Classifications

• • 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
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
  • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
• • 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
  • 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
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1682—Processes
  • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5089—Processes

Definitions

• the present invention relates to Risperidone microspheres and a process for preparing thereof, particularly to a process for preparing Risperidone microspheres having a desired release profile.
• Risperidone is an antipsychotic drug and is chemically known as 3-[2-[4-(6- fluoro-l,2-benzisoxazole-3-yl)-l-piperidyl] ethyl]-6,7,8,9-tetrahydro-2-methyl-4H- pyrido [1,2-a] pyrimidine-4-one.
• Risperidone is approved to treat schizophrenia in adults and children who are at least 13 years old, to treat symptoms of bipolar disorder (manic depression) in adults and children who are at least 10 years old and is also used to treat symptoms of irritability in autistic children who are 5 to 16 years old.
• Risperidone is commercially available in different presentations such as tablet (film coated and oral disintegration tablet), oral solution under the brand name Risperdal ® . It is also approved as long acting injectable formulations under the brand name Risperdal Consta ® and PerserisTM. Risperdal Consta ® , available in dosage strengths of 12.5 mg, 25 mg, 37.5 mg, and 50 mg risperidone, is approved for the treatment of schizophrenia and bipolar disorder as an intramuscular injection administered once every two weeks. It is supplied as a dose pack, consisting of a vial containing the risperidone microspheres, a pre-filled syringe containing diluent.
• Risperidone is micro-encapsulated in 75:25 polylactide-co-glycolide (PLG) at a concentration of 381 mg Risperidone per gram of microspheres.
• PLG polylactide-co-glycolide
• PerserisTM an extended-release once a monthly injectable suspension for subcutaneous use is available in strengths of 90 mg and 120 mg, indicated for the treatment of schizophrenia in adults.
• PerserisTM is supplied as a kit which includes: one pre-filled syringe containing a white to yellow risperidone powder in and one pre-filled syringe containing a colorless /V-methyl-2-pyrrolidone.
• Microspheres may be prepared using any of the methods such as phase separation, spray drying, solvent extraction, and solvent evaporation methods.
• Various methods for the preparation of microspheres containing an active agent, Risperidone have been disclosed in U.S. Patent No. 3,523,906, U.S. Patent No. 5,792,477, U.S. Patent No. 6,194,006, U.S. Patent No. 6,824,822, U.S. Patent No. 9,943,484, U.S. Patent publication No. 2010/0143479 A, WO 2016/019881A1, CN 101292960B, and CN 109718212A.
• the present invention provides Risperidone microspheres that address one or more of the problems known in the art.
• the present invention provides a process for preparing Risperidone microspheres, the process comprises the steps of: i. preparing a first phase (discontinuous) comprising a polymer dissolved in a first solvent and Risperidone dissolved or dispersed in a second solvent, ii. preparing a second phase (continuous) comprising a surfactant dissolved in water followed by addition of the first solvent, iii. combining the first phase and the second phase to form an emulsion, iv. quenching the emulsion obtained in step (iii) to separate Risperidone microspheres, v. treating the separated microspheres with an extraction solvent, followed by washing with water, vi.
• step (v) drying the microspheres obtained in step (v), vii. optionally, repeating the steps (v) and (vi) one or more times, and viii. treating the microspheres obtained in step (vi) or (vii) with a buffer solution followed by drying to obtain Risperidone microspheres.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising the Risperidone microspheres as described herein, and one or more of pharmaceutically acceptable carriers, excipients or diluents.
• compositions refers to the presence of one or more additional components in the compositions.
• microparticles or “micro spheres” are interchangeable and refers to solid particles that contain an active agent dispersed or dissolved within a biodegradable and biocompatible polymer that serves as the matrix of the particle. Both the terms may be used interchangeably.
• first phase or “discontinuous phase” are interchangeable and refers to dispersed phase in an emulsion comprising a polymer dissolved in a first solvent and Risperidone dissolved or dispersed in a second solvent
• second phase or “continuous phase” are interchangeable and refers to dispersion phase in an emulsion comprising a surfactant dissolved in water followed by addition of first solvent.
• wt. % weight % or “% by weight” or w/w % are used interchangeably refers to parts by weight per total weight of system.
• 10 wt. % agent mean 10 parts agent by weight and 90 parts polymer by weight of solvent.
