gtoreq.10 g nalidixic acid lysine .gtoreq.1.5 g nifurtimox lysine
.gtoreq.10 g nicorandil lysine .gtoreq.1.5 g nitrofurantoin lysine
.gtoreq.10 g nifurtimox lysine .gtoreq.1.5 g nizatidine lysine
.gtoreq.10 g nitrofurantoin lysine .gtoreq.1.5 g nystatin lysine
.gtoreq.10 g nizatidine lysine .gtoreq.1.5 g ondansetron lysine
.gtoreq.10 g nystatin lysine .gtoreq.1.5 g oseltamivir lysine
.gtoreq.10 g ondansetron lysine .gtoreq.1.5 g oxcarbazepine lysine
.gtoreq.10 g oseltamivir lysine .gtoreq.1.5 g penicillamine lysine
.gtoreq.10 g oxcarbazepine lysine .gtoreq.1.5 g perindopril lysine
.gtoreq.10 g penicillamine lysine .gtoreq.1.5 g phenobarbital
lysine .gtoreq.10 g perindopril lysine .gtoreq.1.5 g
phenoxymethylpenicillin lysine .gtoreq.10 g phenobarbital lysine
.gtoreq.1.5 g pravastatin sodium lysine .gtoreq.10 g
phenoxymethylpenicillin lysine .gtoreq.1.5 g prednisolone lysine
.gtoreq.10 g pravastatin sodium lysine .gtoreq.1.5 g primaquine
lysine .gtoreq.10 g prednisolone lysine .gtoreq.1.5 g procaterol
lysine .gtoreq.10 g primaquine lysine .gtoreq.1.5 g
propylthiouracil lysine .gtoreq.10 g procaterol lysine .gtoreq.1.5
g pseudoephedrine lysine .gtoreq.10 g propylthiouracil lysine
.gtoreq.1.5 g pyrazinamide lysine .gtoreq.10 g pseudoephedrine
lysine .gtoreq.1.5 g pyridostigmine lysine .gtoreq.10 g bromide
pyrazinamide lysine .gtoreq.1.5 g pyridoxine lysine .gtoreq.10 g
hydrochloride pyridostigmine lysine .gtoreq.1.5 g ranitidine lysine
.gtoreq.10 g bromide pyridoxine lysine .gtoreq.1.5 g ribavirin
lysine .gtoreq.10 g hydrochloride ranitidine lysine .gtoreq.1.5 g
riboflavin lysine .gtoreq.10 g ribavirin lysine .gtoreq.1.5 g
rizatriptan lysine .gtoreq.10 g riboflavin lysine .gtoreq.1.5 g
stavudine lysine .gtoreq.10 g rizatriptan lysine .gtoreq.1.5 g
sulfadiazine lysine .gtoreq.10 g stavudine lysine .gtoreq.1.5 g
sulfamethoxazole lysine .gtoreq.10 g sulfadiazine lysine
.gtoreq.1.5 g sultamicillin lysine .gtoreq.10 g sulfamethoxazole
lysine .gtoreq.1.5 g sumatriptan lysine .gtoreq.10 g sultamicillin
lysine .gtoreq.1.5 g taltirelin lysine .gtoreq.10 g sumatriptan
lysine .gtoreq.1.5 g tegafur lysine .gtoreq.10 g taltirelin lysine
.gtoreq.1.5 g tenofovir disoproxil lysine .gtoreq.10 g tegafur
lysine .gtoreq.1.5 g theophylline lysine .gtoreq.10 g tenofovir
disoproxil lysine .gtoreq.1.5 g thiamine lysine .gtoreq.10 g
theophylline lysine .gtoreq.1.5 g trimetazidine lysine .gtoreq.10 g
thiamine lysine .gtoreq.1.5 g trimethoprim lysine .gtoreq.10 g
trimetazidine lysine .gtoreq.1.5 g voglibose lysine .gtoreq.10 g
trimethoprim lysine .gtoreq.1.5 g zidovudine lysine .gtoreq.10 g
voglibose lysine .gtoreq.1.5 g zolmitriptan lysine .gtoreq.10 g
zidovudine lysine .gtoreq.1.5 g acetylcarnitine lysine .gtoreq.10 g
zolmitriptan lysine .gtoreq.1.5 g capecitabine lysine .gtoreq.10 g
acetylcarnitine lysine .gtoreq.1.5 g cefaclor lysine .gtoreq.10 g
capecitabine lysine .gtoreq.1.5 g cefixime lysine .gtoreq.10 g
cefaclor lysine .gtoreq.1.5 g cefmetazole lysine .gtoreq.10 g
cefixime lysine .gtoreq.1.5 g cefpodoxime proxetil lysine
.gtoreq.10 g cefmetazole lysine .gtoreq.1.5 g cefroxadine lysine
.gtoreq.10 g cefpodoxime proxetil lysine .gtoreq.1.5 g alfoscerate
lysine .gtoreq.10 g cefroxadine lysine .gtoreq.1.5 g cilazapril
lysine .gtoreq.10 g alfoscerate lysine .gtoreq.1.5 g cimetropium
bromide lysine .gtoreq.10 g cilazapril lysine .gtoreq.1.5 g
diacerein lysine .gtoreq.10 g cimetropium bromide lysine
.gtoreq.1.5 g erdosteine lysine .gtoreq.10 g diacerein lysine
.gtoreq.1.5 g famciclovir lysine .gtoreq.10 g erdosteine lysine
.gtoreq.1.5 g gemifloxacin lysine .gtoreq.10 g famciclovir lysine
.gtoreq.1.5 g levosulpiride lysine .gtoreq.10 g gemifloxacin lysine
.gtoreq.1.5 g nabumetone lysine .gtoreq.10 g levosulpiride lysine
.gtoreq.1.5 g oxiracetam lysine .gtoreq.10 g nabumetone lysine
.gtoreq.1.5 g phendimetrazine lysine .gtoreq.10 g oxiracetam lysine
.gtoreq.1.5 g rabeprazole lysine .gtoreq.10 g phendimetrazine
lysine .gtoreq.1.5 g roxatidine acetate lysine .gtoreq.10 g
rabeprazole lysine .gtoreq.1.5 g tamsulosin lysine .gtoreq.10 g
roxatidine acetate lysine .gtoreq.1.5 g terazosin lysine .gtoreq.10
g tamsulosin lysine .gtoreq.1.5 g thioctic lysine .gtoreq.10 g
terazosin lysine .gtoreq.1.5 g tosufloxacin lysine .gtoreq.10 g
thioctic lysine .gtoreq.1.5 g triflusal lysine .gtoreq.10 g
tosufloxacin lysine .gtoreq.1.5 g zaltoprofen lysine .gtoreq.10 g
triflusal lysine .gtoreq.1.5 g etidronic acid lysine .gtoreq.10 g
zaltoprofen lysine .gtoreq.1.5 g zoledronic acid lysine .gtoreq.10
g etidronic acid lysine .gtoreq.1.5 g clodronic acid lysine
.gtoreq.10 g zoledronic acid lysine .gtoreq.1.5 g tiludronic acid
lysine .gtoreq.10 g clodronic acid lysine .gtoreq.1.5 g pamidronic
acid lysine .gtoreq.10 g tiludronic acid lysine .gtoreq.1.5 g
alendronic acid lysine .gtoreq.10 g pamidronic acid lysine
.gtoreq.1.5 g risedronic acid lysine .gtoreq.10 g alendronic acid
lysine .gtoreq.1.5 g ibandronic acid lysine .gtoreq.10 g risedronic
acid lysine .gtoreq.1.5 g abacavir glycine .gtoreq.10 g ibandronic
acid lysine .gtoreq.1.5 g acarbose glycine .gtoreq.10 g abacavir
glycine .gtoreq.1.5 g acetazolamide glycine .gtoreq.10 g acarbose
glycine .gtoreq.1.5 g acyclovir glycine .gtoreq.10 g acetazolamide
glycine .gtoreq.1.5 g albuterol (salbutamol) glycine .gtoreq.10 g
acyclovir glycine .gtoreq.1.5 g allopurinol glycine .gtoreq.10 g
albuterol (salbutamol) glycine .gtoreq.1.5 g amiloride glycine
.gtoreq.10 g allopurinol glycine .gtoreq.1.5 g amisulpride glycine
.gtoreq.10 g amiloride glycine .gtoreq.1.5 g amlodipine glycine
.gtoreq.10 g amisulpride glycine .gtoreq.1.5 g amoxicillin glycine
.gtoreq.10 g amlodipine glycine .gtoreq.1.5 g amphetamine glycine
.gtoreq.10 g amoxicillin glycine .gtoreq.1.5 g atenolol glycine
.gtoreq.10 g amphetamine glycine .gtoreq.1.5 g atropine glycine
.gtoreq.10 g atenolol glycine .gtoreq.1.5 g azathioprine glycine
.gtoreq.10 g atropine glycine .gtoreq.1.5 g benserazide glycine
.gtoreq.10 g azathioprine glycine .gtoreq.1.5 g benznidazole
glycine .gtoreq.10 g benserazide glycine .gtoreq.1.5 g camostat
glycine .gtoreq.10 g benznidazole glycine .gtoreq.1.5 g captopril
glycine .gtoreq.10 g camostat glycine .gtoreq.1.5 g cefdinir
glycine .gtoreq.10 g captopril glycine .gtoreq.1.5 g cefotiam
hexetil glycine .gtoreq.10 g hydrochloride cefdinir glycine
.gtoreq.1.5 g cefprozil glycine .gtoreq.10 g cefotiam hexetil
glycine .gtoreq.1.5 g cefuroxime axetil glycine .gtoreq.10 g
hydrochloride cefprozil glycine .gtoreq.1.5 g chloramphenicol
glycine .gtoreq.10 g cefuroxime axetil glycine .gtoreq.1.5 g
cimetidine glycine .gtoreq.10 g chloramphenicol glycine .gtoreq.1.5
g ciprofloxacin glycine .gtoreq.10 g cimetidine glycine .gtoreq.1.5
g codeine glycine .gtoreq.10 g ciprofloxacin glycine .gtoreq.1.5 g
colchicine glycine .gtoreq.10 g codeine glycine .gtoreq.1.5 g
cyclophosphamide glycine .gtoreq.10 g colchicine glycine
.gtoreq.1.5 g dapsone glycine .gtoreq.10 g cyclophosphamide glycine
.gtoreq.1.5 g dexamethasone glycine .gtoreq.10 g dapsone glycine
.gtoreq.1.5 g didanosine glycine .gtoreq.10 g dexamethasone glycine
.gtoreq.1.5 g diethylcarbamazine glycine .gtoreq.10 g didanosine
glycine .gtoreq.1.5 g methionine glycine .gtoreq.10 g
diethylcarbamazine glycine .gtoreq.1.5 g dolasetron glycine
.gtoreq.10 g methionine glycine .gtoreq.1.5 g doxifluridine glycine
.gtoreq.10 g dolasetron glycine .gtoreq.1.5 g doxycycline glycine
.gtoreq.10 g doxifluridine glycine .gtoreq.1.5 g ergonovine glycine
.gtoreq.10 g doxycycline glycine .gtoreq.1.5 g erythromycin glycine
.gtoreq.10 g ethylsuccinate ergonovine glycine .gtoreq.1.5 g
ethambutol glycine .gtoreq.10 g erythromycin glycine .gtoreq.1.5 g
ethosuximide glycine .gtoreq.10 g ethylsuccinate ethambutol glycine
.gtoreq.1.5 g famotidine glycine .gtoreq.10 g ethosuximide glycine
.gtoreq.1.5 g fluconazole glycine .gtoreq.10 g famotidine glycine
.gtoreq.1.5 g folic acid glycine .gtoreq.10 g fluconazole glycine
.gtoreq.1.5 g furosemide glycine .gtoreq.10 g folic acid glycine
.gtoreq.1.5 g fursultiamine glycine .gtoreq.10 g furosemide glycine
.gtoreq.1.5 g gabapentin glycine .gtoreq.10 g fursultiamine glycine
.gtoreq.1.5 g glipizide glycine .gtoreq.10 g gabapentin glycine
.gtoreq.1.5 g granisetron glycine .gtoreq.10 g glipizide glycine
.gtoreq.1.5 g griseofulvin glycine .gtoreq.10 g granisetron glycine
.gtoreq.1.5 g hydralazine glycine .gtoreq.10 g griseofulvin glycine
.gtoreq.1.5 g hydrochlorothiazide glycine .gtoreq.10 g hydralazine
glycine .gtoreq.1.5 g imidapril glycine .gtoreq.10 g
hydrochlorothiazide glycine .gtoreq.1.5 g isoniazid glycine
.gtoreq.10 g imidapril glycine .gtoreq.1.5 g lamivudine glycine
.gtoreq.10 g isoniazid glycine .gtoreq.1.5 g l-carbocysteine
glycine .gtoreq.10 g lamivudine glycine .gtoreq.1.5 g levetiracetam
glycine .gtoreq.10 g l-carbocysteine glycine .gtoreq.1.5 g
levofloxacin glycine .gtoreq.10 g levetiracetam glycine .gtoreq.1.5
g linezolid glycine .gtoreq.10 g levofloxacin glycine .gtoreq.1.5 g
lisinopril glycine .gtoreq.10 g linezolid glycine .gtoreq.1.5 g
losartan glycine .gtoreq.10 g lisinopril glycine .gtoreq.1.5 g
methotrexate glycine .gtoreq.10 g losartan glycine .gtoreq.1.5 g
methyldopa glycine .gtoreq.10 g methotrexate glycine .gtoreq.1.5 g
s-methylmethionine glycine .gtoreq.10 g methyldopa glycine
.gtoreq.1.5 g metoclopramide glycine .gtoreq.10 g
s-methylmethionine glycine .gtoreq.1.5 g metronidazole glycine
.gtoreq.10 g metoclopramide glycine .gtoreq.1.5 g moxifloxacin
glycine .gtoreq.10 g metronidazole glycine .gtoreq.1.5 g nalidixic
acid glycine .gtoreq.10 g moxifloxacin glycine .gtoreq.1.5 g
nicorandil glycine .gtoreq.10 g nalidixic acid glycine .gtoreq.1.5
g nifurtimox glycine .gtoreq.10 g nicorandil glycine .gtoreq.1.5 g
nitrofurantoin glycine .gtoreq.10 g nifurtimox glycine .gtoreq.1.5
g nizatidine glycine .gtoreq.10 g nitrofurantoin glycine
.gtoreq.1.5 g nystatin glycine .gtoreq.10 g nizatidine glycine
.gtoreq.1.5 g ondansetron glycine .gtoreq.10 g nystatin glycine
.gtoreq.1.5 g oseltamivir glycine .gtoreq.10 g ondansetron glycine
.gtoreq.1.5 g oxcarbazepine glycine .gtoreq.10 g oseltamivir
glycine .gtoreq.1.5 g penicillamine glycine .gtoreq.10 g
oxcarbazepine glycine .gtoreq.1.5 g perindopril glycine .gtoreq.10
g penicillamine glycine .gtoreq.1.5 g phenobarbital glycine
.gtoreq.10 g perindopril glycine .gtoreq.1.5 g
phenoxymethylpenicillin glycine .gtoreq.10 g phenobarbital glycine
.gtoreq.1.5 g pravastatin sodium glycine .gtoreq.10 g
phenoxymethylpenicillin glycine .gtoreq.1.5 g prednisolone glycine
.gtoreq.10 g pravastatin sodium glycine .gtoreq.1.5 g primaquine
glycine .gtoreq.10 g prednisolone glycine .gtoreq.1.5 g procaterol
glycine .gtoreq.10 g primaquine glycine .gtoreq.1.5 g
propylthiouracil glycine .gtoreq.10 g procaterol glycine
.gtoreq.1.5 g pseudoephedrine glycine .gtoreq.10 g propylthiouracil
glycine .gtoreq.1.5 g pyrazinamide glycine .gtoreq.10 g
pseudoephedrine glycine .gtoreq.1.5 g pyridostigmine glycine
.gtoreq.10 g bromide pyrazinamide glycine .gtoreq.1.5 g pyridoxine
glycine .gtoreq.10 g hydrochloride pyridostigmine glycine
.gtoreq.1.5 g ranitidine glycine .gtoreq.10 g bromide pyridoxine
glycine .gtoreq.1.5 g ribavirin glycine .gtoreq.10 g hydrochloride
ranitidine glycine .gtoreq.1.5 g riboflavin glycine .gtoreq.10 g
ribavirin glycine .gtoreq.1.5 g rizatriptan glycine .gtoreq.10 g
riboflavin glycine .gtoreq.1.5 g stavudine glycine .gtoreq.10 g
rizatriptan glycine .gtoreq.1.5 g sulfadiazine glycine .gtoreq.10 g
stavudine glycine .gtoreq.1.5 g sulfamethoxazole glycine .gtoreq.10
g sulfadiazine glycine .gtoreq.1.5 g sultamicillin glycine
.gtoreq.10 g sulfamethoxazole glycine .gtoreq.1.5 g sumatriptan
glycine .gtoreq.10 g sultamicillin glycine .gtoreq.1.5 g taltirelin
glycine .gtoreq.10 g sumatriptan glycine .gtoreq.1.5 g tegafur
glycine .gtoreq.10 g taltirelin glycine .gtoreq.1.5 g tenofovir
disoproxil glycine .gtoreq.10 g tegafur glycine .gtoreq.1.5 g
theophylline glycine .gtoreq.10 g tenofovir disoproxil glycine
.gtoreq.1.5 g thiamine glycine .gtoreq.10 g theophylline glycine
.gtoreq.1.5 g trimetazidine glycine .gtoreq.10 g thiamine glycine
.gtoreq.1.5 g trimethoprim glycine .gtoreq.10 g trimetazidine
glycine .gtoreq.1.5 g voglibose glycine .gtoreq.10 g trimethoprim
glycine .gtoreq.1.5 g zidovudine glycine .gtoreq.10 g voglibose
glycine .gtoreq.1.5 g zolmitriptan glycine .gtoreq.10 g zidovudine
glycine .gtoreq.1.5 g acetylcarnitine glycine .gtoreq.10 g
zolmitriptan glycine .gtoreq.1.5 g capecitabine glycine .gtoreq.10
g acetylcarnitine glycine .gtoreq.1.5 g cefaclor glycine .gtoreq.10
g capecitabine glycine .gtoreq.1.5 g cefixime glycine .gtoreq.10 g
cefaclor glycine .gtoreq.1.5 g cefmetazole glycine .gtoreq.10 g
cefixime glycine .gtoreq.1.5 g cefpodoxime proxetil glycine
.gtoreq.10 g cefmetazole glycine .gtoreq.1.5 g cefroxadine glycine
.gtoreq.10 g cefpodoxime proxetil glycine .gtoreq.1.5 g alfoscerate
glycine .gtoreq.10 g cefroxadine glycine .gtoreq.1.5 g cilazapril
glycine .gtoreq.10 g alfoscerate glycine .gtoreq.1.5 g cimetropium
bromide glycine .gtoreq.10 g cilazapril glycine .gtoreq.1.5 g
diacerein glycine .gtoreq.10 g cimetropium bromide glycine
.gtoreq.1.5 g erdosteine glycine .gtoreq.10 g diacerein glycine
.gtoreq.1.5 g famciclovir glycine .gtoreq.10 g erdosteine glycine
.gtoreq.1.5 g gemifloxacin glycine .gtoreq.10 g famciclovir glycine
