WO2010089775A2

WO2010089775A2 - Improved drug dosage form for controlled delivery of one or more pharmaceutically active agent

Info

Publication number: WO2010089775A2
Application number: PCT/IN2010/000058
Authority: WO
Inventors: Atul Patil; Anil Kadam; Anandi Krishnan; Sameer Paigankar
Original assignee: Getz Pharma Research
Priority date: 2009-02-05
Filing date: 2010-02-03
Publication date: 2010-08-12
Also published as: WO2010089775A3

Abstract

Disclosed is an improved drug delivery system for controlled delivery of one or more pharmaceutical active agent using combination of hydrophobic and hydrophilic polymers in inner core and coating layer of a dosage form. The invention uses specific ratio of ethyl cellulose and hydroxypropyl methylcellulose for obtaining the desired release of active agent.

Description

IMPROVED DRUG DOSAGE FORM FOR CONTROLLED DELIVERY OF ONE OR WlORE

PHARMACEUTICALLY ACTIVE AGENT

Field of the Invention The present invention relates to the field of the drug delivery technology. More particularly the invention relates to a novel drug delivery system for controlled delivery of one or more pharmaceutically active agent to a patient with sustained or ascending release profile using • non-capsule shaped tablet.

Background of the Invention

There are several different drug delivery technologies that are utilized to treat disease. Conventional drug delivery methods typically result in the patient experiencing sever "seesaw" or "peaks and valleys" pattern in the plasma level of the therapeutic agent being administered, as well as often requiring multiple dosages per day. These problems, over the years, were addressed by significant advances that have been made in the design of controlled release drug delivery systems. Such advances have been made in an attempt to overcome shortcomings found in conventional drug delivery and to maintain therapeutically active concentrations in the patient body for longer time.

Controlled release drug delivery systems can be designed to target local area or the systemic circulation and can be administered in variety of ways, including orally, transdermal^, injections, and so forth. In general, controlled release drug delivery systems include both sustained drug delivery systems designed to deliver a drug for a predetermined period of time, and ascending drug delivery systems designed to deliver a drug at a slower rate initially and gradually increase in the rate in the latter stage of drug release.

The present inventors have designed an improved controlled release drug delivery system that utilize non-capsule shaped tablet for delivering one or more pharmaceutically active agent to a patient. The invention aims to provide an improved drug delivery technology to provide accurate delivery rates in relatively easy and inexpensive to manufacture.

Summary of the Invention

The present invention provides for controlled delivery of one or more pharmaceutically active agent to a patient for more than 18 hours using a non-capsule shaped tablet. Approximately 22 hours of drug release is at a substantially ascending rate of release from the tablet with 95% delivery occurring at about 24 hours. The release profile provides therapeutic delivery above the minimum plasma concentration and while keeping the plasma levels below the toxic level and low enough such that side effects will be reduced and the development of tolerance. The delivery profile provides 24 hours of efficacy without high plasma levels. The invention relates, in general, to ascending release of one or more pharmaceutically active agent using a combination of hydrophilic and hydrophobic polymers in inner core and coating layer of a tablet.

In one aspect, the invention provides an orally administrable dosage form comprising an inner core comprising one or more pharmaceutically active agent and combination of hydrophilic and hydrophobic polymers, and a permeable membrane surrounding the inner core. The permeable membrane comprises combination of hydrophilic and hydrophobic polymers with suitable plasticizers.

In another aspect, the invention provides a sustained release orally administrable dosage form to release one or more pharmaceutically active agent over a prolonged period of time at a substantially ascending rate of release using combination of hydrophilic or hydrophobic polymers in inner core and extended release coat.

In one embodiment, the present invention provides a sustained release dosage form of paliparidone or pharmaceutically acid addition salts thereof to release over a prolonged period of time at a substantially ascending rate of release using combination of hydrophilic or hydrophobic polymers in inner core and extended release coat.

These and other features of the present invention will become apparent from the detailed description of the invention.

Description of the Figures Figure 1 depicts the dissolution profile of paliparidone 2.70mg tablets vs. Invega ER tablets in SGF pH 1.2.

Figure 2 depicts the dissolution profile of paliparidone 6.0mg tablets vs. Invega ER tablets in SGF pH 1.2.

