Title of Invention

A METHOD FOR THE PRODUCTION OF A PHARMACEUTICAL COMPOSITION AND THE COMPOSITION

Abstract

ABSTRACT IN/PCT/2001/00825/CHE A METHOD FOR THE PRODUCTION OF A PHARMACEUTICAL COMPOSITION AND THE COMPOSITION A method for the production of a pharmaceutical composition comprising the steps of a) mixing a suitable amount of pharmaceutically active compound of Formula I or a pharmaceutically acceptable salt thereof with a suitable amount of biodegradable polymer b) subjecting said dry mixture to a suitable shear mixing using a single screw extruder under conditions and said homogenous mixture is formed into a strand c) pulverizing said strand and d) pulverizing said pellets to form sustained release microparticles of said biodegradable polymer and said pharmaceutically active compound, wherein said microparticles are having a size distribution in the range of from 10 to 200 |im such that said microparticles are suitable for forming an ejectable formulation. This invention also relates to the pharmaceutical composition.

Full Text

This invention relates a method for the production of a pharmaceutical composition and the composition. Generally it relates to a methods for the production of sustained release compositions containing a biodegradable polymer and a pharmaceutically active molecule, which are useful in the treatment of a variety of diseases, including certain psychoses such as, for example, schizophrenia, obsessive compulsive disorder, anxiety, and bipolar disorders. More specifically, the present invention relates to sustained release compositions of a biodegradable polyester and a pharmaceutically active molecule capable of exerting serotonin receptor antagonist activity at the 5HT2 receptor, method of making the same, and method of treating patients in need of such compositions. It has long been appreciated that the continuous release of certain drugs over an extended period following a single administration could have significant practical advantages in clinical practice. It is also well recognized in the art that delivering a drug to its therapeutic site of action, such as, for example, the central nervous system (CNS) can be a very difficult task because of the numerous chemical and physical barriers which must be overcome in order for such delivery to be successful. A particularly difficult problem is in long term administration of a drug to patients suffering from CNS related diseases. This is particularly true for patients suffering from various CNS related diseases, such as schizophrenia, obsessive compulsive disorders, sleep disorders, depression, anxiety, anorexia and drug addiction. In addition, there is a need to maintain a steady drug level in patients suffering with these diseases so as to provide an improved efficacy in treatment with lower peak drug concentrations. As a result, many methods ha\'e been developed to deHver druss to the CNS effectively. One such me:hod invoK'es preparation of sustained release formulations. The sustamed release formulations may however be of various different types. For examnle, a drug may be chemically modified into a form called a prodrug, thai is capable of transforming into its active form slowly, either before or after crossing the blood-brain barrier. Aji example of such a prodrug delivery system consists of the neurotransmitter dopamine attached to a molecular mask den\'ed from the fa:-5oluble vitamin niacin. The mocirled docamine is taken up into the brain \'.'here it is then slowly stripped I'rom its prodrug m.ask lo \Teld free dopamine. Other common meLhods used to prepare sustamed release formulations mclude formation of micropanicies m which bioactive agents are contained within a comDatible biodegradable polymer, A number of methods are reponed in the an, which use a wide range of organic solvents to prepare such microparacies. For example, US. Pat. No. 4.389,330 describes a method of fonming m.icrocapsuies by dissolving or dispersing an active agent along with a wall forming m^aienal in a solvent. Common solvents used for the I'ormiation of such microcapsules include chlorinated hydrocarbons, particularly, methylene chloride, acetone, alcohols, and the like. However, due to environmental and toxicological considerations it is not possible to make certain of these drug formulations using solvents. Particularly, there are a number of regulatory restnctions in disposing of the solvent and soHd wastes produced during the mianufacmre of these drug formulations. In addition, there are miany disadvantages to the solvent method of producing microparticle drjg formulations. First, this method is uneconomical for an industrial size scale-up. Second, there are also quaHiy concerns such as reproducibility and consistency of the drug distribution in the polymer matrix, thus causing serious reg^ilatory compHance problems. Finally, the solvent method generally produces only the microspheres in powder form. To overcome some of the problem.s of the solvent method of producing m.icropanicies, there are methods known in the an to melt extrude a solid mixture of drug molecules and a variety of poNxnenc binders. For example, U.S. Pat. No. 5,439.688 describes a process for preparing a Dharmaceuiica] composition for the sustained release of a drug molecule. However, all of the drug molecules descnbed therein are svoithetic or naturally occumng peptides, U. S. Par. No. 5.