.gtoreq.1.5 g levosulpiride glycine .gtoreq.10 g gemifloxacin
glycine .gtoreq.1.5 g nabumetone glycine .gtoreq.10 g levosulpiride
glycine .gtoreq.1.5 g oxiracetam glycine .gtoreq.10 g nabumetone
glycine .gtoreq.1.5 g phendimetrazine glycine .gtoreq.10 g
oxiracetam glycine .gtoreq.1.5 g rabeprazole glycine .gtoreq.10 g
phendimetrazine glycine .gtoreq.1.5 g roxatidine acetate glycine
.gtoreq.10 g rabeprazole glycine .gtoreq.1.5 g tamsulosin glycine
.gtoreq.10 g roxatidine acetate glycine .gtoreq.1.5 g terazosin
glycine .gtoreq.10 g tamsulosin glycine .gtoreq.1.5 g thioctic
glycine .gtoreq.10 g terazosin glycine .gtoreq.1.5 g tosufloxacin
glycine .gtoreq.10 g thioctic glycine .gtoreq.1.5 g triflusal
glycine .gtoreq.10 g tosufloxacin glycine .gtoreq.1.5 g zaltoprofen
glycine .gtoreq.10 g triflusal glycine .gtoreq.1.5 g etidronic acid
glycine .gtoreq.10 g zaltoprofen glycine .gtoreq.1.5 g zoledronic
acid glycine .gtoreq.10 g etidronic acid glycine .gtoreq.1.5 g
clodronic acid glycine .gtoreq.10 g zoledronic acid glycine
.gtoreq.1.5 g tiludronic acid glycine .gtoreq.10 g clodronic acid
glycine .gtoreq.1.5 g pamidronic acid glycine .gtoreq.10 g
tiludronic acid glycine .gtoreq.1.5 g alendronic acid glycine
.gtoreq.10 g pamidronic acid glycine .gtoreq.1.5 g risedronic acid
glycine .gtoreq.10 g alendronic acid glycine .gtoreq.1.5 g
ibandronic acid glycine .gtoreq.10 g risedronic acid glycine
.gtoreq.1.5 g abacavir lysine .gtoreq.15 g ibandronic acid glycine
.gtoreq.1.5 g acarbose lysine .gtoreq.15 g abacavir lysine
.gtoreq.1.75 g acetazolamide lysine .gtoreq.15 g acarbose lysine
.gtoreq.1.75 g acyclovir lysine .gtoreq.15 g acetazolamide lysine
.gtoreq.1.75 g albuterol (salbutamol) lysine .gtoreq.15 g acyclovir
lysine .gtoreq.1.75 g allopurinol lysine .gtoreq.15 g albuterol
(salbutamol) lysine .gtoreq.1.75 g amiloride lysine .gtoreq.15 g
allopurinol lysine .gtoreq.1.75 g amisulpride lysine .gtoreq.15 g
amiloride lysine .gtoreq.1.75 g amlodipine lysine .gtoreq.15 g
amisulpride lysine .gtoreq.1.75 g amoxicillin lysine .gtoreq.15 g
amlodipine lysine .gtoreq.1.75 g amphetamine lysine .gtoreq.15 g
amoxicillin lysine .gtoreq.1.75 g atenolol lysine .gtoreq.15 g
amphetamine lysine .gtoreq.1.75 g atropine lysine .gtoreq.15 g
atenolol lysine .gtoreq.1.75 g azathioprine lysine .gtoreq.15 g
atropine lysine .gtoreq.1.75 g benserazide lysine .gtoreq.15 g
azathioprine lysine .gtoreq.1.75 g benznidazole lysine .gtoreq.15 g
benserazide lysine .gtoreq.1.75 g camostat lysine .gtoreq.15 g
benznidazole lysine .gtoreq.1.75 g captopril lysine .gtoreq.15 g
camostat lysine .gtoreq.1.75 g cefdinir lysine .gtoreq.15 g
captopril lysine .gtoreq.1.75 g cefotiam hexetil lysine .gtoreq.15
g hydrochloride cefdinir lysine .gtoreq.1.75 g cefprozil lysine
.gtoreq.15 g cefotiam hexetil lysine .gtoreq.1.75 g cefuroxime
axetil lysine .gtoreq.15 g hydrochloride cefprozil lysine
.gtoreq.1.75 g chloramphenicol lysine .gtoreq.15 g cefuroxime
axetil lysine .gtoreq.1.75 g cimetidine lysine .gtoreq.15 g
chloramphenicol lysine .gtoreq.1.75 g ciprofloxacin lysine
.gtoreq.15 g cimetidine lysine .gtoreq.1.75 g codeine lysine
.gtoreq.15 g ciprofloxacin lysine .gtoreq.1.75 g colchicine lysine
.gtoreq.15 g codeine lysine .gtoreq.1.75 g cyclophosphamide lysine
.gtoreq.15 g colchicine lysine .gtoreq.1.75 g dapsone lysine
.gtoreq.15 g cyclophosphamide lysine .gtoreq.1.75 g dexamethasone
lysine .gtoreq.15 g dapsone lysine .gtoreq.1.75 g didanosine lysine
.gtoreq.15 g dexamethasone lysine .gtoreq.1.75 g diethylcarbamazine
lysine .gtoreq.15 g didanosine lysine .gtoreq.1.75 g methionine
lysine .gtoreq.15 g diethylcarbamazine lysine .gtoreq.1.75 g
dolasetron lysine .gtoreq.15 g methionine lysine .gtoreq.1.75 g
doxifluridine lysine .gtoreq.15 g dolasetron lysine .gtoreq.1.75 g
doxycycline lysine .gtoreq.15 g doxifluridine lysine .gtoreq.1.75 g
ergonovine lysine .gtoreq.15 g doxycycline lysine .gtoreq.1.75 g
erythromycin lysine .gtoreq.15 g ethylsuccinate ergonovine lysine
.gtoreq.1.75 g ethambutol lysine .gtoreq.15 g erythromycin lysine
.gtoreq.1.75 g ethosuximide lysine .gtoreq.15 g ethylsuccinate
ethambutol lysine .gtoreq.1.75 g famotidine lysine .gtoreq.15 g
ethosuximide lysine .gtoreq.1.75 g fluconazole lysine .gtoreq.15 g
famotidine lysine .gtoreq.1.75 g folic acid lysine .gtoreq.15 g
fluconazole lysine .gtoreq.1.75 g furosemide lysine .gtoreq.15 g
folic acid lysine .gtoreq.1.75 g fursultiamine lysine .gtoreq.15 g
furosemide lysine .gtoreq.1.75 g gabapentin lysine .gtoreq.15 g
fursultiamine lysine .gtoreq.1.75 g glipizide lysine .gtoreq.15 g
gabapentin lysine .gtoreq.1.75 g granisetron lysine .gtoreq.15 g
glipizide lysine .gtoreq.1.75 g griseofulvin lysine .gtoreq.15 g
granisetron lysine .gtoreq.1.75 g hydralazine lysine .gtoreq.15 g
griseofulvin lysine .gtoreq.1.75 g hydrochlorothiazide lysine
.gtoreq.15 g hydralazine lysine .gtoreq.1.75 g imidapril lysine
.gtoreq.15 g hydrochlorothiazide lysine .gtoreq.1.75 g isoniazid
lysine .gtoreq.15 g imidapril lysine .gtoreq.1.75 g lamivudine
lysine .gtoreq.15 g isoniazid lysine .gtoreq.1.75 g l-carbocysteine
lysine .gtoreq.15 g lamivudine lysine .gtoreq.1.75 g levetiracetam
lysine .gtoreq.15 g l-carbocysteine lysine .gtoreq.1.75 g
levofloxacin lysine .gtoreq.15 g levetiracetam lysine .gtoreq.1.75
g linezolid lysine .gtoreq.15 g levofloxacin lysine .gtoreq.1.75 g
lisinopril lysine .gtoreq.15 g linezolid lysine .gtoreq.1.75 g
losartan lysine .gtoreq.15 g lisinopril lysine .gtoreq.1.75 g
methotrexate lysine .gtoreq.15 g losartan lysine .gtoreq.1.75 g
methyldopa lysine .gtoreq.15 g methotrexate lysine .gtoreq.1.75 g
s-methylmethionine lysine .gtoreq.15 g methyldopa lysine
.gtoreq.1.75 g metoclopramide lysine .gtoreq.15 g
s-methylmethionine lysine .gtoreq.1.75 g metronidazole lysine
.gtoreq.15 g metoclopramide lysine .gtoreq.1.75 g moxifloxacin
lysine .gtoreq.15 g metronidazole lysine .gtoreq.1.75 g nalidixic
acid lysine .gtoreq.15 g moxifloxacin lysine .gtoreq.1.75 g
nicorandil lysine .gtoreq.15 g nalidixic acid lysine .gtoreq.1.75 g
nifurtimox lysine .gtoreq.15 g nicorandil lysine .gtoreq.1.75 g
nitrofurantoin lysine .gtoreq.15 g nifurtimox lysine .gtoreq.1.75 g
nizatidine lysine .gtoreq.15 g nitrofurantoin lysine .gtoreq.1.75 g
nystatin lysine .gtoreq.15 g nizatidine lysine .gtoreq.1.75 g
ondansetron lysine .gtoreq.15 g nystatin lysine .gtoreq.1.75 g
oseltamivir lysine .gtoreq.15 g ondansetron lysine .gtoreq.1.75 g
oxcarbazepine lysine .gtoreq.15 g oseltamivir lysine .gtoreq.1.75 g
penicillamine lysine .gtoreq.15 g oxcarbazepine lysine .gtoreq.1.75
g perindopril lysine .gtoreq.15 g penicillamine lysine .gtoreq.1.75
g phenobarbital lysine .gtoreq.15 g perindopril lysine .gtoreq.1.75
g phenoxymethylpenicillin lysine .gtoreq.15 g phenobarbital lysine
.gtoreq.1.75 g pravastatin sodium lysine .gtoreq.15 g
phenoxymethylpenicillin lysine .gtoreq.1.75 g prednisolone lysine
.gtoreq.15 g pravastatin sodium lysine .gtoreq.1.75 g primaquine
lysine .gtoreq.15 g prednisolone lysine .gtoreq.1.75 g procaterol
lysine .gtoreq.15 g primaquine lysine .gtoreq.1.75 g
propylthiouracil lysine .gtoreq.15 g procaterol lysine .gtoreq.1.75
g pseudoephedrine lysine .gtoreq.15 g propylthiouracil lysine
.gtoreq.1.75 g pyrazinamide lysine .gtoreq.15 g pseudoephedrine
lysine .gtoreq.1.75 g pyridostigmine lysine .gtoreq.15 g bromide
pyrazinamide lysine .gtoreq.1.75 g pyridoxine lysine .gtoreq.15 g
hydrochloride pyridostigmine lysine .gtoreq.1.75 g ranitidine
lysine .gtoreq.15 g bromide pyridoxine lysine .gtoreq.1.75 g
ribavirin lysine .gtoreq.15 g hydrochloride ranitidine lysine
.gtoreq.1.75 g riboflavin lysine .gtoreq.15 g ribavirin lysine
.gtoreq.1.75 g rizatriptan lysine .gtoreq.15 g riboflavin lysine
.gtoreq.1.75 g stavudine lysine .gtoreq.15 g rizatriptan lysine
.gtoreq.1.75 g sulfadiazine lysine .gtoreq.15 g stavudine lysine
.gtoreq.1.75 g sulfamethoxazole lysine .gtoreq.15 g sulfadiazine
lysine .gtoreq.1.75 g sultamicillin lysine .gtoreq.15 g
sulfamethoxazole lysine .gtoreq.1.75 g sumatriptan lysine
.gtoreq.15 g sultamicillin lysine .gtoreq.1.75 g taltirelin lysine
.gtoreq.15 g sumatriptan lysine .gtoreq.1.75 g tegafur lysine
.gtoreq.15 g taltirelin lysine .gtoreq.1.75 g tenofovir disoproxil
lysine .gtoreq.15 g tegafur lysine .gtoreq.1.75 g theophylline
lysine .gtoreq.15 g tenofovir disoproxil lysine .gtoreq.1.75 g
thiamine lysine .gtoreq.15 g theophylline lysine .gtoreq.1.75 g
trimetazidine lysine .gtoreq.15 g thiamine lysine .gtoreq.1.75 g
trimethoprim lysine .gtoreq.15 g trimetazidine lysine .gtoreq.1.75
g voglibose lysine .gtoreq.15 g trimethoprim lysine .gtoreq.1.75 g
zidovudine lysine .gtoreq.15 g voglibose lysine .gtoreq.1.75 g
zolmitriptan lysine .gtoreq.15 g zidovudine lysine .gtoreq.1.75 g
acetylcarnitine lysine .gtoreq.15 g zolmitriptan lysine
.gtoreq.1.75 g capecitabine lysine .gtoreq.15 g acetylcarnitine
lysine .gtoreq.1.75 g cefaclor lysine .gtoreq.15 g capecitabine
lysine .gtoreq.1.75 g cefixime lysine .gtoreq.15 g cefaclor lysine
.gtoreq.1.75 g cefmetazole lysine .gtoreq.15 g cefixime lysine
.gtoreq.1.75 g cefpodoxime proxetil lysine .gtoreq.15 g cefmetazole
lysine .gtoreq.1.75 g cefroxadine lysine .gtoreq.15 g cefpodoxime
proxetil lysine .gtoreq.1.75 g alfoscerate lysine .gtoreq.15 g
cefroxadine lysine .gtoreq.1.75 g cilazapril lysine .gtoreq.15 g
alfoscerate lysine .gtoreq.1.75 g cimetropium bromide lysine
.gtoreq.15 g cilazapril lysine .gtoreq.1.75 g diacerein lysine
.gtoreq.15 g cimetropium bromide lysine .gtoreq.1.75 g erdosteine
lysine .gtoreq.15 g diacerein lysine .gtoreq.1.75 g famciclovir
lysine .gtoreq.15 g erdosteine lysine .gtoreq.1.75 g gemifloxacin
lysine .gtoreq.15 g famciclovir lysine .gtoreq.1.75 g levosulpiride
lysine .gtoreq.15 g gemifloxacin lysine .gtoreq.1.75 g nabumetone
lysine .gtoreq.15 g levosulpiride lysine .gtoreq.1.75 g oxiracetam
lysine .gtoreq.15 g nabumetone lysine .gtoreq.1.75 g
phendimetrazine lysine .gtoreq.15 g oxiracetam lysine .gtoreq.1.75
g rabeprazole lysine .gtoreq.15 g phendimetrazine lysine
.gtoreq.1.75 g roxatidine acetate lysine .gtoreq.15 g rabeprazole
lysine .gtoreq.1.75 g tamsulosin lysine .gtoreq.15 g roxatidine
acetate lysine .gtoreq.1.75 g terazosin lysine .gtoreq.15 g
tamsulosin lysine .gtoreq.1.75 g thioctic lysine .gtoreq.15 g
terazosin lysine .gtoreq.1.75 g tosufloxacin lysine .gtoreq.15 g
thioctic lysine .gtoreq.1.75 g triflusal lysine .gtoreq.15 g
tosufloxacin lysine .gtoreq.1.75 g zaltoprofen lysine .gtoreq.15 g
triflusal lysine .gtoreq.1.75 g etidronic acid lysine .gtoreq.15 g
zaltoprofen lysine .gtoreq.1.75 g zoledronic acid lysine .gtoreq.15
g etidronic acid lysine .gtoreq.1.75 g clodronic acid lysine
.gtoreq.15 g zoledronic acid lysine .gtoreq.1.75 g tiludronic acid
lysine .gtoreq.15 g clodronic acid lysine .gtoreq.1.75 g pamidronic
acid lysine .gtoreq.15 g tiludronic acid lysine .gtoreq.1.75 g
alendronic acid lysine .gtoreq.15 g
pamidronic acid lysine .gtoreq.1.75 g risedronic acid lysine
.gtoreq.15 g alendronic acid lysine .gtoreq.1.75 g ibandronic acid
lysine .gtoreq.15 g risedronic acid lysine .gtoreq.1.75 g abacavir
glycine .gtoreq.15 g ibandronic acid lysine .gtoreq.1.75 g acarbose
glycine .gtoreq.15 g abacavir glycine .gtoreq.1.75 g acetazolamide
glycine .gtoreq.15 g acarbose glycine .gtoreq.1.75 g acyclovir
glycine .gtoreq.15 g acetazolamide glycine .gtoreq.1.75 g albuterol
(salbutamol) glycine .gtoreq.15 g acyclovir glycine .gtoreq.1.75 g
allopurinol glycine .gtoreq.15 g albuterol (salbutamol) glycine
.gtoreq.1.75 g amiloride glycine .gtoreq.15 g allopurinol glycine
.gtoreq.1.75 g amisulpride glycine .gtoreq.15 g amiloride glycine
.gtoreq.1.75 g amlodipine glycine .gtoreq.15 g amisulpride glycine
.gtoreq.1.75 g amoxicillin glycine .gtoreq.15 g amlodipine glycine
.gtoreq.1.75 g amphetamine glycine .gtoreq.15 g amoxicillin glycine
.gtoreq.1.75 g atenolol glycine .gtoreq.15 g amphetamine glycine
.gtoreq.1.75 g atropine glycine .gtoreq.15 g atenolol glycine
.gtoreq.1.75 g azathioprine glycine .gtoreq.15 g atropine glycine
.gtoreq.1.75 g benserazide glycine .gtoreq.15 g azathioprine
glycine .gtoreq.1.75 g benznidazole glycine .gtoreq.15 g
benserazide glycine .gtoreq.1.75 g camostat glycine .gtoreq.15 g
benznidazole glycine .gtoreq.1.75 g captopril glycine .gtoreq.15 g
camostat glycine .gtoreq.1.75 g cefdinir glycine .gtoreq.15 g
captopril glycine .gtoreq.1.75 g cefotiam hexetil glycine
.gtoreq.15 g hydrochloride cefdinir glycine .gtoreq.1.75 g
cefprozil glycine .gtoreq.15 g cefotiam hexetil glycine
.gtoreq.1.75 g cefuroxime axetil glycine .gtoreq.15 g hydrochloride
cefprozil glycine .gtoreq.1.75 g chloramphenicol glycine .gtoreq.15
g cefuroxime axetil glycine .gtoreq.1.75 g cimetidine glycine
.gtoreq.15 g chloramphenicol glycine .gtoreq.1.75 g ciprofloxacin
glycine .gtoreq.15 g cimetidine glycine .gtoreq.1.75 g codeine
glycine .gtoreq.15 g ciprofloxacin glycine .gtoreq.1.75 g
colchicine glycine .gtoreq.15 g codeine glycine .gtoreq.1.75 g
cyclophosphamide glycine .gtoreq.15 g colchicine glycine
.gtoreq.1.75 g dapsone glycine .gtoreq.15 g cyclophosphamide
glycine .gtoreq.1.75 g dexamethasone glycine .gtoreq.15 g dapsone
glycine .gtoreq.1.75 g didanosine glycine .gtoreq.15 g
dexamethasone glycine .gtoreq.1.75 g diethylcarbamazine glycine
.gtoreq.15 g didanosine glycine .gtoreq.1.75 g methionine glycine
.gtoreq.15 g diethylcarbamazine glycine .gtoreq.1.75 g dolasetron
