U.S. patent application number 11/847219 was filed with the patent office on 2008-03-20 for drug delivery systems comprising solid solutions of weakly basic drugs.
Invention is credited to Luigi Boltri, Italo Colombo, Flavio Flabiani, Jin-Wang Lai, Luigi Mapelli, Gopi Venkatesh.
Application Number | 20080069878 11/847219 |
Document ID | / |
Family ID | 39136847 |
Filed Date | 2008-03-20 |
United States Patent
Application |
20080069878 |
Kind Code |
A1 |
Venkatesh; Gopi ; et
al. |
March 20, 2008 |
Drug Delivery Systems Comprising Solid Solutions of Weakly Basic
Drugs
Abstract
The present invention is directed to pharmaceutical compositions
and dosage forms comprising TPR beads, wherein said TPR beads
comprise a solid dispersion of at least one active pharmaceutical
ingredient in at least one solubility-enhancing polymer, and a TPR
coating comprising a water insoluble polymer and an enteric
polymer, wherein the active pharmaceutical ingredient comprises a
weakly basic active pharmaceutical ingredient having a solubility
of not more than 100 .mu.g/mL at pH 6.8.
Inventors: |
Venkatesh; Gopi; (Vandalia,
OH) ; Boltri; Luigi; (Pessano con Bornago Milan,
IT) ; Colombo; Italo; (Pessano con Bornago Milan,
IT) ; Lai; Jin-Wang; (Vandalia, OH) ;
Flabiani; Flavio; (Pessano con Bornago Milan, IT) ;
Mapelli; Luigi; (Pessano con Bornago Milan, IT) |
Correspondence
Address: |
COOLEY GODWARD KRONISH LLP;ATTN: Patent Group
Suite 1100
777 - 6th Street, NW
WASHINGTON
DC
20001
US
|
Family ID: |
39136847 |
Appl. No.: |
11/847219 |
Filed: |
August 29, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60841893 |
Aug 31, 2006 |
|
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|
60841760 |
Aug 31, 2006 |
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Current U.S.
Class: |
424/468 ;
424/497; 514/221; 514/326; 514/355; 514/356; 514/772.3; 514/772.5;
514/781 |
Current CPC
Class: |
A61K 9/5042 20130101;
A61P 9/12 20180101; A61P 25/18 20180101; A61K 9/5078 20130101; A61K
31/4406 20130101; A61K 9/5005 20130101; A61P 9/10 20180101; A61P
25/08 20180101; A61K 31/4422 20130101; A61K 31/454 20130101; A61K
31/5513 20130101; A61K 9/5026 20130101; A61K 9/5089 20130101; A61K
9/5047 20130101 |
Class at
Publication: |
424/468 ;
424/497; 514/221; 514/326; 514/355; 514/356; 514/772.3; 514/772.5;
514/781 |
International
Class: |
A61K 9/22 20060101
A61K009/22; A61K 31/4406 20060101 A61K031/4406; A61K 31/4422
20060101 A61K031/4422; A61K 31/454 20060101 A61K031/454; A61K
31/5513 20060101 A61K031/5513; A61K 47/30 20060101 A61K047/30; A61K
47/38 20060101 A61K047/38; A61K 9/14 20060101 A61K009/14 |
Claims
1. A pharmaceutical composition comprising TPR beads, wherein said
TPR beads comprise: a solid dispersion of at least one active
pharmaceutical ingredient in at least one solubility-enhancing
polymer; and a TPR coating comprising a water insoluble polymer and
an enteric polymer; wherein the active pharmaceutical ingredient
comprises a weakly basic active pharmaceutical ingredient having a
solubility of not more than 100 .mu.g/mL at pH 6.8.
2. The pharmaceutical composition of claim 1, wherein the
composition provides a therapeutically effective plasma
concentration of the active pharmaceutical ingredient over a period
of at least about 18 hours.
3. The pharmaceutical composition of claim 1, wherein the ratio of
water-insoluble polymer to enteric polymer in the TPR coating
ranges from about 9:1 to about 1:9.
4. The pharmaceutical dosage form of claim 3, wherein the TPR
coating further comprises about 3% to about 30% by weight of a
plasticizer (compared to the total weight of the TPR coating).
5. The pharmaceutical composition of claim 1, wherein the solid
dispersion of the active pharmaceutical ingredient and
solubility-enhancing polymer is deposited on an inert core.
6. The pharmaceutical composition of claim 5, wherein the
solubility-enhancing polymer is selected from the group consisting
of polyvinylpyrrolidone, vinyl acetate/vinyl pyrrolidone
copolymers, methylcellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, polyethylene oxide, polyethylene glycol, and
cyclodextrins.
7. The pharmaceutical composition of claim 5, wherein the solid
dispersion further comprises a pharmaceutically acceptable organic
acid.
8. The pharmaceutical composition of claim 7, wherein the ratio of
organic acid to active pharmaceutical ingredient ranges from about
4/1 to about 1/9 by weight.
9. The pharmaceutical composition of claim 5, wherein the
water-insoluble polymer is selected from the group consisting of
polymers or copolymers of methacrylic acid esters having quaternary
ammonium groups, polyvinyl acetate polymers or copolymers,
cellulose acetate, cellulose acetate butyrate, ethylcellulose, and
mixtures thereof
10. The pharmaceutical composition of claim 5, wherein the TPR
beads comprise IR beads coated with the TPR coating; and the IR
beads comprise inert cores coated with the solid dispersion.
11. The pharmaceutical composition of claim 10, wherein the ratio
of active pharmaceutical ingredient to solubility-enhancing polymer
ranges of from about 6:1 to about 1:9.
12. The pharmaceutical composition of claim 10, wherein the TPR
beads further comprise an enteric coating applied over the solid
dispersion; the enteric coating is up to about 40% of the total
weight of the TPR beads; and the TPR beads provide a lag time of
about 1-4 hours.
13. The pharmaceutical composition of claim 10, wherein the TPR
beads further comprise an enteric coating applied over the TPR
coating; the enteric coating is up to about 40% of the total weight
of the TPR beads; and the TPR beads provide a lag time of up to
about 4 hours.
14. The pharmaceutical composition of claim 10, wherein the TPR
beads further comprise a first enteric coating applied over the
solid dispersion; a second enteric coating applied over the TPR
coating; the first and second enteric coatings are each up to about
40% of the total weight of the TPR beads; and the TPR beads provide
a lag time of up to about 4 hours.
15. The pharmaceutical composition of claim 11, comprising a
combination of IR and TPR beads, wherein the ratio of IR to TPR
beads is 1:9 to 5:5.
16. The pharmaceutical composition of claim 1, wherein said
composition is an orally disintegrating tablet comprising TPR beads
and rapidly-dissolving microgranules; wherein the average particle
size of the TPR beads and rapidly-dissolving microgranules is not
more than 400 .mu.m; the rapidly-dissolving microgranules comprise
particles of at least one disintegrant, and a sugar alcohol and/or
saccharide, said particles having an average particle size of not
more than 30 .mu.m.
17. The pharmaceutical composition of claim 10, comprising TPR
beads, rapidly-dissolving microgranules, and IR beads, wherein the
ratio of IR beads to TPR beads ranges from about 10:90 to about
50:50.
18. The pharmaceutical composition of claim 17, wherein the IR
beads further comprise a taste-masking layer coated over the solid
dispersion; and wherein the taste-masking layer comprises a
water-insoluble polymer or a water-insoluble polymer in combination
with a water-soluble or gastrosoluble pore former.
19. The pharmaceutical composition of claim 1, wherein the one or
more active pharmaceutical ingredients are selected from the group
consisting of analgesics, anti-convulsants, anti-diabetic agents,
anti-infective agents, anti-neoplastic agents, anti-Parkinsonian
agents, anti-rheumatic agents, cardiovascular agents, CNS (central
nervous system) stimulants, dopamine receptor agonists,
anti-emetics, gastrointestinal agents, psychotherapeutic agents,
opioid agonists, opioid antagonists, anti-epileptic drugs,
histamine H.sub.2 antagonists, anti-asthmatic agents, and skeletal
muscle relaxants.
20. The pharmaceutical composition of claim 23, wherein the active
pharmaceutical ingredient is lercanidipine, or pharmaceutically
acceptable salts, solvates, and/or esters thereof.
21. The pharmaceutical composition of claim 17, wherein: the IR
beads further comprise a seal coating comprising hypromellose
applied over the solid dispersion; the solubility-enhancing polymer
comprises a vinylpyrrolidone-vinyl acetate copolymer or polyvinyl
pyrrolidone; the TPR coating comprises a pharmaceutically
acceptable methacrylate ester/methylmethacrylate ester copolymer
and a pH-sensitive methacrylic acid-methylmethacrylate copolymer at
a ratio of 9:1 to 1:9; the weight of the TPR coating is up to about
50% of the weight of the TPR beads; and the active pharmaceutical
ingredient is selected from the group consisting of nifedipine,
nicorandil, lercanidipine, iloperidone, clonazepam, and
pharmaceutically acceptable salts, solvates and/or esters
thereof.
22. A method of preparing the pharmaceutical composition of claim
1, comprising: dissolving the active pharmaceutical ingredient and
sufficient solubility-enhancing polymer in a pharmaceutically
acceptable solvent; removing the pharmaceutically acceptable
solvent from the solution of active pharmaceutical ingredient and
solubility-enhancing polymer, whereby particles of a solid
dispersion comprising molecularly dispersed active pharmaceutical
ingredient and solubility-enhancing polymer are formed; dissolving
a water insoluble polymer and an enteric polymer in a
pharmaceutically acceptable coating solvent, thereby forming a TPR
coating solution; coating the particles of solid dispersion with
the TPR coating solution; removing the coating solvent, thereby
forming TPR beads comprising a TPR coating formed on the particles
of solid dispersion.
23. The method of claim 22, wherein the solution of active
pharmaceutical ingredient and solubility-enhancing polymer is
coated onto inert cores prior to forming the solid dispersion
particles by removing the pharmaceutically acceptable solvent,
whereby IR beads are formed; coating the IR beads with the TPR
coating solution, whereby TPR beads are formed.
24. The method of claim 23, further comprising: granulating at
least one disintegrant with at least one sugar alcohol and/or at
least one saccharide, thereby forming rapidly-dissolving
microgranules; mixing the TPR beads with the rapidly-dissolving
microgranules; compressing the mixture, whereby an orally
disintegrating tablet is formed.
25. The method of claim 23, further comprising: granulating at
least one disintegrant with at least one sugar alcohol and/or at
least one saccharide, thereby forming rapidly-dissolving
microgranules; mixing the TPR beads, IR beads, and the
rapidly-dissolving microgranules; compressing the mixture, whereby
an orally disintegrating tablet is formed.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. provisional
application Nos. 60/841,760 and 60/841,893, both filed Aug. 31,
2006, each of which is herein incorporated by reference in its
entirety for all purposes.
TECHNICAL FIELD
[0002] The present invention relates to modified-release
compositions with improved bioavailability, and methods of making
such compositions. The compositions of the present invention
comprise solid dispersions of at least one active pharmaceutical
ingredient and a timed pulsatile release coating.
