U.S. patent application number 15/477479 was filed with the patent office on 2017-07-20 for stabilization of moisture-sensitive drugs.
The applicant listed for this patent is Amneal Pharmaceuticals LLC. Invention is credited to Marianthi Karakatsani, Anita Kumar, Devjibhai D. Kumbhani, Pallapalayam M. Thangamathesvaran.
Application Number | 20170202801 15/477479 |
Document ID | / |
Family ID | 51492006 |
Filed Date | 2017-07-20 |
United States Patent
Application |
20170202801 |
Kind Code |
A1 |
Karakatsani; Marianthi ; et
al. |
July 20, 2017 |
Stabilization Of Moisture-Sensitive Drugs
Abstract
Described are stability-enhancing formulations of drugs that are
sensitive to moisture. The formulations comprise co-granulates
containing a moisture-sensitive drug and an excipient selected from
fructose, xylitol, maltitol, and mixtures thereof. Also described
are methods of producing a pharmaceutical tablet. The method
comprises forming a blend of a moisture-sensitive drug and a first
excipient selected from fructose, xylitol, maltitol, and mixtures
thereof; spraying the blend with water to produce granules; drying
and milling the granules; mixing a second excipient with the
granules; and compressing into tablets.
Inventors: |
Karakatsani; Marianthi;
(West Chester, OH) ; Kumar; Anita; (Brookhaven,
NY) ; Kumbhani; Devjibhai D.; (Brookhaven, NY)
; Thangamathesvaran; Pallapalayam M.; (Piscataway,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Amneal Pharmaceuticals LLC |
Bridgewater |
NJ |
US |
|
|
Family ID: |
51492006 |
Appl. No.: |
15/477479 |
Filed: |
April 3, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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14772999 |
Sep 4, 2015 |
9629805 |
|
|
PCT/US2014/021824 |
Mar 7, 2014 |
|
|
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15477479 |
|
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61774150 |
Mar 7, 2013 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/284 20130101;
A61K 9/1623 20130101; A61K 47/36 20130101; A61K 9/2893 20130101;
A61K 31/4418 20130101; A61K 31/222 20130101; A61K 31/216 20130101;
A61K 31/4439 20130101; A61K 9/2018 20130101; A61K 9/20 20130101;
A61K 31/235 20130101; A61K 9/2095 20130101 |
International
Class: |
A61K 31/216 20060101
A61K031/216; A61K 9/20 20060101 A61K009/20; A61K 31/4439 20060101
A61K031/4439; A61K 47/36 20060101 A61K047/36; A61K 31/235 20060101
A61K031/235; A61K 31/4418 20060101 A61K031/4418 |
Claims
1. A pharmaceutical formulation comprising a co-granulate
comprising a moisture-sensitive drug and an excipient comprising
fructose.
2. The pharmaceutical formulation of claim 1, wherein the
moisture-sensitive drug and fructose are present in a weight ratio
of about 1:9.
3. The pharmaceutical formulation of claim 1, wherein the
moisture-sensitive drug comprises amlodipine, felodipine,
fesoterodine, isradipine, nifedipine, nimodipine, or
nisoldipine.
4. The pharmaceutical formulation of claim 1, wherein the
moisture-sensitive drug comprises fesoterodine fumarate.
5. The pharmaceutical formulation of claim 1, further comprising a
diluent, a binder, a drug stabilizer, a disintegrant, a glidant, a
lubricant, a release rate modifier, a preservative, an antioxidant,
a coating, a colorant, a flavoring agent, or combinations
thereof.
6. The pharmaceutical formulation of claim 1, wherein the
moisture-sensitive drug comprises a drug compound that is
susceptible to degradation by formation of one or more
impurities.
7. The pharmaceutical formulation of claim 1, wherein
moisture-sensitive drug comprises a drug compound that is
susceptible to degradation by deacylation and formation of an
impurity comprising a deacylated drug compound.
8. A method of producing a pharmaceutical tablet, the method
comprising: forming a blend of a moisture-sensitive drug and a
first excipient comprising fructose; spraying the blend with water
to produce granules; drying and milling the granules; mixing a
second excipient with the granules; and compressing into
tablets.
9. The method of claim 8, wherein a second excipient is selected
from the group consisting of diluent, binder, drug stabilizer,
disintegrant, glidant, lubricant, release rate modifier,
preservative, antioxidant, coating, colorant, flavoring agent, or
combinations thereof.
10. The method of claim 8, wherein the moisture-sensitive drug
comprises amlodipine, felodipine, fesoterodine, isradipine,
nifedipine, nimodipine, or nisoldipine.
11. The method of claim 8, wherein the moisture-sensitive drug
comprises fesoterodine fumarate.
