The present invention relates to extended release pharmaceutical composition of paliperidone and process of preparation thereof.
Paliperidone as disclosed in US 5,158,952, is chemically (±)-3-[2-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6, 7, 8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1, 2-a]pyrimidin-4-one. Paliperidone is a psychotropic agent which belongs to the chemical class of benzisoxazole derivatives, and is an active metabolite of resperidone. It differs from risperidone and related prior art by its substitution on the 1-position of the piperidine moiety. Paliperidone extended release osmotic tablets are currently available in 3, 6, 9 and 12 mg strengths, under the trade name Invega®, marketed by Janssen.
Paliperidone has a long half-life of about a day and therefore is not a typical candidate for the extended delivery. However, immediate release compositions cause side effects such as anxiety, somnolence, dizziness, constipation, extrapyramidal symptoms due to high blood plasma concentration levels, thereby restricting its use. In order to obtain a therapeutic effect with reduced side effects, drug plasma concentrations need to be sustained above a minimum pharmacodynamic concentration and below the threshold maximum tolerable concentrations. In this regard, extended release pharmaceutical compositions of paliperidone are desirable over the immediate release compositions.
A review of the art, shows PCT application WO 0035419 that teaches osmotic dosage forms of risperidone, further WO 04010981 teaches capsule shaped osmotic dosage forms of paliperidone, providing substantiality ascending rate for a prolonged period of time.
For providing the extended release of a drug, apart from the osmotic dosage forms, diffusion systems such as reservoir and matrix diffusion systems, dissolution systems such as matrix dissolution systems and encapsulated dissolution systems, combination of diffusion/dissolution systems, complexation and ion-exchange resin systems are the other available alternative systems. Prior art discloses the osmotic dosage form of paliperidone, however it does not address delivery of extended release paliperidone using diffusion system, dissolution system or combination of
these. These systems are easy to manufacture and are relatively simpler and cost effective.
Our scientists have now formulated an extended release pharmaceutical composition of paliperidone using diffusion system, dissolution system or combination of these, still achieving the desired in-vitro and in-vivo release profiles.
Hence in one general aspect there is provided an extended release pharmaceutical composition of paliperidone comprising dissolution controlled matrix system.
In another general aspect there is provided an extended release pharmaceutical composition of paliperidone comprising dissolution controlled encapsulated system.
In another general aspect there is provided an extended release pharmaceutical composition of paliperidone comprising diffusion controlled membrane coated system.
In another general aspect there is provided an extended release pharmaceutical composition of paliperidone comprising diffusion controlled matrix system.
In another general aspect there is provided an extended release pharmaceutical composition of paliperidone comprising dissolution controlled matrix and diffusion controlled membrane coated systems.
In another general aspect there is provided an extended release pharmaceutical composition of paliperidone comprising:
(a) dissolution controlled matrix system wherein the matrix material comprises an
erodible material, and
(b) diffusion controlled membrane coated system wherein the membrane coating
material comprises hydrophobic porous material.
In another general aspect there is provided an extended release pharmaceutical composition of paliperidone comprising:
(a) dissolution controlled matrix system wherein the matrix material comprises an
erodible material in an amount of about 1% to about 50% w/w, and
(b) diffusion controlled membrane coated system wherein the membrane coating
material comprises hydrophobic porous material in an amount of about at
least 30% w/w.
In another general aspect there is provided an extended release pharmaceutical composition of paliperidone comprising:
(a) dissolution controlled matrix system wherein the matrix material comprises
polyethylene oxide, and
(b) diffusion controlled membrane coated system wherein the membrane coating
material comprises ethyl cellulose.
In another general aspect there is provided a process for the preparation of dissolution and/or diffusion controlled extended release pharmaceutical composition of paliperidone wherein the process comprises the steps of:
(i) blending paliperidone, erodible matrix material and one or more
pharmaceutically acceptable excipients, (ii) optionally granulating the blend of step (i), (iii) compressing the blend/granules of steps (i) or (ii) into tablets using
appropriate tooling, and
(iv) coating the above tablets with a hydrophobic porous material. In another general aspect there is provided a process for the preparation of dissolution and/or diffusion controlled extended release pharmaceutical composition of paliperidone wherein the process comprises the steps of: (i) melting the carrier, (ii) dispersing paliperidone in the molten carrier and cooling to form a
solidified mass,
(iii) screening the solidified mass of step (ii) to form the granules, (iv) blending the granules of step (iii) with an erodible matrix material
and one or more pharmaceutically acceptable excipients, (v) compressing the blend of steps (iv) into tablets using appropriate
tooling, and
(vi) coating the above tablets with a hydrophobic porous material.
