WO2015150942A2

WO2015150942A2 - Improved process for preparing microparticles

Info

Publication number: WO2015150942A2
Application number: PCT/IB2015/051835
Authority: WO
Inventors: Mukesh Kumar; Suhas KAKADE; Peter Markland; Girish Kumar Jain
Original assignee: The WOCKHARDT LIMITED
Priority date: 2014-03-29
Filing date: 2015-03-13
Publication date: 2015-10-08
Also published as: WO2015150942A3

Abstract

There is provided an improved process for preparing microparticles. More particularly, a process is provided for preparing microparticles having a selected release profile for release of drug contained in the microparticles. By subjecting the emulsion to multiple steps including quenching, fine removal by decantation, washing and de-watering in a single vessel followed by lyophilization as a intermediate step that is performed during the preparation of the microparticles, good quality microparticles can be prepared. The process of manufacturing the microparticles according to the invention is simple, robust and requires relativey less control of processing parameters. Further, the resulting microparticles possess excellent shape uniformity, exhibiting lesser agglomerating tendency after intermediate stage drying and good flowability in case of dry powder vial filling.

Description

IMPROVED PROCESS FOR PREPARING MICROPARTICLES

Field Of The Invention

The present invention relates to improved process for preparing microparticles. More particularly, a process is provided for preparing microparticles having a selected release profile for release of drug contained in the microparticles. By subjecting the emulsion to multiple steps including quenching, fine removal by decantation, washing, and de-watering in a single vessel followed by lyophilization as a intermediate step that is performed during the preparation of the microparticles, good quality microparticles can be prepared. The process of manufacturing the microparticles according to the invention is simple, robust and requires relativey less control of processing parameters. Further, the resulting microparticles possess excellent shape uniformity, exhibiting lesser agglomerating tendency after intermediate stage drying and good flowability in case of dry powder.

Background Of The Invention

Several methods are known by which compounds can be encapuslated in the form of polymeric microparticles. It is particularly advantageous to encapsulate a biologically active or pharmaceutical drug within a biocompatible, biodegradable wall-forming material (e.g., a polymer) to provide sustained or delayed release of drugs or other drugs. In these methods, the material to be encapsulated (drugs or other drugs) is generally dissolved, dispersed, or emulsified in a solvent containing the wall forming material. Solvent is then removed from the microparticles to form the finished microparticle product.

U.S. Patent No. 3,737,337 discloses a conventional microencapsulation process wherein a solution of a wall or shell forming polymeric material in a solvent is prepared. The solvent is only partially miscible in water. U.S. Patent No. 5,407,609 dicloses another conventional method of preparing drug containing microparticles. The method includes: (1 ) dissolving/dispersing one or more agents in a solvent containing one or more dissolved wall-forming materials or excipients; (2) dispersing the agent/polymer-solvent mixture into a processing medium to form an emulsion; and (3) transferring all of the emulsion immediately to a large volume of processing medium or other suitable quench medium, to immediately extract the solvent from the microdroplets in the emulsion to form a microencapsulated product, such as microcapsules or microparticles.

U.S. Patent No. 5,650,173 discloses a process for preparing biodegradable, biocompatible microparticles comprising a biodegradable, biocompatible polymeric binder and a biological drug, wherein a blend of at least two substantially non-toxic solvents, free of halogenated hydrocarbons, are used to dissolve both the agent and the polymer.

U.S. Patent No. 5,654,008, discloses a microencapsulation process that uses a static mixer. A first phase, comprising mixture of a drug and a polymer, and a second phase are pumped through a static mixer into a quench liquid to form microparticles containing the drug.

U.S. Patent No. 5,945,126 discloses a continuous process of making microparticles. The process involve step of continuously introducing the dispersed phase and continuous phase in to the reactor vessel under rapid mixing and continuously transporting the emulsion from the reactor vessel to a solvent removal vessel.

U. S. Patent No. 6,194,006 discloses method for preparing microparticles, including performing a degree of substantial intermediate drying of the microparticles by subjecting the microparticles to multistep processes (e.g. de-watering, filtering, vaccume drying and washing). U. S. Patent No. 7,247,319 discloses method for improving flowability of microparticles by subjecting the microparticles to conditioning or ageing at specific temperature over a specific period.

Despite of the various techniques available, it still remains challenging to develop robust process of preparing microparticles. Because of the large number of various formulation and process variables that could potentially interact on the quality and performance of resulting microparticles in an attempt to optimize the quality, it is difficult to predict outcome of any particular adjustment.

For instance, altering process variables (conditions related to the manufacturing process of microparticles, such as temperature, mixing speed, flow rate and drying speed) may alter drug release pattern instead. Also several (intermediate or final) drying steps in the manufacturing process can result in irregular shaped microparticles. The prior art emphasizes use of suitable solvent for preparing polymer and drug solutions. The solubility of the drug and the boiling point of the solvent are the limiting factors for solvent selection. Further, solvents having high boiling point are difficult to remove using conventional quenching techniques i.e. washing with water or multiple washing including washing at higher temperature. The presence of higher residual solvent levels in the microparticles may result in agglomeration of particles during processing. It further may affect the chemical stability of the finished product.

The commercial scale production of microparticles, therefore, requires extensive optimization in process controls. The process further demands several additional measures in order to prevent in process agglomeration and achieve desired degree of residual solvent in the microparticles. The process complexiety thus can make the commercial scale production of microparticles uneconomical and also can reduce the product yield.

Thus, there exists a need in the art for an improved process of manufacturing the microparticles which is simple, robust, requires relativey less control of processing parameters and also having a selected release profile for release of drug in the microparticles.

The process should also enable manufacturing of the microparticles on commercial scale that possess excellent shape uniformity, exhibiting good flowability during vial filling and passage through needle at the time of administration.

Summary Of The Invention

The present invention relates to an improved process for preparing microparticles which is simple, economical, robust, requires relatively less control of processing parameters. The microparticles prepared in accordance with the invention also exhibit controlled release of an effective amount of an drug over an extended period of time. The microparticles prepared acoording to the present invention possess excellent shape uniformity, exhibiting good flowability in case of dry powder vial filling and passage through needle at the time of administration.

In one general aspect of the invention, the process for preparing microparticles comprises:

(1 ) preparing an emulsion that comprises a first phase and a second phase, the first phase comprising a drug or salt thereof, one or more polymers, and one or more solvents for the polymer;

(2) quenching the emulsion to form microparticle suspension followed by fine removal by decantation, washing and de-watering of said microparticle suspension, and

(3) lyophilizing the microparticle suspension as intermediate step to form drug containing microparticles.

In another general aspect of the invention, the process for preparing microparticles comprises:

(1 ) preparing an emulsion that comprises a first phase and a second phase, the first phase comprising a drug or salt thereof, one or more polymers, and one or more solvents for the polymer; (2) quenching the emulsion to form microparticle suspension followed by fine removal by decantation, washing and de-watering of said microparticle suspension;

(3) filtering the microparticle suspension to remove oversized microparticle and/or agglomerates, and

(4) lyophilizing the microparticle suspension to form drug containing microparticles. The resulting lyophilized microparticles may exhibit an initial lag phase and a substantially sigmoidal release profile.

(1 ) preparing an emulsion that comprises a first phase and a second phase, the first phase comprising a drug or salt thereof, one or more polymers, and one or more solvents;

(2) quenching the emulsion to form microparticle suspension followed by fine removal by decantation, washing and de-watering of said microparticle suspension;

(3) lyophilizing the microparticle suspension as a intermediate step to form drug containing microparticles;

(4) washing the microparticles with one or more solvents to form microparticle slurry;

(5) Filtering the microparticle slurry to remove oversized particles and/or agglomerates, and

(6) lyophilizing the microparticle slurry to form drug containing microparticles.