Detailed Description of the Invention

The present invention provides an orally administrable dosage form and method of preparation thereof that is devised for controlled delivery of one or more pharmaceutically active agent in a patient. In particular, it has been found that by using a combination of hydrophobic and hydrophilic polymers in inner core and coating layer an ascending release of pharmaceutically active agent is obtained.

The dosage form includes an inner core containing one or more pharmaceutically active agent and a combination of hydrophilic and hydrophobic polymers, and extended release coating layer. The coating layer is a permeable membrane containing combination of hydrophobic and hydrophilic polymers with plasticizers. The inner core includes one or more pharmaceutically active agent. Specifically, and without limitation, pharmaceutical agent with which present invention is useful includes paliparidone.

In one embodiment, the present invention relates to an orally administrable dosage form for controlled delivery of paliparidone or pharmaceutically acceptable salts, solvates, enantiomers, recimates, resinates or mixtures thereof and the processes for preparing the same.

In another embodiment, pharmaceutical composition of paliparidone with resins is prepared to form paliparidone resinate.

In yet another embodiment, stable pharmaceutical composition of paliperidone with hydrophilic and hydrophobic or either of one is prepared either by aqueous or non aqueous granulation or direct compression or roller compaction to form a paliperidone core.

The term "resinate" in the invention refers to Paliperidone with or without other pharmaceutically acceptable excipients treated with ion exchange resin.

In another embodiment, the ion exchange resins are porous copolymers of Methacrylic acid crosslinked with divinylbenzene. In context of the present invention the ion exchange resins that may be useful include but are not limited to DUOL1TE™.AP143/1083 (Cholestyramine resin USP), AMBERLlTE™.lRP-64 (a porous copolymer of Methacrylic acid crosslinked with divinylbenzene). DUOLITE and AMBERLITE resins are available from Rohm and Haas Co., Philadelphia, Pennsylvania U.S.A. Furthermore, polacrilin resin (Amberlite TM IRP 64) or polacrilin potassium (Amberlite TM IRP 88) is used in resinate of the present invention. In yet another embodiment, the w/w ratios of ion exchange resin to the active can range from about 4:1 to 1 :4 or about 2:1 to 1 :2.

In yet another embodiment, the present invention provides stable pharmaceutical compositions comprising, dispersed with an ion exchange resin with or without pharmaceutically acceptable excipients to form resinate.

Various pharmaceutically acceptable excipients that may form a part of resinate can either hydrophilic or hydrophobic. Hydrophilic or water soluble excipients include but are not limited to celluloses such as carboxymethyl cellulose, hydroxypropyl methylcellulose, carboxymethylamide; potassium methacrylate/divinylbenzene copolymers; polyvinylpyrrolidone; gums such as agrose, gum arabic, gum ghatti, gum karaya, gum tragacanth; hydrophilic colloids such as alginates; other substances such as arbinoglactan, pectin, amylopectin, and the like. Hydrophobic or water-insoluble substances or combinations thereof used in various ratios are exemplified by but are not limited to fatty acid esters such as glyceryl monostearate, glycerol distearate, glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate and glyceryl behenate; celluloses such as ethyl cellulose, low substituted hydroxypropyl cellulose (L-HPC), cellulose acetates and their derivatives; phthalates such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate; cellulose acylate, cellulose diacylate and cellulose triacylate; cellulose acetate, cellulose diacetate and cellulose triacetate; mono-, di- and tri- cellulose alkanylates, mono-, di-, and tri-cellulose arylates and mono-, di- and tri-cellulose ^' adenylates; poiymethacrylic acid based polymers and copolymers such as those sold using the trademark EUDRAGIT (RL, RS and NE-30D); polyvinyl acetate (PVA) copolymers of the above polymers.

It has been found that when ethyl cellulose (EC) a hydrophobic polymer is dissolved with hydroxypropyl methyl cellulose (HPMC) a hydrophilic polymer in a specific ratio in a common solvent such as IPA or DCM or water to form a uniform solution or dispersion and sprayed in a typical spray rate, a desired rate of release is obtained.

The ratio of ethyl cellulose (EC) and hydroxypropyl methyl cellulose (HPMC) is important to the proper functioning of the invention. To obtain desired release profile, the ratio of EC to HPMC needs to be maintained in the range of 90:10 to 30:70. The ratio of EC: HPMC can be altered to adjust the release rate of the pharmaceutically active agent.

