U.S. patent application number 10/746324 was filed with the patent office on 2005-02-03 for serotonin reuptake inhibitor formulations.
This patent application is currently assigned to Andrx Corporation. Invention is credited to Cacace, Janice, Chen, Chih-Ming, Li, Boyong.
Application Number | 20050027011 10/746324 |
Document ID | / |
Family ID | 25134289 |
Filed Date | 2005-02-03 |
United States Patent
Application |
20050027011 |
Kind Code |
A1 |
Chen, Chih-Ming ; et
al. |
February 3, 2005 |
Serotonin reuptake inhibitor formulations
Abstract
A process for preparing amorphous paroxetine hydrochloride or
sertraline hydrochloride is provided, which comprises preparing a
solution in which paroxetine hydrochloride or sertraline
hydrochloride and a water-soluble polymer are dissolved in a
co-solvent of a volatile organic solvent and water. Said solution
is dried to obtain a composition comprising amorphous paroxetine
hydrochloride or sertraline hydrochloride and the water-soluble
matrix.
Inventors: |
Chen, Chih-Ming; (Davie,
FL) ; Li, Boyong; (Davie, FL) ; Cacace,
Janice; (Miami, FL) |
Correspondence
Address: |
DAVIDSON, DAVIDSON & KAPPEL, LLC
485 SEVENTH AVENUE, 14TH FLOOR
NEW YORK
NY
10018
US
|
Assignee: |
Andrx Corporation
Davie
FL
|
Family ID: |
25134289 |
Appl. No.: |
10/746324 |
Filed: |
December 23, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10746324 |
Dec 23, 2003 |
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09785040 |
Feb 16, 2001 |
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6720003 |
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Current U.S.
Class: |
514/649 ;
424/486; 514/651 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61K 9/1635 20130101; A61K 31/4525 20130101; A61K 9/146 20130101;
A61K 9/1652 20130101; A61K 9/2866 20130101; A61K 31/135
20130101 |
Class at
Publication: |
514/649 ;
514/651; 424/486 |
International
Class: |
A61K 009/20; A61K
009/14; A61K 031/137 |
Claims
1-33. (canceled)
34: A process for preparing amorphous paroxetine hydrochloride,
comprising: (a) preparing a solution of paroxetine hydrochloride
and a water-soluble carrier in a co-solvent of a volatile organic
solvent and water, the ratio of said paroxetine hydrochloride and
said water-soluble polymer being about 1:1 to about 1:4, by weight;
and (b) drying said solution to produce a composition comprising
amorphous paroxetine hydrochloride and the water-soluble
polymer.
35: The process of claim 34, wherein the composition of step (b) is
a solid dispersion comprising the amorphous paroxetine
hydrochloride dispersed in the water-soluble polymer.
36: The process of claim 34, wherein the preparation of the
solution of step (a) does not require elevation of temperature.
37: The process of claim 34, wherein the preparation of the
solution of step (a) comprises: dissolving paroxetine free base in
methanol to form a solution of paroxetine free base; adding
hydrochloric acid dissolved in water to said paroxetine free base
solution, said hydrochloric acid being in the amount that is
sufficient to ensure conversion of said paroxetine free base to
paroxetine hydrochloride, to form a solution of paroxetine
hydrochloride in a co-solvent of methanol and water; and adding the
water-soluble polymer into the paroxetine hydrochloride solution to
form the solution of the water- soluble polymer and paroxetine
hydrochloride in the co-solvent.
38: The process of claim 34, wherein the preparation of the
solution of step (a) comprises dissolving paroxetine hydrochloride
in a co-solvent of methanol and water to obtain a paroxetine
hydrochloride solution; and adding to the paroxetine hydrochloride
solution the water-soluble polymer to form the solution of the
paroxetine hydrochloride and the water-soluble polymer in the
co-solvent.
39: The process of claim 34, wherein the volatile organic solvent
is methanol, and the water-soluble polymer is selected from the
group consisting of polyvinylpyrrolidone,
hydroxypropylmethylcellulose, polyethylene glycol and mixtures
thereof, the ratio of the paroxetine hydrochloride and the
water-soluble polymer being about 1:1 to about 1:2, by weight.
40: The process of claim 39, wherein the water-soluble polymer
comprises Povidone K-30, the ratio of the paroxetine hydrochloride
to Povidone K-30 being about 1:2, by weight, and wherein the ratio
of methanol to water in the co-solvent being about 80:20 to about
70:30.
41: The process of claim 34, wherein the weight ratio of the
paroxetine hydrochloride and the water-soluble polymer is about 1:1
to about 1:2.
42: The process of claim 34, wherein concentration the paroxetine
hydrochloride in the solution of step (a) is about 5% to 25%, by
weight.
43: The process of claim 34, wherein the water soluble polymer is
selected from the group consisting of polyvinylpyrrolidone,
hydroxypropylmethylcellulose, polyethylene glycol and mixtures
thereof, the water-soluble polymer comprising about 20% of the
solution of step (a) by weight.
44: The process of claim of 43, wherein the water-soluble polymer
is selected from the group consisting of Povidone K-25, Povidone
K-30, Povidone K-90, Methocel E5.
45: The process of claim 44, wherein the water-soluble polymer is
Povidone K-30.
46: The process of claim 34, wherein the volatile organic solvent
is selected from the group consisting of isopropyl alcohol,
methanol, ethanol and mixtures thereof.
47: The process of claim 34, wherein the co-solvent is
methanol:water.
48: The process of claim 34, wherein the weight ratio of the
volatile organic solvent to water in the solution of step (a) is
about 95:5 to about 60:40.
49: The process of claim 34, wherein the weight ratio of the
volatile organic solvent to water in the solution of step (a) is
about 80:20 to about 70:30.
50: The process of claim 34, wherein the drying of step (b)
involves spray-drying the solution onto a pharmaceutically
acceptable carrier to produce granules comprising the amorphous
paroxetine hydrochloride, the water-soluble carrier and the
pharmaceutically acceptable carrier.
51: The process of claim 50, wherein the solution of step a) is
spray-dried onto the pharmaceutically acceptable carrier to a
weight gain of from about 5% to about 500%.
52: The process of claim 50, wherein the solution of step a) is
sprayed onto the pharmaceutically acceptable carrier to a weight
gain of from 50% to about 300%.
53: The process of claim 50, in which one or more pharmaceutical
excipient is added to the solution of the paroxetine hydrochloride
and water-soluble polymer, and spray-drying said mixture onto the
pharmaceutically acceptable carrier.
54: The process of claim 50, further comprising admixing to the
granules sufficient quantities of at least one pharmaceutically
necessary tableting excipient and compressing said mixture into
tablets suitable form oral administration.
55: The process of claim 54, further comprising the step of
overcoating said tablets with a pharmaceutically acceptable
film-coating.
