Description:FORM 2

THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

STABLE EXTENDED RELEASE COMPOSITION OF GABAPENTIN

SUN PHARMA ADVANCED RESEARCH COMPANY LIMITED
17/B, MAHAL INDUSTRIAL ESTATE, MAHAKALI CAVES ROAD, MUMBAI-400093 MAHARASTRA, INDIA.
A company incorporated under the Companies Act, 1956

The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to a stable extended release pharmaceutical composition comprising a high dose of gabapentin or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipient. The composition shows an improved stability with biphasic controlled drug delivery.

BACKGROUND OF THE INVENTION
Gabapentin (1-(aminomethyl)cyclohexaneacetic acid) is an anti-epileptic drug that is currently available in 100 mg, 300 mg and 400 mg hard shell capsule as well as 600 mg and 800 mg tablet dosage forms, with recommended dosing of 900 mg to 1800 mg total daily dose in three divided dosages. The oral bioavailability is dose-dependent, with approxi mately 60% bioavailability for a dose in the range of 300-400 mg, but with only 35% bioavailability for a dose of 1600 mg (Bourgeois, Epilepsia 36 (Suppl. 5):S1-S7 (1995); Gram, Epilepsia 37 (Suppl. 6):S12-S16 (1996)). The decrease in bioavailability with dose has been attributed to carrier-mediated absorption (Stewart, et al., Pharmaceutical Research 10(2):276-281 (1993).
One of the approaches to achieve a uniform and stable drug release is developing a controlled drug delivery system such as gastro retentive drug delivery system (GERD). Controlled drug delivery systems deliver drug to the body so as to establish therapeutically effective blood levels of the active ingredients and once these blood levels are achieved they continue to maintain constant bloody levels for long duration by delivering the drug to the body at the same rate as the body eliminate the drug.
In general the rate at which an oral controlled drug delivery system delivers the drug into the blood is not the same as the rate at which it releases the drug into a test aqueous fluid because the gastrointestinal fluid's pH, composition and agitation intensity change with the specific location of the drug delivery system in the gastrointestinal tract i.e. from the stomach to the colon, fasted versus fed state, type and amount of food ingested, and also vary from individual to individual.
Further the drug may not be absorbed in the same manner and propensity as we move from the stomach to the colon. Some drugs have an "absorption window" i.e. they are absorbed only from the upper parts of the gastrointestinal tract, whereas there are others whose absorption from the colon is not uniform or complete. Thus, the location of the controlled drug delivery system in the gastrointestinal tract as well as the rate at which the controlled drug delivery system moves from the stomach to the colon represent important factors that need to be considered in the design of an oral controlled drug delivery system.
Gastric retention systems are also beneficial when the drug is effective locally in the stomach. Drugs absorbed in the upper part of the gastrointestinal tract may exhibit variability in absorption due to inter and intra-individual variability in gastric emptying and gastrointestinal motility. This variation in absorption may be addressed by administering a dosage form comprising the drug such that a small part of the drug is available as immediate release, and a large part is available as sustained or controlled release.
Some of the approaches that has been used for achieving spatial control involves increasing the gastric retention of sustained or controlled drug delivery systems by using a composition containing highly swellable polymers in admixture with a gas-generating agent to form systems that are large in size as well as capable of floating on gastric fluids. Some of the patent publication are discussed hereinbelow:
United States Patent No. 4,777,033, discloses an oral sustained release pharmaceutical preparation comprising a lower alkyl ether of cellulose, polyacrylic acid or its pharmaceutically acceptable salt, a drug, and an effective amount of effervescent foaming agent. Tablets of the disclosed system did not remain intact when subjected to dissolution testing.
United States Patent No. 4,844,905, discloses granules comprising a drug containing core; a middle gas-generating layer comprising sodium carbonate and organic acid; and an outer coat of an expandable polymer film. Although intended for remaining in the stomach, the granules have the disadvantage of small size, thus fail in overall purpose of gastric retention.
United States Patent No. 5,651,985, discloses a pharmacologically active composition comprising an active compound dispersed in a homogenous mixture on the molecular level of polyvinylpyrrolidone and a methacrylic acid polymer having an acidic number between 100 and 1,200 mg of KOH/g of polymer solid substance, and optionally a gas-forming additive. The system does not however contain a part of the drug in immediate release form and a part in controlled release form and does not provide a biphasic release pattern. The rate of swelling of these systems is also slow so that they do not achieve the desired large size in a short period of 15 to 30 minutes. Moreover, in order to achieve homogeneity of the two polymers on the molecular level a cumbersome and expensive process such as freeze-drying is required.
PCT publication No. WO 00/15198, discloses a pharmaceutical composition comprising a drug, a gas-generating component, a swelling agent, a viscolyzing agent, and optionally a gel-forming polymer. The system does not however contain a part of the drug in immediate release form and a part in controlled release form and does not provide a biphasic release pattern.
PCT publication No. WO 00/23045, discloses a pharmaceutical composition containing two or three layers and contains an active principle in association with an excipient modifying its release and a system capable of generating carbon dioxide in a swelling polymer hydrophilic matrix. The disclosed system does not however contain a part of the drug in immediate release form and a part in controlled release form and does not provide a biphasic release pattern.
From the reading of the state of the art, it is apparent that there is a need for a stable gastro retentive dosage form, which can remain in spatial location for a longer time thereby providing a desired biphasic extended drug release for the intended time in the body and prevent requirement for multiple dosing.
The inventors in the present application have evaluated various formulation strategies to mitigate the issue associated with smaller size of the gastro-swellable matrix, and stability of the formulation without compromising on the intended drug delivery.

