Field of the Invention
The present invention relates to controlled release pharmaceutical compositions
comprising pregabalin or salts thereof using hydrophobic rate controlling components.
Background of the Invention
Pregabalin is an analog of gamma-aminobutyric acid (GABA). It is useful as antiseizure
therapy for central nervous system disorders such as epilepsy, Huntington's chorea,
cerebral ischemia, Parkinson's disease, tardive dyskinesia, and spasticity.
Pregabalin or (S)-(+) -3-(amino methyl)-5-methylhexanoic acid, binds to the alphas-
delta (a-8) subunit of a calcium channel and is related to the endogenous inhibitory
neurotransmitter [γ] amino butyric acid (GABA), which is involved in the regulation of
brain neuronal activity. Pregabalin exhibits anti-seizure activity and is useful for treating,
among other conditions, epilepsy, pain, physiological conditions associated with
psychomotor stimulants, inflammation, gastrointestinal damage, alcoholism, insomnia,
fibromyalgia, and various psychiatric disorders, including anxiety, depression, mania, and
bipolar disorder. Pregabalin was approved in the United States on Dec 30, 2004, an
immediate release dosage form for use in the treatment of diabetic peripheral neuropathy,
postherpetic neuralgia, and as an adjunctive treatment for partial onset seizures in adults.
Pregabalin is currently available as immediate release Lyrica® in 25, 50, 75, 100, 150,
200, 225, and 300 mg hard shell capsules and is administered in patients two or three
times daily (BID or TID).
The recommended dose of pregabalin is 100 mg three times a day (300 mg/day) for the
treatment of neuropathic pain associated with diabetic peripheral neuropathy and post
herpetic neuralgia. Pregabalin at doses of 150 to 600 mg/day is recommended for
adjunctive therapy for adult patients with partial onset seizures.
To maintain reasonably stable plasma concentrations, it is necessary to resort to frequent
dosing, and the resulting inconvenience to the patient often results in lowered compliance
with the prescribed dosing regimen. Moreover, widely fluctuating plasma concentrations
of the drug may result in administration of less than therapeutic amounts of the drug in a
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conservative dosing regimen, or amounts too large for the particular patient in an
aggressive dosing regimen.
This type of multiple administrations leads to substantial fluctuations in the plasma
concentration of the drug, especially in chronic administration.
The convenience of once daily dosing generally improves patient compliance, especially
for elderly patients and for patients taking multiple medications. Once per day dosing
may also lessen or prevent potentially undesirable dose-related effects by reducing peak
blood levels (Cmax) and may also increase drug efficacy by increasing minimum plasma
concentrations (Cmin).
Once daily dosing of pregabalin, however, presents numerous challenges as pregabalin is
not absorbed uniformly in the gastrointestinal (G1) tract. Pregabalin is absorbed in the
small intestine and in the ascending colon in humans, but is poorly absorbed beyond the
hepatic flexure, thereby suggesting that the mean absorption window for pregabalin is, on
average, about six hours or less - any drug release from a conventional ER dosage form
beyond six hours would thus be wasted because the dosage form has traveled beyond the
hepatic flexure.
Various approaches have been tried out for developing a once daily dosage form of
pregabalin.
WO 2007/052125 A2 relates to a pharmaceutical composition comprising pregabalin, and
matrix forming agent and a swelling agent, the matrix-forming agent comprising
polyvinyl acetate and polyvinylpyrrolidone, and the swelling agent comprising cross-
linked polyvinylpyrrolidone, wherein the pharmaceutical composition is adapted for
once-daily oral dosing.
US 2005/0163848 A1 relates to a complex comprised of pregabalin and a transport
moiety, such as an alkyl sulfate. The complex has an enhanced absorption in the
3

gastrointestinal tract, particularly the lower gastrointestinal tract. The complex, and
compositions and dosage forms prepared using the complex, provide for absorption by
the body of the drug through a period of ten to twenty-four hours, thus enabling a once-
daily dosage form for pregabalin.
US 2002/0119197 Al relates to pharmaceutical dosage form comprising a central core
including a pharmaceutical agent in a controlled-release composition, said core having
two exposed opposite end surfaces and a peripheral surface at an outer edge of said core
extending between said two opposed end surfaces, said peripheral edge surrounded by a
diffusion-limiting sleeve, wherein said sleeve limits the diffusion of fluids into said core.
Pregabalin is a white to off-white, crystalline solid with a pKal of 4.2 and a pKa2 of 10.6.
It is freely soluble in water and both basic and acidic aqueous solutions.
Most of the above-mentioned patent applications disclose controlled delivery systems,
which utilize hydrophilic, polymeric matrices. However, for highly soluble drugs, such
matrices do not provide adequate control over the drug release rate, instead resulting in a
release that approximates first-order kinetics.
Thus there is need to develop stable controlled release compositions of pregabalin, which
provide complete drug release and afford stable plasma levels in a once-a-day dosing
regimen using hydrophobic release controlling agent(s).
A further aspect of the invention provides a solid dosage form, such as a tablet, capsules
pellets, granules, powders and microtablets that are adapted for once daily oral dosing.
Object of the Invention
The controlled release pharmaceutical compositions comprising pregabalin of present
invention may employ any pharmaceutically acceptable form of pregabalin including
base or its pharmaceutically acceptable complexes, salts, polymorphs, hydrates, solvates,
enantiomers or racemates.
4

