DESC:Field of the Invention:
The present invention relates to storage-stable, rapid release compositions comprising a granular component, wherein the granular component comprises amifampridine phosphate. The present invention also provides a process for the preparation of such compositions.

Background of the Invention:
Amifampridine or 3,4 diaminopyridine is a voltage-gated potassium channel blocker. Amifampridine phosphate is described chemically as 3,4-diaminopyridine phosphate with a molecular weight of 207.1 and a molecular formula of C5H7N3 • H3PO4. Amifampridine phosphate is a white, crystalline powder that is freely soluble in water, and slightly soluble in solvents like ethanol, methanol, and acetic acid. Amifampridine is a central nervous system drug used in the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults and pediatric patients of 6 years of age and older. In November 2018 the U.S. Food and Drug Administration (FDA) approved amifampridine tablets under the trade name FIRDAPSE.

U.S. Patent Numbers 11,060,128, 10,793,893, 11,268,128, 11,274,331 and 11,274,332 disclose that amifampridine can be formulated as solid formulations such as powder (micronized particles), granules, capsules, tablets, pills and troches, or liquid formulations such as suspensions, solutions, elixirs, and syrups.

U.S. Publication Number 20150353467 disclose a pharmaceutical composition comprising a stable salt of 3,4-diaminopyridine tartrate or phosphate, wherein the salt is stable at 6 months when stored at 40°C and 75% relative humidity and at least one pharmaceutically acceptable vehicle.

It has surprisingly been found that when storage-stable, rapid release compositions of amifampridine phosphate are formulated in the form of compositions comprising a granular component, wherein the granular component comprises amifampridine phosphate, the said compositions exhibit the desired content uniformity, dissolution, and stability.

OBJECTS OF THE INVENTION
The principal object of the present invention is to provide a storage-stable, rapid release compositions of amifampridine phosphate comprising a granular component, for oral administration.

Another object of the present invention is to provide a storage-stable, rapid release compositions comprising a granular component, wherein the granular component comprises amifampridine phosphate.

Another object of the present invention is to provide a storage-stable, rapid release composition of amifampridine phosphate comprising a granular component, wherein the cumulative dissolution of amifampridine from the said composition is from 85% to 110% by weight.

Yet another object of the present invention is to provide a storage-stable, rapid release composition of amifampridine phosphate comprising a granular component, wherein the said composition is storage stable for a period of at least 18 months.

Yet another object of the present invention is to provide a storage-stable, rapid release composition of amifampridine phosphate comprising a granular component, wherein the said composition has the desired content uniformity.

Yet another object of the present invention is to provide a process for preparation of the said storage-stable, rapid release compositions of amifampridine phosphate.
SUMMARY OF THE INVENTION
The present invention relates to storage-stable, rapid release compositions comprising a granular component, wherein the granular component comprises amifampridine phosphate. The present invention also provides a process for the preparation of such compositions.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to storage-stable, rapid release compositions of amifampridine phosphate comprising a granular component, wherein the granular component comprises amifampridine phosphate.

It has been found that when storage-stable, rapid release compositions of amifampridine phosphate comprise a granular component, wherein the granular component comprises amifampridine phosphate, the said compositions exhibit the desired content uniformity, dissolution, and stability.

‘Amifampridine phosphate’ as used herein includes hydrates or solvates thereof. Amifampridine phosphate can be in crystalline and/or amorphous form.

‘Granular component’, as used herein, refers to the component that is in the form of granules or granulates capable of being further processed and/or compressed into tablets and/or filled into capsules or sachets. The ‘granular component’ is prepared using at least one process selected from wet granulation, dry granulation, fluidized bed granulation, rapid mixer granulation, high-shear mixer granulation, centrifugal wet granulation, steam granulation, spray drying granulation, melt granulation, melt extrusion, freeze-granulation, thermal adhesion granulation, foam granulation, pneumatic dry granulation, moisture-activated dry granulation, roll compaction, slug compaction, co-milling, co-crystallization, solvent evaporation, or co-precipitation.
The storage-stable, rapid release compositions of amifampridine phosphate which comprise a granular component, are in the form of granules, tablets, or capsules. The storage-stable, rapid release compositions are preferably in the form of tablets. The storage-stable rapid release compositions of amifampridine phosphate in accordance with the invention can be administered by the oral route, taken 3 to 4 times daily.

The amount of amifampridine phosphate present in the storage-stable, rapid release compositions in accordance with the invention from 5 mg to 20 mg.