-156,923 describes a process for producing a solid dispersion of a drug dissolved or dispersed in a Dolymer or a diluent using a twin screw extruder. However, none of these prior an references teaches a formation of sustained release pharmaceutical compositions using a melt extmsion process u'hersin such comDOSuions are suitable for the treatment of any of the CNS diseases descnbed hereinabove. Furthermore, none of the pnor an references describes a method for the formation of micropanicles wherein the drug molecules are dissolved in the poivmeric matnx and are useful in formma injectable formulations for the treatment of CNS related diseases, The following references are disclosed as background, U.S. Pat. No. -.389.330 descnbes a microencaDsuianon process for the formation of microcapsules laden with an acnve agent involving a senes of steps usmg a solvent. U.S, Pal, No, 4.SOI,460 describes a process for the preparation of solid pharmaceutical forms by an injection molding or an extrusion process. U.S. Pat. No. 5.360,610 descnbes pol^Tneric microspheres as injectable, drug-delivery systems for use to deliver bioaciive agents to sites within the central nervous system, U.S. Pat. No. 5,439.688 and references cited therein describe processes for preparing priarmaceutical compositions for the sustained and/or controlled release of a drug using a biodegradable polymer and incorporating as the active substance the salts of a natural or synthetic peptide. U.S. Pat. No. 5,456,917 describes a method I'br making an implantable bioerodible material for the sustained release of a medicament. U.S. Pat, No. 5,456.923 describes a method of manufacturing solid dispersion in which a drug is dissolved or dispersed in a pohTner carrier or a diluent. The solid dispersions are formed in a twin screw extruder. U.S. Pat. No. 5.505.963 describes a method for making a pharmaceutical composition n*ee of organic solvents useful for oral administration. The method employs a solidiiled granulates of an active ingredient in admixture with a meltable auxiliary substance which is soluble in the active ingredient at elevated ten^peratures, J- Controlled Release, 2S (!99-) 121-129 describes a review of dmg delivery systems using various kinds of biodegradable pohmers. Pharmacy International, (19S6J- 7 (12), 316-lS, describes a review of controlled dmg release from monolithic bioerodible poKineT devices, .A.ll-of the rei'erences cited herein are incorporated herein by reference in their entirety. ) SUMMARY OF THE I^^ ENTION Accordingly, it is an object of the present invention to provide a melt exirusion method for the formation of microparticles in which the drug molecules are substantially dissolved m the polymer matrix forming a solid solution. It is further an object of the present invention to provide microparticles capable of releasing the drug molecules at- a sustamed release rate over an extended period of time, Fmally, ii is also an object of the present lEvention to provide injectable m.icropanicle formulations for the treatmeni of various CKS diseases includinE diseases or conditions treatable bv antagonizing the effects oi serotonin at the 5H?: receptor. such as schizophrenia, obsessive compulsive disorders, sleep disorders, depression. ar.xiet>\ anorexia and drug addiction. Surprisingly, it has now been found ihat solid solution of a biodegradable polymer and a pharmaceuticalty active molecule can be m^ade by a melt extrusion process. Some of the advantages gained by the practice of the method of the present invention, individually ani'or m combmations. are: a) the pharmaceuticaiiy active compound is essentially dissolved in the biodegradable poivmer matrix forming a solid soJution; b) the compositions of the present invention can be readily formed into microparticles: and c) the compositions of the present invention can be formulated into injectable formulations for the sustained release of the active compound, .^dvanlageouslv. the composidons of the present invention are useful in the treatment of various CNS diseases. Thus, in accordance with the practice of the present invention there is provided a method for the production of a oharmaceuticai composition comprising the steps of: a) mixing a suitable amount of pharm.aceuticaily active molecule capable of exerting serotonin receotor antagonist acti'-'ity with a suitable amount of biodegradable polvmer for a sufficient period of time and a; suitable temperature and pressure conditions to form a dry mi.xture of said pharmaceuncaJiy active molecule sua said poJ\7T:sr. u-herein said biodegradable polymer has a glass transition temperature (Tg) of less than about 60 ^C; b) subjeciin2 said dry muxrure to a suitable shear mixing under suitable temperature and