SUMMARY OF THE INVENTION
The present disclosure relates to a stable extended release composition comprising a higher load of gabapentin or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable excipient. The composition provides a controlled drug release and a long-term stability of the product.
In one aspect the present invention provides a biphasic controlled release tablet composition comprising of:
a core comprising a higher drug load of gabapentin or a pharmaceutically acceptable salt thereof, a water swellable polymer and a diluent; and
three concentric coatings on the core comprising of a barrier coating, a functional coating and a drug containing outer coating;
wherein the barrier coating separates the core from interacting with the functional coating and outer coating;
wherein the outer coating comprises a lower drug load of gabapentin or a pharmaceutically acceptable salt thereof.
In one aspect according to the present invention the composition provides a gastric retention-controlled drug delivery system comprising a controlled release composition, wherein the controlled release composition is capable of swelling to at least four times its original volume and maintaining its physical integrity in gastrointestinal fluids for prolonged periods.
In a further aspect the present invention provides a biphasic gastro-retentive controlled release formulation comprising of an active drug as gabapentin or a pharmaceutically acceptable salt thereof in core and in coating, one or more stabilizer and pharmaceutically acceptable excipients, wherein the said excipients enhance the stability of drug component in the coating.
In yet another aspect the present invention provides a stable gastro retentive controlled release composition of gabapentin, comprising of:
a drug core;
a water swellable polymer; and
the core is enabled for swelling and maintaining the physical integrity of the core and providing extended release of drug in gastrointestinal fluid for a prolonged period of time.
In a further aspect the present invention provides a stable gastro-retentive controlled release composition of gabapentin prepared with a stabilized granulation process, comprising of granulation step wherein the drug is granulated with povidone alcoholic solution to minimize sticking during compression.
In one aspect the present invention relates to a stable extended release tablet composition, prepared by a process characterized by minimal increase in lactam impurity, wherein the process comprises of:
- Incorporating a granulation step with povidone alcoholic solution, drying up to extent, wherein sufficient moisture is present in core for stability and also to overcome sticking issue during compression;
- Incorporating barrier coating to separate drug in core tablets with functional coating ingredients;
- Rapid releasing top coat composition comprising of hygroscopic components to minimize impurity generation, and using an alkalizer & binder mixture retains moisture and provide stability;
wherein the coating step is under taken at a temperature below 40oC, preferably below 35oC,
wherein the granules are dried at a temperature ranging from about 22oC to about 30oC.

DESCRIPTION OF DRAWING:
Fig.1: Dissolution release data (% release Vs Time graph) of formulation with and without sub-coating.

