Stable paliperidone palmitate composition using thermal treatment

Abstract

The present invention is related to a stable pharmaceutical injectable depot microsuspension of Paliperidone Palmitate prepared by wet media milling process including the thermal treatment Thermal treatment incorporated during the manufacturing process produced the injectable depot microsuspension with stable particle size and stable drug release.

Description

[0001] STABLE PALIPERIDONE PALMITATE COMPOSITION USING THERMAL TREATMENT

[0002] FIELD OF THE INVENTION

[0003] This invention is about stable Paliperidone Palmitate (PAP) composition and its process for manufacturing. This composition is prepared by wet media milling process by including a thermal treatment process step for improved storage stability without instability problems caused due to change in particle size and dissolution rate upon storage. The storage stability problem was eliminated by incorporating thermal treatment step during the manufacturing. Composition prepared by this modified process resulted in more stable composition with narrower particle size distribution, and improved storage stability, especially in terms of dissolution rate and particle size.

[0004] BACKGROUND OF THE INVENTION:

[0005] Paliperidone is an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives.

[0006] Paliperidone Palmitate (PAP) is chemically the palmitate ester of paliperidone (9-hydroxy- risperidone), a monoaminergic antagonist that exhibits the characteristic dopamine D2 and serotonin (5 -hydroxytryptamine type 2A) antagonism of the second generation, atypical antipsychotic drugs. Paliperidone (9-OH risperidone) is the major active metabolite of risperidone.

[0007] The chemical name for Paliperidone Palmitate is 3 - ( 2 - ( 4 - ( 6 - fluoro - 3a , 7a - dihydrobenzo [ d ] isoxazol - 3 - yl ) piperidin - 1 - yl ) ethyl ) - 2 - methyl - 4 - oxo - 6 , 7 , 8 , 9 - tetrahydro - 4H pyrido [1, 2-a] pyrimidin - 9 - yl palmitate and is represented by the following structural formula:

[0008] Long-acting injectable antipsychotic drug Paliperidone Palmitate (PAP) is used for schizophrenic patients with poor medication adherence. It is also used to treat mania and at lower doses as maintenance for bipolar disorder (Invega Sustenna package insert http: / / www.janssenlabels.com / package-insert / product-monograph / prescribing information / INVEG A+ SUSTENNA-pi.pdf; Annals of General Psychiatry, 2011, 10:12). Also, it can be used as an adjunct to mood stabilizers or antidepressants. PAP is superior because of long intervals between injections, easy applicability, tolerability, and enhanced patient compliance and provides significant improvement in psychotic symptoms (Newton R, Hustig H, Lakshmana R, et al., Practical guidelines on the use of paliperidone palmitate in schizophrenia, Curr Med Res Opin., 2012; 28: 559—567.; Gonzdlez-Rodriguez A, Catalan R, Penades R, et al., Profile of paliperidone palmitate once-monthly long-acting injectable in the management of schizophrenia: long-term safety, efficacy, and patient acceptability - a review, Patient Prefer Adherence, 2015; 9: 695—706). It has the benefit of maintaining a therapeutic plasma level, it is available in two types of compositions indicated for once-every 28 days injection or every 84 days injection (Corena- McLeod M. Comparative Pharmacology of Risperidone and Paliperidone, Drugs in R&D, 2015, 15 (2): 163—74.; Peng Li, Gretchen L. Snyder, and Kimberly E. Vanover, Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future, Curr Top Med Chem, 2016 Dec; 16(29): 3385-3403.; Karim Sedky, Racha Nazir, Jean-Pierre Lindenmay er, and Steven Lippmann, Paliperidone palmitate: Once-monthly treatment option for schizophrenia, Current Psychiatry, 2010, 9(3), 48-49).

[0009] PAP has been developed as a long-acting, intramuscular, injectable aqueous suspension for the treatment of schizophrenia and other related diseases that are normally treated with antipsychotic medications. Because of extreme low water solubility, paliperidone esters such as PAP dissolve slowly after intramuscular injection before being hydrolyzed to paliperidone and made available in systemic circulation.

[0010] PAP is available commercially and marketed under the brand name of Invega Sustenna®, Invega Trinza® and Invega Hafyera®. It is available as a white to off-white aqueous extended-release injectable suspension for intramuscular injection. The mechanism of action of PAP is unknown, it is believed that it attributes to the antagonism of brain dopamine D2 and serotonin 5-HT2A receptors (Brough, C; Williams, R. Amorphous solid dispersions and nano-crystal technologies for poorly water-soluble drug delivery, Int. J. Pharm. 2013, 453, 157-166.; Mdschwitzer, J.P. Drug nanocrystals in the commercial pharmaceutical development process, Int. J. Pharm. 2013, 453, 142-156). Oral extended-release tablet PAP composition is also available commercially and marketed under the brand name of Invega®.

[0011] Paliperidone is described in US 5,158,952, the process for preparing paliperidone is described in US 6,320,048, compounds related to 3-piperidinyl-l,2-benzisoxazoles are described in US 5,254,556. US 6,077,843 & US 6,555,544 describe injectable depot composition containing 9- hydroxyrisperidone fatty acid ester as an active ingredient for intramuscular or subcutaneous administration. The dosing regimen of PAP for treating patients is disclosed in US patent application publication no. 20090163519. Various conventional pharmaceutical dosage forms, administered orally, rectally, percutaneously, or by parenteral injection including powders, pills, capsules and tablet, oral liquid and injectable solutions for prolonged use, and transdermal patch are exemplified in US 5,158,952. PAP injectable suspension is produced by wet media milling process. The process has been disclosed in US20080214808 and US 9,439,906. Various polymorphic forms of paliperidone are described in US20090061005. Methods of treating psychotic conditions including schizophrenia and related disorders based on polymorphisms in the erbb4 gene are described in US20100144781.

[0012] Risperidone is generic to 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9- tetrahydro-2 -methyl -4H-pyrido[l,2-a]pyrimidin-4-one. The preparation and pharmacological activity thereof are described in EP 0,196,132 (corresponding to U.S. patent no. 4,804,663). Various conventional pharmaceutical dosage forms, including tablets, capsules, drops, suppositories, oral solutions, and injectable solutions are exemplified therein. In practice, risperidone is normally administered as the base in a tablet or in a buffered oral or intramuscular solution. Particular solutions for oral or intramuscular administration are described in WO- 96 / 01652. Currently, PAP can be micronized by using multi step wet media milling process or by air jet milling. Usually sterile air-jet milling is carried out in isolators or by using a restricted access barrier system. Multistep wet media milling process produces a suspension with a range of PAP particle sizes. The multistep wet media milling process requires the use of at least two different sized milling media, wherein a filtration or separation step is required to remove the first milling media before addition of the second milling media.

[0013] Several suspension-based compositions have been in the market that make use of wet media milling include Rapamune® (Pfizer (Wyeth), New York City, NY, USA), Emend® (Merck, Kenilworth, NJ, USA), Tricor®, Eipanthyl® (Abbott Eaboratories, Fournier Pharma, Montreal, QC, Canada), Megace® ES (PAR Pharmaceuticals, Woodcliff Lake, NJ, USA), and Invega Sustenna®, Xeplion® (Janssen, Beerse, Belgium).

[0014] Stability problems are frequently observed in microsuspension or nanosuspension compositions and is a common problem due to Ostwald ripening and particle aggregation (Wang Y, Zheng Y., Zhang L., Wang Q., Zhang D. Stability of nanosuspensions in drug delivery, J Control Release, 2013; 172, 1126-1141). Ostwald ripening is the problem caused by the heterogeneous nature of the PAP microsuspension due to wider particle size distribution. Generally, Ostwald ripening is a result of the difference in solubility between small and large particles, which is responsible for the change in size distribution and particle size (Wu L., Zhang J., Watanabe W., Physical and chemical stability of drug nanoparticles, Adv Drug Deliv Rev. 2011; 63, 456^469). According to Ostwald- Freundlich equation, smaller particles have more saturation solubility than bigger particles and this creates concentration gradient between small and large particles. The molecules in composition disseminate the small particles (higher concentration surrounding areas) from larger particles (surrounded with lower drug concentration) and create an unsaturated solution in the vicinity of large particles which leads to a process of the Ostwald ripening and crystal growth. In other terms, the process of diffusion leaves an unsaturated solution surrounding the small particles, giving rise to drug crystallization on large particles. The stabilizers play an important role here i.e., they reduce the interfacial tension between the solid particles and a liquid medium and thereby avoid the Ostwald ripening. However, it is difficult to eliminate Ostwald ripening by stabilizer alone. Suspension which has narrow particle size distribution (lower particle size span) provides stable suspension.

[0015] U.S. patent application publication no. 20190183896 discloses a process for preparing a micronized paliperidone ester, the process comprising wet media milling a suspension comprising a solid paliperidone ester, at least one suspending agent, and at least one wetting agent in the presence of a plurality of polymeric beads to form the micronized paliperidone ester, wherein the plurality of polymeric beads (consist of polystyrene beads crosslinked with divinylbenzene) has an average diameter from about 0.5 mm to about 1.5 mm, and the micronized paliperidone ester has a particle size distribution from about 1 pm to about 30 pm [DIO: 2-3 pm, D50: 6-8 pm and D90: 15-20 pm], while much smaller particle size is required to achieve composition that releases the drug for one month period. The process described in US20190183896 does not produce fine particles suitable for 1 month release product.

[0016] Additionally, the change of dissolution rate upon storage is another concern for these products. Thus, there is need to develop a manufacturing process that will produce microsuspension with more storage stability.

[0017] SUMMARY OF THE INVENTION

[0018] The present invention provides a process where PAP was suspended in polysorbate solution alone and milled using NETZSCH milling equipment. Other excipients were added only after the milling was completed achieving desired smaller particle size of around 1 micron and smaller. Also, the most important aspect of this invention is that microsuspension is subjected to thermal treatment for 10 minutes or more at a temperature of 40°C or more. Even though the process is a multistep process, it provides a stable microsuspension upon incorporation of a thermal treatment step. Change of particle size, especially DIO and D50 and dissolution rate especially initial release upon storage are concerns for these products. Thermal treatment process step provided more stable composition with consistent dissolution rate and stable particle size upon storage.

[0019] Other aspects of the invention disclosure are described in more detail below.

[0020] DEFINITIONS

[0021] The term “PAP” as used herein refers to Paliperidone Palmitate.