(1 ) preparing a w/o/w emulsion that comprises a first phase and a second phase, the first phase comprising w/o emulsion which comprises of a drug or salt thereof, one or more polymers, and one or more solvents for the polymer;

(2) quenching the w/o/w emulsion to form microparticle suspension followed by fine removal by decantation, washing and de-watering of said microparticle suspension, and

(3) lyophilizing the microparticle suspension to form drug containing microparticles. In another general aspect of the invention, the process for preparing microparticles comprises:

(2) quenching the w/o/w emulsion to form microparticle suspension followed by fine removal by decantation, washing and de-watering of said microparticle suspension;

(1 ) preparing a w/o/w emulsion that comprises a first phase and a second phase, the first phase comprising w/o emulsion which comprises of a drug or salt thereof, one or more polymers, and one or more solvents;

(3) lyophilizing the microparticle suspension to form drug containing microparticles;

(1 ) preparing an s/o/w emulsion that comprises a first phase and a second phase, the first phase comprising s/o suspension which comprises of a drug or salt thereof, one or more polymers, and one or more solvents for the polymer; (2) quenching the s/o/w emulsion to form microparticle suspension followed by fine removal by decantation, washing and de-watering of said microparticle suspension, and

(3) lyophilizing the microparticle suspension to form drug containing microparticles.

(1 ) preparing an s/o/w emulsion that comprises a first phase and a second phase, the first phase comprising s/o suspension which comprises of a drug or salt thereof, one or more polymers, and one or more solvents for the polymer;

(2) quenching the s/o/w emulsion to form microparticle suspension followed by fine removal by decantation, washing and de-watering of said microparticle suspension;

(1 ) preparing an s/o/w emulsion that comprises a first phase and a second phase, the first phase comprising s/o suspension which comprises of a drug or salt thereof, one or more polymers, and one or more solvents;

(6) lyophilizing the microparticle slurry to form drug containing microparticles. The process may employ a vessel that is adapted to perform multiple operations such as quenching, decantation, washing, de-watering and optionally filtration resulting in simplification of the process. In its simplest configuration, the process may employ a single vessel embedded with a filter and several components to perform other operations.

In another general aspect of the invnetion, the filtration of the microparticles is performed in the vessel itself; however, single or multiple filters can be externally connected to the vessel to facilitate the filtration process.

In another general aspect of the invnetion, process for preparing microparticles comprises separate aseptic filteration of drug solution and polymer solution prior to preparation of first phase of the emulsion.

In another general aspect of the invention, the process further comprises, after the lyophilization step, the steps of additional washing the microparticles and final lyophilization of the microparticles.

In another general aspect of the invention, the process further comprises, after the additional wash step, the step of vacuume dessication of microparticles to form dry powder and aseptic filling of the dry powder in vials. Preferably, vaccume dessication is performed in a vibrosifter.

In another general aspect of the invention, the process further comprises, after the washing step, a step of filtering the microparticle suspension, and final filling of the microparticle suspension in vials, preferably under stirring.

In another general aspect of the invention, the washing step is carried out by: introducing the microparticles into a vessel containing an washing medium; and agitating the vessel contents to disperse the microparticles in the washing medium. In another general aspect of the invention, after the washing step; the microparticle suspension is filtered and the resulting suspension is filled in vials. One or more filters may be applied serially. The filter pore size may vary from 25-500 microns, more preferably from 100- 200 microns.

In another general aspect of the invention, the head space in the vials filled with the microparticle suspension is filled with inert gas (e.g. nitrogen).

In another general aspect of the invention, the washing step comprises: introducing the microparticles into a vessel containing an washing medium; agitating the vessel contents to disperse the microparticles in the washing medium; and transferring the microparticles in the form of suspension or slurry from the vessel to a lyophilizer.

In another general aspect of the invention, a method of preparing a stable product of a drug or salt thereof containing microparticles is provided. The process comprises a step of: purging an inert gas in the headspace of the vial containing microparticle composition.

In another general aspect of the invention, the adjusting step to the lyophilization comprises: performing washing of drug microparticles; and optionally, further performing final lyophilization of drug microparticles.

In another general aspect of the invention, the adjusting step to the lyophilization comprises: performing washing of the microparticles; further performing filtration of the microparticles; followed by filling of the microparticles in vials; and final lyophilization of the microparticles in vial. The resulting microparticles may exhibit an initial lag in release of the drug and a substantially sigmoidal release of the drug.

In another general aspect of the invention, a process for preparing a stable product of drug containing microparticles is provided. The product is prepared by a process, which process comprises steps of: (1 ) preparing an emulsion that comprises a first phase and a second phase, the first phase comprising a drug or salt thereof, one or more polymers, and one or more solvents for the polymer;

(3) filtering the microparticle suspension to remove oversized particles;

(4) lyophilizing the microparticle suspension to form drug containing microparticles;

(5) washing and filtering the microparticles;

(6) filling the microparticles in vials and lyophilization, and

(7) optionally, filling the headspace in the vials with inert gas.

In another general aspect of the invention, a process for preparing a stable product of drug containing microparticles is provided. The product is prepared by a process, which process comprises steps of:

(3) filtering the microparticle suspension to remove oversized particles;

(5) washing and filtering the microparticles;

(6) filling the microparticles in vials and lyophilization, and

(7) optionally, filling the headspace in the vials with inert gas.

The w/o/w type composite emulsion according to the present invention can be produced by various methods known in the art. A typical method includes first dissolving the drug, preferably a hydrophilic drug in an aqueous or water miscible solvent to form the inner aqueous phase, and dissolving the polymer in a volatile organic solvent that is not miscible in water to form the organic phase. The inner aqueous phase is poured into the orgnic phase and then mixed to form internal w/o emulsion (first phase). The w/o emulsion is then poured under vigourous mixing onto an external aqueous phase (second phase) that contains water-soluble substances to form the triple w/o/w emulsion. The water-soluble substance may be the part of the inner or external aqueous phase.

In another general aspect of the invention, a process for preparing a stable product of drug containing microparticles is provided. The product is prepared by a process, which process comprises steps of: see calims

(3) filtering the microparticle suspension to remove oversized particles;

(5) washing and filtering the microparticles;

(6) filling the microparticles in vials and lyophilization, and

(7) optionally, filling the headspace in the vials with inert gas.

The s/o/w type composite emulsion according to the present invention can be produced by various methods known in the art. A typical method includes first dissolving the polymer in a volatile organic solvent that is not miscible in water to form the organic phase and adding/dispersing the drug particles. The dispersion is poured into the oil or orgnic phase and then mixed to form internal s/o suspension (first phase). The s/o suspension is then poured under vigourous mixing onto an external aqueous phase that contains water-soluble substances (second phase) to form the s/o/w emulsion.

The process can be used to provide, inter alia, a biodegradable, biocompatible system that can be injected into a patient, the ability to mix microparticles containing different drugs, and the ability to program release by preparing microparticles with selected release profiles and with multiphasic release patterns to give faster or slower rates of drug release as needed. A large proportion of the supernatant solvent and underiblable fines are removed in the vessel by decantation resulting in effective concentration of the slurry and overall simplification (or reduction in total number of steps) of the process. The extent of fine removal can be controlled by varying the decantation time. The upper end of the desired particle size range can be optimized by varying the aperture size of the filtering screens.

Detailed Description Of The Invention

The inventors have devised an improved process of manufacturing the microparticles which is simple, robust, cost effective and requires relativey less control of processing parameters.

In an embodiment, the process provides end formulations in the form of microparticle having smoother surface charactristics, it obviates the difficulties associated with dry microparticle filling in vials due to poor flow properties.