The storage-stable, rapid release compositions of the present invention comprise amifampridine phosphate in concentrations ranging from about 1% to about 75%, preferably from about 1.5% to about 50%, more preferably from about 2% to about 40%, and most preferably from about 2% to about 25% by weight of the composition.

In an embodiment, the storage-stable, rapid release compositions comprise amifampridine phosphate in a concentration ranging from about 2.5% to about 15% by weight of the composition.

In an aspect, the storage-stable, rapid release compositions of the present invention comprise a granular component and an extra-granular component, wherein the granular component comprises amifampridine phosphate.

‘Extra-granular component’, as used herein, refers to the component which when mixed with the granular component, is capable of being compressed into tablets and/or filled into capsules or sachets.

The granular component, in the storage-stable, rapid release compositions of amifampridine phosphate, can range from about 50% to about 99.5% by weight of the composition.

The extra-granular component, in the storage-stable, rapid release compositions of amifampridine phosphate, can range from about 0.5% to about 50% by weight of the composition.

The weight ratio of the granular component and the extra-granular component, in the storage-stable, rapid release compositions, can range from 1: 0.005 to 1:1.

Amifampridine phosphate used in the rapid release compositions has a particle size distribution wherein 90% by volume (d (0.9)) of amifampridine particles have a particle size of not more than 200 microns, preferably not more than 175 microns, and more preferably not more than 150 microns, as determined by the laser diffraction method (Malvern) using the wet method.

In an aspect, amifampridine phosphate used in the rapid release compositions has a particle size distribution wherein 50% by volume (d (0.5)) of amifampridine phosphate particles have a particle size of not more than 100 microns, preferably not more than 80 microns, and more preferably not more than 60 microns, as determined by the laser diffraction method (Malvern) using the wet method.

In another aspect, amifampridine phosphate used in the storage-stable, rapid release compositions has a particle size distribution wherein 10% by volume (d (0.1)) of amifampridine phosphate particles have a particle size of not more than 50 microns, preferably not more than 30 microns, and more preferably not more than 20 microns, as determined by the laser diffraction method (Malvern) using the wet method.

The granular component of the storage-stable, rapid release compositions comprises amifampridine phosphate in a concentration ranging from about 1% to about 75%, preferably from about 1.5% to about 50%, more preferably from about 2% to about 40%, and most preferably from about 2% to about 25%, by weight of the granular component.

In an embodiment, the storage-stable, rapid release compositions comprise amifampridine phosphate in a concentration ranging from about 2.5% to about 15% by weight of the granular component.

In an aspect, the storage-stable, rapid release compositions comprise a granular component and an extra-granular component, wherein the granular component comprises amifampridine phosphate and at least one excipient.

In another aspect, the storage-stable, rapid release compositions comprise a granular component and an extra-granular component, wherein the granular component comprises amifampridine phosphate and at least one excipient selected from diluents, disintegrants, binders, and surfactants.

In another aspect, the storage-stable, rapid release compositions comprise a granular component and an extra-granular component, wherein the granular component comprises amifampridine phosphate, and wherein the extra-granular component comprises at least one excipient.

Excipients in the storage-stable, rapid release compositions of amifampridine may be selected from diluents, disintegrants, binders, lubricants, glidants, surfactants, film-forming agents, and plasticizers.

Diluent(s), in the storage-stable, rapid release compositions of amifampridine phosphate, is selected from microcrystalline cellulose, powdered cellulose, lactose, glucose, sucrose, dextrose, fructose, mannitol, sorbitol, maltodextrin, starch, modified starch, pregelatinized starch, starch 1500, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, cyclodextrin, hypromellose, carboxymethylcellulose, and hydroxypropyl cellulose. The preferred diluent is microcrystalline cellulose.

Storage-stable, rapid release compositions of amifampridine phosphate comprise diluent(s) in concentrations ranging from about 25% to about 99%, preferably from about 50% to about 99%, and more preferably from about 60% to about 99% by weight of the composition.

In one embodiment, the concentration of diluent(s) is about 70% to about 98%, by weight of the composition.

In another embodiment, the concentration of diluent(s) is about 75% to about 98% by weight of the composition.

In another embodiment, the concentration of diluent(s) is about 80% to about 95% by weight of the composition.

In an aspect, the storage-stable, rapid release compositions of amifampridine phosphate comprise a granular component and an extra-granular component, wherein the granular component comprises amifampridine phosphate and at least one diluent.

In another aspect, the storage-stable, rapid release compositions of amifampridine phosphate comprise a granular component and an extra-granular component, wherein the granular component consists essentially of amifampridine phosphate and at least one diluent.

