WO2013077847A1

WO2013077847A1 - Oral dosage forms for delivering gabapentin

Info

Publication number: WO2013077847A1
Application number: PCT/US2011/061735
Authority: WO
Inventors: Zhiqun Shen; Michael HE; Fang-Yu Liu
Original assignee: Handa Pharmaceuticals, Llc
Priority date: 2011-11-21
Filing date: 2011-11-21
Publication date: 2013-05-30

Abstract

The present invention provides oral dosage forms for delivering gabapentin and as well as related methods of treatment. In one embodiment, a gabapentin-containing extended release oral dosage form is provided. The oral dosage form can include a therapeutically effective amount of gabapentin, a hydrophobic rate controlling excipient, and an alkaline material. The oral dosage forms can be prepared utilizing various techniques known in the art, including the manufacturing methodology claimed herein.

Description

ORAL DOSAGE FORMS FOR DELIVERING GABAPENTIN

FIELD OF THE INVENTION

The present invention relates to oral dosage forms for the delivery of gabapentin, as well as related methods. Accordingly, this invention involves the fields of chemistry, pharmaceutical sciences, medicine and other health sciences.

BACKGROUND OF THE INVENTION

Gabapentin is an FDA approved pharmaceutically active agent useful in treating seizures in children and adults as well as post herpetic neuralgia in adults. In addition to seizures and post-herpatic neuralgia, gabapentin has also been used in the treatment of neuropathic pain, restless legs syndrome, essential tremor, bipolar, migraine headaches, and the symptoms of menopause, hormonal imbalances, and chemotherapy. Typically gabapentin is administered multiple times daily utilizing immediate release dosage forms. Extended release dosage forms of gabapentin would allow for less frequent dosing and potentially better patient compliance. However, due to gabapentin's poor absorption in the lower gastrointestinal tract and stability challenges, formulating an extended release oral dosage form has extensive challenges.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides oral dosage forms and compositions for delivering gabapentin to a subject as well as related methods of treatment, use, and manufacture. In one aspect, a gabapentin-containing extended release oral dosage form is provided. The oral dosage form can include a therapeutically effective amount of gabapentin, a hydrophobic rate controlling excipient, and an alkaline material.

In another embodiment, methods for manufacturing extended release gabapentin-containing compositions, including oral dosage compositions, and also oral dosage forms are provided. Such methods may include the steps of admixing a hydrophobic rate controlling excipient, an alkaline material, and gabapentin to form an admixture, forming the admixture into a solid composition, and then curing the solid composition for a period of 1 to 3 hours at a temperature of 65°C to 75°C to form a controlled release oral dosage composition. In some embodiments the composition may then be formed into an oral dosage form.

In yet another embodiment, a method treating a medical condition in a subject for which gabapentin is therapeutically effective is provided. The method can include administering to the subject an oral dosage form as described herein to provide a therapeutically effective dose of gabapentin. In some aspects, multiple doses may be part of a gabapentin regimen. Non-limiting examples of medical conditions that can be treated using the disclosed oral dosage forms and related methods include without limitation, epilepsy, migraine, neuropathic pain, menopause, hot flashes, and combinations thereof.

The present invention additionally encompasses, a method for reducing impurities in a gabapentin-containing composition. In one embodiment, such a method may include admixing gabapentin with an alkaline material at a ratio of gabapentin to alkaline material of about 60:1 to about 10,000: 1. In another embodiment, the gabapentin to alkaline material ratio (W/W) can be about 100:1 to about 400:1. DETAILED DESCRIPTION

Before the present oral dosage forms, compositions and methods regarding gabapentin are disclosed and described, it is to be understood that this invention is not limited to the particular process steps and materials disclosed herein, but is extended to equivalents thereof, as would be recognized by those ordinarily skilled in the relevant arts. It should also be understood that terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting.

It should be noted that, the singular forms "a," "an," and, "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a lubricant" includes reference to one or more of such excipients, and reference to "the carrier" includes reference to one or more of such carriers.

As used herein, the terms an "oral dosage form" refers to a pharmaceutical formulation or composition that has been shaped or sized suitable for oral administration. Generally speaking, such an "oral dosage form" may include a mixture of one or more active agents with a carrier or other excipients.

As used herein, "carrier" or "pharmaceutically acceptable carrier" refers to a substance with which a drug may be combined to achieve a specific dosage form, formulation, or composition for delivery to a subject. In the some aspects of the present invention, the carriers used may or may not enhance or otherwise impact drug delivery. As a general principle, carriers should not react with the drug in a manner that substantially degrades or otherwise adversely affects the drug, except that carriers may react with a drug to prevent it from exerting a therapeutic effect until the drug is released from the carrier. Further, the carrier, or at least a portion thereof must be suitable for administration into a subject along with the drug. The carrier can include a variety of components and excipients. As used herein "gabapentin" refers to the well-known pharmaceutically active ingredient having the IUPAC name 2-[l-(aminomethyl)cyclohexyl]acetic acid.

