U.S. patent application number 17/101375 was filed with the patent office on 2021-03-11 for process for the manufacture of snac (salcaprozate sodium).
This patent application is currently assigned to Emisphere Technologies, Inc.. The applicant listed for this patent is Emisphere Technologies, Inc.. Invention is credited to William Elliot Bay, Joseph Norman Bernadino, George Frederick Klein, Yi Ren, Pingsheng Zhang.
Application Number | 20210070691 17/101375 |
Document ID | / |
Family ID | 1000005237405 |
Filed Date | 2021-03-11 |
United States Patent
Application |
20210070691 |
Kind Code |
A1 |
Bay; William Elliot ; et
al. |
March 11, 2021 |
PROCESS FOR THE MANUFACTURE OF SNAC (SALCAPROZATE SODIUM)
Abstract
Disclosed are improved methods for the synthesis of
N-(8-[2-hydroxybenzoyl]- amino) caprylic acid. Certain compounds
have been found useful for preventing the formation of a colored
impurity when included in an ester hydrolysis reaction. Conducting
ester hydrolysis in anaerobic conditions has also been found to
minimize the formation of the color impurity. Also disclosed are
improved methods for synthesizing the sodium salt of
N-(8-[2-hydroxybenzoyl]-amino) caprylic acid.
Inventors: |
Bay; William Elliot;
(Ridgefield, CT) ; Bernadino; Joseph Norman;
(Stamford, CT) ; Klein; George Frederick;
(Tarrytown, NY) ; Ren; Yi; (Warren, NJ) ;
Zhang; Pingsheng; (Florence, SC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Emisphere Technologies, Inc. |
Roseland |
NJ |
US |
|
|
Assignee: |
Emisphere Technologies,
Inc.
Roseland
NJ
|
Family ID: |
1000005237405 |
Appl. No.: |
17/101375 |
Filed: |
November 23, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16490424 |
Aug 30, 2019 |
10875826 |
|
|
PCT/EP2007/059037 |
Aug 30, 2007 |
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17101375 |
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60842775 |
Sep 7, 2006 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C 231/10 20130101;
C07C 231/12 20130101; C07C 231/24 20130101 |
International
Class: |
C07C 231/10 20060101
C07C231/10; C07C 231/24 20060101 C07C231/24; C07C 231/12 20060101
C07C231/12 |
Claims
1-9. (canceled)
10. A composition comprising a compound of formula: ##STR00004## or
an anion or salt thereof, wherein the composition is essentially
free of pink color bodies.
11. A pharmaceutical formulation comprising the composition of
claim 10.
12. The pharmaceutical formulation of claim 11, further comprising
a pharmaceutically active drug and one or more pharmaceutically
acceptable carriers or excipients.
13. The pharmaceutical formulation of claim 11, wherein the
formulation is in a form suitable for oral administration.
14. The pharmaceutical formulation of claim 13, wherein the form
suitable for oral administration is a tablet form.
15. The pharmaceutical formulation of claim 13, wherein the drug is
present in an amount that is not therapeutically effective when the
drug is orally administered alone.
16. The pharmaceutical formulation of claim 13, wherein the
compound is present in an amount effective to facilitate absorption
of the drug in the gastrointestinal tract such that the amount of
drug in the oral dosage form is therapeutically effective.
17. The pharmaceutical formulation of claim 11, comprising a sodium
salt of the compound of formula ##STR00005##
Description
[0001] The present invention provides new methods for the synthesis
of N-(8-[2-hydroxybenzoyl]-amino) caprylic acid and and its sodium
salts.
[0002] General preparations of N-(8-[2-hydroxybenzoyl]-amino)
caprylic acid (SNAC) are set out in U.S. Pat. No. 5,650,386 and
International Publication Nos. WO 00/46182 and WO 00/59863.