pressure conditions for a sufficient period of time such that said poKmier sof.ens to form a tluidized medium and said pharmaceuticaiiy active molecule is sufficiently dissolved to form a solid solution having substantially homogeneously dispersed mixture of said pharmaceuticallv active molecule and said polymer, and said homogeneous mixture is formed into a strand: c) pelletizing said strand; and d) pulverising said pellets lo form sustained re'iezss micropanicies of the biodesradable polymer and the pharmaceutical composition, vvherein the microparticies are having a size distribution in the range of from about 10 to 200 jim such that the micropanicies are suitable for forming an injectable formulation. In one of the preferred embodiments, a biodegradable polyester is used as the matrix pohTTier to dissolve a pharmaceuticaliN' active moiscuis caoable of exerting serotomn receptor antagonist activity. In this preferred embodiment, the sustained release mucroparticles are formed in a twin screw extruder. In a more preferred embodiment of this invention, the twin screw extruder is made up of at least one left handed element and the extrusion is carried out at a preferred temperamre range of from about 95 °C to about 115 *C. In another preferred embodiment, a solid solution is formed using a polylactide-co-glycoiide poKm.er (PLGA) and a pnarmaceuticaily active compound of Formula I or pharmaceutically acceptable salts thereof In this preferred embodiment, the dry blend of PLG.A Doivmer and comoound I was dried in a "^'acuum oven at a temoeramre of about 25 '^C Formula I such that the moisture content of the dry blend is less than about 0.02 weight percent. The melt extrusion of the dry blend was earned out in a twin screw extruder equipped with at least one left handed element to form a homogeneous mixture in which compound I is substantially dissolved In the PLGA matrix. In this preferred embodiment, pelletizing, pulverizing and sieving of the melt extruded blend affords microparticies having the size distribution of from about 10 io )00 Lira, which are sijiiable for forming injectable fonnulations. In another aspect of this invention, there is also provided a pharmaceutical composition for the sustained release of a medicamentous substance compnsing micropanicies having a size distnbution in the range of from about 10 to 100 um formed of: a) a DjoaegraaaDJe poiymsr m an amount oi aouuL ou tu 7-' pcn^cm uv wtj^^jL, «ii^.w<.i pohtner has a glass transition temperature of less than about and> b) a pharmaceutically active compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of about 5 to 20 percent by weight; 0 CH Formula 1 wherein said compound is subsrantiaJJy dissolved and uniformly dispersed in said polymer. DET.AJLED DESCRIPTION OF THE INVENTION As used herein the foUo-A-ing terms shal! have the assigned meanings and'or definitions: "Biodegradable", "bioabsorbable", "bioresorbable" or 'bioerodible" pol>msr shall mean any polymeric material capable of undergoing a degradation process in a biological environment, such as consumption by a human body and is converted to products that can be readily eliminated from the body, "Drug", "medicament", 'pharmaceutically active" or "therapeutically active" shall mean any orgarjc comoound or substance ha\ing bioactix-ity and adapted or used for a therapeutic purpose. "Microparticles", "microspheres" or "microcapsules" shall mean any free flowing powder consisting substantially of spherical particles of 500 microns or less in diameter, usually 200 microns or less in diameter. "Monolithic" shall mean a composition in which the active agent is substantially homogeneously dispersed throughout an essentially therapeutically inert matrix, "Patient" means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans. The term "pharmaceuticaJly acceptable salt" refers to those salts that are no: substantially toxic at the dosage administered to achieve the desired effect and do not CI tDCTm rrr turrrr /ni n r- «_.> independently possess significant pharmacological activity, ihe salts included within the scope of this term are hydrobromide. hydrochloride, sulfuric, phosphonc, nitnc. formic, acetic, propionic, succinic. giycoJic, lactic. n:a!ic. tartaric, citric, ascorbic, a-keiogJutanc, glutamic, aspartic, maleic. hydroxv-maleic, p>TtJvic, phenyiacetic, benzoic, p-amino benzoic, anthranih'c, p-hydroxybenzoic. salicylic. hydroxyethanesulfonic, ethyienesulfonic, halobenzenesulfonic, toiuenesulfonic. naphthalenesulfonic, methanesulfonic. sulfanilic, and the like. "Phannaceuiically acceptable carrier"' is a solvent, dispersant, excipient, adjuvant or other material having acceptable toxicity, which is mixed with the composition of the present invention in order to permit the formation of a phaimaceutica! composition, i.e., a dosase form capable of administration to the patient. One example of such a carrier is a pharmaceuticaliy acceptable oil r>pically used for parenteral administration. 