Claims:1. A stable extended release pharmaceutical composition comprising Dalfampridine or salts thereof, wherein the composition is free of cellulosic diluents.

2. The stable pharmaceutical composition as claimed in claim 1, wherein the composition comprises atleast one rate-controlling polymer, atleast one non-cellulosic diluent and one or more pharmaceutically acceptable excipients.

3. A stable extended release pharmaceutical composition comprising Dalfampridine or salts thereof, atleast one rate-controlling polymer,atleast one non-cellulosic diluent, andone or more pharmaceutically acceptable excipients.

4. The stable pharmaceutical composition as claimed in claim 3, wherein the composition is free of any cellulosic diluents.

5. The stable pharmaceutical composition as claimed in claim 2 and 3, wherein the rate-controlling polymer is one or more of a hydrophilic polymer, a hydrophobic polymer or a combination thereof.

6. The stable pharmaceutical composition as claimed in claim 5, wherein the hydrophilic polymer comprises one or more of hydroxypropylcellulose, hydroxypropylmethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, cellulosic derivatives, vinyl acetate copolymers, polyethylene oxide, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives, xanthan gum, karaya gum, locust bean gum, guar gum, gelan gum, gum arabic, tragacanth, carrageenan, pectin, carboxymethyl cellulose, agar, alginic acid, sodium alginate,polyvinylpyrrolidine, and mixtures thereof.

7. The stable pharmaceutical composition as claimed in claim 2 and 3, wherein the non-cellulosic diluent is selected from the group consisting of dibasic calcium hydrogen phosphate, tricalcium phosphate, anhydrous calcium phosphate, magnesium aluminium silicates, sucrose derivatives, Polysaccharides, lactose and mannitol and mixtures thereof.

8. The stable pharmaceutical composition as claimed in claim 2 and 3, wherein the pharmaceutically acceptable excipients are selected from binders, lubricants, disintegrants, glidants or combinations thereof.

9. The stable pharmaceutical composition as claimed in claim 1 and 3, wherein the composition exhibits no significant difference in rate and/or extent of absorption of Dalfampridine as compared to extended release formulation commercially marketed under the trade name AMPYRA®.

10. The stable pharmaceutical composition as claimed in claim 1 and 3, wherein the composition contains less than 1.5% of total impurities by weight of Dalfampridine or salts thereof, when stored at 40 0C./75% RH for 3 months.
, Description:FIELD OF THE INVENTION
The present invention relates to stable extended release pharmaceutical compositions of Dalfampridine or salts thereof. The invention also relates to processes for the preparation of such compositions and use thereof for treatment of symptoms of multiple sclerosis (MS) and other neurological disorders.

BACKGROUND OF THE INVENTION
Dalfampridine, also named as 4-aminopyridine, 4-AP, or fampridine, is an organic compound with the chemical formula C5H4N—NH2. It is used as a research tool, in characterizing subtypes of the potassium channel. It has also been used as a drug, to manage some of the symptoms of multiple sclerosis (MS), and is indicated for symptomatic improvement of walking in adults with several variations of the disease.

The approved drug product in the United States, AMPYRA®, is an extended release tablet designed for twice-daily oral administration. Each tablet contains 10 mg active pharmaceutical ingredient which is Dalfampridine and comprises a rate-controlling polymeric matrix comprising of a hydrogel matrix, such as hydroxypropyl methylcellulose, which, when wet, swells to form a hydrogel thus the rate of release of Dalfampridine from the dosage formulation is sustained both by diffusion from the swollen tablet mass and by erosion of the tablet surface over time. The rate of release of Dalfampridine may be controlled both by the amount of polymer per tablet and by the inherent viscosities of the polymers used.