The granular component, of the storage-stable, rapid release compositions of amifampridine phosphate, comprise diluent(s) in a concentration ranging from about 25% to about 99%, preferably from about 50% to about 99%, and more preferably from about 60% to about 99% by weight of the granular component.

In an embodiment, the granular component comprises diluent(s) in a concentration ranging from about 70% to about 98%, by weight of the granular component.

In another embodiment, the granular component comprises diluent(s) in a concentration ranging from about 75% to about 98% by weight of the granular component.

In another embodiment, the granular component comprises diluent(s) in a concentration ranging from about 80% to about 95% by weight of the granular component.

In yet another aspect, the storage-stable, rapid release compositions of amifampridine phosphate comprise a granular component and an extra-granular component, wherein the extra-granular component comprises at least one diluent.

In yet another aspect, the extra-granular component comprises diluent(s) in a concentration ranging from about 50% to about 99%, preferably from about 60% to about 90%, and more preferably from about 70% to about 85% by weight of the extra-granular component.

Disintegrant(s) may be present in concentrations ranging from about 1% to about 10% by weight of the composition and are selected from those known in the art such as sodium starch glycolate, crospovidone, and croscarmellose sodium.

Binder(s) may be present in concentrations from 0.1% to 40% by weight of the composition, and are selected from those known in the art such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose (MC), hydroxyethyl cellulose (HEC), polyvinylpyrrolidone (PVP), polyvinyl alcohol, waxes, fatty alcohols (such as cetyl alcohol), waxes, polyethylene glycol, carbomer, gums (such as xanthan gum, guar gum), alginates, and polymethacrylates.

In an aspect, the storage-stable, rapid release compositions of amifampridine phosphate are free from binders. In another aspect, the storage-stable, rapid release compositions of amifampridine phosphate are free from disintegrants. In another aspect, the storage-stable, rapid release compositions of amifampridine phosphate are free from binders and disintegrants.

In another aspect, the storage-stable composition of amifampridine phosphate comprises a granular component and an extra-granular component, wherein the granular component comprises amifampridine phosphate and microcrystalline cellulose; and an extra-granular component comprises of microcrystalline cellulose, calcium stearate and colloidal silicon dioxide, wherein the storage-stable composition is free of binders.

In another aspect, the storage-stable composition of amifampridine phosphate comprises a granular component and an extra-granular component, wherein the granular component comprises of amifampridine phosphate and microcrystalline cellulose; and an extra-granular component comprises of microcrystalline cellulose, calcium stearate and colloidal silicon dioxide, wherein the storage-stable composition is free of disintegrants.

In another aspect, the storage-stable, rapid release compositions comprises a granular component and an extra-granular component, wherein granular component comprises of amifampridine phosphate and microcrystalline cellulose, wherein the extra-granular component comprises of at least one diluent, at least one lubricant and at least one glidant, wherein the rapid release compositions are free from binders and disintegrants.

In another aspect, the storage-stable, rapid release compositions comprising of a granular component, wherein granular component comprises of amifampridine phosphate and microcrystalline cellulose and an extra-granular component, wherein the extra-granular component comprise of microcrystalline cellulose, calcium stearate and colloidal silicon dioxide, wherein the rapid release compositions are free from binders and disintegrants.

In another aspect, the storage-stable, rapid release compositions comprising of a granular component and an extra-granular component, wherein granular component comprises of 7% to 9% amifampridine phosphate and 72% to 75% microcrystalline cellulose and the extra-granular component comprises of 14% to 16% microcrystalline cellulose, 0.5% to 1.5% calcium stearate and 1.5% to 2.5% colloidal silicon dioxide.

In another aspect, the storage-stable, rapid release compositions comprising of a granular component and an extra-granular component, wherein granular component comprises of 7.91% amifampridine phosphate and 74.17% microcrystalline cellulose and wherein the extra-granular component comprise of 14.90% microcrystalline cellulose, 1.02% calcium stearate and 2.00% colloidal silicon dioxide, wherein the rapid release compositions are free from binders and disintegrants.

In another aspect, the storage-stable, rapid release compositions comprising of a granular component and an extra-granular component, wherein granular component comprises of 7.91% amifampridine phosphate and 78.65% microcrystalline cellulose and wherein the extra-granular component comprise of 10.42% microcrystalline cellulose, 1.02% calcium stearate and 2.00% colloidal silicon dioxide, wherein the rapid release compositions are free from binders and disintegrants.

Lubricant(s) may be present in concentrations ranging from about 0.25% to about 5% by weight of the composition and are selected from those known in the art such as magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, sodium benzoate, palmitic acid, talc, and glyceryl behenate.