DETAIL DESCRIPTION OF THE INVENTION
As used herein, the word “a” or “plurality” before a noun represents one or more of the particular nouns.
For the terms “for example” and “such as,” and grammatical equivalences thereof, the phrase “and without limitation” is understood to follow unless explicitly stated otherwise. As used herein, the term “about” is meant to account for variations due to experimental error. All measurements reported herein are understood to be modified by the term “about,” whether or not the term is explicitly used, unless explicitly stated otherwise. The term “about” as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.
The term “coating” as used herein the description, can be used interchangeably with the term “coat” or “layer” around the core.
The term “drug” as used herein the description, can be used interchangeably to mean “Gabapentin” or “structural analogue of GABA” or “Pharmaceutically acceptable salt thereof”.
The term “shelf life” as used herein, means the shelf life of the drug product, in its form as a product sold for use by consumers, during which period the product is suitable for use by a patient. The shelf life of the drug product can be greater than 3, 6, 12, 18, or preferably 24 months. The shelf life may be achieved when the product is stored at room temperature at about 25° C, protected from light and moisture.
The term “dosage form” or “composition” or “formulation” as used herein the description, can be used interchangeably with the term ‘pharmaceutical composition’ or ‘pharmaceutical formulation’ or ‘pharmaceutical preparation’ or ‘drug product’, wherein the drug product is defined as a composition of Gabapentin or a pharmaceutical acceptable salt thereof with one or more pharmaceutical acceptable excipients.
The term “extended release” or “Controlled release” as used herein the description are used interchangeably to mean an extended release of drug over a time period. Within the meaning of extended release, the term biphasic release can also be defined to provide a portion of drug for release in the initial phase after administration following which remainder of drug is release over a longer period of time up to 18 to 24 hours.
The term “gastro-retentive” as used in the specification is used to refer to a feature of the formulation which facilitates retention in the gastrointestinal system for a long period of time, thereby providing a site-specific drug release within the gastrointestinal tract.
The term “stabilizer” as used in the description, represents the chemical entity responsible for improving the stability of the formulation, and comprises alkali metal stabilizers, alkalizer or pharmaceutical excipient or combination thereof used in the formulation to attain stability from external or internal factors.
The term “about” as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.
The present invention relates to a stable extended release composition comprising of a higher load of gabapentin or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable excipient. The composition provides a controlled drug release and a long-term stability of the product.
In one embodiment the present invention provides a biphasic controlled release gastro-retentive tablet composition comprising of a core comprising a higher drug load of gabapentin or a pharmaceutically acceptable salt thereof, a water swellable polymer and a diluent; and three concentric coatings on the core comprising of a barrier coating, a functional coating and a drug containing outer coating;
wherein the barrier coating separates the core from interacting with the functional coating and outer coating;
wherein the outer coating comprises a lower drug load of gabapentin or a pharmaceutically acceptable salt thereof.
In another embodiment the present invention provides a gastric retention-controlled drug delivery system comprising a controlled release core, wherein the controlled release core is capable of swelling to at least four times its original volume, and maintaining its physical integrity in gastrointestinal fluids for prolonged periods.
In yet another embodiment the present invention provides a biphasic gastro-retentive controlled release formulation comprising of an active drug as gabapentin or a pharmaceutically acceptable salt thereof in core and in coating, one or more stabilizer and pharmaceutically acceptable excipients, wherein the said excipients enhance the stability of drug component in the coating.
In a further embodiment the present invention provides a stable gastro retentive controlled release composition of gabapentin, comprising of:
a drug core;
a water swellable polymer; wherein the core is enabled for swelling and maintaining the physical integrity of the core and providing extended release of drug in gastrointestinal fluid for a prolonged period of time.
In another embodiment the present invention provides a stable gastro-retentive controlled release composition of gabapentin prepared with a stabilized granulation process, comprising of granulation step wherein the drug is granulated with povidone alcoholic solution to minimize sticking during compression.
In yet another embodiment the present invention relates to a stable biphasic extended release tablet composition, prepared by a process with minimal increase in lactam impurity, wherein the process comprises of:
incorporating a granulation step with povidone alcoholic solution, drying up to extent, wherein sufficient moisture is present in core for stability and also to overcome sticking issue during compression;
incorporating barrier coating to separate drug in core tablets with functional coating ingredients; and
rapid releasing top coat composition comprising of hygroscopic components to minimize impurity generation, and using an alkalizer & binder mixture retains moisture and provide stability;
wherein the coating step is under taken at a temperature below 40oC, preferably below 35oC,
wherein the granules are dried at a temperature ranging from about 22oC to about 30oC.
In one embodiment the present invention provides a stable biphasic extended release composition with a higher drug load present in the core at a concentration range of 45% to 80% by weight of the core or 35% to 70% by weight of the composition.
In another embodiment the present invention provides a stable biphasic extended release composition, wherein the water swellable polymer and diluent in the core are present in concentration ranging from about 15% to about 35% by weight of the composition and about 9% to about 28% by weight of the composition respectively, and the ratio of water swellable polymer and diluent in the core is 80:20 to 60:40.
In one aspect of the above embodiment the water swellable polymer and diluent is present in the core at a concentration range of about 18% to about 30% by weight of the composition and about 15% to about 24% by weight of the composition, and the ratio of water swellable polymer and disintegrant in the core is 75:25 to 65:35.
In yet another embodiment the present invention provides a stable biphasic extended release composition, wherein the lower drug load present in the outer coating is present at a concentration ranging from about 35% to about 75% by weight of the outer coating or concentration ranging from about 3.5% to about 15% by weight of the composition.
In one aspect of the above embodiment the present invention provides a stable biphasic extended release composition, wherein the lower drug load present in the outer coating is present at a concentration ranging from about 40% to about 70% by weight of the outer coating or concentration ranging from about 4.5% to about 12.5% by weight of the composition.
In another embodiment the present invention provides a stable biphasic extended release composition, wherein the ratio of alkalizer and povidone in a ratio of 0.1:5 to 4:10 provides for the drug release and higher stability of the formulation. In one aspect the alkalizer is sodium bicarbonate.
In another embodiment the present invention provides a stable biphasic extended release composition, wherein the ratio of sodium bicarbonate and povidone in outermost coating of the composition is in a ratio of 0.1:5 to 4:10 and provides for the drug release and higher stability of the formulation. In one aspect the ratio of sodium bicarbonate and povidone is 1:2.
The alkalizer according to present invention is selected from sodium bicarbonate, potassium bicarbonate, calcium carbonate, magnesium oxide or combination thereof.
In one related embodiment the stable biphasic extended release composition comprises water swellable polymer selected from hydroxy propyl cellulose, hydroxypropylmethyl cellulose or microcrystalline cellulose or combination thereof.
In yet another embodiment according to the present invention the stable biphasic extended release composition comprises a diluent selected from microcrystalline cellulose or mannitol, or combination thereof.
In one exemplary embodiment in the stable biphasic extended release composition according to present invention the core of the composition is devoid of alkalizer, and alkalizer is only present in at least two of the coatings outside core. In one aspect the alkalizer is present in one of the coating outside the core.
In another exemplary embodiment in the stable biphasic extended release composition according to present invention the core of the composition is devoid of alkalizer, and alkalizer is only present in at least in one of the coating outside the core. In an aspect the coating containing the alkalizer is outermost coating. In one related aspect the alkalizer is sodium bicarbonate. In another related aspect the alkalizer is present in combination with povidone.
In yet another exemplary embodiment the stable biphasic extended release composition according to present invention is a controlled release composition and the composition swells to at least three times its original volume while maintaining its physical integrity in gastrointestinal fluid for a prolonged period up to 24 hours.
In one exemplary embodiment the present invention provides a process for preparation of a gastro-retentive tablet composition characterized by a biphasic release of drug gabapentin or a pharmaceutically acceptable salt thereof, wherein the said process comprises of:
granulating a higher drug load in a binder solution to obtain granules;
drying and blending the granules with water swellable polymer, and diluent;
lubricating the blended granules followed by compression to obtain core tablet;
barrier coating the compressed core tablet with coating composition comprising film former and plasticizer;
functional coating the barrier coated core tablet with a film coating comprising methacrylic acid copolymer, thickening agent, alkalizer and plasticizer;
top coating the film coated tablet with a coating comprising lower drug load, alkalizer, binder and coating dispersion to obtain the coated tablet.
In one aspect according to above embodiment the process characteristically prevents any increase in lactam impurities by controlling moisture in core, thereby improving stability and avoid sticking of the core tablet during compression. In one aspect the moisture content in the composition is not more than (NMT) 8%, NMT 7%, NMT 6%, NMT 5%, NMT 4%, NMT 3%. In yet another aspect the granulation step for the core composition is done with povidone and the top coating is done with sodium bicarbonate and povidone.
In yet another embodiment the present invention provides a stable biphasic extended release composition wherein the top coat rapidly releases the lower drug load and the combination of alkalizer and binder in the top coating retains moisture and provide sufficient stability to the composition for a period of 24 months at 25oC /60%RH.