glycine .gtoreq.15 g methionine glycine .gtoreq.1.75 g
doxifluridine glycine .gtoreq.15 g dolasetron glycine .gtoreq.1.75
g doxycycline glycine .gtoreq.15 g doxifluridine glycine
.gtoreq.1.75 g ergonovine glycine .gtoreq.15 g doxycycline glycine
.gtoreq.1.75 g erythromycin glycine .gtoreq.15 g ethylsuccinate
ergonovine glycine .gtoreq.1.75 g ethambutol glycine .gtoreq.15 g
erythromycin glycine .gtoreq.1.75 g ethosuximide glycine .gtoreq.15
g ethylsuccinate ethambutol glycine .gtoreq.1.75 g famotidine
glycine .gtoreq.15 g ethosuximide glycine .gtoreq.1.75 g
fluconazole glycine .gtoreq.15 g famotidine glycine .gtoreq.1.75 g
folic acid glycine .gtoreq.15 g fluconazole glycine .gtoreq.1.75 g
furosemide glycine .gtoreq.15 g folic acid glycine .gtoreq.1.75 g
fursultiamine glycine .gtoreq.15 g furosemide glycine .gtoreq.1.75
g gabapentin glycine .gtoreq.15 g fursultiamine glycine
.gtoreq.1.75 g glipizide glycine .gtoreq.15 g gabapentin glycine
.gtoreq.1.75 g granisetron glycine .gtoreq.15 g glipizide glycine
.gtoreq.1.75 g griseofulvin glycine .gtoreq.15 g granisetron
glycine .gtoreq.1.75 g hydralazine glycine .gtoreq.15 g
griseofulvin glycine .gtoreq.1.75 g hydrochlorothiazide glycine
.gtoreq.15 g hydralazine glycine .gtoreq.1.75 g imidapril glycine
.gtoreq.15 g hydrochlorothiazide glycine .gtoreq.1.75 g isoniazid
glycine .gtoreq.15 g imidapril glycine .gtoreq.1.75 g lamivudine
glycine .gtoreq.15 g isoniazid glycine .gtoreq.1.75 g
l-carbocysteine glycine .gtoreq.15 g lamivudine glycine
.gtoreq.1.75 g levetiracetam glycine .gtoreq.15 g l-carbocysteine
glycine .gtoreq.1.75 g levofloxacin glycine .gtoreq.15 g
levetiracetam glycine .gtoreq.1.75 g linezolid glycine .gtoreq.15 g
levofloxacin glycine .gtoreq.1.75 g lisinopril glycine .gtoreq.15 g
linezolid glycine .gtoreq.1.75 g losartan glycine .gtoreq.15 g
lisinopril glycine .gtoreq.1.75 g methotrexate glycine .gtoreq.15 g
losartan glycine .gtoreq.1.75 g methyldopa glycine .gtoreq.15 g
methotrexate glycine .gtoreq.1.75 g s-methylmethionine glycine
.gtoreq.15 g methyldopa glycine .gtoreq.1.75 g metoclopramide
glycine .gtoreq.15 g s-methylmethionine glycine .gtoreq.1.75 g
metronidazole glycine .gtoreq.15 g metoclopramide glycine
.gtoreq.1.75 g moxifloxacin glycine .gtoreq.15 g metronidazole
glycine .gtoreq.1.75 g nalidixic acid glycine .gtoreq.15 g
moxifloxacin glycine .gtoreq.1.75 g nicorandil glycine .gtoreq.15 g
nalidixic acid glycine .gtoreq.1.75 g nifurtimox glycine .gtoreq.15
g nicorandil glycine .gtoreq.1.75 g nitrofurantoin glycine
.gtoreq.15 g nifurtimox glycine .gtoreq.1.75 g nizatidine glycine
.gtoreq.15 g nitrofurantoin glycine .gtoreq.1.75 g nystatin glycine
.gtoreq.15 g nizatidine glycine .gtoreq.1.75 g ondansetron glycine
.gtoreq.15 g nystatin glycine .gtoreq.1.75 g oseltamivir glycine
.gtoreq.15 g ondansetron glycine .gtoreq.1.75 g oxcarbazepine
glycine .gtoreq.15 g oseltamivir glycine .gtoreq.1.75 g
penicillamine glycine .gtoreq.15 g oxcarbazepine glycine
.gtoreq.1.75 g perindopril glycine .gtoreq.15 g penicillamine
glycine .gtoreq.1.75 g phenobarbital glycine .gtoreq.15 g
perindopril glycine .gtoreq.1.75 g phenoxymethylpenicillin glycine
.gtoreq.15 g phenobarbital glycine .gtoreq.1.75 g pravastatin
sodium glycine .gtoreq.15 g phenoxymethylpenicillin glycine
.gtoreq.1.75 g prednisolone glycine .gtoreq.15 g pravastatin sodium
glycine .gtoreq.1.75 g primaquine glycine .gtoreq.15 g prednisolone
glycine .gtoreq.1.75 g procaterol glycine .gtoreq.15 g primaquine
glycine .gtoreq.1.75 g propylthiouracil glycine .gtoreq.15 g
procaterol glycine .gtoreq.1.75 g pseudoephedrine glycine
.gtoreq.15 g propylthiouracil glycine .gtoreq.1.75 g pyrazinamide
glycine .gtoreq.15 g pseudoephedrine glycine .gtoreq.1.75 g
pyridostigmine glycine .gtoreq.15 g bromide pyrazinamide glycine
.gtoreq.1.75 g pyridoxine glycine .gtoreq.15 g hydrochloride
pyridostigmine glycine .gtoreq.1.75 g ranitidine glycine .gtoreq.15
g bromide pyridoxine glycine .gtoreq.1.75 g ribavirin glycine
.gtoreq.15 g hydrochloride ranitidine glycine .gtoreq.1.75 g
riboflavin glycine .gtoreq.15 g ribavirin glycine .gtoreq.1.75 g
rizatriptan glycine .gtoreq.15 g riboflavin glycine .gtoreq.1.75 g
stavudine glycine .gtoreq.15 g rizatriptan glycine .gtoreq.1.75 g
sulfadiazine glycine .gtoreq.15 g stavudine glycine .gtoreq.1.75 g
sulfamethoxazole glycine .gtoreq.15 g sulfadiazine glycine
.gtoreq.1.75 g sultamicillin glycine .gtoreq.15 g sulfamethoxazole
glycine .gtoreq.1.75 g sumatriptan glycine .gtoreq.15 g
sultamicillin glycine .gtoreq.1.75 g taltirelin glycine .gtoreq.15
g sumatriptan glycine .gtoreq.1.75 g tegafur glycine .gtoreq.15 g
taltirelin glycine .gtoreq.1.75 g tenofovir disoproxil glycine
.gtoreq.15 g tegafur glycine .gtoreq.1.75 g theophylline glycine
.gtoreq.15 g tenofovir disoproxil glycine .gtoreq.1.75 g thiamine
glycine .gtoreq.15 g theophylline glycine .gtoreq.1.75 g
trimetazidine glycine .gtoreq.15 g thiamine glycine .gtoreq.1.75 g
trimethoprim glycine .gtoreq.15 g trimetazidine glycine
.gtoreq.1.75 g voglibose glycine .gtoreq.15 g trimethoprim glycine
.gtoreq.1.75 g zidovudine glycine .gtoreq.15 g voglibose glycine
.gtoreq.1.75 g zolmitriptan glycine .gtoreq.15 g zidovudine glycine
.gtoreq.1.75 g acetylcarnitine glycine .gtoreq.15 g zolmitriptan
glycine .gtoreq.1.75 g capecitabine glycine .gtoreq.15 g
acetylcarnitine glycine .gtoreq.1.75 g cefaclor glycine .gtoreq.15
g capecitabine glycine .gtoreq.1.75 g cefixime glycine .gtoreq.15 g
cefaclor glycine .gtoreq.1.75 g cefmetazole glycine .gtoreq.15 g
cefixime glycine .gtoreq.1.75 g cefpodoxime proxetil glycine
.gtoreq.15 g cefmetazole glycine .gtoreq.1.75 g cefroxadine glycine
.gtoreq.15 g cefpodoxime proxetil glycine .gtoreq.1.75 g
alfoscerate glycine .gtoreq.15 g cefroxadine glycine .gtoreq.1.75 g
cilazapril glycine .gtoreq.15 g alfoscerate glycine .gtoreq.1.75 g
cimetropium bromide glycine .gtoreq.15 g cilazapril glycine
.gtoreq.1.75 g diacerein glycine .gtoreq.15 g cimetropium bromide
glycine .gtoreq.1.75 g erdosteine glycine .gtoreq.15 g diacerein
glycine .gtoreq.1.75 g famciclovir glycine .gtoreq.15 g erdosteine
glycine .gtoreq.1.75 g gemifloxacin glycine .gtoreq.15 g
famciclovir glycine .gtoreq.1.75 g levosulpiride glycine .gtoreq.15
g gemifloxacin glycine .gtoreq.1.75 g nabumetone glycine .gtoreq.15
g levosulpiride glycine .gtoreq.1.75 g oxiracetam glycine
.gtoreq.15 g nabumetone glycine .gtoreq.1.75 g phendimetrazine
glycine .gtoreq.15 g oxiracetam glycine .gtoreq.1.75 g rabeprazole
glycine .gtoreq.15 g phendimetrazine glycine .gtoreq.1.75 g
roxatidine acetate glycine .gtoreq.15 g rabeprazole glycine
.gtoreq.1.75 g tamsulosin glycine .gtoreq.15 g roxatidine acetate
glycine .gtoreq.1.75 g terazosin glycine .gtoreq.15 g tamsulosin
glycine .gtoreq.1.75 g thioctic glycine .gtoreq.15 g terazosin
glycine .gtoreq.1.75 g tosufloxacin glycine .gtoreq.15 g thioctic
glycine .gtoreq.1.75 g triflusal glycine .gtoreq.15 g tosufloxacin
glycine .gtoreq.1.75 g zaltoprofen glycine .gtoreq.15 g triflusal
glycine .gtoreq.1.75 g etidronic acid glycine .gtoreq.15 g
zaltoprofen glycine .gtoreq.1.75 g zoledronic acid glycine
.gtoreq.15 g etidronic acid glycine .gtoreq.1.75 g clodronic acid
glycine .gtoreq.15 g zoledronic acid glycine .gtoreq.1.75 g
tiludronic acid glycine .gtoreq.15 g clodronic acid glycine
.gtoreq.1.75 g pamidronic acid glycine .gtoreq.15 g tiludronic acid
glycine .gtoreq.1.75 g alendronic acid glycine .gtoreq.15 g
pamidronic acid glycine .gtoreq.1.75 g risedronic acid glycine
.gtoreq.15 g alendronic acid glycine .gtoreq.1.75 g ibandronic acid
glycine .gtoreq.15 g risedronic acid glycine .gtoreq.1.75 g
abacavir lysine 5 g to 20 g ibandronic acid glycine .gtoreq.1.75 g
acarbose lysine 5 g to 20 g abacavir lysine .gtoreq.2 g
acetazolamide lysine 5 g to 20 g acarbose lysine .gtoreq.2 g
acyclovir lysine 5 g to 20 g acetazolamide lysine .gtoreq.2 g
albuterol (salbutamol) lysine 5 g to 20 g acyclovir lysine
.gtoreq.2 g allopurinol lysine 5 g to 20 g albuterol (salbutamol)
lysine .gtoreq.2 g amiloride lysine 5 g to 20 g allopurinol lysine
.gtoreq.2 g amisulpride lysine 5 g to 20 g amiloride lysine
.gtoreq.2 g amlodipine lysine 5 g to 20 g amisulpride lysine
.gtoreq.2 g amoxicillin lysine 5 g to 20 g amlodipine lysine
.gtoreq.2 g amphetamine lysine 5 g to 20 g amoxicillin lysine
.gtoreq.2 g atenolol lysine 5 g to 20 g amphetamine lysine
.gtoreq.2 g atropine lysine 5 g to 20 g atenolol lysine .gtoreq.2 g
azathioprine lysine 5 g to 20 g atropine lysine .gtoreq.2 g
benserazide lysine 5 g to 20 g azathioprine lysine .gtoreq.2 g
benznidazole lysine 5 g to 20 g benserazide lysine .gtoreq.2 g
camostat lysine 5 g to 20 g benznidazole lysine .gtoreq.2 g
captopril lysine 5 g to 20 g camostat lysine .gtoreq.2 g cefdinir
lysine 5 g to 20 g captopril lysine .gtoreq.2 g cefotiam hexetil
lysine 5 g to 20 g hydrochloride cefdinir lysine .gtoreq.2 g
cefprozil lysine 5 g to 20 g cefotiam hexetil lysine .gtoreq.2 g
cefuroxime axetil lysine 5 g to 20 g hydrochloride cefprozil lysine
.gtoreq.2 g chloramphenicol lysine 5 g to 20 g cefuroxime axetil
lysine .gtoreq.2 g cimetidine lysine 5 g to 20 g chloramphenicol
lysine .gtoreq.2 g ciprofloxacin lysine 5 g to 20 g cimetidine
lysine .gtoreq.2 g codeine lysine 5 g to 20 g ciprofloxacin lysine
.gtoreq.2 g colchicine lysine 5 g to 20 g codeine lysine .gtoreq.2
g cyclophosphamide lysine 5 g to 20 g colchicine lysine .gtoreq.2 g
dapsone lysine 5 g to 20 g cyclophosphamide lysine .gtoreq.2 g
dexamethasone lysine 5 g to 20 g dapsone lysine .gtoreq.2 g
didanosine lysine 5 g to 20 g dexamethasone lysine .gtoreq.2 g
diethylcarbamazine lysine 5 g to 20 g didanosine lysine .gtoreq.2 g
methionine lysine 5 g to 20 g diethylcarbamazine lysine .gtoreq.2 g
dolasetron lysine 5 g to 20 g methionine lysine .gtoreq.2 g
doxifluridine lysine 5 g to 20 g dolasetron lysine .gtoreq.2 g
doxycycline lysine 5 g to 20 g doxifluridine lysine .gtoreq.2 g
ergonovine lysine 5 g to 20 g doxycycline lysine .gtoreq.2 g
erythromycin lysine 5 g to 20 g ethylsuccinate ergonovine lysine
.gtoreq.2 g ethambutol lysine 5 g to 20 g erythromycin lysine
.gtoreq.2 g ethosuximide lysine 5 g to 20 g ethylsuccinate
ethambutol lysine .gtoreq.2 g famotidine lysine 5 g to 20 g
ethosuximide lysine .gtoreq.2 g fluconazole lysine 5 g to 20 g
famotidine lysine .gtoreq.2 g folic acid lysine 5 g to 20 g
fluconazole lysine .gtoreq.2 g furosemide lysine 5 g to 20 g folic
acid lysine .gtoreq.2 g fursultiamine lysine 5 g to 20 g furosemide
lysine .gtoreq.2 g gabapentin lysine 5 g to 20 g fursultiamine
lysine .gtoreq.2 g glipizide lysine 5 g to 20 g gabapentin lysine
.gtoreq.2 g granisetron lysine 5 g to 20 g glipizide lysine
.gtoreq.2 g griseofulvin lysine 5 g to 20 g granisetron lysine
.gtoreq.2 g hydralazine lysine 5 g to 20 g griseofulvin lysine
.gtoreq.2 g hydrochlorothiazide lysine 5 g to 20 g hydralazine
lysine .gtoreq.2 g imidapril lysine 5 g to 20 g hydrochlorothiazide
lysine .gtoreq.2 g isoniazid lysine 5 g to 20 g imidapril lysine
.gtoreq.2 g lamivudine lysine 5 g to 20 g isoniazid lysine
.gtoreq.2 g l-carbocysteine lysine 5 g to 20 g lamivudine lysine
.gtoreq.2 g levetiracetam lysine 5 g to 20 g l-carbocysteine lysine
.gtoreq.2 g levofloxacin lysine 5 g to 20 g levetiracetam lysine
.gtoreq.2 g linezolid lysine 5 g to 20 g levofloxacin lysine
.gtoreq.2 g lisinopril lysine 5 g to 20 g linezolid lysine
.gtoreq.2 g losartan lysine 5 g to 20 g lisinopril lysine .gtoreq.2
g methotrexate lysine 5 g to 20 g losartan lysine .gtoreq.2 g
methyldopa lysine 5 g to 20 g methotrexate lysine .gtoreq.2 g
s-methylmethionine lysine 5 g to 20 g methyldopa lysine .gtoreq.2 g
metoclopramide lysine 5 g to 20 g s-methylmethionine lysine
.gtoreq.2 g metronidazole lysine 5 g to 20 g metoclopramide lysine
.gtoreq.2 g moxifloxacin lysine 5 g to 20 g metronidazole lysine
.gtoreq.2 g nalidixic acid lysine 5 g to 20 g moxifloxacin lysine
.gtoreq.2 g nicorandil lysine 5 g to 20 g nalidixic acid lysine
.gtoreq.2 g nifurtimox lysine 5 g to 20 g nicorandil lysine
.gtoreq.2 g nitrofurantoin lysine 5 g to 20 g nifurtimox lysine
.gtoreq.2 g nizatidine lysine 5 g to 20 g nitrofurantoin lysine
.gtoreq.2 g nystatin lysine 5 g to 20 g nizatidine lysine .gtoreq.2
g ondansetron lysine 5 g to 20 g
nystatin lysine .gtoreq.2 g oseltamivir lysine 5 g to 20 g
ondansetron lysine .gtoreq.2 g oxcarbazepine lysine 5 g to 20 g
oseltamivir lysine .gtoreq.2 g penicillamine lysine 5 g to 20 g
oxcarbazepine lysine .gtoreq.2 g perindopril lysine 5 g to 20 g
penicillamine lysine .gtoreq.2 g phenobarbital lysine 5 g to 20 g
perindopril lysine .gtoreq.2 g phenoxymethylpenicillin lysine 5 g
to 20 g phenobarbital lysine .gtoreq.2 g pravastatin sodium lysine
5 g to 20 g phenoxymethylpenicillin lysine .gtoreq.2 g prednisolone
lysine 5 g to 20 g pravastatin sodium lysine .gtoreq.2 g primaquine
lysine 5 g to 20 g prednisolone lysine .gtoreq.2 g procaterol
lysine 5 g to 20 g primaquine lysine .gtoreq.2 g propylthiouracil
lysine 5 g to 20 g procaterol lysine .gtoreq.2 g pseudoephedrine
lysine 5 g to 20 g propylthiouracil lysine .gtoreq.2 g pyrazinamide
lysine 5 g to 20 g pseudoephedrine lysine .gtoreq.2 g
pyridostigmine lysine 5 g to 20 g bromide pyrazinamide lysine
.gtoreq.2 g pyridoxine lysine 5 g to 20 g hydrochloride
pyridostigmine lysine .gtoreq.2 g ranitidine lysine 5 g to 20 g
bromide pyridoxine lysine .gtoreq.2 g ribavirin lysine 5 g to 20 g