12. The method of claim 8, wherein the granules are dried and
milled to an average particle size of less than 1200 .mu.m.
13. The method of claim 8, further comprising coating the tablets
with a coating suspension.
14. A tablet for oral administration comprising a co-granulate
consisting of fesoterodine fumarate and fructose in a ratio of
about 1:9, and one or more additional pharmaceutically acceptable
excipients.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 14/772,999, filed Sep. 4, 2015, which is the National Stage
Entry of PCT/US2014/021824, filed Mar. 7, 2014, which claims
priority to U.S. Provisional Application Ser. No. 61/774,150, filed
on Mar. 7, 2013, the contents of which are incorporated herein by
reference in their entireties.
TECHNICAL FIELD
[0002] The present disclosure relates generally to
stability-enhancing formulations of drugs that are sensitive to
moisture.
BACKGROUND
[0003] There are many drug substances that exhibit undesirable
changes when exposed to a moist environment, prior to
administration. Depending on the particular drug, the changes can
result from internal molecular changes such as hydrolysis, or from
reactions with other components of the drug product formulation or
with the atmosphere. Since drug product manufacturing cannot always
be conducted in an environment having a low humidity, there can be
significant drug degradation during the various production
operations, prior to packaging a product. After packaging,
stability of the products can be affected by moisture transfer
through packaging components, as well as reactions involving
components of the package atmosphere. Also, repeatedly opening and
closing a package during normal use can expose the contents to
atmospheric moisture. Due to normal fluctuations in the moisture
content of the atmosphere, undesired changes that will be
experienced with a moisture-sensitive drug are not predictable.
[0004] A frequent result of contact between a sensitive drug
compound and moisture is a reaction that results in formation of
one or more different chemical species. This can be simply a
hydration of the drug molecule that results in different
dissolution or other physical properties, or it can involve a
reaction that produces a different compound having a diminished
intended pharmacological activity. In some instances, a new
molecular entity that is produced can have a radically different
pharmacological activity that is harmful when administered.
[0005] Regulatory agencies require demonstration of drug stability,
before marketing approval can be given. This requirement includes
maintenance of at least a minimum drug content during the expected
shelf-life of the formulated product, while the unopened package is
stored in a specified temperature and humidity environment. Where
the drug is particularly sensitive to moisture, sometimes the
packaging will incorporate a desiccant component to absorb moisture
entering through the packaging materials and/or during repeated
brief openings of the package.
[0006] There have been some approaches developed for reducing the
effects of moisture on sensitive drugs. Sometimes the drug
substance can be combined with a protective hydrophobic material,
such as an oil or polymer. However, this frequently leads to other
undesired effects, such as altering the drug solubility parameters,
and can create difficulties in processing to manufacture a
formulated product.
[0007] According to U.S. Pat. No. 7,807,715 it is necessary to
enhance the chemical stability of fesoterodine and its salts in
formulations, and this can be accomplished by granulating a mixture
of the drug and a stabilizer selected from the group consisting of
sorbitol, xylitol, polydextrose, isomalt, dextrose, and
combinations thereof. The granulate is combined with excipient
materials and compressed into tablet products. This patent, in its
examples, teaches that mannitol, maltitol, and lactose act to
increase the degradation of fesoterodine hydrogen fumarate, during
storage of their granulates under various temperature and humidity
conditions, so would not be desirable in granulation mixtures.
[0008] The drug fesoterodine fumarate is the active ingredient in a
product being sold as TOVIAZ.RTM. tablets to treat urinary
incontinence and frequency problems. Inactive ingredients are
glyceryl behenate, hypromellose, indigo carmine aluminum lake,
lactose monohydrate, soya lecithin, microcrystalline cellulose,
polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and
xylitol. The xylitol apparently is used as a drug stabilizer in the
TOVIAZ product.
[0009] International Patent Application Publication No. WO
2012/098499 describes stabilizing fesoterodine fumarate by forming
a molecular dispersion of the drug with an alkyl
hydroxyalkylcellulose ether, a hydroxyalkylcellulose ether, an
ester of either, or a mixture of any two or more thereof. The
dispersion is said to not contain the drug in its crystalline or
amorphous form, but has suitable stability.
[0010] European Patent Application Publication No. 2 508 173
describes stabilizing fesoterodine, or a salt or solvate thereof,
by granulating with sucrose, polyethylene glycol, cyclodextrin,
maltodextrin, or combinations thereof.
[0011] Considering all of these teachings, it becomes apparent that
predicting the stability of a drug, when it is to be combined with
various excipient substances, is not possible. Considerable effort
is required to find suitable combinations that will deliver a
moisture-sensitive drug in a desired, reproducible manner,
facilitate pharmaceutical dosage form preparation, and provide the
required drug stability during manufacturing, storage, and use.