Alternatively, microparticle suspension or slurry can also be subjected to lyophilization to form solid microparticles which may then be subjected to aseptic powder filling in vials.

The products prepared by the process of the invention may exhibit durations of action ranging from several days to more than 200 days can be obtained, depending upon the type of microparticle and release profile selected.

The microparticles flexibly can be designed to afford treatment to patients with duration of action periods of 3 to 100 days. A 15 to 30 day duration of action period is considered to be particularly advantageous. As readily apparent to one of skill in the relevant art, the duration of action can be controlled by manipulation of the polymer composition, polymer:drug ratio, microparticle size, excipients, and concentration of residual solvent remaining in the microparticle. BRIEF DESCRIPTION OF THE FIGURES:

FIGURE 1 : Flow diagram illustrating one embodiment of a method for preparing the microparticles in accordance with the invention;

FIGURE 2: An embodiment of an equipment configuration for preparing microparticles in accordance with the invention;

FIGURE 3: Manufacturing process flow of Risperidone microparticles;

FIGURE 4: Equipment configuration for preparing Risperidone microparticles;

FIGURE 5: Microscopic picture of the microparticles prepared according to the process of the invention [Involving Intermediate Lyophilization];

FIGURE 6: Microscopic picture of the microparticles prepared according to a process known in the art [Involving intermediate Cold Drying];

FIGURE 7: Scanning Electron Microscopy Images of the Risperidone formulation prepared according to the process of the invention [Involving Intermediate Lyophilization]; (Fig. 7a: at 100x magnification and Fig. 7b: at ^"l OOOx magnification) and

FIGURE 8: Scanning Electron Microscopy Images of the marketed Risperidone long acting formulation prepared according to the prior art process [Involving Intermediate Cold Drying]. (Fig. 8a: at 100x magnification and Fig. 8b: at ^"l OOOx magnification)

The present invention relates to an improved process for preparing good quality microparticles that exhibit controlled release of an effective amount of an drug over an extended period of time. The microparticles possess better shape, which in turn is likely to enable improved flowability during manufacturing, vial filling and passage through needle during administration. Various known methods of preparing the microparticles are based on halogenated solvents such as dichloromethane. However, since halogenated solvents are categorized as class 2 residual solvent [carcinogenic or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity as per ICH Q3C guidelines], it is highly recommended to control its level during manufacturing or in the product. Various methods of preparing microparticles using solvents with low toxic potential such as benzyl alcohol and ethyl acetate are known, however, such processes are having limited capability of controlling the level of residual solvent. The uncontrolled level of the residual solvent in the microparticles may cause instability of the microparticles (mostly due to residual solvent-polymer interactions), agglomeration of the microparticles.

The process in accordance with the invention does not need any additional or specialized component in the process line to circumvent the problem of sieve clogging encountered during various stages. Particluarly, the essential steps such as quenching, decantation, dewatering, and optionally, filtration steps are carried out in a single vessel to concentrate the microparticle slurry.

The invention provides an improved process of preparing microparticles, and the process comprises of:

(1 ) preparing an emulsion that comprises a first phase and a second phase, the first phase comprising the drug, one or more polymers, and one or more solvents for the polymer;

(3) filtering the microparticles to form microparticle suspension, and

(4) lyophilizing the microparticle suspension as a intermediate step to form drug containing microparticles.

The quenching, decantation, washing and de-watering steps of the process are preferably performed in a single vessel. The term "microparticles" as used herein refers to solid particles that contain a drug dispersed or dissolved within a polymer that serves as the matrix of the particle. The polymer is preferably biodegradable and biocompatible.

The term "biodegradable" as used herein refers to a material that should degrade by bodily processes to products readily disposable by the body and should not accumulate in the body. The products of the biodegradation should also be biocompatible with the body. The term "biocompatible" is meant not toxic to the body, is pharmaceutically acceptable, is not carcinogenic, and does not significantly induce inflammation in body tissues. The term "body" preferably refers to the human body, but it should be understood that body can also refer to a non-human animal body. By "% w/w" is meant parts by weight per total weight of microparticle. For example, 10 % w/w drug would mean 10 parts drug by weight and 90 parts polymer by weight.

Preferred drugs that can be encapsulated by the process of the present invention include 1 ,2-benzazoles, more particularly, 3-piperidinyl-substituted 1 ,2- benzisoxazoles and 1 ,2-benzisothiazoles. The most preferred drugs of this kind for treatment by the process of the present invention are 3-[2-[4-(6-fluoro-1 ,2- benzisoxazol-3-yl)-1 -piperidinyl]ethyl]-6,7,8,9-tetr ahydro-2-methyl-4H-pyrido[1 ,2- a]pyrimidin-4-one ("risperidone") and 3-[2-[4-(6-fluro-1 ,2-benzisoxazol-3-yl)-1 - piperidinyl]ethyl]-6,7,8,9-tetra hydro-9-hydroxy-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4- one ("9-hydroxyrisperidone") and the pharmaceutically acceptable salts thereof. Risperidone (which term, as used herein, is intended to include its pharmaceutically acceptable salts) is most preferred.

Other biological drugs that can be incorporated using the process of the present invention include gastrointestinal therapeutic agents such as aluminum hydroxide, calcium carbonate, magnesium carbonate, sodium carbonate and the like; nonsteroidal antifertility agents; parasympathomimetic agents; psychotherapeutic agents; major tranquilizers such as chlorpromazine HCI, clozapine, mesoridazine, metiapine, reserpine, thioridazine and the like; minor tranquilizers such as chlordiazepoxide, diazepam meprobamate, temazepam and the like; rhinological decongestants; sedative-hynotics such as codeine, phenobarbital, sodium pentobarbital, sodium secobarbital and the like; steroids such as testosterone and tesosterone propionate; sulfonamides; sympathomimetic agents; vaccines; vitamins and nutrients such as the essential amino acids; essential fats and the like; antimalarials such 4- aminoquinolines, 8-aminoquinolines, pyrimethamine and the like, anti-migraine agents such as mazindol, phentermine and the like; anti-Parkinson agents such as L- dopa; anti-spasmodics such as atropine, methscopolamine bromide and the like; antispasmodics and anticholinergic agents such as bile therapy, digestants, enzymes and the like; antitussives such as dextromethorphan, noscapine and the like; bronchodilators; cardiovascular agents such as anti-hypertensive compounds, Rauwolfia alkaloids, coronary vasodilators, nitroglycerin, organic nitrates, pentaerythritotetranitrate and the like; electrolyte replacements such as potassium chloride; ergotalkaloids such as ergotamine with and without caffeine, hydrogenated ergot alkaloids, dihydroergocristine methanesulfate, dihydroergocornine methanesulfonate, dihydroergokroyptine methanesulfate and combinations thereof; alkaloids such as atropine sulfate, Belladonna, hyoscine hydrobromide and the like; analgetics, narcotics such as codeine, dihydrocodienone, meperidine, morphine and the like; non-narcotics such as salicylates, aspirin, acetaminophen, d-propoxyphene and the like; antibiotics such as salicylates, aspirin, acetaminophen, d-propoxyphene and the like; antibiotics such as the cephalosporins, chloranphenical, gentamicin, Kanamycin A, Kanamycin B, the penicillins, ampicillin, streptomycin A, antimycin A, chloropamtheniol, metromidazole, oxytetracycline penicillin G, the tetracylines, and the like, anti-cancer agents; anti-convulsants such as mephenytoin, phenobarbital, trimethadione; anti-emetics such as thiethylperazine; antihistamines such as chlorophinazine, dimenhydrinate, diphenhydramine, perphenazine, tripelennamine and the like; anti-inflammatory agents such as hormonal agents, hydrocortisone, prednisolone, prednisone, non-hormonal agents, allopurinol, aspirin, indomethacin, phenylbutazone and the like; prostaglandins; cytotoxic drugs such as thiotepa; chlorambucil, cyclophosphamide, melphalan, nitrogen mustard, methotrexate and the like; antigens of such microorganisms as Neisseria gonorrhea, Mycobacterium tuberculosis, Herpes virus (humonis, types 1 and 2), Candida albicans, Candida tropicalis, Trichomonas vaginalis, Haemophilus vaginalis, Group B Streptococcus ecoli, Microplasma hominis, Hemophilus ducreyi, Granuloma inguinale, Lymphopathia venereum, Treponema pallidum, Brucella abortus, Brucella melitensis, Brucella suis, Brucella canis, Campylobacter fetus, Campylobacterfetus intestinalis, Leptospira pomona, Listeria monocytogenes, Brucella ovis, Equine herpes virus 1 , Equine arteritis virus, IBR-IBP virus, BVD-MB virus, Chlamydia psittaci, Trichomonas foetus, Toxoplasma gondii, Escherichia coli, Actinobacillus equuli, Salmonella abortus ovis, Salmonella aborus equi, Pseudomonas aeruginosa, Corynebacterium equi, Corynebacterium pyogenes, Actinobaccilus seminis, Mycoplasma bovigenitalium, Aspergillus fumigastus, Absidia ramosa, Trypanosoma equiperdum, Babesia caballi, Clostridium tetani, and the like; antibodies that counteract the above microorganisms; and enzymes such as ribonuclease, neuramidinase, trypsin, glycogen phosphorylase, sperm lactic dehydrogenase, sperm hyaluronidase, adenosinetriphosphatase, alkaline phosphatase, alkaline phosphatase esterase, amino peptidase, trypsin, chymotrypsin, amylase, muramidase, acrosomal proteinase, diesterase, glutamic acid dehydrogenase, succinic acid dehydrogenase, beta-glycophosphatase, lipase, ATP-ase alpha-peptate gamma- glutamylotranspeptidase, sterol-3-beta-ol-dehydrogenase, and DPN-di-aprorasse.