'Solid solution" .means Lhat the pharmaceuticaliy active molecule is substandalls' dissolved in the polymer to form a single phase system. "Sustained release" means that a composition when adrndnistered lo a patient is capable of releasing the active molecule at a steady rate for a period of at least 2 weeks, preferably for a oeriod of about 2 weeks to one month or for longer penods if needed. "Therapeutically effective amount" means an amount of the compoiind whjch is effective in treating the named disorder or condition. "Treat" or ""treating" means to alleviate symptoms, eliminate the cause of the symptom either on a temporary OT perm^aneni basis, or to prevent or slow the appearance of symptoms of the named disorder or condition. One of the advantaaes of the present method of the invention is that the microparticles of well deilned size distribution can be obtained in which the pharmaceuticaliy active molecule is dissolved in the biodegradable polymer matrix forming a solid solution. This is achieved by a scalable meh extrusion process, thus avoiding the use of undesirable solvents as used bv the conventional processes. Thus, the method of the present invention not only oft'ers envirorjnental benefits (i.e.. avoids disposal of the solvents) but also provides an economical way of making sustained release drug formulations, .\nother imponant advantage of the method of the present invention is that the wel! defined micropanicles of narrow size distribution can be made by the practice of this invention, which are useful for forming a variety of injectable lorm.ulanons. Yet another advantage gained by the practice of this invention is that solid solution of a biodegradable polymer and a pharmaceuticaliy active molecule can be readily made wherein the active molecule is a neuro-aciive. non-peptidic small molecule and may coniain a reactive group such as hydroxy group. By judicious practice of the method of the present invention Ihe micropaniclss formed are sufastanliaiiy free from any other reactive products of the pharmaceulicailv active molecule and the biodegradable polymer, Surpnsingiy, the method of the present invention offers pharmaceutical compositions in whi'ch the bioavailability of the pharmaceutic ally acdve molecule is enhanced because of the fact thai the active molecule is substantially dissolved in the polymer matrix. Thus, the micropardcies of the composition of the present invention are substantially "monoiithic." That is. Lhe active molecule is dispersed unifonnlv throughout the polymer matnx. It should be noted that many of these features described herein are not readily attainable by most of the conventional methods, including solvent and other melt ;xtrusion methods. In accordance with the practice of the present invention there is provided a method for the production of pharmaceutical composidons, hi the method of the present invenuon. the first step involves mixing of a suitable amount of the pharmaceulicailv active molecule with a suitable am.ount of the biodegradable polymer for a sufilcienr period of time and at suitable temperature and pressure conditions to form a dry mixture. Mixing of the poKTuer and the pharmaceutically active molecule can be done at ambient atmospheric conditions, preferably in the temperature range of from about 20 ^C to 30 °C and at atmospheric pressure. Tne time required for mixing depends upon the quantities of the poKmer and the acuve molecules used and m.ay involve 30 m^inutes to 2 hours or longer. The polymer and the pharmaceutically active molecule may be used as received from. the com.mercial so'urces. generally, m the form of powder or pellets. However, it has been obser\-ed that it is beneficial to ennd the powder or pellets to form a well mixed dry mixture. .\ny of the grinding or milling techniques known in the art may be used for this purpose including cryogenic grinding or nulling methods. It has also been obser\'ed that drying of the dry mixture of po!>m.er and pharmaceutically acdve molecule is also beneficial to remove any residual moisture in the polvmer or the active molecule. .Mnong several benefits, two key benefits of drying the dry mixture are: a) minimization of the degradation of the polymer; and b) minimization of any potential reaction benveen the polymer and the pharmaceutically active molecule, .^jiy of the dr/ing techniques known in the an may be used. For example, drying the mixture under vacuum at about room temperature, i.e., 20 to 30 °C for a period of about 2 to 48 hours or longer provides desirable results. As stated hereinabove, a wide variety of non-peptidic phaimaceuticaliy active molecules having a molecular wsighi less than about 600 may be used in this invention. Tnt expression ■"non-peptidic" as used herein shalJ mean tha! the molecules which are not peptides, that is, molecules that are not formed by the reaction of two or more of the namraliy occurring amino acids. A wide variety of biodegradable polymers may be employed in this invention, however, biodegradable pol^'msrs having a glass transition temDerature (Tg) less than about 60 '^C are paniculariy preferred. As used herein "'glass transition tsmperarjie' refers to the softening temperature of the polymer, i.e., the transition temperature above which a noncrysialline polymer has enough ibermal energy for long segments of each poj)7ner chain to move randomly. In other words, a: a temperature higher than the zlzss transition temperaDjre, the polymer molecules have enough motion to be mobile, and this is rei'erred to herein as a '■fluidized medium." In a second step of the msdiod of the present invention the dr>' mixuire as obtained in the first step is subjected to a suitable shear mixing at suitable temperature and pressure conditions for a sufficient period of time such that the polymer softens to form a iluidized medium.