Therefore, the first object of the present invention provides a controlled release
pharmaceutical compositions comprising therapeutically effective amount of pregabalin
or pharmaceutically acceptable complexes, salts, polymorphs, hydrates, solvates,
enantiomers or racemates thereof wherein the composition comprises pregabalin and
hydrophobic release controlling agent(s), and optionally other pharmaceutically
acceptable excipients.
Yet another object of the present invention provides a controlled release pharmaceutical
compositions comprising therapeutically effective amount of pregabalin or
pharmaceutically acceptable complexes, salts, polymorphs, hydrates, solvates,
enantiomers or racemates thereof wherein the composition comprises pregabalin and
hydrophobic release controlling agent(s), and optionally a wicking agent.
Yet another object of the present invention provides a controlled release pharmaceutical
compositions comprising therapeutically effective amount of pregabalin or
pharmaceutically acceptable complexes, salts, polymorphs, hydrates, solvates,
enantiomers or racemates thereof wherein the composition comprises pregabalin and
hydrophobic release controlling agent(s), optionally a wicking agent and additionally
hydrophilic rate controlling components.
Yet another object of the invention provides controlled release pharmaceutical
compositions comprising pregabalin or pharmaceutically acceptable complexes, salts,
polymorphs, hydrates, solvates, enantiomers or racemates thereof, comprising a core
wherein said core comprises pregabalin or pharmaceutically acceptable complexes, salts,
polymorphs, hydrates, solvates, enantiomers or racemates thereof, with one or more
auxiliary pharmaceutical excipients and a coating layer comprising rate controlling
hydrophobic and hydrophilic agent(s).
Yet another object of the present invention is to provide for controlled release
pharmaceutical compositions comprising therapeutically effective amount of pregabalin
or pharmaceutically acceptable complexes, salts, polymorphs, hydrates, solvates,
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enantiomers or racemates thereof wherein the composition comprises pregabalin and
hydrophobic release controlling agent(s)thereof, in which the compositions exhibit in
vitro release of pregabalin not less than about 80% after 15 hours, especially not less than
about 80% after 12 hours.
Yet another object of the present invention is to provide a controlled release
pharmaceutical composition comprising therapeutically effective amount of pregabalin or
pharmaceutically acceptable complexes, salts, polymorphs, hydrates, solvates,
enantiomers or racemates thereof wherein the composition comprises pregabalin and
hydrophobic release controlling agent(s)thereof, in which the compositions exhibits in
vitro release of pregabalin not less than about 50%, after 7 hours.
Detailed description of the Invention
The dosage forms of the present invention typically contain 25 to 900 mg pregabalin as
base. The dosage forms of the invention optionally may comprise pharmaceutically
acceptable complexes, salts, polymorphs, hydrates, solvates, enantiomers or racemates of
pregabalin.
"Pharmaceutical composition" refers to the combination of one or more drug substances
and one or more excipients.
"Drug product," "pharmaceutical dosage form," "dosage form," "final dosage form" and
the like, refer to a pharmaceutical composition that is administered to a subject in need of
treatment and generally may be in the form of tablets, capsules, sachets containing
powder or granules, pellets, liquid solutions or suspensions, patches, and the like.
The term "controlled release compositions" herein refers to any composition or dosage
form which comprises an active drug and which is formulated to provide a longer
duration of pharmacological response after administration of the dosage form than is
ordinarily experienced after administration of a corresponding immediate release
composition comprising the same drug in the same amount. Controlled release
compositions include, inter alia, those compositions described elsewhere as "extended
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release", "delayed release", "sustained release", "prolonged release", "programmed
release", "time release" and/or "rate controlled" compositions or dosage forms.
The term "wicking agent" is defined as any material with the ability to draw water into
the network of a delivery dosage form. By so doing, a wicking agent provides enhanced
flow channels for the pharmaceutical agent, which has been made predominantly into its
solubilized form.
The hydrophobic release controlling agents are selected from but are not limited to
polyvinyl acetate dispersion, ethyl cellulose, cellulose acetate, cellulose propionate
(lower, medium or higher molecular weight), cellulose acetate propionate, cellulose
acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly (methyl
methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl
methacrylate), and poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl
methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl
acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), waxes such as beeswax,
carnauba wax, paraffin wax, microcrystalline wax, and. ozokerite; fatty alcohols such as
cetostearyl alcohol, stearyl alcohol, cetyl alcohol and myristyl alcohol, and fatty acid
esters such as glyceryl monostearate; glycerol monooleate, acetylated monoglycerides,
tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, zein
and hydrogenated vegetable oils or their mixtures thereof.
The hydrophilic release controlling agents are selected from but are not limited to
hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyethylene
oxide, polyvinyl alcohol, polyvinylpyrrolidone, xanthan gum, guar gum, chitosan and its
derivatives, carbomer, carrageenan, carboxymethyl cellulose, sodium alginate,
polyglycolized glycerides, polyethyleneglycol, or mixture thereof.
The wicking agents are selected from the group comprising hydrophilic, organic,
polymeric, fusible substance or a particulate soluble or insoluble inorganic material.
Suitable hydrophilic, organic, fusible wicking agents include polyethylene glycols
(PEGs) of various molecular weights e.g. 1,000 to 20,000 preferably 4,000 to 10,000 and
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suitable particulate inorganic wicking agents include dicalcium phosphate and lactose. It
is preferred to use a hydrophilic fusible, organic polymeric as wicking agent. Other
examples of wicking agents include high HLB surfactants (for example Tween 20,
Tween 60 or Tween 80; ethylene oxide propylene oxide block copolymers, ionic
surfactants such as sodium lauryl sulfate, sodium docusate, non- swelling hydrophilic
polymers such as cellulose ethers, complexing agents such as: polyvinyl pyrrolidone,
cyclodextrins and non- ionic surface active agents; and micelle forming agents, which
may be surface active agents such as Tweens (Poly (ethylene Oxide) modified sorbitan
monoesters) , Spans (fatty acid sorbitan esters), sodium lauryl sulfate and sodium
docusate.
The term "controlled release pharmaceutical compositions" includes a pharmaceutical
composition that encompasses one or more individual units. The units may be a capsule
or tablet or may be in form of granules, pellets, minitablets or beads.
The compositions of the present invention can also include other materials such as
binders, diluents, anti-adherents, glidants and lubricants.
Diluents may be, for example, any pharmaceutically acceptable, non-toxic diluent.
Particular examples include lactose, dextrose, sucrose, maltose, microcrystalline
cellulose, starch, calcium hydrogen phosphate, mannitol and the like.
Binders may be, for example, starch, sugars, gums, low molecular weight hydroxypropyl
methylcellulose, povidone, hydroxypropyl cellulose, hydroxyethyl cellulose or the like.
Lubricants may be, for example, talc, magnesium stearate, calcium stearate, stearic acid,
sodium stearyl fumarate, sodium benzoate or the like.
Antiadherents and Glidants may be, for example, colloidal silicon dioxide, talc or the
like.
Solid oral dosage forms of the present invention may be prepared by any conventional
techniques for example dry granulation, direct compression, wet granulation, melt
granulation and extrusion-spheronization.
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Examples:
The following examples are intended to be illustrative and non-limiting:
Example: 1

