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WO2016157061A1 - Aseptic wet milling process for paliperidone palmitate - Google Patents

Aseptic wet milling process for paliperidone palmitate Download PDF

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Publication number
WO2016157061A1
WO2016157061A1 PCT/IB2016/051734 IB2016051734W WO2016157061A1 WO 2016157061 A1 WO2016157061 A1 WO 2016157061A1 IB 2016051734 W IB2016051734 W IB 2016051734W WO 2016157061 A1 WO2016157061 A1 WO 2016157061A1
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Prior art keywords
paliperidone palmitate
milling
μιη
particle size
beads
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Ceased
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PCT/IB2016/051734
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French (fr)
Inventor
Mukesh Kumar
Suhas KAKADE
Sopan PHAPAL
Prashant BIRANGAL
Varsha AWALE
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Wockhardt Ltd
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Wockhardt Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

  • the invention relates to a process for micronizing paliperidone palmitate aseptically using wet milling.
  • the aseptic wet milling process uses two types of milling beads sequentially in single equipment to obtain particles of micronized paliperidone palmitate with desired size ranges and having uniform size distribution.
  • Paliperidone palmitate is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives with the chemical name (9RS)-3-[2-[4(6-Fluoro-1 ,2- benzisoxazol-S-y piperidin-l -yllethyll ⁇ -methyl- ⁇ oxo-ej ⁇ -tetrahydro- 4Hpyrido[1 ,2-a]pyrimadin-9-yl hexadecanoate. Its molecular formula is C39H57FN4O4 and its molecular weight is 664.89. The structural formula is:
  • the injection composition of paliperidone palmitate is available commercially and marketed under the brand name of Invega Sustena ® in US market. It is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in dose strengths of 25 mg, 50 mg, 75 mg, 100 mg, and 150 mg of paliperidone.
  • the composition is provided in a prefilled syringe (cyclic- olefin-copolymer) with a plunger stopper and tip cap (bromobutyl rubber).
  • sterile micronization of active ingredient is carried out in air-jet mills fitted in isolators. Jet mills can be operated in sterile conditions by integrating the mill in an isolator or a restricted access barrier system (RABS).
  • RABS restricted access barrier system
  • US Patent No. 6,555,544 discloses a process for preparing submicron particles of an antipsychotic agent.
  • the inventors of the invention surprisingly found that the sterile micronization of paliperidone palmitate by air-jet milling can be avoided and instead as an alternative, less expensive wet media milling can be used to produce particles with desired size range in a single equipment.
  • the inventors of the invention unexpectedly found that the processing time for reducing the particle size of paliperidone palmitate was reduced significantly by utilizing two types of milling beads sequentially.
  • the invention uses wet milling process in such a way that it produces particles of micronized paliperidone palmitate having an effective average particle size of less than 3 ⁇ and having narrow size distribution range. Moreover, the wet milling process may reduce the time to achieve desired particle size.
  • step (b) subjecting the premix of step (a) to wet milling in the presence of first milling beads having size of about 1 .5 mm to obtain a suspension of paliperidone palmitate with reduced effective average particle size;
  • step (c) subjecting the suspension formed in step (b) to wet milling in the presence of second milling beads having size of about 0.3 mm to obtain suspension of micronized paliperidone palmitate having effective average particle size of less than 3 ⁇ ,
  • the process is carried out as a batch processing.
  • the process of wet milling for micronizing paliperidone palmitate wherein the first milling beads reduce the particle size of paliperidone palmitate to an effective average particle size of less than about 40 ⁇ .
  • the particle size is reduced to an effective average particle size of less than about 30 ⁇ , more preferably less than about 20 ⁇ and yet more preferably less than about 10 ⁇ .
  • the process of wet milling for micronizing paliperidone palmitate, wherein the size of first type of milling beads ranges from 0.5 mm to 2.5 mm.
  • the process of wet milling for micronizing paliperidone palmitate wherein the size of second type of milling beads ranges from 0.15 mm to 0.45 mm.
  • the process of wet milling for micronizing paliperidone palmitate wherein the milling beads are made up of material selected from zirconium oxide, yttrium-stabilized zirconium oxide, steel, ceramic material, copper, silicon carbide, porcelain, quartz, aluminum oxide, non-ferrous metal or in special cases of plastics material.
  • a process for micronizing paliperidone palmitate aseptically using wet milling comprising steps of:
  • step (b) subjecting the premix of step (a) to wet milling in the presence of first milling beads to obtain a suspension of paliperidone palmitate particles with reduced effective average size in the range of about 10 to about 39 ⁇ ;
  • step (c) subjecting the suspension formed in step (b) to wet milling in the presence of second milling beads to obtain particles of paliperidone palmitate with effective average size of less than 3 ⁇ ,
  • the process of wet milling for micronizing paliperidone palmitate wherein the 1/4 th particle size reduction takes place in 2/3 of the total processing time when compared to wet media milling by single type of milling beads as against two types of milling beads.
  • the process of wet milling for micronizing paliperidone palmitate wherein the second milling beads reduce the particle size of paliperidone palmitate to an effective average particle size of less than 3 ⁇ .
  • the process of wet milling for micronizing paliperidone palmitate wherein the polydispersity index of the particles of paliperidone palmitate obtained is below 2.0.
  • the polydispersity index of the particles of paliperidone palmitate obtained is below 1 .9, more preferably below 1 .8, more preferably below 1 .7, more preferably below 1 .6 and yet more preferably about 1 .5.
  • dgo means that 10% of the said substance by volume has a particle size over the value stated with d 90 and the other 90% of the substance by volume has a particle size below the value stated with d 90 .
  • D 90 value can be measured by one of the known measuring devices, for instance by a device which measures particle distribution by laser diffraction, for instance, by Malvern Mastersizer.
  • polydispersity index refers to a measure of the distribution of particle sizes for a collection of particles.
  • PDI can be measured by one of the known measuring devices, for instance by a device which measures particle distribution by laser diffraction, for instance, by Malvern Mastersizer.
  • wet 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 apparatus therefore are conventionally known in the art and do not form a critical feature of the invention.
  • the “milling beads” in the method of the 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 essentially resistant to fracture and erosion in the milling process.
  • the milling beads are desirably provided in the form of beads which have smooth ovoid or spherical shapes.
  • the milling beads are provided in the form of one or more of beads, balls or spheres.
  • the milling beads may be made for example of zirconium oxide, yttrium- stabilized zirconium oxide, steel, ceramic material, copper, silicon carbide, porcelain, quartz, aluminum oxide, non-ferrous metal or in special cases of plastics material.
  • the term "aseptic” is used interchangeably with the word “sterile”.
