Description:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULE, 2003
(SECTION 10 and RULE 13)

COMPLETE SPECIFICATION
(See Section 10 and Rule 13)
Amorphous Dispersion and Oral pH Independent Extended-Release Dosage Forms of Paliperidone

Sushen Medicamentos Pvt. Ltd.
A/46, Ashwamegh Industrial Estate, Changodar,
Ahmedabad-382213, Gujarat, INDIA.

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED
Amorphous Dispersion and Oral pH Independent Extended-Release Dosage Forms of Paliperidone
FIELD OF THE INVENTION
The present invention relates to a method for the preparation of spray dried dispersion of paliperidone in an amorphous state. The Invention further relates to an extended-release pharmaceutical composition comprising spray dried dispersion mixed with polymer and other excipients, and compressed & coated to achieve the desired pH independent drug release profile.
BACKGROUND OF THE INVENTION
Paliperidone, a major metabolite of risperidone (9-hydroxyrisperidone), has been approved by the FDA for the treatment of schizophrenia since 2006. Paliperidone is a BCS class II drug. Paliperidone is a weakly alkaline drug with a pH-dependent solubility, the dissolution rate increases with decreasing pH.
Because of the above reasons, bioavailability of oral paliperidone formulations are very low and absorption variations are large depending on stomach condition of each individual including food and disease.
Paliperidone is approved in USA as extended-release tablets and suspension and it has been marketed under the name INVEGA® by Janssen Pharms. Paliperidone is an atypical antipsychotic agent and approved in USA for the treatment of schizophrenia. The commercial Invega® are osmotic pump tablets, and thus show no pH dependency. The delivery system consists of an osmotically active trilayer core surrounded by a subcoat and semipermeable membrane. The trilayer core is composed of two drug layers containing the drug and excipients, and a push layer containing osmotically active components. There are two precision laser-drilled orifices on the drug layer of the tablet. In an aqueous environment, such as the gastrointestinal tract, the water-dispersible overcoat erodes rapidly. Water then enters the tablet through the semipermeable membrane that controls the rate at which water ingress the tablet core, which, in turn, determines the rate of drug delivery. The hydrophilic polymers of the core hydrate and swell creating a gel containing Paliperidone that is then pushed out through the tablet orifices. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool as a tablet shell, along with insoluble core components.
There are various disadvantages associated with osmotic drug-release technology; such as this technology requires highly sophisticated equipments for processes like compression, coating, and laser drilling. Further osmotic drug-release technology requires special excipients like osmogen, osmopolymer, polymer for semipermeable membrane, which ultimately increases the cost of manufacturing. The pharmaceutical industry has utilised a wide range of technologies to attempt to enhance the solubility and/or the rate of dissolution of active pharmaceutical ingredients (APIs).
To increase the solubility of Paliperidone, the use of an amorphous drug, or solid dispersions containing amorphous particles of the drug or the drug in molecularly dispersed form (solid solution), i.e. the use of paliperidone in a non-crystalline state was considered. IN3372/MUM/2012 describe the preparation of the amorphous form of Paliperidone by dissolving the crystalline form of Paliperidone in an organic solvent e.g. ketones, alcohols, esters, nitriles, ethers and hydrocarbons and removing the solvent by, e.g., evaporation, spray-drying or freeze-drying.
WO2008021342 provides amorphous and crystalline forms of Paliperidone and processes for preparing thereof. It discloses the process of preparation of amorphous paliperidone by combining paliperidone and dichloromethane and removing the solvent through evaporation or spray drying technique.
US20180344646A1 discloses the preparation of amorphous dispersion granules (ADG) comprising the steps of dissolving an active pharmaceutical ingredient and a dispersing polymer in a solvent to form a granulation binder; and spraying the granulation binder onto a fluidized substrate comprising at least one tableting agent to form an amorphous dispersion granule are provided.
IN1423/CHE/2011 discloses a method and composition that produces solutions and nano-suspensions to enhance the dissolution rate/solubility of hydrophobic compounds as well as to the solubilized compounds produced by carrying out such process, and are subsequently processed into suitable dosage forms. The method involves primarily solubilising the polymer and surfactant along with the hydrophobic drugs.
The article “Dissolution Rate Enhancement of BCS class II drug, Paliperidone by Spray Drying” disclosed in Research Journal of Pharmaceutical, Biological and Chemical Sciences April 2013 (Volume 4(2):145-155) discloses the appropriate carriers and drug: carrier ratio for preparing the spray dried compositions of Paliperidone (PAL) with different classes of hydrophilic carriers (different grades of polyvinyl pyrrolidones [PVPs, Plasdones] and cellulosic polymers) and concluded that Spray drying of PAL with Plasdones, especially Plasdone K12, reduced drug crystallinity, increased the rate and extent of dissolution.
The prior arts teach us that most of the arts utilized osmotic technology to make the pH independent and bioequivalence product. Few arts disclose the use of non osmotic designs like matrix tablets to match the bioequivalence (BE) study. These designs often incorporate pH dependent polymers, such as Methacrylic acid, carbomer, HPMC, and CAP, to create microenvironmental pH conditions by use of an acidifying agent (fumaric acid) which was not comparable to the Innovator.
To achieve the pH independent in-vitro release profile for paliperidone tablet from non-osmotically designed dosage form and which is comparable to Innovator products having pH independent drug release behaviours manufactured by osmotic technology, the inventor of the present application surprisingly found that the spray drying technics convert the pH dependent API into pH independent by drastically improving its solubility which desired to get the solubility in the selected medium. Further, this SDD (amorphous spray dried dispersion) mixed with polymer and other excipients and compressed and coated to get the desired pH independent profile comparable to Invega®. The obtained novel art is cost effective compared to the Osmotic technology.
OBJECTIVE OF THE INVENTION
Accordingly, an object of the present invention is to provide a process for preparing paliperidone-containing amorphous spray dried dispersion that has improved solubility and rapid dissolution rate, pH-independence drug release, and improved bioavailability.

