CLIAMS:We Claim:

1. A modified release pharmaceutical composition comprising at least one immediate release and at least one extended release component comprising methylphenidate or salts thereof, wherein the immediate release component is in the form of granules.

2. The modified release pharmaceutical composition of claim 1, wherein the granule comprises of methylphenidate or salts thereof and one or more pharmaceutically acceptable excipients.

3. The modified release pharmaceutical composition of claim 1, wherein extended release component comprises core particles coated with one or more layers of methylphenidate, which is further coated with one or more rate controlling substances.

4. The modified release pharmaceutical composition of claim 1, wherein extended release component comprises matrix of methylphenidate, one or more rate controlling substances.

5. The modified release pharmaceutical composition of claim 1, wherein the extended release component is in the form of beads.

6. The modified release pharmaceutical composition of claim 1, wherein the composition is bioequivalent to formulation of methylphenidate marketed under the trade name Metadate CD®.

7. A process for preparation of a modified release capsule, which process comprises steps of:
(a) mixing methylphenidate or salts thereof with one or more pharmaceutically acceptable excipients and granulating with a vehicle to form granules as an immediate release component;
(b) coating inert core particles with one or more layers comprising methylphenidate and one or more pharmaceutically acceptable excipients to form methylphenidate layered particles;
(c) coating a barrier layer over the methylphenidate layered particles;
(d) coating the methylphenidate layered particles with one or more layers comprising one or more rate controlling substances to form extended release component;
(e) filling the immediate release component prepared in step (a) and the extended release component prepared in step (a) in a capsule.

8. A hard gelatin capsule filled with granules comprising methylphenidate or salts thereof and one or more pharmaceutically acceptable excipients, and plurality of beads comprising core particles layered with a methylphenidate or salts thereof which is further coated with one or more rate controlling substances.

Dated this 28th day of March 2013 For Wockhardt Limited

(Dr. Mandar Kodgule)
Authorized Signatory
,TagSPECI:Description

The present invention relates to modified release pharmaceutical compositions of methylphenidate or salts thereof. In particular, the present invention relates to modified release pharmaceutical compositions comprising at least one immediate release and at least one extended release component of methylphenidate or salts thereof. The composition may provide extended and specific release of methylphenidate or salts thereof to achieve therapeutically effective plasma concentration over a period of 12 hours to treat attention deficit disorders when administered to a patient in need thereof. The invention also includes process of preparing such composition.

Methylphenidate Hydrochloride, a scheduled II controlled substance, is currently marketed as a mild central nervous system (CNS) stimulant and the drug of choice for treatment of Attention Deficit Disorder (ADD) and Attention Deficit Hyperactivity Disorder (ADHD) in children.

The drug is well absorbed throughout the gastrointestinal tract. However, it has an extremely short half-life, which necessitates a multi-dose treatment regimen for conventional (immediate release) dosage forms such as currently available 5, 10, and 20 mg tablets. Due to high Cmax, oral administration of 10 and 20 mg Ritalin® is reported to result in notable side effects such as anorexia, weight loss, dizziness, etc.

Furthermore, it requires the hyperactive children to be dosed in school thus causing hardship to school authorities as well as parents. The drawback of methylphenidate is that it also produces a euphoric effect when administered intravenously or through inhalation, thus presenting a high potential for substance abuse.

Sustained release formulations for once-a-day dosing, such as 20 mg Ritalin® tablets currently available from Novartis and Geneva (generic version), were developed with the objective of providing efficacy for 8 hours, thereby improving compliance and reducing the incidence of diversion. However, there are reports which strongly suggest that the sustained release formulations exhibit a slower onset of action/efficacy compared to the immediate release dosage forms.

Osmotic drug delivery based once-a day oral formulation of methylphenidate HCl is also available. The dosage form contains a drug overcoat that is designed to deliver a portion of the dose for rapid onset of action and deliver the remainder of the dose in a controlled manner for about 10 hours.

U.S. Patent No. 5,908,850 discloses a sustained release dosage form containing d-threo-methylphenidate (commonly known as dexmethylphenidate) or pharmaceutically acceptable salts thereof thus minimizing hyperactivity and side effects.