56: The process of claim 50, wherein the pharmaceutically necessary
tableting excipient is selected from the group consisting of a
lubricant, an inert filler, a glidant, a disintegrant and mixtures
thereof.
57 (canceled)
58: The product obtained by the process of claim 34.
59: The product obtained by the process of claim 39.
60: The product obtained by the process of claim 40.
61-74 (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention is related to processes for preparing
solid dispersions comprising paroxetine or sertraline dispersed in
a water-soluble polymer, and preparation of solid oral dosage forms
containing the dispersions. The present invention is also related
to processes for preparing an amorphous paroxetine salt or
sertraline salt, and incorporation of these amorphous drugs into
suitable pharmaceutical dosage forms.
BACKGROUND OF THE INVENTION
[0002] Paroxetine and sertraline are two of the compounds having
anti-depressant properties that are known as selective serotonin
reuptake inhibitors ("SSRI").
[0003] Of these, paroxetine, the chemical name of which is
(-)-trans-4R-(4'-fluoropheyl)-3S-[(3'4'-methylenedioxyphenoxy)methyl]-pip-
eridine, has been identified in the art as having utility in the
treatment of a variety of disease states, including but not limited
to depression, anxiety, obsessive compulsive disorders, panic,
pain, obesity, senile dementia, migraine, bulimia, anorexia,
alcoholism, trichotillomania, dysthymnia, substance abuse, social
phobia, depression arising from premenstrual tension or
adolescence, and premature ejaculation. Patoxetine is-indicated for
the treatment of depression, obsessive compulsive disorder and
panic disorder with or without agoraphobia in a recommended dose of
10 to 60 mg once a day. The antidepressant action of paroxetine and
its efficacy in the treatment of obsessive comnpulsive disorder and
panic disorder is presumed to be linked to potentiation of
serotonergic activity in the central nervous system resulting from
inhibition of neuronal reuptake of serotonin. Generally speaking,
paroxetine hydrochloride is a moderately water-soluble, orally
administered antidepressant having a melting point range of
120.degree. to 138.degree. C. and a solubility of 5.4 mg/ml in
water. Paroxetine is commercially available in the form of
paroxetine hydrochloride hemihydrate, marketed under the name.
Paxil.RTM.(SmithKline Beecham).
[0004] Because of its basicity, it has been considered preferable
that paroxetine be-prepared in the form of an acid addition salt.
However, most of the known salts of paroxetine are considered to
have unsuitable physico-chemical properties for ensuring safe and
efficient handling during production of the final product, since
they are unstable and possess undesirable hygroscopicity.
Furthermore, their formation by crystallization from both aqueous
or non-aqueous solvents provides a low yield.
[0005] A number of patents have addressed the preparation of
paroxetine. For example, U.S. with the subsequent conversion to the
maleic acid salt. The use of the acetate salt of paroxetine is also
known, e.g., from Psychopharmacology 57, 1515-153 (1978). The
limited use of the hydrochloride salt of paroxetine in an aqueous
solution has also been described, e.g., in Acta. Phamacol. et
Toxicol. 44,289-295 (1979). U.S. Pat. No. 4,721,723 (Barnes et al.)
describes crystalline paroxetine hydrochloride hemihydrate,
compositions containing the same and processes for its preparation.
However, the processes described in the Barnes patent require
post-synthetic treatment of the product in order to obtain the
crystalline form, which adds to the difficulty and overall cost of
production.
[0006] U.S. Pat. No. 5,681,962 (Callander) describes a process for
preparing paroxetine, and in particular the hydrochloride
hemi-hydrate form of paroxetine, using diborane as a reducing
agent.
[0007] U.S. Pat. Nos. 5,856,493, 5,900,423 and 5,872,132 (each to
Ward et al.) describe paroxetine hydrochloride anhydrate which is
substantially free of propan-2-ol and methods of preparing the
same, which are stated to overcome problems described in the art by
removing the solvent from the paroxetine salt. The preparation of
the paroxetine hydrochloride anhydrate substantially free of
propan-2-ol is said to comprise crystallizing paroxetine
hydrochloride in either (I) an organic solvent which forms a
solvate with the paroxetine hydrochloride and which is not
removable by conventional drying techniques (e.g., alcohols such as
ethanol); or (II) an organic solvent which does or does not form a
solvate with the paroxetine hydrochloride but which are removable
by conventional vacuum oven drying; and thereafter in the case of
(I) displacing the solvated solvent using a displacing agent (e.g.,
water) or in the case of (II) removing the solvent.
[0008] U.S. Pat. No. 5,874,447 (Benneker, et al.) describes the
preparation of paroxetine sulfonates which are said to exhibit high
solubility. According to the method of that patent, paroxetine (or
a salt and/or base thereof) is mixed together with a sulfonic acid
to form a solution, followed by the separation of the resultant
paroxetine sulfonate from this solution. The resultant sulfonate is
further said to be useful as a reagent in further syntheses, e.g.,
as a start reagent for forming further acid addition salts.
[0009] Amorphous forms of paroxetine have also been reported. For
example, U.S. Pat. No. 4,721,723 (Barnes et al.), in distinguishing
the hemihydrate salt form of paroxetine disclosed therein from
other forms of paroxetine, reports that such hemi-hydrate form is
desirable because amorphous paroxetine hydrochloride is undesirably
hygroscopic and has poor handling qualities.
[0010] U.S. Pat. No.5,672,612 (Ronsen et al.) describes amorphous
paroxetine hydrochloride ethanol composition which is purported to
be substantially non-hydroscopic and free-flowing. Said composition
is prepared by dissolving paroxetine free base in a hydrochloric
acid-ethanol solution followed by drying.
[0011] U.S. Pat. No. 5,955,475 (Krape et al.) describes processes
for preparing a solid dispersion of an anhydrate form of a
paroxetine salt. The processes use the free base of paroxetine, an
oil, which is said to allow the solid dispersion to be prepared at
a low temperature via a fusion process or with decreased organic
solvent volumes via a solvent process, and the formation of a
paroxetine salt during the solid dispersion manufacture process.