Glidant(s) may be present in concentrations ranging from about 0.1% to about 5% by weight of the composition and are selected from those known in the art such as colloidal silicon dioxide, hydrated silicon dioxide, light anhydrous silicic acid, aluminum silicate, titanium oxide, stearic acid, and talc.

The storage-stable, rapid release compositions comprising amifampridine phosphate may optionally be film coated with a film-coating layer comprising film-coating materials and optionally one or more pharmaceutically acceptable excipients selected from plasticizers, colorants, pigments, glidants, lubricants or mixtures thereof. The film coating materials are selected from those known in the art.

In another aspect, the storage-stable, rapid release compositions consist essentially of amifampridine phosphate, at least one diluent, at least one lubricant and at least one glidant.

In another aspect, the storage-stable, rapid release compositions consist essentially of amifampridine phosphate, at least one diluent, at least one lubricant and at least one glidant, wherein the diluent is microcrystalline cellulose, the lubricant is calcium stearate and the glidant is colloidal silicon dioxide.

In another aspect, the storage-stable, rapid release compositions consist of amifampridine phosphate, microcrystalline cellulose, calcium stearate and colloidal silicon dioxide.

In another aspect, the storage-stable, rapid release compositions consist of a granular component and an extra-granular component, wherein granular component comprising amifampridine phosphate and microcrystalline cellulose; wherein the extra-granular component comprises of at least one diluent, at least one lubricant and at least one glidant.

In another aspect, the storage-stable, rapid release compositions consist of a granular component and an extra-granular component, wherein granular component consist of amifampridine phosphate and microcrystalline cellulose; wherein the extra-granular component consist of at least one diluent, at least one lubricant and at least one glidant.

In another aspect, the storage-stable, rapid release compositions consist of a granular component and an extra-granular component, wherein granular component consist of amifampridine phosphate and microcrystalline cellulose; wherein the extra-granular component consist of microcrystalline cellulose, calcium stearate and colloidal silicon dioxide.

In another aspect, the storage-stable, rapid release compositions consist of a granular component and an extra-granular component, wherein granular component consist of 7.91% amifampridine phosphate and 74.17% microcrystalline cellulose; wherein the extra-granular component consist of 14.90% microcrystalline cellulose, 1.02% calcium stearate and 2.00% colloidal silicon dioxide.

In another aspect, the storage-stable, rapid release compositions consist of a granular component and an extra-granular component, wherein granular component consist of 7.91% amifampridine phosphate and 78.65% microcrystalline cellulose; wherein the extra-granular component consist of 10.42% microcrystalline cellulose, 1.02% calcium stearate and 2.00% colloidal silicon dioxide.

The storage-stable, rapid release compositions of amifampridine phosphate are manufactured by a process which comprises the step of granulation.

The process step of granulation provides the granular component of the storage-stable, rapid release composition comprising amifampridine phosphate.

Granulation can be carried out by wet granulation, dry granulation, fluidized bed granulation, rapid mixer granulation, high-shear mixer granulation, centrifugal wet granulation, steam granulation, spray drying granulation, melt granulation, melt extrusion, freeze-granulation, thermal adhesion granulation, foam granulation, pneumatic dry granulation, moisture-activated dry granulation, roll compaction, slug compaction, co-milling, co-crystallization, solvent evaporation, or co-precipitation, or a combination thereof.

In an aspect, the manufacturing process step of granulation comprises adding a granulation liquid to a dry mixture.

Granulation liquid, used in the process step of granulation, comprises a solvent and optionally a binder, wherein the solvent may be selected from water, methanol, ethanol, isopropanol, acetone, dichloromethane, ethyl acetate, or mixtures thereof. In yet another embodiment, the solvent is water.

In an embodiment, the granulation liquid comprises a hydro-alcoholic solvent system, such as a mixture of water and isopropanol, or a mixture of water and methanol, or a mixture of water and ethanol. In another embodiment, the granulation liquid comprises an alcoholic and/or organic solvent system, such as a mixture of isopropanol and dichloromethane, or a mixture of ethanol and dichloromethane, or a mixture of ethanol and isopropanol. In yet another embodiment, the granulation liquid consists of water.

In an aspect, the granulation liquid, used in the process step of granulation, comprises amifampridine phosphate. In another aspect, the granulation liquid comprises amifampridine phosphate and at least one solvent, wherein amifampridine phosphate is dissolved or dispersed in the solvent.

In a preferred aspect, the granulation liquid comprises amifampridine phosphate and water as the solvent.

