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EP-4739687-A1 - STABLE PALIPERIDONE PALMITATE COMPOSITION USING THERMAL TREATMENT

EP4739687A1EP 4739687 A1EP4739687 A1EP 4739687A1EP-4739687-A1

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.

Inventors

  • DESHMUKH, MANJEET
  • MEDICO, Miguel
  • THANOO, Bagavathikan
  • LAGISETTY, Naga Vamsi Krishna

Assignees

  • Eugia Pharma Specialities Limited

Dates

Publication Date
20260513
Application Date
20240628

Claims (20)

  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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, 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.
  19. 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. 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.

Description

STABLE PALIPERIDONE PALMITATE COMPOSITION USING THERMAL TREATMENT FIELD OF THE INVENTION 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. BACKGROUND OF THE INVENTION: Paliperidone is an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. 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. 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: 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). 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. 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®. 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