- As used herein "'shear mixing" means thai mi.xing of the dry mixture at an ele-v-aied temperature, oreferabiy above th; glass transition temperature of the polymer, under shear using any of the methods fcnovvTi in the an. Preferably, shear mixing is carried out m a mixing bowl or an extrasion equipment as described herein. The conditions are maintained such that the phaimaceuticaliy active molecule is allowed to dissolve in the fluidized polymer meditim and form substantially a homogeneous mixture of the pharmaceutically active molecule and the pol\'mer. To obtain hsst benefits torn inis invention, it is critical thai the phaimaceuiicalJy active molecule is suiTiciently miscibis or dissolved in the polymer matrix, as mentioned hereinabove. To determine the extent of pharmaceutically active molecule dissolved in the polymer matrix, a variety of techniques well known in the art may be used depending upon the type of polymer and the active molecule employed. In general, differential scanning calorimetry (DSC) may be used to determine the level of active molecule dissolved in the pohTTier if the active molecule has a denniiive melting poini. From Lhe heat of fusion determined from the melting point peak of the active molecule, it Is possible to compute the extent of active molecule dissolved. Thus, as more active molecule dissolves in the poiyTner the size of the melting peak is reduced correspondingly. The melting peak is completely absent when all of the active molecule is dissolved in the polymer. In addition, the glass transition temperature (T.) of the polymer decreases with increasing solubility of the active molecule. Other techniques, such as scanning electron microscopy (SEM) may also be used to determine the hoinogeneity of the pharmaceutical composition of the present invention. That is, the undissolved pharmaceutically active molecule will appear as a separate nhase. In a third step of the method of the present invention, the iluidized mixture of the polymer and pharmaceutically active molecule is cooled to form a strand and pslleiized. As used herein 'pelletizina" refers to the formation of pellets from the strand formed according to this invention. A.ny of the well known methods in the an may be used to strand and pelletize the mixture of the poiymer and pharmaceutically active molecule. For example, ths moiten nuid may by extruded into 2 strand by passing through an orirlce. Then the strand is taken over a conveyor belt, which is being purged by dry nitrogen or air. The strand is rlnaUy fed into a peiletizer to form pellets. In a fmal step, the pellets fromi the tiiird step are pulverized to form sustamed release microparticles of the biodegradable polymer and the pharmaceutically active moiecule. .^.s used herein "pulverizing" refers to conversion of pellets fomied according to this invention 10 small particulate form using any of the known methods in the art to form the micropanicles of this invention, such as cryogemc mhlling as described herein. The micropanicles so formed are sieved such that they exhibit a size distribution in the range of from about 10 to 200 um, more preferably 10 to 100 ,Lim. Tnese micropanicles are suitable for forming an injectable formulation. .As discussed hereinabove, preferred pharmaceutically active molecules for the practice of the method of presem invention are neuro-active molecules or agents. Examples of ne'uro-active molecules or agents that may be microencapsulated and used according 10 the present invention are neurotransmiuers and neurotrophic factors including such agents as norepinephrine, epinephrine, serotonin, dopamiine. stibstance P, somatostatin, and agonrsts and antagonists of these active raolecuies or agents, PieferTsd pharmaceuiicaliy active molecules are those which are enable of exening serotonin Te-csp:oT anragonisi activity. Panicularly preferred phamiac sun call y active molecules for the practice of the method of present invenhon are 5HT:A receptor antagonists. A most preferred pharmaceutically active molecule is (-^)-isomer of a-(2.3-dimethoxyphenyl)-i[2-(4-riuorophenyl)ethylJ-4-pipendinemethanoL Compound of Formula 1 or a pharmaceutically acceptable salt thereof- Formula I .