  • 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, U.S. Department of Health and Human Services Food and Drug Administration, September 2004.
  • a process of wet milling for micronizing paliperidone palmitate which process employs two types of milling beads namely first type of milling beads and second type of milling beads.
  • the process of wet milling for micronizing paliperidone palmitate said process is carried out as a batch processing employing two types of milling beads sequentially.
  • the process of wet milling for micronizing paliperidone palmitate comprises first milling beads, wherein the size of first type of milling beads ranges from about 0.5 mm to about 2.5 mm.
  • the process of wet milling for micronizing paliperidone palmitate comprises second milling beads, wherein the size of second type of milling beads ranges from about 150 ⁇ to about 450 ⁇ .
  • the process of micronizing paliperidone palmitate aseptically using wet milling wherein the milling process is carried out at 50-3000 rpm.
  • step (b) subjecting the premix of step (a) to wet milling in the presence of first milling beads to obtain a suspension of paliperidone palmitate with reduced effective average particle size;
  • step (c) subjecting the suspension formed in step (b) to wet milling in the presence of second milling beads to obtain suspension of paliperidone palmitate having effective average particle size of less than 3 ⁇ ,
  • the process of wet milling for micronizing paliperidone palmitate wherein the micronized paliperidone palmitate particles have effective average particle size of less than 3 ⁇ .
  • having effective average particle size less than 2.9 ⁇ , more preferably less than 2.7 ⁇ , more preferably less than 2.5 ⁇ , more preferably less than 2.3 ⁇ , yet more preferably less than 2.1 ⁇ and yet more preferably about 2.0 ⁇ .
  • the process of wet milling for micronizing paliperidone palmitate wherein the processing with first milling beads and second milling beads constitute less than 4 hr.
  • processing with first milling beads and second milling beads constitute less than 3.5 hr, more preferably, less than 3 hr and yet more preferably less than 2 hr.
  • the process of wet milling for micronizing paliperidone palmitate wherein the processing with first milling beads and second milling beads constitute about 2 hr.
  • the process of wet milling for micronizing paliperidone palmitate wherein the processing with first milling beads is effected for the 1/4 th to 3/4 th of the total processing time.
  • the process of wet milling for micronizing paliperidone palmitate wherein the processing with second milling beads is effected for the 1/4 th to 3/4 th of the total processing time.
  • the process of wet milling for micronizing paliperidone palmitate wherein the processing with first milling beads is effected for about 30 min and processing with second milling beads is effected for about 1 hr and 30 min.
  • the process of wet milling for micronizing paliperidone palmitate wherein the processing with first milling beads is effected for about 1 hr and processing with second milling beads is effected for about 1 hr.
  • the process of wet milling for micronizing paliperidone palmitate wherein the processing with first milling beads is effected for about 1 hr 30 min and processing with second milling beads is effected for about 30 min.
  • the process of wet milling for micronizing paliperidone palmitate wherein the 1/4 th particle size reduction takes place in 2/3 rd of the total processing time when compared to wet media milling by single type of milling beads as against two types of milling beads, sequentially.
  • the polydispersity index of the micronized paliperidone palmitate is below 2.0.
  • the polydispersity index of the micronized paliperidone palmitate particles is below 1 .9, more preferably below 1 .8, more preferably below 1 .7, more preferably below 1 .6 and yet more preferably about 1 .5.
  • the process of wet milling for micronizing paliperidone palmitate wherein the size of first type of milling beads ranges from 0.5 mm to 2.5 mm.
  • the process of wet milling for micronizing paliperidone palmitate wherein the size of second type of milling beads ranges from 0.15 mm to 0.45 mm.
  • the process of wet milling for micronizing paliperidone palmitate wherein the milling beads are made up of material selected from the group consisting of zirconium oxide, yttrium-stabilized zirconium oxide, steel, ceramic material, copper, silicon carbide, porcelain, quartz, aluminum oxide, non-ferrous metal or in special cases of plastics material.
  • step (b) subjecting the premix of step (a) to wet milling in the presence of first milling beads having size of about 1 .5 mm to obtain a suspension of paliperidone palmitate with reduced effective average particle size range of about 10 ⁇ to 39 ⁇ ;
  • step (c) subjecting the suspension formed in step (b) to wet milling in the presence of second milling beads having size of about 0.3 mm to obtain suspension of micronized paliperidone palmitate having effective average particle size of less than 3 ⁇ ,
  • step (b) subjecting the premix of step (a) to wet milling in the presence of first milling beads having size of about 1 .5 mm to obtain a suspension of paliperidone palmitate with reduced effective average particle size range of about 10 ⁇ to 39 ⁇ ;
  • step (c) subjecting the suspension formed in step (b) to wet milling in the presence of second milling beads having size of about 0.3 mm to obtain suspension of paliperidone palmitate having effective average particle size of about 2 ⁇ , wherein the total process is carried out in single equipment aseptically.
  • the process of wet milling for micronizing paliperidone palmitate wherein the first milling beads reduce the particle size of paliperidone palmitate to an effective average particle size of less than 39 ⁇ .
  • the particle size is reduced to an effective average particle size of less than 30 ⁇ , more preferably less than 20 ⁇ , more preferably less than 15 ⁇ and yet more preferably less than 10 ⁇ .
  • the process of wet milling for aseptically micronizing paliperidone palmitate wherein the obtained particles are having average particle size below 3.0 ⁇ .
  • the process of wet milling for aseptically micronizing paliperidone palmitate wherein the particles having average particle size below 1 .2 ⁇ are obtained after 4 hr of batch processing.
  • the process of wet milling for aseptically micronizing paliperidone palmitate wherein the particles having average particle size below 1 .2 ⁇ are obtained after 4 hr of batch processing.
  • the process of wet milling for aseptically micronizing paliperidone palmitate wherein the particles having average particle size below 1 .2 ⁇ are obtained after 4 hr of batch processing.
  • the process of wet milling for aseptically micronizing paliperidone palmitate wherein the particles having average particle size below 1 .2 ⁇ are obtained after 4 hr of batch processing.
  • the process of wet milling for aseptically micronizing paliperidone palmitate wherein the particles having average particle size below 1 .2 ⁇ are obtained after 4 hr of batch processing.
  • the process of wet milling for aseptically micronizing paliperidone palmitate wherein the particles having average particle size of about 2.0 ⁇ are obtained after about 2 hr of batch processing.
  • the process of wet milling for aseptically micronizing paliperidone palmitate wherein the particles having average particle size of about 2.0 ⁇ are obtained after 2 hr of batch processing in which processing with first milling beads is effected for about 30 min and processing with second milling beads is effected for about 1 hr and 30 min.