Another object of the present invention is to provide a method for the preparation of amorphous spray dried solid dispersion of paliperidone that is cost-effective.

Another object of the invention is to provide a method for the preparation of amorphous spray dried solid dispersion of paliperidone by spray drying.

Another object of the invention is to provide an oral pharmaceutical composition comprising the amorphous spray dried dispersion of paliperidone.

Another object of the invention is to provide oral pH independent extended-release pharmaceutical composition of Paliperidone.

Another object of the invention is to provide an extended-release pharmaceutical composition comprising amorphous spray dried dispersion of paliperidone and one or more pharmaceutically acceptable excipients of the invention wherein the core is coated with release controlling polymer to achieve the target drug release.

Yet another object of the invention is to provide the extended-release pharmaceutical composition comprising the amorphous spray dried dispersion of paliperidone, wherein the dosage form is the tablet.

Another object of the invention, the extended-release pharmaceutical composition comprising the amorphous spray dried dispersion of paliperidone are provided, having in vitro drug release comparable with Invega and pH independent. Another object of the invention is to provide the extended-release pharmaceutical composition comprising the amorphous spray dried dispersion of paliperidone of the present invention, having similar drug release profile in different pH conditions for each strength.
Detailed Description
An "amorphous " as used in the present invention means a state of solid substances exhibiting no definite crystalline structure. The formation of characteristic peak in the form of a diffractogram is the indication of specific amorphous form formation and is considered a critical quality parameter.
An “amorphous spray dried dispersion” or “spray dried dispersion” refers to the spray dried material obtained in an amorphous form through the spray drying of active pharmaceutical ingredient API, polymer solution into dried form to make oral pH independent extended-release solid dosage form of Paliperidone.
The term “pH-independent” for purposes of the present invention is defined as having characteristics (e.g., dissolution) that are substantially unaffected by pH and at any given time show equivalent drug release to that of Invega.
Hereinafter, a preferred embodiment of the present invention will be described in detail. Prior to the description, it should be understood that various modifications are possible to the embodiments of the present invention, and it should be understood that the scope of the invention is not limited to the following embodiments. The embodiments are purposed to merely give a better explanation of the invention to those ordinarily skilled in the art.
The invention relates to a process for the preparation of amorphous spray dried dispersion of paliperidone, prepared by spray-drying technique that has improved solubility and rapid dissolution rate of paliperidone.
The invention further relates to a pharmaceutical composition comprising amorphous spray dried dispersion of paliperidone with polymer, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients such as diluent, disintegrant, glidants, and lubricant.
Paliperidone as such is very less soluble in aqueous media and has pH dependent solubility.
According to one embodiment, the invention relates to a process for preparing amorphous spray dried dispersion of paliperidone, prepared by spray-drying technique, comprising: preparing a solution of Paliperidone and at least one polymer and /or at least one pharmaceutical acceptable excipient in a solvent or mixture of solvents; and drying the solution.
According to another embodiment, the invention relates to the process for preparing amorphous spray dried dispersion of paliperidone, prepared by spray-drying technique, comprising: preparing a solution in which paliperidone, polymer and solvent are dissolved, wherein the solvent are selected from group consisting of 0.1N Hydrochloric acid (HCl), Methanol, Isopropanol (IPA) and Dichloromethane (DCM).
In preferable embodiment, the invention relates to the process for preparing an amorphous spray dried dispersion of paliperidone, prepared by spray-drying technique, comprising: preparing a solution in which paliperidone, polymer and 0.1N HCl are dissolved; and drying the solution.
According to another embodiment, the invention relates to process for preparing an amorphous spray dried dispersion of paliperidone, prepared by spray-drying technique, comprising: preparing a solution in which paliperidone, polymer, and Methanol-IPA mixture are dissolved; and drying the solution.
According to another embodiment, the invention relates to the process for preparing an amorphous spray dried dispersion of paliperidone, prepared by spray-drying technique, comprising: preparing a solution in which paliperidone, polymer and DCM-IPA mixture are dissolved; and drying the solution.
The present inventors carried out series of experiments with many organic and inorganic solvents. However, most solvents except some acids are difficult to form a solid dispersion and some in such solvents did not increase the solubility of paliperidone and were dependent on the change of pH. Some solid dispersions using some solvents were too unstable, difficult to handle and not feasible to commercialize. Surprisingly, the inventor of the current invention found that paliperidone-containing spray dried dispersions using 0.1N HCl overcame the above-described limitations.
According to another embodiment of the present invention, the polymer is selected from the group comprising polymers with high glass transition temperatures and low hygroscopicity, such as Copovidone, Hydroxypropyl Methylcellulose Phthalate (HPMCP), Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS), Hydroxypropyl Beta Cyclodextrin (HPBCD), Hydroxypropyl Methylcellulose (HPMC), Hydroxypropyl Cellulose (HPC), Polymethacrylate, Cellulose Acetate Phthalate (CAP).
An amorphous spray dried dispersion of paliperidone prepared by the methods of the present invention has remarkably improved solubility and dissolution rate and these solubility and dissolution rate are pH-independent.