hydrochloride ranitidine lysine .gtoreq.2 g riboflavin lysine 5 g
to 20 g ribavirin lysine .gtoreq.2 g rizatriptan lysine 5 g to 20 g
riboflavin lysine .gtoreq.2 g stavudine lysine 5 g to 20 g
rizatriptan lysine .gtoreq.2 g sulfadiazine lysine 5 g to 20 g
stavudine lysine .gtoreq.2 g sulfamethoxazole lysine 5 g to 20 g
sulfadiazine lysine .gtoreq.2 g sultamicillin lysine 5 g to 20 g
sulfamethoxazole lysine .gtoreq.2 g sumatriptan lysine 5 g to 20 g
sultamicillin lysine .gtoreq.2 g taltirelin lysine 5 g to 20 g
sumatriptan lysine .gtoreq.2 g tegafur lysine 5 g to 20 g
taltirelin lysine .gtoreq.2 g tenofovir disoproxil lysine 5 g to 20
g tegafur lysine .gtoreq.2 g theophylline lysine 5 g to 20 g
tenofovir disoproxil lysine .gtoreq.2 g thiamine lysine 5 g to 20 g
theophylline lysine .gtoreq.2 g trimetazidine lysine 5 g to 20 g
thiamine lysine .gtoreq.2 g trimethoprim lysine 5 g to 20 g
trimetazidine lysine .gtoreq.2 g voglibose lysine 5 g to 20 g
trimethoprim lysine .gtoreq.2 g zidovudine lysine 5 g to 20 g
voglibose lysine .gtoreq.2 g zolmitriptan lysine 5 g to 20 g
zidovudine lysine .gtoreq.2 g acetylcarnitine lysine 5 g to 20 g
zolmitriptan lysine .gtoreq.2 g capecitabine lysine 5 g to 20 g
acetylcarnitine lysine .gtoreq.2 g cefaclor lysine 5 g to 20 g
capecitabine lysine .gtoreq.2 g cefixime lysine 5 g to 20 g
cefaclor lysine .gtoreq.2 g cefmetazole lysine 5 g to 20 g cefixime
lysine .gtoreq.2 g cefpodoxime proxetil lysine 5 g to 20 g
cefmetazole lysine .gtoreq.2 g cefroxadine lysine 5 g to 20 g
cefpodoxime proxetil lysine .gtoreq.2 g alfoscerate lysine 5 g to
20 g cefroxadine lysine .gtoreq.2 g cilazapril lysine 5 g to 20 g
alfoscerate lysine .gtoreq.2 g cimetropium bromide lysine 5 g to 20
g cilazapril lysine .gtoreq.2 g diacerein lysine 5 g to 20 g
cimetropium bromide lysine .gtoreq.2 g erdosteine lysine 5 g to 20
g diacerein lysine .gtoreq.2 g famciclovir lysine 5 g to 20 g
erdosteine lysine .gtoreq.2 g gemifloxacin lysine 5 g to 20 g
famciclovir lysine .gtoreq.2 g levosulpiride lysine 5 g to 20 g
gemifloxacin lysine .gtoreq.2 g nabumetone lysine 5 g to 20 g
levosulpiride lysine .gtoreq.2 g oxiracetam lysine 5 g to 20 g
nabumetone lysine .gtoreq.2 g phendimetrazine lysine 5 g to 20 g
oxiracetam lysine .gtoreq.2 g rabeprazole lysine 5 g to 20 g
phendimetrazine lysine .gtoreq.2 g roxatidine acetate lysine 5 g to
20 g rabeprazole lysine .gtoreq.2 g tamsulosin lysine 5 g to 20 g
roxatidine acetate lysine .gtoreq.2 g terazosin lysine 5 g to 20 g
tamsulosin lysine .gtoreq.2 g thioctic lysine 5 g to 20 g terazosin
lysine .gtoreq.2 g tosufloxacin lysine 5 g to 20 g thioctic lysine
.gtoreq.2 g triflusal lysine 5 g to 20 g tosufloxacin lysine
.gtoreq.2 g zaltoprofen lysine 5 g to 20 g triflusal lysine
.gtoreq.2 g etidronic acid lysine 5 g to 20 g zaltoprofen lysine
.gtoreq.2 g zoledronic acid lysine 5 g to 20 g etidronic acid
lysine .gtoreq.2 g clodronic acid lysine 5 g to 20 g zoledronic
acid lysine .gtoreq.2 g tiludronic acid lysine 5 g to 20 g
clodronic acid lysine .gtoreq.2 g pamidronic acid lysine 5 g to 20
g tiludronic acid lysine .gtoreq.2 g alendronic acid lysine 5 g to
20 g pamidronic acid lysine .gtoreq.2 g risedronic acid lysine 5 g
to 20 g alendronic acid lysine .gtoreq.2 g ibandronic acid lysine 5
g to 20 g risedronic acid lysine .gtoreq.2 g abacavir glycine 5 g
to 20 g ibandronic acid lysine .gtoreq.2 g acarbose glycine 5 g to
20 g abacavir glycine .gtoreq.2 g acetazolamide glycine 5 g to 20 g
acarbose glycine .gtoreq.2 g acyclovir glycine 5 g to 20 g
acetazolamide glycine .gtoreq.2 g albuterol (salbutamol) glycine 5
g to 20 g acyclovir glycine .gtoreq.2 g allopurinol glycine 5 g to
20 g albuterol (salbutamol) glycine .gtoreq.2 g amiloride glycine 5
g to 20 g allopurinol glycine .gtoreq.2 g amisulpride glycine 5 g
to 20 g amiloride glycine .gtoreq.2 g amlodipine glycine 5 g to 20
g amisulpride glycine .gtoreq.2 g amoxicillin glycine 5 g to 20 g
amlodipine glycine .gtoreq.2 g amphetamine glycine 5 g to 20 g
amoxicillin glycine .gtoreq.2 g atenolol glycine 5 g to 20 g
amphetamine glycine .gtoreq.2 g atropine glycine 5 g to 20 g
atenolol glycine .gtoreq.2 g azathioprine glycine 5 g to 20 g
atropine glycine .gtoreq.2 g benserazide glycine 5 g to 20 g
azathioprine glycine .gtoreq.2 g benznidazole glycine 5 g to 20 g
benserazide glycine .gtoreq.2 g camostat glycine 5 g to 20 g
benznidazole glycine .gtoreq.2 g captopril glycine 5 g to 20 g
camostat glycine .gtoreq.2 g cefdinir glycine 5 g to 20 g captopril
glycine .gtoreq.2 g cefotiam hexetil glycine 5 g to 20 g
hydrochloride cefdinir glycine .gtoreq.2 g cefprozil glycine 5 g to
20 g cefotiam hexetil glycine .gtoreq.2 g cefuroxime axetil glycine
5 g to 20 g hydrochloride cefprozil glycine .gtoreq.2 g
chloramphenicol glycine 5 g to 20 g cefuroxime axetil glycine
.gtoreq.2 g cimetidine glycine 5 g to 20 g chloramphenicol glycine
.gtoreq.2 g ciprofloxacin glycine 5 g to 20 g cimetidine glycine
.gtoreq.2 g codeine glycine 5 g to 20 g ciprofloxacin glycine
.gtoreq.2 g colchicine glycine 5 g to 20 g codeine glycine
.gtoreq.2 g cyclophosphamide glycine 5 g to 20 g colchicine glycine
.gtoreq.2 g dapsone glycine 5 g to 20 g cyclophosphamide glycine
.gtoreq.2 g dexamethasone glycine 5 g to 20 g dapsone glycine
.gtoreq.2 g didanosine glycine 5 g to 20 g dexamethasone glycine
.gtoreq.2 g diethylcarbamazine glycine 5 g to 20 g didanosine
glycine .gtoreq.2 g methionine glycine 5 g to 20 g
diethylcarbamazine glycine .gtoreq.2 g dolasetron glycine 5 g to 20
g methionine glycine .gtoreq.2 g doxifluridine glycine 5 g to 20 g
dolasetron glycine .gtoreq.2 g doxycycline glycine 5 g to 20 g
doxifluridine glycine .gtoreq.2 g ergonovine glycine 5 g to 20 g
doxycycline glycine .gtoreq.2 g erythromycin glycine 5 g to 20 g
ethylsuccinate ergonovine glycine .gtoreq.2 g ethambutol glycine 5
g to 20 g erythromycin glycine .gtoreq.2 g ethosuximide glycine 5 g
to 20 g ethylsuccinate ethambutol glycine .gtoreq.2 g famotidine
glycine 5 g to 20 g ethosuximide glycine .gtoreq.2 g fluconazole
glycine 5 g to 20 g famotidine glycine .gtoreq.2 g folic acid
glycine 5 g to 20 g fluconazole glycine .gtoreq.2 g furosemide
glycine 5 g to 20 g folic acid glycine .gtoreq.2 g fursultiamine
glycine 5 g to 20 g furosemide glycine .gtoreq.2 g gabapentin
glycine 5 g to 20 g fursultiamine glycine .gtoreq.2 g glipizide
glycine 5 g to 20 g gabapentin glycine .gtoreq.2 g granisetron
glycine 5 g to 20 g glipizide glycine .gtoreq.2 g griseofulvin
glycine 5 g to 20 g granisetron glycine .gtoreq.2 g hydralazine
glycine 5 g to 20 g griseofulvin glycine .gtoreq.2 g
hydrochlorothiazide glycine 5 g to 20 g hydralazine glycine
.gtoreq.2 g imidapril glycine 5 g to 20 g hydrochlorothiazide
glycine .gtoreq.2 g isoniazid glycine 5 g to 20 g imidapril glycine
.gtoreq.2 g lamivudine glycine 5 g to 20 g isoniazid glycine
.gtoreq.2 g l-carbocysteine glycine 5 g to 20 g lamivudine glycine
.gtoreq.2 g levetiracetam glycine 5 g to 20 g l-carbocysteine
glycine .gtoreq.2 g levofloxacin glycine 5 g to 20 g levetiracetam
glycine .gtoreq.2 g linezolid glycine 5 g to 20 g levofloxacin
glycine .gtoreq.2 g lisinopril glycine 5 g to 20 g linezolid
glycine .gtoreq.2 g losartan glycine 5 g to 20 g lisinopril glycine
.gtoreq.2 g methotrexate glycine 5 g to 20 g losartan glycine
.gtoreq.2 g methyldopa glycine 5 g to 20 g methotrexate glycine
.gtoreq.2 g s-methylmethionine glycine 5 g to 20 g methyldopa
glycine .gtoreq.2 g metoclopramide glycine 5 g to 20 g
s-methylmethionine glycine .gtoreq.2 g metronidazole glycine 5 g to
20 g metoclopramide glycine .gtoreq.2 g moxifloxacin glycine 5 g to
20 g metronidazole glycine .gtoreq.2 g nalidixic acid glycine 5 g
to 20 g moxifloxacin glycine .gtoreq.2 g nicorandil glycine 5 g to
20 g nalidixic acid glycine .gtoreq.2 g nifurtimox glycine 5 g to
20 g nicorandil glycine .gtoreq.2 g nitrofurantoin glycine 5 g to
20 g nifurtimox glycine .gtoreq.2 g nizatidine glycine 5 g to 20 g
nitrofurantoin glycine .gtoreq.2 g nystatin glycine 5 g to 20 g
nizatidine glycine .gtoreq.2 g ondansetron glycine 5 g to 20 g
nystatin glycine .gtoreq.2 g oseltamivir glycine 5 g to 20 g
ondansetron glycine .gtoreq.2 g oxcarbazepine glycine 5 g to 20 g
oseltamivir glycine .gtoreq.2 g penicillamine glycine 5 g to 20 g
oxcarbazepine glycine .gtoreq.2 g perindopril glycine 5 g to 20 g
penicillamine glycine .gtoreq.2 g phenobarbital glycine 5 g to 20 g
perindopril glycine .gtoreq.2 g phenoxymethylpenicillin glycine 5 g
to 20 g phenobarbital glycine .gtoreq.2 g pravastatin sodium
glycine 5 g to 20 g phenoxymethylpenicillin glycine .gtoreq.2 g
prednisolone glycine 5 g to 20 g pravastatin sodium glycine
.gtoreq.2 g primaquine glycine 5 g to 20 g prednisolone glycine
.gtoreq.2 g procaterol glycine 5 g to 20 g primaquine glycine
.gtoreq.2 g propylthiouracil glycine 5 g to 20 g procaterol glycine
.gtoreq.2 g pseudoephedrine glycine 5 g to 20 g propylthiouracil
glycine .gtoreq.2 g pyrazinamide glycine 5 g to 20 g
pseudoephedrine glycine .gtoreq.2 g pyridostigmine glycine 5 g to
20 g bromide pyrazinamide glycine .gtoreq.2 g pyridoxine glycine 5
g to 20 g hydrochloride pyridostigmine glycine .gtoreq.2 g
ranitidine glycine 5 g to 20 g bromide pyridoxine glycine .gtoreq.2
g ribavirin glycine 5 g to 20 g hydrochloride ranitidine glycine
.gtoreq.2 g riboflavin glycine 5 g to 20 g ribavirin glycine
.gtoreq.2 g rizatriptan glycine 5 g to 20 g riboflavin glycine
.gtoreq.2 g stavudine glycine 5 g to 20 g rizatriptan glycine
.gtoreq.2 g sulfadiazine glycine 5 g to 20 g stavudine glycine
.gtoreq.2 g sulfamethoxazole glycine 5 g to 20 g sulfadiazine
glycine .gtoreq.2 g sultamicillin glycine 5 g to 20 g
sulfamethoxazole glycine .gtoreq.2 g sumatriptan glycine 5 g to 20
g sultamicillin glycine .gtoreq.2 g taltirelin glycine 5 g to 20 g
sumatriptan glycine .gtoreq.2 g tegafur glycine 5 g to 20 g
taltirelin glycine .gtoreq.2 g tenofovir disoproxil glycine 5 g to
20 g tegafur glycine .gtoreq.2 g theophylline glycine 5 g to 20 g
tenofovir disoproxil glycine .gtoreq.2 g thiamine glycine 5 g to 20
g theophylline glycine .gtoreq.2 g trimetazidine glycine 5 g to 20
g thiamine glycine .gtoreq.2 g trimethoprim glycine 5 g to 20 g
trimetazidine glycine .gtoreq.2 g voglibose glycine 5 g to 20 g
trimethoprim glycine .gtoreq.2 g zidovudine glycine 5 g to 20 g
voglibose glycine .gtoreq.2 g zolmitriptan glycine 5 g to 20 g
zidovudine glycine .gtoreq.2 g acetylcarnitine glycine 5 g to 20 g
zolmitriptan glycine .gtoreq.2 g capecitabine glycine 5 g to 20 g
acetylcarnitine glycine .gtoreq.2 g cefaclor glycine 5 g to 20 g
capecitabine glycine .gtoreq.2 g cefixime glycine 5 g to 20 g
cefaclor glycine .gtoreq.2 g cefmetazole glycine 5 g to 20 g
cefixime glycine .gtoreq.2 g cefpodoxime proxetil glycine 5 g to 20
g cefmetazole glycine .gtoreq.2 g cefroxadine glycine 5 g to 20 g
cefpodoxime proxetil glycine .gtoreq.2 g alfoscerate glycine 5 g to
20 g cefroxadine glycine .gtoreq.2 g cilazapril glycine 5 g to 20 g
alfoscerate glycine .gtoreq.2 g cimetropium bromide glycine 5 g to
20 g cilazapril glycine .gtoreq.2 g diacerein glycine 5 g to 20 g
cimetropium bromide glycine .gtoreq.2 g erdosteine glycine 5 g to
20 g diacerein glycine .gtoreq.2 g famciclovir glycine 5 g to 20 g
erdosteine glycine .gtoreq.2 g gemifloxacin glycine 5 g to 20 g
famciclovir glycine .gtoreq.2 g levosulpiride glycine 5 g to 20 g
gemifloxacin glycine .gtoreq.2 g nabumetone glycine 5 g to 20 g
levosulpiride glycine .gtoreq.2 g oxiracetam glycine 5 g to 20 g
nabumetone glycine .gtoreq.2 g phendimetrazine glycine 5 g to 20 g
oxiracetam glycine .gtoreq.2 g rabeprazole glycine 5 g to 20 g
phendimetrazine glycine .gtoreq.2 g roxatidine acetate glycine 5 g
to 20 g rabeprazole glycine .gtoreq.2 g tamsulosin glycine 5 g to
20 g roxatidine acetate glycine .gtoreq.2 g terazosin glycine 5 g
to 20 g tamsulosin glycine .gtoreq.2 g thioctic glycine 5 g to 20 g
terazosin glycine .gtoreq.2 g tosufloxacin glycine 5 g to 20 g
thioctic glycine .gtoreq.2 g triflusal glycine 5 g to 20 g
tosufloxacin glycine .gtoreq.2 g zaltoprofen glycine 5 g to 20 g
triflusal glycine .gtoreq.2 g etidronic acid glycine 5 g to 20 g
zaltoprofen glycine .gtoreq.2 g zoledronic acid glycine 5 g to 20 g
etidronic acid glycine .gtoreq.2 g clodronic acid glycine 5 g to 20
g zoledronic acid glycine .gtoreq.2 g tiludronic acid glycine 5 g
to 20 g clodronic acid glycine .gtoreq.2 g pamidronic acid glycine
5 g to 20 g tiludronic acid glycine .gtoreq.2 g alendronic acid
glycine 5 g to 20 g pamidronic acid glycine .gtoreq.2 g risedronic
acid glycine 5 g to 20 g alendronic acid glycine .gtoreq.2 g
ibandronic acid glycine 5 g to 20 g risedronic acid glycine
.gtoreq.2 g zoledronic acid lysine .gtoreq.2.5 g ibandronic acid
glycine .gtoreq.2 g zoledronic acid lysine .gtoreq.2.6 g zoledronic
acid lysine .gtoreq.2.1 g zoledronic acid lysine .gtoreq.2.7 g
zoledronic acid lysine .gtoreq.2.2 g zoledronic acid lysine
.gtoreq.2.8 g zoledronic acid lysine .gtoreq.2.3 g zoledronic acid
lysine .gtoreq.2.9 g zoledronic acid lysine .gtoreq.2.4 g
zoledronic acid lysine .gtoreq.3.5 g
TABLE-US-00029 TABLE 12 Particular embodiments of compositions of
the present invention comprising: a bisphosphonic acid (left
column), either in the form of a crystalline molecular complex
(e.g., salt or cocrystal) with a coformer or in the form of a free
acid (middle column), and an additional coformer (right column).