  • the process of wet milling for aseptically micronizing paliperidone palmitate wherein the particles having average particle size of about 2.0 ⁇ are obtained after 2 hr of batch processing in which processing with first milling beads is effected for about 1 hr 30 min and processing with second milling beads is effected for about 30 min.
  • a process of wet milling for aseptically preparing a composition comprising micronized paliperidone palmitate and at least one pharmaceutically acceptable excipient.
  • the process of wet milling for aseptically preparing a composition comprising micronized paliperidone palmitate, a surfactant and at least one pharmaceutically acceptable excipient.
  • the process of wet milling for aseptically preparing a composition comprising micronized paliperidone palmitate, polysorbate 20, citric acid monohydrate, disodium hydrogen phosphate anhydrous, polyethylene glycol 4000, sodium dihydrogen phosphate monohydrate, sodium hydroxide, and water for injection.
  • the process of wet milling for aseptically preparing composition comprising:
  • the process of wet milling for aseptically preparing composition comprising:
  • composition comprising micronized paliperidone palmitate obtained by a process comprising steps of:
  • step (b) subjecting the premix of step (a) to mechanical means in the presence of first milling beads to obtain a suspension of paliperidone palmitate with reduced effective average particle size range of about 10 ⁇ to 39 ⁇ ;
  • step (c) subjecting the suspension formed in step (b) to mechanical means in the presence of second milling beads to obtain suspension of paliperidone palmitate having effective average particle size of about 2 ⁇ ,
  • Unmicronized Paliperidone palmitate (sterile grade) was dispersed into the polysorbate solution.
  • the suspension was milled aseptically in the grinding chamber using Yttrium stabilized zirconium beads (1 .5mm) till required particle size was reached.
  • the suspension was filtered aseptically through a 40 micron filter into a sterilized SS container.
  • Water for injections was transferred into a separate SS container, citric acid monohydrate, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide, polyethylene glycol 4000 were added and mixed until dissolved.
  • This solution was sterilized by filtration through sterile 0.22 micron filter and transferred aseptically into milled suspension.
  • the final suspension was mixed until homogeneous.
  • the suspension was filled aseptically into sterile syringes.
  • Micronized Paliperidone palmitate (sterile grade) was dispersed into the polysorbate solution.
  • the suspension was milled aseptically in the grinding chamber using Yttrium stabilized zirconium beads (1 .5mm) till required particle size was reached.
  • the suspension was filtered aseptically through a 40 micron filter into a sterilized SS container.
  • Water for injections was transferred into a separate SS container, citric acid monohydrate, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide, polyethylene glycol 4000 were added and mixed until dissolved.
  • This solution was sterilized by filtration through sterile 0.22 micron filter and transferred aseptically into milled suspension.
  • the final suspension was mixed until homogeneous.
  • the suspension was filled aseptically into sterile syringes.
  • Micronized Paliperidone palmitate (sterile grade) having was dispersed into the polysorbate solution.
  • the suspension was milled aseptically in the grinding chamber using Yttrium stabilized zirconium beads (0.3mm) till required particle size was reached.
  • the suspension was filtered aseptically through a 40 micron filter into a sterilized SS container.
  • Water for injections was transferred into a separate SS container, citric acid monohydrate, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide, polyethylene glycol 4000 were added and mixed until dissolved.
  • This solution was sterilized by filtration through sterile 0.22 micron filter and transferred aseptically into milled suspension.
  • the final suspension was mixed until homogeneous.
  • the suspension was filled aseptically into sterile syringes.
  • Unmicronized Paliperidone palmitate (sterile grade) was dispersed into the polysorbate solution.
  • the suspension was milled aseptically in the grinding chamber using first milling beads (Yttrium stabilized zirconium beads) till required particle size was reached. Then the first milling beads were removed from the grinding chamber and second milling beads (Yttrium stabilized zirconium beads) were introduced.
  • the suspension was milled aseptically in the grinding chamber using second milling beads till required particle size was reached.
  • the suspension was filtered aseptically through a 40 micron filter into a sterilized SS container.
  • Unmicronized Paliperidone palmitate (sterile grade) was dispersed into the polysorbate solution.
  • the suspension was milled aseptically in the grinding chamber using first milling beads (Yttrium stabilized zirconium beads) till required particle size was reached.
  • first milling beads Yttrium stabilized zirconium beads
  • second milling beads Yttrium stabilized zirconium beads
  • the suspension was milled aseptically in the grinding chamber using second milling beads till required particle size was reached.
  • the suspension was filtered aseptically through a 40 micron filter into a sterilized SS container.
  • ethylenediaminetetraacetic acid EDTA
  • disodium hydrogen phosphate anhydrous sodium dihydrogen phosphate monohydrate, sodium hydroxide, polyethylene glycol 4000 were added and mixed until dissolved.
  • This solution was sterilized by filtration through sterile 0.22 micron filter and transferred aseptically into milled suspension. The final suspension was mixed until homogeneous. The suspension was filled aseptically into sterile syringes.
  • Particle Size Data The results for processing time and particle size as obtained are mentioned in table 7. All batches were having batch size of 160 ml.

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Abstract

An aseptic wet milling process for preparing a pharmaceutical composition comprising micronized paliperidone palmitate by using two types of milling beads is disclosed. In particular, the aseptic wet milling process uses two types of milling beads sequentially in a single equipment to obtain particles of micronized paliperidone palmitate with desired size ranges and having uniform size distribution.

Description

Aseptic Wet Milling Process for Paliperidone Palmitate
FIELD OF THE INVENTION
The invention relates to a process for micronizing paliperidone palmitate aseptically using wet milling. In particular, the aseptic wet milling process uses two types of milling beads sequentially in single equipment to obtain particles of micronized paliperidone palmitate with desired size ranges and having uniform size distribution.
BACKGROUND OF THE INVENTION
Paliperidone palmitate is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives with the chemical name (9RS)-3-[2-[4(6-Fluoro-1 ,2- benzisoxazol-S-y piperidin-l -yllethyll^-methyl-^oxo-ej^^-tetrahydro- 4Hpyrido[1 ,2-a]pyrimadin-9-yl hexadecanoate. Its molecular formula is C39H57FN4O4 and its molecular weight is 664.89. The structural formula is:
Figure imgf000002_0001
The injection composition of paliperidone palmitate is available commercially and marketed under the brand name of Invega Sustena® in US market. It is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in dose strengths of 25 mg, 50 mg, 75 mg, 100 mg, and 150 mg of paliperidone. The composition is provided in a prefilled syringe (cyclic- olefin-copolymer) with a plunger stopper and tip cap (bromobutyl rubber). Generally, sterile micronization of active ingredient is carried out in air-jet mills fitted in isolators. Jet mills can be operated in sterile conditions by integrating the mill in an isolator or a restricted access barrier system (RABS). Thus, micronizing an API aseptically by air-jet milling is expensive and requires sophisticated equipments.