[0003] The term "SNAC" as used herein refers to
N-(8-[2-hydroxybenzoyl]-amino) caprylic acid and pharmaceutically
acceptable salts thereof, including its monosodium and disodium
salts. The term "SNAC free acid" refers to
N-(8-[2-hydroxybenzoyl]-amino) caprylic acid. Unless otherwise
noted, the term "SNAC" refers to all forms of SNAC, including all
amorphous and polymorphic forms of SNAC, such as SNAC trihydrate
and those described in U.S. Serial Nos. 60/619,418 and 60/569,476,
both of which, to the extent necessary, are hereby incorporated by
reference.
[0004] The term "therapeutically effective amount" with respect to
a bisphosphonate means an amount of the compound, or a
pharmaceutically acceptable salt thereof, which is effective to
treat, prevent, alleviate or ameliorate symptoms of disease, either
alone or in combination with a carrier, such as SNAC .
[0005] The term "about" or "approximately" means within an
acceptable error range for the particular value as determined by
one of ordinary skill in the art, which will depend in part on how
the value is measured or determined, i.e., the limitations of the
measurement system. For example, "about" can mean within 1 or more
than 1 standard deviations, per practice in the art. Alternatively,
"about" with respect to the formulations can mean a range of up to
10%, preferably up to 5%.
[0006] The term "an amount effective to facilitate absorption of
the bisphosphonate in the gastrointestinal tract such that the
bisphosphonate is therapeutically effective" as applied to SNAC or
its salts means an amount of the carrier that increases absorption
of the bisphosphonate in the gastrointestinal tract such as to
reduce the amount of bisphosphonate as compared to the amount of
bisphosphonate required if administered alone to achieve a
therapeutic effect.
[0007] The term "bisphosphonate is present in an amount not
therapeutically effective when the bisphosphonate is orally
administered alone" means an amount of a bisphosphonate, or a
pharmaceutically acceptable salt thereof, which is not effective to
treat, prevent, alleviate or ameliorate symptoms of disease. For
example, the therapeutically effective amount of ibandronate for
the treatment of osteoporosis is 2.5 mg daily or 150 mg monthly, as
measured by the weight of the free acid. Amounts of ibandronate
less than the above, for their respective dosage periods, would not
be considered therapeutically effective. " [W]hen the
bisphosphonate is orally administered alone" means when the
bisphosphonate is not orally administered with an agent that
facilitates absorption of the bisphosphonate in the
gastrointestinal tract. This term does not exclude conventional
additives normally included in such formulations including, but not
limited to, lactose monohydrate, croscarmellose sodium, povidone,
water, sodium stearyl fumarate, and the like. Preferred oral dosage
forms are tablets, most preferably tablets containing povidone.
[0008] The term "pharmaceutically acceptable," such as
pharmaceutically acceptable carrier, excipient, etc., means
pharmacologically acceptable and substantially non-toxic to the
subject to which the particular compound is administered.
[0009] The term "pharmaceutically acceptable salt" refers to
conventional acid-addition salts or base-addition salts that retain
the biological effectiveness and properties of the compounds of the
present invention and are formed from suitable non-toxic organic or
inorganic acids or organic or inorganic bases. Sample acid-addition
salts include those derived from inorganic acids such as
hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric
acid, sulfamic acid, phosphoric acid and nitric acid, and those
derived from organic acids such as p-toluenesulfonic acid,
salicylic acid, methanesulfonic acid, oxalic acid, succinic acid,
citric acid, malic acid, lactic acid, fumaric acid, and the like.
Sample base-addition salts include those derived from ammonium,
potassium, sodium, and quaternary ammonium hydroxides, such as for
example, tetramethylammonium hydroxide. Chemical modification of a
pharmaceutical compound (i.e., drug) into a salt is a technique
well known to pharmaceutical chemists to obtain improved physical
and chemical stability, hygroscopicity, and solubility of
compounds. See, e.g., H. Ansel et. al., Pharmaceutical Dosage Forms
and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and
1456-1457.