U.S. Patent No. 6,344,215 discloses a modified release dosage methylphenidate capsule comprising immediate and extended release beads, each prepared by layering over the core particles.

The formulations of methylphenidate known in the art are complicated dosage forms. Manufacturing cost of such dosage forms is expected to be very high and hence resulting in a high cost of treatment. Thus, there exist a dire need to develop modified release dosage forms of methylphenidate with moderate cost of goods and having not only a rapid onset of action but also with a significantly longer duration of action.

The present inventors have surprisingly found that it is possible to achieve therapeutically efficacious plasma concentrations with rapid onset of action and maintained it over a 12-hour period, thus eliminating the need to dose children in the school. These objectives can be achieved by devising a new modified release composition of methylphenidate containing both immediate and extended release components of methylphenidate, such that immediate release component of the composition is not in the form of core particles coated with layer of methylphenidate. The composition is simple and economical to manufacture and also involve less number of manufacturing steps.

In one general aspect, there is provided a modified release pharmaceutical composition comprising at least one immediate release and at least one extended release component comprising methylphenidate or salts thereof, wherein the immediate release component is not in the form of core particles coated with layer of methylphenidate.

In another general aspect, there is provided a modified release pharmaceutical composition of methylphenidate or salt thereof comprising at least one immediate release and at least one extended release component of methylphenidate, wherein the immediate release component is in the form of granules comprising methylphenidate or salts thereof and one or more pharmaceutically acceptable excipients.

In another general aspect, there is provided a modified release pharmaceutical composition of methylphenidate or salt thereof comprising at least one immediate release and at least one extended release component of methylphenidate, wherein the immediate release component is in the form of granules and the extended release component comprises core particles coated with one or more layers of methylphenidate, which is further coated with one or more rate controlling substances.

In another general aspect, there is provided a modified release pharmaceutical composition of methylphenidate or salts thereof comprising at least one immediate release and at least one extended release component of methylphenidate, wherein the immediate release component is in the form of granules and the extended release component comprises matrix of methylphenidate, and one or more rate controlling substances.

In another general aspect, there is provided a modified release pharmaceutical composition of methylphenidate or salt thereof comprising at least one immediate release and at least one extended release component of methylphenidate, wherein the immediate release component is in the form of granules comprising methylphenidate and one or more pharmaceutically acceptable excipients, and extended release components are may be in the form of tablets, mini-tablets, granules, pellets, beads, spheroids or mixtures thereof.

In another general aspect, there is provided a modified release pharmaceutical composition of methylphenidate or salt thereof comprising at least one immediate release and at least one extended release component of methylphenidate, wherein the immediate release component is in the form of granules comprising methylphenidate and one or more pharmaceutically acceptable excipients, and the composition retains at least 90% w/w w of the potency of methylphenidate or salts thereof when stored at 400C and 60% relative humidity for 3 months.

In another general aspect, there is provided a modified release pharmaceutical composition of methylphenidate or salt thereof comprising at least one immediate release and at least one extended release component of methylphenidate, wherein the immediate release component is in the form of granules comprising methylphenidate and one or more pharmaceutically acceptable excipients, characterized in that the composition is bioequivalent to the formulation of methylphenidate marketed under the trade name Metadate CD®.

In another general aspect, the immediate release granules as disclosed in the present invention can be prepared by wet granulation, dry granulation or slugging.

In another general aspect, there is provided a process for preparation of a modified release capsule, which process comprises steps of:
(a) mixing methylphenidate or salts thereof with one or more pharmaceutically acceptable excipients and granulating with a vehicle to form granules as an immediate release component
(b) coating inert core particles with one or more layers comprising methylphenidate and one or more pharmaceutically acceptable excipients to form methylphenidate layered particles;
(c) optionally, coating a barrier layer over the methylphenidate layered particles;
(d) coating the methylphenidate layered particles with one or more layers comprising one or more rate controlling substances to form extended release component;
(e) filling the immediate release component prepared in step (a) and the extended release component prepared in step (d) in a capsule.