Further pharmaceutically acceptable excipients may include anionic, cationic and nonionic surfactants. These include but are not limited to anionic surfactants such as chenodeoxycholic acid, 1-octanesulfonic acid sodium salt, sodium deoxycholate, glycodeoxycholic acid sodium salt, N-lauroylsarcosine sodium salt, lithium dodecyl sulfate, sodium cholate hydrate, sodium lauryl sulfate (SLS) and sodium dodecyl sulfate (SDS); cationic surfactants such as cetylpyridinium chloride monohydrate and hexadecyltrimethylammonium bromide; nonionic surfactants such as N-decanoyl-N- methylglucamine, octyl a-D-glucopyranoside, n-Dodecyl b-D-maltoside (DDM), polyoxyethylene sorbitan esters like polysorbates and the like.

Common diluents that can be used so as to add bulk to the core tablet or resinates of the invention include: microcrystalline cellulose (MCC), silicified MCC (e.g. Prosolv™ HD 90), micro fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, and the like.

The Paliperidone Resinate may include a disintegrant which include but are not limited to carboxymethyl cellulose sodium (e.g. Ac-Di-Sol®, Primellose®), crospovidone (e.g. Kollidon®, Polyplasdone®), povidone K-30, polacrilin potassium, starch, Pregelatinised starch and sodium starch glycolate (e.g. Explotab®).The resinate may further, include but are not limited to pharmaceutically acceptable glidants, lubricants, opacifiers, colorants and other commonly used excipients.

The Paliperidone resinate or Paliperidone core tablets may comprise basic organic substances which were used as stabilizers & which are but not limited to oxides such as magnesium oxide, calcium oxide, silicon dioxide; amines such as TRIS (tromethamine), ethanolamine, diethanolamine, triethanolamine, N-methyl-glucamine (meglumine), glucosamine, ethylenediamine, diethyl amine, triethylamine, isopropylamine, diisopropylamine, urea and the like; amino acids such as L-arginine, cysteine, tyrosine, histidine, lysine and the like.

In one of the embodiments of the present invention, a suitable solvent system such as aqueous or alcoholic or hydro-alcoholic or organic may be used in preparing resinate or Paliperidone core tablets.

In another embodiment of the present invention a suitable solvent system comprises solvents such as purified water or acidified water, ethanol, isopropyl alcohol, acetone, methylene chloride and the like. The granulation is done by dissolving the paliperidone in acidified water or methylene chloride to form a clear solution and then granulating the blend containing polymers or resins.

To prepare a suitable resinate the Paliperidone is granulated with resins such as drug adsorbed over the resins additional pH modifiers was added to incorporate the drug within the resin or polymer matrix. Compositions of the invention may be prepared using basic organic substances in combination with or without other pharmaceutically acceptable excipients to form a blend. The blend may further include but is not limited to pharmaceutically acceptable polymers, diluents, binders, disintegrants, glidants, lubricants, opacifiers, colorants and other commonly used excipients.

The Paliperidone compositions comprising Paliperidone resinate or paliperidone as such a blend or both, with or without pharmaceutically acceptable excipients may be in the form of tablets, mini-tablets, tablet in tablet, inlay tablets, MUPS ( Multi unit particulate system) pellets (extruded or fluidized) or beads or spheres or cores that are either encapsulated or compressed into tablets or minitablets or inlay tablets or capsules encapsulating minitablets or pellets (extruded or fluidized) or both, powders or lyophilized powders and the like.

In another embodiment, the stable pharmaceutical paliperidone formulation comprises inlay tablets. An inlay tablet is a compressed solid oral dosage form which has a small tablet placed within a large tablet, such that three sides of a small tablet are within a large tablet and only one surface of the small tablet is exposed.

In context of the present invention, the term "core tablet" refers to non-capsule shaped tablet without any breakline(s), or laser drilling. Further the size, shape and are not limiting towards the scope of the invention.

In an embodiment, inert beads or spheres or cores or seeds or particles or nuclei comprising of water-soluble materials such as sugar spheres, microcrystalline cellulose and the like; water-insoluble materials such as calcium carbonate, dicalcium phosphate anhydrous, dicalcium phosphate monohydrate, Tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like. Further drug layering can be done by powder coating or spray coating onto inert particles. The resulting materials may further compressed as tablets. The core tablets or pellets can further be optionally film coated or enteric coated. The coating can be done by techniques known to one skilled in the art such as spray coating, dip coating, fluidized bed coating and the like. Common diluents that can be used in pharmaceutical formulations of the invention include microcrystalline cellulose (MCC), silicified MCC (e.g. Prosolv™ HD 90), microfine cellulose, lactose, starch, pregelatinized starch, sugar, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like.