Gabapentin is a white to off-white crystalline solid with a pKal of 3.7 and a pKa2 of 10.7. It is freely soluble in water and acidic and basic solutions. The log of the partition coefficient (n-octanol/ 0.05M phosphate buffer) at pH 7.4 is -1.25.

As used herein, "subject" refers to a mammal that may benefit from the administration of a drug composition or method of this invention. Examples of subjects include humans, and may also include other animals such as horses, pigs, cattle, dogs, cats, rabbits, and aquatic mammals. In one specific aspect, a subject is a human.

As used herein, an "effective amount" or a "therapeutically effective amount" of a drug refers to a non-toxic, but sufficient amount of the drug, to achieve therapeutic results in treating a condition for which the drug is thought to be effective. Moreover, an "effective amount" of a non-active agent or drug, such as a carrier, excipients, alkaline substance or other component refers to an amount that is suitable to perform a desired role or task, or achieve a desired result. Such amount is generally the minimum amount required, but can be any suitable amount that is considered non-toxic or that would otherwise interfere with the desired function or activity of the formulation or composition in which the ingredient is included. It is understood that various biological factors may affect the ability of a substance to perform its intended task. Therefore, an "effective amount" or a "therapeutically effective amount" may be dependent in some instances on such biological factors. Further, while the achievement of therapeutic effects may be measured by a physician or other qualified medical personnel using evaluations known in the art, it is recognized that individual variation and response to treatments may make the achievement of therapeutic effects a somewhat subjective decision. The determination of an effective amount is well within the ordinary skill in the art of pharmaceutical sciences and medicine.

As used herein, the term "substantially" refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result. For example, an object that is "substantially" enclosed would mean that the object is either completely enclosed or nearly completely enclosed. The exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained. The use of "substantially" is equally applicable when used in a negative connotation to refer to the complete or near complete lack of an action, characteristic, property, state, structure, item, or result. For example, a composition that is

"substantially free of particles would either completely lack particles, or so nearly completely lack particles that the effect would be the same as if it completely lacked particles. In other words, a composition that is "substantially free of an ingredient or element may still actually contain such item as long as there is no measurable effect thereof.

As used herein, the term "about" is used to provide flexibility to a numerical range endpoint by providing that a given value may be "a little above" or "a little below" the endpoint.

As used herein the terms "formulation" and "composition" may be used interchangeably and refer generally to the combination of at least two ingredients or agents, such as an active agent or drug and a carrier.

As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience.

However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary. In addition, various embodiments and example of the present invention are referred to herein along with alternatives for the various components thereof. It is understood that such embodiments, examples, and alternatives are not to be construed as defacto equivalents of one another, but are to be considered as separate and autonomous representations of the present invention.

Concentrations, amounts, levels and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly recited values of about 1 to about 5, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 2, 3, and 4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc., as well as 1, 2, 3, 4, and 5, individually. This same principle applies to ranges reciting only one numerical value as a minimum or a maximum. Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described.

Reference will now be made in detail to preferred embodiments of the invention. While the invention will be described in conjunction with the preferred embodiments, it will be understood that it is not intended to limit the invention to those preferred embodiments. To the contrary, it is intended to cover alternatives, variants, modifications, and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims.

As outlined above, the present invention provides for a gabapentin-containing extended release oral dosage. The oral dosage form can include a therapeutically effective amount of gabapentin, a hydrophobic rate controlling excipient, and an alkaline material. The oral dosage forms can be prepared utilizing various techniques known in the art, including the manufacturing methodology disclosed herein.

The gabapentin-containing oral dosage forms of the present invention can be formulated to provide extended release of the gabapentin over periods of 8, 12, or 24 hours. In another aspect, the oral dosage forms of the present invention can be formulated for once-a-day administration, twice-a-day administration, or

administration three times daily. The oral dosage forms of the present invention can take a variety of forms known in the art including, but not limited to a tablet, a capsule, a granule, a bead, or combinations thereof. In one particular embodiment, the oral dosage form is a tablet. In another embodiment, the oral dosage form is a bi- layer tablet.

The oral dosage forms of the present invention include gabapentin in therapeutically effective amounts. Amounts of gabapentin in the oral dosage form can range from about 75 mg to about 9600 mg. In one embodiment, the amount of gabapentin present in the oral dosage form can be about 100 mg to about 1200 mg. In another embodiment, the amount of gabapentin present in the oral dosage form can be about 100 mg to about 600 mg. The amount of gabapentin in an oral dosage form can vary depending upon a number of factors including, but not limited to, the indication being treated by the oral dosage form and the intended dosing regimen (e.g. once-a- day, or twice-a-day). Typically the gabapentin can comprise about 40 wt% to about 90 wt% of the oral dosage forms or compositions of the present invention, although values outside this range can be formulated. In one embodiment, the gabapentin can comprise about 45 wt% to about 85 wt% of the oral dosage form or composition.