US patent publication nos. 2008/0214808 and 2009/0163519 disclose micronization of paliperidone palmitate ester by wet milling process.
US Patent No. 6,555,544 discloses a process for preparing submicron particles of an antipsychotic agent.
There still exists an enduring need to develop an alternate, economically less expensive, and robust method for preparing sterile composition comprising paliperidone palmitate with an effective average particle size of less than 3 μιη.
The inventors of the invention surprisingly found that the sterile micronization of paliperidone palmitate by air-jet milling can be avoided and instead as an alternative, less expensive wet media milling can be used to produce particles with desired size range in a single equipment. In addition, the inventors of the invention unexpectedly found that the processing time for reducing the particle size of paliperidone palmitate was reduced significantly by utilizing two types of milling beads sequentially.
The invention uses wet milling process in such a way that it produces particles of micronized paliperidone palmitate having an effective average particle size of less than 3 μιη and having narrow size distribution range. Moreover, the wet milling process may reduce the time to achieve desired particle size.
SUMMARY OF THE INVENTION In one aspect, there is provided a process for micronizing paliperidone palmitate aseptically using wet milling, said process comprising the steps of:
(a) mixing crystalline paliperidone palmitate having effective average particle size in the range of about 40 μιη to about 300 μιη in a sterile vehicle to form a premix;
(b) subjecting the premix of step (a) to wet milling in the presence of first milling beads having size of about 1 .5 mm to obtain a suspension of paliperidone palmitate with reduced effective average particle size; and
(c) subjecting the suspension formed in step (b) to wet milling in the presence of second milling beads having size of about 0.3 mm to obtain suspension of micronized paliperidone palmitate having effective average particle size of less than 3 μιη,
wherein the total process is carried out in single equipment aseptically.
In an embodiment, the process is carried out as a batch processing.
In another aspect, there is provided a process wherein the processing with first milling beads is effected for the 1/4th to 3/4th of the total processing time.
In another aspect, there is provided a process wherein the processing with second milling beads is effected for the 1/4th to 3/4th of the total processing time.
In another aspect, there is provided a process wherein the processing with first milling beads is effected for half of the total processing time and the processing with second milling beads is effected remaining half of the total processing time.
In another aspect, the process of wet milling for micronizing paliperidone palmitate wherein the first milling beads reduce the particle size of paliperidone palmitate to an effective average particle size of less than about 40 μιη. Preferably, the particle size is reduced to an effective average particle size of less than about 30 μιη, more preferably less than about 20 μιη and yet more preferably less than about 10 μιη. In another embodiment, the process of wet milling for micronizing paliperidone palmitate, wherein the size of first type of milling beads ranges from 0.5 mm to 2.5 mm.
In another embodiment, the process of wet milling for micronizing paliperidone palmitate, wherein the size of second type of milling beads ranges from 0.15 mm to 0.45 mm.
In another embodiment, the process of wet milling for micronizing paliperidone palmitate, wherein the milling beads are made up of material selected from zirconium oxide, yttrium-stabilized zirconium oxide, steel, ceramic material, copper, silicon carbide, porcelain, quartz, aluminum oxide, non-ferrous metal or in special cases of plastics material.
In another aspect, a process for micronizing paliperidone palmitate aseptically using wet milling, said process comprising steps of:
(a) mixing particles of paliperidone palmitate with effective average size in the range of about 40 to about 100 μιη in a sterile vehicle to form a premix;
(b) subjecting the premix of step (a) to wet milling in the presence of first milling beads to obtain a suspension of paliperidone palmitate particles with reduced effective average size in the range of about 10 to about 39 μιη; and
(c) subjecting the suspension formed in step (b) to wet milling in the presence of second milling beads to obtain particles of paliperidone palmitate with effective average size of less than 3 μιη,
wherein the total process is carried out in single equipment aseptically.
In another general embodiment, the process of wet milling for micronizing paliperidone palmitate, wherein the 1/4th particle size reduction takes place in 2/3 of the total processing time when compared to wet media milling by single type of milling beads as against two types of milling beads.
In another embodiment, the process of wet milling for micronizing paliperidone palmitate wherein the second milling beads reduce the particle size of paliperidone palmitate to an effective average particle size of less than 3 μιη. Preferably, having effective average particle size below 2.9 μιη, more preferably 2.7 μιη, more preferably 2.5 μιη, more preferably 2.3 μιη, yet more preferably 2.1 μιη and yet more preferably about 2.0 μιη.
In another embodiment, the process of wet milling for micronizing paliperidone palmitate, wherein the polydispersity index of the particles of paliperidone palmitate obtained is below 2.0. Preferably, the polydispersity index of the particles of paliperidone palmitate obtained is below 1 .9, more preferably below 1 .8, more preferably below 1 .7, more preferably below 1 .6 and yet more preferably about 1 .5.
DETAILED DESCRIPTION OF THE INVENTION
Definitions:
The term "effective average particle size" refers to average particle size by volume and it is also shown with dgo in short. In this sense, the term dgo signifies that 10% of the said substance by volume has a particle size over the value stated with d90 and the other 90% of the substance by volume has a particle size below the value stated with d90. D90 value can be measured by one of the known measuring devices, for instance by a device which measures particle distribution by laser diffraction, for instance, by Malvern Mastersizer.
The term "polydispersity index (PDI)" refers to a measure of the distribution of particle sizes for a collection of particles. PDI can be measured by one of the known measuring devices, for instance by a device which measures particle distribution by laser diffraction, for instance, by Malvern Mastersizer. The term "wet 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 apparatus therefore are conventionally known in the art and do not form a critical feature of the invention.
The "milling beads" in the method of the 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 essentially resistant to fracture and erosion in the milling process. The milling beads are desirably provided in the form of beads which have smooth ovoid or spherical shapes. Preferably, the milling beads are provided in the form of one or more of beads, balls or spheres.
The milling beads may be made for example of zirconium oxide, yttrium- stabilized zirconium oxide, steel, ceramic material, copper, silicon carbide, porcelain, quartz, aluminum oxide, non-ferrous metal or in special cases of plastics material.
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, U.S. Department of Health and Human Services Food and Drug Administration, September 2004.
In one aspect, a process of wet milling for micronizing paliperidone palmitate which process employs two types of milling beads namely first type of milling beads and second type of milling beads. In another embodiment, the process of wet milling for micronizing paliperidone palmitate, said process is carried out as a batch processing employing two types of milling beads sequentially.