[0010] The term "color-body" means an impurity that imparts a color
to a substance. Color-bodies may exist in amounts as low as a few
parts per billion and still affect the color of a substance.
[0011] The term "prodrug" refers to compounds that undergo
biotransformation prior to exhibiting their pharmacological
effects. The chemical modification of drugs to overcome
pharmaceutical problems has also been termed "drug latentiation."
Drug latentiation is the chemical modification of a biologically
active compound to form a new compound, which upon in vivo
enzymatic attack will liberate the parent compound. The chemical
alterations of the parent compound are such that the change in
physicochemical properties will affect the absorption, distribution
and enzymatic metabolism. The definition of drug latentiation has
also been extended to include nonenzymatic regeneration of the
parent compound. Regeneration takes place as a consequence of
hydrolytic, dissociative, and other reactions not necessarily
enzyme mediated. The terms prodrugs, latentiated drugs, and
bio-reversible derivatives are used interchangeably. By inference,
latentiation implies a time lag element or time component involved
in regenerating the bioactive parent molecule in vivo. The term
prodrug is general in that it includes latentiated drug derivatives
as well as those substances that are converted after administration
to the actual substance which combines with receptors. The term
prodrug is a generic term for agents, which undergo
biotransformation prior to exhibiting their pharmacological
action
[0012] In some instances, preparation of SNAC may lead to a product
which includes color-bodies. The creation of these color-bodies
appears to not be pH dependent. In order to determine the identity
of a color-body which leads to an observed pink color, a hydrolysis
reaction was performed at reflux for an extended four day period of
time. This yielded very pink SNAC free acid, which was dissolved in
acetone and run through silica gel to achieve some separation of
the impurity. The pink band was extracted into water and dried.
This material was further separated by preparative high-performance
liquid chromatography. The peak was determined to have a molecular
weight of about 724, but the structure has not yet been elucidated.
Applicants hypothesize that trace metals and/or oxygen are
responsible for the formation of the pink color impurity. The
success in avoiding the pink color using EDTA suggests that
contaminating metal plays some role. Other anti-oxidants such as
ascorbic acid (1%), NaHSO.sub.3 (1%), PPh.sub.3 (0.1%) are also
effective at preventing the pink color formation. However,
2,6-di-tert-butyl-4-methylphenol (BHT) (1%) is not effective.
De-gassing by vacuum and pressure N.sub.2 three times are found to
be inconsistent in avoiding the pink color. De-gassing by using
boiled water is successful in avoiding the pink color
[0013] In general, to form essentially pink-free SNAC free acid,
2,4-dioxo-1,3-benzoxazinyloctanoic acid ethyl ester can be reacted
with sodium hydroxide (as a 40% aqueous solution) in water in the
presence of EDTA, e.g., about 0.001 equivalent of EDTA, at elevated
temperature, e.g., about 98.degree. C. After the reaction is
complete, the reaction mixture can be cooled to room temperature,
and then can be charged to a different flask containing a premixed
mixture of about 4 equivalents of HCl and acetone at 20.degree. C.
A solution of sodium hydroxide, e.g., 20% NaOH, can then be added
to the resulting slurry can then added to adjust the pH to about
4.5. The slurry can then be heated, e.g., to about 60.degree. C.
for e.g., 0.5 hour and then can be subsequently cooled to room
temperature and aged for, e.g., 4 hours. The slurry can then be
filtered, washed with water, and dried in high vacuum at elevated
temperature, e.g., about 80.degree. C. to afford SNAC free
acid.
[0014] Alternatively, the reaction can be run as above, but instead
of using EDTA, ascorbic acid, NaHSO.sub.3, or triphenylphosphine
can be used. Also alternatively, the process water can be boiled
prior to use in the hydrolysis reaction.