Thus,.in a first embodiment, Krape, et al. describe a process
wherein a solution is formed of a water soluble polymeric carrier
(e.g., polyethylene glycol or polyvinylpyrrolidne) and a
non-aqueous solvent (e.g., an alcohol such as ethanol); dissolving
paroxetine free base into the solution, wherein the ratio of
polymeric carrier to paroxetine is 4:1 to 1: 1, by weight;
contacting the paroxetine free base in solution with at least one
equivalent of an acid (hydrogen chloride in the form of dry
hydrogen chloride gas or dry hydrogen chloride dissolved into a
non-aqueous solvent) to form a paroxetine salt in solution
(paroxetine hydrogen chloride); and then removing the non-aqueous
solvent by evaporation under vacuum. A second embodiment is
described wherein the paroxetine free base is dissolved into the
solution of polymeric carrier and non-aqueous solvent to form a
mixture having the aforementioned ratio of polymeric carrier to
paroxetine free base, and thereafter the mixture is heated to form
a molten homogeneous melt of polymeric carrier and paroxetine free
base. Thereafter, the molten homogeneous melt of polymeric carrier
and paroxetine free base is contacted with at least one equivalent
of dry hydrogen chloride to form paroxetine hydrogen chloride in
the molten homogeneous melt, and the molten homogeneous melt is
then cooled to form a water soluble solid state dispersion of an
anhydrate form of paroxetine hydrochloride.
[0012] PCT International Application No. W099/56751 (Hein et al.)
describes a process for preparing an amorphous form of paroxetine.
The process involves mixing of paroxetine base or salt with water
and a polymer, and drying said mixture. This aqueous solvent
process purportedly provides an amorphous solid form of paroxetine.
Due to the low solubility of paroxetine, however, heating of
paroxetine solution to 60.degree. C. is required in this process to
prevent recrystallization of a paroxetine salt, especially at
higher concentrations, which is inconvenient and may subject the
drug to decomposition. In addition, use of water as the solvent
might render the. drying step more difficult, especially when large
quantities of the drug solution are involved.
[0013] Like paroxetine, sertraline, also known as
(1S-cis)-4-(3,4-dichloro-
phenyl)-1,2,3-4-tetrahydro-N-methyl-1-naphthalenamine is a
selective serotonin reuptake inhibitor. Sertraline is commercially
available as sertraline hydrochloride, under the trademark Zoloft
(Pfizer). Sertraline is. indicated for treatment of depression,
obsessive-compulsive disorder and panic disorder.
[0014] U.S. Pat. No. 4,356,518, describes sertraline, its salts and
derivatives, and process for preparing the same. U.S. Pat. Nos.
4,772,288; 4,839,104; 4,855,500; 5,082,970; 5,196,607; 5,463,126;
5,422,116; and 5,750,794, each of these patents, also describe
various processes for preparing sertraline.
[0015] Sertraline salts, like those of paroxetine, are reported to
exist in different polymorphic forms. For example, U.S. Pat. No.
5,248,699 reports allegedly novel polymorphic forms of sertraline
hydrochloride, designated as Forms I to V, which are described as
being different from each other in their physical properties,
stability, spectral data and methods of preparation.
[0016] U.S. Pat. No. 5,734,083 also provides a purportedly novel
polymorphic form of sertraline hydrochloride, form T1, and methods
of preparation.
OBJECTS AND SUMMARY OF THE INVENTION
[0017] It is an object of the invention to provide a process for
preparing a solid dispersion comprising a compound that is a
selective serotonin reuptake inhibitor having anti-depressant
properties, such as paroxetine or sertraline, wherein the compound
is dispersed in a water-soluble polymer.
[0018] It is an object of the invention to provide a process for
obtaining an amorphous paroxetine salt or sertraline salt, and
pharmaceutical formulations containing the same.
[0019] It is an object of the invention to provide a process for
preparing substantially non-hygroscopic amorphous paroxetine
hydrochloride or amorphous sertraline hydrochloride.
[0020] It is a further object of the invention to provide a process
for preparing amorphous paroxetine hydrochloride or amorphous
sertraline hydrochloride having good handling properties, which can
be formulated into pharmaceutically acceptable formulations for
oral administration.
[0021] In accordance with the above-mentioned objects and others,
the invention is related in part to a process for preparing an
amorphous (non-crystalline) form of paroxetine hydrochloride or
sertraline hydrochloride. The process comprises preparing a
solution in which paroxetine hydrochloride or sertraline
hydrochloride, along with a water-soluble polymer, is dissolved in
a co-solvent of a volatile organic solvent and water. The solution
is then dried to produce a composition comprising an amorphous form
of paroxetine hydrochloride or sertraline hydrochloride and the
water-soluble polymer. In preferred embodiments, the composition
comprises a solid dispersion, wherein the amorphous paroxetine
hydrochloride or sertraline hydrochloride is dispersed in the
water-soluble polymer. The composition containing the amorphous
drug and the water-soluble polymer may then be further processed
into pharmaceutically acceptable dosage forms.
[0022] In certain preferred embodiments of the invention, the
weight ratio of the volatile organic solvent to water in the
co-solvent is from about 95:5 to about 60:40, more preferably from
about 80:20 to about 70:30. Preferably, the volatile organic
solvent is selected from the group consisting of methanol, ethanol,
isopropyl alcohol and mixtures thereof, with methanol being the
most preferred.
[0023] In certain preferred embodiments of the invention, the
weight ratio of the paroxetine hydrochloride or sertraline
hydrochloride to the water-soluble polymer is not greater than
about 1:4, more preferably from about 1:1 to about 1:4, most
preferably about 1:2.
[0024] In certain embodiments, the concentration of the paroxetine
hydrochloride or sertraline hydrochloride in the solution
containing the drug and the water-soluble polymer is from about 2
to about 30%, preferably from about 5 to about 25%, by weight.
[0025] In certain embodiments, the concentration of the
water-soluble polymer in the solution containing the drug and the
polymer is no greater than about 30%, more preferably about
20%.
[0026] In certain embodiments, the solution containing paroxetine
hydrochloride or sertraline hydrochloride and the water-soluble
polymer may be sprayed onto a pharmaceutically acceptable carrier
(or substrate) and dried. Optionally, before the solution is
sprayed onto the carrier, one or more additional pharmaceutical
ingredients may be mixed into the solution e.g., for stabilization
or to aid processing.
[0027] For example, the pharmaceutical carrier may comprise a
plurality of particles of a material such as microcrystalline
cellulose or calcium phosphate dibasic. In such embodiments, a
granulate is formed via the spraying of the solution onto the
carrier. Additional processing steps may then be undertaken to
prepare a uniform granulate suitable for incorporation into gelatin
capsules in desired unit doses of the active ingredient. Such
additional processing steps may further include the addition of
pharmaceutically acceptable tableting excipients, with the
resultant mixture being compressed into pharmaceutically acceptable
tablets containing a desired unit dose of the drug.
[0028] Alternatively, the pharmaceutically acceptable carrier may
comprise placebo tablets. A sufficient quantity of the amorphous
paroxetine hydrochloride or sertraline hydrochloride solution is
sprayed onto such placebo tablets to incorporate the desired unit
dose of the active ingredient. Thereafter, the coated tablets may
be further processed, for example, via overcoating with a
film-coating containing a barrier agent (such as
hydroxypropylmethylcellulose, acrylic polymers, ethylcellulose and
the like) and/or a colorant.