BACKGROUND OF THE INVENTION
[0003] Many therapeutic agents are most effective when made
available at constant rates, at or near the absorption sites. The
absorption of therapeutic agents made available in this manner
generally results in desired plasma concentrations leading to
maximum efficacy, and minimum toxic side effects. However, it is
often difficult to develop oral pharmaceutical dosage forms which
deliver the desired plasma concentrations of the therapeutic agent
at constant rates due to the complexity of the absorption process,
the many inter-related compositional variables which affect the
rate of release of the therapeutic agent from the dosage form, and
the physicochemical properties of the therapeutic agent itself. For
example, while an orally administered pharmaceutical dosage form
passes through the human digestive tract, the drug should be
released from the dosage form and be available in solution form at
or near the site for absorption from the gastrointestinal (GI)
tract. The dosage form--and hence the therapeutic agent--is
subjected to varying pHs during transit of the GI tract, i.e., pH's
varying from about 1.2 (stomach pH during fasting) to pH's as high
as 4.0 (upon consumption of food) or about 7.4 (bile pH: 7.0-7.4
and intestinal pH: 5 to 7). Moreover, the transit time of a dosage
form in individual parts of the digestive tract may vary
significantly depending on the size of the dosage form and
prevailing local conditions (e.g., permeability changes along the
GI tract; the properties of luminal contents such as pH, surface
tension, volume, agitation, and buffer capacity; and changes
following the ingestion of food). The physicochemical properties of
the drug substance itself which affect plasma concentrations
include its pKa, solubility and crystalline energy, and the
compositional properties of e.g., multiparticulate dosage forms,
including the size or specific surface area of the drug-containing
particles etc. Consequently, it is often difficult to achieve drug
release at constant rates.
[0004] In addition, basic and acidic drugs exhibit pH-dependent
solubility profiles varying by more than 2 orders of magnitude in
the physiological pH range. Of these, the most difficult drugs to
formulate are weakly basic compounds which are practically
insoluble at pH>5 (e.g., have a solubility of 50 .mu.g/mL or
less) and require high doses (e.g., an optimum daily dose of 10 mg
or larger) to be therapeutically effective. At such high doses,
some of the dissolved drug may precipitate upon entering into the
pH environment of the gastrointestinal (GI) tract unless the rate
of absorption is faster than the rate of drug release.
Alternatively, the drug may remain in the supersaturated solution
state, for example facilitated by the presence of bile salts and
lecithin in the gut, at levels of supersaturation well over an
order of magnitude higher than the aqueous solubility are known.
However, supersaturated solutions can precipitate, and there is
evidence that redissolution and absorption of the drug can then
occur at a slower rate. In order to resolve these problems,
different approaches have been developed to increase the solubility
of the weakly basic drugs, for example, the inclusion of organic
acids to form acid addition compounds, or the use of solid
dispersions or solid solutions.
[0005] However, such approaches are not entirely satisfactory
because the solubility of the drugs varies with the physiochemical
properties of the drug itself, as well as the method of preparing
the pharmaceutical formulation. For example, some weakly basic
drugs, such as nifedipine or lercanidipine, do not show significant
solubility enhancement in saturated organic acid solutions, and
solid dispersions tend to provide an undesirable immediate release
of the drug upon oral ingestion.
[0006] The compositions of the present invention provide improved
delivery of weakly basic therapeutic agents (e.g., with a pKa of
less than 14, and which require high doses to maintain target
plasma concentrations) with drug release profiles suitable for
once-daily dosing regimens.
SUMMARY OF THE INVENTION
[0007] In one embodiment, the present invention is directed to a
pharmaceutical composition comprising TPR beads, wherein said TPR
beads comprise a solid dispersion of at least one active
pharmaceutical ingredient and at least one solubility-enhancing
polymer; and a TPR coating comprising a water insoluble polymer and
an enteric polymer; wherein the active pharmaceutical ingredient
comprises a weakly basic active pharmaceutical ingredient having a
solubility of not more than 100 .mu.g/mL at pH 6.8.
[0008] In another embodiment, the present invention is directed to
a method of preparing a pharmaceutical composition, comprising
dissolving an active pharmaceutical ingredient and sufficient
solubility-enhancing polymer in a pharmaceutically acceptable
solvent; removing the pharmaceutically acceptable solvent from the
solution of active pharmaceutical ingredient and
solubility-enhancing polymer, whereby particles of a solid
dispersion of the active pharmaceutical ingredient in the
solubility-enhancing polymer are formed; dissolving a water
insoluble polymer and an enteric polymer in a pharmaceutically
acceptable coating solvent, thereby forming a TPR coating solution;
coating the solid dispersion with the TPR coating solution;
removing the coating solvent, thereby forming TPR beads comprising
a TPR coating formed on the solid dispersion.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 illustrates a cross-section of one embodiment of a
TPR bead of the present invention.
[0010] FIG. 2 illustrates pH-solubility profiles for (a)
ondansetron hydrochloride, (b) carvedilol, (c) dipyridamole, and
(d) clonazepam.
[0011] FIG. 3 illustrates the turbidity profiles for solid
solutions/dispersions of (A) lercanidipine HCl and (B)
nifedipine.
[0012] FIG. 4 illustrates intrinsic dissolution rates (IDR) of
Lercanidipine HCl--(A) Polymorph I, (B) Polymorph II and (C)
Amorphous materials (drug-polymer solid solutions)
[0013] FIG. 5 illustrates the powder X-ray diffraction patterns of
solid dispersions of lercanidipine HCl and (A) Kollidon VA 64 or
(B) Methocel E5.
[0014] FIG. 6 illustrates the powder X-ray diffraction patterns of
solid dispersions of nifedipine and (A) Kollidon VA 64 or (B)
Methocel E5.
[0015] FIG. 7 illustrates the effect of the TPR coating composition
on drug release from TPR beads described in Example 4.
[0016] FIG. 8 illustrates the effect of drug loading on drug
release from TPR beads (i.e., at 10% drug load versus 5% drug load)
described in Example 3.
[0017] FIG. 9 illustrates the effect of the particle size on drug
release from TPR beads coated at 10% drug load and 15% by weight of
Eudragit RL/L coating at 45/40 on 60-80 mesh sugar spheres of
Example 3B, compared to similar TPR beads prepared from 25-30 mesh
sugar spheres of Example 4D.
[0018] FIG. 10 illustrates the effect of TPR coating composition on
drug release from the TPR beads of Example 5.
[0019] FIG. 11 illustrates the drug release profiles from
Lercanidipine HCl TPR beads of Example 8 containing Kollidon VA 64
and tartaric acid.
[0020] FIG. 12 illustrates the effects of TPR coating composition
as well as thickness on the drug release from TPR beads of Example
9.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The present invention is directed to pharmaceutical
compositions comprising the combination of a solid dispersion of at
least one active pharmaceutical ingredient and at least one
solubility-enhancing polymer, with a timed pulsatile release (TPR)
coating comprising a water-insoluble polymer and an enteric
polymer, wherein the active pharmaceutical ingredient comprises a
weakly basic active pharmaceutical ingredient having a solubility
of not more than 100 .mu.g/mL at pH 6.8. The combination of the
solid dispersion of a weakly basic active pharmaceutical ingredient
and the TPR coating provides an improved release profile compared
to the release profile obtained by conventional compositions in
which the weakly basic active pharmaceutical ingredient is not
present in the form of a solid dispersion and/or which lacks a TPR
coating. For example, by suitable manipulation of the composition
comprising at least one TPR coating the release rate can be made to
be approximately constant over 12-18 hours, or the time to maximum
release rate can be delayed relative to using the
solubility-enhancing polymer alone.
[0022] The terms "solid dispersion" or "solid solution" refer to a
substantially amorphous active pharmaceutical ingredient dispersed
in a polymeric matrix, and/or more particularly, at least one
active pharmaceutical ingredient and at least one
crystallization-inhibiting polymer are substantially molecularly
dispersed in the solid state. The term "substantially amorphous"
means that less than 40% of the active pharmaceutical ingredient
forms a separate crystalline phase in the polymeric matrix. In
other embodiments, "substantially amorphous" means that less than
30%, less than 20%, less than 10%, less than 5%, or less than 1% of
the active pharmaceutical ingredient forms a separate crystalline
phase in the polymeric matrix. Alternatively stated, at least 60%,
at least 70%, at least 80%, at least 90%, at least 95%, or at least
99% of the active pharmaceutical ingredient is in the amorphous
state. The term "substantially molecularly dispersed" means that
less than 40% of the active pharmaceutical ingredient forms a
separate crystalline phase in the polymeric matrix, and the
remainder of the active pharmaceutical ingredient is dissolved in
the polymeric matrix. In other embodiments, "substantially
molecularly dispersed" means that less than 30%, less than 20%,
less than 10%, less than 5%, or less than 1% of the active
pharmaceutical ingredient forms a separate crystalline phase in the
polymeric matrix. The solid dispersions of the present invention
include combinations of "substantially molecularly dispersed" and
"substantially amorphous" active pharmaceutical ingredient in the
polymeric matrix, provided that no more than 40% of the active
pharmaceutical ingredient, and in some embodiments or more than
30%, no more than 20%, or more than 10%, no more than 5%, or no
more than 1% of the active pharmaceutical ingredient forms a
crystalline phase in the polymeric matrix.
[0023] The term "active pharmaceutical ingredient" can be used
interchangeably with the term "drug", "therapeutic agent", etc. As
used herein, the term "weakly basic pharmaceutically active
ingredient", as well as reference to any specific drug, includes
the base, pharmaceutically acceptable salts, polymorphs,
stereoisomers, solvates, esters and mixtures thereof. In one
embodiment, the weakly basic active pharmaceutical ingredient of
the compositions of the present invention can refer to a compound
having a pKa of less than 14. In another embodiment, the weakly
basic active pharmaceutical ingredient has a solubility of not more
than about 100 .mu.g/mL at pH 6.8. In another embodiment, the
weakly basic active pharmaceutical ingredient includes at least one
basic nitrogen atom. In yet another embodiment, the weakly basic
active pharmaceutical ingredient has a pKa of less than 14, and a
solubility of not more than about 100 .mu.g/mL at pH 6.8. In yet
another embodiment, the weakly basic active pharmaceutical
ingredient has a pKa of less than 14, and includes at least one
basic nitrogen atom. In yet another embodiment, the weakly basic
active pharmaceutical ingredient as a pKa of less than 14, a
solubility of not more than 100 .mu.g/mL at pH 6.8, and includes a
least one basic nitrogen atom.
[0024] As used herein, the terms "solubility-enhancing polymer" or
"crystallization-inhibiting polymer" refers to a water-soluble
polymer capable, at suitable concentrations, of forming a solid
dispersion, as defined herein, of a weakly basic drug in the
solubility-enhancing polymer, for example by first dissolving both
the drug and polymer in the same solvent system, and then removing
the solvent under appropriate conditions. The weakly basic drug is
maintained substantially as a molecular dispersion, or in amorphous
form during storage, transportation, and commercial distribution of
the composition containing the solid dispersion of the
solubility-enhancing polymer and weakly basic drug.
[0025] As used herein, the term "immediate release" (IR) refers to
release of greater than about 75%, in other embodiments greater
than about 85% of the active pharmaceutical ingredient in one hour
following administration of the composition. The amount of release
can be measured in vivo, or in vitro (using conventional USP
methods as described herein).
[0026] The term "IR beads" refers to particles comprising the
active pharmaceutical ingredient, which have immediate release
properties. IR beads can include any kind of particles comprising
the pharmaceutically active ingredient, e.g. particles of a solid
dispersion of the active pharmaceutical ingredient in a
solubility-enhancing polymer, or an inert core coated with a solid
dispersion of the active pharmaceutical ingredient in a
solubility-enhancing polymer. IR beads also include particles
comprising the solid dispersion, and further coated with a sealant
or protective layer, and which has immediate release properties as
described herein.
[0027] As used herein, the term "rapidly dispersing microgranules"
refers to agglomerated particles comprising primary particles of a
sugar alcohol (e.g., D-mannitol) and/or a saccharide (e.g.,
lactose) in combination with a disintegrant.
[0028] The terms, "lag-time membrane coating", "lag-time polymer
coating", "timed, pulsatile release (TPR) membrane coating", "TPR
polymer coating", or TPR coating, which are interchangeably used in
the present application, refer to a coating comprising a
water-insoluble polymer in combination with an enteric polymer.