[0015] The invention thus provides new methods for synthesizing
N-(8-[2-hydroxybenzoyl]-amino) caprylic acid while avoiding or
reducing the production of a color-body impurity therein comprising
the step of hydrolyzing 2,4-dioxo-1,3-benzoxazinyloctanoic acid
ethyl ester by admixing 2,4-dioxo-1,3-benzoxazinyloctanoic acid
ethyl ester with sodium hydroxide, water, and a member selected
from the group consisting of ethylenediamine tetraacetic acid
(EDTA), ascorbic acid, NaHSO.sub.3, and triphenylphosphine to yield
a reaction mixture.
[0016] The invention also provides methods for synthesizing
N-(8-[2-hydroxy-benzoyl]-amino) caprylic acid while avoiding or
reducing the production of a color-body impurity therein comprising
the step of hydrolyzing 2,4-dioxo-1,3-benz-oxazinyloctanoic acid
ethyl ester by admixing 2,4-dioxo-1,3-benzoxazinyloctanoic acid
ethyl ester with sodium hydroxide and previously boiled water to
yield a reaction mixture.
[0017] In further embodiment, the methods set out above for the
preparation of SNAC free acid also comprise the step of admixing
acetone and hydrochloric acid with the reaction mixture.
[0018] To make SNAC sodium salt, SNAC free acid can be reacted
with, e.g., about 1.02 equivalents of sodium hydroxide (as a 20%
aqueous solution) in 2-propanol at about 40.degree. C. After the
addition is complete, the reaction mixture can be heated at, e.g.,
about 50.degree. C., and cooled, e.g., to about 35.degree. C., and
can then be charged with seed crystal. After stirring at about
35.degree. C. for about 1 hour, a suspension should form that can
be slowly cooled to, e.g., about 30.degree. C. and held at about
30.degree. C. for about 1 hour to yield a thick suspension.
Additional 2-propanol may be added at about 30.degree. C., and the
resulting slurry may then be cooled slowly to about 0.degree. C.
and aged for at least about 4 hours. The slurry can then be
filtered, washed with mixed solvent of 2-propanol and water (about
10 : 1, v/v), and dried in high vacuum at about 90.degree. C., to
yield SNAC sodium salt with a monomodal particle size
distribution.
[0019] Thus, the invention also provides methods for synthesizing
N-(8-[2-hydroxy-benzoyl]-amino) caprylic acid sodium salt,
comprising admixing N-(8-[2-hydroxy-benzoyl]-amino) caprylic acid
suspended in 2-propanol with aqueous sodium hydroxide to form a
solution of N-(8-[2-hydroxybenzoyl]-amino) caprylic acid sodium
salt. In particular, this method employs
N-(8-[2-hydroxybenzoyl]-amino) caprylic acid that has been produced
according to the methods of the present invention, so that the
final N-(8-[2-hydroxybenzoyl]-amino) caprylic acid sodium salt
product has reduced or absent color-body impurity.
[0020] In another embodiment, the method set out above for
synthesizing N-(8-[2-hydroxybenzoyl]-amino) caprylic acid sodium
salt includes the steps of adding additional 2-propanol to the
solution of N-(8-[2-hydroxybenzoyl]-amino) caprylic acid sodium
salt, seeding the solution of N-(8-[2-hydroxybenzoyl]-amino)
caprylic acid sodium salt with crystalline
N-(8-[2-hydroxybenzoyl]-amino) caprylic acid sodium salt to cause
the dissolved N-(8-[2-hydroxybenzoyl]-amino) caprylic acid sodium
salt to precipitate out of the solution, and then adding more
2-propanol to the solution, to yield SNAC sodium salt with a
monomodal particle size distribution.