• the present invention provides Risperidone microspheres having residual solvent content of less than 276 ppm ethyl acetate measured by Gas chromatography and less than 0.68% w/w benzyl alcohol, as measured by HPLC.
• the Risperidone microspheres have a residual solvent content of not more than 50 ppm ethyl acetate and not more than 0.45% w/w benzyl alcohol, as measured by HPLC.
• the present invention provides a process for preparing Risperidone microspheres, the process comprises the steps of: i. preparing a first phase (discontinuous) comprising a polymer dissolved in a first solvent and Risperidone dissolved or dispersed in a second solvent, ii. preparing a second phase (continuous) comprising a surfactant dissolved in the water followed by addition of the first solvent, iii. combining the first phase and the second phase to form an emulsion, iv. quenching the emulsion obtained in step (iii) to separate Risperidone microspheres, v. treating the separated microspheres with an extraction solvent, followed by washing with water, vi.
• step (v) drying the microspheres obtained in step (v), vii. optionally, repeating the steps (v) and (vi) one or more times, and viii. treating the microspheres obtained in step (vi) or (vii) with a buffer solution followed by drying to obtain Risperidone microspheres.
• the polymer used in step (i) may be biodegradable and biocompatible.
• biodegradable refers to a material that is degraded by body metabolic processes to products readily eliminated by the body and is not accumulated in the body.
• Biocompatible refers to a material that is compatible with living tissues, cells, organs, or systems and is non-toxic to a subject.
• polymers include poly (glycolic acid), poly(DL-lactic acid), poly(L-lactic acid), copolymers of the foregoing, poly (lactide-co-glycolide) (PLGA) and the like.
• PLGA poly (lactide-co-glycolide) materials
• Medisorb is a 50:50 poly (DL lactic co-glycolic acid) known as MEDISORB ® 50:50 DL, 65:35 DL, 75:25 DL, 85:15 DL and poly(DL-lactic acid) (DL-PLA).
• PLGA is also commercially available from Boehringer Ingelheim (Germany) under Resomer ® brand, PLGA 50:50 (Resomer ® RG 502), PLGA 75:25 (Resomer ® RG 752) and DL-PLA (Resomer ® RG 206), and from Birmingham Polymers (Birmingham, Ala.).
• the biodegradable and biocompatible polymer according to the present invention is poly(DL-lactide-co-glycolide) copolymer.
• the molar ratio of lactide to glycolide in such a copolymer may be in the range of about 85:15 to about 50:50. In some instances, the molar ratio of lactide to glycolide in the polymer is 75:25.
• the polymer content may range from about 50 to 90 wt. % in the microparticles. In certain embodiments, the polymer content may present in about 50 to 85 wt. %, about 50 to 80 wt. %, about 50 to 75 wt. %, about 50 to 70 wt. %, or about 60 to 70 wt. % in the microparticles. In some instances, the polymer is PLGA 75:25 in the range of about 60 to 70 wt. %.
• the amount of Risperidone incorporated in the microparticles usually ranges from about 10 to 50 wt. %, including about 10 to 40 wt. %, about 20 to 40 wt. %, and about 30 to 40 wt. %. In some instances, the amount of Risperidone incorporated in the microparticles is about 30 to 40 wt. %.
• the first solvent according to the present invention is an organic solvent and may be selected from ethyl acetate, acetone, isopropyl alcohol and the like, or any combination thereof.
• the first solvent is ethyl acetate.
• the second solvent according to the present invention is an organic solvent and may be selected from benzyl alcohol, dichloromethane, chloroform, carbon tetrachloride and the like, or any combination thereof.
• the second solvent is benzyl alcohol.
• the surfactant used according to the present invention may be selected form polysorbate, poloxamer, polyvinyl alcohol and the like, or any combination thereof.
• the surfactant is polyvinyl alcohol.
• the first phase is prepared by mixing a) polymer dissolved in the first solvent, and b) Risperidone dissolved or dispersed in a second solvent.
• concentration of the polymer dissolved in the first solvent is about 5 wt. % to about 25 wt. %, including about 10 wt. % to about 20 wt. %.
• concentration of Risperidone dissolved or dispersed in the second solvent is about 15 wt. % to about 35 wt. %, including about 20 wt. % to about 30 wt. %.
• the second phase is prepared by dissolving surfactant in water followed by addition of first solvent.