[0029] The term, "timed, pulsatile release (TPR) beads" or simply
"TPR beads" refers to a particle comprising the active
pharmaceutical ingredient, coated with a TPR coating. In some
embodiments, TPR beads refer to IR beads coated with a TPR coating,
and the release of the weakly basic pharmaceutically active
ingredient from TPR beads prepared in accordance with certain
embodiments of the present invention is characterized by a
sustained-release profile following a short lag-time.
[0030] The term "lag-time" refers to a time period wherein less
than about 10%, more particularly less than about 5%, more
particularly substantially 0%, of the active pharmaceutical
ingredient is released, and a lag-time of up to about 4 hours, can
be achieved by the TPR coatings of the present invention comprising
a combination of water-insoluble and enteric polymers (e.g.,
Eudragit RL and L polymers).
[0031] As used herein, the terms "solubility-modulating organic
acid" or "organic acid" refer to a water-soluble, pharmaceutically
acceptable organic acid which is capable of increasing the rate
and/or the extent of dissolution of the active pharmaceutical
ingredient in an aqueous solution of the organic acid.
[0032] The term "release rate" refers to the quantity of drug
released in vitro or in vivo from a composition per unit time. The
units of quantity are often expressed as, e.g., % of the total
dose.
[0033] The terms "plasma profile", "plasma concentration",
"C.sub.max", or "C.sub.min" are intended to refer to the
concentration of drug in the plasma of a subject, generally
expressed as mass per unit volume, typically nanograms per
milliliter (ng/mL).
[0034] The term "therapeutically effective amount" refers to the
amount of active pharmaceutical ingredient necessary to provide the
desired pharmacologic result. In practice, the therapeutically
effective amount will vary widely depending on the severity of the
disease condition, age of the subject, and the desired therapeutic
effect.
[0035] The pharmaceutical compositions of the present invention
comprise a solid dispersion of at least one active pharmaceutical
ingredient and at least one solubility-enhancing polymer and a TPR
coating.
[0036] Specific embodiments of the invention will be described in
further detail with reference to the accompanying FIG. 1. FIG. 1
represents a TPR bead 10. The inert particle core 18, the amorphous
layer 16 comprising the weakly basic drug, a
crystallization-inhibiting polymer (also referred to as
solubility-enhancing polymer), and a solubility-enhancing organic
acid, the protective seal-coating layer 14, and the lag-time (also
referred to as TPR or pulsatile-release) coating 12 make up the TPR
bead 10.
[0037] Suitable active pharmaceutical ingredients for the
pharmaceutical compositions of the present invention include weakly
basic drugs. In one embodiment, the active pharmaceutical
ingredient has a pKa value of less than 14. In another embodiment,
the active pharmaceutical ingredient has a solubility of not more
than about 100 .mu.g/mL at pH 6.8. In another embodiment, the
active pharmaceutical ingredient has an elimination half life of
about 3 hours or longer. In another embodiment, the active
pharmaceutical ingredient has a solubility of not more than 50
.mu.g/mL at pH 6.8. In another embodiment, the active
pharmaceutical group ingredient has a ratio of optimal daily dose
(in mg) to solubility at pH 6.8 (in mg/mL) of at least 100. In yet
another embodiment, the active pharmaceutical ingredient has a PKa
value of less than 14, a solubility of not more than about 100
.mu.g/mL at pH 6.8, and an elimination half-life of about 3 hours
or longer. In yet another embodiment, the active pharmaceutical
ingredient has a solubility of not more than about 100 .mu.g/mL at
pH 6.8 and a ratio of optimal daily dose (in mg) to solubility at
pH 6.8 (in mg/mL) of at least 100. In yet another embodiment, the
active pharmaceutical ingredient has a solubility of not more than
about 50 .mu.g/mL at pH 6.8 and a ratio of optimal daily dose (in
mg) to solubility at pH 6.8 (in mg/mL) of at least 100.
[0038] Non-limiting examples of classes of suitable active
pharmaceutical ingredients include, but are not limited to
analgesics, antihypertensives, antianxiety agents, anticlotting
agents, anticonvulsants, anti-diabetic agents, blood
glucose-lowering agents, decongestants, antihistamines,
anti-inflammatory agents, antitussives, antineoplastics, beta
blockers, anti-rheumatic agents, anti-inflammatories, antipsychotic
agents, cognitive enhancers, anti-atherosclerotic agents,
antiobesity agents, anti-impotence agents, anti-infective agents,
anti-infective agents, hypnotic agents, anti-Parkinsonism agents,
anti-Alzheimer's disease agents, anti-depressants, and antiviral
agents, glycogen phosphorylase inhibitors, cholesterol ester
transfer protein inhibitors, CNS (central nervous system)
stimulants, dopamine receptor agonists, anti-emetics,
gastrointestinal agents, psychotherapeutic agents, opioid agonists,
opioid antagonists, anti-epileptic drugs, histamine H.sub.2
antagonists, anti-asthmatic agents, smooth muscle relaxants, and
skeletal muscle relaxants.
[0039] Specific examples of analgesics include acetominophen,
rofecoxib, celecoxib, morphine, codeine, oxycodone, hydrocodone,
diamorphine, pethidine, tramadol, buprenorphene; antihypertensives
include prazosin, nifedipine, lercanidipine, amlodipine besylate,
trimazosin and doxazosin; specific examples of antianxiety agents
include hydroxyzine hydrochloride, lorazepam, buspirone
hydrochloride, pazepam, chlordiazepoxide, meprobamate, oxazepam,
trifluoperazine hydrochloride, clorazepate dipotassium, diazepam;
specific examples of anticlotting agents include abciximab,
eptifibatide, tirofiban, lamifiban, clopidogrel, ticlopidine,
dicumarol, heparin, and warfarin; specific examples of
anticonvulsants include phenobarbital, methylphenobarbital,
clobazam, clonazepam, clorezepate, diazepam, midazolam, lorazepam,
felbamate, carbamezepine, oxcarbezepine, vigabatrin, progabide,
tiagabine, topiramate, gabapentin, pregabaln, ethotoin, phenytoin,
mephenytoin, fosphenytoin, paramethadione, trimethadione,
ethadione, beclamide, primidone, brivaracetam, levetiracetam,
seletracetam, ethosuximide, phensuximide, mesuximide,
acetazolamide, sulthiame, methazolamide, zonisamide, lamotrigine,
pheneturide, phenacemide, valpromide, and valnoctamide; specific
examples of antidiabetic agents include repaglinide, nateglinide,
metformin, phenformin, rosiglitazone, pioglitazone, troglitazone,
miglitol, acarbose, exanatide, vildagliptin, and sitagliptin;
specific examples of blood glucose-lowering agent include
tolbutamide, acetohexamide, tolazamide, glyburide, glimepiride,
gliclazide, glipizide and chlorpropamide; specific examples of
decongestants include pseudoephedrine, phenylephrine, and
oxymetazoline; specific examples of antihistamines include
mepyramine, antazoline, diphenhydramine, carbinoxamine, doxylamine,
clemastine, dimenhydrinate, pheniramine, chlorpheniramine,
dexchlorpheniramine, brompheniramine, tripolidine, cyclizine,
chlorcyclizine, hydroxyzine, meclizine, promethazine, trimeprazine,
cyproheptadine, azatadine, and ketotifen; specific examples of
antitussives include dextromethorphan, noscapine, ethyl morphine,
and codeine; specific examples of antineoplastics include
chlorambucil, lomustine, tubulazole and echinomycin; specific
examples of anti-inflammatory agents include betamethasone,
prednisolone, aspirin, piroxicam, valdecoxib, carprofen, celecoxib,
flurbiprofen and
(+)-N-{4-[3-(4-fluorophenoxy)phenoxy]-2-cyclopenten-1-yl}-N-hyroxyurea;
specific examples of beta-blockers include timolol and nadolol;
specific examples of antitussives include dextromethorphan,
noscapine, ethyl morphine, theobromine, and codeine; specific
examples of anti-neoplastics include actinomycin, dactinomycin,
doxorubicin, daunorubicin, epirurubicin, bleomycin, plicamycin, and
mitomycin; specific examples of beta-blockers include alprenolol,
carteolol, levobunolol, mepindolol, metipranolol, nadolol,
oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol,
acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol,
nebivolol, carvedilol, celiprolol, labetalol, and butaxemine;
specific examples of antirheumatic agents include adalimumab,
azathioprine, chloroquine, hydroxychloroquine, cyclosporine,
D-penicillamine, etanercept, sodium aurothiomalate, auranofin,
infliximab, leflunomide, methotrexate, minocycline, sulfasalazine;
specific examples of anti-inflammatories include steroidal and
nonsteroidal anti-inflammatory drugs such as hydrocortisone,
prednisone, prednisolone, methylprednisolone, dexamethasone,
betamethasone, triamcinolone, beclomethasone, aldosterone,
acetaminophen, amoxiprin, benorilate, diflunisal, faislamine,
diclofenac, aceclofenac, acemetacin, bromfenac, etodolac,
indomethacin, nabumetone, sulindac, tolmetin, carprofen, ketorolac,
mefenamic acid, phenylbutazone, azaanti-inflammatoriespropazone,
matamizole, oxyphenbutazone, sulfinprazone, piroxicam, lornoxicam,
meloxicam, tenoxicam, celecoxib, etoricoxib, lumiricoxib,
parecoxib, rofecoxib, valdecoxib, and numesulide; specific examples
of antipsychotic agents include iloperidone, ziprasidone,
olanzepine, thiothixene hydrochloride, fluspirilene, risperidone
and penfluridole; a specific example of a cognitive enhancer
includes ampakine; specific examples of anti-atherosclerotic,
cardiovascular and/or cholesterol reducing agents include
atorvastatin calcium, cerivastatin, fluvastatin, lovastatin,
mevastatin, pitavastatin, pravastatin, rosuvastatin, and
simvastatin; specific examples of antiobesity agents include
dexadrine, dexfenfluramine, fenfluramine, phentermine, orlistat,
acarbose, and rimonabant; specific examples of anti-impotence
agents include sildenafil and sildenafil citrate; specific examples
of anti-infective agents such as antibacterial, antiviral,
antiprotozoal, antihelminthic and antifungal agents include
carbenicillin indanylsodium, bacampicillin hydrochloride,
troleandomycin, doxycyline hyclate, ampicillin, penicillin G,
azithromycin, oxytetracycline, minocycline, erythromycin,
clarithromycin, spiramycin, acyclovir, nelfinavir, virazole,
benzalkonium chloride, chlorhexidine, econazole, terconazole,
fluconazole, voriconazole, griseofulvin, metronidazole,
thiabendazole, oxiendazole, morantel, cotrimoxazole; specific
examples of hypnotic agents include alfaxalone and etomidate;
specific examples of anti-Parkinsonism agents include levodopa,
bromocriptine, pramipexole, ropinirole, pergolide, and selegiline;
anticholinergics such as trihexyphenidyl, benztropine mesylate,
procyclidine, biperiden, andethopropazine; antihistamines such as
diphenhydramine and dolphenadrine; and amantadine; specific
examples of anti-Alzheimer's disease agents include donepezil
rivastigmine, galantamine, tacrine; specific examples of
antibiotics include minocycline, rifampin, erythromycin, nafcillin,
cefazolin, imipenem, aztreonam, gentamicin, sulfamethoxazole,
vancomycin, ciprofloxacin, trimethoprim, metronidazole,
clindamycin, telcoplanin, mupirocin, azithromycin, clarithromycin,
ofloxacin, lomefloxacin, norfloxacin, nalidixic acid, sparfloxacin,
pefloxacin, amifloxacin, enoxacin, fleroxacin, ternafloxacin,
tosufloxacin, clinafloxacin, sulbactam, clavulanic acid,
amphotericin B, fluconazole, itraconazole, ketoconazole, nystatin;
specific examples of anti-depressants include isocarboxazid;
phenelzine; tranylcypromine; specific examples of antiviral agents
include azidovudine (AZT), didanosine (dideoxyinosine, ddI), d4T,
zalcitabine (dideoxycytosine, ddC), nevirapine, lamivudine (epivir,
3TC), saquinavir (Invirase), ritonavir (Norvir), indinavir
(Crixivan), delavirdine (Rescriptor); specific examples of glycogen
phosphorylase inhibitors include
[R--(R*S*)]-5-chloro-N-[2-hydroxy-3-{methoxymethylamino}-3-oxo-1-(phenylm-
ethyl)propyl-1H-indole-2-carboxamide and
5-chloro-1H-indole-2-carboxylic acid
[(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-o-
-xypropyl]amide; specific examples of cholesterol ester transfer
protein inhibitors include
[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-
-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl
ester,
[2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-triflu-
oromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl
ester,
[2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-eth-y-
l-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid
isopropyl ester; specific examples of CNS stimulants include
caffeine and methylphenidate; specific examples of dopamine
receptor agonists include cabergoline and pramipexole; specific
examples of antiemetics include dolasetron, granisetron,
ondansetron, tropisetron, palonosetron, domperidone, droperidol,
dimenhydrinate, haloperidol, chlorpromezine, promethazine,
prochlorperizine, metoclopramide, and alizapride; specific examples
of gastrointestinal agents include loperamide and cisapride;
specific examples of psychotherapeutic agents include
chlorpromazine, thioridazine, prochlorperizine, haloperidol,
alprazolam, amitriptyline, bupropion, buspirone, chlordiazepoxide,
citalopram, clozapine, diazepam, fluoxetine, fluphenazine,
fluvoxamine, hydroxyzine, lorezapam, loxapine, mirtazepine,
molindone, nefazodone, nortriptyline, olanzepine, paroxetine,
phenelzine, quetiapine, risperidone, sertraline, thiothixene,
tranylcypromine, trazodone, venlafaxine, and ziprasidone; specific
examples of opioid agonists include hydromorphone, fentanyl,
methadone, morphine, oxycodone, and oxymorphone; specific examples
of opioid antagonists include naltrexone; specific examples of
anti-epileptic drugs include sodium valproate, nitrazepam,
phenytoin; specific examples of histamine H.sub.2 antagonists
include famotidine, nizatidine, cimetidine, ranitidine; specific
examples of anti-asthmatic agents include albuterol, montelukast
sodium; specific examples of smooth muscle relaxants include
nicorandil, iloperidone, and clonazepam; and specific examples of
skeletal muscle relaxants include diazepam, lorazepam, baclofen,
carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene,
metaxalone, orphenadrine, pancuronium, tizanidine, dicyclomine,
clonidine, and gabapentin. Each named drug should be understood to
include the neutral form of the drug, as well as pharmaceutically
acceptable salts, solvates, esters, and prodrugs thereof.