In yet another aspect, the granular component is manufactured by a process comprising the step of granulation of a dry mixture with a granulation liquid, wherein the granulation liquid comprises amifampridine phosphate.

In yet another aspect, the granular component is manufactured by a process comprising the step of granulation of a dry mixture with a granulation liquid, wherein the granulation liquid comprises amifampridine phosphate and at least one solvent.

In another aspect, the granular component is manufactured by a process comprising the step of granulation of a dry mixture with a granulation liquid, wherein the granulation liquid comprises amifampridine phosphate and water as the solvent.

In another aspect, the granular component is manufactured by a process comprising the step of granulation of a dry mixture with a granulation liquid, wherein the granulation liquid consists of amifampridine phosphate and a solvent.

In yet another aspect, the granular component is manufactured by a process comprising the step of granulation of a dry mixture with a granulation liquid, wherein the granulation liquid comprises amifampridine phosphate and at least one solvent and is free of binder.

In another aspect, the dry mixture, used in the process step of granulation, comprises amifampridine phosphate. In yet another aspect, the dry mixture, used in the process step of granulation, comprises at least one excipient.

In yet another aspect, the granular component is manufactured by a process comprising the step of granulation of a dry mixture with a granulation liquid, wherein the dry mixture comprises amifampridine phosphate.

In yet another aspect, the granular component is manufactured by a process comprising the step of granulation of a dry mixture with a granulation liquid, wherein the dry mixture comprises amifampridine phosphate and at least one excipient.

In yet another aspect, the granular component is manufactured by a process comprising the step of granulation of a dry mixture with a granulation liquid, wherein the dry mixture comprises amifampridine phosphate and at least one diluent.

In yet another aspect, the granular component is manufactured by a process comprising the step of granulation of a dry mixture with a granulation liquid, wherein the dry mixture consists of amifampridine phosphate and a diluent.

In yet another aspect, the granulation liquid comprises amifampridine phosphate, wherein amifampridine phosphate is dissolved or dispersed in the granulation liquid.

Process for preparing storage-stable, rapid release compositions of amifampridine phosphate further comprise one or more of steps selected from sifting, blending, milling, screening, drying, compression into tablets, and filling into capsules/sachets.

The process for preparing storage-stable, rapid release compositions of amifampridine phosphate comprise one or more of the steps selected from:
(i) preparing a granular component;
(ii) preparing an extra-granular component;
(iii) blending the granular component and extra-granular component; and
(iv) compressing the granular component from step i) or the blend from step iii) into tablets, or filling the granular component from step i) or the blend from step iii) into capsules/sachets.

In another aspect, the granular component is prepared using one or more of the following steps:
(i) sifting and dry mixing one or more excipients;
(ii) preparing a granulation liquid comprising amifampridine phosphate and at least one solvent;
(iii) granulating the dry mix from step (i) with the granulation liquid of step (ii);
(iv) wet-sizing, drying and dry-sizing the granules from step (iii) to give the granular component.

In another aspect, the granular component is prepared using one or more of the following steps:
(i) sifting and dry mixing one or more excipients selected from diluents, disintegrants, and binders;
(ii) preparing a granulation liquid comprising amifampridine phosphate and at least one solvent;
(iii) granulating the dry mix from step (i) with the granulation liquid of step (ii);
(iv) wet-sizing, drying and dry-sizing the granules from step (iii) to give the granular component.

In another aspect, the granular component is prepared using one or more of the following steps:
(i) sifting and dry mixing one or more diluents;
(ii) preparing a granulation liquid comprising amifampridine phosphate and at least one solvent;
(iii) granulating the dry mix from step (i) with the granulation liquid of step (ii);
(iv) wet-sizing, drying and dry-sizing the granules from step (iii) to give the granular component.

In an aspect, the granular component is prepared using one or more of the following steps:
a) sifting excipient(s), and optionally blending the excipient(s);
b) preparing the granulation liquid by dispersing or dissolving amifampridine phosphate and optionally a binder in a solvent;
c) adding the granulation liquid from step b) to the excipient(s) or blend from step a), and mixing to provide granules;
d) optionally wet-sizing the granules from step c);
e) drying the granules;
f) dry-sizing the granules from step e) and sifting, to provide the granular component.

In another aspect, the granular component is prepared using one or more of the following steps:
a) sifting amifampridine phosphate and excipient(s);
b) blending amifampridine phosphate and excipient(s);
c) adding a granulation liquid to the blend from step b), and mixing to provide granules;
d) optionally wet-sizing the granules from step c);
e) drying the granules;
f) dry-sizing the granules from step e) and sifting, to provide the granular component

In another aspect, the granular component is prepared using one or more of the following steps:
a) sifting amifampridine phosphate and excipient(s);
b) blending amifampridine phosphate and excipient(s);
c) dry granulating the blend from step b) by compaction using a roller compacter to provide ribbons;
d) milling the ribbons obtained from step c) to provide granules;
e) dry-sizing and/or sifting the granules from step d), to provide the granular component.