[0022] The term “Microsuspension” as used herein refers to the suspension having particle size of active pharmaceutical ingredient in the range of 0.1 micron to 50 micron. The term “Microsuspension” can be used synonymously with, but not limited to Microspheres, Microsphere suspension, Microspheric suspension, Submicro suspension, Submicrospheres, Nanospheres, Nanosuspension, Nanospheric suspension.

[0023] Compounds useful in the composition and methods include those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, and polymorphs, as well as racemic mixtures and pure isomers of the compounds described herein, where applicable.

[0024] The term “pharmaceutical injectable composition” refers to a composition administered by injection comprising an active ingredient and at least one pharmaceutically acceptable excipient.

[0025] The term “pharmaceutically acceptable excipient” refers to a compound or ingredient that is compatible with the other ingredients in a pharmaceutical composition and not injurious to patient when administered in normal or therapeutically effective amounts.

[0026] The term “One month release composition” or “One Month Composition” or “IM release composition” or “IM Composition” or “1-M release composition” or “1-M composition” refers to a composition that is intended to release drug for a duration of one month.

[0027] The term “Three-month release composition” or “Three Month Composition” or “3M release composition” or “3M Composition” or “3-M release composition” or “3-M composition” refers to a composition that is intended to release drug for a duration of three months.

[0028] The term “depot” refers to a composition which after administration releases slowly in the body over a period of weeks or months. The term “stable” as used herein refers to a state wherein the composition upon storage does not change significantly in its pharmaceutical or physicochemical or therapeutic properties for e.g. particle size distribution, particle size span, dissolution drug release, assay etc.

[0029] The term “long acting” as used herein refers to pharmaceutical compositions that include, but not limited to long release compositions, slow release compositions, controlled release compositions, extended release compositions, sustained release compositions, delayed release compositions, timed release compositions, prolonged release compositions, compositions that provide drug release for long duration for example, 1 month or more than 1 month or more than 3 months or more than 6 months or more.

[0030] The term “thermal treatment” as used herein refers to subjecting the composition during manufacturing process at any point of stage to an increased temperature for a specific period of time.

[0031] The term “wet milling” or “wet media milling” as used herein is intended to mean the grinding of materials with a sufficient quantity of a liquid to form a slurry. The process of wet milling and milling equipment / apparatus are conventionally known in the art and do not form a critical feature of the invention.

[0032] The “milling beads” as used in this invention, preferably are chemically inert and rigid. The term “chemically inert”, as used herein, means that the milling beads do not react chemically with the biologically active compound or the grinding compound. The milling beads are desirably provided in the form of beads which have smooth surface and spherical shapes. Preferably, the milling beads are provided in the form of one or more of beads, balls or spheres. The term “XL-PS” refers to cross-linked polystyrene beads.

[0033] The term “average particle size” refers to average particle size (Dso) by volume, which indicates 50% of the particles by volume are under the specified size in microns. To provide particle size distribution three particle size values Dio,, Dso and D90 are provided. “Particle size span” or “Span” is the value provided to describe the spread of the particle size distribution which is calculated from DIO, D50 and D90 values using the relationship

[0034] Particle size span = (Dw-Dioj / Dso. Span value directly corelates with the width of particle size distribution, which means smaller the span value, narrower is the particle size distribution.

[0035] The term “Dio” means that 10% of all the particles in a sample are smaller than the specified size of D 10. Wherein “D” refers to diameter of particles and “10” is the percentage of particles smaller than the specified size.

[0036] The term “D50” means that 50% of all the particles in a sample are smaller than the specified size of D50. Wherein “D” refers to diameter of particles and “50” is the percentage of particles smaller than the specified size.

[0037] The term “D90” means that 90% of all the particles in a sample are smaller than the specified size of D90. Wherein “D” refers to diameter of particles and “90” is the percentage of particles smaller than the specified size.

[0038] The term “dissolution” refers to the process by which a solid substance dissolves in solvent. “Drug release” is the process by which a drug leaves a drug product and is subjected to absorption, distribution, metabolism, and excretion, eventually becoming available for pharmacologic action. Dissolution and drug release are terms used interchangeably. Dissolution is performed as per the dissolution guidance provided by the FDA. USP Type II Dissolution Apparatus is used at 50 RPM and 25°C and the release media contains 0.489% (w / v) Polysorbate 20 in 0.001 N HC1. The volume of the release media is 900 mb and the examples of the sampling points are 1.5, 5, 8, 10, 15, 20, 30, 45 and 90 minutes.

[0039] The term “aseptic” is used interchangeably with the word “sterile”. In some embodiments, the aseptic processing or fabrication complies with GMP (Good Manufacturing Practice) industry guidelines such as those associated with Guidance for industry- Sterile Drug Products Produced by Aseptic Processing- Current Good Manufacturing Practice, US Department of Health and Human Services Food and Drug Administration, September 2004.

[0040] The term “about,” herein refers to the quantities mentioned, which meant to incorporate deviations of plus or minus ten percent.

[0041] Quantitative values mentioned throughout this invention disclosure, are for exemplary purpose only and may vary.

[0042] “Syringeability” refers to the ability of a composition to be administered successfully with even flow by a syringe and needle without any obstruction, block, or clog.

[0043] “PS-20” refers to polysorbate-20.

[0044] The term “RLD” refers to reference listed drug. For one month release composition RLD is Invega Sustenna® and for three months release composition the RLD is Invega Trinza®.

[0045] BRIEF DESCRIPTION OF THE FIGURES

[0046] Figure - 1 depicts cumulative drug release rate from pharmacokinetic profde in rats between Invega Sustenna® and example 1 (composition without thermal treatment).

[0047] Figure - 2 depicts the relationship between change of particle size compared to initial particle size and storage duration in weeks at 40°C of example 2

[0048] Figure - 3 depicts comparison of cumulative drug release rate from pharmacokinetic profde in rats between non-thermal and thermal treated sample in Example 4.

[0049] Figure - 4 depicts comparison of pharmacokinetic profde of PAP microsuspension for three-month composition between Invega Trinza® and example 5 (composition without thermal treatment).

[0050] Figure - 5 depicts comparison of pharmacokinetic profde between thermal treated scale up batch of one-month composition of PAP and Invega Sustenna®.

[0051] Figure - 6 shows crystallinity of Invega Sustenna® and scale-up batches of Thermal Treated and Non-Thermal Treated PAP Microsuspension. DETAILED DESCRIPTION OF THE INVENTION

[0052] Paliperidone esters may be formulated with pharmaceutical excipients into injectable dosage forms as described in U.S. patent numbers 5,254,556 and 6,077,843 both of which are incorporated herein by reference. Injectable compositions may be formulated in aqueous carriers.

[0053] The present invention provides long-acting stable injectable pharmaceutical composition(s) for controlled release of active pharmaceutical ingredient. Methods for preparing the controlled release pharmaceutical compositions are also provided. The method comprises a step of aseptic wet milling to provide micronized particles of active pharmaceutical ingredient used to achieve controlled release composition. The pharmaceutical compositions disclosed herein are milled using cross-linked polystyrene beads. The pharmaceutical compositions disclosed herein comprise at least one solvent, at least one surfactant, at least one viscosity agent, at least one stabilizer, at least one buffer and at least one active pharmaceutical ingredient. The pharmaceutical compositions disclosed herein are treated with thermal treatment during manufacturing process.

[0054] The present invention provides a stable pharmaceutical injectable composition comprising, Paliperidone palmitate as an active pharmaceutical ingredient, and pharmaceutically acceptable excipients, wherein the composition is manufactured by a process that involves thermal treatment step.

[0055] The present invention provides a stable pharmaceutical injectable composition comprising, Paliperidone palmitate as an active pharmaceutical ingredient, at least one surfactant, at least one viscosity agent, at least one stabilizer, and at least one buffering agent, wherein the composition is manufactured by a process that involves thermal treatment step.

[0056] The present invention provides a stable pharmaceutical injectable composition, wherein the composition is a depot microsuspension comprising: i. Paliperidone palmitate as an active pharmaceutical ingredient, ii. at least one surfactant, iii. at least one viscosity agent, iv. at least one stabilizer, and v. at least one buffering agent. wherein the composition is manufactured by a process comprising the steps: a) Preparing a surfactant solution. b) Mixing crystalline sterile paliperidone palmitate (PAP) in surfactant solution of step (a). c) Subjecting the premix of step (b) to wet milling in the presence of milling beads to obtain a microsuspension of PAP; and d) Adding sterile excipient solutions containing stabilizing agent, viscosity agent and buffer to microsuspension of step (c), wherein the microsuspension is subjected to thermal treatment, wherein the whole process is carried out aseptically and wherein the step of thermal treatment can be incorporated at any stage during the manufacturing.

[0057] The present invention provides a stable injectable pharmaceutical compositions of PAP microsuspension that provide controlled release of an active pharmaceutical ingredient. PAP microsuspension is prepared by aseptic wet media milling process. The process comprising the steps: a) Prepare polysorbate solution. b) Suspend sterile crystalline PAP particles in a sterile polysorbate solution to form a premix microsuspension. c) Subject the premix from step (b) to wet media milling in the presence of milling beads to obtain a microsuspension of PAP having average particle size distribution of about 0.8 ± 0.3 micron for one month release composition or about 7 ± 1 micron for three months release composition. d) Mix with excipients to achieve the final stable microsuspension. e) Subject the microsuspension for thermal treatment by increasing the microsuspension temperature at or above 40°C for the period of 10 minutes or more.

[0058] The thermal treatment can be done at temperature of about 40°C or more. The thermal treatment can be done at specific temperatures of about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C, about 120°C.

[0059] The thermal treatment can be also done at a range of temperature from about 35 °C to about 120°C, about 35°C to about 110°C, about 35°C to about 100°C, about 35°C to about 90°C, about 40°C to about 80°C, preferably about 45°C to about 75°C; preferably about 50°C to about 70°C, preferably about 55°C to about 65°C.

[0060] In a specific embodiment, the thermal treatment can be done at a temperature of about 60°C.