In another embodiment, the process of wet milling for micronizing paliperidone palmitate comprises first milling beads, wherein the size of first type of milling beads ranges from about 0.5 mm to about 2.5 mm.
In another embodiment, the process of wet milling for micronizing paliperidone palmitate comprises second milling beads, wherein the size of second type of milling beads ranges from about 150 μιη to about 450 μιη.
In another embodiment, the process of micronizing paliperidone palmitate aseptically using wet milling, wherein the milling process is carried out at 50-3000 rpm.
In another aspect, there is provided a process of micronizing paliperidone palmitate aseptically using wet milling, said process comprising the steps of:
(a) mixing crystalline paliperidone palmitate having effective average particle size in the range of about 40 μιη to about 300 μιη in a sterile vehicle to form a premix;
(b) subjecting the premix of step (a) to wet milling in the presence of first milling beads to obtain a suspension of paliperidone palmitate with reduced effective average particle size; and
(c) subjecting the suspension formed in step (b) to wet milling in the presence of second milling beads to obtain suspension of paliperidone palmitate having effective average particle size of less than 3 μιη,
wherein the total process is carried out in a single equipment aseptically.
In another general embodiment, the process of wet milling for micronizing paliperidone palmitate wherein the micronized paliperidone palmitate particles have effective average particle size of less than 3 μιη. Preferably, having effective average particle size less than 2.9 μιη, more preferably less than 2.7 μιη, more preferably less than 2.5 μιη, more preferably less than 2.3 μιη, yet more preferably less than 2.1 μιη and yet more preferably about 2.0 μιη.
In another general embodiment, the process of wet milling for micronizing paliperidone palmitate, wherein the processing with first milling beads and second milling beads constitute less than 4 hr. Preferably, processing with first milling beads and second milling beads constitute less than 3.5 hr, more preferably, less than 3 hr and yet more preferably less than 2 hr.
In another general embodiment, the process of wet milling for micronizing paliperidone palmitate, wherein the processing with first milling beads and second milling beads constitute about 2 hr.
In another general embodiment, the process of wet milling for micronizing paliperidone palmitate, wherein the processing with first milling beads is effected for the 1/4th to 3/4th of the total processing time.
In another general embodiment, the process of wet milling for micronizing paliperidone palmitate, wherein the processing with second milling beads is effected for the 1/4th to 3/4th of the total processing time.
In another general embodiment, the process of wet milling for micronizing paliperidone palmitate, wherein the processing with first milling beads is effected for about 30 min and processing with second milling beads is effected for about 1 hr and 30 min.
In another general embodiment, the process of wet milling for micronizing paliperidone palmitate, wherein the processing with first milling beads is effected for about 1 hr and processing with second milling beads is effected for about 1 hr.
In another general embodiment, the process of wet milling for micronizing paliperidone palmitate, wherein the processing with first milling beads is effected for about 1 hr 30 min and processing with second milling beads is effected for about 30 min.
In another general embodiment, the the process of wet milling for micronizing paliperidone palmitate, wherein the 1/4th particle size reduction takes place in 2/3rd of the total processing time when compared to wet media milling by single type of milling beads as against two types of milling beads, sequentially.
In another general aspect, there is provided a process of wet milling for micronizing paliperidone palmitate, wherein the polydispersity index of the micronized paliperidone palmitate is below 2.0. Preferably, the polydispersity index of the micronized paliperidone palmitate particles is below 1 .9, more preferably below 1 .8, more preferably below 1 .7, more preferably below 1 .6 and yet more preferably about 1 .5.
In another general embodiment, the process of wet milling for micronizing paliperidone palmitate, wherein the size of first type of milling beads ranges from 0.5 mm to 2.5 mm.
In another general embodiment, the process of wet milling for micronizing paliperidone palmitate, wherein the size of second type of milling beads ranges from 0.15 mm to 0.45 mm.
In another general embodiment, the process of wet milling for micronizing paliperidone palmitate, wherein the milling beads are made up of material selected from the group consisting of zirconium oxide, yttrium-stabilized zirconium oxide, steel, ceramic material, copper, silicon carbide, porcelain, quartz, aluminum oxide, non-ferrous metal or in special cases of plastics material.
In another aspect, there is provided a process micronizing paliperidone palmitate aseptically using wet milling, said process comprising the steps of:
(a) mixing crystalline paliperidone palmitate having effective average particle size in the range of about 40 μιη to about 100 μιη in a sterile vehicle to form a premix;
(b) subjecting the premix of step (a) to wet milling in the presence of first milling beads having size of about 1 .5 mm to obtain a suspension of paliperidone palmitate with reduced effective average particle size range of about 10 μιη to 39 μιη; and
(c) subjecting the suspension formed in step (b) to wet milling in the presence of second milling beads having size of about 0.3 mm to obtain suspension of micronized paliperidone palmitate having effective average particle size of less than 3 μιη,
wherein the total process is carried out in single equipment aseptically.
In another aspect, there is provided a process for micronizing paliperidone palmitate aseptically using wet milling, said process comprising the steps of:
(a) mixing crystalline paliperidone palmitate having effective average particle size in the range of about 40 μιη to about 100 μιη in a sterile vehicle to form a premix;
(b) subjecting the premix of step (a) to wet milling in the presence of first milling beads having size of about 1 .5 mm to obtain a suspension of paliperidone palmitate with reduced effective average particle size range of about 10 μιη to 39 μιη; and
(c) subjecting the suspension formed in step (b) to wet milling in the presence of second milling beads having size of about 0.3 mm to obtain suspension of paliperidone palmitate having effective average particle size of about 2 μΓη , wherein the total process is carried out in single equipment aseptically.
In another embodiment, the process of wet milling for micronizing paliperidone palmitate wherein the first milling beads reduce the particle size of paliperidone palmitate to an effective average particle size of less than 39 μιη. Preferably, the particle size is reduced to an effective average particle size of less than 30 μιη, more preferably less than 20 μιη, more preferably less than 15 μιη and yet more preferably less than 10 μιη.
In another general embodiment, the process of wet milling for aseptically micronizing paliperidone palmitate, wherein the obtained particles are having average particle size below 3.0 μιη. Preferably, having effective average particle size below 2.9 μιη, more preferably 2.7 μιη, more preferably 2.5 μιη, more preferably 2.3 μιη, yet more preferably 2.1 μιη and yet more preferably about 2.0 μιη.
In another general embodiment, the process of wet milling for aseptically micronizing paliperidone palmitate, wherein the particles having average particle size below 1 .2 μιη are obtained after 4 hr of batch processing. Preferably, after 3.5 hr of batch processing, more preferably, after 3.0 hr of batch processing and yet more preferably after 2.0 hr of batch processing.