In an aspect, the extra-granular component is prepared using one or more of the following steps:
a) sifting at least one excipient selected from diluent(s), disintegrant(s), binder(s), lubricant(s), glidant(s), and surfactant(s);
b) optionally blending the excipients.

In an aspect, a tablet composition is prepared by blending the granular component and extra-granular component, and compressing the blend into tablets. In another aspect, a capsule composition is prepared by blending the granular component and extra-granular component, and filling the blend into capsules.

The storage-stable, rapid release compositions are evaluated in terms of amifampridine content, blend uniformity, content uniformity, dissolution, and total impurities.

Amifampridine content (assay): Percentage of amifampridine content in the compositions, as determined by liquid chromatography, ranges from about 90% to about 110%, preferably from about 95% to about 105% of the label claim.

Blend Uniformity: Blend analysis was conducted on the lubricated blend by sampling from 3-10 different locations of the blender (including top, middle, and bottom locations) using a unit dose sampler. Acceptance criteria is that the % amifampridine content of individual sample should be between 85.0% to 115.0% of labeled amount, and average % amifampridine content of individual samples should be between 90.0% to 110.0% of labeled amount, and relative standard deviation should not be more than 5.0%.

Content Uniformity: Content Uniformity was carried out by sampling the rapid release compositions at least 3 equally distributed time-points during the compression/filling cycle. Acceptance criteria is that the average % amifampridine content of compositions at each time-point is 90%-110% of the target content, and % amifampridine content of individual composition at each time-point is 75%-125% of the target content.

Dissolution: Dissolution of amifampridine from the rapid release compositions is studied in the following conditions and dissolution calculated in terms of average cumulative percentage dissolution of amifampridine at various time-points.
(i) Dissolution Condition 1: in 900ml of 0.01N hydrochloric acid using USP – Type II (Paddle) apparatus at 75 rpm
(ii) Dissolution Condition 3: 900ml of 0.1N hydrochloric acid using USP – Type II (Paddle) apparatus at 75 rpm
(iii) Dissolution Condition 4: 900ml of pH 4.5 acetate buffer using USP – Type II (Paddle) apparatus at 75 rpm
(iv) Dissolution Condition 5: 900ml of pH 6.8 phosphate buffer using USP – Type II (Paddle) apparatus at 75 rpm

Dissolution of amifampridine, from the rapid release compositions of the present invention, is not less than 90% in 45 minutes, preferably not less than 90% in 30 minutes, preferably not less than 85% in 15 minutes. In an aspect, the dissolution is not less than 85% in 20 minutes, preferably not less than 80% in 15 minutes, and more preferably not less than 75% in 10 minutes.

Total impurities: Percentage of total impurities in the rapid release compositions, as determined by liquid chromatography, is not more than 2%, preferably not more than 1%, more preferably not more than 0.5%, and most preferably not more than 0.2%.

Storage stability of rapid release compositions of the present invention was studied in one or more of the following conditions:
• Accelerated Storage Conditions:
400C±20C temperature and 75%±5 % relative humidity (400C/75%RH)
• Room Temperature Storage Conditions:
250C±20C temperature and 60%±5 % relative humidity (250C/60%RH)
300C±20C temperature and 75%±5 % relative humidity (300C/75%RH)
300C±20C temperature and 65%±5 % relative humidity (300C/65%RH)

After specific time periods of storage, the rapid release compositions were analyzed for % amifampridine content, % total impurities and average cumulative % dissolution of amifampridine.

The invention is now illustrated with non – limiting examples.

Comparative Example 1: Directly compressed amifampridine phosphate tablets 10 mg
Amifampridine phosphate (7.9%w/w) and microcrystalline cellulose 200 (89.07%w/w) were blended and co-sifted through 40 mesh ASTM. The mixture was mixed in a blender at about 15 rpm for about 15 minutes, to give a first blend. Colloidal silicon dioxide (1.02%w/w) was sifted through 40 mesh ASTM and mixed with the first blend, in a blender at about 15 rpm for about 5 minutes, to give a second blend. Calcium stearate (0.5%w/w) was sifted through 40 mesh ASTM and mixed with the second blend, in a blender at about 15 rpm for about 2 minutes, to give the lubricated blend. The lubricated blend was directly compressed into tablets using 9 mm, round, standard concave punch tooling.

