FIELD OF INVENTION

The invention relates to a process for preparing a gastroretentive tablet, suitable for once daily dosing comprising a therapeutically effective amount of gabapentin and one or more pharmaceutically acceptable excipients, wherein said tablet is round in shape.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS

Therapeutic agents see their efficiency intimately related to their method of administration. When taken orally, a drug interacts with specific absorption sites located in different portions throughout the gastrointestinal tract (GI), resulting in that certain agents are only absorbed in the stomach, the upper or lower intestine. Therefore, because the drugs are not absorbed uniformly all over the length of the GI tract, the rate of absorption may not be constant and does not allow a most efficient treatment. These may significantly be improved when the method of administration provides a controlled delivery of the active ingredient towards the only implicated sites.

Gabapentin, a structural analogue of Gamma amino butyric acid (GABA), is indicated as adjunctive therapy in the treatment of partial seizures. Gabapentin l-(aminomethyl)cyclohexane acetic acid is 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. Gabapentin currently is also marketed as 300 mg and 600 mg gastroretentive tablets (Gralise®) for the management of postherpetic neuralgia. The oral bioavailability is dose-dependent, with approximately 60% bioavailability for a dose in the range of 300-400 mg, but with only 35% bioavailability for a dose of 1600mg. The decrease in bioavailability with dose has been attributed to carrier-mediated absorption.

Once daily dosing of gabapentin, however, presents numerous challenges. Conventional extended release (ER) compositions are problematic for dosing because gabapentin is not absorbed uniformly in the gastrointestinal (GI) tract. It has been determined that gabapentin is typically absorbed from the upper intestine, i.e., it has a narrow absorption window and is absorbed by active transport through a large neutral amino acid (LNAA) transporter. This transporter is located in the upper small intestine, has limited transport capacity, and becomes saturated at high drug concentrations. Consequently, the plasma levels of gabapentin are not dose proportional and, therefore, higher doses do not give proportionately higher plasma levels. Since the LNAA transporter responsible for gabapentin absorption is present only in the upper region of the intestine, the dosage form used to provide gabapentin should be designed to release gabapentin in the stomach at a rate such that the maximum amount of the drug is available in the intestinal segment.
Conventional dosage forms release most of the gabapentin in the stomach within a short time and, consequently, there is a high likelihood that the drug is incompletely absorbed from the upper region of the intestine.

Gastric-retentive controlled release is particularly and essentially required for the active substances that are absorbed mainly in the stomach and/or in the upper part of the small intestine. In the case of such active substances, if released after passing the stomach, it cannot help showing considerably low bioavailability.

Many attempts have been made to devise an extended release gastro-retentive drug delivery system where the dosage form is small enough to ingest and then is retained in the gastro-intestinal area for a long enough time for the active agent to be dissolved and eventually absorbed. For example, many swelling and expanding systems have been attempted. There are dosage forms that swell and change their size thereby floating to the surface. These are mostly monolithic devices and are comprised of drug and the swelling agent. Swelling significantly increases the dosage form size, which has been found to influence the transit properties. The stomach discharges its contents including the non-disintegrated solid dosage form, through the pylorus into the intestine. A drawback with these types of systems is that a highly swellable unitary matrix restricts the release of sparingly soluble drugs and various strengths are easily derived.

Prior art literature relating to gastroretentive dosage forms of gabapentin are discussed below:

U.S. Patent No. 7,612,112 discloses an extended release dosage form with core comprising active ingredient and one or more excipients surrounded by a semi-permeable membrane comprising a plasticizer and being permeable to a fluid in an environment of use and substantially impermeable to unsolubilized gabapentin, wherein the dosage form as formulated is of sufficient size for retention in the stomach in a fed mode for a period of at least about 5 hrs.