[0061] The thermal treatment can be done for varying time periods from few minutes to days, 5 minutes to 7 days, 5 minutes to 6 days, 5 minutes to 5 days, 5 minutes to 96 hours, preferably 5 minutes to 84 hours, preferably 5 minutes to 72 hours, preferably 5 minutes to 60 hours, preferably 5 minutes to 48 hours, preferably 5 minutes to 36 hours, preferably 5 minutes to 24 hours, preferably 5 minutes to 12 hours, preferably 5 minutes to 6 hours, preferably 5 minutes to 5 hours, preferably 5 minutes to 4 hours, preferably 5 minutes to 3 hours, preferably 5 minutes to 2 hours, preferably 5 minutes to 1 hour, preferably 5 minutes to 50 minutes, preferably 5 minutes to 45 minutes, preferably 5 minutes to 40 minutes, preferably 5 minutes to 35 minutes, preferably 5 minutes to 30 minutes, preferably 5 minutes to 25 minutes, preferably 5 minutes to 20 minutes, preferably 5 minutes to 15 minutes, preferably 5 minutes to 10 minutes, preferably 5 minutes.

[0062] The thermal treatment step can be included at any stage of manufacturing for example before or after milling; or before or after mixing with excipients.

[0063] The obtained PAP compositions with thermal treatment are suitable for injection and for the drug release duration of one month or more, two months or more, three months or more, four months or more, five months or more, six months or more as a sustained release composition.

[0064] Aqueous compositions according to the present invention conveniently further comprise suitable excipients including but not limited to a surfactant, a viscosity agent, a stabilizer, a pH modifier, a solvent, a buffer and optionally one or more of a preservative. Particular ingredients may function as two or more of these agents simultaneously, e.g., behave like a preservative and a buffer, or behave like a buffer and a tonicity agent.

[0065] The prior art reference US20190183896A1 discloses PAP suspension and its manufacturing method without thermal treatment. The present invention differs from US20190183896A1 in that it involves thermal treatment step during mannf rtiirina nrnc ss. The particle size distribution of the final composition disclosed in US20190183896A1 is 2 pm to 3 pm for DIO, 6 pm to 8 pm for D50, and 15 pm to 20 pm for D90, whereas the particle size distribution of the compositions in the present invention with thermal treatment step for one month release composition is 0. 1 pm to 0.6 pm for DIO, 0.7 pm to 1.4 pm for D50, and 1.8 pm to 4.0 pm for D90 and for three month release composition the particle size distribution of the final composition in the present invention is 1.5 pm to 2.5 pm for D10, 4.0 pm to 8.0 pm for D50, and 9.0 pm to 11.0 pm for D90. The compositions of present invention with thermal treatment step produce microsuspension of PAP with particle size range (D10 to D90) of 0.1 to 5 micron (average particle size around 0.9 micron) for one month release composition and with particle size range (D10 to D90) of 0.4 to 15 micron (average particle size around 7 micron) for three -month release composition.

[0066] Dosage form:

[0067] The physical form of the pharmaceutical composition of the present invention may vary. Most preferably the composition can be prepared for parenteral administration.

[0068] For parenteral administration (including but not limited to intramuscular, intravenous, subcutaneous, intradermal, and intraperitoneal), composition may be a microsuspension. The microsuspension may be aqueous, or oil based.

[0069] The composition of the present invention along with active pharmaceutical ingredient (API) conveniently comprises at least one solvent, at least one surfactant, at least one viscosity agent, at least one stabilizer, and at least one buffer. Particular ingredients may function as two or more of these agents simultaneously, e.g., behave like a preservative and a buffer, or behave like a buffer and a tonicity agent.

[0070] Active Pharmaceutical Ingredient (API)

[0071] The microsuspension comprises at least one API or salt thereof. Suitable APIs include, without limit, atypical antipsychotics (e.g., asenapine, amisulpride, lurasidone, aripiprazole, blonanserin, iloperidone, melperone, clozapine, olanzapine, paliperidone, paliperidone esters (e.g., paliperidone palmitate), perospirone, quetiapine, remoxipride, risperidone, sertindole, sulpiride, and ziprasidone). In specific embodiments, the API is a paliperidone ester. Further in more specific embodiments, the paliperidone ester is paliperidone palmitate.

[0072] Any of the above-mentioned APIs may be incorporated in the microsuspension described herein in any suitable form, such as, for example, as a pharmaceutically acceptable salt, uncharged or charged molecule, molecular complex, solvate or hydrate, prodrug, and, if relevant, isomer, enantiomer, racemic mixture, and / or mixtures thereof. Furthermore, the API may be in any of its crystalline, semi-crystalline, amorphous, or polymorphous forms. In an exemplary embodiment, the API may be in a crystalline form.

[0073] The crystalline, semi-crystalline, amorphous, or polymorphous forms may have a particle size of about 10 to about 200 pm. In some embodiments, the crystalline, semi -crystalline, amorphous, or polymorphous forms may have a particle size of about 5 pm, about 10 pm, about 20 pm, about 30 pm, about 40 pm, about 50 pm, about 60 pm, about 70 pm, about 80 pm, about 90 pm, about 100 pm, about 110 pm, about 120 pm, about 130 pm, about 140 pm, about 150 pm, about 160 pm, about 170 pm, about 180 pm, about 190 pm, or about 200 pm. The amount of API in the microsuspension may vary depending upon the active agent. In certain embodiments, the API in the microsuspension is PAP. In certain embodiments, the amount of PAP before milling may range from about 3% w / v to about 60% w / v, from about 4% w / v to about 50% w / v, from about 5% w / v to about 40% w / v, from about 6% w / v to about 35% w / v, from about 7% w / v to about 30% w / v, from about 8% w / v to about 25% w / v, or from about 10% w / v to about 15% w / v of the microsuspension. In certain embodiments, the amount of PAP in the microsuspension may be about 5% w / v, about 8% w / v, about 10% w / v, about 12% w / v, about 14% w / v, about 16% w / v, about 18% w / v, about 20% w / v, about 25% w / v, about 30% w / v, or about 35% w / v of the microsuspension.

[0074] Solvents and Co-solvents

[0075] The composition may be a microsuspension for parenteral administration. For parenteral administration (including but not limited to subcutaneous, intradermal, intramuscular, and intraperitoneal), the preparation may be an aqueous or an oil-based microsuspension. Aqueous microsuspensions may include, but not limited to a sterile diluent such as water, saline solution, a pharmaceutically acceptable polyol such as glycerol, propylene glycol, or other synthetic solvents. Oil-based microsuspensions may comprise mineral oil, sesame, peanut, or olive oil.

[0076] Surfactant

[0077] The microsuspension also comprises at least one surfactant. The surfactant can be an anionic, cationic, a zwitterionic, or non-ionic. The at least one surfactant may comprise amphiphilic compounds that contain polar, hydrophilic moieties as well as non-polar hydrophobic moieties.

[0078] Non-limiting examples of surfactants include polyethylene glycol fatty acid monoesters (e.g., polyethylene glycol laurate or stearate, etc.); polyethylene glycol glycerol fatty acid esters (e.g., polyethylene glycol glycerol laurate, glycerol stearate, glycerol oleate, etc.); polyethylene glycol fatty acid diesters (e.g., polyethylene glycol dilaurate, disterate, dipalmitate, or dioleate, etc.); polyglycerized fatty acids (e.g., polyglyceryl laurate, oleate, or stearate; polyglyceryl mono and dioleate; etc.); sterol derivatives (e.g., polyethylene glycol cholesterol ether, polyethylene glycol cholestanol, polyethylene glycol phyto sterol, etc.); and polyethylene glycol sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80, PEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate, sorbitan tristearate, etc.).

[0079] In an exemplary embodiment, the surfactant may comprise polyethylene glycol sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80, PEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate, sorbitan tristearate, etc.).

[0080] In another exemplary embodiment, more specifically, the surfactant may comprise polysorbate 20.

[0081] The amount of the at least one surfactant present in the microsuspension can and will vary depending upon the identity of the surfactant as well as the identity and / or amount of the other components utilized in the microsuspension. In general, the amount of the at least one surfactant in the microsuspension may range from about 0.1% to about 10% w / v, from about 0.3% to about 8% w / v, from about 0.7% to about 5% w / v, or from about 1% to about 3% w / v of the microsuspension. In some embodiments, the amount of the at least one surfactant in the microsuspension may be about 0.2% w / v, about 0.3% w / v, about 0.5% w / v, about 0.8% w / v, about 1.0% w / v, about 1.2% w / v, about 1.5% w / v, about 1.8% w / v, about 2%w / v, about 2.5%w / v, about 3.0% w / v, about 3.5% w / v, about 4.0% w / v, about 4.5% w / v, or about 5% w / v of the microsuspension.

[0082] Viscosity agent

[0083] The microsuspension comprises at least one viscosity agent. In general, the at least one viscosity agent provides long-term stabilization, facilitate drug adsorption, alter viscosity, or enhance solubility.

[0084] Non-limiting examples of viscosity agents include, polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol, and copolymers thereof); polyethylene glycols (e.g., PEG 300, PEG 400, PEG 600, PEG 1000, PEG 1100, PEG 1900, PEG 2000, PEG 2800, PEG 2900, PEG 3350, PEG 4000, PEG 6000, PEG 8000, PEG 8400, PEG 10,000, PEG 12,000, PEG 14600, PEG 17,000, etc.); and triblock polymer of polypropylene glycol flanked by polyethylene glycol (e.g., poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, poloxamer 407, etc.).

[0085] In an exemplary embodiment, the viscosity agent may comprise polyethylene glycols (e.g., PEG 300, PEG 400, PEG 600, PEG 1000, PEG 1100, PEG 1900, PEG 2000, PEG 2800, PEG 2900, PEG 3350, PEG 4000, PEG 6000, PEG 8000, PEG 8400, PEG 10,000, PEG 12,000, PEG 14600, PEG 17,000, etc.).

[0086] In another exemplary embodiment, more specifically, the viscosity agent may comprise polyethylene glycol 4000 (PEG 4000).

[0087] The amount of the at least one viscosity agent present in the microsuspension can and will vary depending upon the identity of the viscosity agent as well as the identity and / or amount of the other components in the microsuspension. In general, the amount of the at least one viscosity agent in the microsuspension may range from about 2% w / v to about 30% w / v, from about 3% w / v to about 27% w / v, from about 4% w / v to about 23% w / v, from about 5% w / v to about 20% w / v, from about 7% w / v to about 17% w / v, or from about 10% w / v to about 14% w / v of the microsuspension. In some embodiments, the amount of the at least one viscosity agent in the microsuspension may be about 2% w / v, about 3% w / v, about 5% w / v, about 6% w / v, about 7% w / v, about 8% w / v, about 9% w / v, about 10% w / v, about 11% w / v, about 12% w / v, about 13% w / v, about 14% w / v, about 15% w / v, about 16% w / v, about 17% w / v, about 18% w / v, about 19% w / v, or about 20% w / v of the microsuspension.