In another general aspect there is provided a method of treating neurological disorders in mammals, which comprises administering to a mammal in need thereof, the dissolution and/or diffusion controlled extended release pharmaceutical composition of paliperidone.
The term "paliperidone" as used herein includes paliperidone as well as pharmaceutically acceptable salts, enantiomers, hydrates, solvates, metabolites, prodrugs or mixture thereof. The D90 value of the paliperdine varies from about 35 urn to about 50 um, in particular 42 um. The D50 value of the paliperdine varies from about 7 um to about 15 urn, in particular 13 um. The amount of paliperidone may vary from about 1% to about 20% w/w of the total pharmaceutical composition.
The dissolution system may comprise of matrix or encapsulated dissolution systems. The matrix dissolution system works by formulating paliperidone in an erodable matrix. Since paliperidone is water insoluble, the rate with which paliperidone would be available at the absorption site, from these matrices is proportional to the swelling and erosion rates of the matrix forming material. For encapsulated dissolution systems, paliperidone release rate would depend upon the thickness and dissolution rate of the encapsulating membrane.
The diffusion system may comprise of the reservoir or matrix systems. In the reservoir/membrane coated diffusion system, paliperidone particles or cores containing paliperidone are coated with a hydrophobic porous film forming material, the gastrointestinal fluid penetrates the film, dissolves/disperses paliperidone and diffuses it out through the film. In matrix diffusion systems, paliperidone is embedded in the non-erodible matrix forming material or combination of erodible and non-erodible matrix forming materials.
The erodible or non-erodible matrix forming material includes, but is not limited to cellulose derivatives such as ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose, cellulose acetate butyrate, cellulose acetate phthalate; polysaccharides, like alginate; xanthane; carrageenan; scleroglucan; pullulan; dextran; haluronic acid; chitin; chitosan; starch; other natural polymers, like proteins (e.g. albumin, gelatine); natural
rubber; synthetic polymers, like acrylates (e.g. polymethacrylate, poly(hydroxy ethyl methacrylate), poly(methyl methacrylate), poly(hydroxy ethyl methacrylate-co methyl methacrylate), Carbopol 934™.); polyamides (e.g. polyacrylamide, poly(methylene bisacrylamide)); polyanhydrides (e.g. poly(bis carboxyphenoxy)methane); PEO-PPO block-co-polymers (e.g. poloxamers, etc); polyvinyl chloride; polyvinyl pyrrolidone; polyvinyl acetate; polyvinyl alcohol; polyethylene, polyethylene glycols and co-polymers thereof; polyethylene oxides and co-polymers thereof; polypropylene and co-polymers thereof; polystyrene; polyesters (e.g. poly(lactic acid), poly(glycolic acid), poly(caprolactone), etc, and co-polymers thereof, and poly(ortho esters), and co-polymers thereof; resins (e.g. Dowen™, Amberlite™); polycarbonate; cellophane; silicones (e.g. poly(dimethylsiloxane)); polyurethanes; synthetic rubbers (e.g. styrene butadiene rubber, isopropene rubber); others, like shellacs; waxes (e.g. carnauba wax, beeswax, glycowax, castor wax); nylon; stearates (e.g. glycerol palmitostearate, glyceryl monostearate, glyceryl tristearate, stearyl alcohol); lipids (e.g. glycerides, phospholipids); paraffin; cetyl alcohol or combination of any of these, in particular polyethylene oxides. The erodible matrix forming material may be present in an amount of about 1% to about 50% w/w of the dissolution controlled matrix system.
The term "polyethylene oxide" as used herein is a non-ionic homopolymer of the formula -(-0-CH2-CH2-)n-, wherein n represents the average number of oxyethylene groups, n generally being from about 2,000 to about 100,000. It is a water soluble resin which is available as a white powder in several grades having different molecular weights which vary in viscosity profile when dissolved in water. Polyethylene oxide resin is commercially available under the trade name Polyox™ from Union Carbide Corporation. Polyox™ WSR 303 has an average molecular weight of about 5,000,000 to 6,000,000, and a 1% aqueous solution thereof at 25°C has a viscosity of 7,200 to 10,000 cps on a Brookfield RVF, No. 2 spindle at 2 rpm, and a pH of 8 to 10. It is contemplated that mixtures of varying molecular weight polymers may also be employed as a matrix system to obtain the desired tablet release properties.