Each row of the above table represents an individual embodiment of
the present invention. Molecular Complex Additional Coformer as
Bisphosphonic Acid Coformer Excipient zoledronic acid sodium
L-lysine alendronic acid sodium L-lysine ibandronic acid sodium
L-lysine risedronic acid sodium L-lysine tiludronic acid sodium
L-lysine zoledronic acid sodium DL-lysine alendronic acid sodium
DL-lysine ibandronic acid sodium DL-lysine risedronic acid sodium
DL-lysine tiludronic acid sodium DL-lysine zoledronic acid sodium
glycine alendronic acid sodium glycine ibandronic acid sodium
glycine risedronic acid sodium glycine tiludronic acid sodium
glycine zoledronic acid ammonium L-lysine alendronic acid ammonium
L-lysine ibandronic acid ammonium L-lysine risedronic acid ammonium
L-lysine tiludronic acid ammonium L-lysine zoledronic acid ammonium
DL-lysine alendronic acid ammonium DL-lysine ibandronic acid
ammonium DL-lysine risedronic acid ammonium DL-lysine tiludronic
acid ammonium DL-lysine zoledronic acid ammonium glycine alendronic
acid ammonium glycine ibandronic acid ammonium glycine risedronic
acid ammonium glycine tiludronic acid ammonium glycine zoledronic
acid ammonia L-lysine alendronic acid ammonia L-lysine ibandronic
acid ammonia L-lysine risedronic acid ammonia L-lysine tiludronic
acid ammonia L-lysine zoledronic acid ammonia DL-lysine alendronic
acid ammonia DL-lysine ibandronic acid ammonia DL-lysine risedronic
acid ammonia DL-lysine tiludronic acid ammonia DL-lysine zoledronic
acid ammonia glycine alendronic acid ammonia glycine ibandronic
acid ammonia glycine risedronic acid ammonia glycine tiludronic
acid ammonia glycine zoledronic acid L-lysine L-lysine alendronic
acid L-lysine L-lysine ibandronic acid L-lysine L-lysine risedronic
acid L-lysine L-lysine tiludronic acid L-lysine L-lysine zoledronic
acid L-lysine DL-lysine alendronic acid L-lysine DL-lysine
ibandronic acid L-lysine DL-lysine risedronic acid L-lysine
DL-lysine tiludronic acid L-lysine DL-lysine zoledronic acid
L-lysine glycine alendronic acid L-lysine glycine ibandronic acid
L-lysine glycine risedronic acid L-lysine glycine tiludronic acid
L-lysine glycine zoledronic acid DL-lysine L-lysine alendronic acid
DL-lysine L-lysine ibandronic acid DL-lysine L-lysine risedronic
acid DL-lysine L-lysine tiludronic acid DL-lysine L-lysine
zoledronic acid DL-lysine DL-lysine alendronic acid DL-lysine
DL-lysine ibandronic acid DL-lysine DL-lysine risedronic acid
DL-lysine DL-lysine tiludronic acid DL-lysine DL-lysine zoledronic
acid DL-lysine glycine alendronic acid DL-lysine glycine ibandronic
acid DL-lysine glycine risedronic acid DL-lysine glycine tiludronic
acid DL-lysine glycine zoledronic acid nicotinamide L-lysine
alendronic acid nicotinamide L-lysine ibandronic acid nicotinamide
L-lysine risedronic acid nicotinamide L-lysine tiludronic acid
nicotinamide L-lysine zoledronic acid nicotinamide DL-lysine
alendronic acid nicotinamide DL-lysine ibandronic acid nicotinamide
DL-lysine risedronic acid nicotinamide DL-lysine tiludronic acid
nicotinamide DL-lysine zoledronic acid nicotinamide glycine
alendronic acid nicotinamide glycine ibandronic acid nicotinamide
glycine risedronic acid nicotinamide glycine tiludronic acid
nicotinamide glycine zoledronic acid adenine L-lysine alendronic
acid adenine L-lysine ibandronic acid adenine L-lysine risedronic
acid adenine L-lysine tiludronic acid adenine L-lysine zoledronic
acid adenine DL-lysine alendronic acid adenine DL-lysine ibandronic
acid adenine DL-lysine risedronic acid adenine DL-lysine tiludronic
acid adenine DL-lysine zoledronic acid adenine glycine alendronic
acid adenine glycine ibandronic acid adenine glycine risedronic
acid adenine glycine tiludronic acid adenine glycine zoledronic
acid glycine L-lysine alendronic acid glycine L-lysine ibandronic
acid glycine L-lysine risedronic acid glycine L-lysine tiludronic
acid glycine L-lysine zoledronic acid glycine DL-lysine alendronic
acid glycine DL-lysine ibandronic acid glycine DL-lysine risedronic
acid glycine DL-lysine tiludronic acid glycine DL-lysine zoledronic
acid glycine glycine alendronic acid glycine glycine ibandronic
acid glycine glycine risedronic acid glycine glycine tiludronic
acid glycine glycine zoledronic acid free acid L-lysine alendronic
acid free acid L-lysine ibandronic acid free acid L-lysine
risedronic acid free acid L-lysine tiludronic acid free acid
L-lysine zoledronic acid free acid DL-lysine alendronic acid free
acid DL-lysine ibandronic acid free acid DL-lysine risedronic acid
free acid DL-lysine tiludronic acid free acid DL-lysine zoledronic
acid free acid glycine alendronic acid free acid glycine ibandronic
acid free acid glycine risedronic acid free acid glycine tiludronic
acid free acid glycine
TABLE-US-00030 TABLE 13 Particular embodiments of compositions of
the present invention comprising: (from left to right) a
bisphosphonic acid (either in the form of a crystalline molecular
complex (e.g., salt or cocrystal) with a coformer or in the form of
a free acid), an additional coformer, and the ratio of the
additional coformer to bisphosphonic acid (by mass). Each row of
the above table represents an individual embodiment of the present
invention. Mass Ratio of Additional Bisphosphonic Molecular Complex
Additional Coformer:Bisphosphic Acid Coformer Coformer Acid
zoledronic acid sodium L-lysine .gtoreq.5:1 zoledronic acid sodium
L-lysine .gtoreq.6:1 zoledronic acid sodium L-lysine .gtoreq.7:1
zoledronic acid sodium L-lysine .gtoreq.8:1 zoledronic acid sodium
L-lysine .gtoreq.9:1 zoledronic acid sodium L-lysine .gtoreq.10:1
zoledronic acid sodium L-lysine .gtoreq.11:1 zoledronic acid sodium
L-lysine .gtoreq.12:1 zoledronic acid sodium L-lysine .gtoreq.13:1
zoledronic acid sodium L-lysine .gtoreq.14:1 zoledronic acid sodium
L-lysine .gtoreq.15:1 zoledronic acid sodium L-lysine .gtoreq.16:1
zoledronic acid sodium L-lysine .gtoreq.17:1 zoledronic acid sodium
L-lysine .gtoreq.18:1 zoledronic acid sodium L-lysine .gtoreq.19:1
zoledronic acid sodium L-lysine .gtoreq.20:1 zoledronic acid sodium
L-lysine .gtoreq.25:1 zoledronic acid sodium L-lysine .gtoreq.50:1
zoledronic acid sodium L-lysine .gtoreq.750:1 zoledronic acid
sodium L-lysine .gtoreq.2500:1 zoledronic acid sodium L-lysine
.gtoreq.5000:1 zoledronic acid sodium DL-lysine .gtoreq.5:1
zoledronic acid sodium DL-lysine .gtoreq.6:1 zoledronic acid sodium
DL-lysine .gtoreq.7:1 zoledronic acid sodium DL-lysine .gtoreq.8:1
zoledronic acid sodium DL-lysine .gtoreq.9:1 zoledronic acid sodium
DL-lysine .gtoreq.10:1 zoledronic acid sodium DL-lysine
.gtoreq.11:1 zoledronic acid sodium DL-lysine .gtoreq.12:1
zoledronic acid sodium DL-lysine .gtoreq.13:1 zoledronic acid
sodium DL-lysine .gtoreq.14:1 zoledronic acid sodium DL-lysine
.gtoreq.15:1 zoledronic acid sodium DL-lysine .gtoreq.16:1
zoledronic acid sodium DL-lysine .gtoreq.17:1 zoledronic acid
sodium DL-lysine .gtoreq.18:1 zoledronic acid sodium DL-lysine
.gtoreq.19:1 zoledronic acid sodium DL-lysine .gtoreq.20:1
zoledronic acid sodium DL-lysine .gtoreq.25:1 zoledronic acid
sodium DL-lysine .gtoreq.50:1 zoledronic acid sodium DL-lysine
.gtoreq.750:1 zoledronic acid sodium DL-lysine .gtoreq.2500:1
zoledronic acid sodium DL-lysine .gtoreq.5000:1 zoledronic acid
sodium glycine .gtoreq.5:1 zoledronic acid sodium glycine
.gtoreq.50:1 zoledronic acid sodium glycine .gtoreq.750:1
zoledronic acid sodium glycine .gtoreq.2500:1 zoledronic acid
sodium glycine .gtoreq.5000:1 zoledronic acid ammonium L-lysine
.gtoreq.5:1 zoledronic acid ammonium L-lysine .gtoreq.50:1
zoledronic acid ammonium L-lysine .gtoreq.750:1 zoledronic acid
ammonium L-lysine .gtoreq.2500:1 zoledronic acid ammonium L-lysine
.gtoreq.5000:1 zoledronic acid ammonium DL-lysine .gtoreq.5:1
zoledronic acid ammonium DL-lysine .gtoreq.50:1 zoledronic acid
ammonium DL-lysine .gtoreq.750:1 zoledronic acid ammonium DL-lysine
.gtoreq.2500:1 zoledronic acid ammonium DL-lysine .gtoreq.5000:1
zoledronic acid ammonium glycine .gtoreq.5:1 zoledronic acid
ammonium glycine .gtoreq.50:1 zoledronic acid ammonium glycine
.gtoreq.750:1 zoledronic acid ammonium glycine .gtoreq.2500:1
zoledronic acid ammonium glycine .gtoreq.5000:1 zoledronic acid
ammonia L-lysine .gtoreq.5:1 zoledronic acid ammonia L-lysine
.gtoreq.50:1 zoledronic acid ammonia L-lysine .gtoreq.750:1
zoledronic acid ammonia L-lysine .gtoreq.2500:1 zoledronic acid
ammonia L-lysine .gtoreq.5000:1 zoledronic acid ammonia DL-lysine
.gtoreq.5:1 zoledronic acid ammonia DL-lysine .gtoreq.50:1
zoledronic acid ammonia DL-lysine .gtoreq.750:1 zoledronic acid
ammonia DL-lysine .gtoreq.2500:1 zoledronic acid ammonia DL-lysine
.gtoreq.5000:1 zoledronic acid ammonia glycine .gtoreq.5:1
zoledronic acid ammonia glycine .gtoreq.50:1 zoledronic acid
ammonia glycine .gtoreq.750:1 zoledronic acid ammonia glycine
.gtoreq.2500:1 zoledronic acid ammonia glycine .gtoreq.5000:1
zoledronic acid L-lysine L-lysine .gtoreq.5:1 zoledronic acid
L-lysine L-lysine .gtoreq.6:1 zoledronic acid L-lysine L-lysine
.gtoreq.7:1 zoledronic acid L-lysine L-lysine .gtoreq.8:1
zoledronic acid L-lysine L-lysine .gtoreq.9:1 zoledronic acid
L-lysine L-lysine .gtoreq.10:1 zoledronic acid L-lysine L-lysine
.gtoreq.11:1 zoledronic acid L-lysine L-lysine .gtoreq.12:1
zoledronic acid L-lysine L-lysine .gtoreq.13:1 zoledronic acid
L-lysine L-lysine .gtoreq.14:1 zoledronic acid L-lysine L-lysine
.gtoreq.15:1 zoledronic acid L-lysine L-lysine .gtoreq.16:1
zoledronic acid L-lysine L-lysine .gtoreq.17:1 zoledronic acid
L-lysine L-lysine .gtoreq.18:1 zoledronic acid L-lysine L-lysine
.gtoreq.19:1 zoledronic acid L-lysine L-lysine .gtoreq.20:1
zoledronic acid L-lysine L-lysine .gtoreq.25:1 zoledronic acid
L-lysine L-lysine .gtoreq.50:1 zoledronic acid L-lysine L-lysine
.gtoreq.750:1 zoledronic acid L-lysine L-lysine .gtoreq.2500:1
zoledronic acid L-lysine L-lysine .gtoreq.5000:1 zoledronic acid
L-lysine DL-lysine .gtoreq.5:1 zoledronic acid L-lysine DL-lysine
.gtoreq.6:1 zoledronic acid L-lysine DL-lysine .gtoreq.7:1
zoledronic acid L-lysine DL-lysine .gtoreq.8:1 zoledronic acid
L-lysine DL-lysine .gtoreq.9:1 zoledronic acid L-lysine DL-lysine
.gtoreq.10:1 zoledronic acid L-lysine DL-lysine .gtoreq.11:1
zoledronic acid L-lysine DL-lysine .gtoreq.12:1 zoledronic acid
L-lysine DL-lysine .gtoreq.13:1 zoledronic acid L-lysine DL-lysine
.gtoreq.14:1 zoledronic acid L-lysine DL-lysine .gtoreq.15:1
zoledronic acid L-lysine DL-lysine .gtoreq.16:1 zoledronic acid
L-lysine DL-lysine .gtoreq.17:1 zoledronic acid L-lysine DL-lysine
.gtoreq.18:1 zoledronic acid L-lysine DL-lysine .gtoreq.19:1
zoledronic acid L-lysine DL-lysine .gtoreq.20:1 zoledronic acid
L-lysine DL-lysine .gtoreq.25:1 zoledronic acid L-lysine DL-lysine
.gtoreq.50:1 zoledronic acid L-lysine DL-lysine .gtoreq.750:1
zoledronic acid L-lysine DL-lysine .gtoreq.2500:1 zoledronic acid
L-lysine DL-lysine .gtoreq.5000:1 zoledronic acid L-lysine glycine
.gtoreq.5:1 zoledronic acid L-lysine glycine .gtoreq.50:1
zoledronic acid L-lysine glycine .gtoreq.750:1 zoledronic acid
L-lysine glycine .gtoreq.2500:1 zoledronic acid L-lysine glycine
.gtoreq.5000:1 zoledronic acid DL-lysine L-lysine .gtoreq.5:1
zoledronic acid DL-lysine L-lysine .gtoreq.6:1 zoledronic acid
DL-lysine L-lysine .gtoreq.7:1 zoledronic acid DL-lysine L-lysine
.gtoreq.8:1 zoledronic acid DL-lysine L-lysine .gtoreq.9:1
zoledronic acid DL-lysine L-lysine .gtoreq.10:1 zoledronic acid
DL-lysine L-lysine .gtoreq.11:1 zoledronic acid DL-lysine L-lysine
.gtoreq.12:1 zoledronic acid DL-lysine L-lysine .gtoreq.13:1
zoledronic acid DL-lysine L-lysine .gtoreq.14:1 zoledronic acid
DL-lysine L-lysine .gtoreq.15:1 zoledronic acid DL-lysine L-lysine
.gtoreq.16:1 zoledronic acid DL-lysine L-lysine .gtoreq.17:1
zoledronic acid DL-lysine L-lysine .gtoreq.18:1 zoledronic acid
DL-lysine L-lysine .gtoreq.19:1 zoledronic acid DL-lysine L-lysine
.gtoreq.20:1 zoledronic acid DL-lysine L-lysine .gtoreq.25:1
zoledronic acid DL-lysine L-lysine .gtoreq.50:1 zoledronic acid
DL-lysine L-lysine .gtoreq.750:1 zoledronic acid DL-lysine L-lysine
.gtoreq.2500:1 zoledronic acid DL-lysine L-lysine .gtoreq.5000:1
zoledronic acid DL-lysine DL-lysine .gtoreq.5:1 zoledronic acid
DL-lysine DL-lysine .gtoreq.6:1 zoledronic acid DL-lysine DL-lysine
.gtoreq.7:1 zoledronic acid DL-lysine DL-lysine .gtoreq.8:1
zoledronic acid DL-lysine DL-lysine .gtoreq.9:1 zoledronic acid
DL-lysine DL-lysine .gtoreq.10:1 zoledronic acid DL-lysine
DL-lysine .gtoreq.11:1 zoledronic acid DL-lysine DL-lysine
.gtoreq.12:1 zoledronic acid DL-lysine DL-lysine .gtoreq.13:1
zoledronic acid DL-lysine DL-lysine .gtoreq.14:1 zoledronic acid
DL-lysine DL-lysine .gtoreq.15:1 zoledronic acid DL-lysine
DL-lysine .gtoreq.16:1 zoledronic acid DL-lysine DL-lysine
.gtoreq.17:1 zoledronic acid DL-lysine DL-lysine .gtoreq.18:1
zoledronic acid DL-lysine DL-lysine .gtoreq.19:1 zoledronic acid
DL-lysine DL-lysine .gtoreq.20:1 zoledronic acid DL-lysine
DL-lysine .gtoreq.25:1 zoledronic acid DL-lysine DL-lysine
.gtoreq.50:1 zoledronic acid DL-lysine DL-lysine .gtoreq.750:1
zoledronic acid DL-lysine DL-lysine .gtoreq.2500:1 zoledronic acid
DL-lysine DL-lysine .gtoreq.5000:1 zoledronic acid DL-lysine
glycine .gtoreq.5:1 zoledronic acid DL-lysine glycine .gtoreq.50:1
zoledronic acid DL-lysine glycine .gtoreq.750:1 zoledronic acid
DL-lysine glycine .gtoreq.2500:1 zoledronic acid DL-lysine glycine
.gtoreq.5000:1 zoledronic acid nicotinamide L-lysine .gtoreq.5:1
zoledronic acid nicotinamide L-lysine .gtoreq.50:1 zoledronic acid
nicotinamide L-lysine .gtoreq.750:1 zoledronic acid nicotinamide
L-lysine .gtoreq.2500:1 zoledronic acid nicotinamide L-lysine
.gtoreq.5000:1 zoledronic acid nicotinamide DL-lysine .gtoreq.5:1
zoledronic acid nicotinamide DL-lysine .gtoreq.50:1 zoledronic acid
nicotinamide DL-lysine .gtoreq.750:1 zoledronic acid nicotinamide
DL-lysine .gtoreq.2500:1 zoledronic acid nicotinamide DL-lysine
.gtoreq.5000:1 zoledronic acid nicotinamide glycine .gtoreq.5:1
zoledronic acid nicotinamide glycine .gtoreq.50:1 zoledronic acid
nicotinamide glycine .gtoreq.750:1 zoledronic acid nicotinamide
glycine .gtoreq.2500:1 zoledronic acid nicotinamide glycine
.gtoreq.5000:1 zoledronic acid adenine L-lysine .gtoreq.5:1
zoledronic acid adenine L-lysine .gtoreq.50:1 zoledronic acid
adenine L-lysine .gtoreq.750:1 zoledronic acid adenine L-lysine
.gtoreq.2500:1 zoledronic acid adenine L-lysine .gtoreq.5000:1
zoledronic acid adenine DL-lysine .gtoreq.5:1 zoledronic acid
adenine DL-lysine .gtoreq.50:1 zoledronic acid adenine DL-lysine
.gtoreq.750:1 zoledronic acid adenine DL-lysine .gtoreq.2500:1
zoledronic acid adenine DL-lysine .gtoreq.5000:1 zoledronic acid
adenine glycine .gtoreq.5:1 zoledronic acid adenine glycine
.gtoreq.50:1 zoledronic acid adenine glycine .gtoreq.750:1
zoledronic acid adenine glycine .gtoreq.2500:1 zoledronic acid
adenine glycine .gtoreq.5000:1 zoledronic acid glycine L-lysine
.gtoreq.5:1 zoledronic acid glycine L-lysine .gtoreq.50:1
zoledronic acid glycine L-lysine .gtoreq.750:1 zoledronic acid
glycine L-lysine .gtoreq.2500:1 zoledronic acid glycine L-lysine
.gtoreq.5000:1 zoledronic acid glycine DL-lysine .gtoreq.5:1
zoledronic acid glycine DL-lysine .gtoreq.50:1 zoledronic acid
glycine DL-lysine .gtoreq.750:1 zoledronic acid glycine DL-lysine
.gtoreq.2500:1 zoledronic acid glycine DL-lysine .gtoreq.5000:1
zoledronic acid glycine glycine .gtoreq.5:1 zoledronic acid glycine
glycine .gtoreq.50:1 zoledronic acid glycine glycine .gtoreq.750:1
zoledronic acid glycine glycine .gtoreq.2500:1 zoledronic acid
glycine glycine .gtoreq.5000:1 zoledronic acid free acid L-lysine
.gtoreq.5:1 zoledronic acid free acid L-lysine .gtoreq.6:1
zoledronic acid free acid L-lysine .gtoreq.7:1 zoledronic acid free
acid L-lysine .gtoreq.8:1 zoledronic acid free acid L-lysine
.gtoreq.9:1 zoledronic acid free acid L-lysine .gtoreq.10:1
zoledronic acid free acid L-lysine .gtoreq.11:1 zoledronic acid
free acid L-lysine .gtoreq.12:1 zoledronic acid free acid L-lysine
.gtoreq.13:1 zoledronic acid free acid L-lysine .gtoreq.14:1
zoledronic acid free acid L-lysine .gtoreq.15:1 zoledronic acid
free acid L-lysine .gtoreq.16:1 zoledronic acid free acid L-lysine
.gtoreq.17:1 zoledronic acid free acid L-lysine .gtoreq.18:1
zoledronic acid free acid L-lysine .gtoreq.19:1 zoledronic acid
free acid L-lysine .gtoreq.20:1 zoledronic acid free acid L-lysine
.gtoreq.25:1 zoledronic acid free acid L-lysine .gtoreq.50:1
zoledronic acid free acid L-lysine .gtoreq.750:1
zoledronic acid free acid L-lysine .gtoreq.2500:1 zoledronic acid
free acid L-lysine .gtoreq.5000:1 zoledronic acid free acid
DL-lysine .gtoreq.5:1 zoledronic acid free acid DL-lysine
.gtoreq.6:1 zoledronic acid free acid DL-lysine .gtoreq.7:1
zoledronic acid free acid DL-lysine .gtoreq.8:1 zoledronic acid
free acid DL-lysine .gtoreq.9:1 zoledronic acid free acid DL-lysine
.gtoreq.10:1 zoledronic acid free acid DL-lysine .gtoreq.11:1
zoledronic acid free acid DL-lysine .gtoreq.12:1 zoledronic acid
free acid DL-lysine .gtoreq.13:1 zoledronic acid free acid
DL-lysine .gtoreq.14:1 zoledronic acid free acid DL-lysine
.gtoreq.15:1 zoledronic acid free acid DL-lysine .gtoreq.16:1
zoledronic acid free acid DL-lysine .gtoreq.17:1 zoledronic acid
free acid DL-lysine .gtoreq.18:1 zoledronic acid free acid
DL-lysine .gtoreq.19:1 zoledronic acid free acid DL-lysine
.gtoreq.20:1 zoledronic acid free acid DL-lysine .gtoreq.25:1
zoledronic acid free acid DL-lysine .gtoreq.50:1 zoledronic acid
free acid DL-lysine .gtoreq.750:1 zoledronic acid free acid
DL-lysine .gtoreq.2500:1 zoledronic acid free acid DL-lysine
.gtoreq.5000:1 zoledronic acid free acid glycine .gtoreq.5:1
zoledronic acid free acid glycine .gtoreq.50:1 zoledronic acid free
acid glycine .gtoreq.750:1 zoledronic acid free acid glycine
.gtoreq.2500:1 zoledronic acid free acid glycine .gtoreq.5000:1
TABLE-US-00031 TABLE 14 Particular embodiments of compositions of
the present invention comprising: a crystalline molecular complex
(left column), an additional coformer (middle column), and the
ratio of the additional coformer to molecular complex coformer (by
mass) is indicated in the far right column. Each row of the above
table represents an individual embodiment of the present invention.