^y of the known biodegradable polymer may be used under certain specific conditions as described herein. For instance, a polymer having a glass transition temperature lower than 60 ^C may be employed in the formation of microparticles of the present invention, provided that the phaimaceutically active molecules of the present invention are dissolved sufficiently in such a polymer matrix by practicing the method of the present invention. It should farther be noted that such biodegradable polymer is suitable as a raw material in the manufacture of pharmaceutical products and its function is not adversely affected by the shear mixing step (i.e., siep b) of the method of the present invention. Examples of such polymers are polyesters, polyamides, poly anhydrides, polyorlho esters, polycarbonates, poly-(phosphoeslers), poly(phospha2enes}, po!y(iminocarbonstes}, and the like. It should be noted that a mixture containing one or more of these polymers may also be employed. Such polymers are easily prepared as described in the hterature cited herein and they can be obtained commercially from specialized firms known to those of ordinary skill in the pertinent manufacttiring art. Particularly preferred polymers suitable for the method of the present invention are polyesters. Specific examples of polyesters include polylactide, polyglycohde, polylactide-co-glycolide, polyhydroxybutyTate, polycaprolactone, polytanarate, and the like. Two or more mixtures of these polymers may also be used. A particularly preferred polyester is polyiactide-CD-glycohde (PLGA). The PLGA polymer has a number of advantages which render it unique to the method of the present invention. .An advantage of PLGA is that it is similar to materials used in the manufacture of present day bioabsorbable sutures. Another advantage is that this material is biocompatible with the tissue of the CNS. Still another advantage is thai this matenal is biodegradable within the tissues of the CNS without producing any toxic byproducts of degradation. An important advantage of this maiena!, as it relates to this invention, is the abilit}-' to modify the duration of drug release by manipulating the polymer's biodegradation kinetics. I.e., by modifying the ratio of lactide and glycolide in the polymer. This is panicularlv important because the ability to deliver neuro-active molecules at a controlled rate over a predetermined period of time is a more etTective and desirable therapy over current procedures for administration, Micropaiticles miade with this polymer serve two functions: they protect drugs from degradation and "they release drjgs at 2 controlled rate over a predesired time. As stated hereinabove, although polymers have been previously reponed for use in the microencapsulation of dr.:gs including PLCA. uhe physical, chemical and medical parameters of the microencapsulating polymer for pharmaceutically active molecules to be used in accordance with the present invention are narrow. This is especially true for the formation 0: sustained release injectable nharmaceuticai compositions for delivering to the CN'S active drags according to the present invention, For instance, the PLGA poKTner that is suitable in the method of the present invention may have a wide ranee of average molecular weight provided that its glass transition temperature is less than 60 °C, However, preferably, the average molecular weight of PLG.A pohTner is in the range of from about 20,000 to about 100,000, and is more preferably between about 30,000 and 45,000. The PLGA polymer further contains 45 to 90 mole percent of lactide and 10 to 55 mole percent of glycolide units respectively. Dry mixing of the polymer and "Jie pharmaceutical ly active molecule in step (a) is conducted at ambient tem.perature, i,e,. at around the atmospheric temperature and pressure conditions. More preferably, the dry mixing is carried oui at a temperature in the range of about 20 ~C to about 30 "C at atmospheric pressure conditions. Tne shear mixing of the dr\' mixture in step (b) of the method of the present invention may be carried out using a variety of techniques known in the an. For example, mixing bowl equipped with a heatins element and mixing blades may be used. Several different types of mixing bowls are available from commercial sources. .Another preferred method of carrs^ng out the shear mixing is by an extrader. Both single screw as well as t\^'in screw extinders may be employed to carry out the shear mixing in step (b) of the method of the present invention. The twin screw extruder is particularly preferred. The twin screw extruder is preferably a forward discharge extruder pelletizsr characterized by the use of a couple of screws, which differentiate the machine from the single screw extruder. The single screw extruder has a single screw and often uses a prefabncated screw, and thus screw elements can not be varied as in the r^in screw exiruder as described further below. To be more specific, the twin screw extruder compnses a metering feeder unit, a barrel (cylinder], screws, paddle means, screw shafts, barrel heater-cooler means, exit dies {cooling die, heating die. molding die) and extrudate cutter and provides for a free variation of compounding pressure and temperature through a choice of screw