[0088] Stabilizer

[0089] The microsuspension may comprise at least one stabilizer which help stabilize the composition by multiple mechanisms, for example by adjusting pH or preventing degradation, etc. thereby enhancing stability of the composition. Non-limiting examples of a stabilizer include organic or inorganic acids and bases, for example, acetic acid, fumaric acid, citric acid monohydrate, tartaric acid, benzoic acid, formic acid, hydrochloric acid, malic acid, lactic acid, phosphoric acid, sorbic acid, sulfuric acid, potassium carbonate, sodium carbonate, sodium bicarbonate, and sodium hydroxide. In certain embodiment, the stabilizer may comprise sodium hydroxide and citric acid monohydrate. In a specific embodiment the stabilizer may comprise citric acid monohydrate.

[0090] In an exemplary embodiment, the stabilizer may comprise citric acid monohydrate.

[0091] In general, the amount of the at least one stabilizer in the microsuspension may range from about 0. 1% w / v to about 10% w / v, from about 0.2% w / v to about 8% w / v, from about 0.3% w / v to about 6% w / v, from about 0.4% w / v to about 5% w / v, or from about 0.5% w / v to about 3% w / v of the microsuspension. In certain embodiments, the amount of stabilizer in the microsuspension may be about 0.5% w / v, about 1.0% w / v, about 1.5% w / v, about 2.0% w / v, about 2.5% w / v, or about 3.0% w / v of the microsuspension.

[0092] Buffer:

[0093] The microsuspension may comprise at least one buffer to modify the pH of the composition. The buffering agent can and will vary depending on the pH of the microsuspension. Suitable buffering agents are salt of weak acids such as without limitation, carbonates, citrates, gluconates, phosphates, acetates, tartrates, borates, phthalates, etc. and should be used in amount sufficient to render the dispersion neutral to very slightly basic (up to the pH value of about 8.5), preferably in the pH range of about 7 to about 7.5.

[0094] The pH of the microsuspension may range from about 6 to about 9, from about 7 to about 8, or from about 7 to about 7.5. In certain embodiment the pH of the microsuspension may range from about 6 to about 8, preferably in the range of about 6.5 to about 7.5. In certain embodiment, the pH of the microsuspension may be about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5.

[0095] Non-limiting examples of the buffer include the sodium or potassium salt of phthalate, phosphate, borate, citrate and acetate. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dehydrate and other such materials known to those of ordinary skill in the art.

[0096] In an exemplary embodiment, the buffer may comprise but not limited to, alkali metal citrate, citric acid / sodium citrate, potassium hydrogen tartrate, sodium hydrogen tartrate, potassium hydrogen phthalate, sodium hydrogen phthalate, potassium dihydrogen phosphate, sodium hydroxide, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous and / or mixtures thereof.

[0097] In another exemplary embodiment, particularly preferred is the use of a mixture of disodium hydrogen phosphate anhydrous and sodium dihydrogen phosphate monohydrate for rendering the solution isotonic, neutral and less prone to flocculation of the suspended ester therein.

[0098] In another exemplary embodiment, particularly preferred is the use of a mixture of disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate and sodium hydroxide.

[0099] In yet another exemplary embodiment, particularly preferred is the use of a mixture of sodium dihydrogen phosphate monohydrate and sodium hydroxide.

[0100] In general, the amount of the at least one buffer in the microsuspension may range from about 0. 1% w / v to about 10% w / v, from about 0.2% w / v to about 8% w / v, from about 0.3% w / v to about 6% w / v, from about 0.4% w / v to about 5% w / v, or from about 0.5% w / v to about 3% w / v of the microsuspension. In certain embodiments, the amount of buffer in the microsuspension may be about 0.2% w / v, about 0.3% w / v, about 0.5% w / v, about 1.0% w / v, about 1.5% w / v, about 2.0% w / v, about 2.5% w / v, or about 3.0% w / v of the microsuspension. Paliperidone (hydroxyl risperidone) is an antipsychotic drug available in the market as oral tablet and injectable solution for daily administration. For convenience and compliance, a depot composition is preferred. PAP is an ester derivative of paliperidone with palmitic acid. PAP is hydrophobic and water insoluble, while paliperidone is soluble. Upon administration by injection, the ester bond cleavage (hydrolysis) leads to the availability of paliperidone. Controlled ester cleavage could lead to sustained availability of the active moiety, paliperidone. Since PAP is hydrophobic and crystalline ester hydrolysis occurs primarily on the surface of the drug particles, therefore particle size of the drug particles is the controlling factor for the rate of drug release (drug availability). The crystalline sterile PAP having an average particle size less than 70 micron is used during manufacturing of the PAP microsuspension of the present invention, the average particle size used can be in the range from about 10 micron to about 70 micron.

[0101] Duration of sustained release composition and the drug release pattern is generally controlled by particle size of the PAP in the injecting microsuspension. It is common to report the diameter of the particle size as volume distribution defined at DIO, D50 and D90 levels representing the fraction of volume population at 10%, 50% and 90% levels and particle size span is defined as D90-D10 / D50. Particle size distribution pattern could be narrow (low span) or wider (high span). PAP microsuspension having D50 around 1 micron is suitable for one month release and D50 around 7 micron is suitable for three-month release. The desired particle size for PAP microsuspension depends on the intended duration of release. The desired particle size for PAP microsuspension is directly proportional to the intended duration of release.

[0102] Several process parameters during wet milling controls the particle size reduction rate and the final particle size distribution pattern. These parameters are starting particle size of sterile PAP, type and diameter of milling beads, number of milling beads in the milling chamber (bead load), milling speed and re -circulation rate of microsuspension. It is possible to achieve the desired average particle size (D50) however it may not be possible to achieve the desired particle size distribution which includes D10 and D90 level with all possible variables. This invention provides an additional procedure that could be used to alter the particle size distribution and thereby achieve the desired particle size distribution.

[0103] After the required particle size is achieved, it is expected that the particle size and dissolution rate should not change upon storage. PAP available in the market as Invega Sustenna® and Invega Trinza®, both are room temperature storage products. For room temperature storage products, the recommended accelerated storage stability is 40°C for six months, or at least 30°C for six months period (Guidance for Industry Q1A(R2) Stability Testing of New Drug Substances and Products). Storage stability of several compositions that were prepared under various milling conditions and particle size distributions were placed on storage stability at 25°C, 30°C and 40°C and studied. Under all storage conditions it was observed that the population of smaller particles (D10) increased considerably, average size (D50) showed high to moderate increase and D90 increased slightly. The dissolution rate, which is the important property that ascertain the sustained release characteristics of the formulation changed considerably upon storage. Drug release (Dissolution) rate of PAP microsuspension directly correlates to in-vivo drug release duration and drug release pattern in humans. Hence, a stable dissolution rate upon storage of the product is very critical. In the past attempts were made without any success to achieve PAP microsuspension that does not change the particle size and drug release rate upon storage and considerable increase of D10 upon storage could be the main cause for the decrease of dissolution rate. The present inventors have surprisingly found during course of achieving a desired PAP microsuspension that by including a unique process step i.e., subjecting the microsuspension to the thermal treatment during manufacturing process, even for a limited period of time resulted in more stable microsuspension in terms of particle size and drug release rate.

[0104] The manufacturing process of PAP microsuspension involves micronizing sterile PAP aseptically using wet media milling, said process comprising steps: a) The polysorbate solution was prepared by dissolving polysorbate in water, followed by heating it at a suitable temperature for a specific period of time, then cooling and adding sufficient quantity of water to make up the volume. Then, the polysorbate solution was filtered through sterilizing grade filter. b) Crystalline sterile PAP having an average particle size less than 70 micron was mixed or suspended in polysorbate solution of step (a) to form a premix microsuspension. c) Premix microsuspension of step (b) was subjected to wet media milling in the presence of cross-linked polystyrene (XL-PS) milling beads having size in the range of about 0.2 mm to 2.0 mm to obtain a microsuspension of PAP with particle size 0.1 to 5 micron (average particle size around 0.9 micron) for one month release composition or 0.4 to 15 micron (average particle size around 7 micron) for three -month release composition. d) Sterile excipient solution comprising stabilizer(s), viscosity agent(s) and buffer(s) was added to the PAP microsuspension. e) Microsuspension was subjected to thermal treatment by increasing the microsuspension temperature at or above 40°C for the period of 10 minutes or more.

[0105] Wherein the total process was carried out aseptically.

[0106] The product that was subjected to thermal treatment showed better storage stability compared to the product that was not subjected to thermal treatment.

[0107] In another aspect, the manufacturing process of PAP microsuspension involves a process for micronizing PAP aseptically using wet media milling, said process comprising steps: a) The polysorbate solution was prepared by dissolving polysorbate in water, followed by heating it at a suitable temperature for a specific period of time, then cooling and adding sufficient quantity of water to make up the volume. Then, the polysorbate solution was filtered through sterilizing grade filter. b) Crystalline sterile PAP having an average particle size less than 70 micron was mixed in polysorbate solution of step (a) to form a premix microsuspension. c) Premix microsuspension of step (b) was subjected to wet media milling in the presence of cross-linked polystyrene (XL-PS) milling beads having size in the range of about 0.2 mm to 2.0 mm to obtain a microsuspension of PAP with particle size 0. 1 to 5 micron (average particle size around 0.9 micron) for one month release composition or 0.4 to 15 micron (average particle size around 7 micron) for three-month release composition. d) Microsuspension was subjected to thermal treatment by increasing the microsuspension temperature at or above 40°C for the period of 10 minutes or more. e) Sterile excipient solution comprising stabilizer(s), viscosity agent(s) and buffer(s) was added to the PAP microsuspension.

[0108] Wherein the total process was carried out aseptically. The product that was subjected to thermal treatment showed better storage stability compared to the product that was not subjected to thermal treatment.

[0109] In yet another aspect, the manufacturing process of PAP microsuspension involves a process for micronizing PAP aseptically using wet media milling, said process comprising steps: a) The polysorbate solution was prepared by dissolving polysorbate in water, followed by heating it at a suitable temperature for a specific period of time, then cooling and adding sufficient quantity of water to make up the volume. Then, the polysorbate solution was filtered through sterilizing grade filter. b) Crystalline sterile PAP having an average particle size less than 70 micron was mixed in polysorbate solution of step (a) to form a premix microsuspension. c) Premix microsuspension of step (b) was subjected to thermal treatment by increasing the premix microsuspension temperature to or above 40°C for the period of 10 minutes or more. d) Then, the thermally treated premix microsuspension was subjected to wet media milling in the presence of cross-linked polystyrene (XL-PS) milling beads having size in the range of about 0.2 mm to 2.0 mm to obtain a microsuspension of PAP with particle size 0.1 to 5 micron (average particle size around 0.9 micron) for one month release composition or 0.4 to 15 micron (average particle size around 7 micron) for three-month release composition. e) Sterile excipient solution comprising stabilizer(s), viscosity agent(s) and buffer(s) was added to the PAP microsuspension.