Another advantage of the preparation method of the present invention is that it is cost effective because of non-osmotic technology.

According to another embodiment, a drug-polymer solution prepared in a common volatile organic solvent(s) is mechanically or pneumatically atomized into fine droplets followed by solvent evaporation at an extremely fast rate using a drying gas inside a drying chamber and the solid particles formed are collected in a cyclone.
The preparation method and solid dispersion of the present invention will be described in detail below.
(I) General method of Manufacturing of spray dried dispersions
1) Preparation of drug solution,
2) Preparation of polymeric solution,
3) Mixing of dug solution to the polymeric solution,
4) The prepared drug/polymer solution, in the desired ratio, was spray dried.

(II) Preparation of pH-independent amorphous spray dried dispersion of paliperidone
1) Preparation of complex solution of Paliperidone, polymer, and solvent,
2) The prepared drug-polymer solution, in the desired ratio, was spray dried using a spray drying machine with a suitable nozzle diameter,
3) The solutions of step 1 were fed to the nozzle via a peristaltic pump (flow rate of 5-15 ml/min),
4) The solutions were sprayed as atomized sprays by the force of compressed nitrogen,
5) The solvents in the droplets were evaporated in the drying chamber (inlet temperature of 80°C -150°C), and;
6) The spray dried products were collected in the amorphous form in a collection vessel.
According to another embodiment of the present invention, there is provided a pharmaceutical solid composition of Paliperidone SDD, wherein the SDD comprises paliperidone in an amount of at least 0.05 weight percent (wt%), preferably at least 0.5 wt %, more preferably at least 0.15 wt % and most preferably at least 0.35 wt %, based on the total weight of the SDD.
According to another embodiment, the amount of active pharmaceutical ingredient as a ratio by weight to the polymer used in the present invention for preparing paliperidone-containing solid dispersion is from 1:1 to 1:5.
In a preferred embodiment of the present invention, the amount of active pharmaceutical ingredient as a ratio by weight to the polymer used in the present invention for preparing paliperidone-containing solid dispersion is from 1:1 to 1:3.
According to one embodiment of the present invention, the pharmaceutical composition comprising Paliperidone SDD and one or more pharmaceutically acceptable excipients are disclosed. The present invention provides a stable oral solid pharmaceutical composition comprising Paliperidone SDD and one or more pharmaceutically acceptable excipients.
The pharmaceutical compositions of the present invention can be any solid dosage form for example, but not limited to, granules, tablets, and capsules. The core dosage forms can be prepared by any of the means using excipients well known to person skilled in the art.
According to one embodiment of the present invention, the pharmaceutical tablet composition comprises a core and at least one coating layer covering the core is disclosed, wherein the core contains a spray dried dispersion (SDD) of paliperidone and a pharmaceutically acceptable excipient.
According to an embodiment of the present invention, the pharmaceutical tablet composition is extended release pharmaceutical composition comprising an amorphous spray dried dispersion of paliperidone and one or more pharmaceutically acceptable excipient wherein the core is coated with release controlling polymers to achieve the target drug release.
The "extended release" as used herein refers to the release of an active ingredient from a pharmaceutical composition or dosage form, in which the active ingredient is released over an extended period of time and/or at particular location and is taken to encompass sustained release, controlled release, modified release, prolonged release, delayed release and the like.
According to another embodiment of the present invention, there are provided oral pharmaceutical compositions of Paliperidone SDD and one or more pharmaceutically acceptable excipients. Examples of pharmaceutical excipients include but are not limited to diluent, matrix forming materials, lubricant, binders, glidants, disintegrants. A combination of excipients may also be used. The amount of excipient(s) employed will depend upon how much active agent is to be used. One excipient can perform more than one function.
According to another embodiment of the present invention, there is provided pharmaceutical solid composition of Paliperidone SDD, wherein the pharmaceutical excipients present in an amount at most 0.5 wt %, preferably at most 10 wt %, more preferably at most 40 wt % and most preferably at most 90 wt % excipient, based on the total weight of the tablets. The total weight (or weight percent) of all the ingredients presents in the tablets add up to 100 wt %.

In a preferred embodiment of the invention, the compressed core comprises paliperidone SDD; an absorbent such as Colloidal silicon dioxide; a binder such as microcrystalline cellulose; a diluent such as lactose (including lactose monohydrate), mannitol, sorbitol, or xylitol; matrix forming material such as Hypromellose K15 M / Poloxamer 188; and a lubricant such as magnesium stearate.