In one embodiment the present invention provides a process for preparation of stable biphasic extended release composition wherein the preparation process is carried out under low temperature condition, wherein the drying of the granules is carried out at a temperature in the range of about 22oC to about 30oC, and wherein coating is carried out at a temperature below about 40oC, preferably below about 35oC.
The term “stable” as used herein, refers to a chemical stability of the composition which means that the upon storage under the temperature and humidity at controlled room temperature condition of 25°C/60% RH for at least 12 months, 18 months or 24 months.
The term “stable” as used herein, also refers to physical stability which means that the composition retains its structural integrity and does not rupture in a significant way after exposure to storage conditions which means the composition is stable when stored under the temperature and humidity conditions of 40°C./75% RH and 30°C./75% RH for at least 3 months or at controlled room temperature condition of 25°C/60% RH for at least 12 months, 18 months or 24 months.
In yet another embodiment according to present invention the disclosed stable biphasic extended release composition comprises gabapentin or a pharmaceutically acceptable salt thereof and at least one alkalizer, wherein the alkalizer is present at least in a top coating with binder and provides for control of moisture during granulation. In one aspect the presence of binder and alkalizer in the top coating during granulation promotes the stability of the formulation.
In one embodiment according to present invention the disclosed stable biphasic extended release composition comprises gabapentin or a pharmaceutically acceptable salt thereof and a combination of two or more alkalizer, in an amount and ratio effective for controlling the moisture content and promoting stability of the formulation.
In one exemplary embodiment the present invention provides a biphasic gastro-retentive extended release tablet comprising gabapentin or a pharmaceutical acceptable salt thereof comprising a core with a higher drug load of gabapentin or a pharmaceutically acceptable salt thereof, a water swellable polymer and a diluent; and concentric coatings on the core, wherein the outer coating comprises a lower drug load of gabapentin or a pharmaceutically acceptable salt thereof.
In one aspect of the above embodiment the coating is selected from a barrier coating, a functional coating and a drug containing outer coating. In yet another aspect the barrier coating separates the core from interacting with the functional coating and outer coating.
In another aspect of the above embodiment the lower drug containing outer coating further comprises a combination of an alkalizer and povidone. In one aspect the said combination comprises of sodium bicarbonate and povidone.
In some aspect according to above embodiments the higher drug load is present in the core at a concentration range of about 45% to about 80 by weight of the core or about 35% to about 70% by weight of the composition. In one aspect the higher drug load is present in the core at a concentration range of about 50% to about 70% by weight of the core or about 40% to about 60% by weight of the composition.
In one embodiment the present invention provides a stable biphasic gastro-retentive extended release pharmaceutical composition comprising of gabapentin or a pharmaceutically acceptable salt thereof in core of the formulation and an alkalizer in at least one coating surrounding the core, wherein the said alkalizer is present in an outer most coating surrounding the core of composition in combination with povidone and is characterized by a lower level of lactam impurity in the composition.
In one related aspect of the above embodiment the alkalizer is an alkali metal salt selected from sodium bicarbonate, potassium bicarbonate, calcium carbonate, magnesium oxide or mixture thereof.
In some aspects of the above embodiment the alkalizer is present in the composition in a concentration range of about 0.1% w/w to about 10% w/w of the composition, preferably about 0.1% w/w to about 5% w/w, more preferably about 0.1 to about 3% w/w. In one aspect the alkalizer is sodium bicarbonate.
In some aspects of the above embodiments in the pharmaceutical composition disclosed herein the level of lactam impurity in the composition is not more than specified limits.
In another embodiment the present invention provides a stable biphasic extended release gastro-retentive pharmaceutical composition comprising gabapentin or a pharmaceutically acceptable salt thereof, at least one stabilizer, and one or more pharmaceutically acceptable excipient, wherein the composition the stabilizer is present at least in one of the outer coating in combination with povidone and is characterized by a level of lactam impurity level below specification limits upon storage at 25°C/60% RH for a period of 24 months.
In another embodiment the present invention provides a stable biphasic extended release gastro-retentive pharmaceutical composition comprising gabapentin or a pharmaceutically acceptable salt thereof, at least one stabilizer, and one or more pharmaceutically acceptable excipient, wherein the composition the stabilizer is present at least in one of the outer coating in combination with povidone and is characterized by a level of lactam impurity level below specification limits upon storage at 40oC/75%RH for a period of at least 6 months.
In one exemplary embodiment according to present invention the stable biphasic extended release gastro-retentive composition of gabapentin prepared by a process comprising of:
a) granulating a higher drug load in a binder solution to obtain granules;
b) drying and blending the granules with water swellable polymer and diluent;
c) lubricating the blended granules followed by compression to obtain core tablet;
d) barrier coating the compressed core tablet with coating composition comprising film former and plasticizer;
e) functional coating the barrier coated core tablet with a film coating comprising methacrylic acid copolymer, thickening agent, alkalizer and plasticizer;
f) top coating the film coated tablet with a coating comprising lower drug load, alkalizer, binder and coating dispersion to obtain the coated tablet,
wherein the use of alkalizer and binder solution in the top coating promotes the stability of the composition.
In one related aspect of the above embodiment the binder is povidone.
In another related aspect the alkalizer is sodium bicarbonate and is present in at least two coatings surrounding the core.
In yet another related aspect the alkalizer is present in outermost coating surrounding the core in combination with binder. In one aspect the binder is povidone.
In one related aspect of the above embodiment the combination of alkalizer and binder in the outermost coating provides significant improvement in stability of the formulation for a longer period of time.
In one related aspect of the above embodiment the process according to present invention is carried out under low temperature condition, thereby preventing increase in level of Lactam impurity and providing long term stability. In one aspect according to above embodiment the coating process is carried out under low temperature condition, preferably at a temperature below 40oC, more preferably at a temperature below 35oC. In another related aspect according to the above embodiment the granules in the composition are dried at a temperature below 35oC, preferably below 30oC.
The composition according to present invention may be present in the form of solid oral dosage form such as tablet, caplet, pellet or granules.
The composition according to present invention comprises one or more pharmaceutically acceptable excipients selected from one or more of carrier or vehicles, diluents, fillers, binders, disintegrants, polymer, lubricants, glidants, plasticizer, anti-adherents, film formers, thickening agents, coating agents, wetting agents, alkalizing agent, and mixtures thereof.
Suitable diluents are selected from the group comprising of lactose, microcrystalline cellulose, starch, pregelatinized starch, calcium sulphate, calcium carbonate, powdered cellulose, mannitol, sorbitol, xylitol, lactitol, magnesium carbonate, and mixtures thereof.
Suitable binders are selected from the group comprising of cellulose derivatives (for example methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose (HPMC / Hypromellose), ethylcellulose, hydroxyl ethyl cellulose, L-hydroxy propyl cellulose); polyvinylpyrrolidone (for example povidone, copovidone); starch (for example corn starch, pre-gelatinized starch and hydroxypropyl starch); polymethacrylates (for example Eudragit RS, RL); and mixtures thereof.
Suitable disintegrants may be selected from the group consisting of low substituted hydroxypropyl cellulose, crospovidone, crosscarmellose sodium, sodium starch glycolate, starch derivatives; and mixtures thereof.
Suitable lubricants are selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, and mixtures thereof.
Suitable glidants or antiadherents are selected from the group consisting of talc, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, tribasic calcium phosphate; and mixtures thereof.
Non-limiting examples of suitable coating agents selected from the group comprising of aqueous and non-aqueous coating agents selected from hypromellose, polyvinyl acetate, polyethylene glycol, cellulose acetate, ethyl cellulose, or combination thereof.
Additional excipients present in the coating include one or more of film forming polymers, plasticizers, thickening agents, anti-adherents, opacifiers, colorants, pigments, antifoaming agents, and polishing agents.
Suitable film-forming polymers are selected from the group comprising of hydroxypropylmethyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate trimellitate, and methacrylic acid copolymers, e.g., Eudragit®, polyvinylpyrrolidone, polyvinylalcohol, polyethylene glycol, and mixtures thereof. Other suitable film-forming polymers which are known in the art may also be used. Many suitable film coating products which are commercially available, e.g., Opadry®, Colorezy and Opaglos® may be used.
Suitable thickening agent are selected from the group comprising of polycarbophil, sodium starch glycolate or mixture thereof.
Suitable plasticizers are selected from the group consisting of propylene glycol, triethyl citrate, tributyl citrate, dibutyl sebacate, acetyl tributyl citrate, glyceryl monostearate, triacetin, polyethylene glycol, diethyl phthalate, acetylated monoglycerides, diacetylated monoglycerides, cetyl alcohol, and mixtures thereof.
Suitable opacifiers are selected from the group consisting of titanium dioxide, manganese dioxide, iron oxide, silicon dioxide, and mixtures thereof.
Suitable coloring agents are selected from FDA approved colorants such as iron oxide, lake of tartrazine, allura red, titanium dioxide, and mixtures thereof.
Suitable polishing agents are selected from the group consisting of polyethylene glycols of various molecular weights or mixtures thereof, talc, surfactants (glycerol monostearate and poloxamers), fatty alcohols (stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol), waxes (carnauba wax, candelilla wax and white wax), and mixtures thereof.
Various solvents that may be employed during the preparation of the composition of the present invention are selected from the group consisting of water, methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, and mixtures thereof.
The coating may be carried out by using any conventional coating techniques known in the art, such as spray coating in a conventional coating pan or fluidized bed processor, or dip coating.
The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