[0040] As discussed above, the solubility of some drugs is pH
dependent, and can be enhanced by the addition of an organic acid.
However, the solubility of other drugs is only slightly affected by
the addition of organic acids, as shown below in Tables 1 and 2 and
FIG. 2.
[0041] Table 1 lists the solubility enhancement of weakly basic
drugs in organic acid buffers (see also FIG. 2). Three distinct
groups can be identified. Group A drugs, as represented by
ondansetron hydrochloride, exhibit a dramatic increase in
solubility of the weakly basic active in a buffer with a trace of
fumaric acid. For example, the solubility of ondansetron of about
26 mg/mL in the buffer containing only 0.05 mg/mL of fumaric acid,
remains unchanged upon increasing the concentration of fumaric acid
in the buffer up to 5 mg/mL. In Group B, represented by
dipyridamole, carvedilol, and iloperidone, the solubility of the
weakly basic drug increases with increasing concentration of the
acid. In Group C, represented by clonazepam, the organic acid has
very limited impact, i.e., the solubility enhancement amounts
typically to less than 3-fold. For example, the solubilities of
clonazepam are about 11.6 and 6.9 .mu.g/mL in buffers at pH 2.3 and
6.8 containing a higher and lower concentration of fumaric acid,
respectively. TABLE-US-00001 TABLE 1 Solubilities of Weakly Basic
Drugs in Organic Acids Solubility of Ondansetron Solubility of
Concentration Hydrochloride in Dipyridamole ofFumaric Acid Start
End Fumaric Acid Start in Fumaric (mg/mL) pH pH (mg/mL) pH Acid
(mg/mL) 5 2.13 2.01 26.9 2.98 6.24 2.5 2.26 2.14 27.0 3.42 1.80 1
2.48 2.40 26.1 3.68 0.93 0.25 2.79 2.75 26.2 3.88 0.65 0.05 3.19
3.49 26.0 4.33 0.27 0.01 3.64 4.05 26.1 4.71 0.13 0.0025 4.15 4.33
26.1 6.28 0.006 Solubility (mg/mL) Solubility (mg/mL) Solubility
(mg/mL) of Carvedilol in of Clonazepam of Clonazepam Tartaric Acid
in Fumaric Acid in Aspartic Acid pH pH \pH of Buffer (mg/mL) of
Buffer (mg/mL) of Buffer \(mg/mL) 2.12 2.51 2.3 0.0116 2.28 1.36
2.8 0.0103 2.84 0.029 2.54 0.731 3.2 0.0096 2.92 0.023 2.94 0.508
3.7 0.0098 3.00 0.022 3.64 0.121 4.8 0.0095 3.32 0.021 5.46 0.105
5.5 0.0093 4.21 0.018 5.90 0.028 6.2 0.0072 6.39 0.018 6.8
0.0069
[0042] TABLE-US-00002 TABLE 2 Solubility of Nifedipine in Buffers
Phosphate Fumaric Aspartic Buffer Acid Acid pH .mu.g/mL pH .mu.g/mL
pH .mu.g/mL 4.45 5.1 2.20 7.1 2.88 5.7 5.4 5.2 3.28 6.2 3.90 5.7
6.52 5.2 4.24 5.6 4.84 5.3 7.53 5.2 5.22 5.3 5.83 5.4
[0043] In one embodiment of the pharmaceutical compositions of the
present invention, the active pharmaceutical ingredient is
nifedipine. In another embodiment, the active pharmaceutical
ingredient is lercanidipine. It is to be understood, however, that
the scope of the present invention is not limited to any particular
active pharmaceutical ingredient.
[0044] Suitable solubility-enhancing polymers useful in the
pharmaceutical compositions of the present invention include but
are not limited to polyvinylpyrrolidone (PVP or povidone),
copolymers of vinyl acetate/vinylpyrrolidone (e.g. Kollidon VA 64),
methylcellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose (hypromellose), hydroxypropylmethylcellulose
acetate succinate (HPMCAS), polyethylene oxide, polyethylene
glycol, and cyclodextrin.
[0045] The type and amount of solubility-enhancing polymer is
selected so that the combination of active pharmaceutical
ingredient and solubility-enhancing polymer form a solid dispersion
as defined herein. Some of the solubility-enhancing polymers useful
for preparing solid solutions/dispersions are conventionally used
as binders. However, in order to provide a solid dispersion of the
active pharmaceutical ingredient, the ratio of solubility-enhancing
polymer to active pharmaceutical ingredient is generally
significantly higher than the ratio of polymeric binder to active
pharmaceutical ingredient in conventional pharmaceutical
formulations. (In conventional pharmaceutical formulations, the
ratio of polymeric binder to active pharmaceutical ingredient is
typically less than 1/9, for example about 1/50 to about 1/20.) In
one embodiment, the ratio of solubility-enhancing polymer to active
pharmaceutical ingredient in the solid dispersion ranges from 9/1
to 1/6 (by weight). In another embodiment, the ratio the
solubility-enhancing polymer to active pharmaceutical ingredient in
the solid dispersion ranges from about 3/1 to about 1/3 (by
weight). In yet another embodiment, the ratio the
solubility-enhancing polymer to active pharmaceutical ingredient in
the solid dispersion ranges from about 2/1 to about 1/2 (by
weight), or about 1/1.
[0046] The solid dispersion can be in the form of particles (e.g.,
granules, pellets, beads, and the like), or alternatively can be
layered on to an inert core. For example, the active pharmaceutical
ingredient and solubility-enhancing polymer can be dissolved in a
pharmaceutically acceptable solvent (or mixture of solvents) and
coated onto the inert core. Upon removal of the solvent, the solid
dispersion is formed as a coating on the inert core. Any
pharmaceutically acceptable inert material can be used as an inert
core, for example sugar spheres or beads (e.g., Celphere.RTM.),
cellulose spheres, a silicon dioxide spheres, or the like, with a
suitable particle size distribution (e.g. from about 20-25 mesh to
35-40 mesh sugar spheres for making coated beads for incorporation
into a capsule formulation and sugar spheres or cellulose spheres
having a narrow particle size distribution in the range of about
50-100 mesh for making coated beads for incorporation into an ODT
formulation. The thickness of the solid dispersion layer and
relative amounts of active pharmaceutical ingredient and
solubility-enhancing polymer can be adjusted to provide a
therapeutically effective amount of the active pharmaceutical
ingredient. For example, the inert cores layered with a solid
dispersion of the active pharmaceutical ingredient can contain 2%
to about 50% by weight of the active pharmaceutical ingredient
(relative to the total weight of the drug-coated inert core).
[0047] The solid dispersion of the pharmaceutical compositions of
the present invention is coated with a TPR coating comprising a
water-insoluble polymer and an enteric polymer, for example the TPR
coatings described in U.S. Pat. No. 6,627,223, herein incorporated
by reference for all purposes. The TPR coating modulates the
release of the active pharmaceutical ingredient to provide a
therapeutically effective level of the active pharmaceutical
ingredient in the plasma of a patient, e.g. for a 12-24 hour
period. In some embodiments, the TPR coating can delay the release
of the active pharmaceutical ingredient for a short lag-time (e.g.,
up to about four hours). In addition, the TPR coating can provide a
sustained therapeutic level of the drug over an extended period,
e.g. up to about 12, up to about 18, or up to about 24 hours.
[0048] Suitable water-insoluble polymers include cellulose
derivatives (e.g. ethylcellulose), polyvinyl acetate (Kollicoat
SR30D from BASF), neutral copolymers based on ethyl acrylate and
methylmethacrylate, copolymers of acrylic and methacrylic acid
esters with quaternary ammonium groups, such as Eudragit NE, RS or
RS30D, RL or RL30D and the like.
[0049] Enteric polymers are insoluble at the low pH levels found in
the stomach, but are relatively soluble at the higher pH levels
found in the intestinal tract. Suitable enteric polymer include
acid substituted cellulose esters (e.g., cellulose acetate
phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl
methylcellulose acetate succinate), polyvinyl acetate phthalate,
pH-sensitive methacrylic acid-methamethacrylate copolymers and
shellac. Commercially available enteric polymers are sold under the
trade name "Eudragit" (e.g., Eudragit L100, S100, L30D)
manufactured by Rhom Pharma, Cellacefate (cellulose acetate
phthalate) from Eastman Chemical Co., Aquateric (cellulose acetate
phthalate aqueous dispersion) from FMC Corp. and Aqoat
(hydroxypropyl methylcellulose acetate succinate aqueous
dispersion) from Shin Etsu K. K.
[0050] The ratio of water-insoluble polymer to enteric polymer in
the TPR coating can vary from about 1/9 to about 9/1 (by weight).
In one embodiment, the ratio of water-insoluble polymer to entelic
polymer can vary from about 1/4 to about 4/1, or about 1/3 to about
3/1 (by weight). The total weight of the enteric coating can range
from about 5-50% of the total weight of the TPR bead. In one
embodiment, the total weight of the TPR coating on the TPR bead
ranges from about 10% to about 25% by weight, based on the total
weight of the TPR bead.