Example 2: Table 1 provides the formulation details of storage-stable, rapid release compositions of Amifampridine Phosphate (10mg) comprising a granular and an extra-granular component.

Table 1: Formulation details of storage-stable, rapid release compositions of Amifampridine Phosphate
Ingredients in the Composition Quantity
(% w/w of composition)
Example 2A Example 2B
Granular Component
Microcrystalline cellulose 74.17% 78.65%
Amifampridine phosphate (equivalent to 10mg of amifampridine) 7.91% 7.91%
Extra-granular Component
Microcrystalline cellulose 14.90% 10.42%
Colloidal silicon dioxide 1.02% 1.02%
Calcium stearate 2.00% 2.00%

Example 3: Storage-stable, rapid release compositions of Example 2A and Example 2B, were manufactured using the following process:
Granular Component: Microcrystalline cellulose and amifampridine phosphate were sifted through 40 mesh ASTM and blended to give a dry mixture. Water (granulation liquid) was added to the dry mixture and mixed for about 5 minutes to give granules. The granules were dried till the loss on drying was about 2-5% was achieved and the dried granules sifted through 20 mesh ASTM, to provide the Granular Component.
Extra-granular Component: Microcrystalline cellulose and colloidal silicon dioxide were sifted through 40 mesh ASTM and blended with the granular component for about 15 minutes. Further, calcium stearate (sifted through 60 mesh ASTM) was added and blended for about 5 minutes to provide the Lubricated Blend.
Tablet Composition: The Lubricated Blend was compressed into tablets using 9 mm, round, standard concave punch tooling.

Example 4: Storage-stable, rapid release compositions of Example 2A and Example 2B, were manufactured using the following process:
Granular Component: Microcrystalline cellulose (MCC) was sifted through 40 mesh ASTM. Amifampridine phosphate was added to purified water, under stirring, to prepare the granulation liquid. The granulation liquid was added to the sifted microcrystalline cellulose and mixed for about 5 minutes to give granules. The granules were dried till the loss on drying of about 3.5% was achieved, and the dried granules sifted through 20 mesh ASTM, to provide the granular component.

Extra-granular component and Tablet Composition was prepared in accordance with the process provided in Example 3.

Example 5: Storage-stable, rapid release compositions of Example 2A and Example 2B, were manufactured using the following process:
Granular Component: Microcrystalline cellulose was sifted through 40 mesh ASTM. Amifampridine phosphate was added, under stirring, to a hydro-alcoholic solvent system of purified water and isopropanol, to prepare the granulation liquid. The granulation liquid was added to the sifted microcrystalline cellulose and mixed for about 5 minutes to give granules. The granules were dried and sifted through 20 mesh ASTM, to provide the granular component.

Extra-granular Component and Tablet Composition was prepared in accordance with the process provided in Example 3.

Example 6: Storage-stable, rapid release compositions of Example 2A and Example 2B, were manufactured using the following process:
Granular Component: Microcrystalline cellulose and amifampridine phosphate were sifted through 40 mesh ASTM and blended to give a dry mixture. The blend was dry granulated by compaction using a roller compacter to provide ribbons, and the ribbons milled to provide granules. The granules were sifted through 20 mesh ASTM, to provide the granular component.
Extra-granular Component and Tablet Composition was prepared in accordance with the process provided in Example 3.

Evaluation:
Blend Uniformity: Lubricated blend of Example 2B was evaluated for blend uniformity at three locations at the top (T1, T2, T3), three locations in the middle (M1, M2, M3) and four locations at the bottom (B1, B2, B3, B4), of the blender. The results are provided in Table 2.
Table 2: Blend Uniformity of Lubricated blend of Example 2B
Example T1 T2 T3 M1 M2 M3 B1 B2 B3 B4
% Content 96.0 98.2 98.2 97.9 99.7 96.9 94.9 98.2 97.5 97.7
Average 97.5 %
RSD 1.4

Content Uniformity: Content Uniformity of amifampridine tablets of Example 2A and 2B were evaluated and compared with the Content Uniformity of Comparative Example 1. The results are provided in Table 3.

Table 3: Content Uniformity of Comparative Example 1, Example 2A and Example 2B

Example Comparative Example 1 Example 2A Example 2B
Average Assay 78% 98.2% 96.7%
Assay Range 54.8%-100.5% 97.7%-98.6% 94.1%-98.2%

Dissolution: Dissolution study of amifampridine tablets of Example 2A and 2B was studied under different dissolution conditions. The results are provided in Table 4.