EXAMPLES
Example 1: Gabapentin ER formulation:
Sr. no. Component Quantity in % by wt. of composition
CORE
1. Active 40-85%
2. Binder for granulation stage 0.5 – 1.5%
3. Vehicle* q. s.
4. Binder for compression stage 0.5 – 1.0%
5. Diluent 3 – 8%
6. Polymer 8 – 15%
7. Diluent 5 – 15%
8. Lubricant 1.5 – 4%
9. Lubricant 0.5 – 2%
BARRIER COATING
10. Film former 1 – 4%
11. Plasticizer 0.05 – 0.5%
12. Glidant 0.1 – 0.5%
13. Vehicle q. s.
14. Aq. Vehicle* q. s.
FILM COATING
15. Thickening agent 0.2 – 1%
16. Diluent 2 – 8%
17. Plasticizer 0.05 – 0.5%
18. Film former 2 – 7%
19. Glidant 0.1 – 0.5%
20. Wetting agent 0.01 -0.2%
21. Plasticizer 0,2 – 1%
22. Disintegrant 0.5 – 2.5%
23. Alkalizing agent 0.5 – 2.5%
24. Vehicle* q. s.
TOP COATING
25. Active 2 – 10%
26. Binder 0.2 – 1.5%
27. Alkalizing agent 0.1 – 1%
28. Film former 2 – 10%
29. Vehicle* q. s.
30. Aq. Vehicle* q. s.
*Not present in the final product, evaporates during drying process.