Sr.
No. Ingredient Mg/Unit dose
CORE
1. Pregabalin 75.00
2. Microcrystalline Cellulose (Avicel PH 101) 73.00
3. HPMC E5 2.00
4. Purified Water Q.S.
Total: 150.00
EXTENDED RELEASE COATING
1. Ethyl Cellulose (N50) 9.80
2. HPMC E5 4.20
3. Triethyl Citrate 1.40
4. Talc 4.60
5. Isopropyl Alcohol 80.00
6. Dichloromethane 320.00
Total Weight 170.00 mg
Brief Manufacturing Procedure:
1. Mix Pregabalin with Microcrystalline Cellulose and sift them through a suitable
sieve and load the blend in RMG.
2. Prepare HPMC E5 solution in suitable quantity of water.
3. Granulate the blend of step 1 with binder solution of step 2.
4. Extrudate the wet mass through 1 mm sieve using extruder and spheronize using
spheronizer.
5. Dry the pellets at a suitable temperature in FBD and size them to suitable
fractions.
6. Disperse Ethyl cellulose, HPMC E5, Triethylcitrate and Talc in the Isopropyl
alcohol and Dichloromethane solution.
7. Coat pellets with the above coating composition in FBP to get the build up of
approximately in a range of 12-18 % to get the desired profile.
8. The coated pellets can either be filled in the capsules or compressed as tablets.
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Example: 2