Table 4: Dissolution Study of Tablets of Example 2A and Example 2B
Example Dissolution Condition Average Cumulative % Dissolution of Amifampridine
15 min 30 min
Example 2A Condition 1 (0.01N HCl) 96 96
Example 2B Condition 1 (0.01N HCl) 86 95
Condition 2 (0.1N HCl) 85 96
Condition 3 (pH 4.5) 81 92
Condition 4 (pH 6.8) 78 92

Storage Stability: Tablets of Example 2B were packed in HDPE Bottle with 1g silica gel packs, and PVC-PVDC blister packs, and subjected to accelerated and room-temperature storage conditions. After 6 months of storage the tablets were analyzed for amifampridine content, total impurities, and dissolution. The results of storage stability are provided in Table 5.

Table 5: Storage Stability of tablets of Example 2B after 6 months
Condition % Amifampridine Content % Total Impurities Average Cumulative % Dissolution of Amifampridine at 30 minutes
Initial 97.4 0 95
HDPE Bottle with 1g silica gel Pack
40°C/75% RH 95.8 BQL 90
30°C/75%RH 97.4 BQL 92
25°C/60% RH 97.4 BQL 93
PVC/PVDC Blister Pack
40°C/75% RH 94.9 BQL 85
30°C/75% RH 96.0 BQL 91
30°C/65% RH 95.8 BQL 92
25°C/60% RH 96.6 BQL 92
BQL=Below Quantification Limit

Thus, the storage-stable, rapid release compositions of the present invention, comprising a granular component, wherein the granular component comprises amifampridine phosphate, was found to provide the desired blend uniformity, content uniformity, dissolution, and storage stability.
,CLAIMS:1. A storage-stable, rapid release composition of amifampridine phosphate, wherein the composition comprises a granular component and an extra-granular component; wherein the granular component comprises amifampridine phosphate from 2% to 40% by weight of the composition.

2. The storage-stable rapid release composition as claimed in claim 1, wherein the granular component ranges from about 50% to about 99.5% by weight of the composition and the extra-granular component ranges from about 0.5% to about 50% by weight of the composition.

3. The storage-stable composition as claimed in claim 1, wherein the composition further comprises at least one excipient selected from diluents, lubricants, glidants, surfactants, film-forming agents, and plasticizers.

4. The storage-stable rapid release composition as claimed in claim 1, wherein the granular component comprises amifampridine phosphate and microcrystalline cellulose and the extra-granular component comprises of microcrystalline cellulose, calcium stearate and colloidal silicon dioxide.

5. The storage-stable rapid release composition as claimed in claim 1, wherein the composition comprises of a granular component and an extra-granular component, wherein granular component comprises of 7% to 9% amifampridine phosphate and 72% to 75% microcrystalline cellulose and the extra-granular component comprises of 14% to 16% microcrystalline cellulose, 0.5% to 1.5% calcium stearate and 1.5% to 2.5% colloidal silicon dioxide.

6. The storage-stable rapid release composition as claimed in claim 1, wherein the composition comprises of a granular component and an extra-granular component, wherein the granular component comprises amifampridine phosphate and microcrystalline cellulose; and
the extra-granular component comprises of microcrystalline cellulose, calcium stearate and colloidal silicon dioxide,
wherein the storage-stable composition is free of binders.

7. The storage-stable rapid release composition as claimed in claim 1, wherein storage-stable rapid release composition comprises of a granular component and an extra-granular component, wherein the granular component comprises amifampridine phosphate and microcrystalline cellulose; and
the extra-granular component comprises of microcrystalline cellulose, calcium stearate and colloidal silicon dioxide,
wherein the storage-stable composition is free of disintegrants.

8. A process for preparing storage-stable, rapid release compositions of amifampridine phosphate, comprising one or more of the steps selected from:
(i) preparing a granular component,
(ii) preparing an extra-granular component,
(iii) blending the granular component and extra-granular component, and
iv) compressing the granular component from step i) or the blend
from step iii) into tablets, or filling the granular component from
step i) or the blend from step iii) into capsules/sachets.

9. The process as claimed in claim 8, wherein the preparation of the compositions comprises steps of:
(i) preparing a granular component by wet granulating amifampridine phosphate and diluent;
(ii) preparing an extra-granular component comprising of diluent lubricant and glidant;
(iii) blending the granular component and the extra-granular component; and
(iv) compressing the resultant blend into tablet.

10. The process as claimed in claim 9, wherein the diluent is selected microcrystalline cellulose, lubricant is calcium stearate and glidant is colloidal silicon dioxide.