Binders can include in the pharmaceutical compositions of the present invention to help hold tablets together after compression. Some typical binders are acacia, guar gum, alginic acid, dextrin, maltodextrin, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. KLUCEL®), hydroxypropyl methylcellulose (e.g. METHOCEL®), carboxymethylcellulose sodium, povidone (e.g. Povidone K - 90 D, KOLLIDON®, PLASDONE®) and starch. Pharmaceutical compositions may further include but are not limited to pharmaceutically acceptable glidants, lubricants, opacifiers, colorants and other commonly used excipients.

The compositions for tablet may further include additional pharmaceutically acceptable excipients, including one or more of glidants, lubricants, surfactants and other commonly used excipients. Formulation of present invention may include antioxidants including, but not limited to, ascorbic acid and its esters, butylated hydroxy toluene (BHT), butylated hydroxy anisole (BHA), α-tocopherol, cystein, citric acid, propyl gallate, and sodium bisulfate.

Basic organic substances that can be used as stabilizers in this invention are but not limited to amines such as TRIS (tromethamine), ethanolamine, diethanolamine, triethanolamine, N- methyl-glucamine (meglumine), glucosamine, ethylenediamine, diethyl amine, triethylamine, isopropylamine, diisopropylamine, urea and the like; amino acids such as L-arginine, cysteine, tyrosine, histidine, lysine and the like.

The process for manufacturing the formulation of present invention is not limited to the processes described in the application and the formulation can be prepared by using any of the processes known to one skilled in the art. The active ingredient can be granulated by wet granulation or dry granulation with or without excipients. The granules of active(s) are prepared by sifting the actives and excipients through the desired mesh size sieve and then are mixed using a rapid mixer granulator or planetary mixer or mass mixer or ribbon mixer or fluid bed processor or any other suitable device. The blend can be granulated, such as by adding a solution of a binder whether aqueous or alcoholic or hydro-alcoholic in a low or high shear mixer, fluidized bed granulator and the like. The granules can be dried using a tray drier or fluid bed drier or rotary cone vacuum drier and the like. The sizing of the granules can be done using an oscillating granulator or comminuting mill or any other conventional equipment equipped with a suitable screen. Alternatively, granules can be prepared by extrusion and spheronization, or roller compaction. The dried granulate particles are sieved, and then mixed with lubricants and disintegrants.

Alternatively the manufacture of granules may be done by direct compression by mixing the directly compressible excipients with active(s). The blend so obtained can either be compressed using a suitable device, such as a multi-station rotary machine to form compressed slugs or by roller compaction to form slugs, which are passed through a multimill, fluid energy mill, ball mill, colloid mill, roller mill, hammer mill, or the like, equipped with a suitable screen. The milled slugs are then mixed with lubricants and disintegrants.

In another aspect of the invention, the inlay tablets can be made of various sizes and shapes, as desired. The techniques and processes known to a person skilled in the art of making inlay tablets fall within the scope of this invention. The small tablet is formed by compression and then placed into a cavity, into which the granulated or powdered mixture that will comprise the larger tablet is added and the larger tablet will be compressed around the smaller tablet. Exposure of a surface of the smaller tablet is achieved by contact of that surface with the surface of a compression die, and placing the granules or powder mixture over the smaller tablet before the final compression step. Paliperidone can be present as a small tablet placed within a large tablet that is containing hydrophilic or hydrophobic polymers. The tablets can further be optionally film coated or enteric coated or coated with control release polymers. The coating can be done by techniques known to one skilled in the art such as spray coating, dip coating, fluidized bed coating and the like.

In one of the embodiments of the present invention, a suitable solvent system such as aqueous or alcoholic or hydro-alcoholic or organic may be used in the granulation or coating. In another embodiment of the present invention a suitable solvent system comprises solvents such as purified water, ethanol, isopropyl alcohol, acetone, methylene chloride and the like.