The oral dosage forms and compositions of the present invention can be formulated to provide extended release of the gabapentin. In some aspects, the extended release profile of the oral dosage forms can be achieved, at least in part, through the inclusion of a hydrophobic rate controlled excipient in the oral dosage form. Non- limiting examples of hydrophobic rate controlling excipients that can be used include beeswax, white wax, emulsifying wax, hydrogenated vegetable oil, micro crystalline wax, cetyl alcohol, stearyl alcohol, a free wax acid, an ester of a free wax acid, triglycerides, saturated fatty acids (e.g., stearic acid), propylene glycol monostearate, glycerol monostearate, carnauba wax, palm wax, candelilla wax, lignite wax, ozokerite, ceresin wax, lardaceine, China wax, and mixtures thereof. In one embodiment, the hydrophobic rate controlling excipient can be a hydrogenated vegetable oil. Non- limiting examples of hydrogenated vegetable oil that can be used include hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated arachis oil, hydrogenated soybean oil, and combinations thereof.

The hydrophobic rate controlling excipient can be present in the oral dosage form or composition in nearly any amount that is sufficient to provide a composition or oral dosage form with desired physical or drug release performance characteristics. In one aspect, the amount of hydrophobic rate controlling excipients can be present in amounts of about 40 mg to about 200 mg. In another embodiment, the hydrophobic rate controlling excipient can be present in the oral dosage form in amounts of about 50 to about 150 mg. In another aspect, the amount of rate controlling excipient can vary depending on the amount of the gabapentin present in the oral dosage form and/or the intended release profile for the oral dosage form. Generally, the hydrophobic rate controlling excipient can comprise about 3 wt% to about 35 wt% of the oral dosage form or composition. In one embodiment, the hydrophobic rate controlling excipient can comprise about 5wt% to about 25 wt% of the oral dosage form or composition.

The oral dosage forms and compositions of the present invention can also include an alkaline material. The alkaline material can function to stabilize and/or reduce the amount of impurities formed in the gabapentin-containing oral dosage forms. Accordingly, the oral dosage forms and compositions of the present invention can have reduced degradation rates or reduced rates of impurity formation and/or improved stability as compared to compositionally analogous gabapentin-containing compositions or oral dosage forms without the alkaline material. Non- limiting examples of alkaline materials that can be used include magnesium oxide, sodium carbonate, sodium hydroxide, and mixtures thereof. In one embodiment, the alkaline material is magnesium oxide. The alkaline material can be present in the oral dosage form in amounts of about 1 mg to about 6 mg, depending on the amounts of gabapentin in the dosage form. Generally the oral alkaline material can comprise about 0.1 wt% to about 10 wt% of the oral dosage form or composition. In one embodiment, the alkaline material comprises about 0.3 wt% to about 3 wt% of the oral dosage form or composition. In some embodiments, the alkaline material can be present in the oral dosage form or composition such that the ratio (W/W) of gabapentin to the alkaline material can be about 60: 1 to about 10,000: 1. In one embodiment, the gabapentin to alkaline material ratio (W/W) can be about 100: 1 to about 400:1.

The oral dosage forms and compositions of the present invention can also include one or more additional pharmaceutically acceptable excipient. Non-limiting examples of excipients that can be included in the oral dosage forms and compositions include fillers, binders, lubricants, glidants, antiadherents, flavoring agents, disintegrants, surfactants, and coloring agents.

Non-limiting examples of acceptable fillers, sometimes referred to as diluents, include mannitol, lactitol, dextrose, sucrose, maltose, starch, micro crystalline cellulose, lactose, isomalt, and combinations thereof.

Examples of binders that can be used in the oral dosage forms and

compositions include, but are not limited to copovidone, hydro xypropylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium,

polyvinylpyrrolidone, sugars, starches, and combinations thereof.

Glidants or lubricants that can be used in the oral dosage forms and compositions of the present invention include, but are not limited to colloidal silicon dioxides, talc, magnesium stearate, calcium stearate, stearic acid, polyethylene glycols, silicon dioxide, and combinations thereof.

Examples of surfactants that can be included in the oral dosage forms and compositions include without limitation, sodium lauryl sulfate, polysorbates, sodium taurochloate, and combinations thereof.

Flavoring agents that can be used in the present invention include without limitation peppermint, spearmint, wintergreen, cinnamon, coconut, coffee, chocolate, vanilla, menthol, liquor ice, anise, apricot, caramel, pineapple, strawberry, raspberry, grape, cherry, mixed berry, tropical fruits, mint, and mixtures thereof.

The oral dosage forms and compositions of the present invention can in some embodiments, be coated with a coating. Various coating types known in the art can be utilized in the present invention. Examples of coating types include without limitation, film coatings, enteric or pH dependent coatings, delayed release coatings, and the like. In one embodiment, the oral dosage form or composition is coated with a film coating. When an enteric or pH dependent coating is included with the oral dosage form or composition, any known and compatible enteric coating material can be used. Non-limiting examples of such material can include zein, shellac, methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl

methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate, or mixtures thereof.