• the surfactant used may range from about 0.5 wt. % to about 10 wt. %, including about 1 wt. % to about 5 wt. %.
• the first solvent used may range from about 5 wt. % to about 25 wt. % including, about 10 wt. % to about 20 wt. %.
• the first phase and the second phase are combined to form an emulsion.
• the first phase and the second phase are combined through mixing to form an emulsion.
• the mixing can be achieved using any suitable method/equipment such as static mixer, stirrer homogenizer, propeller, and impeller.
• the first and second phases are pumped through a static mixer to form an emulsion.
• the emulsion obtained above is added to a quench media under stirring, to obtain microparticles containing the Risperidone encapsulated in the polymeric matrix material.
• the quenching does not dissolve microparticles.
• the microparticles are then stirred in the quench media in order to remove most of the organic solvent from the microparticles, resulting in the formation of hardened microparticles.
• the quench media according to the present invention may be selected from water, mixture of water and surfactant, mixture of water, surfactant and a solvent.
• the quench media is a mixture of water, surfactant and solvent.
• the surfactant is selected from polysorbate, poloxamer, and polyvinyl alcohol
• the solvent may be ethyl acetate, acetone, or isopropyl alcohol.
• the solvent may present up to 5 wt. % in the mixture. In some instances, the solvent may present from about 2 wt. % to about 4 wt. %.
• the quench media is a mixture of ethyl acetate and polyvinyl alcohol in water.
• the volume of quench media used may be 10 to 15 times the saturated volume i.e., 10 times the quench volume needed to absorb completely the volume of solvent in the emulsion.
• the temperature at which quenching is carried out is of importance. In certain embodiments, the quenching is carried out at a temperature of about 0-20°C, including about 1-10°C, for a period of 1-30 hrs, such as 4-20 hrs.
• the microparticles are isolated or separated from quench media. Any conventional methods such as filtration, decantation, centrifugation, sieving and the like, can be used for isolating the microparticles. In certain embodiments, the microspheres are separated by sieving.
• the unentrapped drug if any, is removed by extraction using an extraction solvent.
• the extraction solvent may be removed and replaced with a fresh extraction solvent.
• the extraction solvent is selected from water, alcohol and a mixture thereof.
• the alcohol is methanol, ethanol, propanol, isopropanol or a mixture thereof.
• the extraction solvent may range from about 5 wt. % to about 50 wt. % by weight, including, from about 15 wt. % to about 30 wt. % of water. In some instances, the extraction solvent is ethanol or aqueous ethanol.
• the microparticles obtained from the above extraction step are subjected to a washing step.
• the washing may be carried out with a washing solution selected from water, or a mixture of water and a solvent.
• the solvent in the washing solution is alcohol.
• the alcohol is selected from a group comprising methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol and a mixture thereof.
• the washing may be affected one or more times.
• the microspheres obtained are dried.
• the drying may be carried out by employing vacuum under nitrogen (N2) atmosphere at a temperature of from about 20 to 30°C for a period of about 4 to 72 hrs.
• the microspheres are dried at a temperature from about 25°C to about 30°C under N2 atmosphere.
• the extraction of microspheres using extraction solvent followed by drying steps may be repeated one or more times.
• a suitable buffer solution for this purpose may be selected from a group comprising phosphate buffer, phosphate buffer saline solution, a mixture of ethanol and phosphate buffer, a mixture of ethanol and phosphate buffer saline.
• the buffer solution is having a concentration in the range of 50 to 90 % & ethanol ranges from 10 to 50 %.
• the buffer solution comprises about 80% phosphate buffer saline and 20 % ethanol.
• the buffer solution is a mixture of ethanol and phosphate buffer.
• the ratio of ethanol to phosphate buffer is from about 0.1 to 1.
• the temperature of this step is also important to achieve the desired control of Risperidone from microspheres. If the temperature is too high, it may cause softening of the matrix polymer of the microparticles and may result in clumping or sticking. Similarly, if the temperature is too low, it may cause the matrix material to become too hard, thereby retarding the release of the drug.
• a temperature ranging from about 10°C to 60°C is desirable and effective in controlling the release rate of the drug. In some instances, the temperature is from about 20 to 50°C, e.g., from about 25 to 45°C, or from about 30 to 45°C, or from about 35 to 45°C.