[0051] The enteric and water-insoluble polymers used in forming the
TPR coating is can be plasticized. Representative examples of
suitable plasticizers that can be used to plasticize the TPR
coating layer include triacetin, tributyl citrate, triethyl
citrate, acetyl tri-n-butyl citrate, diethyl phthalate, castor oil,
dibutyl sebacate, acetylated monoglycerides and the like or
mixtures thereof. The plasticizer, when present, can comprise about
3 to 30% of the total weight of the TPR coating. In one embodiment,
the plasticizer comprises about 10 to 25% of the total weight of
the TPR coating. The type and amount of plasticizer depends on the
nature of the water-insoluble and enteric polymers of the TPR
layer, and the nature of the coating system (e.g., aqueous or
solvent based, solution or dispersion based, and the total solids
content of the coating system).
[0052] In addition to the solid dispersion (comprising a least one
active pharmaceutical ingredient and at least one solubility
enhancing polymer) and the TPR coating, the pharmaceutical
compositions of the present invention can further comprise
additional pharmaceutically acceptable ingredients or excipients.
Examples of suitable excipients for use in the compositions or
dosage forms of the present invention include fillers, diluents,
glidants, disintegrants, binders, lubricants etc. Other
pharmaceutically acceptable excipients include acidifying agents,
alkalizing agents, preservatives, antioxidants, buffering agents,
chelating agents, coloring agents, complexing agents, emulsifying
and/or solubilizing agents, flavors and perfumes, humectants,
sweetening agents, wetting agents etc.
[0053] Examples of suitable fillers, diluents and/or binders
include lactose (e.g. spray-dried lactose, .alpha.-lactose,
.beta.-lactose, Tabletose.RTM., various grades of Pharmatose.RTM.,
Microtose.RTM. or Fast-Floc.RTM.), microcrystalline cellulose
(various grades of Avicel.RTM., Elcema.RTM., Vivacel.RTM., Ming
Tai.RTM. or Solka-Floc.RTM.), hydroxypropylcellulose,
L-hydroxypropylcellulose (low substituted), hydroxypropyl
methylcellulose (HPMC) (e.g. Methocel E, F and K, Metolose SH of
Shin-Etsu, Ltd, such as, e.g. the 4,000 cps grades of Methocel E
and Metolose 60 SH, the 4,000 cps grades of Methocel F and Metolose
65 SH, the 4,000, 15,000 and 100,000 cps grades of Methocel K; and
the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH),
methylcellulose polymers (such as, e.g., Methocel A, Methocel A4C,
Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium
carboxymethylcellulose, carboxymethylene,
carboxymethylhydroxyethylcellulose and other cellulose derivatives,
sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins,
starches or modified starches (including potato starch, maize
starch and nice starch), calcium phosphate (e.g. basic calcium
phosphate, calcium hydrogen phosphate, dicalcium phosphate
hydrate), calcium sulfate, calcium carbonate, sodium alginate,
collagen etc.
[0054] Specific examples of diluents include e.g. calcium
carbonate, dibasic calcium phosphate, tribasic calcium phosphate,
calcium sulfate, microcrystalline cellulose, powdered cellulose,
dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol,
sorbitol, starch, pregelatinized starch, sucrose, sugar etc.
[0055] Specific examples of disintegrants include e.g. alginic acid
or alginates, microcrystalline cellulose, low-substituted
hydroxypropyl cellulose and other cellulose derivatives,
croscarmellose sodium, crospovidone, polacrillin potassium, sodium
starch glycolate, starch, pregelatinized starch, carboxymethyl
starch (e.g. Primogel.RTM. and Explotab.RTM.) etc. Specific
examples of binders include e.g. acacia, alginic acid, agar,
calcium carrageenan, sodium carboxymethylcellulose,
microcrystalline cellulose, dextrin, ethylcellulose, gelatin,
liquid glucose, guar gum, hydroxypropyl methylcellulose,
methylcellulose, pectin, PEG, polyethylene oxides, povidone,
pregelatinized starch etc.
[0056] Specific examples of glidants and lubricants include stearic
acid, magnesium stearate, calcium stearate or other metallic
stearates, talc, waxes and glycerides, light mineral oil, PEG,
glyceryl behenate, colloidal silica, hydrogenated vegetable oils,
corn starch, sodium stearyl fumarate, polyethylene glycols, alkyl
sulfates, sodium benzoate, sodium acetate etc.
[0057] Other excipients include e.g. flavoring agents, coloring
agents, taste-masking agents, pH-adjusting agents, buffering
agents, preservatives, stabilizing agents, anti-oxidants, wetting
agents, humidity-adjusting agents, surface-active agents,
suspending agents, absorption enhancing agents, agents for modified
release etc.
[0058] Antioxidants used to improve long term chemical stability of
the amorphous solid solution/dispersion include e.g. ascorbic acid,
ascorbyl palmitate, butylated hydroxyanisole, butylated
hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium
metabisulfite, propyl gallate, sodium formaldehylde sulfoxylate,
sodium metabisulfite, sodium thiosulfate, sulfur dioxide,
tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or
other tocopherol derivatives, etc.
[0059] In addition, the pharmaceutical compositions of the present
invention can further comprise a pharmaceutically acceptable
organic acid. The pharmaceutically acceptable organic acid can
further improve or modulate the release profile of the active
pharmaceutical ingredient (e.g. rate and extent of release).
Suitable pharmaceutically acceptable organic acids useful in the
compositions of the present invention include, but are not limited
to, citric acid, fumaric acid, aspartic acid, tartaric acid and
succinic acid. In some embodiments, the solid dispersion of active
pharmaceutical ingredient and solubility enhancing polymer includes
at least one pharmaceutically acceptable organic acid in an amount
ranging from about 10-90% of the weight of the solid dispersion. In
other embodiments, the amount organic acid ranges from 25-75% by
weight of a solid dispersion.
[0060] The compositions of the present invention can also include
one or more additional coating layers (e.g., protective or sealant
layers, compressible coatings, enteric layers, taste-masking
layers, etc.). For example, the additional coating layer(s) can
include one or more protective or sealant coating(s) comprising
e.g., Opadry Clear or Pharmacoat 603 (hydroxypropylmethylcellulose
coating compositions), or hydroxypropylcellulose, or
ethylcellulose. The protective or sealant coating can be applied
between the solid dispersion and the TPR coating, on top of the TPR
coating, or multiple protective were sealant coatings, e.g. between
the solid dispersion in the TPR coating as well as on top of the
TPR coating. The additional coating layer(s) can also include a
compressible coating, e.g. a layer of highly plasticized ethyl
cellulose or hydroxypropylcellulose deposited over IR beads,
taste-masked IR beads or TPR beads comprising solid
dispersions.
[0061] Other embodiments of the pharmaceutical composition of the
present invention can include one or more enteric layers comprising
one or more enteric polymers as described herein. The optional
enteric layers can be deposited between the solid dispersion and
the TPR coating, and/or deposited over the TPR coating.
[0062] The pharmaceutical compositions of the present invention can
include any combination of protective or sealant layers,
compressible coatings, and enteric layers which provide the desired
handling properties and drug release properties.
[0063] The pharmaceutical compositions of the present invention can
be formulated into various oral dosage forms, for example capsules
(e.g., gelatin or HPMC capsules), tablets, or orally disintegrating
tablets (ODT). Tablets differ from ODT dosage forms in that tablets
are intended to be swallowed intact and rapidly disperse upon
entering the stomach, while ODTs rapidly disintegrate on contact
with saliva in the oral cavity, forming a smooth suspension of
particles which are easily swallowed.
[0064] In some embodiments, the dosage forms of the present
invention comprise only TPR beads. In other embodiments, the dosage
forms of the present invention can comprise blends of immediate
release (IR) beads and TPR beads (i.e., as described herein). IR
beads comprise a solid dispersion of the active pharmaceutical
ingredient in a solubility-enhancing polymer, and release the
active pharmaceutical ingredient essentially immediately (e.g.,
.gtoreq.75% release of the drug within about 60 minutes of
administration). IR beads can comprise particles of a solid
dispersion, or a solid dispersion of the active pharmaceutical
ingredient in a solubility-enhancing polymer "layered" onto an
inert core, as described herein. IR beads can also optionally
include one or more protective or select layers. The IR beads can
then be converted to TPR beads by adding a TPR coating.
[0065] When the dosage forms of the present invention comprise
blends of IR and TPR beads, the IR beads can be uncoated,
optionally coated with a sealant or protective coating, and/or
optionally coated with a taste masking layer. The taste masking
layer can include e.g. any of the taste masking compositions
described in U.S. application Ser. Nos. 11/213,266, 11/248,596, and
11/256,653, each of which is herein incorporated by reference in
their entirety. Specifically, suitable taste masking layers
comprise one or more pharmaceutically acceptable water-insoluble
polymers combined with one or more pore forming agents.
Non-limiting examples of suitable pharmaceutically acceptable
water-insoluble polymers for the taste masking layer include, e.g.
ethylcellulose, cellulose acetate, cellulose acetate butyrate,
polyvinyl acetate, and methacrylate polymers (e.g., Eudragit RL,
RS, and NE and 30D). Non-limiting examples of suitable pore forming
agents include sodium chloride, calcium carbonate, calcium
phosphate, calcium saccharide, calcium succinate, calcium tartrate,
ferric acetate, ferric hydroxide, ferric phosphate, magnesium
carbonate, magnesium citrate, magnesium hydroxide, magnesium
phosphate, polyvinyl pyrrolidone, crospovidone, Eudragit E100,
Eudragit EPO, and mixtures thereof. The ratio of water-insoluble
polymer to pore former in the taste masking layer ranges from about
95/5 to about 50/50, or in some embodiments about 85/15 to about
65/35. The amount of taste masking layer applied to the IR bead can
range from about 5% to about 50% of the total weight of the coated
IR bead, in some embodiments about 10% to about 50% of the total
weight of the coated IR bead.
[0066] When the dosage forms of the present invention comprise
blends of IR and TPR beads, the ratio of IR to TPR beads ranges
from about 1/9 to about 5/5, and in some embodiments, from about
1/4 to about 1/1 (by weight).
[0067] When pharmaceutical compositions of the present invention
are formulated into an ODT dosage form, the compositions further
comprise a disintegrant. The disintegrant can be in the form of
rapidly dispersing microgranules comprising at least one
disintegrant in combination with at least one sugar alcohol and/or
saccharide. Non-limiting examples of suitable disintegrants include
crospovidone (crosslinked polyvinylpyrrolidone), starch, cellulose,
sodium starch glycolate, and sodium carboxymethylcellulose.
Non-limiting examples of sugar alcohols include arabitol,
erythritol, lactitol, maltitol, mannitol, sorbitol, and xylitol.
Non-limiting examples of suitable saccharides include lactose,
sucrose, and maltose.
[0068] The ratio of the disintegrant to the sugar alcohol and/or
saccharide in the rapidly dispersing microgranules ranges from
about 1/99 to about 10/90, and in some embodiments is about 5/95
(by weight).
[0069] The ratio of coated drug-containing beads (i.e., coated
beads comprising the solid solution) to rapidly dispersing
microgranules in the ODT dosage form varies from about 1/9 to 1/1
and in some embodiments from about 1:4 to about 1:2.
[0070] Since ODT dosage forms disintegrate rapidly in the oral
cavity of a patient, the organoleptic properties of the ODT are an
important consideration. For example, the ODT should be formulated
to provide good "mouthfeel" and taste characteristics. "Mouthfeel"
describes how a product feels in the mouth. In order to obtain a
"mouthfeel" which is not gritty, the TPR beads, rapidly dispersing
microgranules, and optional IR beads should have an average
particle size of 400 .mu.m or less, in some embodiments 300 .mu.m
or less, and in still other embodiments, 200 .mu.m or less. In one
embodiment, the primary particles comprising the rapidly dispersing
microgranules (i.e., particles of a disintegrant and sugar alcohol
and/or saccharide which are agglomerated to form the rapidly
dispersing microgranules) have an average particle size of 30 .mu.m
or less, in other embodiments 25 .mu.m or less, and in still other
embodiments 20 .mu.m or less.