U.S. Patent No. 7,438,927 discloses gastric retained dosage form of gabapentin, wherein the dosage form comprises a single polymer matrix comprising at least one swellable hydrophilic polymer that swells in a dimensionally unrestrained manner by imbibing water to increase its size to promote gastric retention of the dosage form in the stomach of the mammal. Upon contact with water, gabapentin is released by diffusion from the dosage form for at least 5hrs. It also relates to the combination of polyethylene oxide and hydroxypropylmethyl cellulose in different ratios for gastroretentive dosage forms of gabapentin in the examples as mentioned in the patent.

U.S. Patent No. 6,723,340 discloses controlled release tablet for soluble drugs, wherein said tablet comprises a solid monolithic matrix with drug dispersed therein, with said matrix comprising a combination of polyethylene oxide and hydroxypropylmethyl cellulose. The patent also discloses that the matrix comprises the said polymers at a weight ratio that causes the said matrix to swell on contact with gastric fluid to a size large enough to provide gastric retention.

U.S. Patent No. 6,488,962 discloses controlled release oral dosage form comprising solid monolithic matrix and said matrix is non-circular in shape and having first and second orthogonal axes of unequal length in which the dimension, shape of tablets is critical to ensure that tablet does not pass through pyrolic sphincter.

Thus, there remains a need for a gastroretentive dosage form of gabapentin suitable for once daily dosing which is capable of gastric retention and provides sustained release of gabapentin which has an easy to formulate release portion comprising gabapentin and a gastro-retentive portion such that upon swelling of the gastro-retentive portion the release of gabapentin is not restricted.

In general, it is believed that only tablets of non-circular and/or non-spherical shape with
the specific dimensions are critical which can enhance the gastric retention period in stomach.

However, the inventors surprisingly found that, enhanced retention of tablet in stomach for longer period of time can be achieved by preparing the round shape gastroretentive dosage form which prevents the tablets not to pass easily from the stomach through the pylorus valve.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to a process for preparing gastroretentive tablet suitable for once daily dosing comprising therapeutically effective amount of gabapentin or its pharmaceutically acceptable salts, esters, prodrugs etc., with atleast one pharmaceutically acceptable excipient, wherein said tablet is preferably round in shape.

More particularly, the invention relates to a process for preparing round shaped gastroretentive tablets comprising therapeutically effective amount of gabapentin or its pharmaceutically acceptable salts, esters, prodrugs etc., suitable for once daily dosing which is capable of gastric retention and provides sustained release of gabapentin drug over a prolonged period of time.

An objective of the invention relates to the process of preparing round shaped gastroretentive tablet comprising gabapentin or its pharmaceutically acceptable salts, esters, prodrugs etc., suitable for once daily dosing using spray granulation method, particularly using top spray granulation method.

An objective of the invention relates to process for preparing round shaped gastroretentive tablet comprising therapeutically effective amount of gabapentin or its pharmaceutically acceptable salts, esters, prodrugs etc., wherein said tablet is prepared by coating gabapentin with a polymer in a suitable solvent to form granules using top spray granulation method and further adding together with one or more pharmaceutically acceptable excipients and finally compressing into a tablet using round tablet tooling.

Another objective of the invention relates to a round shape gastroretentive tablet of gabapentin wherein the tablet prepared according to the invention has comparative in-vitro dissolution profile with that of the commercially available tablet of Gralise™.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to a process for preparing round shape gastroretentive tablet comprising therapeutically effective amount of gabapentin or its pharmaceutically acceptable salts, esters, prodrugs etc. with atleast one pharmaceutically acceptable excipient suitable for once daily dosing, wherein said tablet is preferably round in shape.
The wording herein below is implied with the concept of invention as follows:

"Gabapentin" as used herein refers to gabapentin as base and/or their pharmaceutically acceptable salts, solvates, enantiomers, esters and polymorphs thereof.

A "therapeutically effective amount" of gabapentin herein is a daily dosage amount that, when administered as part of a regimen, provides therapeutic benefit in the treatment of a condition or disorder for which the GABA agonist is indicated. Suitable daily dosage amounts are likely to be found in a range from about 100 mg to about 1200 mg, preferably about 100 mg to about 800 mg, for example about 300 mg or 600 mg of gabapentin.