The gabapentin containing oral dosage forms and compositions of the present invention can be made utilizing known pharmaceutical manufacturing techniques including wet and dry granulation, melt blending, extrusion, and the like. In one embodiment, the extended released gabapentin-containing compositions and oral dosage forms of the present invention can be manufacturing by admixing a hydrophobic rate controlling excipient, an alkaline material, and gabapentin to form an admixture, forming the admixture into a solid composition, and curing the solid composition for a period of 1 to 3 hours at a temperature of 65°C to 75°C to form a controlled release oral dosage form.

The manufacturing method for the oral dosage forms and compositions can further be such that the admixing step includes granulating the hydrophobic rate controlling excipient with the alkaline material to form a hydrophobic granule. In a further, embodiment, the gabapentin can be granulated with the hydrophobic granule to form the admixture. In one embodiment the granulation can be achieved using rolling or slugging. In another embodiment, the method can further include the step of blending the admixture with one or more excipients prior to the forming of the solid composition. In another embodiment, the method can include the step of tableting the solid composition to form gabapentin tablets prior to the curing step.

The oral dosage compositions of the present invention can be utilized to treat any condition for which gabapentin is known to be therapeutically effective. Non- limiting examples of medical conditions that can be treated using the disclosed oral dosage forms and related methods include epilepsy, migraine, neuropathic pain, menopause, hot flashes, and combinations thereof.

Additionally, a method for reducing impurities in a gabapentin-containing composition is provided. The method comprising admixing gabapentin with an alkaline material at a ratio of gabapentin to alkaline material of about 60: 1 to about 10,000:1. In one embodiment, the gabapentin to alkaline material ratio (W/W) can be about 100:1 to about 400: 1.

EXAMPLES

Example 1 - Manufacturing process for extended release gabapentin-containing oral dosage composition

Compositions and oral dosage forms in accordance with embodiments of the present invention can be made according to the following methodology. A suspension of an alkaline material in water can be prepared by dispersing the alkaline material in the water and stirring until a uniform composition is made. A pre- weighed amount of a hydrophobic rate controlling excipient can be charged into a bowl of a granulator and the hydrophobic rate controlling excipient can be granulating with the alkaline material. The granules from the granulation can be dried, e.g. with a fluid bed drier, milled and screened.

The milled and screened granules of the alkaline material and the hydrophobic rate controlling excipient can then be granulated with gabapentin, and one or more additional excipients, e.g. filler. The new granulated composition can be mixed, compacted, milled, and/or screened to form an active agent-containing composition. Following the screening active agent-containing composition can be mixed with additional excipients such as fillers, binders, or flow agents to form a final blend. The final blend is then cured by heating the final blend at a temperature of about 65°C to 80°C for about 2 hours. It is noteworthy that in some embodiments the final blend can be formed into an oral dosage form prior to the curing step. Forming of the oral dosage form can be by compression tableting techniques or other techniques known in the art.

Examples 2 and 3 - Gabapentin-containing extended release tablets

Gabapentin-containing extended release oral dosage forms, namely tablets, in accordance with one embodiment of the present invention are prepared and have the compositional formulation set forth in Table I

TABLE I

Example 3 is prepared as follows: A MgO suspension is prepared utilizing an overhead mixer. Approximately 33.4 g of MgO and 200 g of purified water, USP are disposed in the mixer and stirred for about 15 minutes to form a uniform suspension. About 1042.3 g of Lubritab® (hydrogenated cottonseed oil) is charged into the bowl of an high-shear granulator (model KG5; 5 L) that is set with an impeller speed of 250 RPM and a chopper speed of 3000 rpm. Granulating is started by spraying the MgO dispersion at about 52 g/min and continues until the suspension solution is exhausted. 20 ml of additional purified water, USP is used to rinse the suspension container and is sprayed into the granulation. The granulated composition is mixed for an additional 30 seconds to a minute after spraying is complete. The wet granulation product is then dried utilizing a fluid bed dryer (Glatt GPCG-3) with the following settings: Filter bag: 5μηι; Inlet air temperature: 50°C; Product temperature reached 37°C; Adjust Inlet air temperature: 55°C, Product temperature reached 39°C; Dried to final product temperature of 43°C. The dried composition is screened and milled through a Sweco of 60-mesh.

The dried composition is then dry granulated with gabapentin and the excipients lactitol and talc in amounts shown in Table III.

TABLE III

The ingredients of Table III are placed in a 4 quart V-b lender and mixed for a period of about 15 minutes. Following blending, the composition is charged into a roller compactor (Vector Freund, model TF Labo) with the following settings: Pressure 2; roller speed 13 rpm; screw speed 40 rpm. The ribbons formed by the roller compactor are then milled using a Fitzmill with the following settings: Screen Hole size 1.65 mm; Blades - Impact forward; Rotor Speed 1800 RPM.