• the treatment with buffer may be carried out for a time period of about 1 to 72 hrs.
• the microparticles after the drying are treated with the buffer solution at a temperature of about 20 to 50°C for a time period of about 1 to 5 hrs.
• the buffer solution treated microparticles are finally dried. Any conventional method can be used for drying the microparticles.
• the microparticles are dried by use of dry compressed air or vacuum under N2 atmosphere at a temperature ranging from about 20 to 50°C for a period of about 30 to 40 hrs.
• the present invention provides a process for production of Risperidone microspheres, comprising the steps of: i. preparing a first phase (discontinuous) comprising PLGA dissolved in ethyl acetate and Risperidone dissolved or dispersed in benzyl alcohol, ii. preparing a second phase (continuous) comprising a polyvinyl alcohol dissolved in water followed by addition of ethyl acetate. iii. combining the first phase and the second phase under the influence of mixing using a static mixture to form an emulsion, iv.
• step (iii) quenching the emulsion of step (iii) to separate Risperidone microspheres, with a mixture of ethyl acetate and polyvinyl alcohol in water, v. treating the separated microspheres with an extraction solvent such as ethanol followed by washing with water, vi. drying the microspheres obtained in step (v), vii. treating the dried microspheres obtained in step (vi) with a buffer solution such as a mixture of ethanol and phosphate buffer saline followed by drying to obtain Risperidone microspheres.
• an extraction solvent such as ethanol followed by washing with water
• a buffer solution such as a mixture of ethanol and phosphate buffer saline followed by drying to obtain Risperidone microspheres.
• the Risperidone microparticles prepared according to the present invention are stored in dry form and may be filled in vials.
• the amount of Risperidone present in 1 gm of microparticles is in the range from 100 mg to 500mg.
• the Risperidone microspheres obtained as per the present invention may be administered at a dose of 12.5 mg, 25 mg, 37.5 mg, or 50 mg of Risperidone as intramuscular injection.
• the microspheres prepared as per the present invention release Risperidone over a period of 2 weeks.
• the microparticles prepared as per the present invention have a reproducible control over the initial burst release of Risperidone from microparticles.
• the microparticles prepared as per the present invention provide a control over the undesired excessive drug release, and irregularity in the amount of drug released (i.e., from batch to batch) which is expected to impact safety and efficacy.
• the microparticles prepared as per the present invention provide a control on excess burst release thereby providing effective amount of drug required for maintaining the sustained-release of drug throughout the dosing period.
• the invention provides the use of Risperidone microparticles prepared by the process of the invention for the manufacture of a medicament to treat schizophrenia and bipolar disorder.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising Risperidone microspheres as disclosed herein or obtained by the method as described herein, and one or more of pharmaceutically acceptable carriers, excipients or diluents.
• phrases "pharmaceutically acceptable” is employed herein to refer to those compounds or active agents, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
• materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15
• a pharmaceutically acceptable carrier including a physiologically acceptable agent, depends, for example, on the route of administration of the composition.
• a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin or as an eye drop).
• routes of administration including, for example orally (for example, drenches as in aqueous or non-a
• the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
• the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
• the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the active agent which produces a therapeutic effect.
• Actual dosage levels of the active ingredient in the pharmaceutical composition may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, without being toxic to the patient.
• the selected dosage level will depend upon a variety of factors including the route of administration, the time of administration, the rate of excretion of the active ingredient being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated and like factors well known in the medical arts.
• a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.
• the physician or veterinarian could start doses of the pharmaceutical composition or active agent at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
• Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).
• wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, coating agents, release agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
• the Risperidone microparticles, compositions and methods of the present invention may be utilized to treat a subject in need thereof.
• the subject is a mammal such as a human or a non-human mammal.
• the Risperidone microparticles, compositions and methods of the present invention are useful in treating a subject having schizophrenia and/or bipolar disorder.
• the present invention provides a method of treating a subject having schizophrenia and/or bipolar disorder.
• the method comprises administering a therapeutically effective amount of Risperidone microparticles or the compositions as provided herein to a subject in need thereof.
• therapeutically effective amount refers to that amount of the active agent being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.
• the present invention provides a method for administration of the Risperidone microparticles.
• the Risperidone microparticles prepared according to the present invention may be suspended in the pharmaceutically acceptable diluent and administered every 2 weeks by deep intramuscular (IM) deltoid or gluteal injection.