Mass Ratio of Additional Additional Coformer:Molecular Molecular
Complex Coformer Complex Coformer zoledronic acid, sodium
zoledronate and water complex L-lysine .gtoreq.5:1 characterized by
an X-ray powder diffraction pattern having peaks at about 8.1,
13.3, 21.5, 24.6, and 25.6 .+-. 0.2 degrees two-theta ammonium
zoledronic acid salt and water complex L-lysine .gtoreq.5:1
characterized by an X-ray powder diffraction pattern having strong
peaks at about 11.0, 14.6, 15.4, 19.9, and 29.4 .+-. 0.2 degrees
two-theta zoledronic diammonia water complex characterized by an
L-lysine .gtoreq.5:1 X-ray powder diffraction pattern having strong
peaks at about 12.2, 13.0, 14.1, 17.1, and 19.3 .+-. 0.2 degrees
two- theta zoledronic acid, L-lysine, and water complex
characterized L-lysine .gtoreq.5:1 by an X-ray powder diffraction
pattern having peaks at about 9.0, 14.4, 18.1, 26.0, and 29.6 .+-.
0.2 degrees two-theta zoledronic acid, L-lysine, and water complex
characterized L-lysine .gtoreq.5:1 by an X-ray powder diffraction
pattern comprising peaks at about 9.6, 10.7, 14.3, 21.4, 23.5 .+-.
0.2 degrees two theta zoledronic acid DL-lysine and water complex
characterized L-lysine .gtoreq.5:1 by an X-ray powder diffraction
pattern comprising peaks at about 8.3, 11.8, 12.3, 15.8, and 20.8
.+-. 0.2 degrees two-theta zoledronic acid, DL-lysine, and water
complex L-lysine .gtoreq.5:1 characterized by an X-ray powder
diffraction pattern comprising peaks at about 9.1, 14.7, 18.0,
21.2, and 26.0 .+-. 0.2 degrees two-theta zoledronic acid,
DL-lysine, and water complex L-lysine .gtoreq.5:1 characterized by
an X-ray powder diffraction pattern comprising peaks at about 9.7,
10.8, 14.4, 18.9, 21.4 .+-. 0.2 degrees two theta zoledronic acid,
zoledronic, DL-lysine, ethanol, and water L-lysine .gtoreq.5:1
complex characterized by an X-ray powder diffraction pattern
comprising peaks at about 8.8, 9.7, 17.6, 23.1, and 26.5 .+-. 0.2
degrees two-theta zoledronic acid, adenine, and water complex
characterized L-lysine .gtoreq.5:1 by an X-ray powder diffraction
pattern comprising peaks at about 13.6, 15.9, 19.7, 27.9, and 29.5
.+-. 0.2 degrees two- theta zoledronic acid, nicotinamide, and
water complex L-lysine .gtoreq.5:1 characterized by an X-ray powder
diffraction pattern comprising peaks at about 13.1, 15.2, 21.0,
23.9, and 26.5 .+-. 0.2 degrees two-theta zoledronic acid and
glycine complex characterized by an L-lysine .gtoreq.5:1 X-ray
powder diffraction pattern comprising peaks at about 10.2, 17.8,
19.9, 22.9, and 28.1 .+-. 0.2 degrees two-theta zoledronic acid,
sodium zoledronate and water complex L-lysine .gtoreq.40:1
characterized by an X-ray powder diffraction pattern having peaks
at about 8.1, 13.3, 21.5, 24.6, and 25.6 .+-. 0.2 degrees two-theta
ammonium zoledronic acid salt and water complex L-lysine
.gtoreq.40:1 characterized by an X-ray powder diffraction pattern
having strong peaks at about 11.0, 14.6, 15.4, 19.9, and 29.4 .+-.
0.2 degrees two-theta zoledronic diammonia water complex
characterized by an L-lysine .gtoreq.40:1 X-ray powder diffraction
pattern having strong peaks at about 12.2, 13.0, 14.1, 17.1, and
19.3 .+-. 0.2 degrees two- theta zoledronic acid, L-lysine, and
water complex characterized L-lysine .gtoreq.40:1 by an X-ray
powder diffraction pattern having peaks at about 9.0, 14.4, 18.1,
26.0, and 29.6 .+-. 0.2 degrees two-theta zoledronic acid,
L-lysine, and water complex characterized L-lysine .gtoreq.40:1 by
an X-ray powder diffraction pattern comprising peaks at about 9.6,
10.7, 14.3, 21.4, 23.5 .+-. 0.2 degrees two theta zoledronic acid
DL-lysine and water complex characterized L-lysine .gtoreq.40:1 by
an X-ray powder diffraction pattern comprising peaks at about 8.3,
11.8, 12.3, 15.8, and 20.8 .+-. 0.2 degrees two-theta zoledronic
acid, DL-lysine, and water complex L-lysine .gtoreq.40:1
characterized by an X-ray powder diffraction pattern comprising
peaks at about 9.1, 14.7, 18.0, 21.2, and 26.0 .+-. 0.2 degrees
two-theta zoledronic acid, DL-lysine, and water complex L-lysine
.gtoreq.40:1 characterized by an X-ray powder diffraction pattern
comprising peaks at about 9.7, 10.8, 14.4, 18.9, 21.4 .+-. 0.2
degrees two theta zoledronic acid, zoledronic, DL-lysine, ethanol,
and water L-lysine .gtoreq.40:1 complex characterized by an X-ray
powder diffraction pattern comprising peaks at about 8.8, 9.7,
17.6, 23.1, and 26.5 .+-. 0.2 degrees two-theta zoledronic acid,
adenine, and water complex characterized L-lysine .gtoreq.40:1 by
an X-ray powder diffraction pattern comprising peaks at about 13.6,
15.9, 19.7, 27.9, and 29.5 .+-. 0.2 degrees two- theta zoledronic
acid, nicotinamide, and water complex L-lysine .gtoreq.40:1
characterized by an X-ray powder diffraction pattern comprising
peaks at about 13.1, 15.2, 21.0, 23.9, and 26.5 .+-. 0.2 degrees
two-theta zoledronic acid and glycine complex characterized by an
L-lysine .gtoreq.40:1 X-ray powder diffraction pattern comprising
peaks at about 10.2, 17.8, 19.9, 22.9, and 28.1 .+-. 0.2 degrees
two-theta zoledronic acid, sodium zoledronate and water complex
L-lysine .gtoreq.750:1 characterized by an X-ray powder diffraction
pattern having peaks at about 8.1, 13.3, 21.5, 24.6, and 25.6 .+-.
0.2 degrees two-theta ammonium zoledronic acid salt and water
complex L-lysine .gtoreq.750:1 characterized by an X-ray powder
diffraction pattern having strong peaks at about 11.0, 14.6, 15.4,
19.9, and 29.4 .+-. 0.2 degrees two-theta zoledronic diammonia
water complex characterized by an L-lysine .gtoreq.750:1 X-ray
powder diffraction pattern having strong peaks at about 12.2, 13.0,
14.1, 17.1, and 19.3 .+-. 0.2 degrees two- theta zoledronic acid,
L-lysine, and water complex characterized L-lysine .gtoreq.750:1 by
an X-ray powder diffraction pattern having peaks at about 9.0,
14.4, 18.1, 26.0, and 29.6 .+-. 0.2 degrees two-theta zoledronic
acid, L-lysine, and water complex characterized L-lysine
.gtoreq.750:1 by an X-ray powder diffraction pattern comprising
peaks at about 9.6, 10.7, 14.3, 21.4, 23.5 .+-. 0.2 degrees two
theta zoledronic acid DL-lysine and water complex characterized
L-lysine .gtoreq.750:1 by an X-ray powder diffraction pattern
comprising peaks at about 8.3, 11.8, 12.3, 15.8, and 20.8 .+-. 0.2
degrees two-theta zoledronic acid, DL-lysine, and water complex
L-lysine .gtoreq.750:1 characterized by an X-ray powder diffraction
pattern comprising peaks at about 9.1, 14.7, 18.0, 21.2, and 26.0
.+-. 0.2 degrees two-theta zoledronic acid, DL-lysine, and water
complex L-lysine .gtoreq.750:1 characterized by an X-ray powder
diffraction pattern comprising peaks at about 9.7, 10.8, 14.4,
18.9, 21.4 .+-. 0.2 degrees two theta zoledronic acid, zoledronic,
DL-lysine, ethanol, and water L-lysine .gtoreq.750:1 complex
characterized by an X-ray powder diffraction pattern comprising
peaks at about 8.8, 9.7, 17.6, 23.1, and 26.5 .+-. 0.2 degrees
two-theta zoledronic acid, adenine, and water complex characterized
L-lysine .gtoreq.750:1 by an X-ray powder diffraction pattern
comprising peaks at about 13.6, 15.9, 19.7, 27.9, and 29.5 .+-. 0.2
degrees two- theta zoledronic acid, nicotinamide, and water complex
L-lysine .gtoreq.750:1 characterized by an X-ray powder diffraction
pattern comprising peaks at about 13.1, 15.2, 21.0, 23.9, and 26.5
.+-. 0.2 degrees two-theta zoledronic acid and glycine complex
characterized by an L-lysine .gtoreq.750:1 X-ray powder diffraction
pattern comprising peaks at about 10.2, 17.8, 19.9, 22.9, and 28.1
.+-. 0.2 degrees two-theta zoledronic acid, sodium zoledronate and
water complex L-lysine .gtoreq.1000:1 characterized by an X-ray
powder diffraction pattern having peaks at about 8.1, 13.3, 21.5,
24.6, and 25.6 .+-. 0.2 degrees two-theta ammonium zoledronic acid
salt and water complex L-lysine .gtoreq.1000:1 characterized by an
X-ray powder diffraction pattern having strong peaks at about 11.0,
14.6, 15.4, 19.9, and 29.4 .+-. 0.2 degrees two-theta zoledronic
diammonia water complex characterized by an L-lysine .gtoreq.1000:1
X-ray powder diffraction pattern having strong peaks at about 12.2,
13.0, 14.1, 17.1, and 19.3 .+-. 0.2 degrees two- theta zoledronic
acid, L-lysine, and water complex characterized L-lysine
.gtoreq.1000:1 by an X-ray powder diffraction pattern having peaks
at about 9.0, 14.4, 18.1, 26.0, and 29.6 .+-. 0.2 degrees two-theta
zoledronic acid, L-lysine, and water complex characterized L-lysine
.gtoreq.1000:1 by an X-ray powder diffraction pattern comprising
peaks at about 9.6, 10.7, 14.3, 21.4, 23.5 .+-. 0.2 degrees two
theta zoledronic acid DL-lysine and water complex characterized
L-lysine .gtoreq.1000:1 by an X-ray powder diffraction pattern
comprising peaks at about 8.3, 11.8, 12.3, 15.8, and 20.8 .+-. 0.2
degrees two-theta zoledronic acid, DL-lysine, and water complex
L-lysine .gtoreq.1000:1 characterized by an X-ray powder
diffraction pattern comprising peaks at about 9.1, 14.7, 18.0,
21.2, and 26.0 .+-. 0.2 degrees two-theta zoledronic acid,
DL-lysine, and water complex L-lysine .gtoreq.1000:1 characterized
by an X-ray powder diffraction pattern comprising peaks at about
9.7, 10.8, 14.4, 18.9, 21.4 .+-. 0.2 degrees two theta zoledronic
acid, zoledronic, DL-lysine, ethanol, and water L-lysine
.gtoreq.1000:1 complex characterized by an X-ray powder diffraction
pattern comprising peaks at about 8.8, 9.7, 17.6, 23.1, and 26.5
.+-. 0.2 degrees two-theta zoledronic acid, adenine, and water
complex characterized L-lysine .gtoreq.1000:1 by an X-ray powder
diffraction pattern comprising peaks at about 13.6, 15.9, 19.7,
27.9, and 29.5 .+-. 0.2 degrees two- theta zoledronic acid,
nicotinamide, and water complex L-lysine .gtoreq.1000:1
characterized by an X-ray powder diffraction pattern comprising
peaks at about 13.1, 15.2, 21.0, 23.9, and 26.5 .+-. 0.2 degrees
two-theta zoledronic acid and glycine complex characterized by an
L-lysine .gtoreq.1000:1 X-ray powder diffraction pattern comprising
peaks at about 10.2, 17.8, 19.9, 22.9, and 28.1 .+-. 0.2 degrees
two-theta zoledronic acid, sodium zoledronate and water complex
L-lysine .gtoreq.1000 .gtoreq. 5000:1 characterized by an X-ray
powder diffraction pattern having peaks at about 8.1, 13.3, 21.5,
24.6, and 25.6 .+-. 0.2 degrees two-theta ammonium zoledronic acid
salt and water complex L-lysine .gtoreq.1000 .gtoreq. 5000:1
characterized by an X-ray powder diffraction pattern having strong
peaks at about 11.0, 14.6, 15.4, 19.9, and 29.4 .+-. 0.2 degrees
two-theta zoledronic diammonia water complex characterized by an
L-lysine .gtoreq.1000 .gtoreq. 5000:1 X-ray powder diffraction
pattern having strong peaks at about 12.2, 13.0, 14.1, 17.1, and
19.3 .+-. 0.2 degrees two- theta zoledronic acid, L-lysine, and
water complex characterized L-lysine .gtoreq.1000 .gtoreq. 5000:1
by an X-ray powder diffraction pattern having peaks at about 9.0,
14.4, 18.1, 26.0, and 29.6 .+-. 0.2 degrees two-theta zoledronic
acid, L-lysine, and water complex characterized L-lysine
.gtoreq.1000 .gtoreq. 5000:1 by an X-ray powder diffraction pattern
comprising peaks at about 9.6, 10.7, 14.3, 21.4, 23.5 .+-. 0.2
degrees two theta zoledronic acid DL-lysine and water complex
characterized L-lysine .gtoreq.1000 .gtoreq. 5000:1 by an X-ray
powder diffraction pattern comprising peaks at
about 8.3, 11.8, 12.3, 15.8, and 20.8 .+-. 0.2 degrees two-theta
zoledronic acid, DL-lysine, and water complex L-lysine .gtoreq.1000
.gtoreq. 5000:1 characterized by an X-ray powder diffraction
pattern comprising peaks at about 9.1, 14.7, 18.0, 21.2, and 26.0
.+-. 0.2 degrees two-theta zoledronic acid, DL-lysine, and water
complex L-lysine .gtoreq.1000 .gtoreq. 5000:1 characterized by an
X-ray powder diffraction pattern comprising peaks at about 9.7,
10.8, 14.4, 18.9, 21.4 .+-. 0.2 degrees two theta zoledronic acid,
zoledronic, DL-lysine, ethanol, and water L-lysine .gtoreq.1000
.gtoreq. 5000:1 complex characterized by an X-ray powder
diffraction pattern comprising peaks at about 8.8, 9.7, 17.6, 23.1,
and 26.5 .+-. 0.2 degrees two-theta zoledronic acid, adenine, and
water complex characterized L-lysine .gtoreq.1000 .gtoreq. 5000:1
by an X-ray powder diffraction pattern comprising peaks at about
13.6, 15.9, 19.7, 27.9, and 29.5 .+-. 0.2 degrees two- theta
zoledronic acid, nicotinamide, and water complex L-lysine
.gtoreq.1000 .gtoreq. 5000:1 characterized by an X-ray powder
diffraction pattern comprising peaks at about 13.1, 15.2, 21.0,
23.9, and 26.5 .+-. 0.2 degrees two-theta zoledronic acid and
glycine complex characterized by an L-lysine .gtoreq.1000 .gtoreq.
5000:1 X-ray powder diffraction pattern comprising peaks at about
10.2, 17.8, 19.9, 22.9, and 28.1 .+-. 0.2 degrees two-theta
zoledronic acid, sodium zoledronate and water complex D,L-lysine
.gtoreq.5:1 characterized by an X-ray powder diffraction pattern
having peaks at about 8.1, 13.3, 21.5, 24.6, and 25.6 .+-. 0.2
degrees two-theta ammonium zoledronic acid salt and water complex
D,L-lysine .gtoreq.5:1 characterized by an X-ray powder diffraction
pattern having strong peaks at about 11.0, 14.6, 15.4, 19.9, and
29.4 .+-. 0.2 degrees two-theta zoledronic diammonia water complex
characterized by an D,L-lysine .gtoreq.5:1 X-ray powder diffraction
pattern having strong peaks at about 12.2, 13.0, 14.1, 17.1, and
19.3 .+-. 0.2 degrees two- theta zoledronic acid, L-lysine, and
water complex characterized D,L-lysine .gtoreq.5:1 by an X-ray
powder diffraction pattern having peaks at about 9.0, 14.4, 18.1,
26.0, and 29.6 .+-. 0.2 degrees two-theta zoledronic acid,
L-lysine, and water complex characterized DL-lysine .gtoreq.5:1 by
an X-ray powder diffraction pattern comprising peaks at about 9.6,
10.7, 14.3, 21.4, 23.5 .+-. 0.2 degrees two theta zoledronic acid
DL-lysine and water complex characterized DL-lysine .gtoreq.5:1 by
an X-ray powder diffraction pattern comprising peaks at about 8.3,
11.8, 12.3, 15.8, and 20.8 .+-. 0.2 degrees two-theta zoledronic
acid, DL-lysine, and water complex DL-lysine .gtoreq.5:1
characterized by an X-ray powder diffraction pattern comprising
peaks at about 9.1, 14.7, 18.0, 21.2, and 26.0 .+-. 0.2 degrees
two-theta zoledronic acid, DL-lysine, and water complex DL-lysine
.gtoreq.5:1 characterized by an X-ray powder diffraction pattern
comprising peaks at about 9.7, 10.8, 14.4, 18.9, 21.4 .+-. 0.2
degrees two theta zoledronic acid, zoledronic, DL-lysine, ethanol,
and water DL-lysine .gtoreq.5:1 complex characterized by an X-ray
powder diffraction pattern comprising peaks at about 8.8, 9.7,
17.6, 23.1, and 26.5 .+-. 0.2 degrees two-theta zoledronic acid,
adenine, and water complex characterized DL-lysine .gtoreq.5:1 by
an X-ray powder diffraction pattern comprising peaks at about 13.6,
15.9, 19.7, 27.9, and 29.5 .+-. 0.2 degrees two- theta zoledronic
acid, nicotinamide, and water complex DL-lysine .gtoreq.5:1
characterized by an X-ray powder diffraction pattern comprising
peaks at about 13.1, 15.2, 21.0, 23.9, and 26.5 .+-. 0.2 degrees
two-theta zoledronic acid and glycine complex characterized by an
DL-lysine .gtoreq.5:1 X-ray powder diffraction pattern comprising
peaks at about 10.2, 17.8, 19.9, 22.9, and 28.1 .+-. 0.2 degrees
two-theta zoledronic acid, sodium zoledronate and water complex
DL-lysine .gtoreq.40:1 characterized by an X-ray powder diffraction
pattern having peaks at about 8.1, 13.3, 21.5, 24.6, and 25.6 .+-.