A final blend composition for Example 3 is prepared by taking the above formed dry gabapentin granulation and blending it with Mannitol and Talc in the amounts provided in Table IV. Example 2 was made in a similar manner as described for Example 3 except that additional Lubritab was added along with the mannitol and talc during the final blending step.

TABLE IV

The above formed final blend composition is then tableted into modified capsule- shaped tablets utilizing a rotary tablet press. The physical properties of the tablets are set forth in Table V

TABLE V

Once formed, each of the tablets is cured by loading the tablets into a tray lined with wax paper and allowing the tablets to cure at a temperature of 72±3°C for 2 hours.

Example 4 - Coated Gabapentin-containing extended release tablet and process of manufacture

Gabapentin-containing extended release coated tablets in accordance with one embodiment of the present invention are prepared and has the compositional formulation set forth in Table VI TABLE VI

The tablets of Example 4 are made in a manner similar to the tablets of Examples 2 and 3. Specifically, a MgO suspension is made by mixing 2.48 g MgO in 50 g purified water and mixing for 30 minutes. The MgO suspension is then wet granulated with 100 g of Lubritab® and the wet granulate is dried in an over at 45°C for 30 minutes, 50°C for 30 minutes, and then 55°C for 2.5 hours. After drying the granules are passed through a 60 mesh sieve. The granules are then charged into a V- blended with Lactitol and Gabapentin and mixed for 15 minutes at 24 RPM.

Magnesium stearate is then added to the V-b lender and the composition is mixed for about 5 minutes to form a final blend. The final blend is then compressed into tablets using a rotary tablet press. The tablets were then coated with Opadry Purple utilizing a lab scale pan coater. The tablets have theoretical weight gains upon coated of about 3.0%. Following coating, the tablets are cured in an oven at 70°C for 2 hours.

Example 5 - Dissolution testing of Examples 2-4

The dissolution of tablets of Examples 2-4 is performed in two separate mediums, the first being a hydrochloride Acid solution- pH 1.2 and the second being a medium potassium phosphate buffer - pH 6.8. Dissolution was accomplished utilizing a basket-type dilution apparatus (USP Type 1) with a stir rate of 100 rpm. Results for dissolution in the pH 1.2 medium are shown in Table VII and results for dissolution in the pH 6.8 medium are shown in Table VIII.

TABLE VII

TABLE VIII

Example 6 -Gabapentin-containing extended release tablet and stability testing thereof

Gabapentin-containing extended release tablets in accordance with one embodiment of the present invention are prepared in a manner similar to the tablets of Example 4, without coating, and have the compositional formulation set forth in Table

TABLE IX

After curing, 25 of the tablets of Example 6 were packaged into a 50 cc HDPE bottle, with one 1-g silica gel desiccant pouch in the bottle. The tablets in the bottle were placed in a stability chamber at 60°C/60%RH and stability testing was performed at various time intervals. Results of the stability testing are shown in Table X.

TABLE X

ND= Not Detectable

Examples 7-9 - Bi-Layer Gabapentin-containing extended release tablets and their manufacture

Gabapentin-containing extended release tablets in accordance with embodiments of the present invention are prepared using compositional formulations set forth in Table XI.

TABLE XI

Lubritab was pre-treated with alkaline material with method 1 described below

2Lubritab was pre-treated with alkaline material with method 2 described below

3Magnesium Oxide was pre-washed with purified water as described below

5

The tablets of Examples 7-9 were prepared utilizing hydrogenated vegetable oil

Lubritab® that had been pretreated using one of the following methods, specifically, Examples 7 and 8 were made using pre-treating hydrogenated vegetable oil pre- treated utilizing Method 1 described below while Example 9 was prepared using pre- 10 treated hydrogenated vegetable oil pre-treated utilizing Method 2. Examples 7 and 8 were made utilizing pre-washed MgO prepared in utilizing the method set forth below.

Method 1 - Pre-treatment of hydrogenated vegetable oil

1) 0.025 g of Ethanediamine is added into 300g of purified water and mixed 15 well

2) lOOg hydrogenated vegetable oil, type 1 (Lubritab®) is added to the mixture of Step 1 and dispersed and mixed for a period of 3 hours 3) The hydrogenated vegetable oil is collected by vacuum filtration and washed 3 times until pH of filtrate is about 5-6

4) The hydrogenated vegetable oil is then rinsed with 200g absolute alcohol and any remaining alcohol is drawn off using a vacuum

5) The hydrogenated vegetable oil is then dried in an oven at 45°C for about

0.5 hour, at 50°C for 0.5 hour and at 55°C for 1 hour, until LOD is less than 0.5%

6) The dried hydrogenated product is screened using a 60 mesh sieve.