The term "gastroretentive" denotes dosage forms which effect sustained release of the active ingredient in comparison with conventional dosage forms, such as customary tablets or capsules, while avoiding an undesirably high initial dose, the release being affected continuously over a relatively long period and controlled at a therapeutically effective level by prolonged retention of the dosage form in the stomach.

The term "swelling" is used herein in reference to the ability of an ingredient to increase its dimensions, usually upon contact with a medium. Preferably, "swelling" is characterized by increasing the dimensions of the initial tablet to the size that would not readily be cleared from the stomach. The gastro¬retentive portion is primarily comprised of swellable material such that the size of the drug delivery system is greater than 1 cm after swelling. In a preferred embodiment, the gastro-retentive portion swells upon contact with fluids, such as gastric fluid, which results in an increase in total volume of dosage form of less than 30% i.e., tablet, preferably the increase in total volume of dosage form of less than 20%, more preferably the increase in total volume of dosage form of less than 30%. The 1 cm minimum size is the size necessary to produce gastric retention by not allowing the drug delivery system to pass through the pylorus of the stomach.

According to an embodiment of the invention, there is provided a process for preparing a gastroretentive dosage form, comprising a therapeutically effective amount of gabapentin suitable for once daily dosing wherein the solid dosage form is in the form of tablets or capsules, more preferably the dosage form according to the invention is preferably in the form of tablets.

According to an embodiment of the invention, it shows that modifying the dimensions and shape of the tablet leads significant influence on the enhanced gastric retention period of the tablet. Particularly, the tablet with round shape is not passed easily through the open pyloric valve of stomach and so retained in the stomach for longer period of time to enhance the gastric retention period of said gastroretentive dosage form.

According to an embodiment of the invention, it includes the process for preparing gastroretentive tablet by granulation method. Granulation methods that can be used include, for example, single pot, fluid bed top spray granulation, high shear granulation/fluid bed drying combination, continuous fluid bed granulation, fluidized spray drying, pellet production line, and others. Preferably, the granulation method is a top spray fluid bed granulation.

The process of fluid bed granulation involves the suspension of polymer or binder within an air stream while a granulation solution is sprayed down onto the fluidized bed. The particles are wetted gradually when it passes through the spray zone during the process, due to moisture and the presence of the polymer or binder within the spray solution the resulting particles will be tacky in nature. These particles get into contact with other wetted particles which results in formation of larger particles.

According to an embodiment of the invention, it relates to a process for preparing the round shaped gastroretentive tablet comprising therapeutically effective amount of gabapentin suitable for once daily dosing comprising the steps of:

(i) preparing gabapentin granules by spray coating individual gabapentin particles with the solution comprising atleast one polymer or binder;

(ii) mixing atleast one hydrogel matrix forming material and optionally one or more excipients with the granules obtained in step (i) to form a blend;

(iii) lubricating the above blend and compressing the lubricated blend to form the tablets, and

(iv) optionally coating the tablet.

According to an embodiment of the invention, it includes the process of preparing the round shaped gastroretentive tablet which comprises the steps of:

(i) preparing intragranular mixture that comprises gabapentin with a polymer or binder
which is prepared by spraying the solution onto gabapentin particles;

(ii) the intra-granular mixture is blended with additional polymer or binder and one or more excipients to form a matrix blend portion of tablet;

(iii) lubricating the blend and compressing the lubricated blend to form the tablets, and

(iv) optionally coating the tablet.