The hydrophobic porous material for membrane coating covers any hydrophobic porous material or combination of hydrophobic material with a hydrophilic material.
Examples of hydrophobic porous material includes, but is not limited to, cellulose derivatives such as ethyl cellulose, butyl cellulose, cellulose acetate, cellulose propionate, polyvinyl acetate, polyvinyl butyrate, ethyl acrylate-methyl methacrylate-ethyl ammonium trimethyl chloride methacrylate copolymer and N-vinyl-2-pyrrolidone cellulose ether, cellulose ester, polyvinyl ester, acrylic acid type polymer having a quaternary ammonium-alkyl group, and Plasdone™ K-90, homopolymer of N-vinyl-2-pyrrolidone, polyvinylpyrolidone, or combination thereof, in particular ethyl cellulose. The hydrophobic porous film forming material may be present in an amount of about 1% to about 50% w/w of the diffusion controlled membrane coated system. The coating solution may be applied till the weight gain is 5-25% w/w of the pharmaceutical composition.
The term "ethyl cellulose" as used herein is an ethyl ether of cellulose. Commercially available examples of ethyl cellulose compositions include products such as, Surelease™, Aquacoat™, Ethocel™, and mixtures thereof.
The pharmaceutical compostion of paliperdone may further comprise one or more pharmaceutically inert excipients may be selected from the group consisting of solubility enhancers/solubilizers, fillers, binders, lubricant/glidants coloring agents, plasticizers and opacifiers.
Specific examples of solubility enhancers include polyethylene glycols, surfactants, propylene glycol, glycerol, mono- alcohols, higher alcohols, DMSO, dimethylformamide, N. N- dimethylacetamide, 2-pyrolidone, N-(2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, 1- dodecylazacycloheptan-2-one and other n-substituted- alkyl azacycloalkyl-2-ones, preferably polyethylene glycol.
Specific examples of fillers or diluents include lactose, pregelatinized starch, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulphate, kaolin, starch, and the like.
Specific examples of lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, talc,
hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like.
Specific examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arable, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
Coloring agents includes any FDA approved color for oral use.
Specific examples of plasticizers include triethylcitrate, dibutylsebacate, acetylated triacetin, tributylcitrate, glyceroltributyrate, monoglyceride, rape oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethyl phthalate, diethylmalate, dtothylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate and the like.
Specific examples of opacifiers include titanium dioxide, manganese dioxide, iron oxide, silicon dioxide, and mixtures thereof
The term "pharmaceutical composition" as used herein includes tablet, granule, pellet, spheroid, capsule, pills, and the like. These compositions may be prepared by techniques known in the art such as wet granulation, dry granulation, direct compression, extrusion-spheronization, hot melt granulation or hot melt extrusion. The wet granulation process involves use of water or any other suitable granulating fluid. The dry granulation may involve use of roller compacter or any suitable technique. The hot melt granulation or hot melt extrusion involves the use of a carrier such as cetyl alcohol, polyethylene glycol, poly ethyleneoxide, polyvinyl pyrrolidine, polyvinyl alcohol, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethylethyl cellulose, hydroxypropylmethyl cellulose phthalate, polyacrylates, polymethylacrylates, urea and sugars such as mannitol, in particular cetyl alcohol.
Specific examples of granulating fluid/solvents for coating include acetone, ethanol, isopropyl alcohol, methylene chloride or combination thereof.
The pharmaceutical compositions may be further coated with one or more non¬functional coating layers, if desired, comprising film forming polymers with/without coating additives.
Examples of film-forming polymers include ethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethyl cellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit ®; and the like. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used.
Coating may be performed by applying solution/suspension using any conventional coating technique known in the prior art such as spray coating in a conventional coating pan orfluidized bed processor; dip coating or compression coating.
In one of the embodiment, the extended release pharmaceutical composition of paliperidone may be prepared by a process comprising the steps of:
(i) blending paliperidone, erodible matrix material and one or more
pharmaceutically acceptable excipients,
(ii) formulating the blend of step (i) into suitable pharmaceutical composition.
In another embodiment, the extended release pharmaceutical composition of paliperidone may be prepared by a process comprising the steps of:
(i) blending paliperidone and one or more pharmaceutically acceptable
excipients, (ii) formulating the blend of step (i) into suitable pharmaceutical composition,
and
(iii) coating the above pharmaceutical composition with a hydrophobic porous material.
