Description

The present invention relates to preparation of microparticles containing an drug. More particularly  the present invention relates to an improved process for the preparation of good quality microparticles.

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 pharmaceutically 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 extraction medium  to immediately extract the solvent from the microdroplets in the emulsion to form a microencapsulated product  such as microcapsules or microspheres.

U.S. Patent No. 5 650 173 discloses a process for preparing biodegradable  biocompatible microparticles comprising a biodegradable  biocompatible polymeric binder and a biologically 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 an 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).

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  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.

The commercial scale production of microparticles  therefore  requires extensive optimization and in process controls. The process further demands several additional measures in order to prevent in process agglomeration and achieve desired degree of drying of 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 posses excellent shape uniformity  exhibiting good flowability during vial filling and passage through needle at the time of administration.

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 invetion posses excellent shape uniformity  exhibiting good flowability during vial filling and passage through needle at the time of administration.

The advantages of the invention are also accomplished by maintaining and processing the microparticles as a suspension during manufacturing which has various significant advantages in preparing end formulation.

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 drug  one or more polymers  and one or more solvents for the polymer;
(2) quenching and washing of the emulsion to form 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:
(1) preparing an emulsion that comprises a first phase and a second phase  the first phase comprising drug  one or more polymer  and one or more solvent for the polymer;
(2) quenching  extraction  washing and de-watering the emulsion to form microparticles containing the drug;
(3) filtering the microparticles to form microparticle suspension; 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.

The process may employ a vessel that is adapted to perform multiple operations such as quenching  de-watering  washing 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 the 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 washing the microparticles and final lyophilization of the microparticles.

In another general aspect of the invention  the process further comprises  after the washing step  the optional 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 extraction medium; agitating the vessel contents to disperse the microparticles in the extraction 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.

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 extraction medium; agitating the vessel contents to disperse the microparticles in the extraction 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 drug 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 the microparticles; and optionally  further performing final lyophilization of the 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 vials filling of the micoparticles; and final lyophilization of the microparticles. The resulting microparticles may exhibit in 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:
(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;
(2) quenching  extraction  washing and de-watering the emulsion in a vessel to form microparticles containing the drug;
(3) filtering the microparticles to form microparticle suspension;
(4) lyophilizing the microparticle suspension to form drug containing microparticles.
(5) washing the microparticles;
(6) filling the microparticles in vials; and
(7) filling the headspace in the vials with inert gas.

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 volume of the solvent is removed in the vessel by decantation resulting in simplification (reduction in total number of steps) of the process. Further  due to absence of vibration mechanism in the vessel  the possibility of wear and tear of the vibrator and vessel may be avoided.

The process provides end formulations in the form of microparticle suspension or slurry  it obviates the difficulties with dry microparticle filling in vials and poor flow properties through syringe needle.

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 during duration of action periods of 30 to 100 days. A 60 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 the general process of preparing the microparticles in accordance with the invention;

FIGURE 2: An equipment configuration for preparing microparticles in accordance with the invention. The embodiment shown in FIGURE 2 is suitable for performing lyophilization of microparticle suspension; and

FIGURE 3: Microscopic picture of the microparticles prepared according to the process of the invetion.

FIGURE 4: Microscopic picture of the microparticles prepared according to a process known in the art.

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.

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

The process in accordance with the invention does not need any additional or specialized component in the process line to circumvent the problem of agglomeration or sticking of the microparticles encountered during various stages (e.g. the washing step). Particluarly  the essential steps such as quenching  extraction  dewatering  and optionally  filtration steps are carried out in a single vessel to concentrate the emulsion.

The invention relates to 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;
(2) quenching  extraction  washing and de-watering the emulsion to form microparticles containing the drug;
(3) filtering the microparticles to form microparticle suspension; and
(4) lyophilizing the microparticle suspension to form drug containing microparticles.
The quenching  extraction  washing and de-watering steps of the process are preferably performed in a single vessel.

The term "microparticles" or "microspheres" 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.

With reference now to the drawings  FIGURE 1 illustrates the general process of preparing the microparticles in accordance with the invention. In a step 3  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 for the polymer.