[0071] In one embodiment, and ODT dosage form comprising the
composition of the present invention comprises TPR beads and
rapidly dispersing microgranules as described herein. The ODT
dosage form can further comprise additional excipients, for example
compression aids (e.g., microcrystalline cellulose) and/or
additional disintegrants (which may be the same or different from
the disintegrants of the rapidly dispersing microgranules). The ODT
dosage form can also include a lubricant (e.g., magnesium
stearate), or may not include lubricants if compressed in
externally lubricated die system. In one embodiment, an ODT dosage
form of the present invention disintegrates on contact with saliva
in the oral cavity in about 60 seconds, forming an easy-to-swallow
suspension with good "mouthfeel". In another embodiment, an ODT
dosage form of the present invention disintegrates on contact with
saliva in the oral cavity in about 30 seconds, forming an
easy-to-swallow suspension with good "mouthfeel".
[0072] In one embodiment, the TPR beads of the dosage form (e.g.,
tablet, ODT, or capsule) can comprise an inert core coated with the
solid dispersion of drug and solubility enhancing polymer, then
coated with a TPR layer, and optionally coated with one or more
sealant layers or enteric layers.
[0073] When present, the IR beads of the dosage form (e.g., tablet,
ODT, or capsule) can comprise an inert core coated with the solid
dispersion of drug and solubility enhancing polymer, and optionally
coated with a sealant layer and/or taste masking layer as described
herein. Such high are beads can also serve as an "intermediate" for
preparing TPR beads--when coated with a TPR layer, IR beads are
converted to TPR beads.
[0074] Alternatively, IR beads can be prepared by forming particles
of the solid dispersion (e.g. by spray drying, grinding "bulk" or
larger particulate forms of the solid dispersion, or granulating
one or more pharmaceutically acceptable excipients (e.g., a filler,
binder, disintegrant, etc.) with the solid dispersion, which can
then be optionally extruded and spheronized. Such IR
particles/beads/pellets can then be converted to TPR beads upon
coating with a TPR layer.
[0075] The dosage forms of the present invention may include one or
more different types of TPR beads (e.g., TPR beads with different
TPR layers, or with different combinations of sealant and/or
enteric layers). For example, TPR beads having different TPR layers
can exhibit different lag time characteristics and/or different
release rate characteristics, thereby providing the dosage form
with different overall drug release characteristics. It is its
forms which include different types of TPR beads can also
optionally include IR beads to provide some immediate release
characteristics. For example, in one embodiment, a once-daily
dosage form comprises a mixture of IR beads (comprising an active
pharmaceutical ingredient with an elimination half-life of about 7
hours) which allows immediate release and a second population of
TPR beads with a lag-time of up to about 4 hours, which provides a
delayed, sustained-release profile of the drug over about 12-20
hours, and maintains therapeutically effective plasma
concentrations over about 18-24 hrs.
[0076] The solid solution or dispersion of an active pharmaceutical
ingredient in the solubility-enhancing polymer can be prepared by
dissolving the active pharmaceutical ingredient and the
solubility-enhancing polymer in a pharmaceutically acceptable
solvent or a mixture of solvents. The solution of active
pharmaceutical ingredient and solubility-enhancing polymer is then
dried under conditions which promote formation of a solid solution
of the active pharmaceutical ingredient in the solubility-enhancing
polymer. As discussed above, the formation of a molecularly
dispersed solid dispersion is favored by relatively high levels of
solubility-enhancing polymer relative to the active pharmaceutical
ingredient. In addition, solid dispersions can also be formed by
rapidly removing the solvent from the solution of active
pharmaceutical ingredient and solubility enhancing polymer, for
example by spray drying, or by coating the solution of active
pharmaceutical ingredient and solubility-enhancing polymer onto an
inert core (forming a drug-layered bead), e.g. using fluidized bed
coating methods. Alternatively, solid dispersions can also be
prepared by dissolving the active pharmaceutical ingredient into a
melt of the solubility-enhancing polymer, e.g. by polymer extrusion
methods, such as by compounding in a twin screw extruder. If
necessary to obtain a suitable particle size (e.g. a particle size
of less than 400 .mu.m for ODT dosage forms), particles of the
solid dispersion can optionally be milled (to reduce the particle
size), or granulated (e.g. rotogranulation, or granulation followed
by extrusion-spheronization) in the presence of suitable
excipients. The solid dispersion can also be formed into 1-2 mm
diameter "mini-tablets", e.g. formed by compressing particles of
the solid dispersion, optionally with excipients such as
compression aids, lubricants etc., using round beveled punches of
the appropriate dimensions.
[0077] In one embodiment, the solid dispersion is prepared by
granulating the solubility enhancing polymer, the weakly basic drug
and optionally other pharmaceutically acceptable excipients (e.g.,
binders, diluents, fillers) in a high-shear granulator, or a fluid
bed granulator, such as Glatt GPCG granulator, and granulated to
form agglomerates. The wet mass from the high-shear granulator can
also be extruded and spheronized to produce spherical particles
(pellets).
[0078] When the solid dispersion is prepared by solvent processing
methods, as discussed above, the pharmaceutically acceptable
solvent can be a single solvent, or a mixture of solvents.
Non-limiting examples of suitable solvents include water, ketones
such as acetone, alcohols such as ethanol, and mixtures thereof
(e.g., aqueous acetone, 95% ethanol, etc.).
[0079] Once prepared, the solid dispersion particles (e.g.,
spray-dried solid dispersion of drug/polymer, drug-layered beads,
granulated solid dispersion, mini-tablets, etc.) may be optionally
coated with a protective sealant coat (e.g., Pharmacoat.TM. 603 or
Opadry.RTM. Clear).
[0080] The solid dispersion particles prepared as described above
can be referred to as IR (immediate release) beads or particles,
because such beads or particles would substantially immediately
release the active pharmaceutical ingredient if administered in
this form. The IR beads or particles prepared as described above
are then coated with a TPR coating solution comprising a
water-insoluble polymer and an enteric polymer dissolved in a
pharmaceutically acceptable solvent. Any suitable coating process
can be used to apply the TPR coating, for example fluidized bed
coating methods, etc.
[0081] In some embodiments, it is desirable to apply a plurality of
coatings to the IR beads or particles, in addition to the TPR
coating. For example, in some embodiments the IR beads are first
coated with an enteric coating (e.g. comprising at least one
enteric polymer, described herein, dissolved in a pharmaceutically
acceptable solvent), dried to remove the coating solvents, then
coated with the TPR coating as described above. In other
embodiments, the IR beads are coated with an enteric polymer
coating, a TPR coating, and then a second enteric polymer coating.
In yet other embodiments, the IR beads are coated with a first TPR
coating, an enteric polymer coating, and then a second TPR coating,
wherein the first and second TPR coatings are independently either
the same or different. In still other embodiments, sealant layers
(as described herein) are coated onto the IR beads prior to
applying the TPR and/or enteric polymer coating layers. In still
other embodiments, a sealant layer can be applied after applying
the TPR and/or enteric polymer coating layers.
[0082] In pharmaceutical dosage forms which contain a mixture of
TPR and IR beads, the IR beads can be coated with a taste masking
layer. For example, any of the IR beads described herein can be
coated with a solution comprising a pharmaceutically acceptable
solvent, a water-insoluble polymer, and optionally a pore former,
using any suitable coating technique such as fluidized bed coating
or coacervation.
[0083] Pharmaceutical dosage forms can then be prepared from TPR
beads, e.g. by compressing TPR beads into tablets, compressing TPR
beads and a disintegrant (e.g. rapidly dispersing microgranules)
into an ODT, or filling a capsule with the TPR beads using
conventional methods. These pharmaceutical dosage forms can
optionally contain additional excipients, as well as IR beads, as
described herein. In one embodiment, the composition of the present
invention, and optionally additional excipients and/or IR beads, is
compressed into tablets using an externally lubricated tablet
press. In another embodiment, the composition of the present
invention, rapidly disintegrating microgranules, optionally
additional excipients and/or IR beads, is compressed into an
ODT.
[0084] Pharmaceutical dosage forms comprising the compositions of
the present invention release therapeutically effective levels of
the active pharmaceutical ingredient over a 12-18 hour period, for
example as shown in FIGS. 7-12. The drug release profile for
compositions work dosage forms of the present invention can be
evaluated in vitro using various dissolution testing methods, such
as United States Pharmacopoeia Apparatus 1 (baskets @100 rpm) or
Apparatus 2 (paddles @50 rpm) and a two-stage dissolution
methodology (testing in 700 mL of 0.1N HCl (hydrochloric acid) for
the first 2 hours and thereafter in 900 mL at pH 6.8 obtained by
adding 200 mL of a pH modifier). Drug/acid-release with time is
determined by HPLC on samples obtained at selected intervals.
[0085] In one embodiment, the compositions of the present invention
provide a therapeutically effective plasma concentration of the
active pharmaceutical ingredient over a period of at least about 12
hours when dissolution tested by United States Pharmacopoeia (USP)
dissolution methodology using a two-stage dissolution medium (first
2 hours in 0.1N HCl followed by testing in a buffer at pH 6.8).
[0086] In order to assess the type of in vitro release profile
needed to achieve a once-daily plasma concentration profile, a
modeling exercise is typically performed using the pharmacokinetic
parameters for the drug using the software program, WinNonlin.TM.
Standard Version 2.1 or equivalent (e.g., GastroPlus.RTM.) to fit a
1-compartment first order model with a lag-time assuming first
order elimination kinetics. The primary parameters are then input
into another program, Stella Version 6.01 using a previously
established model with slight modifications. Different in vitro
release profiles are generated, and from target once-daily release
profiles, desired in vitro release (medium, target and fast)
profiles are generated by deconvolution.
[0087] The following non-limiting examples illustrate capsule
dosage forms which exhibit one or more drug release "pulses" and a
predetermined delayed-onset. The in vitro drug-release profile or
the corresponding in vivo plasma concentration profile upon oral
administration of the dosage form can be designed to provide the
desired profile to achieve maximum therapeutic efficacy and enhance
patient compliance (e.g., by providing a once-a-day dosage form) by
adjusting the amount or thickness of the TPR layer, and optionally
adjusting the number and type of additional layers (e.g., enteric
or sealant layers). The dosage forms of the present invention
provide improved drug release profiles which maintain drug plasma
concentrations at levels which minimize side-effects associated
with the drug release profile of conventional dosage forms.
EXAMPLE 1
[0088] Turbidity Measurements
[0089] A concentrated solution (3 mL) of lercanidipine
hydrochloride in acetone (0.5 mg/ml) was added to 200 mL of a
buffer solution (pH 6.0) containing Kollidon VA 64, Methocel E5
(hypromellose), polyethylene glycol (PEG 6000), cyclodextrin or
Kollidon 14 PF (polyvinyl pyrrolidone) at the ratio of 1:2 by
weight with respect to the polymer. It is evident from FIG. 3A that
the drug solutions showed improved stability thus strongly reducing
the risk of crystallization of the conjugated base of lercanidipine
HCl.
[0090] Intrinsic Dissolution Rate Measurements
[0091] Intrinsic dissolution rates were determined for two
different polymorphs of lercanidipine hydrochloride as well as
amorphous materials (e.g., amorphous drug and 1:2 solid solutions
of lercanidipine hydrochloride with Methocel E5 and Kollidon VA
64). The data are shown in FIG. 4. While the crystalline polymorphs
exhibit poor dissolution rates as well as extent of dissolution,
the solid solutions exhibit significantly higher dissolution rates
as well as extent of dissolution.