• the preferred diluent comprises citric acid anhydrous, disodium hydrogen phosphate dihydrate, polysorbate 20, sodium carboxymethyl cellulose, sodium chloride, sodium hydroxide, and water for injection.
• Risperidone microspheres were prepared by the following steps: i) Preparation of first phase (discontinuous phase):
• the first phase was prepared by
• the second phase was prepared by dissolving PVA (30.0 gm) in water (2970.0 gm) for injection and ethyl acetate (208.86 gm) was added to the solution. iii) Mixing of first phase and second phase:
• step iii) was added to a quench medium which is prepared by mixing PVA (750 gm) and (875.0 gm) ethyl acetate in water, at a temperature of 10°C for 4- 24 hrs and separated the microspheres.
• a quench medium which is prepared by mixing PVA (750 gm) and (875.0 gm) ethyl acetate in water, at a temperature of 10°C for 4- 24 hrs and separated the microspheres.
• step (iv) The microspheres of step (iv) were extracted with ethanol (1.6 kg) under stirring at room temperature for 4-6 hrs, followed by washing with water and separated the microspheres by sieving. vi) Drying:
• step v) The microspheres of step v) were dried under nitrogen and under vacuum for 30-40 hr at a temperature of 2-10°C. vii) Buffer treatment:
• step vi) The dried microspheres of step vi) were treated with a solution of phosphate buffer saline and 20-30% w/w ethanol, maintaining the temperature between 35 to 45°C for 1-5 hr and, followed by washing with water and separated the microspheres by sieving. viii) Washing and drying:
• step (vii) The microspheres obtained in step (vii) were washed with water and finally dried under nitrogen and vacuum for 20-25 hr at a temperature 30-35°C to obtain Risperidone microspheres.
• Microspheres were prepared using the procedure depicted in the steps i-vi) and step viii) of the Example 1 but avoiding the step of buffer wash or treatment (step vii).
• In vitro release studies were performed in a USP IV (Flow-Through Cell) apparatus using HEPES (4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid) buffer having a pH 7.4 as release media at 45°C.
• Test results comparing microspheres prepared as per the example 1 and reference example are provided in Table 1 below.
• the microspheres prepared as per the invention contained low solvent load compared to that of the microspheres prepared as per the reference example.
• Table 1 Comparative assay and other test results of Example 1 and reference example
• Dissolution profile of microspheres prepared according to example 1 and reference example were subjected to fit factors to compare dissolution profiles in a pairwise fashion. These indices are known as the difference factor (fl) and the similarity factor (/2).
• a comparative analysis of the dissolution profile of the microspheres prepared according to Example 1 and reference example is provided in table 2.
• the microspheres prepared as per the invention had a good control in the initial release when compared to that of the microspheres prepared as per the reference example.
• Table 2 Comparative dissolution profile of microspheres prepared as per both examples in USP IV at 45 °C.
• ⁇ 2 i.e., similarity factor should be more than 50 to show that the profiles are similar. In the case of above examples, it is 31.41. Similarly, dissimilarity factor fl should be 0- 15 to prove similarity. In the case of above examples, f2 and fl are 31.41 and 68.44 respectively. Thus, the results of fl and f2 indicate dissimilarity and show the significant effect of buffer washing on controlling the initial burst release.
• microspheres prepared as per Example 1 are compared with that of the Marketed reference (Risperdal Costa ® ) and the results are tabulated in table 3.
• the dissolution profile of microspheres prepared as per the example 1 is similar to that of the marketed reference and the dissolution profile is tabulated in table 4.
• Table 3 Comparative assay and other test results of Risperdal Costa ® and microspheres prepared as per Example 1
• Table 4 Comparative dissolution profile of Risperdal Costa ® and microspheres prepared as Example 1 in USP IV at 45 °C.
• the microspheres prepared as per the Example 1 are loaded for stability at 2-8°C (Long term condition) and at 25°C/60%RH (accelerated condition) and the microspheres prepared are stable for at least 3 months (3M) at all the tested conditions.
• the results are tabulated in table 5 and table 6.
• Table 5 Assay and other test parameters of microspheres prepared according to Example 1 stored at different stability conditions.
• Table 6 Dissolution profile of microspheres prepared according to Example 1 stored at different stability conditions.

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