[0029] The invention is also directed to a method of treating human
patients, comprising administering effective amounts of the
amorphous paroxetine hydrochloride or sertraline hydrochloride
formulations prepared in accordance with the invention to human
patients.
[0030] The invention is further related to a method of treating
depression, obsessive compulsive disorder and/or panic disorder in
humans comprising orally administering an effective dose of a
pharmaceutically acceptable solid dispersion of amorphous
paroxetine hydrochloride or sertraline hydrochloride prepared in
accordance with the processes set forth herein.
[0031] The present invention is also directed to a process for
preparing a solid dispersion comprising an active ingredient
dispersed in a water-soluble polymer, the active ingredient being
selected from the group consisting of paroxetine free base, a
paroxetine salt, sertraline free base, a sertraline salt, and
mixtures thereof. The process comprises preparing a solution in
which the active ingredient and the water-soluble carrier are
dissolved in a co-solvent of a volatile organic solvent and water,
and drying said solution to produce a solid dispersion comprising
the active ingredient dispersed in the water-soluble polymer.
[0032] The term "paroxetine," as used in the present invention,
refers to paroxetine in a salt form or free base form. The "free
base" form of paroxetine is a viscous oil at standard temperature
and pressure whereas the "salt form" is the acid addition product
of paroxetine.
[0033] The term "sertraline," as used in the present invention
refers both to the free base form of sertraline as well as its salt
form.
[0034] By "bioavailable" it is meant for purposes of the present
invention that the paroxetine or sertraline is released from the
formulation and becomes available in the body at the intended site
of drug action.
DETAILED DESCRIPTION OF THE INVENTION
[0035] The present invention is in part directed to a process for
preparing a solid dispersion comprising an active ingredient
dispersed in a water-soluble polymer, the active ingredient being
selected from the group consisting of paroxetine free base, a
paroxetine salt, sertraline free base, a sertraline salt, and
mixtures thereof. The process comprises preparing a solution in
which the active ingredient and the water-soluble carrier are
dissolved in a co-solvent of a volatile organic solvent and water,
and drying said solution to produce a solid dispersion comprising
the active ingredient dispersed in the water-soluble polymer.
[0036] In certain preferred embodiments of the invention, when the
active ingredient is a paroxetine salt or sertraline salt, and the
solid dispersion obtained from the processes of the present
invention comprises an amorphous form of the active ingredient, one
function the water-soluble polymer in the solution serves is to
prevent recrystallization of the paroxetine or sertraline salt.
Thus, the lower limit of polymer in the solution is that amount
which prevents the paroxetine salt or sertraline salt from
recrystallizing. The upper limit of polymer in the solution is such
that the ratio of paroxetine or sertraline salt to the polymer is
preferably not greater than about 1:4. One skilled in the art will
appreciate that the amount of polymer added will be dependent upon
factors such as the physical properties of the polymer, the
processing conditions, and the intended final product. In certain
preferred embodiments, when the active ingredient is a paroxetine
or sertraline salt, the drug:polymer ratio is from about 1:1 to
about 1:4, and most preferably about 1:2.
[0037] In certain preferred embodiments, the active ingredient
comprises a paroxetine salt or a sertraline salt, and the solid
dispersion produced by the process comprises an amorphous form of
the active ingredient dispersed in a water-soluble polymer.
[0038] The order in which the ingredients. (e.g., active
ingredient, the water-soluble polymer, the volatile organic
solvent, water) are added in preparing the solution containing the
active ingredient and the water-soluble polymer may be varied.
Preferably, the solution containing the drug and the water-soluble
polymer in the co-solvent may be prepared at ambient temperature
(without heating) and pressure, e.g., by stirring the mixture
containing the ingredients until a clear solution is obtained. The
solution is subsequently dried to produce the solid dispersion,
wherein the active ingredient is dispersed in the water-soluble
carrier.
[0039] In certain embodiments of the invention, the solution
containing the acid addition salt of paroxetine or sertraline and
the water-soluble polymer is prepared by adding acid in water
(e.g., 1N HCl) to a solution in which paroxetine or sertraline free
base is dissolved in the volatile organic solvent (e.g., methanol).
The acid is added in a sufficient amount to ensure conversion of
the paroxetine or sertraline free base to the corresponding acid
addition salt thereof (e.g., at least the stoichiometric amount of
the acid, preferably more than the stoichiometric amount). This
step results in a solution of the acid addition salt of paroxetine
or sertraline in the co-solvent of the volatile organic solvent and
water. Subsequently, the water-soluble polymer is added to said
solution to obtain the solution in which the active ingredient and
the water-soluble polymer are dissolved in the co-solvent, which
may then be dried to obtain the solid dispersion of the amorphous
acid addition salt of paroxetine or sertraline.
[0040] In certain preferred embodiments, the process of preparing
the solution of the acid addition salt of paroxetine or sertraline
and the water-soluble polymer may start with the salt form of the
drug, rather than the free base form, followed by addition of the
acid. For example, paroxetine hydrochloride is dissolved in the
co-solvent of a volatile organic solvent (e.g., methanol) and
water. An excess amount of hydrochloric acid (e.g., hydrochloric
acid diluted in water) may be added to this solution to stabilize
paroxetine HCl in solution. A water-soluble polymer may be added to
the same solvent along with the drug, or before or after the
addition of the drug, to obtain the solution of the drug and the
polymer.
[0041] Preferably, the paroxetine salt is paroxetine hydrochloride
and the sertraline salt is sertraline hydrochloride. However, other
salts of paroxetine and sertraline may also be used to prepare the
solid dispersions according to the process of the present
invention. As used in this application, the term "paroxetine salt"
or "sertraline salt" refers to acid addition salts. Such salts
include mineral or organic acid salts of the basic piperidine
residue; and the like. Acceptable non-toxic salts include those
derived from inorganic acids such as hydrobromic, sulfuric,
sulamic, phosphoric, nitric and the like; and the salts prepared
from organic acids such as acetic, propionic, succinic, glycolic,
stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethanesulfonic, ethanedisulfonic, oxalic,
isethionic, and the like. Further suitable salts can be found in
Remington's Pharmaceutical Sciences, 17.sup.th ed., Mack Publishing
Co., Easton, Pa., 1985, p. 1418, which is incorporated herein by
reference.
[0042] In certain embodiments, the concentration of the drug in the
solution of the drug and the polymer is from about 2% to about 30%,
by weight, more preferably from about 5% to about 25%.
[0043] Preferably, the concentration of the water-soluble polymer
in the solution containing the active ingredient and the polymer is
no greater than about 30%, more preferably about 20% by weight.