Multiple Sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS) with both inflammatory and degenerative components. It is the most common neurologic, disabling disease in young adults (Frohman, 2003, The Medical Clinics of North America, 87(4): 867-897, viii-ix). Permanent neurological dysfunction can result from incomplete recovery from acute relapses or as a consequence of slow progression of disability. Overall, about 75-85% of MS individuals have some degree of ambulatory impairment and over half need assistance both indoors and outdoors (Kraft et al., 1986, Arch Phys Med Rehabil 67: 164-168; Weinshenker et al, 1989, Brain 112: 133-146). More than one third do not retain the ability to walk 20 years after the diagnosis (Schapiro, 1991, A Rehabilitation Approach to Management, Demos, New York).
Dalfampridine is known in the art for its potency in improving walking capacity in patients with multiple sclerosis. However, compositions comprising Dalfampridine have been reported to exhibit substantial degradation upon storage. It is believed that the drug reacts with some of the excipients present in the formulation leading to increase in the level of the impurities as well as formation of unidentified impurities during storage.

US20170071923A1provides a sustained release oral dosage form containing Dalfampridine that can be administered once daily. The dosage form includes Dalfampridine as the active pharmaceutical ingredient and the excipients comprising osmotic agents in a tablet core.

WO2017058869A1 discloses sustained release 4-aminopyridine tablets, which include a core and a coating. The sustained release tablets of the invention are generally suitable for once daily oral administration for the treatment of neurological disorders.

CN106551914A relates to a sustained release tablet comprising a Dalfampridine-containing tablet core, wherein the Dalfampridine-containing tablet core comprises of an adhesive agent, which results in a simple formulation with uniform drug content.

The prior art references emphasize on the development pharmaceutical compositions of Dalfampridine with improved release profile suitable for once daily administration, however, there is no disclosure or teaching/suggestion in the art about how to develop commercially viable formulations of Dalfampridine with improved stability.

Therefore, it would be desirable to develop new pharmaceutical compositions comprising Dalfampridine that are more stable against degradation over storage period and simultaneously, provide desired extended release of the drug

Surprisingly, it has been found that stable extended release dosage form of Dalfampridine can be prepared using non-cellulosic diluents, that upon storage, exhibits an impurity profile that is within desired levels and at the same time is bioequivalent to the marketed formulation.

SUMMARY OF THE INVENTION

Anobject of the present invention is to provide stable extended release pharmaceutical dosage forms comprising a therapeutically effective amount of Dalfampridine and exhibiting improved impurity profile upon storage.

Another object of the present invention is to provide stable extended release pharmaceutical dosage forms, comprising a therapeutically effective amount of Dalfampridine, free of cellulosic diluents; and exhibiting improved impurity profile upon storage.

Yet another object of the invention is to provide stable extended release pharmaceutical dosage forms, free of cellulosic diluents, and comprising a therapeutically effective amount of Dalfampridine, atleast onerate-controlling polymer, atleastone non-cellulosic diluent, and optionally one or more pharmaceutically acceptable excipients; and exhibiting improved impurity profile upon storage.

Another object of the invention is to provide stable extended release pharmaceutical dosage forms, free of cellulosic diluents, and comprising a therapeutically effective amount of Dalfampridine, atleast one rate-controlling polymer, atleast one non-cellulosic diluent, and optionally one or more pharmaceutically acceptable excipients, characterized in that the extended release pharmaceutical compositions of the present invention are bioequivalent to the marketed formulation and exhibit improved impurity profile upon storage.

Further, another object of the invention is to provide stable extended release pharmaceutical dosage forms, free of cellulosic diluents, and comprising a therapeutically effective amount of Dalfampridine, atleast one rate-controlling polymer, atleast one non-cellulosic diluent, and optionally one or more pharmaceutically acceptable excipients, wherein about 20% to about 40% of said Dalfampridine is released after 2 hours; from about 45% to about 65% of said Dalfampridine is released after 8 hours; not less than about 70% of said Dalfampridine is released after 24 hours.

Yet another object of the invention is to provide a simple and cost-effective method for preparation of stable extended release pharmaceutical dosage forms comprising a therapeutically effective amount of Dalfampridine.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides to stable extended release pharmaceutical dosage forms comprising a therapeutically effective amount of Dalfampridine and methods of preparing the same.
The term “Dalfampridine” used throughout the specification refers to Dalfampridine, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.
Typically, the pharmaceutical compositions of the present invention comprise the Dalfampridine in an amount equivalent to 0.5 to 20 mg, preferably 5 to 15 mg of Dalfampridine.
The term “stable” as used herein refers to physical stability and/or chemical stability of the active agent in a topical composition, wherein changes in the drug assay values and/or impurities content are less than about 10%, during stability study storage of the composition at 25° C. and 60% relative humidity (RH), or 30° C. and 65% RH, or 40° C. and 75% RH, for durations such as 3, 6, 12, 18, or 24 months.
The term "extended release" as used herein in relation to the dosage form means which is not immediate release and is taken to encompass controlled release, prolonged release, timed release, retarded release, sustained release and delayed release. Extended release can be used interchangeably with prolonged release, programmed release, timed release, sustained release, controlled release and other such dosage forms.