SUMMARY
[0012] A first aspect of the present invention is directed to a
pharmaceutical formulation. In a first embodiments, a
pharmaceutical formulation comprises a co-granulate comprising a
moisture-sensitive drug and an excipient selected from the group
consisting of fructose, a mixture of xylitol and maltitol, and
combinations thereof.
[0013] In a second embodiment, the pharmaceutical formulation of
the first embodiment is modified, wherein the excipient is
fructose.
[0014] In a third embodiment, the pharmaceutical formulation of the
second embodiment is modified, wherein the moisture-sensitive drug
and fructose are present in a weight ratio of about 1:9.
[0015] In a fourth embodiment, the pharmaceutical formulation of
the first embodiment is modified, wherein the excipient is a
mixture of xylitol and maltitol.
[0016] In a fifth embodiment, the pharmaceutical formulation of the
fourth embodiment is modified, wherein the moisture-sensitive drug,
xylitol, and maltitol are present in a weight ratio in the range of
about 1:2:2 to 1:2:7.
[0017] In a sixth embodiment, the pharmaceutical formulation of the
fourth and fifth embodiments is modified, wherein the
moisture-sensitive drug, xylitol, and maltitol are present in a
weight ratio of about 1:2:4.
[0018] In a seventh embodiment, the pharmaceutical formulation of
the first through sixth embodiments is modified, wherein the
moisture-sensitive drug comprises fesoterodine fumarate.
[0019] In an eighth embodiment, the pharmaceutical formulation of
the first through seventh embodiments is modified wherein the
pharmaceutical formulation further comprises a diluent, a binder, a
drug stabilizer, a disintegrant, a glidant, a lubricant, a release
rate modifier, a preservative, an antioxidant, a coating, a
colorant, a flavoring agent, or combinations thereof.
[0020] A second aspect of the present invention is directed to a
method. In a ninth embodiment, a method of producing a
pharmaceutical tablet comprises: forming a blend of a
moisture-sensitive drug and a first excipient selected from the
group consisting of fructose, a mixture of xylitol and maltitol,
and combinations thereof; spraying the blend with water to produce
granules; drying and milling the granules; mixing a second
excipient with the granules; and compressing into tablets.
[0021] In a tenth embodiment, the method of the ninth embodiment is
modified, wherein the first excipient is fructose.
[0022] In an eleventh embodiment, the method of the ninth
embodiment is modified, wherein the first excipient is a mixture of
xylitol and maltitol.
[0023] In a twelfth embodiment, the method of the ninth through
eleventh embodiments is modified, wherein the second excipient is
selected from the group consisting of diluent, binder, drug
stabilizer, disintegrant, glidant, lubricant, release rate
modifier, preservative, antioxidant, coating, colorant, flavoring
agent, or combinations thereof.
[0024] In a thirteenth embodiment, the method of the ninth through
twelfth embodiments is modified, wherein the moisture-sensitive
drug comprises fesoterodine fumarate.
[0025] In a fourteenth embodiment, the method of the ninth through
twelfth embodiments is modified, wherein the granules are dried and
milled to an average particle size of less than 1200 .mu.m.
[0026] In a fifteenth embodiment, the method of the ninth through
twelfth embodiments is modified wherein the method further
comprises coating the tablets with a coating suspension.
[0027] A third aspect of the present invention is directed to a
table. In a sixteenth embodiment, a tablet for oral administration
comprises a co-granulate consisting of fesoterodine fumarate and
fructose in a ratio of about 1:9, and one or more additional
pharmaceutically acceptable excipients.
DETAILED DESCRIPTION
[0028] Numerous moisture-sensitive drugs are known, such as
amlodipine, felodipine, fesoterodine, isradipine, nifedipine,
nimodipine, nisoldipine, etc. Mention of any drug compound is
intended to include the base drug as well as any of its salts,
esters, solvates, etc. that will be useful for delivering the drug.
In the following discussion, fesoterodine is used as a
representative for moisture-sensitive drugs, for purposes of
brevity. However, the scope of the present disclosure is not to be
limited to this particular drug.
[0029] Moisture sensitivity is intended to encompass any undesired
changes in a drug substance that occur as a result of exposure to
moisture, such as atmospheric humidity. Such changes can involve
drug compound degradation that forms one or more impurities,
changes in physical characteristics, morphological changes,
etc.