Preferably, an embodiment of the invention relates to a process for preparing the round shaped gastroretentive tablet comprising therapeutically effective amount of gabapentin suitable for once daily dosing comprising the steps of:

(i) preparing gabapentin granules by spray coating individual gabapentin particles with a hydrophobic polymer solution comprising atleast one hydrophobic polymer, atleast one pore former in an organic solvent;

(ii) mixing atleast one hydrogel matrix forming material and optionally one or more excipients with the granules obtained in step (i) to form a blend;

(iii) lubricating the above blend and compressing the lubricated blend to form the tablets using appropriate round tooling;

(iv) optionally coating the tablet.

Further, an embodiment of the invention relates to a process for preparing the round shaped gastroretentive tablet comprising therapeutically effective amount of gabapentin suitable for once daily dosing comprising the steps of:

(i) preparing intragranular mixture of gabapentin with binder, aqueous or non aqueous solvent by top spray granulation;

(ii) preparing extragranular mixture with polyethylene oxide as a sole release controlling agent and optionally a binder;

(iii) mixing the intragranular and extragranular portion together to make the final blend;

(iv) lubricating the above blend and compressing the lubricated blend into tablets using appropriate round tooling and

(v) optionally coating the tablet using Opadry™.

According to an embodiment of the invention, it includes the gastroretentive tablet preferably compressed in a rotary tableting machine to obtain round shape tablets of a diameter of about 14 mm, with hardness of about 12 to 16 kP and with thickness of about 7.33 to 7.51 mm.

The gastroretentive tablet of the invention in addition to the active ingredient may comprise one or more pharmaceutically acceptable excipients which include, but are not limited to binders, disintegrants, lubricants, release controlling polymers, and the like.
Binders may include, but are not limited to acacia, alginic acid, carbomer copolymer, carbomer interpolymer, copovidone, microcrystalline cellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydroxypropyl cellulose, maltose, methylcellulose, polyethylene oxide, polyvinylpyrrolidone, povidone, starch, or sodium carboxymethylcellulose, Kollidon® SR which is commercially available and their combinations thereof.

Disintegrant may include, but are not limited to cross-linked polypyrollidone commercially available as Crospovidone™ & Polyplasdone™, sodium starch glycolate, maize starch, pregelatinized starch, salts of carboxy methyl cellulose, microcrystalline cellulose, alginic acid, sodium alginate, guar gum, low-substituted hydroxypropyl
cellulose and their combinations thereof.

Lubricants may include, but are not limited to silica, colloidal silicon dioxide, magnesium trisilicate, talc, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, glyceryl behenate and their combinations thereof.

The hydrophobic polymer may include, but are not limited to water-insoluble polymers selected from a group consisting of ethyl cellulose, cellulose acetate, cellulose acetate phthalate, polymethyacrylates, calcium silicates and combinations thereof and the like; the waxes selected from hydrogenated castor oil, hydrogenated vegetable oil, bees wax, carnauba wax, microcrystalline wax, ozocarite, fatty acid and esters such as stearic acid, glyceryl monostearate; glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, zein, and combination thereof and the like. The most preferred hydrophobic polymer is ethyl cellulose.

The pore formers may include but are not limited to water-soluble polymers like hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone and polyethylene glycol, or other water soluble excipients, such as lactose and mannitol. Particularly preferred pore former is polyvinyl pyrrolidone.

The water-swellable polymer forming the hydrogel matrix in accordance with this invention is any polymer that is non-toxic, that swells in a dimensionally unrestricted manner upon imbibitions of water, and that provides for sustained release of an incorporated drug. Release controlling water swellable polymers may include but are not limited to, polyalkylene oxides, cellulosic polymers, acrylic acid polymers, maleic anhydride polymers, polymaleic acid, po!y(acryIamides), poly(o!efinic alcohol)s, poly(N-vinyl lactams), polyols, polyoxyethylated saccharides, polyoxazolines, polyvinylamines, polyvinyl alcohol, polyimines, polysaccharides, polyurethane hydrogels, zein, shellac-based polymers or derivatives or mixtures thereof.

Preferably, release controlling water swellable polymers used in the invention are polyalkylene oxides and their derivatives and most preferably polyethylene oxide with average molecular weight ranging from about 1,000,000 to about 8,000,000.