Other suitable drugs include estrogens such as diethyl stilbestrol, 17-beta-estradiol, estrone, ethinyl estradiol, mestranol, and the like; progestins such as norethindrone, norgestryl, ethynodiol diacetate, lynestrenol, medroxyprogesterone acetate, dimesthisterone, megestrol acetate, chlormadinone acetate, norgestimate, norethisterone, ethisterone, melengestrol, norethynodrel and the like; and the spermicidal compounds such as nonylphenoxypolyoxyethylene glycol, benzethonium chloride, chlorindanol and the like.

Still other suitable drugs include antifungals, antivirals, anticoagulants, anticonvulsants, antidepressants, antihistamines, hormones, vitamins and minerals, cardiovascular agents, peptides and proteins, nucleic acids, immunological agents, antigens of such bacterial organisms as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyrogenes, Carynebacterium diptheriae, Bacillus anthracis, Clostridium tetani, Clostridium botulinum, Clostridium perfingens, Streptococcus mutans, Salmonella typhi, Haemophilus parainfluenzae, Bordetella pertussis, Francisella tularensis, Yersinia pestis, Vibrio cholerae, Legionella pneumophila, Mycobacteium leprae, Leptspirosis interrogans, Borrelia burgdorferi, Campylobacter jejuni, antigens of such viruses as smallpox, influenza A and B, respiratory syncytial, parainfluenza, measles, HIV, varicella-zoster, herpes simplex 1 and 2, cytomeglavirus, Epstein-Barr, rotavirus, rhinovirus, adenovirus, papillomavirus, poliovirus, mumps, rabies, rubella, coxsackieviruses, equine encephalitis, Japanese encephalitis, yellow fever, Rift Valley fever, lymphocytic choriomeningitis, hepatitis B, antigens of such fungal protozoan, and parasitic organisms such as Cryptococcuc neoformans, Histoplasma capsulatum, Candida albicans, Candida tropicalis, Nocardia asteroides, Rickettsia ricketsii, Rickettsia typhi, Mycoplasma pneumoniae, Chlamydial psittaci, Chlamydial trachomatis, Plasmodiumfalcipatum, Trypanosoma brucei, Entamoeba histolytica, Taxoplasma gondii, Trichomonas vaginalis, Schistosoma mansoni. These antigens may be in the form of whole killed organisms, peptides, proteins, glycoproteins, carbohydrates, or combinations thereof.

Still other macromolecular biodrugs that may be chosen for incorporation include, but are not limited to, blood clotting factors, hemopoietic factors, cytokines, interleukins, colony stimulating factors, growth factors, and analogs and fragments thereof.

The w/o/w type emulsions prepared in accordance with the present invention are particularly advantageous in that it permits blending of hydrophilic and/or water- soluble drugs, such as peptides, which exhibit no major solubility in carrier solvents such as methylene chloride or ethyl acetate can be dispersed in the polymer phase as an aqueous drug solution. Drugs particularly suitable for preparing the w/o/w emulsion includes, but are not limited to somatostatin, leuprolide, octreotide and goserelin.

The s/o/w type emulsions prepared in accordance with the present invention are particularly advantageous in that it permits blending of hydrophobic and/or water- insoluble drugs, such as proteins, which are critical due to physical and chemical in stability in the dissolved state during emulsification. Drugs particularly suitable for preparing the s/o/w emulsion includes, but are not limited to octreotide, leuprolide and goserelin.

Suitable solvents for preparing inner and/or external aqueous phase comprises one or more solvents including water, water-soluble alcohols, glycols and other water soluble solvents along with water-soluble substances and optional additives.

The preferable water-soluble substances used in the present invention include water- soluble proteins, water-soluble synthetic polymers, water-soluble polysaccharides and the derivatives thereof. The water-soluble proteins include casein, sodium caseinate, .beta.-lactoglobulin, . alpha. -lactalbumin, albumin, gelatin, soybean protein, and of these casein, sodium caseinate, .beta.-lactoglobulin and .alpha.-lactalbumin are preferable. The water-soluble synthetic polymers include polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, polyvinyl methyl ether and poly(sodium acrylate), and of these polyvinyl alcohol and polyvinyl pyrrolidone are preferable. The water-soluble polysaccharides or the derivatives thereof include xanthan gum, gelan gum, dextran, pullulan, gum arabic, carrageenan, locust bean gum, dextrin, guar gum, pectin, sodium alginate, hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethylcellulose and carboxylmethylcellulose, and of these xanthan gum and hydroxypropylcellulose are preferable.

Suitable solvents for preparing drug and polymer solution includes, but not limited to alkanes, cycloalkanes, cycloalkanones, cycloalcohols, and the like containing at least about 6 carbon atoms and up to about 20 carbon atoms. Preferred solvents include benzyl alcohol, ethyl acetate, methylene chloride, chloroform, diethyl carbonate, methyl ethyl ketone cyclooctane, cyclohexane, cyclohexanone, n-pentadecane, n- hexadecane, cyclohexanol, and the like. Particularly preferred solvent for drug is benzyl alcohol and ethyl acetate for polymer.

Inventors of the present invention have found that known methods to reduce the level of residual solvent, particularly non-volatile such as benzyl alcohol, requires significantly drying of the microparticles at intermediate stage with simultaneous requirement of keeping the microparticles cold. Additionally, the process require additional washing and subsequent heating of the microparticles with third phase solvent (e.g. 25% ethanol). Microparticles prepared by conventional method (involving intermediate cold drying) require ageing to ensure smooth flow of the microparticles. The resulting microparticles, however, may formed with wrinkled surface and thus affecting flow properties.