Example 2: Gabapentin ER formulation prepared in 300 mg and 600 mg:
Sr. no. Ingredients (Qty. (mg/tab)) 300 mg 600 mg
A B C D E F
1. Gabapentin 255 255 255 510 510 510
2. Povidone 4.6 5.1 5.6 9.2 10.2 11.2
3. Isopropyl Alcohol* q. s. q. s. q. s. q. s. q. s. q. s.
4. Povidone 4.6 5.1 5.6 -- -- --
5. Microcrystalline Cellulose (PH 102) 40.5 45 49.5 40.5 45 49.5
6. Hydroxypropyl Cellulose 90 100 110 90 100 110
7. Mannitol 58.5 65 75.5 58.5 65 75.5
8. Hydrogenated vegetable oil Type 1 18 20 22 18 20 22
9. Magnesium stearate 9 10 11 9 10 11
Total wt. of core 480.2 505.2 534.2 735.2 760.2 789.2
10. Hydroxypropylmethylcellulose 16.7 18.6 20.5 16.7 18.6 20.5
11. Polyethylene Glycol 6000 1.6 1.8 2.0 1.6 1.8 2.0
12. Talc 2.1 2.3 2.5 2.1 2.3 2.5
13. Isopropyl Alcohol* q. s. q. s. q. s. q. s. q. s. q. s.
14. Purified Water* q. s. q. s. q. s. q. s. q. s. q. s.
15. Polycarbophil 5 5.5 6.6 5 5.5 6.6
16. Mannitol 39.7 44.1 48.6 39.7 44.1 48.6
17. Polyethylene Glycol 400 1.4 1.6 1.8 1.4 1.6 1.8
18. Methacrylic Acid Copolymer NF (Type C) / Methacrylic Acid-Ethyl Acrylate Copolymer (1:1) 36.6 40.7 44.7 36.6 40.7 44.7
19. Talc / Purified Talc IP/BP 2.4 2.7 3 2.4 2.7 3
20. Polysorbate 20 [Tween 20- LQ-(SG)] NF 0.5 0.6 0.7 0.5 0.6 0.7
21. Diethyl Phthalate NF 4.9 5.5 6.1 4.9 5.5 6.1
22. Sodium Starch Glycolate
(pH 5.5 To 7.5) IP 11.9 13.2 14.5 11.9 13.2 14.5
23. Sodium Bicarbonate 10 11 12.1 10 11.0 12.1
24. Isopropyl Alcohol* q. s. q. s. q. s. q. s. q. s. q. s.
25. Gabapentin 40.5 45 49.5 81 90 99
26. Povidone 5.4 6 6.6 5.4 6 6.6
27. Sodium Bicarbonate 2.7 3 3.3 2.7 3 3.3
28. Opadry II 40.5 45 49.5 40.5 45 49.5
29. Isopropyl Alcohol* q. s. q. s. q. s. q. s. q. s. q. s.
30. Purified water* q. s. q. s. q. s. q. s. q. s. q. s.
Total wt. of Tablet 702.1 751.7 806.2 997.6 1051.8 1110.7
*Not present in the final product, evaporates during drying process.
Note – Opadry II white 85F18422 contains: Polyethylene glycol / Macrogol, polyvinyl alcohol, titanium dioxide and talc.
Manufacturing process of Example 2 formulations:
Stage 1: Granulation:
1) Dissolving binder in alcoholic vehicle under stirring till a clear solution is obtained and adding gabapentin to the solution in granulator to obtain a wet mass.
2) Drying the wet mass in fluid bed drier and collecting dried granules followed by milling to achieve particles of desired size.
Stage II: Compression:
3) Sifting diluents, binder, polymer through suitable sieve and blending with the dried granules in blender.
4) Adding lubricants to the above blended granules and lubricating in blender.
5) Compressing the above lubricated blend.
Stage III: Barrier Coating of Compressed Core Tablets:
6) Dispersing film former in alcoholic vehicle under stirring to obtain a dispersion.
7) Dissolving plasticizer in purified water under stirring to obtain a solution.
8) Adding the solution to the dispersion under stirring to get a clear solution.
9) Adding glidant to the above clear solution under stirring till a uniform dispersion is obtained.
10) Filtering the obtained dispersion through suitable size mesh and loading the compressed core from stage II in tablet coating machine, followed by spraying the dispersion on the tablet in the coating machine.
11) Drying the barrier coated tablets.
Stage IV: Film Coating of Barrier Coated Tablets:
12) Dissolving plasticizers and wetting agent in alcoholic vehicle under stirring.
13) Adding film former slowly to the above solution under stirring to get clear solution.
14) Adding thickening agent, diluent, glidant, disintegrant and alkalizer to the above clear solution under stirring to get a uniform dispersion followed by filtering through suitable size mesh.
15) Loading the barrier coated tablets from stage III in tablet coating machine and spraying the above dispersion on the tablets in coating machine till desired weight gain is achieved followed by drying to get the film coated tablet.
Stage V: Top Coating of Film Coated Tablets:
16) Dissolving gabapentin, binder and alkalizer in purified water and alcoholic vehicle under stirring to get clear solution.
17) Adding film former (Opadry-II) to the above solution under stirring to get uniform dispersion followed by filtering through suitable size mesh.
18) Loading the film coated tablets from Stage IV in tablet coating machine and spraying the above dispersion on the tablets in coating machine till desired weight gain, followed by drying the top coated tablets in coating machine to obtain the coated tablet.