In another general embodiment, the process of wet milling for aseptically micronizing paliperidone palmitate, wherein the particles having average particle size of about 2.0 μιη are obtained after about 2 hr of batch processing.
In another general embodiment, the process of wet milling for aseptically micronizing paliperidone palmitate, wherein the particles having average particle size of about 2.0 μιη are obtained after 2 hr of batch processing in which processing with first milling beads is effected for about 30 min and processing with second milling beads is effected for about 1 hr and 30 min. In another general embodiment, the process of wet milling for aseptically micronizing paliperidone palmitate, wherein the particles having average particle size of about 2.0 μιη are obtained after 2 hr of batch processing in which processing with first milling beads is effected for about 1 hr 30 min and processing with second milling beads is effected for about 30 min.
In another general aspect, there is provided a process of wet milling for aseptically preparing a composition comprising micronized paliperidone palmitate and at least one pharmaceutically acceptable excipient.
In another embodiment, the process of wet milling for aseptically preparing a composition comprising micronized paliperidone palmitate, a surfactant and at least one pharmaceutically acceptable excipient.
In another embodiment, the process of wet milling for aseptically preparing a composition comprising micronized paliperidone palmitate, polysorbate 20, citric acid monohydrate, disodium hydrogen phosphate anhydrous, polyethylene glycol 4000, sodium dihydrogen phosphate monohydrate, sodium hydroxide, and water for injection.
In another embodiment, the process of wet milling for aseptically preparing a composition comprising:
(a) 10 to 20% of micronized paliperidone palmitate,
(b) 0.5 to 5.0 % of polysorbate 20,
(c) 0.1 to 1 .0 % of citric acid monohydrate,
(d) 0.1 to 1 .0 % of disodium hydrogen phosphate anhydrous,
(e) 0.5 to 5.0 % of polyethylene glycol 4000,
(f) 0.1 to 1 .0 % of sodium dihydrogen phosphate monohydrate,
(g) 0.1 to 1 .0 % of sodium hydroxide, and
(h) q.s. of water for injection In another embodiment, the process of wet milling for aseptically preparing composition comprising:
(a) 15.07% of micronized paliperidone palmitate,
(b) 1 .16 % of polysorbate 20,
(c) 0.48 % of citric acid monohydrate,
(d) 0.48 % of disodium hydrogen phosphate anhydrous,
(e) 2.90 % of polyethylene glycol 4000,
(f) 0.24 % of sodium dihydrogen phosphate monohydrate,
(g) 0.27 % of sodium hydroxide, and
(h) q.s. of water for injection
In another embodiment, the process of wet milling for aseptically preparing composition comprising:
(a) 10 to 20% of micronized paliperidone palmitate,
(b) 0.5 to 5.0 % of polysorbate 20,
(c) 0.1 to 1 .0 % ethylenediaminetetraacetic acid (EDTA),
(d) 0.1 to 1 .0 % of disodium hydrogen phosphate anhydrous,
(e) 0.5 to 5.0 % of polyethylene glycol 4000,
(f) 0.1 to 1 .0 % of sodium dihydrogen phosphate monohydrate,
(g) 0.1 to 1 .0 % of sodium hydroxide, and
(h) q.s. of water for injection
In another embodiment, the process of wet milling for aseptically preparing composition comprising:
(a) 15.07% of micronized paliperidone palmitate,
(b) 1 .93 % of polysorbate 20,
(c) 0.50 % of ethylenediaminetetraacetic acid (EDTA),
(d) 0.48 % of disodium hydrogen phosphate anhydrous,
(e) 2.90 % of polyethylene glycol 4000,
(f) 0.24 % of sodium dihydrogen phosphate monohydrate,
(g) 0.27 % of sodium hydroxide, and (h) q.s. of water for injection
In another aspect, there is provided a composition comprising micronized paliperidone palmitate obtained by a process comprising steps of:
(a) mixing crystalline paliperidone palmitate having effective average particle size in the range of about 40 μιη to about 100 μιη in a sterile vehicle to form a premix;
(b) subjecting the premix of step (a) to mechanical means in the presence of first milling beads to obtain a suspension of paliperidone palmitate with reduced effective average particle size range of about 10 μιη to 39 μιη; and
(c) subjecting the suspension formed in step (b) to mechanical means in the presence of second milling beads to obtain suspension of paliperidone palmitate having effective average particle size of about 2 μιη,
wherein the total process is carried out in single equipment aseptically.
The invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
The invention now will be described in particularity with the following illustrative examples; however, the scope of the invention is not intended to be, and shall not be, limited to the exemplified embodiments below.
EXAMPLES
Comparative Example A:
Table 1
Sr. Quantity
Ingredients
No. (% w/w)
1 Paliperidone Palmitate 15.07
2 Polysorbate 20 1 .16 3 Citric acid monohydrate 0.48
4 Disodium hydrogen phosphate
anhydrous 0.48
5 Polyethylene glycol 4000 2.90
6 Sodium dihydrogen phosphate
monohydrate 0.24
7 Sodium hydroxide 0.27
8 Water for injection Qs
Manufacturing Process:
Unmicronized Paliperidone palmitate (sterile grade) was dispersed into the polysorbate solution. The suspension was milled aseptically in the grinding chamber using Yttrium stabilized zirconium beads (1 .5mm) till required particle size was reached. The suspension was filtered aseptically through a 40 micron filter into a sterilized SS container. Water for injections was transferred into a separate SS container, citric acid monohydrate, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide, polyethylene glycol 4000 were added and mixed until dissolved. This solution was sterilized by filtration through sterile 0.22 micron filter and transferred aseptically into milled suspension. The final suspension was mixed until homogeneous. The suspension was filled aseptically into sterile syringes.
Comparative Example B:
Table 2
Sr. Quantity
Ingredients
No. (% w/w)
1 Paliperidone Palmitate 15.07
2 Polysorbate 20 1 .16
3 Citric acid monohydrate 0.48
4 Disodium hydrogen phosphate 0.48 anhydrous
5 Polyethylene glycol 4000 2.90
6 Sodium dihydrogen phosphate
monohydrate 0.24
7 Sodium hydroxide 0.27
8 Water for injection Qs
Manufacturing Process:
Micronized Paliperidone palmitate (sterile grade) was dispersed into the polysorbate solution. The suspension was milled aseptically in the grinding chamber using Yttrium stabilized zirconium beads (1 .5mm) till required particle size was reached. The suspension was filtered aseptically through a 40 micron filter into a sterilized SS container. Water for injections was transferred into a separate SS container, citric acid monohydrate, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide, polyethylene glycol 4000 were added and mixed until dissolved. This solution was sterilized by filtration through sterile 0.22 micron filter and transferred aseptically into milled suspension. The final suspension was mixed until homogeneous. The suspension was filled aseptically into sterile syringes.