[0021] The present invention also provides solid pharmaceutical
dosage forms for oral administration comprising a bisphosphonate,
or a pharmaceutically acceptable salt thereof, which bisphosphonate
is present in an amount not therapeutically effective when the
bisphosphonate is orally administered alone; and SNAC, prepared
according to the methods disclosed herein, which is present in an
amount effective to facilitate absorption of the bisphosphonate in
the gastrointestinal tract such that the bisphosphonate is
therapeutically effective. The ratio of bisphosphonate to SNAC is
from about 1:30 to about 1:1, respectively. These novel solid
pharmaceutical dosage forms are useful in the treatment or control
of bone diseases characterized by increased bone resorption, such
as osteoporosis and hypercalcemia of cancer, as well as the
treatment or control of pain that accompanies such disorders. The
present invention also provides a method for treating such
disorders employing the solid pharmaceutical dosage forms and a
method for preparing the pharmaceutical dosage forms.
[0022] Oral administration of the bisphosphonate with the SNAC
produced according to the invention described herein results in an
increased bioavailability of the bisphosphonate compared to oral
administration of the bisphosphonate alone, thereby enabling a
lowering of the dose of the bisphosphonate while still achieving
equivalent efficacy of the bisphosphonate. Oral administration of
the bisphosphonate with the SNAC may result in a reduction of the
approximately 2 hour period of fasting before taking the
bisphosphonate and is expected to reduce the approximately 30-60
minute period of sitting or standing upright after taking the
bisphosphonate.
[0023] As set out above, the present invention provides a novel
solid pharmaceutical dosage form for oral administration comprising
a bisphosphonate, or a pharmaceutically acceptable salt thereof,
which bisphosphonate is present in an amount not therapeutically
effective when the bisphosphonate is orally administered alone; and
SNAC , or a pharmaceutically acceptable salt thereof, prepared
according to the methods of the present invention, which SNAC is
present in an amount effective to facilitate absorption of the
bisphosphonate in the gastrointestinal tract such that the
bisphosphonate is therapeutically effective. The ratio of
bisphosphonate to SNAC is from about 1:30 to about 1:1,
respectively. The dosage form may be administered to a mammal,
e.g., a human.
[0024] The bisphosphonates in the present invention may be selected
from a wide variety of bisphosphonates and pharmaceutically
acceptable salts thereof. Bisphosphonates may be represented by the
formula: (HO).sub.2(O)P--C(R.sup.1)(R.sup.2)--P(O) (OH).sub.2. In
the above formula, R.sup.1 may be selected from the group
consisting of OH, Cl, and H; and R.sup.2 may be selected from the
group consisting of (CH.sub.2).sub.3NH.sub.2, Cl,
CH.sub.2-1-pyrrolidinyl, CH.sub.3, CH.sub.2CH.sub.2N(CH.sub.3)
(CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), N-cycloheptyl, H,
(CH.sub.2).sub.5NH.sub.2, (CH.sub.2).sub.2N(CH.sub.3).sub.2,
(CH.sub.2).sub.2NH.sub.2, CH.sub.2-3-pyridinyl, S-4-chlorophenyl,
CH.sub.2-2-imidazo-pyridinyl, and CH.sub.2-2-imidazolyl.