[0092] Powder X-Ray Diffraction
[0093] Lercanidipine hydrochloride and Methocel E5 (hypromellose)
at a ratio of 1:1 and 1:2 were dissolved in a solvent mixture of
dichloromethane-methanol (1 to 1, v/v) and the solutions were dried
to a residual solvent level of less than 1% (w/w). Analogously, 1:1
and 1:2 co-precipitates of lercanidipine hydrochloride and Kollidon
VA 64 were prepared. Powder X-ray diffraction patterns were
generated on all the four samples. XRD patterns for
lercanidipine-Kollidon VA 64 solid solutions are shown in FIG. 5
demonstrating that the solid solution of lercanidipine HCl and
Kollidon VA 64 at the ratio of 1:2 is almost totally amorphous.
EXAMPLE 2
[0094] Turbidity Measurements
[0095] A concentrated solution (3 mL) of Nifedipine in acetone (0.5
mg/mL) was added to 200 mL of a buffer solution (pH 6.0) containing
Kollidon VA 64, Methocel E5 (hypromellose), polyethylene glycol
(PEG 6000), cyclodextrin or Kollidon 14 PF (polyvinyl pyrrolidone)
at a nifedipine/polymer ratio of 1:2 by weight. The transmittance
of the nifedipine/polymer solutions was monitored over time as
shown in FIG. 3B. The more stable solutions exhibited a slower
decline in transmittance over time, due to slower crystallization
of nifedipine from solution. Methocel E5, Kollidon VA 64, and
Kollidon 14 PF exhibited greater stabilization.
[0096] Powder X-Ray Diffraction
[0097] Two co-precipitates of nifedipine and Methocel E5
(hypromellose) were prepared at a nifedipine/Methocel ratio of 1:1
and 1:2 by dissolving the nifedipine and Methocel in a mixture of
dichloromethane-methanol (1:1, v/v), then drying the solutions to a
residual solvent level of less than 1% (w/w). Using the same
method, 1:1 and 1:2 co-precipitates of nifedipine and Kollidon VA
64 were also prepared. All four samples were analyzed by powder
X-ray diffraction; XRD patterns for nifedipine-Kollidon VA 64 solid
solutions are shown in FIG. 6. The presence of sharp peaks in the
XRD pattern for the 1:1 co-precipitate indicates that nifedipine
present in crystalline form. The broad, relatively featureless XRD
pattern of the 1:2 co-precipitate indicates that nifedipine is
almost totally non-crystalline, and forms a solid dispersion in the
Kollidon VA 64.
EXAMPLE 3
[0098] 3A--Nifedipine IR Beads (Nominal Nifedipine Loading:
10%)
[0099] Kollidon VA 64 (800 g) was slowly added to a 72.5/22.5/5
mixture of 95% ethanol/acetone/water (4930 g/1530 g/340 g) while
vigorous stirring until dissolved, and then nifedipine (400 g) was
slowly until dissolved. A Glatt GPCG 3 equipped with a 7'' bottom
spray/8'' column height Wurster insert, 20 mm partition gap,
air-distribution plate B (250 .mu.m screen), 1.0 mm nozzle port,
atomization air pressure of 1.5 bar, and 3.2 mm inner diameter
tubing, was charged with 2584 g of 25-30 mesh Sugar Spheres. About
40 g of talc was homogenized into the nifedipine/polymer solution
to minimize static build-up. The nifedipine solution, at a solids
content of 15% by weight, was sprayed onto the sugar spheres at a
spray rate of 8-17 g/min and outlet flap at .about.60-80% (air
velocity: .about.85-115 m.sup.3/hr) while maintaining the product
temperature at about 36-40.degree. C. The resulting
nifedipine-layered beads (batch size: 3724 g) were dried in the
Glatt unit at 40.degree. C. for about 45 min to minimize the
residual solvent level in the product. A 98.5% yield of useable
beads (600-1200 .mu.m) was obtained.
[0100] 2800 g of nifedipine-layered beads were provided with
coating weight of 2% (i.e., weight of the coating relative to the
weight of uncoated beads) protective seal-coat of Opadry.RTM. Clear
(at 8% by weight solids; product temperature: 37-41.degree. C.;
spray rate: 5-12 g/min), and were further dried at 40.degree. C. in
the Glatt unit for about 45 min to drive off residual
solvent/moisture. The measured potency was 9.81% (% nifedipine)
compared to the target potency of 10% nifedipine.
[0101] 3B--Nifedipine TPR Beads (TPR Coating: Eudragit RL/Eudragit
L/TEC/talc at a Ratio of 45/40/10/5)
[0102] Nifedipine IR beads (700 g) having a nominal drug loading of
10%, prepared as described above in 3A, were coated by spraying a
45/40/10/5 solution of Eudragit RL/Eudragit L/TEC/talc in 45/55
acetone/ethanol (the talc was suspended in the solution using an
Ultraturrex homogenizer) at a solids content of 10% solids, to
provide coatings of up to 20% by weight (samples were pulled at
coating weights of 5%, 10%, and 15%).
[0103] The TPR coating solution was prepared by first slowly adding
the Eudragit RL polymer to the solvent mixture to achieve a clear
solution while stirring. Next, the Eudragit L polymer and then the
plasticizer (triethylcitrate or "TEC") were slowly added and
allowed to dissolve in the solution. Talc was separately
homogenized in the solvent mixture before being added to the
dissolved polymers and plasticizer. A Glatt GPCG 1 equipped with a
4'' bottom spray Wurster insert, 20 mm partition gap,
air-distribution plate B (250 .mu.m screen), 1.0 mm nozzle port,
atomization air pressure of 1.5 bar, and 3.2 mm inner-diameter
tubing, and a T165P dedicated filter bag, was used to apply the TPR
coating solution to the nifedipine IR beads. The TPR coating
solution was sprayed at a spray rate of 4-11 g/min, outlet flap at
.about.20-30% (air velocity: .about.2.0-2.5 m/s), and at a product
temperature of 35-38.degree. C. The coated beads were dried in the
Glatt at 40.degree. C. for 45 minutes to drive off excess residual
solvents. The dried beads were sieved to discard any doubles (i.e.,
two or more beads adhered together by the TPR coating), if formed.
TPR beads having coating weights of about 5% and 15% were assayed
for potency and drug release profile using HPLC methodology.
[0104] 3C--Nifedipine IR Beads (Nominal Nifedipine Loading: 5% by
Weight)
[0105] Nifedipine IR beads having a nominal drug load of 5% by
weight were prepared following the procedures described above in
3A. 190 g of nifedipine and 380 g of Kollidon VA 64 were layered on
3154 g of 25-30 mesh sugar spheres. The measured potency was
determined to be 4.81% nifedipine (compared to the theoretical
nominal potency of 5% nifedipine).
[0106] 3D--Nifedipine TPR Beads (Coating: 40/45/10/5 Eudragit
RL/L/TEC/talc)
[0107] Nifedipine IR beads (700 g) having a nominal nifedipine
loading of 5%, prepared as described in 3C above, were coated with
a TPR coating solution of 45/40/10/5 Eudragit RL/Eudragit
L/TEC/talc in a Glatt GPCG 1, following the procedures described in
3B above, at coating levels of 5%, 10%, 15% and 20% by weight. TPR
beads having coating weights of about 5% and 15% were assayed for
potency and drug release profile using HPLC methodology.
EXAMPLE 4
[0108] 4A--Nifedipine IR Beads (60-80 Mesh Sugar Spheres)
[0109] Nifedipine IR beads (nominal nifedipine loading: 10% by
weight) were prepared by spraying a 1:2 solution of
nifedipine/Kollidon VA 64 onto 60-80 mesh sugar spheres in a Glatt
GPCG 3, following procedures similar to those described above in
3A.
[0110] 4B--Nifedipine TPR Beads (TPR Coating: 35/50/10/5 Eudragit
RL/Eudragit L/TEC/talc)
[0111] Nifedipine IR beads (700 g) prepared as described above in
4A, were coated by spraying a 35/50/10/5 solution of Eudragit
RL/Eudragit L/TEC/talc at a coating weight of 20%, in a Glatt GPCG
1, following the procedures described above in 3B, and were dried
in the Glatt at 40.degree. C. for 10 minutes to drive off excess
residual solvent. The dried beads were sieved to discard any
doubles, if formed. TPR beads having coating weights of 5%, 10% and
15% were assayed for potency and drug release profile using HPLC
methodology.
[0112] 4C--Nifedipine TPR Beads (TPR Coating: 40/45/10/5 Eudragit
RL/Eudragit L/TEC/talc)
[0113] Nifedipine IR beads (700 g), prepared as described above in
4A, were coated by spraying a 40/45/10/5 solution of Eudragit
RL/Eudragit L/TEC/talc at a coating weight of 20% in a Glatt GPCG
1, following procedures similar to those described above in 3B.
[0114] 4D--Nifedipine TPR Beads (TPR Coating: 45/40/10/5 Eudragit
RL/Eudragit L/TEC/talc)
[0115] Nifedipine IR beads (700 g), prepared as described above in
3B, were coated by spraying a 45/40/10/5 solution of Eudragit
RL/Eudragit L/TEC/talc at coating weight of 20% in a Glatt GPCG 1,
following procedures similar to those described above in 2A, and
were dried in the Glatt at 40.degree. C. for 10 minutes to drive
off excess residual solvent. TPR beads having coating weights of
15% and 20% were assayed for potency and drug release profile using
HPLC methodology.
Drug Release Profiles of Examples 3 and 4
[0116] FIG. 7 shows the effect of the TPR coating compositions on
the release of nifedipine from the TPR beads of Example 4.
Increasing the enteric polymer content (Eudragit L) in the TPR
coating increases the rate of nifedipine release. FIG. 8 shows the
effect of nifedipine loading on nifedipine release from the TPR
beads of Example 3. Increasing the nifedipine loading from 5% to
10% lowers the rate of nifedipine release. FIG. 9 shows the effect
of the particle size on drug release from TPR beads of Example 3B
and 4D (25-30 mesh or 600-700 .mu.m and 60-80 mesh or 170-250
.mu.m, respectively) at the same TPR coating composition and
coating weight. The smaller beads of example 4D show faster
nifedipine release.
EXAMPLE 5
[0117] 5A--Model Drug IR Beads (Drug Loading: 10%)
[0118] Povidone (PVP K29/32, 128.2 g) was slowly added to
72.5/22.5/5 95% ethanol/acetone/water at 6% solids, with vigorous
stirring until dissolved, then a weakly basic analog of lamotrigine
(128.2 g) was slowly added until dissolved. A Glatt GPCG 3 equipped
with a 6'' bottom spray/8'' column height Wurster insert, 20 mm
partition gap, air-distribution plate D (200 mesh screen), 1.0 mm
nozzle port, atomization air pressure of 1.0 bar, and 14 mm
single-head tubing was charged with 1000 g of 25-30 mesh Sugar
Spheres (Chris Hansen). The sugar spheres were coated with the drug
solution at a spray rate of 8 mL/min, an outlet flap at 28-30% (air
velocity: 3.6-4.2 m/s/pressure: 10.5-8 Pa), while maintaining the
product temperature at about 32.5-33.5.degree. C. The drug-layered
beads were then coated with a protective seal-coat of Pharmacoat
603 at a coating weight of 2% and dried in the Glatt unit for about
10 min to drive off residual solvent/moisture. The coated beads
were then sieved through 20-30 mesh screens.