Comparative Example C:
Table 3
Sr. Quantity
Ingredients
No. (% w/w)
1 Paliperidone Palmitate 15.07
2 Polysorbate 20 1 .16
3 Citric acid monohydrate 0.48
4 Disodium hydrogen phosphate
anhydrous 0.48
5 Polyethylene glycol 4000 2.90 6 Sodium dihydrogen phosphate
monohydrate 0.24
7 Sodium hydroxide 0.27
8 Water for injection Qs
Manufacturing Process:
Micronized Paliperidone palmitate (sterile grade) having was dispersed into the polysorbate solution. The suspension was milled aseptically in the grinding chamber using Yttrium stabilized zirconium beads (0.3mm) till required particle size was reached. The suspension was filtered aseptically through a 40 micron filter into a sterilized SS container. Water for injections was transferred into a separate SS container, citric acid monohydrate, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide, polyethylene glycol 4000 were added and mixed until dissolved. This solution was sterilized by filtration through sterile 0.22 micron filter and transferred aseptically into milled suspension. The final suspension was mixed until homogeneous. The suspension was filled aseptically into sterile syringes.
Example 1
Table 4
Figure imgf000018_0001
Manufacturing Process:
Unmicronized Paliperidone palmitate (sterile grade) was dispersed into the polysorbate solution. The suspension was milled aseptically in the grinding chamber using first milling beads (Yttrium stabilized zirconium beads) till required particle size was reached. Then the first milling beads were removed from the grinding chamber and second milling beads (Yttrium stabilized zirconium beads) were introduced. The suspension was milled aseptically in the grinding chamber using second milling beads till required particle size was reached. The suspension was filtered aseptically through a 40 micron filter into a sterilized SS container. Water for injections was transferred into a separate SS container, citric acid monohydrate, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide, polyethylene glycol 4000 were added and mixed until dissolved. This solution was sterilized by filtration through sterile 0.22 micron filter and transferred aseptically into milled suspension. The final suspension was mixed until homogeneous. The suspension was filled aseptically into sterile syringes.
Example 2:
Table 5
Figure imgf000019_0001
Manufacturing Process: Unmicronized Paliperidone palmitate (sterile grade) was dispersed into the polysorbate solution. The suspension was milled aseptically in the grinding chamber using first milling beads (Yttrium stabilized zirconium beads) till required particle size was reached. Then the first milling beads were removed from the grinding chamber and second milling beads (Yttrium stabilized zirconium beads) were introduced. The suspension was milled aseptically in the grinding chamber using second milling beads till required particle size was reached. The suspension was filtered aseptically through a 40 micron filter into a sterilized SS container. Water for injections was transferred into a separate SS container, ethylenediaminetetraacetic acid (EDTA), disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodium hydroxide, polyethylene glycol 4000 were added and mixed until dissolved. This solution was sterilized by filtration through sterile 0.22 micron filter and transferred aseptically into milled suspension. The final suspension was mixed until homogeneous. The suspension was filled aseptically into sterile syringes.
Example 3:
Table 6
Figure imgf000020_0001
Manufacturing Process: As described in Example 2.
Particle Size Data: The results for processing time and particle size as obtained are mentioned in table 7. All batches were having batch size of 160 ml.
Table 7
Figure imgf000021_0001
(6 urn)

Claims

CLAIMS We claim:
1. A process for micronizing paliperidone palmitate aseptically using wet milling, said process comprising the steps of:
a) mixing crystalline paliperidone palmitate having effective average particle size in the range of about 40 μιη to about 300 μιη in a sterile vehicle to form a premix;
b) subjecting the premix of step (a) to wet milling in the presence of first milling beads having size about 1 .5 mm to obtain a suspension of paliperidone palmitate with reduced effective average particle size; and c) subjecting the suspension formed in step (b) to wet milling in the presence of second milling beads having size about 0.3 mm to obtain suspension of micronized paliperidone palmitate having effective average particle size of less than 3 μιη,
wherein the total process is carried out in a single equipment aseptically.
2. The process of claim 1 , wherein the process is carried out as a batch processing.
3. The process of claim 1 , wherein the processing with first milling beads is effected for the 1/4th to 3/4th of the total processing time.
4. The process of claim 1 , wherein the processing with second milling beads is effected for the 1/4th to 3/4th of the total processing time.
5. The process of claim 1 , wherein the polydispersity index of the micronized paliperidone palmitate particles is below 2.5.
6. The process of claim 1 , wherein the polydispersity index of the micronized paliperidone palmitate particles is below 1 .8.
7. The process of claim 1 , wherein the polydispersity index of the micronized paliperidone palmitate particles is about 1 .5.
8. The process of claim 1 , wherein the first and second milling beads are made up of material selected from zirconium oxide, yttrium-stabilized zirconium oxide, steel, ceramic material, copper, silicon carbide, porcelain, quartz, aluminum oxide, non-ferrous metal or in special cases of plastics material.
9. A process for micronizing paliperidone palmitate aseptically using wet milling, said process comprising the steps of:
a) mixing particles of paliperidone palmitate with effective average size in the range of about 40 μιη to about 100 μιη in a sterile vehicle to form a premix;
b) subjecting the premix of step (a) to wet milling in the presence of first milling beads having size of about 1 .5 mm to obtain a suspension of paliperidone palmitate particles with reduced effective average size in the range of about 10 μιη to about 39 μιη; and
c) subjecting the suspension formed in step (b) to wet milling in the presence of second milling beads having size of about 0.3 mm to obtain particles of micronized paliperidone palmitate with effective average particle size of less than 3 μιη,
wherein the total process is carried out in a single equipment aseptically.
10. The process of claim 1 or 9, wherein the micronized paliperidone palmitate particles have effective average particle size of less than 2.5 μιη.
1 1 . The process of claim 1 or 9, wherein the micronized paliperidone palmitate particles have effective average size is about 2.0 μιη.
12. The process of claim 1 or 9, wherein the polydispersity index of the micronized paliperidone palmitate particles is below 2.0
13. The process of claim 1 or 9, wherein the polydispersity index of the micronized paliperidone palmitate particles is about 1 .5.
14. The process of claim 1 or 9, wherein the 1/4th particle size reduction takes place in 2/3rd of the total processing time when compared to wet media milling by single type of milling beads as against two types of milling beads.
15. A pharmaceutical composition comprising micronized paliperidone palmitate particles having effective average particle size of less than 3 μιη prepared by a process of claim 1 or 9.