[0044] Suitable volatile organic solvent(s) useful in the processes
of the invention are both capable of dissolving the active
ingredient, as well as the water-soluble polymer, and are
chemically inert with respect to both the active ingredient and the
polymer. Examples of suitable volatile organic solvents include but
are not limited to methanol, ethanol, propanol (including both
n-propanol and i-propanol), butanol (including n-butanol,
i-butanol, and s-butanol), toluene, benzene supercritical liquid
CO.sub.2, chloroform, methylene chloride, acetonitrile, ketones
(e.g. dimethylketone, methylethylketone, and diethylketone),
dimethylformamide, dimethylsulfoxide, esters (a non-limiting
example being ethyl acetate), ethers (non-limiting examples being
diethylether, dipropylether), 1,4-dioxane, tetrahydrofuran,
pentanes, hexanes, heptanes, trichloroethene, and/or suitable
mixtures thereof. In preferred embodiments, the volatile organic
solvent is selected from the group consisting of methanol, ethanol,
isopropyl alcohol and mixtures thereof, the most preferred volatile
organic solvent being methanol.
[0045] In preferred embodiments of the present invention, suitable
water-soluble polymers are selected from the group consisting of
polyvinylpyrrolidone ("PVP"), hydroxypropylmethyl-cellulose
("HPMC"), polyethyleneglycol ("PEG") and mixtures thereof. When the
polymer is PVP, it is preferred that the PVP has an average
molecular weight from about 2000 to about 3 million, and more
preferably from about 7,000 to about 1,500,000. Most preferred PVP
has an average molecular weight of about 40,000 (such as Povidone
K30) or about 1,500,000 (such as Povidone K90). Both Povidone K30
and K90 are commercially available from BASF, Midland, Mich. When
the polymer is PEG, it is preferred that the PEG has an average
molecular weight from about 1,000 to about 20,000. When the polymer
is HPMC, low viscosity grades of HMPC, such as commercially
available Methocel E5 or Methocel E3 LV (both available from Dow
Chemical Co.), are preferred. In certain embodiments, the
water-soluble polymer is Povidone K25.
[0046] Other suitable water soluble polymers include,.but are not
limited to, hydroxypropylcellulose, methyl cellulose, carboxymethyl
cellulose, sodium carboxymethyl cellulose, cellulose acetate
phthalate, cellulose acetate butyrate, hydroxyethyl cellulose,
ethyl cellulose, polyvinyl alcohol, polypropylene, dextrans,
dextrins, hydroxypropyl-beta-cyclodextr- in, chitosan, copolymers
of lactic and glycolic acid, lactic acid polymers, glycolic acid
polymers, polyorthoesters, polyanyhydrides, polyvinyl chloride,
polyvinyl acetate, ethylene vinyl acetate, lectins, carbopols,
silicon elastomers, polyacrylic polymers, maltodextrins, and
alpha-, beta-, and gamma-cyclodextrins, and suitable mixtures of
the foregoing.
[0047] Once the solution containing both the active ingredient and
the water soluble polymer in the co-solvent is prepared; the
co-solvent is evaporated to dryness to obtain a co-precipitate of
the active ingredient and the water soluble polymer, which is a
solid dispersion, comprising the active ingredient dispersed in the
water-soluble polymer. In certain preferred embodiments, when the
active ingredient is a paroxetine salt or sertraline salt, the
solid dispersion obtained from the drying step comprises amorphous
paroxetine or sertraline salt, e.g., amorphous paroxetine
hydrochloride or sertraline hydrochloride. In certain embodiments
of the invention, before the co-solvent is removed, additional
pharmaceutical excipients may be added to the solution of the
active ingredient and the water-soluble polymer to obtain a
mixture, e.g., to aid the processing or for stabilization. Such
pharmaceutical excipients may include but are not limited to, for
example, a surfactant (e.g., polysorbate 80), a stabilizer (e.g.,
hydrochloric acid or citric acid), an antioxidant, a glidant (e.g.
talc or silicon dioxide), a diluent and/or mixtures thereof.
[0048] The stabilizer added to the solution containing the active
ingredient and the water soluble polymer suitable in the present
invention includes pharmaceutically acceptable inorganic acids and
organic acids. Preferably, the stabilizer is the same acid as the
acid addition portion of the active ingredients. The stabilizer can
be added before or after the addition of active ingredient and the
water soluble polymer. Preferably the stabilizer is added before
the addition. of active ingredient and the water soluble
polymer.
[0049] The surfactant added to the solution containing the active
ingredient and the water soluble polymer is chosen based partly on
its compatibility with the other ingredients of the mixture,
particularly the polymer. Suitable surfactants include
pharmaceutically acceptable non-ionic surfactants, anionic
surfactants, cationic surfactants, amphoteric
(amphipathic/amphophilic) surfactants or mixtures thereof.
Preferably, the surfactant is nonionic. Preferably, the surfactant
when included in the drug/polymer solution comprises from about
0.05% to about 2% of the mixture, by weight, and more preferably
from about 0.1% to about 1%, by weight.
[0050] In preferred embodiments, the removal of the co-solvent from
the solution (or the mixture, when additional pharmaceutical
excipient(s) are added to the solution) containing the active
ingredient and the water soluble polymer, or from a mixture
obtained by adding one or more additional pharmaceutical
ingredients to the solution, may be carried out by, e.g., by spray
drying the solution or mixture according to conventional techniques
well known to those skilled in the art.
[0051] Once dried, the solid dispersion or "solid solution"
comprising the active ingredient and the water-soluble polymer is
obtained. A solid dispersion is defined as "the dispersion of one
or more active ingredients in an inert carrier or matrix at
solid-state prepared by the melting (fusion), solvent or
melting-solvent method" (W. A. Chiou and R. Riegelman, J. Pharm.
Sci., 60, 1281, 1971). Alternatively, Corrigan (O. I. Corrigan,
Drug Dev. Inc. Pharm., 11, 697, 1985), has defined the solid
dispersion as a "product formed by converting a fluid drug-carrier
combination to the solid state." For practical purposes, the term
"solid dispersion" has been considered synonymous with oral dosage
forms, which usually contain a carrier having a higher water.
solubility than the medicament. For purposes of the present
invention, term "solid dispersion" is considered to be
interchangeable with the term "solid solution."
[0052] In certain embodiments, the solution or the mixture
described above, which contains the active ingredient and the water
soluble polymer, may be sprayed onto a pharmaceutically acceptable
carrier and dried to produce a granulate containing the active
ingredient and the water soluble polymer, preferably to a weight
gain of from about 5% to about 500%, more preferably from about 10%
to about 40%, and most preferably from about 50% to about 300%.