In another embodiment, the extended release pharmaceutical composition of paliperidone may be prepared by a process comprising the steps of:
(i) blending paliperidone, erodible matrix material and one or more
pharmaceutically acceptable excipients, (ii) formulating the blend of step (i) into suitable pharmaceutical composition,
and
(iii) coating the above pharmaceutical composition with a hydrophobic porous material.
In another embodiment, the extended release pharmaceutical composition of paliperidone may be prepared by a process comprising the steps of:
(i) blending paliperidone, polyethylene oxide and one or more
pharmaceutically acceptable excipients,
(ii) directly compressing the blend of step (i) into tablets using appropriate tooling, and coating the above tablets with ethyl cellulose.
In another general aspect there is provided a process for the preparation of dissolution and/or diffusion controlled extended release pharmaceutical composition of paliperidone wherein the process comprises the steps of: (i) melting the carrier, (ii) dispersing paliperidone in the molten carrier and cooling to form a
solidified mass,
(iii) screening the solidified mass of step (ii) to form the granules, (iv) blending the granules of step (iii) with polyethylene oxide and one
or more pharmaceutically acceptable excipients, (v) compressing the blend of steps (iv) into tablets using appropriate
tooling, and
(vi) coating the above tablets with coating the above tablets with ethyl cellulose.
The invention is further illustrated by the following examples, which is for illustrative purpose only and should not be construed as limiting the scope of the invention in any way.
Example 1-4(Table Removed)

Procedure:
1. Paliperidone was blended with ingredients 2-5.
2. Magnesium stearate was added to the blend of step 1.
3. The mixture cf step 2 was compressed into tablets using suitable
tooling.
4. The tablets of step 3 were coated with the coating solution until 10%
w/w (for example 1) or 18% w/w (for examples 2-4) weight is gained.
Example 5

(Table Removed)
Procedure:
1. Cetyl alcohol was melted at about 50°C.
2. Paliperidone was dispersed in the molten cetyl alcohol and allowed to
cool at room temperature to form a solidified mass.
3. The solidified mass of step 2 was screened through a suitable sieve to
form the granules.
4. The ingredients 3-5 were added to the granules of step 3 and blended
for few minutes.
5. The blend of step 4 was compressed into tablets using suitable tooling.
6. The tablets of step 5 were coated with the coating solution until 3% w/w
is gained.

WE CLAIM:
1. An extended release pharmaceutical composition of paliperidone
comprising dissolution controlled matrix and diffusion controlled
membrane coated systems.
2. The extended release pharmaceutical composition of claim 1,
comprising:
(i) dissolution controlled matrix system wherein the matrix material
comprises an erodible material, and (ii) diffusion controlled membrane coated system wherein the
membrane coating material comprises hydrophobic porous
material.
3. The extended release pharmaceutical composition of claim 1, wherein
the paliperidone is present in an amount of 1% to 20% w/w of the total
composition.
4. The extended release pharmaceutical composition of claim 2, wherein
the matrix material is polyethylene oxide present in an amount of 1% to
50% w/w of dissolution controlled matrix system.
5. The extended release pharmaceutical composition of claim 2, wherein
the membrane coating material ethyl cellulose present in an amount of
about at least 30% w/w of the diffusion controlled membrane coated
system.
6. The extended release pharmaceutical composition of any of the
preceding claims may further comprise one or more pharmaceutically
inert excipients selected from the group consisting of solubility
enhancers/solubilizers, fillers, binders, lubricant/glidants coloring
agents, plasticizers and opacifiers.
7. The extended release pharmaceutical composition of any of the
preceding claims wherein the pharmaceutical composition may be
selected from the group consisting of tablet, granule, pellet, spheroid,
capsule, pills, and the like.
8. The extended release pharmaceutical composition of any of the
preceding claims, wherein the pharmaceutical composition is prepared
by a process comprising the steps of:
(i) blending paliperidone, erodible matrix material and one or more
pharmaceutically acceptable excipients, (ii) optionally granulating the blend of step (i), (iii) compressing the blend/granules of steps (i) or (ii) into tablets
using appropriate tooling, and (iv) coating the above tablets with a hydrophobic porous material.
9. An extended release pharmaceutical composition of paliperidone, and
process of preparation thereof, as described and illustrated in the
examples herein.