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

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

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; non-steroidal antifertility agents; parasympathomimetic agents; psychotherapeutic agents; major tranquilizers such as chlorpromazine HCl  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 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 the like. Various commercially available poly(lactide-co-glycolide) materials (PLGA) may be used in the method of the present invention. For example  poly (d l-lactic-co-glycolic acid) is commercially available from Alkermes  Inc. (Blue Ash  Ohio). A suitable product commercially available from Alkermes  Inc. is a 50:50 poly(d l-lactic-co-glycolic acid) known as MEDISORB® 5050 DL. This product has a mole percent composition of 50% lactide and 50% glycolide. Other suitable commercially available products are MEDISORB® 6535 DL  7525 DL  8515 DL and poly(d l-lactic acid) (100 DL). Poly(lactide-co-glycolides) are also commercially available from Boehringer Ingelheim (Germany) under its Resomer® mark  e.g.  PLGA 50:50 (Resomer® RG 502)  PLGA 75:25 (Resomer® RG 752) and d l-PLA (Resomer® RG 206)  and from Birmingham Polymers (Birmingham  Ala.). 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 may be detrimental in the quality and release profile of the microparticles. The molecular weight should be high enough to permit the formation of satisfactory polymer coatings  i.e.  the polymer should be a good film former. Usually  a satisfactory molecular weight is in the range of 5 000 to 500 000 daltons  preferably about 150 000 daltons. However  since the properties of the film are also partially dependent on the particular polymeric matrix material being used  it is very difficult to specify an appropriate molecular weight range for all polymers. The molecular weight of the polymer is also important from the point of view 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 multiphasic release patterns.

The formulation prepared by the process of the present invention contains an 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  extraction  de-watering  washig and optionally  filtration). The vessel contains quench liquid for the quench or primary extraction 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 a de-watering step  primary extraction step and multiple washing steps.
The objective of de-watering step is to concentrate the microparticles from the dilute suspension that is formed during extraction 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 fo the waste such as supernatent containing fines. The vessel is also provided with multiple inlets and outlets for quench  extraction solvents and water in order to recycle in the vessel.

It is of particular importance that multiple operations D (quenching  washing and optionally extraction and de-watering) are carried out in the vessel which makes the overall process simple and robust.

In an embodiment  the extraction  de-watering and washing in the vessel is performed at room temperature or 37°C ± 10°C. The temperature of the extraction 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 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.

It is significant to maintain microsphere temprature substantially below 10° C during and/or after lyophilization to preapre good quality  smooth and free flowing microspheres. Due to non-aggregation property  such microspheres can be advantageously filled in vials or ready to use for processing on the formulation development line.

The microparticles are  optionally  washed F in suitable washing solvent (preferably  organic solvent  e.g. ethanol) to remove or extract any further residual solvent. The microparticles then filtered G through a filter to remove smaller particles and liquid that drop through the screen that is removed as waste. The filtration G may be performed by employing inline sieving as the microparticles pass through the process tubings.

In an embodiment  solvent removal after washing F of the microparticles is performed by decantation.

The microparticles formed in the form of slurry of suspension can be fillied in vials H  preferably under stirring using suitable vial filling assembly and lyophilized I to form solid microparticles. The moisture content of the microparticles is maintained  preferably less than about 1%  more preferably approximately equal to about 0.2%. 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.
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 illustrates an equipment configuration for preparing microparticles in line with the general process as depicted in FIGURE 1. The equipment configuration shown in FIGURE 2 is particularly well suited for performing lyophilization of the microparticle suspension. 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  preferably comprising 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  poly(vinyl alcohol) (PVA)  carboxymethyl cellulose  gelatin  poly(vinyl 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 120.

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 is a static mixer or inline homogenizer (commercially available as  e.g. Silverson inline homogenizer) 03. 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 microparticles containing drug encapsulated in the polymeric matrix material. The microparticles are then preferably stirred in a quench or extraction tank 05 containing a 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 or extraction tank 05 is connected with a quench tank 04 as source of quench liquid.

Following the movement of the microparticles from mixing means 03 and entrance into quench or extraction 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)  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 multiple washing  and optionally to extraction 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 alsoprovided with a port for removal of waste.