In another general aspect, there is provided a process for preparation of a modified release capsule, which process comprises steps of:
(a) mixing methylphenidate or salts thereof with one or more pharmaceutically acceptable excipients followed by slugging and milling to form granules as an immediate release component
(b) coating inert core particles with one or more layers comprising methylphenidate and one or more pharmaceutically acceptable excipients to form methylphenidate layered particles;
(c) optionally, coating a barrier layer over the methylphenidate layered particles;
(d) coating the methylphenidate layered particles with one or more layers comprising one or more rate controlling substances to form extended release component;
(e) filling the immediate release component prepared in step (a) and the extended release component prepared in step (d) in a capsule.

In another general aspect, there is provided a method of treating ADD or ADHD by administering the patient in need thereof the modified release pharmaceutical composition of methylphenidate or salts thereof as substantially described throughout the specification.

The present invention relates to a novel modified release composition comprising one or more immediate release components and one or more extended release components of methylphenidate or salts thereof, wherein the immediate release components are present in the form of granules.

Preferably, immediate release component is in the form of granules comprising methylphenidate or salts thereof and one or more pharmaceutically acceptable excipients. Such compositions may provide rapid onset of action as well as a significantly longer duration of action. The composition also involves simple and economical manufacturing process.

In one embodiment, the modified release pharmaceutical composition comprises of at least one immediate release and at least one extended release components comprising methylphenidate or salts thereof, wherein the immediate release component is not in the form of core particles coated with layer of methylphenidate.

In another embodiment, the modified release pharmaceutical composition comprises of at least one immediate release and at least one extended release components comprising methylphenidate or salts thereof, wherein granules comprises of methylphenidate or salts thereof and one or more pharmaceutically acceptable excipients.

In another embodiment, the modified release pharmaceutical composition comprises of at least one immediate release and at least one extended release components comprising methylphenidate or salts thereof, wherein the extended release component comprises of core particles coated with one or more layers of methylphenidate, which is further coated with one or more rate controlling substances.

In another embodiment, the modified release pharmaceutical composition comprises of at least one immediate release and at least one extended release components comprising methylphenidate or salts thereof, wherein the extended release component comprises of matrix of methylphenidate, and one or more rate controlling substances.

In another embodiment, the modified release unit dosage form of the present invention retains at least 90% w/w of the potency of methylphenidate or salts thereof when stored at 25°C and 40% relative humidity or at 400C and 25% relative humidity for 3 months.

In another embodiment, the modified release composition of the present invention is bioequivalent to formulation of methylphenidate marketed under the trade name Metadate CD®.

In another embodiment, the modified release unit dosage form of the present invention is characterized in that it provides therapeutically effective plasma concentration of methylphenidate or salt thereof over a period of 12 hours.

The granules as disclosed in the present invention can be prepared by the methods known to those skilled in the art such as wet granulation, dry granulation or slugging.

The term “component” used throughout the specification refers to dry blend or mixture (e.g. powder), mini-tablet, tablet, pellet, bead or granule prepared by standard methods known to the person skilled in the art, including but not limited to compression, granulation, spray coating, and extrusion/spheronization.

The term “methylphenidate” used throughout the specification refers to not only methylphenidate per se, but also its other pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.

The term "modified release" used throughout the specification shall apply to dosage forms, matrices, particles, coatings, portions thereof, or compositions that alter the release of an active ingredient in any manner. Types of modified release include controlled, prolonged, sustained, extended, delayed, and the likes.

The term “matrix” used throughout the specification refers to the dispersion of drug within one or more release modifying substances and optionally one or more pharmaceutical excipients, or mixture thereof.

In a preferred embodiment, the immediate release component of the present invention is in the form of a granules comprising of methylphenidate and one or more pharmaceutically acceptable excipients.

In an embodiment, the extended release components are in the form of beads. The beads may be matrix type or of inert core coated with one or more drug layers and optionally coated with one or more barrier coating

In a further embodiment, the extended release component of the present invention may be comprised of an inert particle such as a commercially available non-pareil sugar sphere. Methylphenidate is layered on the sugar spheres from an aqueous solution of the drug and a binder such as polyvinylpyrrolidone (PVP). "Methylphenidate" as used herein includes all optical isomers of the compound and all pharmaceutically acceptable salts thereof. The drug layered beads are provided with up to 4%, preferably up to 2% w/w barrier coat using a film-former, such as hydroxypropylmethylcellulose (HPMC) (e.g., Opadry Clear).