The "dosage form" according to the present invention include but is not limited to tablets, pellets, beads, granules, capsules, microcapsules and tablets in capsules.

"Therapeutically effective amount" means that the amount of active agent, which halts or reduces the progress of the condition being treated or which otherwise completely or partly cures or acts palliatively on the condition. A person skilled in the art can easily determine such an amount by routine experimentation and with an undue burden.

Dalfampridine is believed to react with cellulosic diluents, which jeopardizes the stability of the composition and leads to increased formation of impurities; thus by avoiding the use of cellulosic diluents, the present invention provides an improved product with better stability and release profile.

An embodiment of the present invention provides stable extended release pharmaceutical dosage forms, comprising a therapeutically effective amount of Dalfampridine, free of cellulosic diluents; and exhibiting improved impurity profile upon storage.

Another embodiment of the present invention provides stable extended release pharmaceutical dosage forms, comprising a therapeutically effective amount of Dalfampridine, atleast one rate-controlling polymer, atleast one non-cellulosic diluent, and optionally one or more pharmaceutically acceptable excipients, and exhibiting improved impurity profile upon storage.

Accordingly, rate-controlling polymers suitable for use in the present invention may include one or more of hydrophilic and hydrophobic polymers or mixtures thereof.

Suitable hydrophilic polymers may include one or more of hydroxypropylcellulose, hydroxypropylmethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, cellulosic derivatives, vinyl acetate copolymers, polyethylene oxide, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives, Eudragit RS, Eudragit RL, xanthan gum, karaya gum, locust bean gum, guar gum, gelan gum, gum arabic, tragacanth, carrageenan,pectin, carboxymethyl cellulose, agar, alginic acid, sodium alginate,polyvinylpyrrolidine, and mixtures thereof.The preferred hydrophilic polymer is hydroxypropyl methylcellulose or any commercially available grade thereof such as Methocel.

Suitable hydrophobic polymers include one or more of ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil, glycerol monostearate, stearylalcohol, glyceryl behenate, polyanhydrides, methyl acrylates and the like.

Typically, the rate-controlling polymers are present in the formulations of the present invention in an amount ranging from about 5 to about 90 wt. %; preferably from about 20 to about 75 wt.%.

Suitable non-cellulosic diluent may include, but are not limited to one or more of dibasic calcium hydrogen phosphate, tricalcium phosphate, anhydrous calcium phosphate, magnesium aluminium silicates, Sucrose derivatives, Polysaccharides, lactose and mannitol and mixtures thereof. The preferred diluent is dibasic calcium phosphate.

Typically, the non-cellulosic diluents are present in the formulations of the present invention in an amount ranging from about 20 to about 60 wt. %; preferably from about 30 to about 50 wt.%.

"Optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optionally pharmaceutical excipients" indicates that a formulation so described may or may not include pharmaceutical excipients other than those specifically stated to be present, and that the formulation so described includes instances in which the optional excipients are present and instances in which they are not.

The pharmaceutical dosage forms of the present invention may comprise additional pharmaceutically acceptable excipients selected from the group consisting lubricants, disintegrants, binders, glidants, colorants, sweeteners, plasticizers and the like.

Suitable lubricants and glidants may include one or more of talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, powdered cellulose, starch, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate, kaolin; and the like. Preferred lubricants for use in the present invention are talc and magnesium stearate. The amount of lubricant in the composition ranges from 0.1% to 3% w/w of composition.

Suitable disintegrants may include, but not limited to one or more of croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone and the like.

Suitable binders may include one or more of hydroxyethyl cellulose, hydroxypropyl cellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone (e.g. Povidone K 30), pregelatinized starch, sodium alginate, gums, synthetic resins and the like. Preferred binder for use in the present invention is polyvinyl pyrrolidone.