[0030] In some instances, drug stability is evidenced by a slow
rate of degradant compound formation, over time. The period of
time, during which a drug must remain stable, i.e., maintain its
potency and/or impurity content in a formulation, varies according
to commercial specifications set by the manufacturer. For example,
a particular product might be required to maintain certain potency
specifications for a period of six months, one year, two years, or
some other time following manufacturing. The established shelf life
of a product presumes maintenance in the original packaging, in
specified temperature and humidity environments. Fesoterodine
fumarate is used to treat urinary incontinence and has the
structural formula shown below. A chemical name for the drug is
isobutyric acid
24(R)-3-diisopropylammonium-1-phenylpropyll-4-(hydroxymethyl)
phenyl ester hydrogen fumarate.
##STR00001##
[0031] When exposed to moisture, fesoterodine tends to degrade,
forming inter alia a deacylated molecule having the structural
formula shown below, or a salt thereof. This degradant can be used
as a marker for fesoterodine degradation.
##STR00002##
[0032] Products containing fesoterodine can be analyzed for their
fesoterodine content and the contents of the various degradant
impurities, using high performance liquid chromatography (HPLC)
methods.
[0033] Degradation of fesoterodine and other moisture-sensitive
drugs can be inhibited by co-granulation of the drug with certain
excipients, and use of the granulates to prepare the desired solid
dosage forms such as tablets and capsules. Particularly useful
excipients for co-granulation are fructose and mixtures of xylitol
and maltitol.
[0034] Several sugars and sugar alcohols have been tested to
determine their suitability for co-granulation with fesoterodine.
The experiments involved wet granulating the drug with varying
proportions of excipient, using small amounts of water. In the
cases of xylitol and maltitol, respectively having mean particle
sizes of 300 .mu.m and 200 .mu.m, it was found that simply mixing
the drug and excipient powders formed hard agglomerated particles
that would not pass easily through a 40 mesh sieve (having 0.42 mm
openings), indicating that further processing the mixtures into
formulated products might involve some difficulties. Several other
excipients were found to not stabilize the drug, some of them even
appearing to promote degradation of the drug.
[0035] It has now been determined that fructose, and mixtures of
xylitol and maltitol, can advantageously be used in co-granulations
with moisture-sensitive drugs to promote stability of the drugs in
their pharmaceutical formulations.
[0036] Co-granulation can be conducted as a wet process or a dry
process. In a wet process, a moving bed of a mixture of powdered
ingredients, including a drug substance, is sprayed with a small
quantity of a liquid to form granules. The liquid can be aqueous or
non-aqueous, and can optionally contain one or more dissolved or
dispersed excipients, such as a binder or antioxidant. In some
instances, the liquid will be a neat liquid ingredient, such as
water, an alcohol, a substituted or unsubstituted hydrocarbon, etc.
It is not necessary that the liquid ingredient is capable of
dissolving some portion of a drug or solid excipient in the powder
mixture, as typically it is only required to wet the particles.
However, liquids having a degree of solvent properties frequently
are used. After the spraying is completed, the granules may be
sized by passing through a sieve and are dried. Dry granules can
further be subjected to a size reduction procedure, if desired.
[0037] Dry granulation may include passing a powder mixture through
a roller compactor, then crushing and sizing the compacted
material. Alternatively, a powder mixture can be compacted by a
compression process called "slugging," producing large (e.g., about
25 mm) flat tablets or plates, which are then crushed and
sized.
[0038] Following the granulation procedure, drug-containing
granules can be mixed with desired excipients and the mixture can
be compressed into tablets or filled into capsules.
[0039] Solid pharmaceutical dosage units contain one or more drug
substances, together with any desired number of excipients, such
as, but not limited to, one or more of diluents, binders, drug
stabilizers, disintegrants, glidants, lubricants, release rate
modifiers, preservatives, antioxidants, coatings, colorants,
flavoring agents, etc.
[0040] Various useful fillers or diluents according to the present
application include, but are not limited to, starches, cellulose
derivatives, sugars, and the like. Various grades of lactose
include, but are not limited to, lactose monohydrate, lactose DT,
lactose anhydrous, and others. Different starches include, but are
not limited to, maize starch, potato starch, rice starch, wheat
starch, pregelatinized starch, and others. Different cellulose
compounds that can be used include crystalline cellulose and
powdered cellulose. Other useful diluents include, but are not
limited to, carmellose, sugar alcohols such as mannitol, sorbitol,
and xylitol, calcium carbonate, magnesium carbonate, dibasic
calcium phosphate, and tribasic calcium phosphate.
[0041] Various useful binders according to the present application
include, but are not limited to, hydroxypropyl celluloses in
various grades, hydroxypropyl methylcelluloses (e.g., Methocel.TM.
products) and useful in various grades, polyvinylpyrrolidones (such
as grades K25, K29, K30, and K90), copovidones (e.g., Plasdone.TM.