Sr.
No. Ingredient Mg/ Unit dose
CORE
1. Pregabalin 75.00
2. Hydrogenated Vegetable Oil 93.00
3. Magnesium Stearate 2.00
Total: 170.00 mg
Brief Manufacturing Procedure:
1) Mix Pregabalin and Hydrogenated Vegetable Oil material at suitable temperature
with continuous stirring.
2) Maintain the temperature of the melt mass for a sufficient period of time.
3) Cool the melted mass at room temperature until a hard mass is obtained.
4) Sift the mass through a suitable sieve.
5) Store the final granules in a well-closed container.
6) These granules can either be filled in the capsules or compressed as tablets.
Example: 3

Sr.
No. Ingredient Mg/ Unit dose
CORE
1. Pregabalin 150.00
2. Lactose monohydrate 128.00
3. Ethylcellulose 40.00
4. Isopropyl Alcohol Q.S.
5. Colloidal silicon dioxide 11.60
6. Talc 6.40
7. Magnesium Stearate 4.00
8 Total Weight 340.00 mg
Brief Manufacturing Procedure:
1. Mix Pregabalin with Lactose monohydrate, Ethyl cellulose, Colloidal silicon
dioxide and Talc in a suitable blender.
2. Lubricate the blend with Magnesium stearate.
3. The above lubricated blend is compressed into tablets.
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Example: 4

Sr.
No. Ingredient Mg/Capsule
CORE
1. Pregabalin 75.00
2. Lactose monohydrate 50.00
3. Starch 14.00
4. Purified Water Q.S.
5. Aerosil 4.00
6. Talc 4.00
7. Magnesium Stearate 3.00
Total 150.00
EXTEI VDED RELEASE COATING
1. Ethyl Cellulose (N50) 9.80
2. HPMC E5 4.20
3. Triethyl Citrate 1.00
4. Talc 5.00
5. Isopropyl Alcohol 80.00
6. Dichloromethane 320.00
Total Weight 170.00 mg
1. Mix Pregabalin with Lactose monohydrate, Starch and load the blend in RMG.
2. Granulate the powder mass of step 1 with suitable quantity of water.
3. Sift the above granulated mass through a suitable sieve.
4. Dry the granules in suitable dryer.
5. Lubricate the dried granules with aerosil, talc and magnesium stearate.
6. Compress the above blend into minitablets or into a single tablet.
7. Disperse Ethyl cellulose, HPMC E5, Triethylcitrate and Talc in the Isopropyl
alcohol and Dichloromethane solution.
8. Coat tablet or minitablet with the solution of step 7 to get the build up of
approximately in a range of 10-18 % to get the desired profile.
9. Alternatively the coated Minitablets can be filled into a capsule of suitable size.
Example: 5

Sr.
No. Ingredient Mg/Capsule
CORE
1. Pregabalin 75.00
2. Lactose monohydrate 40.00
3. Starch 8.00
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4. Microcrystalline cellulose 20.00
4. Aerosil 4.00
5. Magnesium Stearate 3.00
Total 150.00
EXTENDED RELEASE COATING
1. Ethyl Cellulose (N50) 9.80
2. HPMC E5 4.20
3. Triethyl Citrate 1.00
4. Talc 5.00
5. Isopropyl Alcohol 80.00
6. Dichloromethane 320.00
Total Weight 170.00 mg
1. Mix Pregabalin with Lactose monohydrate, Starch and Microcrystalline cellulose
2. Lubricate the dried granules with aerosil and magnesium stearate.
3. Compress the above blend into minitablets or into a single tablet.
4. Disperse Ethyl cellulose, HPMC E5, Triethylcitrate and Talc in the Isopropyl
alcohol and Dichloromethane solution.
5. Coat tablet or minitablet with the coating solution of Step 4 to get the build up of
approximately in a range of 12-18 % to get the desired profile.
6. Coated Minitablets can be filled into a capsule of suitable size.
Dated this 23rd day of November 2007
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A controlled release pharmaceutical composition which comprises therapeutically effective amount of pregabalin or salts thereof as active ingredient, a hydrophobic release controlling agent(s) and optionally other pharmaceutically acceptable excipients thereof.