Extended release components are prepared by coating drug coated/barrier coated beads as mentioned above with a solution or an aqueous dispersion of a dissolution rate controlling polymer thereby forming an extended release membrane coating on the IR bead.

The release controlling substances which can be used may be selected from the group consisting of hydrophilic agents (e.g. water-soluble polymers), lipophilic agents (water-insoluble polymers) and inert matrix agents, wherein the hydrophilic agents are selected from the group of pharmaceutical excipients which generate a gel in contact with water, including cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and the like; noncellulose polysaccharides such as galactomannanes, guar gum, carob gum, gum arabicum, alginates, pectins, and the like; polyvinylpyrrolidone; polyvinylacetate polymers and copolymers; acrylic acid polymers and copolymers, polyethylene oxide and mixtures thereof; the lipophilic agents are selected from the group consisting of waxes such as white wax, bees wax, carnauba wax and the like; fatty acids and alcohols such as stearic acid, palmitic acid, lauric acid and the like, and cetyl alcohol, cetostearyl alcohol, stearyl alcohol and the like; fatty acids esters such as monostearates of propylene glycol and fatty acid esters of sucrose, sucrose distearate and the like; and glycerides such as mono-, di- or triglycerides, e.g. palmitin, stearin, behenic, laurin, myristin, hydrogenated vegetable, castor, cottonseed oils, glyceril behenate and the like; ethyl cellulose; acrylic acid polymers and copolymers (available commercially under Eudragit® brand); and mixtures thereof; and the inert agents are selected from the group consisting of thermoplastic polymers, which are insoluble and indigestible in the gastrointestinal fluids, such as polyvinyl chloride, polyethylene, vinyl acetate/vinyl chloride copolymers, polymethylmethacrylates, polyamides, silicones, ethyl cellulose, polystyrene, and mixtures thereof.

Preferred examples of rate controlling substances include, but are not limited to, ethylcellulose (e.g., Aquacoat® ECD-30), neutral copolymers based on ethylacrylate and methylmethacrylate, and copolymers of acrylic and methacrylic acid esters having quaternary ammonium groups. The membrane coated beads are also typically seal coated with HPMC to produce extended release beads.

The immediate release and extended release components are filled into hard gelatin capsules at predetermined ratios to produce modified release capsule. Ratios of immediate release and extended release components found to provide desirable release profiles ranges from about 10:90 to 50:50, preferably from 20:80 to 40:60, and most preferably at a ratio of 30:70.

In the extended release component, the amount of methylphenidate layered on the core (sugar sphere) can be varied widely. A typical dose is expected to be from about 10 to 60 mg of methylphenidate. Immediate release components typically will account for about 20 to 40% of the dose. The methylphenidate content in the drug layered components may range from 5 to 20% w/w. Those skilled in the art will be able to select an appropriate amount of drug for coating onto the core to achieve the desired dosage. Generally, the rate controlling substance coatings on the methylphenidate coated core particle vary from 5 to 25%, preferably from 5 to 20% and more preferably from 5 to 10% by weight based on the total weight of the coated particle, depending on the coating materials and solvents selected.

The thickness of the membrane layer or the type of rate controlling substance selected depends on the desired release profile, and is optimized for achieving a desired in vitro release profile, which is predicted based on the in vitro/in vivo correlations and efficacy study results. Preferably, the release profile provides an immediate bolus of drug and extended release of the drug at a relatively constant rate for an extended period of time (over 12 hours or more).

The composition according to the present invention may comprise one bead population, which provides only an extended release profile and granules of methylphenidate with one or more pharmaceutical excipients exhibiting immediate release.

The modified release composition of the present invention can be prepared by methods known to the person skilled in the art.