[0053] The pharmaceutically acceptable carrier may be a
pharmaceutically acceptable carrier material selected from such
materials known to those skilled in the art, for example,
microcrystalline cellulose or calcium phosphate dibasic. Other
suitable pharmaceutically acceptable carriers include, but are not
limited to, calcium phosphate dihydrate, calcium sulfate dihydrate,
cellulose derivatives, dextrose, lactose, anhydrous lactose,
spray-dried lactose, lactose monbhydrate, mannitol, starches,
sorbitol and sucrose. Further examples of the carrier include
hydroxypropylmethylcellulose,. hydroxypropylcellulose, methyl
cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose,
polyvinylpyrrolidone, polyethyleneglycol, cellulose acetate
butyrate, hydroxyethyl cellulose, ethyl cellulose, polyvinyl
alcohol, polypropylene, dextrans, dextrins,
hydroxypropyl-beta-cyclodextrin, chitosan, copolymers of lactic and
glycolic acid, lactic acid polymers, glycolic acid polymers,
polyorthoesters, polyanyhydrides, polyvinyl chloride, polyvinyl
acetate, ethylene vinyl acetate, lectins, carbopols, silicon
elastomers, polyacrylic polymers, maltodextrins, fructose,
inositol, trehalose, maltose raffinose, and alpha-, beta-, and
gamma-cyclodextrins, and suitable mixtures of the foregoing.
[0054] In certain embodiments, the drug:polymer solution or mixture
may be sprayed onto a pharmaceutically acceptable carrier
comprising multiparticulates (e.g., microcrystalline cellulose),
preferably to a weight gain of from about 10% to about 400%, more
preferably from about 50% to about 300%. The spray-drying procedure
may be carried out in a fluid-bed processor with a Wuster apparatus
at a suitable temperature and spray rate to form granules, e.g., at
a temperature of about 40-50.degree. C. and a spray rate of about
40-120 ml/min. Next, the granules are preferably milled, e.g., by
being passed through a mesh screen, e.g., a 16, 20 or 30 mesh
stainless steel screen. It is preferred that the spray drying of
the solution (or the mixture) results in a homogenous solid
dispersion which is substantially free of the solvents. For
purposes of the present invention, substantially free means that
the solid dispersion contains less than 20% by weight of residual
solvent, more preferably less than 5%, and most preferably less
than 3%
[0055] Alternatively, the paroxetine hydrochloride-polymer solution
(or mixture) may be spray-dried onto a placebo tablet, which may
result in the weight gain of from about 5% to about 500%.
[0056] Once the co-solvent is evaporated from the solution (or
mixture) containing the active ingredient and a water-soluble
polymer, the solid dispersion of the drug is obtained, which may be
formulated into suitable oral dosage forms, including tablets or
capsules.
[0057] If the solid dispersion is prepared as a granulate, such
granulate may then be blended with other excipients and compressed
into tablets.
[0058] When the granulate is to be tableted, it is preferably
admixed with suitable amounts of one or more pharmaceutically
acceptable excipients, including but not limited to disintegrants
such as cross linked polyvinylpyrrolidone and sodium starch
glycolate; fillers such as microcrystalline cellulose, lactose,
calcium phosphate dibasic, and the like; glidants such as talc and
silicon dioxide; lubricants such as magnesium stearate and
acetylated monoglycerides; binders; coloring agents; flavoring
agents; stabilizers such as citric acid or alginic acid; and/or
preservatives.
[0059] Sufficient quantities of pharmaceutically necessary
tableting excipients may be admixed with the granulate, e.g., via
blending the ingredients together in a V-blender for a sufficient
period of time to provide a smooth mixture, e.g., about 5 minutes.
If desired, the mixture may then be compressed into tablets
suitable for oral administration.
[0060] The mixture, in an amount sufficient to make a uniform batch
of tablets, may then subjected to tableting in a conventional
production scale tableting machine at normal compression pressure,
e.g., about 2000-1600 lbs/sq in. However, the mixture should not be
compressed to such a degree that there is subsequent difficulty in
its hydration when exposed to gastric fluid.
[0061] Optionally, the tablets may be overcoated with a
pharmaceutically acceptable film-coating, e.g., for aesthetic
purposes (e.g., including a colorant), for stability purposes
(e.g., coated with a moisture barrier), for taste-masking purposes,
etc. For example, the tablets may be overcoated with a film
coating, preferably containing a pigment and a barrier agent, such
as hydroxypropylmethylcellulose and/or a polymethylmethacrylate. An
example of a suitable material which may be used for such a
hydrophilic coating is hydroxypropylmethylcellulose (e.g.,
Opadry.RTM., commercially available from Colorcon, West Point,
Pa.). In further embodiments of the present invention, the tablet
coating may be comprised of an enteric coating material, alone or
in combination with a hydrophobic polymer coating. Examples of
suitable enteric polynmers include cellulose acetate phthalate,
hydroxypropylmethylcellulo- se phthalate, polyvinylacetate
phthalate, methacrylic acid copolymer, shellac,
hydrokypropylmethylcellulose succinate, cellulose acetate
trimellitate, and mixtures of any of the foregoing. A suitable
commercially available enteric material is sold under the trademark
Eudragit.TM. L 100-555. Hydrophobic polymers capable of slowing the
release rate of the active agent include derivatives of acrylic
acid (such as esters of acrylic acid, methacrylic acid, and
copolymers thereof) celluloses and derivatives thereof (such as
ethylcellulose), polyvinylalcohols, and the like. Any
pharmaceutically acceptable manner known to those skilled in the
art may be used to apply the coatings. For example, the coating may
be applied using a coating pan or a fluidized bed. An organic,
aqueous or a mixture of an organic and aqueous solvent is used for
the hydrophobic polymer or enteric coating. Examples of suitable
organic solvents are, e.g., isopropyl alcohol, ethanol, and the
like, with or without water. Aqueous solvents are preferred for the
overcoating procedures. The optional coatings applied to the dosage
form of the present invention may comprise from about 0.5% to about
30% by weight of the final solid dosage form.
[0062] Alternatively, the granulate may be incorporated into unit
doses containing therapeutically effective amounts of paroxetine or
sertraline, and the unit doses incorporated into gelatin
capsules.
[0063] Some drugs exist in polymorphic forms, with different
polymorphic forms exhibiting different bioavailability and/or
physical properties (e.g., stability). The term "polymorphism"
refers to different physical forms, such as crystalline forms or
non-crystalline ("amorphous") forms. Paroxetine is an example of a
drug that exhibits polymorphism.
[0064] The present invention is also directed to the preparation of
amorphous paroxetine hydrochloride according to the processes
disclosed above (e.g., preparing a solution in which paroxetine
hydrochloride and a water-soluble polymer are dissolved in a
co-solvent of a volatile organic solvent and water; and drying said
solution to produce a composition comprising amorphous paroxetine
hydrochloride and the water-soluble polymer) as well as obvious
modifications known to those skilled in the art. The, processes may
be used to obtain a stable, substantially non-hygroscopic,
amorphous form of paroxetine hydrochloride that is suitable for
formulation into solid oral dosage forms, including immediate and
sustained release dosage forms.