The microparticles can be mixed by size or by type so as to provide for the delivery of drug to the patient in a multiphasic manner and/or in a manner that provides different drugs to the patient at different times, or a mixture of drugs at the same time. For example, secondary antibiotics, vaccines, or any desired drug, either in microparticle form or in conventional, unencapsulated form can be blended with a primary drug and provided to the patient.

Preferred examples of polymer matrix materials include poly(glycolic acid), poly(d,l- lactic acid), poly(l-lactic acid), copolymers of the foregoing, and poly (glycolide), poly (d,l-lactide), poly (l-lactide), and copolymers of the forgoing, and the like. Various commercially available poly(lactide-co-glycolide) materials (PLG) may be used in the method of the present invention. For example, poly (d,l-lactic-co-glycolide) is commercially available from Evonik. A suitable product commercially available from Evonik (Lakeshore Biomatrials) is a 50:50 poly(d,l-lactic-co-glycolic acid) known as 5050 DLG 7E. This product has a mole percent composition of 50% lactide and 50% glycolide. Other suitable commercially available products are Lakeshore Biomatrials® 6535DLG7E, 8515 DLG 7E, 7525 DLG7E and poly(d, l-lactide) (100 DL 7E). Poly(lactide-co-glycolides) are also commercially available from Evonik under its Resomer® mark, e.g., PLG 50:50 (Resomer® RG 502), PLG 75:25 (Resomer® RG 752, Resomer® RG 757) and d.l-PLA (Resomer® R 205 S), and from Durect (Cupertino, California) under Lactel® brand. These copolymers are available in a wide range of molecular weights and ratios of lactic acid to glycolic acid. The most preferred polymer for use in the practice of the invention is the copolymer, poly(d,l-lactide-co-glycolide). It is preferred that the molar ratio of lactide to glycolide in such a copolymer be in the range of from about 85:15 to about 50:50.

The molecular weight of the polymeric matrix material is important in the quality and release profile of the microparticles.. Usually, a satisfactory molecular weight is in the range of 5,000 to 500,000 daltons, preferably about 150,000 daltons.. The molecular weight of the polymer is also important from the view point of its influence upon the biodegradation rate of the polymer. For a diffusional mechanism of drug release, the polymer should remain intact until all of the drug is released from the microparticles and then degrade. The drug can also be released from the microparticles as the polymeric excipient bioerodes. By an appropriate selection of polymeric materials a microparticle formulation can be made in which the resulting microparticles exhibit both diffusional release and biodegradation release properties. This is useful in according to multiphasic release patterns.

With reference now to the drawings, FIGURE 1 illustrates the general process of preparing the microparticles in accordance with the invention. In a step C, a first phase A and a second phase B are combined to form an emulsion. One of the two phases is discontinuous, and the other of the two phases is continuous. The first phase A preferably comprises a drug, a polymer, and one or more solvents.

In an embodiment, the drug solution and polymer solution are aseptically filtered separately prior to preparation of first phase A.

In another embodiment, the process of FIGURE 1 can be modified to contemplate the preparation of w/o/w triple emulsion in which the internal w/o emulsion (first phase) is formed by pouring phase A, which itself comprise said w/o emulsion it in an external aqueous phase, phase B comprising water-soluble substance and optional additives (second phase) with vigorous stirring.

In another embodiment, the process of FIGURE 1 can be modified to contemplate the preparation of s/o/w emulsion in which the internal s/o suspension (first phase) is formed by pouring phase A, which itself comprise said s/o emulsion it in an external aqueous phase, phase B comprising water-soluble substance and optional additives (second phase) with vigorous stirring.

In another embodiment, phase A and B are subjected to sterile filtration in order to achieve the sterile product. The sterile phase A and B can be then combined in step C to form an emulsion.

In another embodiment, step C comprises mixing phase A and phase B using static mixers or in line homogenizers known in the art to form an emulsion.

The formulation prepared by the process of the present invention contains a drug dispersed in the microparticle polymeric matrix material. The amount of such agent incorporated in the microparticles usually ranges from about 1 % w/w to about 90 % w/w, preferably 30 to 50 % w/w, more preferably 35 to 45 % w/w.

The emulsion is transferred into a vessel for performing multiple operations D (quenching, decantation, de-watering, washig and in-line sieving). The vessel contains quench liquid for the quenching step. The primary purpose of the quench step is to extract or remove residual solvent from the microparticles that are formed. In a preferred embodiment of the present invention, quench step is followed by decantation step, a washing step, a de-watering step, and optionally multiple washing steps.

The objective of de-watering step is to concentrate the microparticles from the dilute suspension that is formed during washing step to a concentrated slurry prior to subsequent lyophilization E of the microparticles. The vessel is provided with ports for removal of waste. Preferably, the ports are provided at particular height for removal of the waste including the supernatant containing fine particles in the supernatant waste stream. The decantation step is particularly important as a mechanism to remove fines. The vessel is also provided with multiple inlets and outlets for quench, washing solvents and water in order to recycle in the vessel. It is of particular importance that multiple operations D (quenching, decantation, washing and de-watering) are carried out in the vessel which makes the overall process simple and robust.

In an embodiment, the quenching, decantation, washing and de-watering in the vessel is performed at room temperature or 37°C ± 10°C. The temperature of the washing medium allows the microparticles to be dispersed without agglomeration caused by elevated temperatures.

The vessel may also comprise of filter. Preferbly, the filter is placed before the ports in the vessel in order to retain microparticles in the vessel. The filtration causes smaller microparticles of desired fines and liquid to pass through the screen, while larger particles are retained. The smaller particles and liquid that drop through the screen are removed as waste. Size of the filter may range from about 25 microns to about 200 microns. Preferred size of the filter is 75 microns.

In an embodiment, the filter may not be the integral component of vessel, but fitted in fluid connection with the vessel.

The filtered microparticles are in the form of suspension or slurry. The microparticle slurry is then subjected to lyophilization E using suitable lyophilizer. The lyophilizer is in fluid communication with the filter. The slurry may optionally be concentrated by decantation before bulk lyophilization

The non-volatile solvent based known process may result in the microparticles which possess limited holding time after cold drying due to tendency of the microparticles to agglomerate. The process thus requires intense mixing mechanism in order to disperse the agglomerated microparticles during its washing.

The inventors have found that if the microparticle slurry is subjected to the intermediate lyophilization E, the withstanding period for which microparticles remain non-aggregated is relatively more than that exhibited by the microparticles sbjected to conventional intermediate drying (e.g. cold drying). Particularly, the microparticles remain non-aggregated for at least 2 hours, more preferably 1 hour after removing from the lyophilizer. Such longer withstanding period is significant during bulk manufacturing of the microparticles at industrial scale.

The lyophilization cycle typically includes a freezing step, a primary drying step, and a secondary drying step. The temperature and the duration of the freezing step is selected to insure that all components of the microparticle slurry are completely frozen. This can be determined by an examination of the freezing point of the test solution or dispersion. Typically, this is kept below -50° C.

The primary drying step involves the sublimation of the solvent components of the microparticle slurry in vaccume. The temperature of the drying step must be high enough to provide a sufficient rate of sublimation of the solvent components yet low enough to insure that all components of the microparticle slurry remain frozen. Since sublimation provides considerable cooling to the product, temperatures for the primary drying step are much higher than those for the freezing step. Preferably temperatures for primary drying is in the range of -35°C to -5°C.

After primary drying, residual amounts of solvent which could not be removed by sublimation are removed by a secondary drying step. To remove these residual solvents, the temperature is raised to near ambient or higher. Secondary drying temperature Particularly advantageous for risperidone microparticles was found to be upto 40°C.