The diluent used in the pharmaceutical composition of the present invention, but are not limited to, is selected from the group consisting of lactose (including lactose monohydrate), starch, sorbitol, mannitol, Sucrose, colloidal silica, spray dried lactose, lactose anhydrous, calcium dihydrogen phosphate, calcium phosphate dibasic anhydrous, microcrystalline cellulose and their mixture. The diluent is used either alone or in combination in the range of about 10% to 40 % weight by weight of total weight of tablet.
The lubricant is used to give a good free flowability during capsule filling and packing of powder, granule, and pellet, or to prevent tableting problems like Sticking and capping. The lubricants used in the pharmaceutical composition of the present invention, but are not limited to, is selected from the group consisting of colloidal silica, talc, magnesium stearate and their mixture. The lubricant is used either alone or in combination in the range of about 0.2% to 4.0 % weight by weight of the total weight of the tablet.
The glidant used in the pharmaceutical composition of the present invention, but are not limited to, is selected from the group of colloidal silicon dioxide, Cornstarch, Talc. The binder is used either alone or in combination in the range of about 10% to 40 % weight by weight of the total weight of the tablet.
The binders used in the pharmaceutical composition of the present invention, but are not limited to, is selected from the group consisting of starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose such as products known under the registered trademarks Avicel; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC), ethyl cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, polypropylene glycol, tragacanth, combinations thereof and other materials known to one of ordinary skill in the art and mixtures thereof. The binder is used either alone or in combination in the range of about 10 % to 40 % weight by weight of the total weight of the tablet.
The matrix forming materials used in the pharmaceutical composition of the present invention, but are not limited to, are from the group consisting of Hypromellose K15 M, Poloxamer 188, Hypromellose K4M, K100M, K100LV, and their mixture. The binder is used either alone or in combination in the range of about 10% to 60 % weight by weight of the total weight of the tablet.
The core tablets comprising spray dried dispersion of paliperidone and one or more pharmaceutical excipients can be prepared by processes well known to those of skill in the art. For example, core tablets can be prepared by wet granulation, dry granulation, melt granulation, and the like. In an embodiment, the core tablets comprising spray dried dispersion of paliperidone are prepared by wet granulation.
In a further embodiment, the core dosage forms comprising spray dried dispersion of paliperidone are then coated with a suitable release controlling composition to control the release rate of spray dried dispersion of Paliperidone, the release controlling composition comprises release controlling polymer.
Suitable release controlling polymers include but are not limited to Ethylcellulose, Hydroxypropyl methylcellulose (HPMC), Hypromellose phthalate, Acrylic and Methacrylic acid, IPA, Water, Acetone, Triethyl cellulose (TEC), Water, Opadry.
The controlled release properties of the pharmaceutical composition of the present invention may be demonstrated by monitoring the dissolution of the active ingredient. The dissolution of the active ingredient may be monitored using standard procedures well known to those skilled in the art.
In an embodiment, comparative dissolution studies were conducted between the pharmaceutical composition of the present invention and commercially available Invega® of similar strengths. These studies were performed across different pH conditions i.e. at pH 1.2, pH 4.5, and pH 6.8. The dissolution profile was determined using the Paddle Method at rotation speed of 50 rpm in 500 mL dissolution media for 24 hours. The results obtained are presented in Table 1(a), 1(b), 1(c), Tables 2(a), 2(b), 2(c), and Tables 3(a), 3(b), 3(c) of Example 9.
According to an embodiment, the pharmaceutical composition of the present invention provides drug release when measured in 500 mL buffer having 1.2 pH, Acetate buffer of 4.5 pH, and phosphate buffer of 6.8 pH compared with the commercially available Invega® in such a way that:
a) about 30% or more of total paliperidone releases after 8 hours of measurement in said apparatus,
b) about 60% or more of total paliperidone releases after 14 hours of measurement in said apparatus, and;
c) about 100% of total paliperidone releases after 24 hours of measurement in said apparatus
In yet another embodiment, the extended-release dosage form of the present invention provides comparable drug release to the commercially available Invega® for an extended period of time.
“Extended period of time” means a continuous period of time of greater than about 2 hours, preferably, greater than about 4 hours, more preferably, greater than about 6 hours, more preferably greater than about 8 hours, still more preferably, greater than about 18 hours, most preferably, greater than about 18 hours and up to about 24 hours.
According to another embodiment, the extended release dosage form of the present invention provides similar drug release in all three tested pH environments for each strength.
A paliperidone containing spray dried dispersion made by the method of the present invention has improved bioavailability, reduced variation in intra- and inter-individuals, and good stability. That is, the present invention provides a method for preparing a paliperidone-containing spray dried dispersion that can release paliperidone without change according to the stomach condition of an individual (for example, dietary condition, food, and disease) because its solubility and dissolution rate are not changed in extensive pH range. The method of the present invention is economical because it cannot require special excipients like osmogen, osmopolymer, polymer for semipermeable membrane, which ultimately increases cost of manufacturing.
The present invention has been described by way of example only, and it is to be recognized that modifications thereto which fall within the scope and spirit of the appended claims, and which would be obvious to a skilled person based upon the disclosure herein, are also considered to be included within the invention.