S 630), powdered acacia, gelatin, guar gum, carbomers (e.g.,
Carbopol.TM. products), methylcelluloses, polymethacrylates, and
starches. A binder may optionally be included in a granulating
fluid.
[0042] Modification of drug release into fluids of the
gastrointestinal tract sometimes is desirable. For example, a very
soluble drug that is rapidly metabolized by the body can desirably
be released from a pharmaceutical dosage form over a period of
hours, following oral administration. This can be accomplished by
including polymeric substances in the body of a tablet. Suitable
polymeric substances for this purpose include the "binder"
materials described above, as well as polymers described below as
being useful for forming coatings.
[0043] Various useful disintegrants include, but are not limited
to, carmellose calcium, carboxymethylstarch sodium, croscarmellose
sodium, crospovidones, examples of commercially available
crospovidone products including but not limited to crosslinked
povidones, Kollidon.TM. CL from BASF (Germany), Polyplasdone.TM.
XL, XI-10, and INF-10 from ISP Inc. (USA), and low-substituted
hydroxypropyl celluloses. Examples of low-substituted hydroxypropyl
celluloses include, but are not limited to, low-substituted
hydroxypropylcellulose LH11, LH21, LH31, LH22, LH32, LH2O, LH30,
LH32 and LH33 (all supplied by Shin-Etsu Chemical Co., Ltd.). Some
other useful disintegrants include sodium starch glycolate,
colloidal silicon dioxide, and various starches.
[0044] In embodiments, formulations of the present application
contain at least one antioxidant, for enhancing the stability of a
drug. The antioxidant may be present either as a part of the
composition or a packaging component. The antioxidant is present in
amounts effective to retard decomposition of the drug that is
susceptible to oxidation. In embodiments, the content of an
antioxidant in the formulations ranges from about 0.001 to 10
weight percent, with respect to the active agent content.
Non-limiting examples of antioxidants include one or more of
ascorbic acid and its salts, tocopherols, sulfite salts such as
sodium metabisulfite or sodium sulfite, sodium sulfide, butylated
hydroxyanisole, butylated hydroxytoluene, ascorbyl palmitate, and
propyl gallate. Other suitable antioxidants will be readily
recognized by those skilled in the art.
[0045] Useful lubricants include magnesium stearate, glyceryl
monostearate, palmitic acid, talc, carnauba wax, calcium stearate
sodium, sodium or magnesium lauryl sulfate, calcium soaps, zinc
stearate, polyoxyethylene monostearates, calcium silicate, silicon
dioxide, hydrogenated vegetable oils and fats, stearic acid, and
any combinations thereof.
[0046] One or more glidant materials, which improve the flow of
powder blends, pellets, etc. and help to minimize dosage form
weight variations, can be used. Useful glidants include, but are
not limited to, silicon dioxide, talc, kaolin, and any combinations
thereof.
[0047] Coloring agents can be used to color code compositions, for
example, to indicate the type and dosage of the therapeutic agent
therein. Suitable coloring agents include, without limitation,
natural and/or artificial compounds such as FD&C coloring
agents, natural juice concentrates, pigments such as titanium
oxide, silicon dioxide, iron oxides, zinc oxide, any combinations
of two or more thereof, and the like.
[0048] Solid pharmaceutical dosage forms may be provided with outer
coatings that modify the release characteristics of the contained
drug or drugs, after administration. Other types of coatings are
merely esthetic, or serve to protect the dosage forms against
physical damage, moisture ingress, etc. during packaging, shipping,
and use. The coatings typically comprise at least one
pH-independent or pH-dependent polymer as the major ingredient,
frequently also including any one or more of various additives.
[0049] Suitable pH-independent polymers that are considered to be
water-soluble include both solution formers and polymeric
substances that do not form true solutions, but swell upon contact
with water to form colloidal dispersions having the appearance of
solutions. Representative members include, but are not limited to:
polyvinyl alcohols; cellulose ethers, such as methylcelluloses
having nominal viscosities in the range of about 3 to about 5000
mPas, hydroxyethyl celluloses having nominal viscosities in the
range of about 3 to about 5000 mPas, hydroxyethylmethyl celluloses
having nominal viscosities in the range of about 100 to 70000 mPas,
hydroxypropyl celluloses ("HPC") having nominal viscosities in the
range of about 10 to about 5000 mPas, and hydroxypropyl
methylcelluloses (hypromelloses or "HPMC"), of various grades such
as "E", "F", and "K," having nominal viscosities in the range of
about 1 to about 20000 mPas; polyvinylpyrrolidones (povidones or
"PVP") having nominal molecular weights in the range of about 4000
to about 1,300,000; copovidone; macrogols having molecular weights
in the range of about 400 to about 8000; graft copolymers of
polyvinyl alcohols and macrogols; polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol graft copolymers; and
polymethacrylates. The viscosities are usually measured using a 2%
by weight aqueous solution, at 20.degree. C.