It is significant to maintain microparticle temprature substantially below 10° C during and/or after intermediate (first) lyophilization to preapre good quality, smooth and free flowing microparticles. Due to non-aggregation property, such microparticles can be advantageously used for processing. Reconstitution of the lyophilized cake with wash medium results in a suspension of discrete substantially non-aggregated microparticles. The microparticles are, optionally, washed and decanted F in suitable washing solvent (preferably, organic solvent, e.g. ethanol) to remove or extract any further residual solvent.

Washing of the microparticles is preferably done using at least two parts of the washing solvents differing at least in their temperatures. The microparticles are sequentially washed with different parts of the washing solvents. In an embodiment, two parts of ethanol, one having temperature about 2°C to about 8°C and other having temperature of 25°C are used.

It was also foud that gradually increasing the temperature of the wash media to the specified value, preferably from 25° to 40°C, more preferably upto 35°C, preferably by recirculating hot water, results in good quality microparticles having lesser residual solvents.

The microparticles suspension may optionally be recirculated in the washing tank several times, preferably with the help of peristaltic pump through a sieve assembly for specified duration of time in order to have a uniform slurry.

The microparticles then filtered through a in-line sieving G to remove oversized particles The microparticles slurry is subjected to in-process assay to determine the concentrationt of drug in slurry, and thus determine the quantity of microparticles to be filled in each vial. The slurry may optionally be concentrated by decantation followed by supernatant removal from the slurry reservoir.

The pre-analyzed microparticles formed in the form of slurry or suspension can be fillied in vials H to desired concentration, preferably under stirring using suitable vial filling assembly and then lyophilized I to form solid microparticles. The moisture content of the microparticles is maintained, preferably less than about 1 .5%, more preferably approximately equal to about 0.5%. The residual solvents level can be controlled accurately by optimizing pressure and temperature during further lyophilization I.

Alternatively, after the lyophilization E, the microparticles can be collected directly without washing F, and filled in vials H. In an embodiment, after the lyophilization E, the microparticles are subjected to vaccume dessication to form dry powder, which dry powder is then aseptically filled in vials. Preferably, vaccume dessication is performed in vibrosifter.

Suitable carriers may be added to the microparticle suspension prior to lyophilization E or I in order to reduce sticking of the microparticles. The preferred carrier is mannitol.

With reference now to FIGURE 2, it illustrates an equipment configuration for preparing microparticles in line with the general process as depicted in FIGURE 1. In a preferred embodiment of the present invention, the equipment contained within the dotted line boundary shown grey area denotes aseptic processing region of the process, which has significance in manufacturing sterile end product.

In an embodiment, the process of preparing the microparticles according to the invention may be partially or completely aseptic. Alternatively, the end product prepared through such process can be subjected to terminal sterilization using various sterilization methods known in the art.

In a further embodiment, the end product is subjected to terminal sterilization when process of prearing the microparticles is partially or completely non-aseptic.

A first phase 01 is provided. First phase 01 is preferably the discontinuous phase, comprising a polymer dissolved in one or more solvents, and a drug. The drug can be dissolved or dispersed in the same or a different solvent than the solvent(s) in which the polymer is dissolved. A second phase 02 is preferably the continuous phase, which preferably comprises water as the continuous processing medium. Preferably, an emulsifying agent such as a surfactant or a hydrophilic colloid may be added to the continuous phase to prevent the microdroplets from agglomerating and to control the size of the microdroplets in the emulsion.

Examples of compounds that can be used as surfactants or hydrophilic colloids include, but are not limited to, polyvinyl alcohol) (PVA), carboxymethyl cellulose, gelatin, polyvinyl pyrrolidone), Tween 80, Tween 20, and the like. The concentration of surfactant or hydrophilic colloid in the continuous phase will be from about 0.1 % to about 10% by weight based on the continuous processing medium, depending upon the surfactant, hydrophilic colloid, the discontinuous phase, and the continuous processing medium used. A preferred continuous phase is 0.1 to 10 % w/w, more preferably 0.5 to 2 % w/w, solution of PVA in water. Although not absolutely necessary, it is preferred to saturate the continuous phase with at least one of the solvents forming the discontinuous phase. This provides a stable emulsion, preventing transport of solvent out of the microparticles prior to quench step 10.

First phase 01 and second phase 02 are combined under the influence of mixing means to form an emulsion. A preferred type of mixing means 03 is a static mixer or inline homogenizer (commercially available as, e.g. Silverson inline homogenizer). Other mixing means suitable for use with the present invention include, but are not limited to, devices for mechanically agitating the first and second phases, such as homogenizers, propellers, impellers, stirrers, and the like.

Preferably, the discontinuous and continuous phases 01 and 02 are pumped through mixing means 03 to form an emulsion, and into a large volume of quench liquid, to obtain microparticles containing the drug encapsulated in the polymeric matrix material.

In an embodiment, the discontinuous and continuous phases 01 and 02 are pumped through a membrane filter for sterilization. The membrane filter is in fluid communication with the mixing means 03. First and second phases 01 and 02 are mixed in mixing means 03 to form an emulsion. The emulsion formed comprises droplets containing drug dispersed in the polymeric matrix material. The emulsion is then preferably stirred in a quench tank 05 containing a filtered quench liquid in order to remove most of the solvent from the microparticles, resulting in the formation of hardened microparticles. The quench liquid may contain suitable amount of solvent of phase 01 to control the rate of extraction of the solvent from the discontinuous phase 01. The quench tank 05 is connected with a quench tank 04 as source of quench liquid (before filtration).

In an embodiment, the process of FIGURE 2 can be modified to contemplate the preparation of w/o/w triple emulsion in which the internal w/o emulsion (first phase) is formed by pouring phase 01 , which itself comprise said w/o emulsion it in an external aqueous phase, phase 02 comprising water-soluble substance and optional additives (second phase) with vigorous stirring.

In an embodiment, the process of FIGURE 2 can be modified to contemplate the preparation of s/o/w emulsion in which the internal s/o suspension (first phase) is formed by pouring phase 01 , which itself comprise said s/o emulsion it in an external aqueous phase, phase 02 comprising water-soluble substance and optional additives (second phase) with vigorous stirring.

The emulsion is then preferably stirred in a quench tank 05 containing a filtered quench liquid in order to remove most of the solvent from the microparticles, resulting in the formation of hardened microparticles. The quench liquid may contain suitable amount of solvent of phase 01 to control the rate of extraction of the solvent from the discontinuous phase 01. The quench tank 05 is connected with a quench tank 04 as source of quench liquid (before filtration).

Following the movement of the microparticles from mixing means 03 and entrance into quench tank 05, the continuous processing medium is diluted, and much of the solvent in the microparticles is removed by extraction. In this extractive quench step (step D of Figure 1 ), the microparticles can be suspended in the same continuous phase (second phase 02) used during emulsification, with or without hydrophilic colloid or surfactant, or in another quench liquid. The quench liquid removes a significant portion of the solvent from the microparticles, but does not dissolve them. During the extractive quench step, the quench liquid containing dissolved solvent can, optionally, be removed and replaced with fresh quench liquid.

Upon completion of quench step in quench tank 05, the microparticles are then subjected to decantation, multiple washing, and de-watering in the quench tank 05 itself. The tank 05 is used to carry out multiple functions; such as de-watering, multiple washing and, optionally, final filtration. The quench tank is provided with multiple ports for introduction and removal of solvents. The quench tank is also provided with a port for removal of waste.

In an embodiment, fine removal or de-watering step from the quench tank 05 is executed by decantation. The decantation valves 06 are provided to the quench tank 05 at a specified height in order to remove supernatant without disturbing the settled microparticles.