geometry, rotationai speed, and screw elements to be mounted on the screw shafts. Funhermore, if necessary, the barrel can be used in a vanety of combinations of length and t>'pe according to the intended use and its temperature can also be controlled as desired, Tlius, the nvin screw extrude: processes the feed with two screws and provides for change of the combination of axial screw elements so that it has many definitive advantages over the single screw extruder, namely: (1) Compared with the single screw extruder, the twin screw extruder features positive conveying of materials between screws, which allows for easier compounding of shear sensitive or low viscosity materials. Thus, for example, mjxing of dissimilar materials, such as oil and water, can be done better with a twin screw extruder. (2) .Mso, compared with the single screw extruder, the twin screw extruder is by far superior in shear force, compounding effect and transpon capacity. Furthermore, it should be noted that judicious selection of the screw elements is extremely critical to obtain desired intended benefit from the practice of the method of the present invention. It is believed that the appropriate selection of the screw elements can affect the extent of solubility of the pharmaceuticaliy active molecule m the polymer matrix. The screw elements further affect the homogeneity of the pharmaceutica] composition. For example, it has been obsen^ed diat the use of one or more of left handed elements m.mimizes the polvmer desradation and increases the solubility of the pharmaceuticaliy active molecule in the polymer mainx. In addition, it has been observed that proper selection of kneading elements fiirther improves the unifonn mixing and solubility of the pharmaceuticaliy active molecule in the polymer matrix. Tne processing parameters such as pressure, temperature, feed rate of pol>Tner and the pharmaceuticaliy active molecule, and amounts and feed rates of additives, if used any, are dependent on the type of pharmaceuticaliy active molecule and of polymer, and the shear mixing equipment used. But it is important to select a combination of parameters such that the pharmaceuticaliy active molecule, polymer, etc. will be maintained at temperatures below their decomposition points and vary the operating parameters according to the desired charactenstics of the products. Thus, it is critical that the glass transition temperature CT.) of :hs polymer assd herein is preferab/y below 60 X such that the shear mixing can be cam'ed oui ai moderate temperatures as described below. In general, shear mixing in step (b) is carried out at a temperature in the range of about 60 =C to about 140 °C. preferably from about 80 °C to aboui 120 °C. and more preferably from about 95 "C to about 115 'C. The compoimding weight ratio of the phanr.aceutically active molecule to 6e oc'r.Tner IS varied depending upon the :\vt of pharmaceutically active molecule, poiymer. and the intended use of the pharmaceuiical composition. Preferably; the weight ratio of the pharmaceutically active molecule and the polymer is in the range of from about 5:95 to about 25:"5, more preferably from about 10:90 to about 20:S0, and most preferably from about ;0:90 to about 15:S5. As stated hereinabove, an imDortant beneilt obtained from the practice of the present invention is that the pharmaceutically active molecule is sufilciently dissolved m the nolymer matrix. Tnz extent of pharmaceuticaliy active moiecuie dissolved in the polymer matrix is controlled depending upon the intended end use and intended rate of release of the pharmaceutically active molecule. Preferably, at least 50 weight percent of the pharmaceuticaliy active molecule is dissolved in the polymer, more preferably the pharmaceutically active molecule is dissolved in the polymer at least to an extent of about 90 weight percent, based on the total weight of the pharmaceutically active moiecuie present in the pharmaceutical comoosition. As stated hereinabove, the pharmaceutical compositions in the form of micropanicies are particularly suitable tn injectable formulations, that is. in parenteral administration. For parenteral administration, the m.icroparticies m.ay be dispersed and'or dissolved in a physiologically acceptable pharmaceutical earner and administered as either a suspension or solution. Illustrative of suitable pharmaceutical carriers are water, saline, dextrose solutions. fructose solutions, ethanoL or oils of animal, vegetable or synthetic origin. The pharmaceuiical earner m.ay also contain preser\-atives. such as benzyl alcohol, buffers, etc., as are known in the art. Some oils ^^-hich may be used for intramuscular mjecnon are sesame. olive, arachnis, maize, almond, cottonseed, peanut and castor oil. with sesame oil being Dreferred. The sustained release fcrmularion is preferably administered inrramusculariy, subcuianeousiy or intravenously with intramuscular administration preferred although other routes of administration such as oral, transdermal, nasal spray, etc. could be used if appropnate to the needs