The pharmaceutical compositions may contain surfactants, which can include anionic, cationic and nonionic surfactants. These include but are not limited to anionic surfactants such as chenodeoxycholic acid, 1-octanesulfonic acid sodium salt, sodium deoxycholate, glycodeoxycholic acid sodium salt, N-lauroylsarcosine sodium salt, lithium dodecyl sulfate, sodium cholate hydrate sodium lauryl sulfate (SLS), sodium dodecyl sulfate (SDS); cationic surfactants such as cetylpyridinium chloride monohydrate and hexadecyltrimethylammonium bromide; nonionic surfactants such as N-decanoyl-N-methylglucamine, octyl a-D- glucopyranoside, n-Dodecyl b-D-maltoside (DDM), polyoxyethylene sorbitan esters like polysorbates and the like.

^•Various excipients that may be used in context of the present invention are but are not limited to, water soluble substances of various grades including: celluloses such as carboxymethyl cellulose, hydroxypropyl methylcellulose, carboxymethylamide; potassium methacrylate/divinylbenzene copolymers; polyvinylpyrrolidone; gums such as agrose, gum arabic, gum ghatti, gum karaya, gum tragacanth; hydrophilic colloids such as alginates; other substances such as arbinoglactan, pectin, amylopectin, and the like. Water-insoluble substances or combinations thereof used in various ratios are exemplified by, but are not limited to fatty acid esters such as glyceryl monostearate, glycerol distearate, glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate and glyceryl behenate; celluloses such as ethyl cellulose, low substituted hydroxypropyl cellulose (L-HPC), cellulose acetates and their derivatives; phthalates such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate; cellulose acylate, cellulose diacylate and cellulose triacylate; cellulose acetate, cellulose diacetate and cellulose triacetate; mono-, di- and tri-cellulose alkanylates, mono-, di-, and tri-cellulose arylates and mono-, di- and tri-cellulose adenylates; polymethacrylic acid based polymers and copolymers such as those sold using the trademark EUDRAGIT (RL, RS and NE-30D); Zein; copolymers of the above polymers or mixtures of any two or more in various ratios and proportions as required are within the scope of this invention without limitation.

The following examples will further illustrate certain aspects of the invention in greater detail and are not intended to limit the scope of the invention.

Example 1

Liquid paliperidone

Table No. 1

S No. Ingredients mg/tab

1. Paliperidone 1.5 - 15. 00

Manufacturing Process:

1. Paliperidone was dispersed in Propylene Glycol

2. Methylene Chloride was added in the above dispersion to obtain a clear solution

3. Thus liquid paliperidone prepared granulated with pharmaceutically acceptable excipients such as Zeopharm or Neusillin or Dibasic calcium Phosphate

Example 2 Paliperidone Resinate

Table No. 2

Method for the preparation of Paliperidone Resinate:

1 part of Paliperidone is dispersed in acidified water 3 parts of polacrilin resin (Amberlite IRP 64 or IRP 88 or Cholestyramine resin LJSP) is added in the above solution and stirred for 1-3 hours. The dispersion obtained is filtered and dried at 60°C to a loss on drying (LOD) < 10 % w/w. The dried resinate was sifted through # 40 mesh.

Example 3

Table No.3

In this approach paliparidone is embedded in solublized/suspension state on excipients (micro-embedding process).

Common Procedure:

1. Paliperidone was dispersed or solublized in PEG or Polypropylene Glycol using methylelene chloride as a co solvent and was granulated with excipients number 4 or 5 or 6 or 8 and was mixed with excipients no.7. This process of granulation done in Rapid mixer granulator or in Fluid bed processor by top spray (Solublization process hastened with addition of pH modifier or surfactant if required).

2. Extra granular material sifted through ASTM # 30 and was blended with for 10 mins.

3. Lubricants sifted through ASTM # 40 and granules of step 2 were blended for 5 mins.

4. Final lubricated blend was compressed with round shape punches of suitable dimensions.

5. The said tablets was coated with rate controlling polymers in Ganscoater using non aqueous or aqueous solvents or readymade pseudo latex as exemplified in Example No.9 & Table No. 9

Propylene Glycol, a Non Volatile Solvent (Ref. Handbook of Excipients), would essentially entrap the paliperidone in a liquid state on the cavity of highly porous excipients.

Example 4

Table No.4

Same composition used for both lower and higher strength, necessary adjustment done with diluents to adjust the weight.