Illustrative nonlimiting examples of bisphosphonates include
alendronate [Fosamax.RTM., R.sup.1.dbd.OH,
R.sup.2.dbd.(CH.sub.2).sub.3NH.sub.2], clodronate [R'.dbd.Cl,
R.sup.2.dbd.Cl], EB-1053 [R'.dbd.OH,
R.sup.2.dbd.CH.sub.2-1-pyrrolidinyl], etidronate [Didrocal.RTM.,
R.sup.1.dbd.OH, R.sup.2.dbd.CH.sub.3], ibandronate [Boniva.RTM.,
R.sup.1.dbd.OH,
R.sup.2.dbd.CH.sub.2CH.sub.2N(CH.sub.3)(CH.sub.2CH.sub.2CH.sub.2CH.sub.2C-
H.sub.3)], incadronate [R'.dbd.H, R.sup.2.dbd.N-cycloheptyl],
medronate [R'.dbd.H, R.sup.2.dbd.H], neridronate [R'.dbd.OH,
R.sup.2.dbd.(CH.sub.2).sub.5NH.sub.2], olpadronate [R'.dbd.OH,
R.sup.2.dbd.(CH.sub.2).sub.2N(CH.sub.3).sub.2], pamidronate
[Aredia.RTM., R.sup.1.dbd.OH,
R.sup.2.dbd.(CH.sub.2).sub.2NH.sub.2], risedronate [Actonel.RTM.,
R.sup.1.dbd.OH, R.sup.2.dbd.CH.sub.2-3-pyridinyl], tiludronate
[Skelid.RTM., R.sup.1.dbd.H, R.sup.2.dbd.S-4-chlorophenyl], YH529
[R'.dbd.OH, R.sup.2.dbd.CH.sub.2-2-imidazo-pyridinyl], and
zoledronate [Zometa.RTM., R.sup.1.dbd.OH,
R.sup.2.dbd.CH.sub.2-2-imidazolyl]. In particular, the
bisphosphonate is alendronate or ibandronate, or a pharmaceutically
acceptable salt thereof. Most particularly, the bisphosphonate is
ibandronate, or a pharmaceutically acceptable salt thereof.
[0025] Ibandronate is disclosed in U.S. Pat. No. 4,927,814, which
disclosure is incorporated herein by reference. Ibandronate may be
represented by the following formula:
##STR00001##
[0026] Ibandronate is commercialized as the sodium salt,
3-(N-methyl-N-pentyl)-amino-1-hydroxypropane-1,1-diphosphonic acid,
monosodium salt, monohydrate (Boniva.RTM.). Ibandronate has the
molecular formula C.sub.9H.sub.22NO.sub.7P.sub.2Na.H.sub.2O and a
molecular weight of 359.24. Ibandronate sodium is a white- to
off-white powder, which is freely soluble in water and practically
insoluble in organic solvents.
[0027] The ratio of bisphosphonate to SNAC is such that absorption
of the orally administered bisphosphonate in the gastrointestinal
tract is facilitated over that of absorption of the bisphosphonate
when orally administered alone. The ratio of bisphosphonate to SNAC
according to the present invention may vary within limits. The
ratio of bisphosphonate to SNAC may be adjusted to the requirements
in each particular case including the particular bisphosphonate
being administered, the particular SNAC being employed, the
condition being treated, as well as the patient being treated. The
ratio of bisphosphonate to SNAC is preferably such that absorption
of the orally administered bisphosphonate in the gastrointestinal
tract is at least 2 times, preferably 3 times, more preferably 4
times, and most preferably 5 times greater than that of the
bisphosphonate when orally administered alone. In general, in the
case of oral administration to adult humans weighing approximately
70 Kg, the ratio of bisphosphonate to SNAC , as measured by weight
of each compound as the free acid in the pharmaceutical
composition, is from about 1:30 to about 1:1, preferably about
1:20, more preferably about 1:10, and most preferably about 1:5,
respectively.
[0028] The therapeutically effective amount or dosage of
bisphosphonate according to this invention can vary within wide
limits. Such dosage will be adjusted to the individual requirements
in each particular case including the condition being treated, the
patient being treated, as well as the specific bisphosphonate being
administered.
[0029] For example, the recommended oral dose of ibandronate for
the treatment of osteoporosis, when administered alone, to adult
humans weighing approximately 70 Kg is 2.5 mg once daily or 150 mg
once monthly. In the present invention, the daily dose of
ibandronate for the treatment of osteoporosis, when administered
with SNAC, is lowered to from about 1.25 mg to about 0.25 mg,
preferably from about 1 mg to about 0.4 mg, more preferably from
about 0.65 mg to about 0.5 mg, and most preferably about 0.5 mg.