In an embodiment, height of the decantation port is kept at about 10 to 30% above from the bottom of the tank.

In a further embodiment, a filter is provided as internal component of the quench tank 05. In a further embodiment, the filter 07 is connected externally in fluid communication with the quench tank 05. The filtration causes over-sized particles to retain.

The size of filter pores may range from about 100 microns to about 300 microns. Preferably, the size of filter pores is about 200 microns.

Upon completion of the filtration of the microparticle suspension through filter 07, the microparticle suspension is transferred to a lyophilizer 08. Various commercially available lyophilizers can be used. After the completion of lyophilization (step E of Figure 1 ), the dried microparticles need to be transferred to another washing tank 09 containing washing medium to carry out wash step (step F of Figure 1 ). Wash step F is preferably carried out in washing tank 09, using an washing medium.. The advantage of the washig step F is to reduce stickiness of the microparticles, particularly by removing benzyl alocohol and/or ethanol in case of benzyl alcohol and/or ethanol based microparticles, which in turn aid in improving chemical stability of the microparticles.

The washing tank 09 is preferably smaller in size/volume than quench tank 05; consequently the volume of washing medium in washing tank 09 will be less than the volume of quench medium in quench tank 05.

The washing tank 09 preferably has an impeller or other form of agitating device used to agitate the tank contents, but preferably does not include any baffles. The smaller volume of the tank 09 allows intense agitation so that the microparticles can be dispersed in the washing medium.

After wash step F is completed in washing tank 09, the microparticles are again screend (step G of Figure 1 ) via screen 10 to separate microparticles of desired size and liquid. The smaller microparticles are dropped through the screen, while larger particles (or particle agglomerates) are retained. In an embodiment, the size of the screen in the filter is 225 microns, 150 microns or 125 microns. In a further embodiment, VibroSifter or scalping screen can be used for oversized particle removal.

The microparticles in the form of slurry obtained after filtration G can be stored in suitable reservoir 11 which is in fluid communication with suitable vial filling assmebly. In an embodiment, the vial filling assembly comprises a stirring mechanism to avoid the sedimentation of the microparticles and ensure accurate filing of the microparticles slurry in the vials. The micoparticle filled vials are then subjected to final lyophilization (step I of Figure 1 ) to form solid microparticles. Alternatively, microparticle slurry in reservoir 11 can be subjected to final lyophilization (step I of Figure 1 ) to form solid microparticles which may then be subjected to aseptic powder filling in vials.

The quality of the microparticles prepared according to the improved process of the invention (FIGURE 5) is comparable to microparticles prepared according to the prior art process (FIGURE 6).

The present 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 present invention.

Example 1 : Process of preparing the microparticles according to an

embodiment of the invention:

A dispersed phase containing 20-26% w/w drug in benzyl alcohol and 10-20 % w/w polymer in ethyl acetate was prepared by mixing drug and polymer solutions. The solutions were filtered through a filter (0.2μ) and mixed or the two solutions were filtered through a filter (0.2μ) after mixing. A continuous phase containing 0.2-2 % w/w polyvinyl alcohol and 2-8 % w/w ethyl acetate was prepared by mixing both the solvents. Emulsion of the dispersed and continuous phases in weight ratio ranging from 1 :2 to 1 :20 was prepared by using static mixer or homogenizer or inline homogenizer.

The emulsion was then transferred to a vessel and subjected to quenching by adding and stirring for about 1 to 12 hours in 0.1 -2 L/gm of quenching phase of water containing 1 -5 % w/w of ethyl acetate. The temperature of the quenching phase was maintained 5° C to 10° C to form microparticle suspension. The microparticle suspension was then subjected to decantation for about 5-60 minutes to concentrate the microparticle suspension to approximately 1/10 of the original volume by discarding about 90% supernatant containing fines as waste.

Microparticle suspension was further subjected to quenching by adding the quench media in the vessel and stirring for about 15-120 minutes at room temperature. The additional quench media contain water (about 90% of the quench volume). The resulting microparticle suspension in the vessel was again subjected to decantation for about 5-60 minutes to concentrate the microparticle suspension to approximately 1/10 of the original volume.

An additional quench media containing water (about 90% of the quench volume) having temperature of about 37° C was added to the microparticle suspension in the vessel and the mixture was then stirred for 15-120 minutes. The mixture of the microparticle suspension and quench media in the vessel was again decanted for about 5-60 minutes to concentrate the microparticle suspension to approximately 1/10 of the original volume followed by sieving the microparticle suspension through about 150 micron sieve to remove oversized particles.

The microparticles were then introduced to a lyophilizer and effectively lyophilized under cold condition (temperature less than about 10° C).

The solid microparticles prepared after lyophilization were dispersed in about 10-40 % w/w of ethanol (with temperature of 5-10^SC in 2-10% of the initial quench volume) followed by addition of another 10-40 % w/w of ethanol (with temperature of 25-40^sC. Final wash volume was in the range of 0.025 to 0.5L/gm. The microparticle suspension was then decanted for about 5-60 minutes to concentrate the microparticle suspension to approximately 1 /10 of the original volume by discarding about 90% supernatant containing a portion of ethanol as waste.

The resulting microparticle slurry was sieved through a screen of 100-200 micron size and transferred to vial filling line, filled in the vials under stirring, and finally lyophilized by optimized control of temperature and pressure to control residual solvents. Alternatively, the resulting microparticle suspension can be dried by vacuum desiccation / bulk lyophilization and then subjected to aseptic dry powder filling in vials. The preferred size of the microparticles is in the range of 20 to 1000 microns, more preferably between 50 to 200 microns.

Example 2: Process of preparing Risperidone microparticles:

A pharmaceutical composition comprising microparticles of Risperidone were prepared in accordance with the present invention. Manufacturing process flow and equipment configuration for preparing Risperidone microparticles is shown in Figure 3 and 4 respectively. Detailed process of manufacturing the microparticles is narrated below- Dispersed phase solutions containing 20-26% w/w risperidone in benzyl alcohol and 10-20 % w/w poly (lactide-co-glycolide) in ethyl acetate were prepared by mixing aprropriately. The two solutions were filtered through a filter (0.2μ) and mixed. A continuous phase containing 0.2-2 % w/w polyvinyl alcohol and 2-8 % w/w ethyl acetate was prepared by mixing both the components. Emulsion of the dispersed and continuous phases in weight ratio ranging from 1 :2 to 1 :20 was prepared by using static mixer.

The emulsion was then transferred to a jacketed vessel and subjected to quenching by adding and stirring for about 1 to 12 hours in 0.1 -2 L/gm of quenching phase of water containing 1 -5 % w/w of ethyl acetate. The temperature of the quenching phase was maintained at 5°C to 10°C to form microparticle suspension. The microparticle suspension was then subjected to settling for about 5-60 minutes. The top 90% of the supernatant was removed through decantation port in order to concentrate the microparticle suspension to approximately 1/10 of the original volume.

Microparticle suspension was further subjected to washing by adding cold water as wash media in the vessel and stirring for about 15-120 minutes. The resulting microparticle suspension in the vessel was again subjected to settling for about 5-60 minutes. The top 90% of the supernatant was removed through decantation port in order to concentrate the microparticle suspension to approximately 1/10 of the original volume.

The microparticle slurry was then subjected to in line screening through about 150 - 300 micron sieve to remove oversized particles. The slurry was then collected in a round bottom flask equipped with decantation port. About 80% of the supernatant was decanted off to further concentrate the slurry.

The microparticles slurry was then introduced to a lyophilizer and effectively lyophilized using bulk lyophilization tray.