[0110] Wherein the total process was carried out aseptically.

[0111] The product that was subjected to thermal treatment showed better storage stability compared to the product that was not subjected to thermal treatment.

[0112] The thermal treatment step can be included at any stage of manufacturing for example before or after milling; or before or after mixing with excipients. Obtained compositions were suitable for injection for the drug release duration of one month or three months or more as a sustained release composition.

[0113] In an embodiment, forming the microsuspension is carried in a batch or continuous process. In an exemplary embodiment, forming the microsuspension is carried out in a continuous process.

[0114] In an exemplary embodiment, the finished pharmaceutical injectable composition comprises excipients such as, surfactant(s) from 0.005 g / mL to 0.02 g / mL, viscosity agent(s) from 0.010 g / mL to 0.040 g / mL, stabilizer(s) from 0.001 g / mL to 0.007 g / mL, buffering agent(s) from 0.001 g / mL to 0.007 g / mL and water for injection. The pH of the composition may range from pH about 6.0 to about 8.0, preferably in the range from pH about 6.5 to about 7.5.

[0115] In an exemplary embodiment, the finished pharmaceutical injectable composition comprises excipients such as, surfactant such as polysorbate 20 from 0.005 g / mL to 0.02 g / mL, viscosity agent such as polyethylene glycol (PEG) 4000 from 0.010 g / mL to 0.040 g / mL, stabilizer such as citric acid monohydrate from 0.001 g / mL to 0.007 g / mL, buffering agents such as sodium hydroxide from 0.001 g / mL to 0.003 g / mL, disodium hydrogen phosphate anhydrous from 0.001 g / mL to 0.007 g / mL, sodium dihydrogen phosphate monohydrate from 0.001 g / mL to 0.003 g / mL or mixture thereof and water for injection. The pH of the composition may range from pH about 6.0 to about 8.0, preferably in the range from pH about 6.5 to about 7.5.

[0116] In an exemplary embodiment, the finished pharmaceutical injectable composition comprises 0.012 g / mL polysorbate 20, 0.030 g / mL polyethylene glycol (PEG) 4000, 0.005 g / mL citric acid monohydrate, 0.0028 g / mL sodium hydroxide, 0.005 g / mL disodium hydrogen phosphate anhydrous, 0.0026 g / mL sodium dihydrogen phosphate monohydrate or mixtures thereof and water for injection. The pH of the composition may range from pH about 6.0 to about 8.0, preferably in the range from pH about 6.5 to about 7.5.

[0117] In an exemplary embodiment, the finished pharmaceutical injectable composition comprises excipients such as 3.62 gm polysorbate 20, 9.0 gm polyethylene glycol (PEG) 4000, 1.5 gm citric acid monohydrate, 0.84 gm sodium hydroxide, 1.5 gm disodium hydrogen phosphate anhydrous, 0.76 gm sodium dihydrogen phosphate monohydrate or mixture thereof and water for injection. The pH of the composition may range from pH 6.0 to 8.0, preferably in the range from pH 6.5 to 7.5.

[0118] In an exemplary embodiment, the finished pharmaceutical injectable composition comprises excipients such as, surfactant(s) from 0.005 g / mL to 0.02 g / mL, viscosity agent(s) from 0.001 g / mL to O.lg / mL, stabilizer(s) from 0.0001 g / mL to 0.01 g / mL, buffering agent(s) from 0.001 g / mL to 0.01 g / mL and water for injection. The pH of the composition may range from pH about 6.0 to about 8.0, preferably in the range from pH about 6.5 to about 7.5.

[0119] In an exemplary embodiment, the finished pharmaceutical injectable composition comprises excipients such as, surfactant such as polysorbate 20 from 0.005 g / mL to 0.02 g / mL, viscosity agent such as polyethylene glycol (PEG) 4000 from 0.001 g / mL to O.lg / mL, stabilizer such as citric acid monohydrate from 0.0001 g / mL to 0.01 g / mL, buffering agents such as sodium hydroxide from 0.001 g / mL to 0.01 g / mL, sodium dihydrogen phosphate monohydrate from 0.001 g / mL to 0.01 g / mL or mixture thereof and water for injection. The pH of the composition may range from pH about 6.0 to about 8.0, preferably in the range from pH about 6.5 to about 7.5.

[0120] In an exemplary embodiment, the finished pharmaceutical injectable composition comprises 0.01 g / mL polysorbate 20, 0.075 g / ml polyethylene glycol (PEG) 4000, 0.0075 g / mL citric acid monohydrate, 0.0054 g / mL sodium hydroxide, 0.006 g / mL sodium dihydrogen phosphate monohydrate or mixtures thereof and water for injection. The pH of the composition may range from pH about 6.0 to about 8.0, preferably in the range from pH about 6.5 to about 7.5.

[0121] In an exemplary embodiment, the finished pharmaceutical injectable composition comprises excipients such as 4.01 gm polysorbate 20, 45.03 gm polyethylene glycol (PEG) 4000, 9.0 gm citric acid monohydrate, 6.52 gm sodium hydroxide, 7.2 gm sodium dihydrogen phosphate monohydrate or mixture thereof and water for injection. The pH of the composition may range from pH 6.0 to 8.0, preferably in the range from pH 6.5 to 7.5.

[0122] A kit is also contemplated by this invention and the pharmaceutical composition according to the present invention may be packaged accordingly. The composition of the invention may be supplied in vials or in pre-filled syringes or auto injectors or jet injectors or other injection devices with or without needles in the form of microsuspension. There is further provided by the present invention a method of treating schizophrenia, schizoaffective disorder, and other related disorders, by administering a pharmaceutical composition comprising PAP.

[0123] The present invention further provides use of a pharmaceutical composition comprising PAP, in the manufacture of a medicament for the treatment of schizophrenia, schizoaffective disorder and other related disorders.

[0124] The most important property of a depot injection product is maintaining a sustained delivery of the drug from the composition at the desired release rate. Release rate could be determined by injecting the composition in warm blooded animal and following the drug concentration in the blood. For the easy screening of compositions and for the quality control testing it is common to develop an in-vitro drug release test which is also known as dissolution test. For depot compositions, which release the drug for longer period, it is common to develop an accelerated in- vitro drug release test and qualify by showing relationship to in-vivo pharmacokinetic profde. In- vitro drug release test has to be validated by showing correlation to the in-vivo pharmacokinetics. Thus, the composition that releases the drug for a month or longer could be tested within a week, or within a day by the accelerated drug release method. To qualify the method, it is a common practice to prepare depot injection compositions with varying drug release properties and showing the in-vitro in-vivo correlation (IVIVC). In-vitro drug release method for PAP suspension product was developed by Janssen pharmaceuticals and justified by performing a human pharmacokinetic study with five compositions having extra slow release, slow release (two compositions), intermediate release and a fast-releasing compositions (Summary basis of approval for NDA#022264). In this invention the same in-vitro method was used and compared with the PAP suspension from Janssen (Invega Sustenna®) to verify the method. Additionally, an animal PK study was performed for the PAP microsuspension produced using cross-linked polystyrene beads along with Invega Sustenna®. The pharmacokinetic study batches were prepared purposely with varying particle size, ranging from 0.79 micron to 1.29 micron.

[0125] It is observed that the dissolution rate decreased upon storage, especially at the earlier period of storage. Thermal treated samples showed a comparatively slower and stable dissolution rate. Evaluation was performed to understand whether this change of dissolution rate is due to a change in drug crystallinity. Comparison of X-Ray diffraction and DSC revealed that the decreased dissolution rate is not due to increased drug crystallinity. Thermal treated sample is not more crystalline than the non-thermal treated samples.

[0126] The invention is further illustrated by the following examples or embodiments which are provided merely to be exemplary of the invention and do not limit the scope of the invention.

[0127] EXAMPLES

[0128] Example 1

[0129] Paliperidone Palmitate microsuspension for one month release duration was prepared at the batch size of 150 mL by the wet media milling process. Prepared 0.02 gm / gm polysorbate-20 (PS-20) solution by dissolving 3.62 g PS-20 in 156.8 g water by heating the mixture for 30 min at 50°C, then cooling to 25 °C and adding q.s. to 180 gm weight with water. Filtered the PS-20 solution through 0.2 pm sterilizing grade filter. Suspended 23.4 gm of PAP having 26-micron average particle size (D10 = 6 pm, D50 = 26 pm, D90 = 57 pm) in 90 gm polysorbate-20 solution. The microsuspension was mixed for a minimum of 30 minutes using an overhead motor driven stirrer equipped with stainless steel propeller stirrer. Milling equipment (Model - Delta Vita 15S from Netzsch) was prepared for the operation by loading autoclaved cross-linked polystyrene (XL-PS) beads (0.7 mm diameter) in the grinding chamber. Bead loading in the milling chamber was 90% (for example for the grinding chamber with 15 mb volume, the volume of XL-PS beads added was 13.5 mL). Loading of XL-PS beads could be achieved by direct addition of the beads into the chamber or by suspending the beads in sterile polysorbate-20 solution and load into the chamber. If the beads are loaded as a microsuspension, the polysorbate-20 solution should be removed. If loading the XL-PS beads is by suspending in PS-20 solution, the beads should be washed by pumping water and should be dried by air or nitrogen. Instead of loading autoclaved XL-PS beads, non-autoclaved beads could be loaded in the chamber and steam sterilized in-situ. The mill was equipped with a 0.4 mm retaining screen which retains the XL-PS beads in the chamber.

[0130] In an embodiment, for the preparation of the PAP injection composition, PAP microsuspension was added into the holding tank equipped as part of the wet mill and re-circulated the microsuspension using the peristaltic pump which was also equipped as part of the mill. Temperature was maintained at around 20°C during the entire operation by jacketing the holding tank and the milling chamber. In this example milling was performed at 1000 RPM agitator speed during the entire process, bead diameter was 0.7 mm and re-circulation rate of the microsuspension was 90 mL / min. Milling was continued until required particle size reached around 1.1 micron.