EXAMPLES
EXAMPLE 1-
Preparation of an amorphous spray dried dispersion of paliperidone
Paliperidone and polymer in a ratio 1:3 was dissolved in 0.1 N hydrochloric acid (HCl) for making a spray-drying solution. The solution was then sprayed and dried using a spray-dryer to make an amorphous spray dried dispersion of paliperidone.
EXAMPLE 2
Preparation of an amorphous spray dried dispersion of paliperidone
Paliperidone and polymer in ratio 1:3 were dissolved in IPA-DCM to make a spray-drying solution. The solution was then sprayed and dried using a spray dryer to make a paliperidone-containing spray dried dispersion. Spraying conditions were as follows: spray pump speed: 4-10 rpm, spraying velocity 15-30 L/min, spray-drying pressure 2-4.5 kg/L, inlet air temperature 80-150° C. and outlet air temperature 70-150° C.
EXAMPLE 3
Preparation of an amorphous spray dried dispersion of paliperidone
Paliperidone and polymer in ratio 1:3 was dissolved in IPA-Methanol for making a spray-drying solution. The solution was then sprayed and dried using a spray-dryer to make a paliperidone-containing spray dried dispersion (SDD). Spraying conditions were as follows: spray pump speed 4-10 rpm, spraying velocity 15-30 L/min, spray-drying pressure 2-4.5 kg/L, inlet air temperature 80-150° C. and outlet air temperature 70-150° C.
EXAMPLE 4: Pharmaceutical Composition of Paliperidone SDD
S.No. Ingredients % W/W
1. Paliperidone SDD
1.a Paliperidone Drug Substance 0.5 to 3.5
1.b HPMC E5/ Copovidone/ HPMCP/ HPMCAS/ HPBCD/ HPMC/ Polymethacrylate/ HPC/CAP 3.5 to 10.5
1.c 0.1N HCl/ IPA: DCM/ IPA:Methanol qs
2. Compression
2.a Lactose Monohydrate 10-40
2.b Microcrystalline Cellulose 10-40
2.c Colloidal silicon dioxide 0.5-4.0
2.d Magnesium Stearate 0.2-4.0
2.e Hypromellose K15 M / Poloxamer 188 10-60
2.f Purified Water/IPA qs
3. Coating
3.a Ethyl cellulose qs
3.b HPMC qs
3.c IPA qs
3.d Water qs
3.e Opadry qs

EXAMPLE 5 Pharmaceutical Composition of Paliperidone SDD
S.No. Ingredients Example 5a
Example 5b Example 5c
% W/W/ Tablet % W/W/ Tablet % W/W/ Tablet
1. Paliperidone SDD
1.a Paliperidone Drug Substance 1.056 2.090 3.103
1.b HPMC E5/ Copovidone/ HPMCP/ HPMCAS/ HPBCD/ HPMC/ Polymethacrylate/ HPC/CAP 3.169 6.271 9.310
1.c 0.1N HCl QS QS QS
2. Compression
2.a Lactose Monohydrate 16.55 16.38 16.21
2.b Microcrystalline Cellulose 16.55 16.38 16.21
2.c Colloidal silicon dioxide 0.99 0.98 0.97
2.d Magnesium Stearate 0.49 0.49 0.48
2.e Hypromellose K15 M / Poloxamer 188 51.34 50.80 50.28
2.f Purified Water/IPA QS QS QS
3. Coating
3.a Ethyl cellulose QS QS QS
3.b HPMC QS QS QS
3.c IPA QS QS QS
3.d Water QS QS QS
3.e Opadry QS QS QS

EXAMPLE 6 Pharmaceutical Composition of Paliperidone SDD
S.No. Ingredients Quantity mg/Tablet
1. Paliperidone SDD
1.a Paliperidone Drug Substance 3
1.b HPMC E5/ Copovidone/ HPMCP/ HPMCAS/ HPBCD/ HPMC/ Polymethacrylate/ HPC/CAP 9
1.c 0.1N HCl/ IPA-DCM/IPA-Methanol QS
2. Compression
2.a Lactose Monohydrate 47.00
2.b Microcrystalline Cellulose 47.00
2.c Colloidal silicon dioxide 2.80
2.d Magnesium Stearate 1.40
2.e Hypromellose K15 M / Poloxamer 188 145.80
2.f Purified Water/IPA QS
3. Coating
3.a Ethyl cellulose QS
3.b HPMC QS
3.c IPA QS
3.d Water QS
3.e Opadry QS
Total Weight 284

Manufacturing Procedure
A. Mix paliperidone SDD with Colloidal silicon dioxide; microcrystalline cellulose; lactose (including lactose monohydrate), mannitol, sorbitol, or xylitol; Hypromellose K15 M / Poloxamer 188; and magnesium stearate,
B. Compress the lubricated blend into tablets by using suitable punches.
C. Coat the core tablet of step B using coating solution prepared by dissolving Ethyl cellulose, HPMC, Opadry, IPA and water.