In an embodiment  solvent removal from the quench tank 05 in the de-watering step is executed by decantation. The decantation valves 06 are provided to the quench tank 05 in order to elute the solvent.

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 smaller microparticles of desired fines and liquid to pass through the screen  while larger particles and desired particles are retained. The smaller particles and liquid that pass through the screen are removed as waste.
The size of filter pores may range from about 20 microns to about 200 microns. Preferably  the size of filter pores is about 75 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 E  the dried microparticles need to be transferred to another washing tank 09 containing extraction medium to carry out wash step F. Wash step F is preferably carried out in washing tank 09  using an extraction medium. The size of the washing tank may range from about 5 to about 200 litres. The advantage of the washig step F is that reduce stickiness of the microparticles.

The washing tank 09 is preferably smaller in size/volume than quench tank 05; consequently the volume of extraction medium in washing tank 09 will be less than the volume of extraction 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 filtered G via filter 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.
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 in the vials.

Alternatively  the micoparticle filled vials can be subjected to final lyophilization I to form solid microparticles.

The quality of the microparticles prepared according to the improved process of the invention (FIGURE 3) is comparable to microparticles prepared according to the prior art process (FIGURE 4).

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:

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 2:1 to 20:1 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. The decantation port screen of size selected from the range of about 50-150 micron was used.

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 5-10ºC in 2-10% of the initial quench volume) followed by addition of another 10-40 % w/w of ethanol (with temperature of 25-40ºC. 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 microparticles were then filtered  dried and filled aseptically into vials or alternatively  the resulting microparticles were sieved through a filter of 100-200 micron size and transferred to vial filling line  filled in the vials under stirring  and finally lyophilizing the microparticle filled vials by optimized control of temperature and pressure to control residual solvents.

We Claim-

1. A process for preparing microparticles comprising:
(1) preparing an emulsion that comprises a first phase and a second phase  the first phase comprising drug  one or more polymers  and one or more solvents for the polymer;
(2) quenching and washing of the emulsion to form microparticle suspension; and
(3) lyophilizing the microparticle suspension to form drug containing microparticles.

2. The process of claim 1  wherein quenching and washing of the emulsion is performed in a single vessel.

3. The process of claim 1  wherein the first phase is prepared by a process comprising the steps of:
(1) separately preparing solution of drug and one or more polymers;
(2) aseptically filtering the drug solution and polymer solution; and
(3) mixing the filtered drug solution and polymer solution

4. The process of claim 1  wherein the lyophilized microparticles are filled in the vials with inert gas purging.

5. The process of claim 1  wherein the process of washing comprises solvent and fines removal by decantation.

6. A process for preparing microparticles comprising:
(1) preparing an emulsion that comprises a first phase and a second phase  the first phase comprising drug  one or more polymers  and one or more solvents for the polymer;
(2) quenching and washing of the emulsion to form microparticle suspension; and
(3) lyophilizing the microparticle suspension to form drug containing microparticles 
characterized in that said process does not involve the step of washing the microparticles after lyophilization.

7. The process of claim 6  wherein quenching and washing of the emulsion is performed in a single vessel.

8. A process for preparing microparticles comprising:
(1) preparing an emulsion that comprises a first phase and a second phase  the first phase comprising drug  one or more polymers  and one or more solvents for the polymer;
(2) quenching and washing of the emulsion to form microparticle suspension;
(3) lyophilizing the microparticle suspension to form drug containing microparticles;
(4) washing the microparticles with one or more solvents; and
(5) lyophilizing the microparticles to form drug containing microparticles.

9. The pharmaceutical composition of claim 8  wherein the lyophilized
microparticles are filled in the vials with inert gas purging.

10. A pharmaceutical composition of the drug containing microparticles prepared by a process  which process comprising steps 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;
(2) quenching and washing of the emulsion to form microparticle suspension; and
(3) lyophilizing the microparticle suspension to form drug containing microparticles.

Dated 16th day of May  2012 For Wockhardt Limited

(Mandar Kodgule)
Authorized Signatory