[0050] Water-insoluble pH-independent polymers include substances
such as methylcelluloses, ethylcelluloses, cellulose acetates, and
others. As is known in the art, some polymers have an aqueous
solubility that depends on their molecular weights.
[0051] Various pH-dependent polymers for use in the present
application include, but are not limited to, polymers and
copolymers of acrylic and methacrylic acids, cellulose acetate
butyrates, cellulose acetate phthalates, hydroxypropyl
methylcellulose phthalates and succinates, poly(methyl
methacrylate), poly(ethylmethacrylate), poly(butylmethacrylate),
poly(isobutylmethacrylate), poly(hexlmethacrylate),
poly(isodecylmethacrylate), poly(lauryl methacrylate), poly(phenyl
methacrylate), poly(methyl acrylate), poly(isopropyl acrylate),
poly(isobutyl acrylate), poly(octadecyl acrylate), and any mixtures
of two or more thereof. Useful additives for coatings include, but
are not limited to, plasticizers, antiadherents, opacifiers,
solvents, and optionally colorants, lubricants, pigments, antifoam
agents, and polishing agents.
[0052] Various useful plasticizers include, but are not limited to,
substances such as castor oil, diacetylated monoglycerides, dibutyl
sebacate, diethyl phthalate, glycerin, polyethylene glycol,
propylene glycol, triacetin, and triethyl citrate, and mixtures
thereof. The type of plasticizer depends upon the type of coating
agent. An opacifier such as titanium dioxide may also be present in
amounts ranging from about 0.5-20%, based on the total weight of
the coating.
[0053] Anti-adhesives are frequently used in film coating processes
to avoid sticking effects during film formation and drying. An
example of a useful anti-adhesive for this purpose is talc. An
anti-adhesive is frequently present in the film coating in amounts
about 0.5-15%, based upon the total weight of the coating.
[0054] Various solvents that can be used in processes of preparing
pharmaceutical formulations of the present application include, but
are not limited to, water, methanol, ethanol, acetone, diacetone,
polyols, polyethers, oils, esters, alkyl ketones, methylene
chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl
acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl
ether, diethylene glycol monobutyl ether, diethylene glycol
monoethyl ether, dimethylsulfoxide, N,N-dimethylformamide,
tetrahydrofuran, and any mixtures of two or more thereof.
[0055] The foregoing lists of excipient substances are not
exhaustive, but are representative of members of the various
categories. Those skilled in the art will be aware of many other
useful substances, and their use is specifically contemplated
herein. Also, it is well-known that many excipients can serve more
than one purpose in pharmaceutical formulations. Co-processed
excipients, such as combinations of lactose and starch,
microcrystalline cellulose and colloidal silica, etc. can sometimes
have advantages over using the individual components.
[0056] Particle sizes of powders and suspended powders may be
determined using any of conventional technologies, including sieve
sizing, optical microscopy, Coulter Counter.TM. electrical zone
sensing methods, laser light diffraction (such as with equipment
sold by Malvern Instruments Ltd. and Horiba Instruments, Inc.),
etc. Particle size distributions frequently are represented by
terms such as D.sub.10, D.sub.50, D.sub.90, and the like, where the
numerical portion is the percentage of measured particles having a
dimension that does not exceed the given size. For example,
D.sub.90=10 um means that 90 percent of the particles have sizes
that do not exceed 10 .mu.m in any dimension. Suspended particle
sizes optionally can be measured using various physiological media
to form the suspensions, e.g., simulated gastric fluid (pH 1.2),
acetate buffer (pH 4.5) and simulated intestinal fluid (pH
5.5-7.5), or using water or a buffered or unbuffered aqueous
medium.
[0057] Pharmaceutical products can be tested for their drug
dissolution characteristics, such as using test 711 "Dissolution"
in United States Pharmacopeia 24, United States Pharmacopeial
Convention, Inc., Rockville, Md., 1999 ("USP"). Various fluids can
be used as the dissolution media, including acids, buffers,
simulated digestive tract fluids, etc., and many of these are
defined in various monographs of the USP. An example of a procedure
uses "Apparatus 2," which has a vessel containing a medium that is
stirred with a rotating paddle. Typically, a dosage unit is
immersed into the medium and samples of the medium are withdrawn at
intervals for drug content analysis, frequently using HPLC
techniques.