EXAMPLE 7 Pharmaceutical Composition of Paliperidone SDD
S.No. Ingredients Quantity mg/Tablet
1. Paliperidone SDD
1.a Paliperidone Drug Substance 6
1.b HPMC E5/ Copovidone/ HPMCP/ HPMCAS/ HPBCD/ HPMC/ Polymethacrylate/ HPC/CAP 18
1.c 0.1N HCl/ IPA-DCM/IPA-Methanol QS
2. Compression
2.a Lactose Monohydrate 47.00
2.b Microcrystalline Cellulose 47.00
2.c Colloidal silicon dioxide 2.80
2.d Magnesium Stearate 1.40
2.e Hypromellose K15 M / Poloxamer 188 145.80
2.f Purified Water/IPA QS
3. Coating
3.a Ethyl cellulose QS
3.b HPMC QS
3.c IPA QS
3.d Water QS
4.e Opadry QS
Total Weight 287

Manufacturing Procedure
A. Mix paliperidone SDD with Colloidal silicon dioxide; microcrystalline cellulose; lactose (including lactose monohydrate), mannitol, sorbitol, or xylitol; Hypromellose K15 M / Poloxamer 188; and magnesium stearate,
B. Compress the lubricated blend into tablets by using suitable punches.
C. Coat the core tablet of step B using coating solution prepared by dissolving Ethyl cellulose, HPMC, Opadry, IPA and water.
EXAMPLE 8 Pharamceutical Composition of Paliperidone SDD
S.No. Ingredients Quantity mg/Tablet
1. Paliperidone SDD
1.a Paliperidone Drug Substance 9
1.b HPMC E5/ Copovidone/ HPMCP/ HPMCAS/ HPBCD/ HPMC/ Polymethacrylate/ HPC/CAP 27
1.c 0.1N HCl/ IPA-DCM/IPA- Methanol QS
2. Compression
2.a Lactose Monohydrate 47.00
2.b Microcrystalline Cellulose 47.00
2.c Colloidal silicon dioxide 2.80
2.d Magnesium Stearate 1.40
2.e Hypromellose K15 M / Poloxamer 188 145.80
2.f Purified Water/IPA QS
3. Coating
3.a Ethyl cellulose QS
3.b HPMC QS
3.c IPA QS
3.d Water QS
4.e Opadry QS
Total Weight 290

Manufacturing Procedure
A. Mix paliperidone SDD with Colloidal silicon dioxide; microcrystalline cellulose; lactose (including lactose monohydrate), mannitol, sorbitol, or xylitol; Hypromellose K15 M / Poloxamer 188; and magnesium stearate,
B. Compress the lubricated blend into tablets by using suitable punches.
C. Coat the core tablet of step B using coating solution prepared by dissolving Ethyl cellulose, HPMC, Opadry, IPA and water.

EXAMPLE 9 Comparative dissolution study in dissolution media of varying pH
The formulations containing 3mg, 6mg, and 9 mg were subjected to comparative dissolution study with INVEGA® 3mg, 6 mg and 9mg, respectively at pH 1.2, pH 4.5, and pH 6.8. In vitro Dissolution test carried out using Paddle Method in 500 ml of dissolution media, at rotation speed of 50 RPM for 24 hours and the results obtained are presented in below table:
Table 1(a): Comparative Drug Release Profile of Invega 3mg And Test 3mg at pH 6.8
Invega 3 mg Test 3 mg
Media pH 6.8 Phosphate Buffer
Volume 500
RPM 50 / Paddle with sinker
Time point (hr) Avg. % RSD Avg. % RSD
1 2 7.4 0 10.2
2 3 4.2 0 9.8
4 5 4.6 4 8.8
6 12 6.5 10 8.6
8 21 4.8 23 5.5
12 42 5.0 42 4.2
14 55 5.0 56 3.2
18 80 2.8 78 2.1
24 101 2.5 98 2.0
Table 1(b): Comparative Drug Release Profile of Invega 6mg And Test 6mg at pH 6.8
Invega 6 mg Test 6 mg
Media pH 6.8 Phosphate Buffer
Volume 500
RPM 50 / Paddle with sinker
Time point (hr) Avg. % RSD Avg. % RSD
1 0 8.2 0 16.2
2 1 8.0 1 9.8
4 3 5.5 5 8.6
6 14 4.6 12 7.6
8 25 2.5 20 7.6
12 45 2.1 43 7.5
14 54 2.0 53 2.2
18 80 2.0 82 2.3
24 98 1.6 102 1.2
Table 1(c): Comparative Drug Release Profile of Invega 9mg And Test 9mg at pH 6.8
Invega 9 mg Test 9 mg
Media pH 6.8 Phosphate Buffer
Volume 500
RPM 50 / Paddle with sinker
Time point (hr) Avg. % RSD Avg. % RSD
1 1 13.4 0 20.0
2 1 4.5 3 9.6
4 4 4.2 8 5.5
6 11 6.4 13 5.0
8 19 7.4 22 4.0
12 40 6.4 42 3.3
14 52 5.9 58 3.0
18 78 6.0 77 2.0
24 99 2.8 100 1.2
Table 2(a) Comparative Drug Release Profile of Invega 3mg And Test 3mg at pH 1.2
Invega 3 mg Test 3 mg
Media pH 1.2 Buffer
Volume 500
RPM 50 / Paddle with sinker
Time point (hr) Avg. % RSD Avg. % RSD
1 0 7.4 0 10.2
2 1 4.2 0 9.8
4 7 4.6 8 8.8
6 13 6.5 12 8.6
8 19 4.8 23 5.5
12 45 5.0 42 4.2
14 53 5.0 53 3.2
18 80 2.8 78 2.1
24 101 2.5 98 2.0