The monthly dose of ibandronate for the treatment of osteoporosis,
when administered with SNAC, is lowered to from about 75 mg to
about 15 mg, preferably from about 60 mg to about 25 mg, more
preferably from about 40 mg to about 30 mg, and most preferably
about 30 mg.
[0030] The recommended oral dose of ibandronate for the treatment
of hypercalcemia of cancer or the treatment of metastatic bone
pain, when administered alone, to adult humans weighing
approximately 70 Kg is 50 mg once daily. In the present invention,
the daily dose of ibandronate for the treatment of hypercalcemia of
cancer or the treatment of metastatic bone pain, when administered
with SNAC, is lowered to from about 25 mg to about 5 mg, preferably
from about 20 mg to about 8 mg, more preferably from about 13 mg to
about 10 mg, and most preferably about 10 mg.
[0031] The anticipated oral dose of ibandronate for the treatment
of hypercalcemia of cancer or the treatment of metastatic bone
pain, when administered alone, to adult humans weighing
approximately 70 Kg is 350 mg weekly. In the present invention, the
anticipated weekly dose of ibandronate for the treatment of
hypercalcemia of cancer or the treatment of metastatic bone pain,
when administered with SNAC, is expected to be lowered to from
about 175 mg to about 35 mg, preferably from about 140 mg to about
56 mg, more preferably from about 90 mg to about 70 mg, and most
preferably about 70 mg.
[0032] The pharmaceutical dosage forms of the present invention may
be prepared by simply admixing the bisphosphonate with the SNAC
prior to administration. The dosage forms may also be prepared by
admixing an aqueous solution of the bisphosphonate with the SNAC,
just prior to administration. The solutions may optionally contain
additives such as lactose monohydrate, croscarmellose sodium,
povidone, water, sodium stearyl fumarate, and the like. Preferably,
the solid pharmaceutical dosage form is prepared by intimately
contacting the bisphosphonate with the SNAC.
[0033] The dosage forms are preferably in tablet or capsule form.
In one embodiment, the dosage form is a tablet and includes
povidone. In another embodiment, the dosage form is a capsule and
includes povidone. Povidone is preferably present in the dosage
form in an amount from about 2% to about 30%, preferably from about
10% to about 20%, most preferably from about 12% to about 15%, by
weight of the total composition.
[0034] The SNAC may also be used to form microspheres containing
the bisphosphonate. Microspheres are particularly useful for the
oral administration of active agents, which do not pass, or only
fractionally pass, through the gastrointestinal tract or are
susceptible to chemical or enzymatic cleavage in the
gastrointestinal tract. Methods for preparing microspheres are
known and are disclosed, for example, in U.S. Pat. No. 5,650,386,
which disclosure is incorporated herein by reference.
[0035] In another embodiment, the present invention provides a
method for treating osteoporosis comprising orally administering to
a subject, in need thereof, a novel solid pharmaceutical dosage
form of the present invention. In yet another embodiment, the
present invention provides a method for treating hypercalcemia of
cancer comprising orally administering to a subject, in need
thereof, a novel solid pharmaceutical dosage form of the present
invention. In still yet another embodiment, the present invention
provides a method for treating metastatic bone pain comprising
orally administering to a subject, in need thereof, a novel solid
pharmaceutical dosage form of the present invention. The dosage
forms utilized in the aforementioned methods contain
[0036] In still yet another embodiment, the present invention
provides a method for preparing a solid pharmaceutical dosage form
for oral administration comprising admixing:
[0037] (a) a bisphosphonate, or a pharmaceutically acceptable salt
thereof, which bisphosphonate is present in an amount not
therapeutically effective when the bisphosphonate is orally
administered alone; and
[0038] (b) SNAC prepared according to the methods of the present
invention which is present in an amount effective to facilitate
absorption of the bisphosphonate in the gastrointestinal tract such
that the bisphosphonate is therapeutically effective;
[0039] where the ratio of bisphosphonate to SNAC is from about 1:30
to about 1:1, respectively.