Method 2 - Pre-treatment of hydrogenated vegetable oil

1) 0.010 g Sodium Hydroxide is added into 200 g absolute alcohol and mixed until any solids are dissolved

2) lOOg of hydrogenated vegetable oil, type 1 (Lubritab® is dispersed into and mixed well with the components of Step 1. The mixing is for a period of about 3 hours.

3) The hydrogenated vegetable oil is collected by vacuum filtration after mixing

4) The collected hydrogenated vegetable oil is dispersed in 200g absolute alcohol and mixed for about 0.5 hours.

5) Wash the hydrogenated using purified water three times or until the pH of the filtrate is 5-6.

6) Disperse the hydrogenated vegetable oil in 200g purified water and mix for about 0.5 hours followed by removal of the water by filtration under vacuum 7) Dry the hydrogenated vegetable oil in an oven at 45°C for 0.5 hour, at

50°C for 0.5 hour and then at 55°C for 1 hour, until LOD is less than 0.5%

8) Screen the dried hydrogenated vegetable oil using a 60 mesh sieve.

Method 3 - Pre- washing of MgO

1) 50g Magnesium Oxide is added into 200g purified water and mixed for 3 hours, after which time the MgO is collected by filtration with vacuum

2) The MgO is washed 3 times using purified water and remaining water is removed by filtration with vacuum between each washing and after final washing.

3) The MgO is dried in an oven at 70°C for 3 hours, until LOD is less than 2.50%.

4) The dried MgO is screened using a 60 mesh sieve.

The active agent-containing layers of Examples 7 and 8 are made by combining Lactitol and MgO in a plastic bag and mixing manually for about 5 minutes. Gabapentin was then placed into the same bag and manually for 5 minutes. The mixture from the bag was added into a V-blender along with the pre-treated Lubritab and the components were mixed in the blender for about 15 minutes. The magnesium stearate was then added to the blender and the components were mixed for an addition 5 minutes.

The placebo layers of Examples 7 and 8 are prepared by combining lactose 200M into a blender with a 40% Plasdone solution and mixing for about 10 minutes. The wet granules from the blender are dried using a fluid bed drier at inlet temperature of 70°C for 2 hours. Pre-treated Lubritab® and the dried granules are then combined into a V-blender and mixed for about 15 minutes. The final blends of the active-agent layers and the placebo layers are compressed into bi-layer tablets using a rotary tablet press (9.5* 18mm punch) (Relative humidity cannot exceed 40%). The bi-layer tablets are then cured in an oven at 70°C for 2 hours.

The bi-layer tablets of Example 9 are prepared by preparing the active agent- containing blend and the placebo blend separately. The active agent-containing blend is prepared by combining the pre-treated Lubritab and Lactitol in a plastic bag and mixing manually for about 5 minutes. The gabapentin and the mixture from the plastic bag are combined into a V-blender and mixed for about 1 minutes. The magnesium stearate is then added and the components are blended for an addition 5 minutes. The placebo blend is prepared by putting lactose 200 M into a blender and spray with 10% (w/w) Lactitol solution and mixing for about 10 minutes. The granules are removed from the blender and dried using a fluid bed dryer at inlet temperature of 70°C for about 2 hours. The dried granules and pre-treated Lubritab® are then placed in a V-blender and blended for about 15 minutes. The final blends of both the active and placebo portions are compressed into bi-layer tablets using a rotary tablet press. The tablets are then cured in an oven at 70°C for about 2 hours.

After curing, the stability of tablets of each of Examples 7-9 was tested in a manner similar to Example 6. The results of the stability testing are shown in Table XII.

TABLE XII

Example 10 - Gabapentin-containing extended release tablets and their stability

Gabapentin-containing extended release tablets are prepared as described in Example 2 utilizing the same compositional formulation. The physical properties of the tablets are set forth in Table XIII.

TABLE XIII

The stability of tablets of each of Examples 10 was tested in a manner similar to Example 6. The results are shown in Table XIV.

TABLE XIV

Examples 11-13 - Gabapentin-containing extended release tablets and their manufacture, and stability

Gabapentin-containing extended release tablets in accordance with embodiments of the present invention are prepared using compositional formulations set forth in Table XV.

TABLE XV

The tablets of Examples 11-13 are prepared by mixing MgO with purified water for about 30 minutes to form a MgO suspension. The MgO suspension is used to form a granulation with Lubritab by mixing in a mixer for about 5-10 minutes. The mixture is then dried in an oven.. The dried composition is passed through a 60 mesh sieve. The dried Lubritab-MgO granules are then combined with Gabapentin, lactitol, and 1% talc into a V-b lender and mixed for about 10 minutes. The blend is then compressed into large tablets using a conventional rotary tablet press. The tablets are then ground into granules manually and passed through a 20 mesh sieve. A final blend composition is then made by combining the sieved gabapentin composition with a filler (mannitol or Isomalt) and 2% Talc in a V-b lender and mixing for about 15 minutes. The final blend is then compressed into tablets using a rotary tablet press. The tablets are then cured in an oven at 70°C for 2 hours.