[0131] In separate container excipient solution was prepared by mixing water (59.6 gm), sodium hydroxide (0.84 gm), citric acid monohydrate (1.5 gm), disodium hydrogen phosphate anhydrous (1.5 gm), sodium dihydrogen phosphate monohydrate (0.76 gm), and polyethylene glycol 4000 (9.0 gm). The solution was mixed until dissolved and filtered through sterilizing grade 0.22 micron filter.

[0132] After the desired average particle size was reached for the PAP, 36.6 gm of excipient solution was added into milling microsuspension in the tank. The resulting microsuspensions were confirmed for the assay (target 156 mg / mL) and pH (target 7.0). It was filled into plastic pre-filled syringe (PFS) and stoppered with coated plug stopper. The composition of the microsuspension is shown in Table- 1 and properties of the PAP microsuspension are shown in Table-2 and compared to the commercial product, Invega Sustenna® for reference.

[0133] In vitro release of PAP microsuspension was performed in USP Type-II apparatus in 900 mL 0.00 IM HC1 containing 0.489% polysorbate-20 at 25°C. The microsuspension was mixed at 50 RPM and the amount of released drug (dissolved and become available) was determined by filtering an aliquot and analyzing by HPLC or UPLC with UV detection. Drug release rate was determined with sampling points at 1.5 min, 8 min, 15 min, 30 min and 90 min.

[0134] Table-1: Composition of the PAP Microsuspension

[0135] Table-2: Properties of PAP Microsuspension

[0136] Rat model is suitable to evaluate the paliperidone palmitate extended-release composition (Rats and rabbits as pharmacokinetic screening tools for long acting intramuscular depot: Case study with paliperidone palmitate suspension, http: / / www.tandfonline.com / loi / ixen20'). Rats (Wistar rats) were injected with PAP microsuspension having PAP concentration 156 mg / mL soon after the manufacturing of batches. Each composition was injected into six rats in thigh muscles by intramuscular injection. The dose was 30 mg / Kg. Injection volume was 50 to 60 microliter calculated based on the weight of the individual rat. Blood samples were collected into pre-labelled vacutainer tubes at pre-dose (0 hour), 0.5-hour, 1 hour, 2 hours, 6 hours, 24 hours, 3 days, 6 days, 7 days, 8 days, 10 days, 12 days, 14 days, 18 days, 22 days, 28 days, 34 days, 41 days, 50 days, and 60 days post dosing. Pre-dose and post-dose samples were collected by retro-orbital bleeding and kept cold on ice prior to processing. The collected blood samples were centrifuged (at 4°C for 10 minutes at 2300g) to collect serum. Collected serum was stored at -70 ± 5 °C until analysis. Analysis of paliperidone in serum was performed by LC-MS. From the drug level cumulative drug release rate was calculated by integrating area under the curve . Figure- 1 compares the in-vivo drug release rate from the compositions, it shows that drug released in sustained manner.

[0137] Sample was subjected to storage stability in PFS. Particle size distribution upon storage and drug release by the accelerated dissolution test. Table-3 shows the storage stability data for Example- 1.

[0138] As shown in Table-3, increase of particle size was observed upon storage at all distribution levels, Dio, Dso, D90 and the increase is more pronounced for Dio and D50 level. The drug release rate decreased considerably upon storage.

[0139] Table-3: Particle size and drug release rate comparison upon storage for example-1

[0140] Example-2

[0141] Example 2 of the PAP microsuspension was prepared using the procedure of example 1. The average particle size (D50) of the microsuspension is around 1.04 micron. A portion of the resulting microsuspension was subjected to a thermal treatment study by subjecting to about 40°C to about 60°C for specific duration of about 7 hours to about 8 hours and cooled back to the ambient temperature.

[0142] The PAP microsuspension from Example-2 with 60°C thermal treatment resulted D50 around 1.88 micron. Thermal treated suspension was subjected to 40°C storage for up to six weeks. For comparison the microsuspension without thermal treatment was also subjected to 40°C storage stability study. Experimentation showed a bulk suspension, from which a portion was heated and maintained at 60°C for about 7 hours to about 8 hours which showed stable particle size upon storage for the tested period of six weeks at 40°C. The DIO size of non-thermal treated sample increased more than 3-fold while the DIO remained same for the thermal treated sample. As observed, for non- thermal treated sample the D50 size increase is less compared to DIO size increase, and D90 size remained same for the thermal treated and non-thermal treated samples. For thermal treated samples, DIO, D50 and D90 remained the same as initial. Comparative storage stability study shows the PAP microsuspension subjected to thermal treatment had stable particle size (Table-4 and Fig. 2).

[0143] Table-4: Change of particle size (micron) upon storage at 40° c

[0144] Example-3 Example 3 of the PAP microsuspension was prepared using the procedure of example 1, however the batch size was 600 mb instead of 150 mb. Half of the sample (around 300 mL) was collected during the milling when the average particle size (D50) reached around 0.9 micron. The remaining 300 mL microsuspension was milled further until the particle size reached around 0.5 micron. The samples were studied for stability without thermal treatment and with thermal treatment. The thermal treatment process followed was as follows. To each portion, excipient solutions were added to achieve desired final composition and sample was subjected to a thermal treatment at about 60°C for the specified period of time (as shown in Table-5) and were cooled back to ambient temperature. After thermal treatment the ideal D50 average particle size was 0.7 pm to 1.4 pm, 0.1 pm to 0.6 pm for DIO and 1.8 pm to 4.0 pm for D90.

[0145] Table-5: Particle size change during thermal treatment at about 60°C

[0146] Samples before and after thermal treatment (50 Hours at about 60°C) were filled into 1 mb pre- filled syringe (PFS) made of cyclic olefin polymer (COP) barrel and stoppered with Flurotec coated bromobutyl plug stopper. Filled PFS samples were subjected to storage stability at 25°C, 30°C, and 40°C RH for up to 6 months. Table-6A compares the storage stability results at 25°C, Table-6B compares the storage stability result at 30°C and Table-6C compares the storage stability result at 40°C.

[0147] Particle size data shows the non-thermal treated sample upon storage changed the particle size, especially D10 value increased considerably, D50 value increased slightly and D90 value remained similar, or decreased slightly in some cases. The particle size span decreased upon storage. The particle size change is more while storing the product under accelerated storage conditions (30°C and 40°C). Even at higher storage temperature, thermal treated samples did not show particle size change.

[0148] In vitro release (dissolution) of PAP microsuspension was performed using the same process as mentioned in example 1. Impurity comparison showed that thermal treatment process did not increase the impurity. Impurity was studied for all samples under all storage conditions. Storage stability result showed without thermal treatment the particle size increased, especially D10 and D50 upon storage. Upon 12 months storage at 25°C Table-6A), the D10 size increased by about 63% for non-thermal treated sample and D50 increased by about 35% while the D10 change for thermal treated sample for the same 12 months period was about 0% and D50 change was about 5% only. For example, for non-thermal treated sample 6 months storage at 30°C (Table-6B) resulted in about 140% increase for D10 and about 45% increase for D50. However, for the thermal treated sample at 30°C for 6 months there was no D10 size increase and the D50 size increase is only about 7%. Similarly, non-thermal treated sample upon 6 months storage at 40°C (Table-6C) resulted D10 size increase of about 225% and D50 size increase was about 64%, whereas for the thermal treated samples, there was no D10 size increase and D50 size increase was only about 20%.

[0149] Dissolution (drug release) shows (Table 6A, 6B & 6C) that the drug release rate reduced considerably for non-thermal treated sample upon storage which is a major concern. The drug release rate for thermal treated sample remained consistent under all storage conditions. Thermal treated samples exhibited (Table 6A, 6B & 6C) drug release of not more than 15% at 1.5 minutes, 10% to 40% at 8 minutes, 20% to 55% at 15 minutes, 45% to 80% at 30 minutes and not less than 80% at 90 minutes. Thus, thermal treated samples showed better storage stability showing consistent particle size and drug dissolution rate. Impurity profile is low for the thermal treated samples under all storage conditions, same as non-thermal treated samples.

[0150] Table-6A: Storage stability comparison of example-3 at 25°C

[0151] Table-6B: Storage stability comparison of example-3 at 30°C

[0152] No Change in appearance such as color.

[0153] 10

[0154] Table-6C: Storage stability comparison of example-3 at 40°C

[0155] Example 4: Animal pharmacokinetic comparison of thermal treated samples

[0156] Animal pharmacokinetic comparison was performed with thermal treated samples, control sample and Invega Sustenna® in Rats (Wistar rats) following the same procedure as in example 1. The pharmacokinetic result converted to cumulative drug release rate is shown in Figure-3. It shows that the drug release is in sustained manner. The result shows pharmacokinetic profile of thermal treated samples provided ideal pharmacokinetic results with respect to FDA requirement.

[0157] Example 5: Paliperidone Palmitate for three months release

[0158] Example 5 is Paliperidone Palmitate microsuspension for three months release duration. Paliperidone Palmitate microsuspension for three months release duration was prepared at the batch size of 250 m . 0.02 gm / gm polysorbate-20 (PS-20) solution was prepared by dissolving 4.01 gm PS-20 in 190.03 gm water by heating the mixture for 30 minutes at 50°C, cooling to 25 °C and q.s. to 200 gm weight with water. PS-20 solution was filtered through 0.2 pm sterilizing grade filter. 76.84 gm of PAP was suspended having 26-micron average particle size (D10 = 6.44 micron, D50 = 25.69 micron, D90 = 56.90 micron) in 123.17 gm polysorbate 20 solution. The microsuspension was mixed for a minimum of 30 minutes using an overhead motor driven stirrer equipped with stainless steel propeller stirrer. Milling equipment (Model - Delta Vita 15S from Netzsch) was prepared for the operation by loading autoclaved cross-linked polystyrene (XL-PS) beads (0.7 mm diameter) in the grinding chamber. Bead loading in the milling chamber was 90% (for example for the grinding chamber with 15 m volume the volume ofXE-PS beads added was 13.5 mb). The mill was equipped with a 0.4 mm retaining screen which retains the XE-PS beads in the chamber. PAP micro suspension was added into the holding tank equipped as part of the wet mill and re-circulated the microsuspension using the peristaltic pump which was also equipped as part of the mill. Temperature was maintained at around 20°C during the entire operation by jacketing the holding tank and the milling chamber. In this example milling was performed at 1000 RPM agitator speed during the entire process, bead diameter was 0.7 mm and re-circulation rate of the microsuspension was 180 mb / min. Milling was continued until required particle size reached around 7 micron.