The aqueous and non-aqueous solvents according to the invention are selected from water, isopropyl alcohol, ethanol, methylene chloride, acetone and their mixtures thereof.

The prepared tablets can be coated further by functional coating or non functional coating. The coating composition can be prepared by dispersing the coating polymers in aqueous solvent.

The film coat used in the invention may comprise polymers such as cellulose derivatives such as one which is commercially available as Instacoat™ or Opadry™.
In yet another embodiment of the invention, there is provided a process for preparing a gastroretentive tablet comprising a therapeutically effective amount of gabapentin suitable for once daily dosing wherein the tablet provides sustained release of gabapentin over a period of atleast 18 hrs and also has comparative invitro dissolution profile when compared with commercially available Gralise™ tablets

In yet another embodiment of the invention, there is provided a gastroretentive tablet which is particularly advantageous for treating patients suffering from the management of postherpetic neuralgia and treatment of partial seizures as adjunctive therapy as it provides a sustained release of the active gabapentin at a relatively constant level directly at the site of optimum absorption in the upper small intestine.

The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.Brief Manufacturing Process:

1. Solution of stearic acid and polyvinyl pyrrolidone was prepared in isopropyl alcohol.

2. Gabapentin was coated with the above solution by top spray granulation process.

3. Polyethylene oxide was added to the granules obtained.

4. The blend was then lubricated with magnesium stearate and compressed using appropriate round tooling.

5. The tablets were optionally film coated subsequently.

6. Gabapentin was coated with the above solution by top spray granulation process.

7. Polyethylene oxide was added to the granules obtained.

8. The blend was then lubricated with magnesium stearate and compressed using appropriate tooling.

9. The tablets were optionally film coated subsequently.Brief Manufacturing Process:

1. Solution of stearic acid and polyvinyl pyrrolidone was prepared in Isopropyl alcohol.

2. Gabapentin was coated with the above solution by top spray granulation process.

3. Polyethylene oxide, sodium starch glycolate were added to the granules obtained.

4. The blend was then lubricated with magnesium stearate and compressed using
appropriate tooling.

5. The tablets were optionally film coated subsequently.

Brief Manufacturing Process:

1. Solution of ethyl cellulose and polyvinyl pyrrolidone was prepared in Isopropyl alcohol.

2. Gabapentin was coated with the above solution by top spray granulation process.

3. The polyethylene oxide (PEO WSR 303 and PEO WSR N80), sodium starch glycolate were added to the granules obtained.

4. The blend was then lubricated with magnesium stearate and compressed using appropriate tooling.

5. The tablets were optionally film coated subsequently.

Brief Manufacturing Process:

1. Solution of copovidone was prepared in purified water.

2. Gabapentin was granulated with the above solution by top spray granulation process.

3. Polyethylene oxide was added to the gabapentin granules.

4. Blend is then lubricated with magnesium stearate.

5. Final blend is compressed into tablets using 14.0 mm round shape tooling.

6. The tablets were optionally film coated subsequently.Brief Manufacturing Process:

1. Solution of copovidone was prepared in purified water.

2. Gabapentin was granulated with the above solution by top spray granulation process.

3. Polyethylene oxide and KoUidon SR were added to the gabapentin granules.

4. Blend is then lubricated with magnesium stearate.

5. Final blend is compressed into tablets using 14.0 mm round shape tooling.

6. The tablets were optionally film coated subsequently.

Dissolution Study:

The drug release profile of the prepared tablets of example 1-4, were tested in 900 ml of dissolution media using 0.06N HCl at 37°C ± 0.5°C and in 40-mesh basket USP Type-I apparatus, rotated at 100 rpm and the corresponding values are depicted in Table-1.Also, comparative invitro dissolution study of example 5-6 with commercial available Gralise™ tablets were studied using USP Type-I (basket) apparatus, in 0.1 N HCl, pH 4.5 acetate buffer and pH 6.8 phosphate buffer at 37°C ± 0.5°C rotated at 100 rpm and prepared formulations exhibit similar drug release profile to that of commercially available formulation which are shown in Table-2.