[0065] The procedure for obtaining a solid dispersion of amorphous
paroxetine hydrochloride and polymer can be applied to obtain solid
dispersions containing different amorphous salts of paroxetine or
to obtain solid dispersions containing amorphous salts of
sertraline.
DETAILED DESCRIPTION OF THE CERTAIN PREFERRED EMBODIMENTS
[0066] The following examples illustrate various aspects of the
present invention. They are not to be construed to limit the claims
in any manner whatsoever.
EXAMPLE 1
[0067] In Example 1, an oral solid dosage form containing amorphous
paroxetine hydrochloride is prepared. The amorphous paroxetine
hydrochloride is prepared by forming a solution in which paroxetine
hydrochloride and a water-soluble polymer (e.g.,
polyvinylpyrrolidone) are dissolved in a co-solvent of a volatile
organic solvent (e.g., methanol) and water, and drying said
solution to obtain a composition comprising amorphous paroxetine
hydrochloride and the water-soluble polymer. The composition is
thereafter compressed into tablets.
[0068] 1. Granulating (Paroxetine HCl Granules)
1TABLE A Ingredient: mg/tablet % weight kg Paroxetine HCl, USP
(Anhydrous) 44.43 20.0 2.750 Hydrochloric Acid, NF (37.6% w/w) *
0.073 Purified Water, USP ** 7.352 Methyl Alcohol, NF (Methanol) **
17.325 Povidone K30, USP 88.86 40.00 5.500 Microcrystalline
Cellulose, 88.86 40.00 5.500 NF (Avicel PH 101) Total: 222.14
100.00 13.750 * 10% excess of HCl (0.1:1 molar ratio to paroxetine)
which will evaporate during granulation. ** Evaporated during
granulation.
[0069] Paroxetine HCl Anhydrous, 2.75 kg, is dissolved in a
co-solvent of methanol (17.325 kg) and water (7.352 kg) with 0.073
kg of hydrochloric acid. 5.50 kg of Povidone K30 is added to the
solution and stirred until a clear solution is obtained. The
solution is sprayed onto microcrystalline cellulose in a fluid bed
processor with a Wuster apparatus at a temperature of 40-50.degree.
C. and a spray rate of 40-120 ml/min to form granules containing
the solid dispersion of amorphous paroxetine in PVP. The granules
are sized through a mill equipped with a 16 mesh screen to yield
Paroxetine HCl Granules (amorphous).
[0070] 2. Blending (Paroxetine HCl Blend)
2TABLE B Ingredient: mg/tablet % weight kg Paroxetine HCl Granules
222.14 55.53 24.210 (Amorphous) Crospovidone, NF 40.00 10.00 4.360
(Polyplasdone XL-10) Microcrystalline Cellulose, 135.89 33.97
14.810 NF (Avicel PH 102) Magnesium Stearate, NF 2.00 0.50 0.218
Total: 400.03 100.00 43.598
[0071] Paroxetine HCl Granules, 24.210 kg, are blended with 4.360
kg crospovidone, 14.810 kg microcrystalline cellulose and 0.218 kg
magnesium stearate to yield a Paroxetine HCl Blend.
[0072] 3. Tableting (Paroxetine HCl Tablets, 40 mg (Uncoated))
3 TABLE C Ingredient: mg/tablet % weight kg Paroxetine HCl Blend
400.03 100.00 43.460
[0073] The Paroxetine HCl Blend is compressed into tablets with a
tablet weight of 400 mg to yield Paroxetine HCl Tablets (core
tablets).
[0074] 4. Film Coating and Polishing (Paroxetine HCl Tablets, 40 mg
(Coated))
4TABLE D Ingredient: mg/tablet % weight kg Paroxetine HCl Tablet,
40 mg 400.03 96.97 42.430 (Uncoated) Opadry Pink, YS-1-14778A 12.38
3.00 1.313 Ethanol, SDA 3A 190 Proof 11.812 Candelilla Wax Powder,
FCC 0.12 0.03 0.013 Total: 412.53 100.00 43.756
[0075] The core tablets, 42.430 kg, are coated with a solution of
1.313 kg Opadry.RTM. Pink in 11.812 kg of ethanol using standard
pan coating procedure. The film coated tablets are then polished by
sprinkling 0.013 kg candelilla wax powder onto the tablets while
the pan is rotating to yield Paroxetine HCl Tablets, 40 mg
(coated).
EXAMPLE 2
[0076] In Example 2, tablets containing amorphous paroxetine
hydrochloride are prepared by dissolving paroxetine free base in a
volatile organic solvent (e.g., methanol). Hydrochloric acid in
water is then added to the paroxetine free base solution to form a
solution of paroxetine hydrochloride in a co-solvent of a volatile
organic solvent (e.g., methanol) and water. Subsequently, a
water-soluble polymer (e.g., polyvinylpyrrolidone or "PVP") is
added and the solution is sprayed onto a substrate (in this
instance, microcrystalline cellulose) to produce granules
containing a solid dispersion of paroxetine hydrochloride in
PVP.
[0077] 1. Preparation of 1N HCl (3.646% w/w) and Paroxetine HCl
Solution
5 TABLE A Ingredient: % weight kg Hydrochloric Acid, NF (10%) 36.46
6.563 Purified Water, USP 63.54 11.437 Total 100.00 18.000
[0078]
6TABLE B Ingredient: mg/tablet % weight kg Paroxetine Base 40.00
89.15 5.000 Hydrochloric Acid, 4.43 10.85* 0.609 NF (1N, 3.646%
w/w) (16.699 kg of 1N HCl) Methyl Alcohol, NF (Methanol) * 34.113
Total 44.43 100.00 55.811 * containing 10% more HCl (1.1:1 molar
ratio to paroxetine) which will evaporate during granulation and is
not accounted for mg/tablet but for batch size and % weight.
[0079] Paroxetine Base, 5 kg, is dissolved in 34.1 kg of methanol
and then 16.7 kg (1:1.1 molar ratio to paroxetine base) of 1
hydrochloric acid is added to the solution under stirring to yield
paroxetine HCl solution in a co-solvent of methanol and water.
[0080] 2. Granulating (Paroxetine HCl Granules)
7TABLE C Ingredient: mg/tablet % weight kg Paroxetine HCl Solution,
44.43 20.0 2.777 (10%, MeOH:H.sub.2O = 70:30) Povidone K30, 88.86
40.0 5.553 USP (polyvinylpyrrolidone) Microcrystalline Cellulose,
88.86 40.0 5.553 NF (Avicel PH 101) Total 222.14 100.00 13.884
[0081] 5.553 kg of Povidone K30 is added to 2.777 kg of Paroxetine
HCl solution and stirred until a clear solution is obtained. The
solution is sprayed onto 5.553 kg microcrystalline cellulose in a
fluid bed processor with a Wuster apparatus at a temperature of
40-50.degree. C. and a spray rate of granules are sized through a
mill equipped with a 16 mesh screen to yield Paroxetine HCl
Granules (amorphous).