[0159] In a separate container excipient solution-I was prepared by mixing water (22.94 gm), sodium hydroxide (6.52 gm), citric acid monohydrate (9.0 gm), sodium dihydrogen phosphate monohydrate (7.2 gm). The solution was mixed until dissolved and filtered through sterilizing grade 0.22 micron filter. In the second container excipient solution-II was prepared by mixing water (45 gm), and PEG 4000 (45.03 gm), mixed the solution until dissolved and filtered through sterilizing grade 0.45 micron filter.

[0160] After the desired average particle size is reached for the PAP, 36.95 gm of excipient solution-II and 9.36 gm of excipient solution-I were added into milling microsuspension in the tank and mixed. The resulting microsuspensions were confirmed for the assay (target 312 mg / mL) and pH (target 7.0). It was filled into plastic pre-filled syringe (PFS) and stoppered with coated plug stopper. The composition of the microsuspension is shown in Table-7 and properties of the PAP microsuspension are shown in Table-8 and compared to the commercial product, Invega Trinza® for reference.

[0161] Table-7: Composition of the PAP Microsuspension

[0162] Table-8: Properties of PAP Microsuspension

[0163] Rats (Wistar rats) were injected with PAP microsuspension having PAP concentration 312 mg / mL soon after the manufacturing of batches. Each composition was injected into six rats in thigh muscles by intramuscular injection. The dose was 90 mg / Kg. Injection volume was around 0.3 mL / Kg, actual injection volume calculated based on the weight of the individual rat. Blood samples were collected into pre-labelled vacutainer tubes at pre-dose (0 hour), at 0.5-hour, 1 hour, 2 hours, 6 hours, 24 hours, 3 days, 6 days, 7 days, 8 days, 10 days, 12 days, 14 days, 18 days, 22 days, 30 days, 45 days, 60 days, 75 days, and 90 days post dosing. Pre-dose and post-dose samples were collected by retro-orbital bleeding and kept cold on ice prior to processing. The collected blood samples were centrifuged (at 4°C for 10 minutes at 2300 g) to collect serum. Collected serum was stored at -70 ± 5°C until analysis. Analysis of paliperidone in serum was performed by LC-MS. From the drug level cumulative drug release rate was calculated by integrating area under the curve. Figure-4 compares the in-vivo drug release rate from the compositions.

[0164] Examples 6: Storage stability of paliperidone palmitate three-month composition A batch identical to example 5 was prepared. Example-6 had an average particle size of 7 micron. Samples were subjected to storage stability. Table-9 shows the storage stability data of Example 6. As shown in Table-9, a slight increase of particle size was observed upon storage at Dio, Dso distribution levels and the increase is more pronounced for Dio level.

[0165] Table-9: Particle Size Comparison upon Storage for Example-6

[0166] Example-7: Thermal treatment for stable Paliperidone Palmitate three-month composition PAP composition was produced identical to example 5. PAP microsuspension in polysorbate-20 solution was milled using cross-linked polystyrene beads for 190 min. Excipient solutions were added to achieve desired composition. The samples were studied without and with thermal treatment. Thermal treatment was performed after measuring particle size and span. Half the portion of prepared PAP composition was subjected to thermal treatment at about 60°C for the specified period of time (as shown in Table-10). Both thermal treated and non-thermal treated portions were studied for storage stability. Table- 10 shows the change of particle size over the duration of thermal treatment and particle size span. Thermal treated PAP microsuspension showed lower particle size span. These samples were cooled back to ambient temperature.

[0167] Table-10: Particle size upon thermal treatment at about 60° C

[0168] Thermal treated and non-thermal treated samples were confirmed for the assay (target 312 mg / mL) and pH (target 7.0) and were filled into 2.25 mb pre-filled syringe (PFS) made of cyclic olefin polymer (COP) barrel and stoppered with Flurotec coated bromobutyl plug stopper. Fill volume was 1.315 mb to have 410 mg dose per PFS. Filled PFS samples were subjected to storage stability at 25°C, 30°C, and 40°C. Table-l lA compares the storage stability result at 25°C, Table- 1 IB compares the storage stability result at 30°C and Table- 11C compares the storage stability result at 40°C. Thermal treated samples exhibited (Table 11A, 1 IB & 11C) drug release of not more than 10% at 5 minutes, not more than 20% at 30 minutes, 10% to 35% at 60 minutes, 25% to 55% at 120 minutes, 45% to 75% at 240 minutes and 55% to 85% at 360 minutes.

[0169] Table-llA: Storage Stability Comparison at25°C

[0170] Table-llB: Storage Stability Comparison at30°C

[0171] Table-llC: Storage Stability Comparison at40°C No Change in appearance such as color.

[0172] Benefits of thermal treatment are same for one-month and three-month compositions. Impurity profile showed that thermal treatment process did not increase the impurity. Impurity was studied for all samples under all storage conditions and was found within acceptable limits. Particle size (DIO and D5O) of non-thermal treated samples increased upon storage and the increase was faster at higher temperature storage. Dissolution (drug release) shows that the drug release rate reduced for non-thermal treated sample upon storage. The drug release rate for thermal treated samples remained consistent under all storage conditions. Thus, thermal treated samples showed better storage stability showing consistent particle size and drug dissolution rate under all storage conditions.

[0173] Example 8: Pharmacokinetic profile comparison of Scale-up batch of Paliperidone Palmitate one month release composition and commercial product (Invega Sustenna®)

[0174] Scale-up thermal treated batch of Paliperidone Palmitate one month release composition was subjected to rat pharmacokinetic study along with Invega Sustenna®. Rats (Wistar rats) were injected with PAP microsuspension having concentration 156 mg / mL. Each composition was injected into ten rats in thigh muscles by intramuscular injection. The dose was 30 mg / Kg. Injection volume was around 0.2 mL / Kg, actual injection volume calculated based on the weight of the individual rat so that rats received 30 mg / Kg dose. Blood samples were collected into prelabelled vacutainer tubes at pre-dose (0 hour), at 0.5-hour, 1 hour, 2 hours, 6 hours, 24 hours, 72 hours, 144 hours, 168 hours, 192 hours, 240 hours, 288 hours, 336 hours, 432 hours, 528 hours, and 672 hours post dosing. Pre-dose and post-dose samples were collected by retro-orbital bleeding and kept cold on ice prior to processing. The collected blood samples were centrifuged (at 4°C for 10 minutes at 2300 g) to collect serum. Collected serum was stored at -70 ± 5 °C until analysis. Analysis of paliperidone in serum was performed by LC-MS. Figure-5 compares the concentration of paliperidone for the compositions over the time. Table- 12 shows properties of scale-up batch of one month release formulation and Invega Sustenna®.

[0175] Table-12: Properties of Scale-up batch of One Month Release Formulation and Invega Sustenna®

[0176] No Change in appearance such as color. *Below Detection Limit

[0177] Scale-up batch fdled at 156 mg strength in PFS was tested and subjected to storage stability. Samples were stored at 25°C (RH60%) for 12 months, 30°C (RH=65%) for 6 months and 40°C (RH=75%) for 3 months for the PFS stored at horizontal orientation. Stability data (Table 13) shows the product is stable and no trend observed for particle size change. Other properties such as appearance, pH, HPLC impurities, syringeability performance remained same as initial and there was no major change in the dissolution rate upon storage. Table 13: Initial Properties and Properties Upon Storage at Horizontal Orientation for

[0178] Thermal Treated Scale-Up Batch of One Month Release Composition

[0179] * White milky suspension, M = Month(s), * BDL = Below detection limit (LOD = 0.016%), ND=Not detected, CVF = Cumulative Volume Fraction

[0180] For comparison, Invega Sustenna® was stored at 25°C and 30°C for up to six months and compared against the scale-up batch of PAP of one month release composition (Table-14). The comparison showed slightly slower drug release for both Invega Sustenna® and scale-up batch and the % decrease of release was 14% to 21% and the decrease is more during the initial time 10 points of dissolution.

[0181] Table-14: Dissolution Rate of Invega Sustenna® (Uot# KEB4E00) Upon Storage at 25°C and 30°C

[0182] 15 Example 9: Crystallinity of thermal treated and non-thermal treated scale-up batches

[0183] Crystallinity of scale-up batch of Paliperidone Palmitate one month release microsuspension subjected to thermal treatment (RDI-20-210416), non-thermal treatment batch (RDI-20-1126) and Invega Sustenna® (LFB1X01-RLD) were compared as shown in Figure 6. Data showed similar crystallinity of thermal treatment batch compared to non-treated batch and Invega Sustenna®.

Claims

WE CLAIM:

1. A stable pharmaceutical injectable composition comprising: i. Paliperidone palmitate as an active pharmaceutical ingredient, and ii. pharmaceutically acceptable excipients, wherein the composition is manufactured by a process that involves thermal treatment.

2. A stable pharmaceutical injectable composition comprising, i. Paliperidone palmitate as an active pharmaceutical ingredient, ii. at least one surfactant, iii. at least one viscosity agent, iv. at least one stabilizer, and v. at least one buffering agent, wherein the composition is manufactured by a process that involves thermal treatment.

3. A stable pharmaceutical injectable composition, wherein the composition is a depot microsuspension comprising: i. Paliperidone palmitate as an active pharmaceutical ingredient, ii. at least one surfactant, iii. at least one viscosity agent, iv. at least one stabilizer, and v. at least one buffering agent. wherein the composition is manufactured by a process comprising the steps: e) Preparing a surfactant solution. f) Mixing crystalline sterile paliperidone palmitate (PAP) in surfactant solution of step (a). g) Subjecting the premix of step (b) to wet milling in the presence of milling beads to obtain a microsuspension of PAP; and h) Adding sterile excipient solutions containing stabilizing agent, viscosity agent and buffer to microsuspension of step (c), wherein the microsuspension is subjected to thermal treatment, wherein the whole process is carried out aseptically and wherein the thermal treatment can be incorporated at any stage during the manufacturing.

4. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, is administered by intramuscular, intravenous, subcutaneous, intradermal or intraperitoneal route.

5. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, wherein the composition is prepared by a process of wet milling the composition comprising: i. Paliperidone palmitate as an active pharmaceutical ingredient, ii. at least one surfactant, iii. at least one viscosity agent, iv. at least one stabilizer, and v. at least one buffering agent.wherein the process involves a thermal treatment by increasing the temperature in the range of 40°C to 85°C for a period in the range of 5 minutes to 120 hours, at any stage during the manufacturing.

6. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, wherein the composition is prepared by a process comprising: a) Preparing a surfactant solution. b) Mixing crystalline sterile paliperidone palmitate (PAP) in surfactant solution of step (a). c) Subjecting the premix of step (b) to wet milling in the presence of milling beads to obtain a microsuspension of PAP. d) Adding sterile excipient solutions containing stabilizing agent, viscosity agent and buffer to microsuspension of step (c); and e) Subjecting the microsuspension to thermal treatment by increasing the microsuspension temperature in the range of 40°C to 85°C for a period in the range of 5 minutes to 120 hours. wherein the whole process is carried out aseptically.

7. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims wherein the composition is prepared by a process comprising: a) Preparing a surfactant solution. b) Mixing crystalline sterile paliperidone palmitate (PAP) in surfactant solution of step (a), c) Subject the premix of step (b) to thermal treatment by increasing the microsuspension temperature in the range of 40°C to 85°C for a period in the range of 5 minutes to 120 hours. d) Subjecting the premix of step (c) to wet milling in the presence of milling beads to obtain a microsuspension of PAP; and e) Adding sterile excipient solutions containing stabilizing agent, viscosity agent and buffer. wherein the whole process is carried out aseptically.

8. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims wherein the composition is prepared by a process comprising: a) Preparing a surfactant solution, b) Mixing crystalline sterile paliperidone palmitate (PAP) in surfactant solution of step (a), c) Subject the premix of step (b) to wet milling in the presence of milling beads to obtain a microsuspension of PAP, d) Subjecting the PAP microsuspension of step (c) to thermal treatment by increasing the microsuspension temperature in the range of 40°C to 85°C for a period in the range of 5 minutes to 120 hours; and e) Adding sterile excipient solutions containing stabilizing agent, viscosity agent and buffer. wherein the whole process is carried out aseptically.

9. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims wherein said composition has stable particle size and stable drug release upon storage for at least 12 months at temperature of 25°C.

10. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, wherein at least one surfactant is selected from polyethylene glycol fatty acid monoesters (e.g., polyethylene glycol laurate or stearate, etc.); polyethylene glycol fatty acid diesters (e.g., polyethylene glycol dilaurate, disterate, dipalmitate, or dioleate, etc.); polyethylene glycol glycerol fatty acid esters (e.g., polyethylene glycol glycerol laurate, glycerol stearate, glycerol oleate, etc.); polyglycerized fatty acids (e.g., polyglyceryl laurate, oleate, or stearate; polyglyceryl mono and dioleate; etc.); sterol derivatives (e.g., polyethylene glycol cholesterol ether, polyethylene glycol cholestanol, polyethylene glycol phyto sterol, etc.); and polyethylene glycol sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80, PEG- 10 sorbitan laurate, PEG-20 sorbitan monolaurate, sorbitan tristearate, etc.).

11. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, wherein at least one surfactant is selected from polyethylene glycol sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80, PEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate, sorbitan tristearate, etc.).

12. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, wherein at least one surfactant selected is polysorbate 20.

13. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, wherein at least one viscosity agent is selected from polyalkylene glycols (e.g., polyethylene glycol, polypropylene glycol, and copolymers thereof); polyethylene glycols (e.g., PEG 300, PEG 400, PEG 600, PEG 1000, PEG 1100, PEG 1900, PEG 2000, PEG 2800, PEG 2900, PEG 3350, PEG 4000, PEG 6000, PEG 8000, PEG 8400, PEG 10,000, PEG 12,000, PEG 14600, PEG 17,000, etc.); and triblock polymer of polypropylene glycol flanked by polyethylene glycol (e.g., poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, poloxamer 407, etc.).

14. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, wherein at least one viscosity agent is selected from polyethylene glycols (e.g., PEG 300, PEG 400, PEG 600, PEG 1000, PEG 1100, PEG 1900, PEG 2000, PEG 2800, PEG 2900, PEG 3350, PEG 4000, PEG 6000, PEG 8000, PEG 8400, PEG 10,000, PEG 12,000, PEG 14600, PEG 17,000, etc.).

15. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, wherein at least one viscosity agent selected is PEG 4000.

16. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, wherein at least one stabilizer is selected from acetic acid, citric acid monohydrate, benzoic acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, malic acid, phosphoric acid, sorbic acid, sulfuric acid, tartaric acid, potassium carbonate, sodium carbonate, sodium bicarbonate, and sodium hydroxide.

17. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, wherein at least one stabilizer selected is citric acid monohydrate.

18. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, wherein at least one b'Tferino aannt se terl from alkali metal citrate, citricacid / sodium citrate, potassium hydrogen tartrate, sodium hydrogen tartrate, potassium hydrogen phthalate, sodium hydrogen phthalate, potassium dihydrogen phosphate, sodium hydroxide, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous.

19. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, at least one buffering agent is selected from sodium hydroxide, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous or mixture thereof.

20. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims wherein the composition comprises paliperidone palmitate as an active ingredient, polysorbate 20 as a surfactant, PEG 4000 as a viscosity agent, citric acid monohydrate as a stabilizer, and sodium hydroxide, sodium dihydrogen phosphate monohydrate or disodium hydrogen phosphate anhydrous or mixture thereof as a buffer, prepared by wet media milling process.

21. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, comprising active pharmaceutical ingredient 0.156 g / mL, surfactant(s) from 0.005 g / mL to 0.02 g / mL, viscosity agent(s) from 0.010 g / mL to 0.040 g / mL, stabilizer(s) from 0.001 g / mL to 0.007 g / mL, buffering agent(s) from 0.001 g / mL to 0.007 g / mL and water for injection, prepared by wet media milling process including thermal treatment.

22. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, comprising paliperidone palmitate 0.156 g / mL as an active pharmaceutical ingredient, surfactant such as polysorbate 20 from 0.005 g / mL to 0.02 g / mL, viscosity agent such as polyethylene glycol (PEG) 4000 from 0.010 g / mL to 0.040 g / mL, stabilizer such as citric acid monohydrate from 0.001 g / mL to 0.007 g / mL, buffering agents such as sodium hydroxide from 0.001 g / mL to 0.003 g / mL, disodium hydrogen phosphate anhydrous from 0.001 g / mL to 0.007 g / mL, sodium dihydrogen phosphate monohydrate from 0.001 g / mL to 0.003 g / mL or mixture thereof and water for injection, prepared by wet media milling process including thermal treatment.

23. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, comprising 0.156 g / mL paliperidone palmitate, 0.012 g / mL polysorbate 20, 0.030 g / mL polyethylene glycol (PEG) 4000, 0.005 g / mL citric acid monohydrate, 0.0028 g / mL sodium hydroxide, 0.005 g / mL disodium hydrogen phosphate anhydrous, 0.0026 g / mL sodium dihydrogen phosphate monohydrate or mixtures thereof and water for injection, prepared by wet media milling process including thermal treatment.

24. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, comprising 23.4 gm paliperidone palmitate, 3.62 gm polysorbate 20, 9.0 gm polyethylene glycol (PEG) 4000, 1.5 gm citric acid monohydrate, 0.84 gm sodium hydroxide, 1.5 gm disodium hydrogen phosphate anhydrous, 0.76 gm sodium dihydrogen phosphate monohydrate or mixture thereof and water for injection, prepared by wet media milling process including thermal treatment.

25. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, comprising active pharmaceutical ingredient 0.312 g / mL, surfactant(s) from 0.005g / mL to 0.02 g / mL, viscosity agent(s) from 0.001 g / mL to 0.1 g / mL, stabilizer(s) from 0.0001 g / mL to 0.01 g / mL, buffering agent(s) from 0.001 g / mL to 0.01 g / mL and water for injection, prepared by wet media milling process including thermal treatment.

26. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, comprising paliperidone palmitate 0.312 g / mL as an active pharmaceutical ingredient, surfactant such as polysorbate 20 from 0.005 g / mL to 0.02 g / mL, viscosity agent such as polyethylene glycol (PEG) 4000 from 0.001 g / mL to 0. Ig / mL, stabilizer such as citric acid monohydrate from 0.0001 g / mL to 0.01 g / mL, buffering agents such as sodium hydroxide from 0.001 g / mL to 0.01 g / mL, sodium dihydrogen phosphate monohydrate from 0.001 g / mL to 0.01 g / mL or mixture thereof and water for injection, prepared by wet media milling process including thermal treatment.

27. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, comprising 0.312 g / mL paliperidone palmitate, 0.01 g / mL polysorbate 20, 0.075 g / ml polyethylene glycol (PEG) 4000, 0.0075 g / mL citric acid monohydrate, 0.0054 g / mL sodium hydroxide, 0.006 g / mL sodium dihydrogen phosphate monohydrate or mixtures thereof and water for injection, prepared by wet media milling process including thermal treatment.

28. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, comprising 76.84 gm paliperidone palmitate, 4.01 gm polysorbate 20, 45.03 gm polyethylene glycol (PEG) 4000, 9.0 gm citric acid monohydrate, 6.52 gm sodium hydroxide, 7.2 gm sodium dihydrogen phosphate monohydrate or mixture thereof and water for injection, prepared by wet media milling process including thermal treatment.

29. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, wherein the said composition is intended for releasing drug for a duration of 1 month and exhibits dissolution release of not more than 15% at 1.5 minutes, 10% to 40% at 8 minutes, 20% to 55% at 15 minutes, 45% to 80% at 30 minutes and not less than 80% at 90 minutes.

30. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, wherein the said composition is intended for releasing drug for a duration of 3 months and exhibits dissolution release of not more than 10% at 5 minutes, not more than 20% at 30 minutes, 10% to 35% at 60 minutes, 25% to 55% at 120 minutes, 45% to 75% at 240 minutes and 55% to 85% at 360 minutes.

31. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, wherein the said composition is intended for releasing drug for a duration of 1 month, has particle size distribution characterized by Dio from 0. 1 to 0.6 micron, Dso from 0.7 to 1.4 micron, D90 from 1.8 to 4.0 micron, and span is not more than 3.5.

32. The stable pharmaceutical injectable composition as claimed in any one of the preceding claims, wherein the said composition is intended for releasing drug for a duration of 3 month, has particle size distribution characterized by Dio from 1.5 to 2.5 micron, Dso from 4.0 to 8.0 micron, D90 from 9.0 to 11.0 micron, and Span is not more than 3.0.

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