[0119] 5B--Model Drug TPR Beads (TPR Coating: 50/35/15
EC-10/HP-55/TEC)
[0120] The IR beads (1000 g), prepared as described above in 4A,
were coated by spraying a solution of 50/35/15 EC-10/HP-55/TEC
dissolved in 90/10 acetone/water (7400/822.2; 7.5% solids) at a
coating weight of up to 40% by weight (samples were pulled at
coating levels of about 20%, 25%, 30% and 35%). EC-10
(ethylcellulose, Ethocel Premium 10 cps from Dow Chemicals, 333.3
g) was slowly added to 90/10 acetone/water with continuous
agitation for not less than 30 minutes, until dissolved. Then HP-55
(hydroxypropyl methylcellulose from Shin Etsu, 233.3 g) and TEC
(100 g) were added to the EC-10 solution until dissolved. The TPR
coating solution was applied with a Glatt GPCG 3 equipped with a
6'' bottom spray/8'' column height Wurster insert, 20 mm partition
gap, air-distribution plate D (200 mesh screen), 0.8 mm nozzle
port, atomization air pressure of 1.0 bar, and 14 mm single-head
tubing, PB 3% dedicated filter bag. The TPR coating solution was
sprayed onto the IR beads at a spray rate of 10-15 mL/min, outlet
flap at about 28% (air velocity: 3.4-3.8 m/s/pressure: 7-7.5 Pa),
while maintaining the product temperature at about 32-34.degree.
C., and dried in the Glatt at the same temperature for 10 minutes
to drive off excess residual solvent. The dried beads were sieved
to discard any doubles if formed.
[0121] 5C--Model Drug TPR Beads (Coating: 35/50/15
EC-10/HP-55/TEC)
[0122] The IR beads (1000 g), prepared as described above in 5A,
were coated with a 35/50/15 EC-10/HP-55/TEC TPR coating solution at
a coating weight of 20%, 25%, 30%, 35%, and 40%, following
procedures similar to those described above.
[0123] 5D--Model Drug TPR Beads (Coating: 60/25/15
EC-10/HP-55/TEC)
[0124] The IR beads (1000 g), prepared as described above in 4A,
were coated with a 60/25/15 EC-10/HP-55/TEC TPR coating solution at
a coating weight of 5%, 10%, 15%, and 20%, following procedures
similar to those described above.
[0125] FIG. 10 shows the effect of the coating composition and/or
coating level on the drug release from TPR beads at the same drug
load of Example 5. Increasing the enteric polymer content in the
TPR coating from 25% by weight to 50% by weight results in a
significant increase in the rate of drug release from TPR
beads.
EXAMPLE 6
[0126] 6A--Nifedipine IR Beads (Nifedipine/VA 64/Fumaric Acid)
[0127] Nifedipine IR beads were prepared by layering a 1/2/1
solution of Nifedipine/VA 64/fumaric acid dissolved in
ethanol/acetone/water, onto 25-30 mesh sugar spheres in a Glatt
GPCG 3, and a nominal nifedipine loading of 10% by weight, using
procedures similar to those described above.
[0128] 6B--Nifedipine IR Beads (Coating: Eudragit
RL/L/TEC/talc)
[0129] IR beads (700 g), prepared as described in 6A above, were
coated with a 35/50/10/5 Eudragit RL/Eudragit L/TEC/talc TPR
coating at a coating weight of up to 30% (samples were pulled at a
coating level of 10%, 15%, 20%, and 25%), using procedures similar
to those described above. TPR beads having coating weights of 15%
and 20% were assayed for potency and drug release profile using
HPLC methodology.
[0130] 6C--Nifedipine TPR Beads (Dual Coating)
[0131] IR beads (700 g), prepared as described in 6A above, were
coated in the fluid bed coater, GPCG 1, with an inner enteric
coating layer comprising 85/10/5 Eudragit L/TEC/talc at a coating
weight of 10%. Eudragit L100 was slowly added to ethanol vigorous
stirring until dissolved, about 90 minutes. Then TEC (triethyl
citrate) was slowly added to the solution until dissolved, followed
by the addition, with constant stirring, of suspended talc. These
enteric coated beads were then coated with a TPR layer of
35/50/10/5 Eudragit RL/Eudragit L/TEC/talc at coating weight of up
to 30% (samples were pulled at a coating level of 10%, 15%, 20%,
and 25%). Each layer was applied using procedures and processing
conditions similar to those described above. TPR beads having TPR
coating weights of 15% and 20% were assayed for potency and drug
release profile using HPLC methodology.
EXAMPLE 7
[0132] 7A--Nifedipine IR Beads (Nifedipine/VA 64/Aspartic Acid)
[0133] Nifedipine IR beads were prepared by coating a 1/2/1
solution of Nifedipine/VA 64/aspartic acid in 72.5/22.5/5
ethanol/acetone/water onto 25-30 mesh sugar spheres in a Glatt GPCG
3, using procedure similar to those described above, to provide a
nominal nifedipine loading of 10% by weight. Because aspartic acid
was not soluble in the coating solution, it was homogenized in the
coating solvent using an Ultraturrex homogenizer, before being
added to the solution of nifedipine and Kollidon VA 64, and further
homogenized.
[0134] 7B--Nifedipine TPR Beads (Coating 35/50/15 RL/L-55/TEC)
[0135] Nifedipine IR beads (700 g), prepared as described in 7A
above, were coated with 35/50/10/5 Eudragit RL/Eudragit L/TEC/talc
at a coating weight of up to 30% (samples were pulled at a coating
level of 10%, 15%, 20%, and 25%) using procedures similar to those
described above. In TPR beads having coating weights of 15% and 20%
were assayed for potency and drug release profile by HPLC
methodology.
EXAMPLE 8
[0136] 8A--Lercanidipine HCl IR Beads (Lercanidipine/VA 64/Tartaric
Acid)
[0137] Lercanidipine HCl (93 g) was slowly added to ethanol (4808
g), and stirted until dissolved. Kollidon VA 64 (186 g) followed by
tartaric acid (21 g) were then slowly added until dissolved. A
Glatt GPCG 1 equipped with a 6'' bottom spray column height Wurster
insert, 200 mm partition gap, air-distribution plate C (50 mesh
screen), 0.8 mm nozzle port, atomization air pressure of 1.5 bar,
was charged with 2100 g of 30-35 mesh Sugar Spheres (2322 g). The
Sugar Spheres were coated with the lercanidipine/VA 64/tartaric
acid coating solution by spraying at a spray rate of 11 g/min,
outlet flap at 45-50% (air flow: 90-105 m.sup.3/h), while
maintaining the product temperature at about 32-34.degree. C. The
lercanidipine-layered beads were coated with a protective seal coat
of Opadry Clear at a coating weight of 2%, and dried in the Glatt
unit for about 15 min at 45.degree. C. to drive off residual
solvent/moisture, then sieved through 25 mesh screens.
[0138] 8B--Lercanidipine TPR Beads (Coating: EC-10/HP-55/DEP at
1:4:1)
[0139] Lercanidipine HCl IR beads (930 g), prepared as described in
8A above, were coated by spraying the IR beads in a Glatt fluid
granulator with a 1/4/1 solution of EC-10/HP-55/DEP in 98/2
acetone/water, at a coating weight of 27%, using procedures similar
to those described above. The composition of the resulting TPR
coating was 16.4% EC-10, 65.6% HP-55, 18% DEP (diethyl
phthalate).
[0140] 8C--Lercanidipine TPR Beads (Dual Layer Coating)
[0141] Eudragit L100 was slowly added to ethanol vigorous stirring
until dissolved, about 90 minutes. Then TEC (triethyl citrate) was
slowly added to the solution until dissolved, followed by the
addition, with constant stirring, of suspended talc. An inner
enteric coating of 74.1/7.4/18.5 Eudragit L100/TEC/talc, prepared
as described above, was applied onto IR beads prepared as described
in 8A above, at a coating weight of 20%. The resulting
enteric-coated IR beads were then coated with a 16.4/65.6/18
EC-10/HP-55/DEP TPR coating solution to a coating weight of 10%
using procedures similar to those described in 8B above.
[0142] 8D--Lercanidipine TPR Beads (Triple Layer Coating)
[0143] An inner enteric coating of 80/20 HP-55/DEP was applied at a
20% coating weight onto IR beads prepared as described in 8A above,
using procedures similar to those described above. The
enteric-coated beads were then coated with a 16.4/65.6/18
EC-10/HP-55/DEP TPR coating solution to a coating weight of 25%,
following procedures similar to those described above. These beads
were then further coated with an outer enteric coating layer of
Eudragit S100/TEC/talc at a ratio of 74.1/7.4/18.5 to a coating
weight of 10% using procedures similar to those described above.
The outer enteric coating layer was prepared by slowly adding
Eudragit S100 to ethanol with vigorous stirring until dissolved,
about 90 minutes. Then TEC (triethyl citrate) was slowly added to
the Eudragit S100 until dissolved, followed by the addition, with
constant stirring, of suspended talc. The drug-release profiles for
TPR Beads of Examples 8B, 8C, and 8D were dissolution tested using
a 2-stage methodology (i.e., first 2 hours in 0.1N HCl and 0.3%
Tween 80, and subsequently at pH 6.8). The results of the
dissolution testing are shown in FIG. 11.
EXAMPLE 9
[0144] 9A--Nifedipine IR Beads (Nifedipine/VA 64/Tartaric Acid)
[0145] Nifedipine IR beads were prepared by layering a 1/2/1
solution of nifedipine/VA 64/fumaric acid dissolved in
ethanol/acetone/water onto 25-30 mesh sugar spheres in a Glatt GPCG
3, at a nominal nifedipine loading 10% by weight.
[0146] 9B--Nifedipine TPR Beads (Coating 35/50/15 RL/L-55/TEC)
[0147] Nifedipine IR beads (1000 g), prepared as described in 9A
above, were coated by spraying a solution of Ethocel Premium 10 cps
(EC-10), hypromellose phthalate (HP-55) and diethyl phthalate
(DEP), dissolved in acetone/water, at coating weights of up to 30%
(samples were pulled at a coating level of 10%, 15%, 20%, and 25%)
in a Glatt fluid granulator, using procedures similar to those
described above. The spraying solution had the following
composition: 1.23% EC-10, 4.92% HP-55, 1.35% DEP; solvent: 90.65%
acetone and 1.85% water.
EXAMPLE 10
[0148] 10A--IR Beads (Drug Load: 16.67%)
[0149] Povidone (PVP K29/32, 666.7 g) was slowly added to 16.6/83.4
ethanol/acetone with vigorous stirring until dissolved. Iloperidone
(333.3 g), was slowly added until dissolved. 25-30 Mesh Sugar
Spheres (1000 g) were then coated with the drug solution (8.17%
solids) in a Glatt GPCG 3, using procedures similar to those
described above. The drug-layered beads were coated with a
protective seal-coat of Pharmacoat 603 at a coating weight of 2%.
The IR beads were dried in the unit for about 10 min to drive off
residual solvent/moisture and sieved to discard doubles if
formed.
[0150] 10B--TPR Beads (Dual coating: 45/40/15 EC-10/HP-55/TEC over
HP-55/TEC)
[0151] IR beads (1800 g), prepared as described in 10A above, were
coated by spraying a 80/20 enteric coating solution of HP-55/TEC
solution in 95/5 acetone/water at a coating weight of 8%. The
enteric coated beads (850 g) were then coated with a 45/40/15
EC-10/HP-55/TEC TPR coating solution in 90/10 acetone/water mixture
(7.5% solids) at a coating weight of up to 50% (samples were pulled
at a coating level of 20%, 30%, and 40%) in a Glatt GPCG 3, using
procedures similar to those described above, and dried in the Glatt
at about 50.degree. C. for 10 minutes to drive off excess residual
solvent and sieved to discard any doubles if formed.
[0152] 10C--TPR Beads (Dual Coating: 30/55/15 EC-10/HP-55/TEC Over
HP-55/TEC)
[0153] The enteric coated beads (530 g), prepared as described in
10B above, were coated by spraying with a 30/55/15 EC-10/HP-55/TEC
TPR coating solution in 90/10 acetone/water (7.5% solids) at a
coating weight of up to 50% (samples were pulled at a coating level
of 20%, 30%, and 40%) in a Glatt GPCG 3, using procedures similar
to those described above. Representative drug release profiles from
TPR beads coated at two different TPR compositions/levels are shown
in FIG. 12.
* * * * *