The solid microparticles prepared after lyophilization were dispersed in about 10-40 % v/v of ethanol (with temperature of 5-10^SC in 2-10% of the initial quench volume) under intense stirring on magnetic stirrer in a jacketed vessel. This was followed by addition of another 10-40 % v/v of ethanol (with temperature of 20-30^sC). Final wash volume was in the range of 0.025 to 0.5L/gm. The temperature of the microparticle suspension was raised gradually to higher temperature in the range of 25°C to 40°C. The microparticles were then allowed to settle for about 5-60 minutes. The slurry was concentrated by decantation to approximately 1/10 of the original volume.

Lastly, 10% ethanol solution was added to the wash tank and the slurry was stirred for 25-30 minutes. It was re-circulated at high flow rate through an inline screening device equipped with a screen ranging from 100- 200 micron in pore size. The slurry was subjected again to settling. Top 90% of the supernatant was again removed to concentrate the slurry. It was then transferred to a 1 L glass bottle through the same inline screening device. The screen was equipped with a provision to provide external vibration to facilitate the screening process.

The slurry was then analyzed for the drug content and then filled appropriately in 5 ml vials under stirring. Finally the vials were subjected to lyophilization and then were stoppering and sealing. Table 1

Risperidone microparticles were prepared according to the process of Example 2 and a process in which lyophilization I was replaced with cold drying. Table 1 summarizes the effect of two intermediate drying methods on dispersibility of the risperidone microparticles at different hold times after drying.

Example 3: Process of preparing leuprolide microparticles according to an embodiment of the invention:

65.0 g of leuprorelin acetate and 10.3 g of gelatin were weighed and completely dissolved in 66 ml of water for injection in a round bottm flask. To this solution, 521 .9 g of a lactic acid/glycolic acid copolymer [lactic acid/glycolic acid in ratio of 75:25 with average molecular weight of about 1 1 ,000] was dissolved in 873.6 g of dichloromethane (methylene chloride) was added, followed by stirring and emulsification using the autominimixer for 10 minutes to yield a w/o emulsion (first phase). 150 liters of a 0.1 % aqueous solution of polyvinyl alcohol (external aqueous or second phase) was poured in a 200 liter tank followed by addition of the w/o emulsion (first phase) to the solution (second phase). The mixture was then stirred to yield a w/o/w emulsion.

The w/o/w emulsion was then subjected to further processing as discussed under Example 1 or 2 to form leuprolide microparticle slurry or lyophilized powder filled in vials.

Example 3: Process of preparing octreotide microparticles according to an embodiment of the invention:

3.547 g of the PLGA polymers were dissolved into 17.7 ml dichloromethane to give a 20 % (w/v) polymer solution. 1 .453 g of octreotide pamoate is weighed into a glass beaker and the polymer solution is poured over the drug substance and stirred to form a s/o suspension. The s/o suspension was homogenized with a mixer. Separately, 10.00 g of polyvinylalcohol (PVA) 3.62 g KH₂P0₄ and 15.14 g Na₂HP0₄ were dissolved in 2.00 L deionized water to form a 0.5% PVA solution buffered to pH 7.4.

The s/o suspension was mixed with the 0.5 % PVA solution by pumping the s/o suspension with the help of a flexible tube pump at a rate of 10 ml/min into a turbine and by pumping the aqueous solution with a gear pump at a rate of 200 ml/min into the same turbine. The two solutions are mixed in the turbine to form s/o/w emulsion.

The s/o/w emulsion was then subjected to further processing as discussed under Example 1 or 2 to form leuprolide microparticle slurry or lyophilized powder filled in vials.

Claims

Claims:

1 . A process for preparing microparticles comprising:

(a) preparing an emulsion that comprises a first phase and a second phase, the first phase comprising a drug or salt thereof, a polymer, and a solvent;

(b) quenching the emulsion to form microparticle suspension followed by fine removal by decantation, washing and de-watering of said microparticle suspension;

(c) lyophilizing the microparticle suspension of step (b) to form drug containing microparticles, and

(d) washing the microparticles of step (c) after lyophilization.

2. The process of claim 1 , wherein the process further comprises:

(a) washing the microparticles of step (c) with a solvent to form microparticle slurry;

(b) Filtering the microparticle slurry to remove oversized particles and/or agglomerates, and

(c) lyophilizing the microparticle slurry to form drug containing microparticles.

3. The process of claim 1 or 2, wherein the drug is risperidone or its salt.

4. A process for preparing microparticles comprising:

(a) preparing a w/o/w emulsion that comprises a first phase and a second phase, the first phase comprising w/o emulsion which comprises of a drug or salt thereof, a polymer, and a solvent;

(b) quenching the w/o/w emulsion to form microparticle suspension followed by fine removal by decantation, washing and de-watering of said microparticle suspension;

(c) lyophilizing the microparticle suspension to form drug containing microparticles, and

(d) washing the microparticles after lyophilization.

5. The process of claim 4, wherein the process further comprises:

6. The process of claim 4 or 5, wherein the drug is somatostatin, Risperidone, leuprolide, octreotide and goserelin or salt thereof.

7. A process for preparing microparticles comprising:

(1 ) preparing an s/o/w emulsion that comprises a first phase and a second phase, the first phase comprising s/o suspension which comprises of a drug or salt thereof, a polymer, and a solvent;

(3) lyophilizing the microparticle suspension to form drug containing microparticles, and

(4) washing the microparticles after lyophilization.

8. The process of claim 7, wherein the process further comprises:

(a) washing the microparticles of step (c) with a solvents to form microparticle slurry;

9. The process of claim 7 or 8 wherein the drug is somatostatin, Risperidone, leuprolide, octreotide and goserelin or salt thereof.

10. The process of claim 1 , 4, or 7, wherein the quenching, fine removal by decantation, washing and de-watering of the emulsion is performed in a single vessel.

1 1 . The process of claim 1 , 4, or 7, wherein the first phase is prepared by a process comprising the steps of:

(a) separately preparing drug solution and a polymer solution;

(b) aseptically filtering the drug solution and a polymer solution;

(c) mixing the filtered drug solution and a polymer solution, and

(d) optionally, filtering the mixture of drug solution and a polymer solution.

12. The process of claim 1 , 4, or 7 wherein the polymer in the first phase of the emulsion comprises a biodegradable polymer.

13. The process of claim 1 , 4, or 7, wherein the lyophilization step comprises freezing at temperature up to -50° C, primary drying at temperature in the range of -35°C to -5°C and secondary drying at temperature up to 40° C.

14. A pharmaceutical composition of a drug containing microparticles prepared by a process, which process comprising steps of:

(a) preparing an emulsion that comprises a first phase and a second phase, the first phase comprising risperidone or salt thereof, a polymer, and one or more solvents for the polymer;

(b) quenching the emulsion to form microparticle suspension followed by decantation, washing and de-watering of said microparticle suspension, and

(c) lyophilizing the microparticle suspension to form drug containing

microparticles, and optionally, process further comprises

(d) washing the microparticles of step (c) with a solvent to form microparticle slurry;

(e) Filtering the microparticle slurry to remove oversized particles and/or agglomerates, and

(f) lyophilizing the microparticle slurry to form drug containing microparticles.

15. A pharmaceutical composition of a drug containing microparticles prepared by a process, which process comprising steps of:

(a) preparing a w/o/w or s/o/w emulsion that comprises a first phase and a second phase, the first phase comprising w/o emulsion which comprises of a drug or salt thereof, a polymer, and a solvent for the polymer;

(b) quenching the w/o/w or s/o/w emulsion to form microparticle suspension followed by decantation, washing and de-watering of said microparticle suspension, and

(c) lyophilizing the microparticle suspension to form drug containing

microparticles and optionally, process further comprises