0.2 degrees two-theta ammonium zoledronic acid salt and water
complex DL-lysine .gtoreq.40:1 characterized by an X-ray powder
diffraction pattern having strong peaks at about 11.0, 14.6, 15.4,
19.9, and 29.4 .+-. 0.2 degrees two-theta zoledronic diammonia
water complex characterized by an DL-lysine .gtoreq.40:1 X-ray
powder diffraction pattern having strong peaks at about 12.2, 13.0,
14.1, 17.1, and 19.3 .+-. 0.2 degrees two- theta zoledronic acid,
L-lysine, and water complex characterized DL-lysine .gtoreq.40:1 by
an X-ray powder diffraction pattern having peaks at about 9.0,
14.4, 18.1, 26.0, and 29.6 .+-. 0.2 degrees two-theta zoledronic
acid, L-lysine, and water complex characterized DL-lysine
.gtoreq.40:1 by an X-ray powder diffraction pattern comprising
peaks at about 9.6, 10.7, 14.3, 21.4, 23.5 .+-. 0.2 degrees two
theta zoledronic acid DL-lysine and water complex characterized
DL-lysine .gtoreq.40:1 by an X-ray powder diffraction pattern
comprising peaks at about 8.3, 11.8, 12.3, 15.8, and 20.8 .+-. 0.2
degrees two-theta zoledronic acid, DL-lysine, and water complex
DL-lysine .gtoreq.40:1 characterized by an X-ray powder diffraction
pattern comprising peaks at about 9.1, 14.7, 18.0, 21.2, and 26.0
.+-. 0.2 degrees two-theta zoledronic acid, DL-lysine, and water
complex DL-lysine .gtoreq.40:1 characterized by an X-ray powder
diffraction pattern comprising peaks at about 9.7, 10.8, 14.4,
18.9, 21.4 .+-. 0.2 degrees two theta zoledronic acid, zoledronic,
DL-lysine, ethanol, and water DL-lysine .gtoreq.40:1 complex
characterized by an X-ray powder diffraction pattern comprising
peaks at about 8.8, 9.7, 17.6, 23.1, and 26.5 .+-. 0.2 degrees
two-theta zoledronic acid, adenine, and water complex characterized
DL-lysine .gtoreq.40:1 by an X-ray powder diffraction pattern
comprising peaks at about 13.6, 15.9, 19.7, 27.9, and 29.5 .+-. 0.2
degrees two- theta zoledronic acid, nicotinamide, and water complex
DL-lysine .gtoreq.40:1 characterized by an X-ray powder diffraction
pattern comprising peaks at about 13.1, 15.2, 21.0, 23.9, and 26.5
.+-. 0.2 degrees two-theta zoledronic acid and glycine complex
characterized by an DL-lysine .gtoreq.40:1 X-ray powder diffraction
pattern comprising peaks at about 10.2, 17.8, 19.9, 22.9, and 28.1
.+-. 0.2 degrees two-theta zoledronic acid, sodium zoledronate and
water complex DL-lysine .gtoreq.750:1 characterized by an X-ray
powder diffraction pattern having peaks at about 8.1, 13.3, 21.5,
24.6, and 25.6 .+-. 0.2 degrees two-theta ammonium zoledronic acid
salt and water complex DL-lysine .gtoreq.750:1 characterized by an
X-ray powder diffraction pattern having strong peaks at about 11.0,
14.6, 15.4, 19.9, and 29.4 .+-. 0.2 degrees two-theta zoledronic
diammonia water complex characterized by an DL-lysine .gtoreq.750:1
X-ray powder diffraction pattern having strong peaks at about 12.2,
13.0, 14.1, 17.1, and 19.3 .+-. 0.2 degrees two- theta zoledronic
acid, L-lysine, and water complex characterized DL-lysine
.gtoreq.750:1 by an X-ray powder diffraction pattern having peaks
at about 9.0, 14.4, 18.1, 26.0, and 29.6 .+-. 0.2 degrees two-theta
zoledronic acid, L-lysine, and water complex characterized
DL-lysine .gtoreq.750:1 by an X-ray powder diffraction pattern
comprising peaks at about 9.6, 10.7, 14.3, 21.4, 23.5 .+-. 0.2
degrees two theta zoledronic acid DL-lysine and water complex
characterized DL-lysine .gtoreq.750:1 by an X-ray powder
diffraction pattern comprising peaks at about 8.3, 11.8, 12.3,
15.8, and 20.8 .+-. 0.2 degrees two-theta zoledronic acid,
DL-lysine, and water complex DL-lysine .gtoreq.750:1 characterized
by an X-ray powder diffraction pattern comprising peaks at about
9.1, 14.7, 18.0, 21.2, and 26.0 .+-. 0.2 degrees two-theta
zoledronic acid, DL-lysine, and water complex DL-lysine
.gtoreq.750:1 characterized by an X-ray powder diffraction pattern
comprising peaks at about 9.7, 10.8, 14.4, 18.9, 21.4 .+-. 0.2
degrees two theta zoledronic acid, zoledronic, DL-lysine, ethanol,
and water DL-lysine .gtoreq.750:1 complex characterized by an X-ray
powder diffraction pattern comprising peaks at about 8.8, 9.7,
17.6, 23.1, and 26.5 .+-. 0.2 degrees two-theta zoledronic acid,
adenine, and water complex characterized DL-lysine .gtoreq.750:1 by
an X-ray powder diffraction pattern comprising peaks at about 13.6,
15.9, 19.7, 27.9, and 29.5 .+-. 0.2 degrees two- theta zoledronic
acid, nicotinamide, and water complex DL-lysine .gtoreq.750:1
characterized by an X-ray powder diffraction pattern comprising
peaks at about 13.1, 15.2, 21.0, 23.9, and 26.5 .+-. 0.2 degrees
two-theta zoledronic acid and glycine complex characterized by an
DL-lysine .gtoreq.750:1 X-ray powder diffraction pattern comprising
peaks at about 10.2, 17.8, 19.9, 22.9, and 28.1 .+-. 0.2 degrees
two-theta zoledronic acid, sodium zoledronate and water complex
DL-lysine .gtoreq.1000:1 characterized by an X-ray powder
diffraction pattern having peaks at about 8.1, 13.3, 21.5, 24.6,
and 25.6 .+-. 0.2 degrees two-theta ammonium zoledronic acid salt
and water complex DL-lysine .gtoreq.1000:1 characterized by an
X-ray powder diffraction pattern having strong peaks at about 11.0,
14.6, 15.4, 19.9, and 29.4 .+-. 0.2 degrees two-theta zoledronic
diammonia water complex characterized by an DL-lysine
.gtoreq.1000:1 X-ray powder diffraction pattern having strong peaks
at about 12.2, 13.0, 14.1, 17.1, and 19.3 .+-. 0.2 degrees two-
theta zoledronic acid, L-lysine, and water complex characterized
DL-lysine .gtoreq.1000:1 by an X-ray powder diffraction pattern
having peaks at about 9.0, 14.4, 18.1, 26.0, and 29.6 .+-. 0.2
degrees two-theta zoledronic acid, L-lysine, and water complex
characterized DL-lysine .gtoreq.1000:1 by an X-ray powder
diffraction pattern comprising peaks at about 9.6, 10.7, 14.3,
21.4, 23.5 .+-. 0.2 degrees two theta zoledronic acid DL-lysine and
water complex characterized DL-lysine .gtoreq.1000:1 by an X-ray
powder diffraction pattern comprising peaks at about 8.3, 11.8,
12.3, 15.8, and 20.8 .+-. 0.2 degrees two-theta zoledronic acid,
DL-lysine, and water complex DL-lysine .gtoreq.1000:1 characterized
by an X-ray powder diffraction pattern comprising peaks at about
9.1, 14.7, 18.0, 21.2, and 26.0 .+-. 0.2 degrees two-theta
zoledronic acid, DL-lysine, and water complex DL-lysine
.gtoreq.1000:1 characterized by an X-ray powder diffraction pattern
comprising peaks at about 9.7, 10.8, 14.4, 18.9, 21.4 .+-. 0.2
degrees two theta zoledronic acid, zoledronic, DL-lysine, ethanol,
and water DL-lysine .gtoreq.1000:1 complex characterized by an
X-ray powder diffraction pattern comprising peaks at about 8.8,
9.7, 17.6, 23.1, and 26.5 .+-. 0.2 degrees two-theta zoledronic
acid, adenine, and water complex characterized DL-lysine
.gtoreq.1000:1 by an X-ray powder diffraction pattern comprising
peaks at about 13.6, 15.9, 19.7, 27.9, and 29.5 .+-. 0.2 degrees
two- theta zoledronic acid, nicotinamide, and water complex
DL-lysine .gtoreq.1000:1 characterized by an X-ray powder
diffraction pattern comprising peaks at about 13.1, 15.2, 21.0,
23.9, and 26.5 .+-. 0.2 degrees two-theta zoledronic acid and
glycine complex characterized by an DL-lysine .gtoreq.1000:1 X-ray
powder diffraction pattern comprising peaks at about 10.2, 17.8,
19.9, 22.9, and 28.1 .+-. 0.2 degrees two-theta zoledronic acid,
sodium zoledronate and water complex DL-lysine .gtoreq.5000:1
characterized by an X-ray powder diffraction pattern having peaks
at about 8.1, 13.3, 21.5, 24.6, and 25.6 .+-. 0.2 degrees two-theta
ammonium zoledronic acid salt and water complex DL-lysine
.gtoreq.5000:1 characterized by an X-ray powder diffraction pattern
having strong peaks at about 11.0, 14.6, 15.4, 19.9, and 29.4 .+-.
0.2 degrees two-theta zoledronic diammonia water complex
characterized by an DL-lysine .gtoreq.5000:1 X-ray powder
diffraction pattern having strong peaks at about 12.2, 13.0, 14.1,
17.1, and 19.3 .+-. 0.2 degrees two-
theta zoledronic acid, L-lysine, and water complex characterized
DL-lysine .gtoreq.5000:1 by an X-ray powder diffraction pattern
having peaks at about 9.0, 14.4, 18.1, 26.0, and 29.6 .+-. 0.2
degrees two-theta zoledronic acid, L-lysine, and water complex
characterized DL-lysine .gtoreq.5000:1 by an X-ray powder
diffraction pattern comprising peaks at about 9.6, 10.7, 14.3,
21.4, 23.5 .+-. 0.2 degrees two theta zoledronic acid DL-lysine and
water complex characterized DL-lysine .gtoreq.5000:1 by an X-ray
powder diffraction pattern comprising peaks at about 8.3, 11.8,
12.3, 15.8, and 20.8 .+-. 0.2 degrees two-theta zoledronic acid,
DL-lysine, and water complex DL-lysine .gtoreq.5000:1 characterized
by an X-ray powder diffraction pattern comprising peaks at about
9.1, 14.7, 18.0, 21.2, and 26.0 .+-. 0.2 degrees two-theta
zoledronic acid, DL-lysine, and water complex DL-lysine
.gtoreq.5000:1 characterized by an X-ray powder diffraction pattern
comprising peaks at about 9.7, 10.8, 14.4, 18.9, 21.4 .+-. 0.2
degrees two theta zoledronic acid, zoledronic, DL-lysine, ethanol,
and water DL-lysine .gtoreq.5000:1 complex characterized by an
X-ray powder diffraction pattern comprising peaks at about 8.8,
9.7, 17.6, 23.1, and 26.5 .+-. 0.2 degrees two-theta zoledronic
acid, adenine, and water complex characterized DL-lysine
.gtoreq.5000:1 by an X-ray powder diffraction pattern comprising
peaks at about 13.6, 15.9, 19.7, 27.9, and 29.5 .+-. 0.2 degrees
two- theta zoledronic acid, nicotinamide, and water complex
DL-lysine .gtoreq.5000:1 characterized by an X-ray powder
diffraction pattern comprising peaks at about 13.1, 15.2, 21.0,
23.9, and 26.5 .+-. 0.2 degrees two-theta zoledronic acid and
glycine complex characterized by an DL-lysine .gtoreq.5000:1 X-ray
powder diffraction pattern comprising peaks at about 10.2, 17.8,
19.9, 22.9, and 28.1 .+-. 0.2 degrees two-theta zoledronic acid,
sodium zoledronate and water complex glycine .gtoreq.5:1
characterized by an X-ray powder diffraction pattern having peaks
at about 8.1, 13.3, 21.5, 24.6, and 25.6 .+-. 0.2 degrees two-theta
ammonium zoledronic acid salt and water complex glycine .gtoreq.5:1
characterized by an X-ray powder diffraction pattern having strong
peaks at about 11.0, 14.6, 15.4, 19.9, and 29.4 .+-. 0.2 degrees
two-theta zoledronic diammonia water complex characterized by an
glycine .gtoreq.5:1 X-ray powder diffraction pattern having strong
peaks at about 12.2, 13.0, 14.1, 17.1, and 19.3 .+-. 0.2 degrees
two- theta zoledronic acid, L-lysine, and water complex
characterized glycine .gtoreq.5:1 by an X-ray powder diffraction
pattern having peaks at about 9.0, 14.4, 18.1, 26.0, and 29.6 .+-.
0.2 degrees two-theta zoledronic acid, L-lysine, and water complex
characterized glycine .gtoreq.5:1 by an X-ray powder diffraction
pattern comprising peaks at about 9.6, 10.7, 14.3, 21.4, 23.5 .+-.
0.2 degrees two theta zoledronic acid DL-lysine and water complex
characterized glycine .gtoreq.5:1 by an X-ray powder diffraction
pattern comprising peaks at about 8.3, 11.8, 12.3, 15.8, and 20.8
.+-. 0.2 degrees two-theta zoledronic acid, DL-lysine, and water
complex glycine .gtoreq.5:1 characterized by an X-ray powder
diffraction pattern comprising peaks at about 9.1, 14.7, 18.0,
21.2, and 26.0 .+-. 0.2 degrees two-theta zoledronic acid,
DL-lysine, and water complex glycine .gtoreq.5:1 characterized by
an X-ray powder diffraction pattern comprising peaks at about 9.7,
10.8, 14.4, 18.9, 21.4 .+-. 0.2 degrees two theta zoledronic acid,
zoledronic, DL-lysine, ethanol, and water glycine .gtoreq.5:1
complex characterized by an X-ray powder diffraction pattern
comprising peaks at about 8.8, 9.7, 17.6, 23.1, and 26.5 .+-. 0.2
degrees two-theta zoledronic acid, adenine, and water complex
characterized glycine .gtoreq.5:1 by an X-ray powder diffraction
pattern comprising peaks at about 13.6, 15.9, 19.7, 27.9, and 29.5
.+-. 0.2 degrees two- theta zoledronic acid, nicotinamide, and
water complex glycine .gtoreq.5:1 characterized by an X-ray powder
diffraction pattern comprising peaks at about 13.1, 15.2, 21.0,
23.9, and 26.5 .+-. 0.2 degrees two-theta zoledronic acid and
glycine complex characterized by an glycine .gtoreq.5:1 X-ray
powder diffraction pattern comprising peaks at about 10.2, 17.8,
19.9, 22.9, and 28.1 .+-. 0.2 degrees two-theta zoledronic acid,
sodium zoledronate and water complex glycine .gtoreq.40:1
characterized by an X-ray powder diffraction pattern having peaks
at about 8.1, 13.3, 21.5, 24.6, and 25.6 .+-. 0.2 degrees two-theta
ammonium zoledronic acid salt and water complex glycine
.gtoreq.40:1 characterized by an X-ray powder diffraction pattern
having strong peaks at about 11.0, 14.6, 15.4, 19.9, and 29.4 .+-.
0.2 degrees two-theta zoledronic diammonia water complex
characterized by an glycine .gtoreq.40:1 X-ray powder diffraction
pattern having strong peaks at about 12.2, 13.0, 14.1, 17.1, and
19.3 .+-. 0.2 degrees two- theta zoledronic acid, L-lysine, and
water complex characterized glycine .gtoreq.40:1 by an X-ray powder
diffraction pattern having peaks at about 9.0, 14.4, 18.1, 26.0,
and 29.6 .+-. 0.2 degrees two-theta zoledronic acid, L-lysine, and
water complex characterized glycine .gtoreq.40:1 by an X-ray powder
diffraction pattern comprising peaks at about 9.6, 10.7, 14.3,
21.4, 23.5 .+-. 0.2 degrees two theta zoledronic acid DL-lysine and
water complex characterized glycine .gtoreq.40:1 by an X-ray powder
diffraction pattern comprising peaks at about 8.3, 11.8, 12.3,
15.8, and 20.8 .+-. 0.2 degrees two-theta zoledronic acid,
DL-lysine, and water complex glycine .gtoreq.40:1 characterized by
an X-ray powder diffraction pattern comprising peaks at about 9.1,
14.7, 18.0, 21.2, and 26.0 .+-. 0.2 degrees two-theta zoledronic
acid, DL-lysine, and water complex glycine .gtoreq.40:1
characterized by an X-ray powder diffraction pattern comprising
peaks at about 9.7, 10.8, 14.4, 18.9, 21.4 .+-. 0.2 degrees two
theta zoledronic acid, zoledronic, DL-lysine, ethanol, and water
glycine .gtoreq.40:1 complex characterized by an X-ray powder
diffraction pattern comprising peaks at about 8.8, 9.7, 17.6, 23.1,
and 26.5 .+-. 0.2 degrees two-theta zoledronic acid, adenine, and
water complex characterized glycine .gtoreq.40:1 by an X-ray powder
diffraction pattern comprising peaks at about 13.6, 15.9, 19.7,
27.9, and 29.5 .+-. 0.2 degrees two- theta zoledronic acid,
nicotinamide, and water complex glycine .gtoreq.40:1 characterized
by an X-ray powder diffraction pattern comprising peaks at about
13.1, 15.2, 21.0, 23.9, and 26.5 .+-. 0.2 degrees two-theta
zoledronic acid and glycine complex characterized by an glycine
.gtoreq.40:1 X-ray powder diffraction pattern comprising peaks at
about 10.2, 17.8, 19.9, 22.9, and 28.1 .+-. 0.2 degrees two-theta
zoledronic acid, sodium zoledronate and water complex glycine
.gtoreq.750:1 characterized by an X-ray powder diffraction pattern
having peaks at about 8.1, 13.3, 21.5, 24.6, and 25.6 .+-. 0.2
degrees two-theta ammonium zoledronic acid salt and water complex
glycine .gtoreq.750:1 characterized by an X-ray powder diffraction
pattern having strong peaks at about 11.0, 14.6, 15.4, 19.9, and
29.4 .+-. 0.2 degrees two-theta zoledronic diammonia water complex
characterized by an glycine .gtoreq.750:1 X-ray powder diffraction
pattern having strong peaks at about 12.2, 13.0, 14.1, 17.1, and
19.3 .+-. 0.2 degrees two- theta zoledronic acid, L-lysine, and
water complex characterized glycine .gtoreq.750:1 by an X-ray
powder diffraction pattern having peaks at about 9.0, 14.4, 18.1,
26.0, and 29.6 .+-. 0.2 degrees two-theta zoledronic acid,
L-lysine, and water complex characterized glycine .gtoreq.750:1 by
an X-ray powder diffraction pattern comprising peaks at about 9.6,
10.7, 14.3, 21.4, 23.5 .+-. 0.2 degrees two theta zoledronic acid
DL-lysine and water complex characterized glycine .gtoreq.750:1 by
an X-ray powder diffraction pattern comprising peaks at about 8.3,
11.8, 12.3, 15.8, and 20.8 .+-. 0.2 degrees two-theta zoledronic
acid, DL-lysine, and water complex glycine .gtoreq.750:1
characterized by an X-ray powder diffraction pattern comprising
peaks at about 9.1, 14.7, 18.0, 21.2, and 26.0 .+-. 0.2 degrees
two-theta zoledronic acid, DL-lysine, and water complex glycine
.gtoreq.750:1 characterized by an X-ray powder diffraction pattern
comprising peaks at about 9.7, 10.8, 14.4, 18.9, 21.4 .+-. 0.2
degrees two theta zoledronic acid, zoledronic, DL-lysine, ethanol,
and water glycine .gtoreq.750:1 complex characterized by an X-ray
powder diffraction pattern comprising peaks at about 8.8, 9.7,
17.6, 23.1, and 26.5 .+-. 0.2 degrees two-theta zoledronic acid,
adenine, and water complex characterized glycine .gtoreq.750:1 by
an X-ray powder diffraction pattern comprising peaks at about 13.6,
15.9, 19.7, 27.9, and 29.5 .+-. 0.2 degrees two- theta zoledronic
acid, nicotinamide, and water complex glycine .gtoreq.750:1
characterized by an X-ray powder diffraction pattern comprising
peaks at about 13.1, 15.2, 21.0, 23.9, and 26.5 .+-. 0.2 degrees
two-theta zoledronic acid and glycine complex characterized by an
glycine .gtoreq.750:1 X-ray powder diffraction pattern comprising
peaks at about 10.2, 17.8, 19.9, 22.9, and 28.1 .+-. 0.2 degrees
two-theta zoledronic acid, sodium zoledronate and water complex
glycine .gtoreq.1000:1 characterized by an X-ray powder diffraction
pattern having peaks at about 8.1, 13.3, 21.5, 24.6, and 25.6 .+-.