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190183896A1 (en) * 2017-12-14 2019-06-20 SpecGx LLC One step milling process for preparing micronized paliperidone esters
CN110279659A (en) * 2019-07-08 2019-09-27 华裕(无锡)制药有限公司 Palmitinic acid 9-hydroxy-risperidone preparation and preparation method thereof
GR1009869B (en) * 2019-07-12 2020-11-12 Φαρματεν Α.Β.Ε.Ε. Long acting injectable pgarmaceutical composition comprising paliperidone palmitate and method of preparation thereof
US11304951B1 (en) 2020-11-30 2022-04-19 Janssen Pharmaceutica Nv Dosing regimens associated with extended release paliperidone injectable formulations
US11324751B1 (en) 2020-11-30 2022-05-10 Janssen Pharmaceutica Nv Dosing regimens associated with extended release paliperidone injectable formulations
WO2022111860A1 (en) * 2020-11-30 2022-06-02 Janssen Pharmaceutica Nv Dosing regimens associated with extended release paliperidone injectable formulations
WO2025008726A1 (en) * 2023-07-03 2025-01-09 Eugia Pharma Specialities Limited Stable paliperidone palmitate composition using thermal treatment
US12472184B2 (en) 2021-08-20 2025-11-18 Janssen Pharmaceutica Nv Dosing regimens associated with extended release paliperidone injectable formulations

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999030687A1 (en) * 1997-12-16 1999-06-24 Smithkline Beecham Plc Pharmaceutical compositions containing micronized bicyclic drugs
US20030064998A1 (en) * 1997-11-17 2003-04-03 Francois Marc Karel Jozef Aqueous suspensions of submicron 9-hydroxyrisperidone fatty acid esters
US20080214808A1 (en) 2005-04-25 2008-09-04 Thomas Frederik Ernestine Spittaels Preparation of Aseptic 3-[2-[4-((6-Fluoro-1,2-Benzisoxazol-3-Yl)-1-Piperidinyl]-6,7,8,9-Tetrahydro-9-Hydroxy-2-Methyl-4H-Pyrido[1,2-a]Pyrimidin-4-One Palmitate Ester
US20090163519A1 (en) 2007-12-19 2009-06-25 An Vermeulen Dosing regimen associated with long acting injectable paliperidone esters

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030064998A1 (en) * 1997-11-17 2003-04-03 Francois Marc Karel Jozef Aqueous suspensions of submicron 9-hydroxyrisperidone fatty acid esters
US6555544B2 (en) 1997-11-17 2003-04-29 Janssen Pharmaceutica, N.V. Aqueous suspensions of submicron 9-hydroxyrisperidone fatty acid esters
WO1999030687A1 (en) * 1997-12-16 1999-06-24 Smithkline Beecham Plc Pharmaceutical compositions containing micronized bicyclic drugs
US20080214808A1 (en) 2005-04-25 2008-09-04 Thomas Frederik Ernestine Spittaels Preparation of Aseptic 3-[2-[4-((6-Fluoro-1,2-Benzisoxazol-3-Yl)-1-Piperidinyl]-6,7,8,9-Tetrahydro-9-Hydroxy-2-Methyl-4H-Pyrido[1,2-a]Pyrimidin-4-One Palmitate Ester
US20090163519A1 (en) 2007-12-19 2009-06-25 An Vermeulen Dosing regimen associated with long acting injectable paliperidone esters

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190183896A1 (en) * 2017-12-14 2019-06-20 SpecGx LLC One step milling process for preparing micronized paliperidone esters
WO2019118722A1 (en) * 2017-12-14 2019-06-20 SpecGx LLC One step milling process for preparing micronized paliperidone esters
JP2021506757A (en) * 2017-12-14 2021-02-22 スペックジーエックス エルエルシー One-step grinding method for preparing pulverized paliperidone ester
AU2018383636B2 (en) * 2017-12-14 2024-01-18 SpecGx LLC One step milling process for preparing micronized paliperidone esters
CN110279659A (en) * 2019-07-08 2019-09-27 华裕(无锡)制药有限公司 Palmitinic acid 9-hydroxy-risperidone preparation and preparation method thereof
GR1009869B (en) * 2019-07-12 2020-11-12 Φαρματεν Α.Β.Ε.Ε. Long acting injectable pgarmaceutical composition comprising paliperidone palmitate and method of preparation thereof
EP4025187B1 (en) 2020-11-30 2024-01-03 Janssen Pharmaceutica NV Dosing regimens associated with extended release paliperidone injectable formulations
US11304951B1 (en) 2020-11-30 2022-04-19 Janssen Pharmaceutica Nv Dosing regimens associated with extended release paliperidone injectable formulations
WO2022111860A1 (en) * 2020-11-30 2022-06-02 Janssen Pharmaceutica Nv Dosing regimens associated with extended release paliperidone injectable formulations
WO2022111858A1 (en) * 2020-11-30 2022-06-02 Janssen Pharmaceutica Nv Dosing regimens associated with extended release paliperidone injectable formulations
US11439647B2 (en) 2020-11-30 2022-09-13 Janssen Pharmaceutica Nv Dosing regimens associated with extended release paliperidone injectable formulations
KR20230116013A (en) * 2020-11-30 2023-08-03 얀센 파마슈티카 엔.브이. Dosage Regimens Associated with Extended Release Paliperidone Injectable Formulations
US11324751B1 (en) 2020-11-30 2022-05-10 Janssen Pharmaceutica Nv Dosing regimens associated with extended release paliperidone injectable formulations
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AU2021387679B2 (en) * 2020-11-30 2024-01-18 Janssen Pharmaceutica Nv Dosing regimens associated with extended release paliperidone injectable formulations
WO2022111859A1 (en) * 2020-11-30 2022-06-02 Janssen Pharmaceutica Nv Dosing regimens associated with extended release paliperidone injectable formulations
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US12053474B2 (en) 2020-11-30 2024-08-06 Janssen Pharmaceutica Nv Dosing regimens associated with extended release paliperidone injectable formulations
EP4385564A3 (en) * 2020-11-30 2024-10-09 JANSSEN Pharmaceutica NV Dosing regimens associated with extended release paliperidone injectable formulations
KR102794804B1 (en) 2020-11-30 2025-04-10 얀센 파마슈티카 엔브이 Dosage regimen associated with extended-release paliperidone injectable formulations
US12208100B2 (en) 2020-11-30 2025-01-28 Janssen Pharmaceutica Nv Dosing regimens associated with extended release paliperidone injectable formulations
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WO2025008726A1 (en) * 2023-07-03 2025-01-09 Eugia Pharma Specialities Limited Stable paliperidone palmitate composition using thermal treatment

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