Suitable plasticizers may include, but not limited to one or more of polyols such as glycerol, propylene glycol, polyethylene glycol (PEG), urea, or other known plasticizers such as triethyl citrate, dibutyl+ or dimethyl phthalate or water.
Another embodiment of the present invention provides a simple and cost-effective method for preparation of stable extended release pharmaceutical dosage forms comprising a therapeutically effective amount of Dalfampridine.

The pharmaceutical compositions of the present invention can be prepared by various methods known in the art such as by dry granulation, wet granulation, melt granulation, direct compression, double compression, extrusion spheronization, layering and the like.

Extended release pharmaceutical dosage forms according to the present invention are manufacturedpreferably as per the following procedure:
i) Blending the active agent, rate-controlling polymer(s), non-cellulosic diluent (s) and one or more pharmaceutically acceptable excipient(s),
ii) Subjecting the blend to lubrication,
iii) Compressing the lubricated blend into suitable dosage form.

The pharmaceutical dosage forms of the invention may further be coated. The coating may be a functional or non-functional coating. The preferred coating of this invention is comprised of a commercial film-coating product designed for aqueous film coating containing the water-soluble, film-forming resin, such a product is commercially available under the trade name Opadry White.
These coating comprises one or more excipients selected from the group comprising coating agents, opacifiers, fillers, polishing agents, colouring agents, antitacking agents and the like.

Present invention further provides a method of treating multiple sclerosis or a symptom thereof in a subject in need thereof, the method comprises administering an extended release pharmaceutical composition comprising Dalfampridine or salts thereof as substantially described herein before.

The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations changes may be made by those skilled in the art, without departing from the spirit of the invention.

The following examples further illustrate the invention but should not be construed as in any way limiting its scope. In particular, the processing conditions are merely exemplary and can be readily varied by one of ordinary skill in the art.

Examples:
Example 1: Extended release tabletsof Dalfampridine by direct compression method

Component % w/w
Dalfampridine 2.5
Hydroxypropyl methyl cellulose 60.0
Calcium hydrogen phosphate 36.5
Colloidal silicon dioxide 0.4
Magnesium Stearate 0.2
Opadry 0.4
Purified water Q.S.

Procedure:
Mixture of Dalfampridine,hydroxypropyl methyl cellulose, calcium hydrogen phosphate and colloidal silicon dioxidewas lubricated with magnesium stearate. The lubricated blend was then compressed into tablets. The tablets were finally coated with Opadry dispersion in purified water.

Example 2: Extended release composition of Dalfampridine by direct compression method

Component % w/w
Dalfampridine 2.5
Hydroxyethyl cellulose 46.0
Lactose monohydrate 49.9
Colloidal silicon dioxide 0.4
Magnesium Stearate 0.8
Opadry 0.4
Purified water Q.S.

Procedure:
Mixture of Dalfampridine, hydroxyethyl cellulose, lactose monohydrate and colloidal silicon dioxide was lubricated with magnesium stearate. The lubricated blend was then compressed into suitable solid oral dosage forms. The solid oral dosage forms were finally coated with Opadry dispersion in purified water.

Example 3: Extended release composition of Dalfampridine by direct compression method

Component % w/w
Dalfampridine 2.5
Polyvinyl acetate 38.0
Povidone 21.4
Lactose monohydrate 36.5
Colloidal silicon dioxide 0.4
Magnesium Stearate 0.8
Opadry 0.4
Purified water Q.S.

Procedure:
Mixture of Dalfampridine, polyvinyl acetate, povidone, lactose monohydrate and colloidal silicon dioxide was lubricated with magnesium stearate. The lubricated blend was then compressed into suitable solid oral dosage forms. The solid oral dosage forms were finally coated with Opadry dispersion in purified water.

Example 4: Extended release composition of Dalfampridine by dry granulation method

Component % w/w
Dalfampridine 2.5
Magnesium aluminometasilicate 4.8
Methyl cellulose 33.7
Lactose monohydrate 36.0
Colloidal silicon dioxide 0.4
Magnesium Stearate 0.8
Opadry 0.4
Purified water Q.S.