Swelling Index Study:

The tablets of Example 5 and 6 were studied for their swelling capacity and a measurement index called as swelling index was calculated which was also compared with Gralise tablets, the shape of which were non-circular. The procedure of measuring the swelling index involved the following steps:

1. Weighed the tablets of each example individually.

2. Transferred individually weighed tablets in baskets (10 mesh) and weighed again.

3. Transferred the basket containing said tablet into a USP dissolution apparatus containing 900 ml of pH 1.2 buffers as dissolution media and conducted the dissolution at 50 rpm.

4. Removed the basket containing the tablet at specified interval, dried it properly and weighed again.

5. Calculated the increase in tablet weight by subtracting initial weight of basket containing said tablets and weight as specified interval.

Swelling index is calculated as

The results of said swelling index studies are tabulated below:

Stability Study;

The tablets of Example 5 were subjected to accelerated stability testing which were kept at 40°C and 75% relative humidity for 24 weeks and the corresponding results are depicted in Table - 4. Also, the tablets of Example 6 were subjected to accelerated stability testing which were kept at 40°C and 75% relative humidity for 12 weeks and the corresponding results are depicted in Table - 5.

CLAIM:

1. An oral gastroretentive tablet comprising a therapeutically effective amount of gabapentin and one or more pharmaceutically acceptable excipient, wherein said tablet is round in shape.

2. The oral gastroretentive tablet according to claim 1, wherein said tablet has a diameter of about 14 mm, thickness of about 7.33-7.51 mm and hardness of about 12-16 kP.

3. A process for preparing an oral round gastroretentive tablet comprising a therapeutically effective amount of gabapentin or its pharmaceutically acceptable salts, esters, or its prodrugs, wherein said process involves the steps of:

i. preparing intragranular mixture of gabapentin with binder, aqueous or non aqueous solvent by spray granulation;

ii. preparing extragranular mixture with polyethylene oxide and optionally a binder;

iii. mixing the intragranular and extragranular portion together to make the final blend;

iv. lubricating the final blend;

v. compressing the lubricated blend into tablets using round tooling;

vi. optionally coating the tablet using Opadry™.

4. A process for preparing an oral round gastroretentive tablet comprising a therapeutically effective amount of gabapentin or its pharmaceutically acceptable salts, esters, or its prodrugs, wherein said process involves the steps of:

i. preparing intragranular mixture of gabapentin with binder, aqueous or non aqueous solvent by spray granulation;

ii. preparing extragranular mixture with polyethylene oxide and Kollidon SR and optionally a binder;

iii. mixing the intragranular and extragranular portion together to make the final blend;

iv. lubricating the final blend;

v. compressing the lubricated blend into tablets using round tooling;

vi. optionally coating the tablet using Opadry™.

5. A process for preparing round shaped oral gastroretentive tablet according to claim 3 or 4, wherein the spray granulation is performed using a fluidized bed processer using a top or bottom spray method.

6. A process for preparing round shaped oral gastroretentive tablet according to claim 3 or 4, wherein said binder is selected from a group consisting of acacia, carbomer copolymer, copovidone, ethyl cellulose, gelatin, guar gum, hydroxypropyl cellulose, methylcellulose, polyethylene oxide, polyvinylpyrrolidone, povidone, starch, or sodium carboxymethylcellulose and combinations thereof.

7. A round gastroretentive tablet of gabapentin of following unit formula:

8. A round gastroretentive tablet of gabapentin of following unit formula:9, An oral gastroretentive tablet comprising a therapeutically effective amount of gabapentin and one or more pharmaceutically acceptable excipient, as herein described and exemplified, wherein said tablet is round in shape.