Table 2(b) Comparative Drug Release Profile of Invega 6mg And Test 6mg at pH 1.2
Invega 6 mg Test 6 mg
Media pH 1.2 Buffer
Volume 500
RPM 50 / Paddle with sinker
Time point (hr) Avg. % RSD Avg. % RSD
1 0 8.2 0 16.2
2 1 8.0 3 9.8
4 4 5.5 6 8.6
6 11 4.6 16 7.6
8 23 2.5 26 7.6
12 40 2.1 43 7.5
14 56 2.0 59 2.2
18 78 2.0 80 2.3
24 98 1.6 102 1.2
Table 2(c) Comparative Drug Release Profile of Invega 9mg And Test 9mg at pH 1.2
Invega 9 mg Test 9 mg
Media pH 1.2 Buffer
Volume 500
RPM 50 / Paddle with sinker
Time point (hr) Avg. % RSD Avg. % RSD
1 1 28.9 0 20.2
2 1 11.7 0 10.0
4 4 9.8 6 9.8
6 11 7.5 13 5.2
8 20 9.4 23 4.5
12 41 7.0 42 5.5
14 52 7.1 55 2.2
18 77 6.1 80 2.2
24 97 2.9 99 1.0
Table 3(a) Comparative Drug Release Profile of Invega 3mg And Test 3mg at pH 4.5
Invega 3 mg Test 3 mg
Media pH 4.5 Acetate Buffer
Volume 500
RPM 50 / Paddle with sinker
Time point (hr) Avg. % RSD Avg. % RSD
1 0 7.4 0 10.2
2 1 4.2 1 9.8
4 6 4.6 3 8.8
6 13 6.5 15 8.6
8 20 4.8 22 5.5
12 42 5.0 40 4.2
14 56 5.0 56 3.2
18 77 2.8 78 2.1
24 101 2.5 99 2.0
Table 3(b) Comparative Drug Release Profile of Invega 6mg And Test 6mg at pH 4.5
Invega 6 mg Test 6 mg
Media pH 4.5 Acetate Buffer
Volume 500
RPM 50 / Paddle with sinker
Time point (hr) Avg. % RSD Avg. % RSD
1 0 8.2 1 16.2
2 1 8.0 1 9.8
4 8 5.5 10 8.6
6 13 4.6 14 7.6
8 22 2.5 23 7.6
12 45 2.1 43 7.5
14 58 2.0 59 2.2
18 81 2.0 80 2.3
24 98 1.6 102 1.2
Table 3(c) Comparative Drug Release Profile of Invega 9mg And Test 9mg at pH 4.5
Invega 9 mg Test 9 mg
Media pH 4.5 Acetate Buffer
Volume 500
RPM 50 / Paddle with sinker
Time point (hr) Avg. % RSD Avg. % RSD
1 1 15.0 0 24.0
2 1 10.6 2 10.1
4 4 9.9 6 5.5
6 11 9.2 12 6.0
8 19 8.6 22 5.2
12 39 4.5 40 4.2
14 50 5.2 53 4.3
18 75 4.5 78 2.0
24 95 3.2 100 2.0

Dated this 5th day of April 2024
Digitally/E- Signed by
Name: Kirti Atul Kathiriya
IN/PA 3421

I/ We CLAIM,
1. An amorphous spray dried dispersion comprising Paliperidone and at least one polymer.

2. The amorphous spray dried dispersion according to claim 1, wherein the polymer is selected from the group of polymers with high glass transition temperatures and low hygroscopicity.

3. The amorphous spray dried dispersion according to claim 1, wherein the polymer is selected from the group comprising of Copovidone, Hydroxypropyl Methylcellulose Phthalate, Hydroxypropyl Methylcellulose Acetate Succinate, Hydroxypropyl Beta Cyclodextrin, Hydroxypropyl Methylcellulose, Hydroxypropyl Cellulose, Polymethacrylate and Cellulose Acetate Phthalate.

4. The amorphous spray dried dispersion according to claim 1, wherein the weight ratio of the Paliperidone to the polymer is 1:1 to 1:5.

5. The amorphous spray dried dispersion according to claim 1, wherein the said amorphous spray dried dispersion of paliperidone is pH independent.

6. A method of preparing amorphous spray dried dispersion of paliperidone, wherein the method comprising the following steps:
a) Providing a complex solution of Paliperidone and at least one polymer and /or at least one pharmaceutical acceptable excipient in a solvent or mixture of solvents,
b) Spraying the resultant solution as atomized spray by the force of compressed nitrogen,
c) Simultaneous evaporation or removal of the solvent from the solution obtained in step a) at inlet temperature of 80-150 °C,
d) Isolating the amorphous spray dried dispersion of Paliperidone,
e) Optionally, solvent from a solution obtained in step (a) is removed using spray drying.

7. The method of preparing amorphous spray dried dispersion according to claim 6, wherein the polymer is selected from the group Copovidone, Hydroxypropyl Methylcellulose Phthalate, Hydroxypropyl Methylcellulose Acetate Succinate, Hydroxypropyl Beta Cyclodextrin, Hydroxypropyl Methylcellulose, Hydroxypropyl Cellulose, Polymethacrylate, Cellulose Acetate Phthalate.