Procedure:
Mixture of Dalfampridine, magnesium aluminometasilicate, methyl cellulose, lactose monohydrate and colloidal silicon dioxide was granulated using a roller compactor and then lubricated with magnesium stearate. The lubricated granules were then compressed into suitable solid oral dosage forms. The solid oral dosage forms were finally coated with Opadry dispersion in purified water.

Example 5: Extended release composition of Dalfampridine by wet granulation method

Component % w/w
Dalfampridine 2.5
Hydroxypropyl cellulose 63.5
Lactose monohydrate 32.4
Colloidal silicon dioxide 0.4
Magnesium Stearate 0.8
Opadry 0.4
Purified water Q.S.

Procedure:
The dry mix material was granulated using a binder solution and dried. The dry granules were then lubricated and the lubricated granules were then compressed into suitable solid oral dosage forms. The solid oral dosage forms were finally coated with Opadry dispersion in purified water.

Example 6: Stability Data of Example 1
The stability study of this formulation was conducted at 40 0C. /75% RH over the period of 3 months.

The amount of the impurities measured in the formulation after the storage period indicates that the formulation of the invention is stable under stress conditions.

Pack: HDPE Bottle with desiccant canister
Test Specification with limits Time in Months
Initial 1 2 3
Related Substances Dalfampridine N-Oxide – NMT 0.2% w/w ND ND ND ND
3-Amino pyridine - NMT 0.2% w/w ND ND ND ND
2-Amino pyridine - NMT 0.2% w/w ND ND ND ND
Hydroxy Dalfampridine - NMT 0.2% w/w ND ND 0.02 ND
N,N'-di (4-piydinyl)metandiamina - NMT 2.0% w/w 0.12 0.16 0.19 0.26
Unknown – NMT 0.2% w/w ND 0.06 0.04 0.05
Total - NMT 2.5% w/w 0.12 0.22 0.25 0.27
ND: Not Detected; NMT: Not More Than

The amount of impurity refers to the percent by weight of Dalfampridine or salts thereof.

Pack: Blister pack
Test Specification with limits Time in Months
Initial 1 2 3
Related Substances Dalfampridine N-Oxide – NMT 0.2% w/w ND ND ND ND
3-Amino pyridine - NMT 0.2% w/w ND ND ND ND
2-Amino pyridine - NMT 0.2% w/w ND ND ND ND
Hydroxy Dalfampridine - NMT 0.2% w/w ND ND ND ND
N,N'-di (4-piydinyl)metandiamina - NMT 2.0% w/w 0.12 0.17 0.13 0.25
Unknown – NMT 0.2% w/w ND 0.05 0.13 0.06
Total - NMT 2.5% w/w 0.12 0.22 0.26 0.31
ND: Not Detected; NMT: Not More Than

The amount of impurity refers to the percent by weight of Dalfampridine or salts thereof.

Example 6: Stability Data of Comparative Example 1
A comparative formulation was prepared with the same excipients in similar quantities as used in Example 1; except for the diluents used in the formulations. In the comparative example, a cellulosic diluent, for example,microcrystalline cellulose, was used instead of non-cellulosic diluents.

The accelerated stability study of this formulation was conducted at40 0C. /75% RH over the period of 3 months.

The amount of the impurities measured in the formulation after the storage period indicates that the formulation is not stable under stress conditions.

Pack: HDPE Bottle with desiccant canister
Test Specification with limits Time in Months
Initial 1 2 3
Related Substances Dalfampridine N-Oxide – NMT 0.2% w/w ND ND ND ND
3-Amino pyridine - NMT 0.2% w/w ND ND ND ND
2-Amino pyridine - NMT 0.2% w/w ND ND ND ND
Hydroxy Dalfampridine - NMT 0.2% w/w ND ND ND ND
N,N'-di (4-piydinyl)metandiamina - NMT 2.0% w/w 0.08 0.18 0.28 0.26
Unknown – NMT 0.2% w/w ND 0.46 1.96 2.24
Total - NMT 2.5% w/w 0.08 0.64 2.24 2.5
ND: Not Detected; NMT: Not More Than

The amount of impurity refers to the percent by weight of Dalfampridine or salts thereof.