Common Procedure:

1. Paliperidone was sifted together with excipients no.2, 3, & 4 through ASTM # 40 and was used directly for direct compression with extra granular excipients or if required was granulated with non aqueous solvents like methanol or methylene chloride.( granulation was taken in FBP or RMG process) 2. Extra granular material was sifted through ASTM # 30 and blended with above dried granules for 10 mins

3. Lubricants sifted through ASTM # 40 and granules of step 2 were blended for 5 mins

4. Final lubricated blend was compressed with round or oval shape punches of suitable dimensions. 5. The said tablets were coated with rate controlling polymers in Ganscoater using non aqueous or aqueous solvents or readymade pseudo latex as exemplified in Example No.9 & Table No. 9

The process can be altered by using the Liquid Paliperidone in the core tablet or Paliperidone Resinate as prepared in the Example 1 or Example 2.

Example 5

Table No.5

Common Procedure:

1. Paliperidone sifted together with excipients no.2, 3, or 4 or 5 or 6 through ASTM # 40 and can be used directly for direct compression with extra granular excipients or if required was granulated with non aqueous solvents like methanol or methylene chloride.( granulation was taken in FBP or RMG process)

2. Extra granular material was sifted through ASTM # 30 and are proposed to blend with above dried granules for 10 mins

4. Final lubricated blend was compressed with round or oval shape punches of suitable dimensions.

5. The said tablets was coated with rate controlling polymers in Ganscoater using non aqueous or aqueous solvents or readymade pseudo latex as exemplified in Example No.9 & Table No. 9.

The process can be altered by using the_Liquid Paliperidone in the core tablet or Paliperidone Resinate as prepared in the Example 1 or Example 2. Example 6

General Procedure: 1. Paliperidone is proposed to dissolve in water with Tartaric acid or PEG. This solution then used to granulate the excipients 5 or 6 & 7 in FBP to get uniform free flowing granules.

2. Excipient 8 was added and blended to for 10 mins with above dried granules 3. Lubricants numbers 9,10 &11 was sifted through ASTM # 40 or ASTM #60 with granules of step 2 and was blended for 5 mins

4. Final lubricated blend was compressed with round s/c shape punches of suitable dimensions.

Example 7

Process essentially involves the drug layering of paliperidone over celphere along with or without rate controlling polymers and would essentially compressed along with excipients of high compressibility. Rate controlling polymers for the drug could be hydrophobic or hydrophilic polymers, such as ethyl cellulose, Eudragit RLPO/RSPO, PVA & HPMC, Acacia, Eudragit NE 3OD, Xanthan Gum, Sodium Alginate.

Table No.7

General Procedure: 1. Drug Layering: Drug & povidone dissolved in Methylene chloride and sprayed over seal coated or non seal coated celphere of suitable size and fraction. (100 -300 micron) the process was carried out in Wurster ( Bottom spray)

2. ER Coating: Ethyl cellulose dissolved in IPA: Methylene chloride along with Plasticizer, (A pore forming HPMC or Povidone was incorporated along with this polymer to control or regulate the release profile.)

3. These pellets then blended together with extra granular excipients 8,9,10 & 11 , excipients being sifted through suitable sieves and blended together for better uniformity of the pellets across the blend

4. Final lubricated blend compressed with round s/c shape punches of suitable dimensions.

5. The said tablets coated if require with rate controlling polymers in Ganscoater in perforated coating pan using non aqueous or aqueous solvents or readymade pseudo latex solutions to delay or to control the release further with coating composition as exemplified in Example No.9 & Table No. 9.

The MUPS (multiple units of paliperidone were compressed as tablet as IR beads and then (c ore Tablet Containing MUPS Paliperidone) were coated with ER coating as exemplified in the Example No.9 & Table No. 9 to achieve dissolution profile similar to Invega ER tablets mfg. by Janssen. Paliperidone Beads compressed as tablet and coated as exemplified in Example No.9 & Table No. 9

Example 8

Table No.8

General Procedure: 1. Drug granulation: Drug & Povidone added in molten Glyceryl Behenate and was granulated with Excipient no.4 and was dried this process was carried out in RMG or in FBP with top spray granulation.