Table-1: Active Pharmaceutical Ingredient (API) (Gabapentin) description:
Sr. No. Tests Specifications
1 Description white to off-white, crystalline powder
2 Particle size (Malvern) 90% Particles between 300 to 800 microns
50% Particles above 100 microns

Example 4: Dissolution of Gabapentin Extended Release Tablets 300 mg & 600 mg:
Dissolution parameters: For dissolution testing a Type-II dissolution apparatus with #10 sinker was used at an RPM of 50 and dissolution media as pH 1.2 Buffer (Hydrochloric acid + Sodium chloride buffer) 1000 ml volume.
Table-2: Dissolution Data:
Time (hr) % Release (mean (minimum – maximum))
GBP ER Tabs 300 mg GBP ER Tabs 600 mg
1 15 (14-16) 16 (15-16)
4 44 (42-46) 39 (38-39)
12 92 (90-94) 86 (83-90)
18 99 (97-103) 100 (97-102)

Observation:
Dissolution profile of Gabapentin ER Tablets 300 mg is similar to Gabapentin ER Tablets 600mg.

Example 5: Comparative Bioequivalence Study of Ex-2 formulation with Gralise® 600 mg
An open label, balanced, randomized, two treatment, two period, two sequence, single oral dose, crossover comparative bioavailability study of Gabapentin Extended Release Tablet 600 mg (Example 2) with marketed Gralise® Tablet 600 mg, in healthy, adult, human subjects under fed conditions.
Comparative Dissolution Data of Gralise® 600mg vs Gabapentin Extended Release Tablets 600 mg (Ex-2): Test parameters for dissolution testing: - A type-II dissolution apparatus with #10 sinker was used at an RPM of 50 and dissolution media as pH 1.2 Buffer (Hydrochloric acid + Sodium chloride buffer) 1000 ml volume.
Table-3: Dissolution Data:
Time (hr) % Release (mean (minimum – maximum))
Gralise® 600mg GBP ER Tabs 600 mg*
1 19 (17-19) 16 (15-16)
4 50 (47-51) 39 (38-39)
12 92 (90-94) 86 (83-90)
18 100 (98-101) 100 (97-102)
*Batch with 15% drug outside and 85% inside without sub coating
Table-4: Bioequivalence test result:
Bioequivalence study results
Parameters Test (GBP ER Tabs 600mg) vs Reference (Gralise® 600mg)
Cmax 91.35%
(83.24% – 100.26%)
AUC0-t 91.71%
(82.60% - 101.83%)
AUC0-8 91.91%
(82.79% - 102.03%)

Conclusion: Gabapentin ER Tablets 600 mg batch (Example 2) was prepared with 15% drug in top coating & bioequivalence study was conducted. Bioequivalence study results were found satisfactory.