The stability of tablets of each of Examples 11-13 was tested in a manner similar to Example 6. The results are shown in Table XVI.

TABLE XVI

All individual impurity<0.2%

2 One individual impurity>0.2%

The stability of tablets of each of Examples 11-13 was also tested at 40°C and 75%RH and the results of that testing is shown in Table XVII.

TABLE XVII

All individual impurity<0.1% Examples 14-16 - Gabapentin-containing extended release tablets and their manufacture, and dissolution

Gabapentin-containing extended release tablets in accordance with embodiments of the present invention are prepared using compositional formulations set forth in Table XVIII.

TABLE XVIII

Examples 14-16 were prepared utilizing preparation techniques similar to those described for Examples 11-13. The physical properties of the tablets of each of the examples are shown in Table XIX.

TABLE XIX

The dissolution of tablets of Examples 14-16 is performed in two separate mediums, the first being a hydrochloride Acid solution- pH 1.2 and the second being a medium potassium phosphate buffer - pH 6.8. Dissolution was accomplished utilizing a basket-type dilution apparatus (USP Type 1) with a stir rate of 100 rpm. Results for dissolution in the pH 1.2 medium is shown in Table XX and results for dissolution in the pH 6.8 medium is shown in Table XXI. It is noteworthy that the 300 mg gabapentin tablets of Example 14 had a similar dissolution to the 600 mg gabapentin tablets. TABLE XX

TABLE XXI

Time Points (Hours)

Examples 17- 1200 mg Gabapentin-containing extended release tablets and their manufacture, and dissolution

1200 mg Gabapentin-containing extended release tablets in accordance with embodiments of the present invention are prepared using compositional formulations set forth in Table XVIII.

TABLE XXII

The tablets of Example 17 were prepared using a manufacturing process similar to the process described in Example 4. The dissolution of the tablets of Example 17 is performed in two separate mediums, the first being a hydrochloride Acid solution- pH 1.2 and the second being a medium potassium phosphate buffer - pH 6.8. Dissolution was accomplished utilizing a basket-type dilution apparatus (USP Type 1) with a stir rate of 100 rpm. Results for dissolution in the pH 1.2 medium is shown in Table XXII and results for dissolution in the pH 6.8 medium is shown in Table XXIII. It is noteworthy that the 1200 mg gabapentin tablets of Example 17 had a similar dissolution to the 600 mg gabapentin tablets Example 4. For ease of comparison, the dissolution profile of Example 4 is shown alongside the dissolution profile of Example 17.

TABLE XXII

TABLE XXIII

It has to be understood that the above-described various types of compositions, dosage forms and/or modes of applications are only illustrative of preferred embodiments of the present invention. Numerous modifications and alternative arrangements may be devised by those skilled in the art without departing from the spirit and scope of the present invention and the appended claims are intended to cover such modifications and arrangements. Thus, while the present invention has been described above with particularity and detail in connection with what is presently deemed to be the most practical and preferred embodiments of the invention, it will be apparent to those of ordinary skill in the art that variations including, but not limited to, variations in size, materials, shape, form, function and manner of operation, assembly and use may be made without departing from the principles and concepts set forth herein.

Claims

CLAIMS What is claimed is:

1. An extended release oral dosage form containing gabapentin, comprising: a therapeutically effective amount of gabapentin,

a hydrophobic rate controlling excipient, and

an alkaline material.

2. The oral dosage form of claim 1 , wherein the gabapentin is present in the oral dosage form in an amount of about 100 mg to about 9600 mg of gabapentin.

3. The oral dosage form of claim 1 , wherein the gabapentin is present in the oral dosage form in an amount of about 100 mg to about 1200 mg.

The oral dosage form of claim 1, wherein the gabapentin is present in the oral dosage form in an amount of about 100 mg to about 600 mg.

The oral dosage form of claim 1, wherein the gabapentin comprises about 40 wt% to about 90 wt% of the oral dosage form.

The oral dosage form of claim 1, wherein the gabapentin comprises about 45 wt% to about 85 wt% of the oral dosage form.

The oral dosage form of claim 1, wherein the hydrophobic rate controlling excipient is selected from the group consisting of beeswax, white wax, emulsifying wax, hydrogenated vegetable oil, micro crystalline wax, cetyl alcohol, stearyl alcohol, a free wax acid, an ester of a free wax acid, propylene glycol monostearate, glycerol monostearate, carnauba wax, palm wax, candelilla wax, lignite wax, ozokerite, ceresin wax, lardaceine, China wax, triglycerides, saturated fatty acids, and mixtures thereof.

8. The oral dosage form of claim 1 , wherein hydrophobic rate controlling

excipient is a hydrogenated vegetable oil.

9. The oral dosage form of claim 8, wherein the hydrogenated vegetable oil is selected from the group consisting of hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated arachis oil, hydrogenated soybean oil, and combinations thereof.