[0058] An example of a HPLC method for analyzing fesoterodine
fumarate and its degradants was described by B. V. R. Reddy et al.,
"A Validated Stability-Indicating HPLC Assay Method for
Determination of Fesoterodine Fumarate," RASAYAN Journal of
Chemistry, Vol. 5(2), pages 239-245, 2012.
[0059] The following examples describe certain specific aspects and
embodiments in greater detail, are provided solely for purposes of
illustration, and should not be construed as limiting the scope of
the disclosure in any manner
EXAMPLE 1
[0060] The effects of excipient substances on the stability of
fesoterodine hydrogen fumarate are studied by mixing powders of the
drug and excipients, then storing samples of the mixtures open to
the atmosphere at 40.degree. C. and 75% relative humidity, for 2
days or 5 days. Xylitol alone and maltitol alone are used as
comparator excipients. The amounts of drug-related degradant
impurities are determined in the prepared mixtures and stored
samples, using a HPLC procedure. Results are shown in the following
table, where amounts of drug degradants are expressed as
percentages of the initial drug concentration. In the table, "DF"
is deacyl fesoterodine and drug:excipient proportions are by
weight.
TABLE-US-00001 Degradant Content DF Total Mixture Initial 2 Days 5
Days Initial 2 Days 5 Days Drug + xylitol (1:2) 0.116 0.126 0.137
0.324 0.321 0.370 Drug + xylitol (1:6) 0.102 0.128 0.119 0.283
0.309 0.406 Drug + xylitol (1:9) 0.108 0.139 0.136 0.314 0.406
0.403 Drug + fructose (1:9) 0.104 0.384 -- 0.365 0.866 -- Drug +
maltitol (1:3) 0.110 0.335 0.478 0.383 0.540 0.816 Drug + maltitol
(1:6) 0.112 0.358 0.515 0.315 0.582 0.868 Drug + maltitol (1:9)
0.116 0.433 0.549 0.310 0.625 0.893 Drug + maltitol (1:12) 0.108
0.586 0.796 0.297 0.831 1.236 Drug + xylitol + maltitol (1:2:2)
0.108 0.120 0.124 0.320 0.295 0.329 Drug + xylitol + maltitol
(1:2:4) 0.111 0.132 0.131 0.345 0.335 0.339 Drug + xylitol +
maltitol (1:2:7) 0.120 0.127 0.128 0.396 0.303 0.372
EXAMPLE 2
[0061] An extended release tablet formulation is prepared, using
the ingredients in the table below.
TABLE-US-00002 Ingredient mg/Tablet Fesoterodine fumarate 8
Fructose, granular 72 Water* 2 StarLac .RTM..dagger. 77.5
Hypromellose (Methocel .RTM. K100M Premium) 120 Hypromellose
(Methocel K4M Premium) 24 Talc (500 grade) 8.5 Glyceryl behenate
(COMPRITOL .RTM. 888 ATO) 10 Coating OPADRY .RTM. AMB 80W105004
(dark blue)** 15 Water* 60 .dagger.A spray-dried composition
containing 85% .alpha.-lactose monohydrate and 15% maize starch,
from Meggle Group. *Evaporates during processing, not present in
the final product. **OPADRY AMB products, from Colorcon, are
formulated moisture barrier coating compositions containing a
polyvinyl alcohol polymer.
[0062] Formulation process:
[0063] 1. Fesoterodine fumarate and fructose are blended, then
granulated by spraying with water. The granules are dried and
milled to an average particle size not exceeding 1200 .mu.m.
[0064] 2. StarLac and the hypromellose ingredients are blended,
then mixed with the granules. Talc and glyceryl behenate are
sequentially added with blending.
[0065] 3. The mixture is compressed into tablets, coated with the
coating suspension, and dried.
[0066] Tablets prepared as above and commercial TOVIAZ fesoterodine
tablets, 8 mg are tested for their drug dissolution characteristics
using the USP dissolution method in apparatus 2 (paddle) with 900
mL of phosphate buffer (pH 6.8) and 75 rpm stirring. The results
are shown in the following table, wherein the numeric values are
cumulative percentages of the label drug content that dissolve.
TABLE-US-00003 Time TOVIAZ (hours) (Lot No. V111327) Example 2 0 0
0 1 14 11 2 24 22 4 40 41 6 52 56 8 62 69 12 76 83 16 85 93 20 89
98
[0067] Prepared tablets are analyzed for their drug degradant
impurities, both as prepared and following four weeks of storage,
open to the atmosphere at 40.degree. C. and 75% relative humidity.
Results obtained using a HPLC procedure are shown in the table
below, where numeric values are percentages of the label drug
content.