In another general aspect, there is provided a process for preparation of a modified release capsule, which process comprises steps of:
(a) mixing methylphenidate or salts thereof with one or more pharmaceutically acceptable excipients and granulating with a vehicle to form granules as an immediate release component
(b) coating inert core particles with one or more layers comprising methylphenidate and one or more pharmaceutically acceptable excipients to form methylphenidate layered particles;
(c) optionally, coating a barrier layer over the methylphenidate layered particles;
(d) coating the methylphenidate layered particles with one or more layers comprising one or more rate controlling substances to form extended release component;
(e) filling the immediate release component prepared in step (a) and the extended release component prepared in step (d) in a capsule.

An aqueous or a pharmaceutically acceptable solvent medium may be used for preparing extended release component of methylphenidate containing core particles. The type of film forming binder that is used to bind the water soluble drug to the inert sugar sphere is not critical but usually water soluble, alcohol soluble or acetone/water soluble binders are used. Binders such as polyvinylpyrrolidone (PVP), polyethylene oxide, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polysaccharides such as dextran, corn starch may be used at concentrations of 0.5 to 5% w/w. Methylphenidate may be present in this coating formulation up to 55% w/w, preferably up to about 40% w/w, and most preferably up to about 20% w/w, depending on the viscosity of the coating formulation.

The modified release composition of methylphenidate or salts thereof may be developed in the form a capsule, a tablet, a caplet and a mini-tablet. Preferably the dosage form is in the form of a capsule.

In an embodiment, the modified release composition in accordance of the present invention is in the form of a hard gelatin capsule filled with a dry blend comprising methylphenidate or salts thereof and one or more pharmaceutically acceptable excipients, and plurality of beads comprising core particle layered with a methylphenidate composition which is further coated with one or more rate controlling substances.

The term "pharmaceutically acceptable excipients" includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering an active pharmaceutical ingredient. Each excipient should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Excipients include diluents, binders, disintegrants, glidants, lubricants, flavoring, and others.

The composition of the present invention may comprise one or more pharmaceutically acceptable excipients selected from, but not limited to, diluent, binder, disintegrant, glidant, lubricant, stabilizing agent, and flavoring agents.

Diluents increase the bulk of a solid pharmaceutical composition. Exemplary diluents for solid compositions include, but are not limited to, microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates, potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compressed may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Exemplary binders for solid pharmaceutical compositions include, but are not limited to, acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate and starch.

Disintegrants increase the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach, for example. Exemplary disintegrants include, but are not limited to, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate and starch.

Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Exemplary excipients that may function as glidants include, but not limited to, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.

A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Exemplary lubricants include, but are not limited to, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.

The present invention further provides a method of treating a method of treating ADD or ADHD by administering the patient in need thereof the modified release pharmaceutical composition of methylphenidate or salts thereof as substantially described throughout the specification.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1: Methylphenidate Extended Release Capsule
Table 1

Sr. No. Ingredient Mg/cap
Immediate release granules – Part I
1 Methylphenidate 18
2 Microcrystalline Cellulose 42
Total weight 60
Drug loading and functional coating – Part II
3 Methylphenidate 42
4 Sugar sphere 158
5 Polyvinylpyrrolidone 2.1
Total weight 202.1
Seal coating
6 Opadry clear YS1R7006 6
Total weight 208.1
Sustained release coating on Part II Functional coated pellet
7 Ethyl cellulose* 18.729
8 Dibutyl sebacetate 2.081
Total weight 228.91
9 Size ‘0’ EHGC 1
Total weight 288.91
* Dry polymer weight – calculation to be done based on dispersion quantity

Process: A mixture of Methylphenidate and Microcrystalline Cellulose was blended in a rotary mixer granulator. The blend was granulated with water in a rotary mixer granulator. The granules were dried and sifted through sieve of suitable mesh size. A solution of Methylphenidate and Polyvinylpyrrolidone was sprayed on sugar spheres using fluid bed coater. The drug loaded pellets were further seal coated using opadry clear in fluid bed coater. The seal coated Pellets are further coated using ethyl cellulose and dibutyl sebacetate based coating in fluid bed coater to form pellets. The granules and pellets were filled in size ‘0’ hard gelatin capsules.