2. The dried & sifted granules then blended with Excipient no.5

3. Lubricant sifted through ASTM # 40 and or ASTM # 60 and blended with granules of step 2

Example 9

ER Coating composition

Table No.9

Manufacturing Process:

1. Ethyl Cellulose 7 cps dispersed in IPA (70%) & 30 % Methylene chloride added to form a clear solution

2. To this clear solution HPMC or RLPO was added under constant stirring

3. In another solution preparation RSPO dissolved in Acetone and IPA to form a clear solution & In which RLPO was added to form a rate controlling polymeric solution.

It is expected that the desired release for Paliperidone can be obtained by altering the ratio of EC: HPMC or EC: RLPO or RLPO: RSPO to get a desired ascending type release similar to that of Invega ER Tablets. Example 1 to Example 8 can be used to form a core paliperidone tablets and then further coated with polymeric composition as mentioned in the Example 9 to deliver the Paliperidone in GIT. Using the example of table no.4 and coating composition of Example No.9 & Table No. 9 following drug release profile was obtained in SGF pH 1.2.

As explained above we can change the core as required using any of the above examples and a combination of polymers to provide a ascending type of drug 'release which is similar to or comparable to Invega tablets. It appears that the profile obtained is a typical ascending type release as is comparable to the Invega tablets release profile.

Table No.10

Table No.11

Innovator (Invega) Example 4 - 7.5% EC Example 4 - 10% :HPMC (98:2) :HPMC (98:2)

From FDA FOI ( Freedom of Information ) documents submitted by Janssen for the approval of NDA of Paliperidone ER OROS it appears that the dissolution profile is similar across the strengths that is from 1.5 mg to 9.0 mg , hence a similar approach was chosen to prepare core of similar composition as mentioned in example No.4, Hence using the examples of table no.4 and coating composition of Example 9 & Table No. 9 following drug release profile was obtained in SGF pH 1.2 for Paliperidone 6.0 mg / tablet.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.

Claims

I . An orally administrable dosage form comprising (1) an inner core comprising (a) one or more pharmaceutical active agent and (b) combination of hydrophilic and hydrophobic polymers, and (2) a permeable membrane covering the inner core.

2. The dosage form of claim 1 , wherein the permeable membrane is an extended release coating layer.

3. The dosage form of claim 1 , wherein the permeable membrane comprises combination of hydrophilic and hydrophobic polymers with pharmaceutically acceptable excipient.

4. The dosage form of claim 3, wherein the hydrophobic polymer is ethyl cellulose.

5. The dosage form of claim 3, wherein the hydrophilic polymer is hydroxypropyl methyl cellulose.

6. The dosage form of claim 3, wherein ratio of the hydrophobic polymer to hydrophilic polymer is in the range of 90:10 to 30:70.

7. The dosage form of claim 1, wherein the dosage form is for controlled delivery of the active agent.

8. The dosage form of claim 1 , wherein the dosage form is tablet or pellets.

9. The dosage form of claim 1 , wherein the dosage form is non-capsule shaped tablet.

10. An orally administrable dosage form comprising (1) an inner core comprising (a) therapeutically effective amount of paliparidone or pharmaceutically acid addition salts, solvates, enantiomers, recimates, resinates or mixtures thereof and (b) combination of hydrophilic and hydrophobic polymers, and (2) a permeable . membrane, wherein the permeable membrane is covering the inner core.

I I . The dosage form of claim 10, wherein the permeable membrane is an extended release coating layer.

12. The dosage form of claim 10, wherein the permeable membrane comprises combination of hydrophilic and hydrophobic polymers with pharmaceutically acceptable excipient.

^■ 13. The dosage form of claim 12, wherein the hydrophobic polymer is ethyl cellulose,

14. The dosage form of claim 12, wherein the hydrophilic polymer is hydroxypropyl methyl cellulose.

15. The dosage form of claim 12, wherein ratio of the hydrophobic polymer to hydrophilic polymer is in the range of 90:10 to 30:70.

16. The dosage form of claim 10, wherein the dosage form is for controlled delivery of paliparidone or pharmaceutically acid addition salts, solvates, enantiomers, recimates, resinates or mixtures thereof.

17. The dosage form of claim 10, wherein the dosage form is for ascending release of paliparidone or pharmaceutically acid addition salts, solvates, enantiomers, recimates, resinates or mixtures thereof.

18. The dosage form of claim 10, wherein the dosage form is tablet.

19. The dosage form of claim 10, wherein the dosage form is non-capsule shaped tablet.