Example 6: Comparative study of Gabapentin ER Tablets 600 mg (Ex-2) with & without Sub coating.
Test parameters for dissolution testing:- A type-II dissolution apparatus with #10 sinker was used at an RPM of 50 and dissolution media as pH 4.5 acetate Buffer 1000 ml volume.
Table-5: Dissolution Data:
Time (hr) % Release (mean (minimum – maximum))
GBP ER Tabs 600mg (*) GBP ER Tabs 600 mg (Ex-2)
1 41 (40-43) 17 (16-17)
2 41 (40-43) 26 (25-27)
4 43 (41-44) 42 (41-43)
6 49 (48-51) 55 (54-57)
8 59 (57-60) 66 (64-68)
12 79 (77-80) 84 (80-87)
18 92 (92-94) 99 (94-103)
24 98 (97-99) 103 (99-106)
* Batch with 42% drug outside and 58% inside with sub coating
Ex-2: Batch with 15% drug outside and 85% inside without sub coating.
Observation:
Both the batches were evaluated for dissolution impact of sub-coating and it was found that the batch with sub coating shows no significant change in release profile up to 5 hours’ time point, which signifies a potential interaction of gabapentin with sub coating components. Whereas the Example-2 formulation without sub-coating the composition was found to provide a biphasic release profile as can be seen in the Table-5 and Figure-1.
Therefore, from the experiments it was found that Sub coating have a significant impact on release profile of Gabapentin ER Tablets at initial time point, this is possibly due to interaction of Gabapentin API and sub coating components (alginic acid), hence sub coating was not part of final composition.
Further it was observed that functional coating in Gabapentin ER Tablets on direct contact with core tablets shows increased impurities in excipient compatibility study. Hence, barrier coating was incorporated between core tablets and functional coating in the currently disclosed formulation. , Claims:WE CLAIM:
1. A biphasic gastro-retentive controlled release tablet composition comprising of:
a core comprising a higher drug load of gabapentin or a pharmaceutically acceptable salt thereof, a water swell able polymer and a diluent; and
three concentric coatings on the core comprising of a barrier coating, a functional coating and a drug containing outer coating;
wherein the barrier coating separates the core from interacting with the functional coating and outer coating;
wherein the outer coating comprises a lower drug load of gabapentin or a pharmaceutically acceptable salt thereof.
2. The biphasic composition as claimed in claim 1, wherein the higher drug load is present in the core at a concentration range of 45% to 80% by weight of the core or 30% to 55% by weight of the composition.
3. The biphasic composition as claimed in clam 1, wherein the water swell able polymer and diluent in the core are present in concentration range of 20% to 50% by weight of the core and 10% to 30% by weight of the composition respectively, and the ratio of water swell able polymer and diluents in the core is 40:60 to 60:40.
4. The biphasic composition as claimed in claim 1, wherein the lower drug load present in the outer coating is present at a concentration range of 35% to 75% by weight of the outer coating or 3.5% to 15% by weight of the composition.
5. The biphasic composition as claimed in claim 1, wherein the composition alkalizer and povidone are present in the outer coating in a ratio of 0.1:9.9 to 4:6 is critical for the stability of the formulation.
6. The biphasic composition as claimed in claim 1, wherein the water swellable polymer is selected from hydroxy propyl cellulose, hydroxypropylmethyl cellulose, polyethylene oxide or microcrystalline cellulose, xylitol, lactitol, sucrose or combination thereof.
7. The biphasic composition as claimed in claim 1, wherein the diluent is selected from microcrystalline cellulose, mannitol, lactitol, xylitol, sucrose or combination thereof.
8. The biphasic composition as claimed in claim 1, wherein the core is devoid of alkalizer, and alkalizer is only present in at least two of the coatings outside core.
9. The biphasic composition as claimed in claim 1, wherein the alkalizer is selected from sodium bicarbonate, potassium bicarbonate, calcium carbonate, magnesium oxide or combination thereof.
10. The biphasic composition as claimed in claim 1, wherein the composition is a controlled release composition and the tablet core swells to at least three times its original volume while maintaining its physical integrity in gastrointestinal fluid for a prolonged period, at least for 24 hours.
11. A process for preparation of a modified release or controlled release tablet composition characterized by a biphasic release of drug gabapentin or a pharmaceutically acceptable salt thereof, wherein the said process comprises of:
g) granulating drug with alcoholic binder solution to obtain granules;
h) drying granules and blending with water swellable polymer, and diluent;
i) lubricating the blended granules followed by compression to obtain core tablet;
j) barrier coating the compressed core tablet with coating composition comprising film former and plasticizer;
k) functional coating the barrier coated core tablet with a film coating composition comprising of enteric polymer e.g. methacrylic acid or methacrylate copolymer, thickening agent, alkalizer and plasticizer;
l) top coating the functional coated tablet with a coating composition comprising of lower drug load, alkalizer, binder and coating dispersion to obtain the coated tablet;
m) optional, finishing coat.
12. The process as claimed in claim 11, wherein the process characteristically prevents any increase in lactam impurity, by controlling moisture in core and coated tablet, thereby avoid sticking during compression & improving stability of the composition.
13. The process as claimed in claim 11, wherein the top coat provides rapid releases of the lower drug load and core provides extended release of larger drug load required for therapeutic level in the blood.
14. The process as claimed in claim 11, wherein the top coat contains the lower drug load and the combination of alkalizer and binder, which retains moisture and provide stability to the composition for a period of about 18 months at 25oC /60%RH.
15. The process as claimed in claim 11, wherein the process is carried out under low temperature condition, wherein the drying of the granules is carried out at a temperature in the range of about 20oC to about 30oC, and wherein coating process is carried out at a temperature below about 40oC, preferably below about 35oC.
Dated this 11th day of April, 2023


Bishram Singh Chouhan
General Manager, Sun Pharmaceutical Industries Limited
For Sun Pharma Advanced Research Company Limited