[0040] The examples are presented for purposes of demonstrating,
but not limiting, the methods of this invention.
EXAMPLES
Example 1
Production of SNAC Free Acid
##STR00002##
[0041] A dry, clean, 500 ml half jacketed, 4-neck round bottom
flask, equipped with a mechanic stirrer, thermo couple, chiller,
and an addition funnel, was charged with 153 g of water, 22 mg of
EDTA (0.08 mmol), and 30 g of 2,4-dioxo-1,3-benzoazinyl-octanoic
acid ethyl ester (76.49 mmol). The mixture was stirred for 30
minutes at 20.+-.5.degree. C. Then 29.22 g of 40% NaOH solution
(292.18 mmol) was added to the mixture. The mixture was heated to
.about.97.degree. C. and held for 20 hours. The mixture was then
cooled to 20.+-.5.degree. C. The batch was charged to an addition
funnel, and the flask was charged with 29 g of acetone and 36.25 g
of 31% HCl. The batch in the first flask was transferred to the
acetone/HCl solution over 40 minutes while maintaining temperature
<30.degree. C. After the transfer, the pH of the batch was
adjusted to .about.4.5 with 20% NaOH solution. The mixture was
heated to .about.60.degree. C., held for 0.5 h, and then cooled to
20.+-.5.degree. C. The batch was held at 20.+-.5.degree. C. for at
least 2 hours. The solid was filtered, washed with water, and dried
at 80.+-.5.degree. C. under vacuum overnight to give 20.4 g (95%
yield) of SNAC free acid.
Example 2
Formation of SNAC Sodium Salt
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[0043] A 1L, halt jacketed, 4-neck round bottom tlask equipped with
a mechanical stirrer, a thermo couple, an additional funnel, and a
condenser, was charged with 46.35 g of SNAC free acid (165.9 mmol),
and 180 ml of iPrOH and stirred at room temperature (rt). The
suspension was heated to 40.degree. C. To the resulting suspension
was added 33.84 g of 20% NaOH (169.2 mmol) solution over a span of
30 minutes. The suspension has become a clear solution when about
only half of the base was added. After the full amount of base was
added, the clear solution was at pH=9.0. The reaction temperature
was then raised to 50.degree. C. and was stirred at 50.degree. C.
for 30 minutes. The almost colorless clear solution was cooled to
35.degree. C. in one hour. The clear solution was then seeded with
100 mg of crystalline SNAC sodium salt (0.33 mol) and stirred at
35.degree. C. for one hour. The clear solution has become a milky
light suspension. The suspension was further cooled to 30.degree.
C. in one hour and hold at 30.degree. C. for one hour, it has
become a very thick white suspension. 180 ml of i-PrOH was added
over a span of one hour. The internal temperature was kept at
30.degree. C. through out the addition. The stirring actually
became easier after the addition. The suspension was then cooled to
0.degree. C. in a span of one hour and was aged at that temperature
for 18 hours. The solid was filtered on a coarse sintered glass
funnel and filtration was very fast. The solid was air-dried for
one hour. The resulting white solid was transferred to a
crystallization dish and was dried at 35.degree. C. for 6 hours and
at 90.degree. C. with nitrogen bleeding for additional 18 hours. It
was cooled in an oven to rt under vacuum (needs to be less than
40.degree. C.) before removal from the oven. In total 46.8 g (93.6%
yield) white solid was collected, which was found to by anhydrous
SNAC sodium salt, with a monomodal particle size distribution. The
water content was found to be 0.52%, as judged by Karl Fischer
titration. The aqueous solution of the salt has pH=7.0. Water
content needs to be carefully monitored during drying process to
make sure the water level is below 1%, preferably below 0.5%.
Before filtration, the reaction content may be aged at 0.degree. C.
overnight. No quality deterioration was observed. The anhydrous
monomodal SNAC sodium salt product has good solubility in water,
significantly higher than that of a trihydrate form.
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