[0082] The granules are then compressed into tablets after blending
with other pharmaceutically acceptable excipients based on the
procedure set forth in Example 1.
EXAMPLE3
[0083] A solution of Paroxetine HCl in a co-solvent of methanol and
water is prepared in accordance with the procedure set forth in
Example 1 or Example 2. The prepared solution contains
approximately 10% of paroxetine HCl (w/w). Next, a water-soluble
polymer is added to the paroxetine HCl solution and stirred until
clear solution is obtained. In Example 3A, the polymer added is
polyvinylpyrrolindone (PVP), commercially available as Povidone
K-30 or Povidone K-90. In Example 3B, the polymer added is
hydroxypropylmethylcellulose (HPMC), preferably low viscosity
grades of HPMC, e.g., HPMC commercially available as Methocel E5 or
Methocel E3 LV, from Dow Chemical Co. In Example 3C, the polymer
added is polyethyleneglycol (PEG), preferably PEG of MW of about
3,000 to 20,000. For each of Examples 3A-3C, the polymer is added
until a drug to polymer ratio of 1:2, by weight, is achieved.
[0084] In Examples 3A-3C, the solution containing paroxetine
hydrochloride and the water-soluble polymer is sprayed onto a
substrate (in this instance, microcrystalline cellulose).
[0085] The solution containing paroxetine hydrochloride and the
water-soluble polymer is sprayed onto the microcrystalline
cellulose in a fluid bed processor with a Wuster apparatus at a
temperature of 40-50.degree. C. and a spray rate of 40-120 ml/min
to form granules.
[0086] A sufficient quantity of the paroxetine HCl granules,
amounting to a suitable unit dose of paroxetine (e.g., 40 mg) may
then be loaded into gelatin capsules. Alternatively, the paroxetine
HCl granules are compressed into tablets, for example, in
accordance with the procedures set forth in Example 1 or 2. The
tablets may then be overcoated with a film coating for aesthetics
(e.g., with a pigment) and/or for purposes of providing a moisture
barrier, for example, in accordance with the procedures set forth
in Example 1 or 2.
EXAMPLE 4
[0087] A solution of Paroxetine HCl in a co-solvent of methanol and
water is prepared in accordance with the procedure set forth in
Example 1 or Example 2. The prepared solution contains
approximately 10% of paroxetine HCl (w/w). Next, a water-soluble
polymer is added to the paroxetine HCl solution and stirred until
clear solution is obtained. In Example 4A, the polymer added is
polyvinylpyrrolindone (PVP), commercially available as Povidone
K-30 or Povidone K-90. In Example 4B, the polymer added is
hydroxypropylmethylcellulose (HPMC), preferably low viscosity
grades of HPMC, e.g., HPMC commercially available as Methocel E5 or
Methocel E3 LV, from Dow Chemical Co. In Example 4C, the polymer
added is polyethyleneglycol (PEG), preferably PEG of MW of about
3,000 to 20,000. For each of Examples 4A-4C, the polymer is added
until a drug to polymer ratio of 1:2, by weight, is achieved.
[0088] In Examples 4A-4C, the solution containing paroxetine
hydrochloride and the water-soluble polymer is sprayed onto
commercially available placebo tablets. Additional ingredients may
be added to the solution before it is sprayed onto the placebo
tablets to aid processing and/or stabilization. The procedure used
to spray the paroxetine HCl onto the placebo tablets may employ
techniques well known to those skilled in the art.
[0089] The tablets of Examples 4A-4C may then be overcoated with a
film coating for aesthetics (e.g., with a pigment) and/or for
purposes of providing a moisture barrier, for example, in
accordance with the procedures set forth in Example 1 or 2.
EXAMPLE 5
[0090] A solution of Paroxetine HCl in a co-solvent of methanol and
water is prepared in accordance with the procedure set forth in
Example 1 or Example 2. The prepared solution contains
approximately 10% of paroxetine:HCl (w/w). Next, a water-soluble
polymer is added to the paroxetine HCl solution and stirred until
clear solution is obtained. In Example 5A, the polymer added is
polyvinylpyrrolindone (PVP), commercially available as Povidone
K-30 or Povidone K-90. In Example 5B, the polymer added is
hydroxypropylmethylcellulose (HPMC), preferably low viscosity
grades of HPMC, e.g., HPMC commercially available as Methocel E5 or
Methocel E3 LV, from. Dow Chemical Co. In Example 5C, the polymer
added is polyethyleneglycol (PEG), preferably PEG of MW of about
3,000 to 20,000. For each of Examples 5A-5C, the polymer is added
until a drug to polymer ratio of 1:2, by weight, is achieved.
[0091] In Examples 5A-5C, the solution containing paroxetine
hydrochloride and the water-soluble polymer is spray dried
according to conventional techniques well known to those skilled in
the art. Additional ingredients may be added to the solution to aid
processing and/or for stabilization before the spray drying
procedure. Thereafter, the spray-dried product is compressed into
tablets, adding excipients as necessary (e.g., a sufficient amount
of a lubricant such as magnesium stearate; and a sufficient amount
of a filler such as microcrystalline cellulose).
[0092] The tablets of Examples 5A-5C are then overcoated with a
film coating for aesthetics (e.g., with a pigment) and/or for
purposes of providing a moisture barrier, for example, in
accordance with the procedures set forth in Example 1 or 2;
EXAMPLE6
[0093] In Example 6, an oral solid dosage form containing amorphous
sertraline hydrochloride is prepared similar to the oral solid
dosage form containing amorphous paroxetine of Example 1. The
amorphous sertraline hydrochloride is prepared by forming a
solution in which sertraline hydrochloride and a water-soluble
polymer (e.g., polyvinylpyrrolidone) are dissolved in a co-solvent
of a volatile organic solvent (e.g., methanol) and water, and
drying said solution to obtain a composition comprising amorphous
sertraline hydrochloride and the water-soluble polymer. The
composition is thereafter compressed into tablets.
[0094] The examples provided above are not meant to be exclusive.
Many other variations of the present invention would be obvious to
those skilled in the art, and are contemplated to be within the
scope of the appended claims. For example, it will be recognized by
those skilled in the art that a wide variety of pharmaceutically
acceptable polymers may be utilized in the formulations of the
invention, all of which are contemplated to be within the scope of
the appended claims. Further, a wide variety of pharmaceutical
excipients may be added for their intended purpose, depending upon
the particular type of final formulation being prepared, as
described herein.
* * * * *