10. The oral dosage form of claim 1, wherein the hydrophobic rate controlling excipient is present in the oral dosage form in an amount of about 50 mg to about 150 mg.

11. The oral dosage form of claim 1, wherein the hydrophobic rate controlling excipient comprises about 3 wt% to about 35 wt% of the oral dosage form.

12. The oral dosage form of claim 1, wherein the hydrophobic rate controlling excipient comprises about 5wt% to about 25 wt% of the oral dosage form.

13. The oral dosage form of claim 1, wherein the alkaline material is selected from the group consisting of magnesium oxide, sodium carbonate, sodium hydroxide, and mixtures thereof.

14. The oral dosage form of claim 1, wherein the alkaline material is magnesium oxide.

15. The oral dosage form of claim 1, wherein the alkaline material is present in the oral dosage form in an amount of 1 mg to about 6 mg.

16. The oral dosage form of claim 1, wherein the alkaline material is comprises about 0.1 wt% to about 10 wt% of the oral dosage form.

17. The oral dosage form of claim 1, wherein the alkaline material comprises about 0.3 wt% to about 3 wt% of the oral dosage form.

18. The oral dosage form of claim 1, wherein the oral dosage form includes at least one component selected from the group consisting of a filler, a binder, a lubricant, a glidant, an antiadherent, a flavoring agent, a disintegrant, a surfactant, and a coloring agent.

19. The oral dosage form of claim 18, wherein the oral dosage form includes a filler selected from the group consisting of mannitol, lactitol, dextrose, sucrose, maltose, starch, microcrystalline cellulose, lactose, isomalt, and combinations thereof.

20. The oral dosage form of claim 18, wherein the oral dosage form includes a surfactant selected from a group consisting of sodium lauryl sulfate, polysorbates, sodium taurochloate, and combinations thereof.

21. The oral dosage form of claim 18, wherein the oral dosage form includes a binder selected from the group consisting of copovidone, hydroxypropylcellulose, hydroxypropyl methylcellulose,

carboxymethylcellulose sodium, polyvinylpyrrolidone, sugars, starches, and combinations thereof.

22. The oral dosage form of claim 18, wherein the oral dosage form includes a glidant or lubricant selected from the group consisting of colloidal silicon dioxides, talc, magnesium stearate, calcium stearate, stearic acid, polyethylene glycols, silicon dioxide, and combinations thereof.

23. The oral dosage form of claim 1, wherein the oral dosage is coated with a film coating.

24. The oral dosage form of claim 1, wherein the oral dosage form is a member selected from the group consisting of: a tablet, a capsule, granules, beads, and combinations thereof.

25. The oral dosage form of claim 1, wherein the oral dosage form is a tablet.

26. The oral dosage form of claim 1, wherein the tablet is a bi-layer tablet.

27. The oral dosage form of claim 1, wherein the oral dosage form has a reduced rate of degradation of gabapentin.

28. The oral dosage form of claim 1, wherein the oral dosage form is formulated for twice-a-day administration.

29. The oral dosage form of claim 1, wherein the oral dosage form is formulated for once-a-day administration.

30. A method of treating or preventing a medical condition in a subject, for which gabapentin is an effective treatment, comprising:

administering a therapeutically effective amount of gabapentin in an oral dosage form as recited in any of the preceding claims to the subject.

31. The method of claim 26, wherein the medical condition is epilepsy.

32. The method of claim 27, wherein the medical condition is selected from the group consisting of epilepsy, migraine, neuropathic pain, menopause, hot flashes, and combinations thereof.

33. A method of manufacturing a extended release gabapentin-containing oral dosage composition, comprising

admixing a hydrophobic rate controlling excipient, an alkaline material, and gabapentin to form an admixture;

forming the admixture into a solid composition; and

curing the solid composition for a period of 1 to 3 hours at a temperature of 65°C to 75°C to form a controlled release oral dosage composition.

34. The method of claim 33, wherein the admixing step includes granulating the hydrophobic rate controlling excipient with the alkaline material to form a hydrophobic granule.

35. The method of claim 34, wherein the gabapentin is granulated with the hydrophobic granule to form the admixture.

36. The method of claim 33, wherein the granulation is done by roller compaction or slugging.

37. The method of claim 33, further comprising the step of blending the admixture with one or more excipients prior to forming the solid composition.

38. The method of claim 33, further comprising the step of tableting the solid composition to form gabapentin tablets prior to the curing step.

39. The method of claim of claim 33, wherein the oral dosage form is selected from the group consisting of a tablet, a capsule, and a granule.

40. A method of reducing impurities in a gabapentin containing composition comprising,

admixing gabapentin with an alkaline material at a gabapentin to alkaline material ratio (W/W) of about 60:1 to about 10,000: 1.

41. The method of claim 39, wherein the ratio (W/W) of the gabapentin to the alkaline material is about 100: 1 to about 400: 1.