TABLE-US-00004 Impurity Initial Stored Deacyl fesoterodine 0.053
0.146 Total 0.305 0.461
EXAMPLE 3
[0068] An extended release tablet formulation is prepared, using
the ingredients in the table below.
TABLE-US-00005 Ingredient mg/Tablet Fesoterodine fumarate 8 Xylitol
16 Maltitol 32 Water* 1.5 StarLac 95.5 Hypromellose (Methocel K100M
Premium) 120 Hypromellose (Methocel K4M Premium) 24 Talc (500
grade) 8.5 Glyceryl behenate (COMPRITOL 888 ATO) 10 Coating Opadry
AMB 80W105004 (dark blue) 15 Water* 60 *Evaporates during
processing, not present in the final product.
[0069] The formulation process is similar to that described in
Example 2, except that a mixture of maltitol and xylitol is used
for granulation with the drug, instead of fructose.
[0070] Tablets prepared as above and commercial TOVIAZ fesoterodine
tablets, 8 mg are tested for their drug dissolution characteristics
using the USP dissolution method in apparatus 2 (paddle) with 900
mL of phosphate buffer (pH 6.8) and 75 rpm stirring. The results
are shown in the following table, wherein the numeric values are
cumulative percentages of the label drug content that dissolve.
TABLE-US-00006 Time TOVIAZ (hours) (Lot No. V111327) Example 3 0 0
0 1 14 14 2 24 24 4 40 40 6 52 52 8 62 62 12 76 76 16 85 84 20 89
89
[0071] Prepared tablets are analyzed for their drug degradant
impurities, both as prepared and following four weeks of storage,
open to the atmosphere at 40.degree. C. and 75% relative
humidity.
[0072] Results obtained using a HPLC procedure are shown in the
table below, where numeric values are percentages of the label drug
content.
TABLE-US-00007 Impurity Initial Stored Deacyl fesoterodine 0.052
0.200 Total 0.288 0.492
EXAMPLE 4
[0073] Tablets containing 4 mg (Formulation A) or 8 mg (Formulation
B) of fesoterodine fumarate are prepared using the ingredients in
the following table.
TABLE-US-00008 Kilograms Formulation Formulation Ingredient A B
Fesoterodine fumarate 0.5 1 Fructose, granular 9 9 Water* 0.25 0.25
StarLac 10.187 9.687 Hypromellose (Methocel K100M Premium) 15 15
Hypromellose (Methocel K4M Premium) 3 3 Talc (500 grade) 1.063
1.063 Glyceryl behenate (COMPRITOL 888 ATO) 1.25 1.25 Coating
OPADRY AMB 80W99006 (light blue) 1.875 -- OPADRY AMB 80W105004
(dark blue) -- 1.875 Water* 7.5 7.5 *Evaporates during processing,
not present in the final product.
[0074] Formulation process:
[0075] 1. Milled fesoterodine fumarate (D.sub.90.ltoreq.10 .mu.m)
and fructose are passed through a 20 mesh sieve and blended in a
high shear mixer, then water is sprayed onto the mixture. The
formed granules are briefly kneaded, then dried at about 45.degree.
C. until the loss on drying at 65.degree. C. is 0.5% or less.
Granules are passed through a comminuting mill having a screen with
1.02 mm round holes and 30% open area.
[0076] 2. StarLac and the hypromellose ingredients are passed
through a 20 mesh sieve and blended with the granules, then talc
(passing through a 30 mesh sieve) is added and blended. Glyceryl
behenate is passed through a 30 mesh sieve, added to the blender,
and blending is continued to achieve uniformity. 3. The blend is
compressed to form tablets weighing 320 mg and having a hardness
about 10 kiloponds.
[0077] 4. The coating suspension is sprayed onto tablets in a
coating pan, and the coated tablets are dried.
[0078] Further specific aspects and embodiments are described in
the following paragraphs A-F.
[0079] A. A pharmaceutical formulation comprising a co-granulate
containing a moisture-sensitive drug and fructose.
[0080] B. The pharmaceutical formulation of paragraph A, wherein a
weight ratio of drug to fructose is about 1:9.
[0081] C. A pharmaceutical formulation comprising a co-granulate
containing a moisture-sensitive drug, xylitol, and maltitol.
[0082] D. The pharmaceutical formulation of paragraph C, wherein a
weight ratio of drug to xylitol to maltitol is about 1:2:4.
[0083] E. The pharmaceutical formulation listed in any of
paragraphs A-D, wherein a drug is fesoterodine fumarate.
[0084] F. Tablets prepared according to the procedure described in
any of Examples 2-4.
* * * * *