0.2 degrees two-theta ammonium zoledronic acid salt and water
complex glycine .gtoreq.1000:1 characterized by an X-ray powder
diffraction pattern having strong peaks at about 11.0, 14.6, 15.4,
19.9, and 29.4 .+-. 0.2 degrees two-theta zoledronic diammonia
water complex characterized by an glycine .gtoreq.1000:1 X-ray
powder diffraction pattern having strong peaks at about 12.2, 13.0,
14.1, 17.1, and 19.3 .+-. 0.2 degrees two- theta zoledronic acid,
L-lysine, and water complex characterized glycine .gtoreq.1000:1 by
an X-ray powder diffraction pattern having peaks at about 9.0,
14.4, 18.1, 26.0, and 29.6 .+-. 0.2 degrees two-theta zoledronic
acid, L-lysine, and water complex characterized glycine
.gtoreq.1000:1 by an X-ray powder diffraction pattern comprising
peaks at about 9.6, 10.7, 14.3, 21.4, 23.5 .+-. 0.2 degrees two
theta zoledronic acid DL-lysine and water complex characterized
glycine .gtoreq.1000:1 by an X-ray powder diffraction pattern
comprising peaks at about 8.3, 11.8, 12.3, 15.8, and 20.8 .+-. 0.2
degrees two-theta zoledronic acid, DL-lysine, and water complex
glycine .gtoreq.1000:1 characterized by an X-ray powder diffraction
pattern comprising peaks at about 9.1, 14.7, 18.0, 21.2, and 26.0
.+-. 0.2 degrees two-theta zoledronic acid, DL-lysine, and water
complex glycine .gtoreq.1000:1 characterized by an X-ray powder
diffraction pattern comprising peaks at about 9.7, 10.8, 14.4,
18.9, 21.4 .+-. 0.2 degrees two theta zoledronic acid, zoledronic,
DL-lysine, ethanol, and water glycine .gtoreq.1000:1 complex
characterized by an X-ray powder diffraction pattern comprising
peaks at about 8.8, 9.7, 17.6, 23.1, and 26.5 .+-. 0.2 degrees
two-theta zoledronic acid, adenine, and water complex characterized
glycine .gtoreq.1000:1 by an X-ray powder diffraction pattern
comprising peaks at about 13.6, 15.9, 19.7, 27.9, and 29.5 .+-. 0.2
degrees two- theta zoledronic acid, nicotinamide, and water complex
glycine .gtoreq.1000:1 characterized by an X-ray powder diffraction
pattern comprising peaks at about 13.1, 15.2, 21.0, 23.9, and 26.5
.+-. 0.2 degrees two-theta zoledronic acid and glycine complex
characterized by an glycine .gtoreq.1000:1 X-ray powder diffraction
pattern comprising peaks at about 10.2, 17.8, 19.9, 22.9, and 28.1
.+-. 0.2 degrees two-theta zoledronic acid, sodium zoledronate and
water complex glycine .gtoreq.5000:1 characterized by an X-ray
powder diffraction pattern having peaks at about 8.1, 13.3, 21.5,
24.6, and 25.6 .+-. 0.2
degrees two-theta ammonium zoledronic acid salt and water complex
glycine .gtoreq.5000:1 characterized by an X-ray powder diffraction
pattern having strong peaks at about 11.0, 14.6, 15.4, 19.9, and
29.4 .+-. 0.2 degrees two-theta zoledronic diammonia water complex
characterized by an glycine .gtoreq.5000:1 X-ray powder diffraction
pattern having strong peaks at about 12.2, 13.0, 14.1, 17.1, and
19.3 .+-. 0.2 degrees two- theta zoledronic acid, L-lysine, and
water complex characterized glycine .gtoreq.5000:1 by an X-ray
powder diffraction pattern having peaks at about 9.0, 14.4, 18.1,
26.0, and 29.6 .+-. 0.2 degrees two-theta zoledronic acid,
L-lysine, and water complex characterized glycine .gtoreq.5000:1 by
an X-ray powder diffraction pattern comprising peaks at about 9.6,
10.7, 14.3, 21.4, 23.5 .+-. 0.2 degrees two theta zoledronic acid
DL-lysine and water complex characterized glycine .gtoreq.5000:1 by
an X-ray powder diffraction pattern comprising peaks at about 8.3,
11.8, 12.3, 15.8, and 20.8 .+-. 0.2 degrees two-theta zoledronic
acid, DL-lysine, and water complex glycine .gtoreq.5000:1
characterized by an X-ray powder diffraction pattern comprising
peaks at about 9.1, 14.7, 18.0, 21.2, and 26.0 .+-. 0.2 degrees
two-theta zoledronic acid, DL-lysine, and water complex glycine
.gtoreq.5000:1 characterized by an X-ray powder diffraction pattern
comprising peaks at about 9.7, 10.8, 14.4, 18.9, 21.4 .+-. 0.2
degrees two theta zoledronic acid, zoledronic, DL-lysine, ethanol,
and water glycine .gtoreq.5000:1 complex characterized by an X-ray
powder diffraction pattern comprising peaks at about 8.8, 9.7,
17.6, 23.1, and 26.5 .+-. 0.2 degrees two-theta zoledronic acid,
adenine, and water complex characterized glycine .gtoreq.5000:1 by
an X-ray powder diffraction pattern comprising peaks at about 13.6,
15.9, 19.7, 27.9, and 29.5 .+-. 0.2 degrees two- theta zoledronic
acid, nicotinamide, and water complex glycine .gtoreq.5000:1
characterized by an X-ray powder diffraction pattern comprising
peaks at about 13.1, 15.2, 21.0, 23.9, and 26.5 .+-. 0.2 degrees
two-theta zoledronic acid and glycine complex characterized by an
glycine .gtoreq.5000:1 X-ray powder diffraction pattern comprising
peaks at about 10.2, 17.8, 19.9, 22.9, and 28.1 .+-. 0.2 degrees
two-theta
TABLE-US-00032 TABLE 15 Particular embodiments of unit doses of a
pharmaceutical composition of the present invention comprising: a
bisphosphonic acid (left column), an amino acid, present as either
a molecular complex coformer, additional coformer or both molecular
complex coformer and additional coformer (middle column), and
amount of the amino acid in a unit dose of bisphos- phonic acid
(right column). Each row of the above table represents an
individual embodiment of the present invention. Amount of Amount of
Amino Bisphosphonic Acid per Unit Dose Bisphosphonic Acid per Unit
of Bisphosphonic Acid Dose of Amino Acid Acid zoledronic acid
40-120 mg lysine .gtoreq.500 mg zoledronic acid 40-120 mg lysine
.gtoreq.750 mg zoledronic acid 40-120 mg lysine .gtoreq.1000 mg
zoledronic acid 40-120 mg lysine .gtoreq.1250 mg zoledronic acid
40-120 mg lysine .gtoreq.1500 mg zoledronic acid 40-120 mg lysine
.gtoreq.1750 mg zoledronic acid 40-120 mg lysine .gtoreq.2000 mg
zoledronic acid 40-120 mg lysine .gtoreq.2250 mg zoledronic acid
40-120 mg lysine .gtoreq.2500 mg zoledronic acid 40-120 mg lysine
.gtoreq.2750 mg zoledronic acid 40-120 mg lysine .gtoreq.3000 mg
zoledronic acid 40-120 mg L-lysine .gtoreq.500 mg zoledronic acid
40-120 mg L-lysine .gtoreq.750 mg zoledronic acid 40-120 mg
L-lysine .gtoreq.1000 mg zoledronic acid 40-120 mg L-lysine
.gtoreq.1250 mg zoledronic acid 40-120 mg L-lysine .gtoreq.1500 mg
zoledronic acid 40-120 mg L-lysine .gtoreq.1750 mg zoledronic acid
40-120 mg L-lysine .gtoreq.2000 mg zoledronic acid 40-120 mg
L-lysine .gtoreq.2250 mg zoledronic acid 40-120 mg L-lysine
.gtoreq.2500 mg zoledronic acid 40-120 mg L-lysine .gtoreq.2750 mg
zoledronic acid 40-120 mg L-lysine .gtoreq.3000 mg zoledronic acid
40-120 mg DL-lysine .gtoreq.500 mg zoledronic acid 40-120 mg
DL-lysine .gtoreq.750 mg zoledronic acid 40-120 mg DL-lysine
.gtoreq.1000 mg zoledronic acid 40-120 mg DL-lysine .gtoreq.1250 mg
zoledronic acid 40-120 mg DL-lysine .gtoreq.1500 mg zoledronic acid
40-120 mg DL-lysine .gtoreq.1750 mg zoledronic acid 40-120 mg
DL-lysine .gtoreq.2000 mg zoledronic acid 40-120 mg DL-lysine
.gtoreq.2250 mg zoledronic acid 40-120 mg DL-lysine .gtoreq.2500 mg
zoledronic acid 40-120 mg DL-lysine .gtoreq.2750 mg zoledronic acid
40-120 mg DL-lysine .gtoreq.3000 mg zoledronic acid 40-120 mg
glycine .gtoreq.500 mg zoledronic acid 40-120 mg glycine
.gtoreq.750 mg zoledronic acid 40-120 mg glycine .gtoreq.1000 mg
zoledronic acid 40-120 mg glycine .gtoreq.1250 mg zoledronic acid
40-120 mg glycine .gtoreq.1500 mg zoledronic acid 40-120 mg glycine
.gtoreq.1750 mg zoledronic acid 40-120 mg glycine .gtoreq.2000 mg
zoledronic acid 40-120 mg glycine .gtoreq.2250 mg zoledronic acid
40-120 mg glycine .gtoreq.2500 mg zoledronic acid 40-120 mg glycine
.gtoreq.2750 mg zoledronic acid 40-120 mg glycine .gtoreq.3000 mg
zoledronic acid 50-250 mg lysine .gtoreq.500 mg zoledronic acid
50-250 mg lysine .gtoreq.750 mg zoledronic acid 50-250 mg lysine
.gtoreq.1000 mg zoledronic acid 50-250 mg lysine .gtoreq.1250 mg
zoledronic acid 50-250 mg lysine .gtoreq.1500 mg zoledronic acid
50-250 mg lysine .gtoreq.1750 mg zoledronic acid 50-250 mg lysine
.gtoreq.2000 mg zoledronic acid 50-250 mg lysine .gtoreq.2250 mg
zoledronic acid 50-250 mg lysine .gtoreq.2500 mg zoledronic acid
50-250 mg lysine .gtoreq.2750 mg zoledronic acid 50-250 mg lysine
.gtoreq.3000 mg zoledronic acid 50-250 mg L-lysine .gtoreq.500 mg
zoledronic acid 50-250 mg L-lysine .gtoreq.750 mg zoledronic acid
50-250 mg L-lysine .gtoreq.1000 mg zoledronic acid 50-250 mg
L-lysine .gtoreq.1250 mg zoledronic acid 50-250 mg L-lysine
.gtoreq.1500 mg zoledronic acid 50-250 mg L-lysine .gtoreq.1750 mg
zoledronic acid 50-250 mg L-lysine .gtoreq.2000 mg zoledronic acid
50-250 mg L-lysine .gtoreq.2250 mg zoledronic acid 50-250 mg
L-lysine .gtoreq.2500 mg zoledronic acid 50-250 mg L-lysine
.gtoreq.2750 mg zoledronic acid 50-250 mg L-lysine .gtoreq.3000 mg
zoledronic acid 50-250 mg DL-lysine .gtoreq.500 mg zoledronic acid
50-250 mg DL-lysine .gtoreq.750 mg zoledronic acid 50-250 mg
DL-lysine .gtoreq.1000 mg zoledronic acid 50-250 mg DL-lysine
.gtoreq.1250 mg zoledronic acid 50-250 mg DL-lysine .gtoreq.1500 mg
zoledronic acid 50-250 mg DL-lysine .gtoreq.1750 mg zoledronic acid
50-250 mg DL-lysine .gtoreq.2000 mg zoledronic acid 50-250 mg
DL-lysine .gtoreq.2250 mg zoledronic acid 50-250 mg DL-lysine
.gtoreq.2500 mg zoledronic acid 50-250 mg DL-lysine .gtoreq.2750 mg
zoledronic acid 50-250 mg DL-lysine .gtoreq.3000 mg zoledronic acid
50-250 mg glycine .gtoreq.500 mg zoledronic acid 50-250 mg glycine
.gtoreq.750 mg zoledronic acid 50-250 mg glycine .gtoreq.1000 mg
zoledronic acid 50-250 mg glycine .gtoreq.1250 mg zoledronic acid
50-250 mg glycine .gtoreq.1500 mg zoledronic acid 50-250 mg glycine
.gtoreq.1750 mg zoledronic acid 50-250 mg glycine .gtoreq.2000 mg
zoledronic acid 50-250 mg glycine .gtoreq.2250 mg zoledronic acid
50-250 mg glycine .gtoreq.2500 mg zoledronic acid 50-250 mg glycine
.gtoreq.2750 mg zoledronic acid 50-250 mg glycine .gtoreq.3000 mg
zoledronic acid 40-120 mg lysine 500 mg-1000 mg zoledronic acid
40-120 mg lysine 750 mg-1250 zoledronic acid 40-120 mg lysine 1000
mg-1500 mg zoledronic acid 40-120 mg lysine 1250 mg-1750 mg
zoledronic acid 40-120 mg lysine 1500 mg-2000 mg zoledronic acid
40-120 mg lysine 1750 mg-2250 mg zoledronic acid 40-120 mg lysine
.gtoreq.2000 mg-2500 mg.sup. zoledronic acid 40-120 mg lysine
.gtoreq.2250 mg-2750 mg.sup. zoledronic acid 40-120 mg lysine
.gtoreq.2500 mg-3000 mg.sup. zoledronic acid 1-100 mg lysine 500
mg-1000 mg zoledronic acid 1-100 mg lysine 750 mg-1250 zoledronic
acid 1-100 mg lysine 1000 mg-1500 mg zoledronic acid 1-100 mg
lysine 1250 mg-1750 mg zoledronic acid 1-100 mg lysine 1500 mg-2000
mg zoledronic acid 1-100 mg lysine 1750 mg-2250 mg zoledronic acid
1-100 mg lysine .gtoreq.2000 mg-2500 mg.sup. zoledronic acid 1-100
mg lysine .gtoreq.2250 mg-2750 mg.sup. zoledronic acid 1-100 mg
lysine .gtoreq.2500 mg-3000 mg.sup. zoledronic acid 100-200 mg
lysine 500 mg-1000 mg zoledronic acid 100-200 mg lysine 750 mg-1250
zoledronic acid 100-200 mg lysine 1000 mg-1500 mg zoledronic acid
100-200 mg lysine 1250 mg-1750 mg zoledronic acid 100-200 mg lysine
1500 mg-2000 mg zoledronic acid 100-200 mg lysine 1750 mg-2250 mg
zoledronic acid 100-200 mg lysine .gtoreq.2000 mg-2500 mg.sup.
zoledronic acid 100-200 mg lysine .gtoreq.2250 mg-2750 mg.sup.
zoledronic acid 100-200 mg lysine .gtoreq.2500 mg-3000 mg.sup.
zoledronic acid 200-300 mg lysine 500 mg-1000 mg zoledronic acid
200-300 mg lysine 750 mg-1250 zoledronic acid 200-300 mg lysine
1000 mg-1500 mg zoledronic acid 200-300 mg lysine 1250 mg-1750 mg
zoledronic acid 200-300 mg lysine 1500 mg-2000 mg zoledronic acid
200-300 mg lysine 1750 mg-2250 mg zoledronic acid 200-300 mg lysine
.gtoreq.2000 mg-2500 mg.sup. zoledronic acid 200-300 mg lysine
.gtoreq.2250 mg-2750 mg.sup. zoledronic acid 200-300 mg lysine
.gtoreq.2500 mg-3000 mg.sup. zoledronic acid 40-120 mg glycine 500
mg-1000 mg zoledronic acid 40-120 mg glycine 750 mg-1250 zoledronic
acid 40-120 mg glycine 1000 mg-1500 mg zoledronic acid 40-120 mg
glycine 1250 mg-1750 mg zoledronic acid 40-120 mg glycine 1500
mg-2000 mg zoledronic acid 40-120 mg glycine 1750 mg-2250 mg
zoledronic acid 40-120 mg glycine .gtoreq.2000 mg-2500 mg.sup.
zoledronic acid 40-120 mg glycine .gtoreq.2250 mg-2750 mg.sup.
zoledronic acid 40-120 mg glycine .gtoreq.2500 mg-3000 mg.sup.
zoledronic acid 100-200 mg glycine 500 mg-1000 mg zoledronic acid
100-200 mg glycine 750 mg-1250 zoledronic acid 100-200 mg glycine
1000 mg-1500 mg zoledronic acid 100-200 mg glycine 1250 mg-1750 mg
zoledronic acid 100-200 mg glycine 1500 mg-2000 mg zoledronic acid
100-200 mg glycine 1750 mg-2250 mg zoledronic acid 100-200 mg
glycine .gtoreq.2000 mg-2500 mg.sup. zoledronic acid 100-200 mg
glycine .gtoreq.2250 mg-2750 mg.sup. zoledronic acid 100-200 mg
glycine .gtoreq.2500 mg-3000 mg.sup. zoledronic acid 200-300 mg
glycine 500 mg-1000 mg zoledronic acid 200-300 mg glycine 750
mg-1250 zoledronic acid 200-300 mg glycine 1000 mg-1500 mg
zoledronic acid 200-300 mg glycine 1250 mg-1750 mg zoledronic acid
200-300 mg glycine 1500 mg-2000 mg zoledronic acid 200-300 mg
glycine 1750 mg-2250 mg zoledronic acid 200-300 mg glycine
.gtoreq.2000 mg-2500 mg.sup. zoledronic acid 200-300 mg glycine
.gtoreq.2250 mg-2750 mg.sup. zoledronic acid 200-300 mg glycine
.gtoreq.2500 mg-3000 mg.sup.
* * * * *