8. The method of preparing amorphous spray dried dispersion according to claim 6, wherein the solvent used is selected from group comprising of 0.1N HydroChloric Acid, Methanol, Isopropyl Alcohol, Dichloromethane and mixture thereof.

9. An oral pharmaceutical composition, comprises amorphous spray dried dispersion of Paliperidone and one or more pharmaceutical excipients.

10. The oral pharmaceutical composition according to claim 9, wherein the said oral pharmaceutical composition comprising a core and at least one coating layer wherein the core comprises 0.5 wt % to 3.5 wt % paliperidone based on the total weight of the spray dried dispersion.

11. The oral pharmaceutical composition according to claim 9, wherein the pharmaceutical composition further comprises an adsorbent, a diluent, a matrix forming materials, a lubricant, a binder, a glidants, a disintegrants and one or more pharmaceutically acceptable excipient.

12. The oral pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is tablet.

13. The oral pharmaceutical composition according to claim 9, wherein the tablet is prepared in the form of extended-release tablet, sustained release tablet or controlled release tablet.

14. The oral pharmaceutical composition according to claim 9, wherein the coating layer comprises release controlling polymer selected from group comprising of Ethyl cellulose, Hydroxypropyl Methylcellulose and Opadry.
Dated this 5th day of April 2024
Digitally/E- Signed by,
Name: Kirti Atul Kathiriya
IN/PA 3421

ABSTRACT

Amorphous Dispersion and Oral pH Independent Extended-Release Dosage Forms of Paliperidone
The present invention relates to a method for the preparation of spray dried dispersion of paliperidone in an amorphous state. The invention further relates to a pharmaceutical composition comprising spray dried dispersion mixed in polymer and compressed & coated to achieve the desired pH independent drug release profile.
, Claims:I/ We CLAIM,
1. An amorphous spray dried dispersion comprising Paliperidone and at least one polymer.

2. The amorphous spray dried dispersion according to claim 1, wherein the polymer is selected from the group of polymers with high glass transition temperatures and low hygroscopicity.

3. The amorphous spray dried dispersion according to claim 1, wherein the polymer is selected from the group comprising of Copovidone, Hydroxypropyl Methylcellulose Phthalate, Hydroxypropyl Methylcellulose Acetate Succinate, Hydroxypropyl Beta Cyclodextrin, Hydroxypropyl Methylcellulose, Hydroxypropyl Cellulose, Polymethacrylate and Cellulose Acetate Phthalate.

4. The amorphous spray dried dispersion according to claim 1, wherein the weight ratio of the Paliperidone to the polymer is 1:1 to 1:5.

5. The amorphous spray dried dispersion according to claim 1, wherein the said amorphous spray dried dispersion of paliperidone is pH independent.

6. A method of preparing amorphous spray dried dispersion of paliperidone, wherein the method comprising the following steps:
a) Providing a complex solution of Paliperidone and at least one polymer and /or at least one pharmaceutical acceptable excipient in a solvent or mixture of solvents,
b) Spraying the resultant solution as atomized spray by the force of compressed nitrogen,
c) Simultaneous evaporation or removal of the solvent from the solution obtained in step a) at inlet temperature of 80-150 °C,
d) Isolating the amorphous spray dried dispersion of Paliperidone,
e) Optionally, solvent from a solution obtained in step (a) is removed using spray drying.

7. The method of preparing amorphous spray dried dispersion according to claim 6, wherein the polymer is selected from the group Copovidone, Hydroxypropyl Methylcellulose Phthalate, Hydroxypropyl Methylcellulose Acetate Succinate, Hydroxypropyl Beta Cyclodextrin, Hydroxypropyl Methylcellulose, Hydroxypropyl Cellulose, Polymethacrylate, Cellulose Acetate Phthalate.

8. The method of preparing amorphous spray dried dispersion according to claim 6, wherein the solvent used is selected from group comprising of 0.1N HydroChloric Acid, Methanol, Isopropyl Alcohol, Dichloromethane and mixture thereof.

9. An oral pharmaceutical composition, comprises amorphous spray dried dispersion of Paliperidone and one or more pharmaceutical excipients.

10. The oral pharmaceutical composition according to claim 9, wherein the said oral pharmaceutical composition comprising a core and at least one coating layer wherein the core comprises 0.5 wt % to 3.5 wt % paliperidone based on the total weight of the spray dried dispersion.

11. The oral pharmaceutical composition according to claim 9, wherein the pharmaceutical composition further comprises an adsorbent, a diluent, a matrix forming materials, a lubricant, a binder, a glidants, a disintegrants and one or more pharmaceutically acceptable excipient.

12. The oral pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is tablet.

13. The oral pharmaceutical composition according to claim 9, wherein the tablet is prepared in the form of extended-release tablet, sustained release tablet or controlled release tablet.

14. The oral pharmaceutical composition according to claim 9, wherein the coating layer comprises release controlling polymer selected from group comprising of Ethyl cellulose, Hydroxypropyl Methylcellulose and Opadry.