of the patient The microparticies may be admixed with any inert carrier and utilized in laboratorv assays in order to determine the concentration of the pharmacsutically active moiecuie released from the microparticies inciuding the unne, serum, etc. of the patients as is known in the art. Accordingly, the suspension or solution formed in accordance with the method of the present invention when administered io a paiieni releases the pharmaceutically active molec'jie for a penod of at least about 2 weeks at a dose sufficient to antagonize the effects of serotonin at the 5HT;A receptor, more prei'erably for a period of from about 2 weeks to about one month. However, suspension or solution capable of releasing the active molecule lonser than one month may also be prepared if there is a need to administer such a suspension or solution to a patient in need thereof In one of the preferred embodim.ents. there is provided a method for the production of pharmaceutical composition, which compnses the following steps. In step (a) of this preferred embodiment, suitable amount of pharmaceuiically active molecule capable of exening serotonin receptor antagonist activity is mixed with a suitable amount of biodegradable polyester for a sufficient period of time and at a temperature in the range of from about 20 °C to 30 "C and at atmospheric pressure conditions to form a well mixed dry mixture of the pharmaceuiically active molecule and the polyester, ."^ny of the polyesters described hereinabove may be used in this embodiment. As described hereinabove, ihe polyester should have a glass transition temperature (Tg) of less than about 60 "^C. In step (b) of this preferred embodiment, the dry mixture from, step (a) is fed into s twin screw extruder equipped with suitable kneading and mixing elements ai suitable temperatiite and pressure condiiior^ for a sufficient period of time such that said polymer softens 10 form a fmidized medium and at least 50 weight percent of Lhe phaimaceuticaily active molecule is dissolved in the iluidized polyester medium to form a substantially homogeneously dispersed mixture of the pharmaceutically active molecule and the polyester, The homogeneous mixture is then formed into a strand as described hereinabove. In a more preferred form of this embodimeni it has been observed that utilization of at least one left handed element in building the screw remarkably improves the quality of the microparticies that are formed. The microparticies of this embodiment feature more of the pharmaceuricaliy active molecule dissolved in the polyester raatnx, and thus are mors homoeeneous. In addition, it has been observ^ed that use of a narrow temperature range of about 95 '^C to about 115 °C. further improves the quality of the pharmaceutical compositions. In step (c) of this preferred embodiment the strand of pharmaceutical compositions from step (b) is pelletized as described hereinabove. Finally, in step (d) of this preferred embodimentl the pellets are pulverized to form an injectable sustained release microparticles of the pharmaceutical composition as described herein. The microparticles are then sieved to form uniform microparticles havins a size distribution in the range of from about 10 to 200 |im. In yei another preferred embodiment of the method of the present invention the solid solution containing the PLGA polymer and Compound I are formed as described hereinabove. In this preferred embodiment, the dry blending or mixing of PLGA and Comoound I is conducted at a temperature of about 25 ^C. Preferred weight ratio of PLG.A to Compound I is in the range of from about 10:90 to 15:S5. In this embodiment, it has been obser»'ed thai dr>-ing of the dry mixture under vacuum ai a temperature of about 25 °C for a period of about 16 hours improves the quality of the micropanicles. Panicularly, it is bsneilcial to dry the mixture to such an extent that the moisture content of the mixture is less than about 0.02 weight percent. The moisture content of the dr;' mixture may be determmed by any of the techniques icnov.-n m Lhe art, such as, for example, Karl Fisher Method. Drying minimizes any degradation of the PLGA poiymer and substantially reduces the formation of any transesterificaiion product betv.'een PLGA and Compound 1. In yet another facet of this invention there is also provided a pharmaceutical composition for the sustained release of a medicamentous substance comprising microparticles having a size dismbution m the range of from about 10 to 100 um formed of: a) a biodegradable poh.mer. as described hereinabove, in an amount of about SO to 95 percent by v.-ei2ht. whersin the po]>7ner has a glass U"ansition temperature (Tg) of less than about 60 °C: and b) a pharmaceutically active Compound L as described herein, or a phaimaceutically acceptable salt thereof in an amount of about 5 to 20 percent by weight; wherein Compound 1 is substantially dissolved and uniformly dispersed in the PLGA matnx. In a more preferred embodiment of this aspect of the invention, the preferred poiymer is polylactide-co-slvcolide poKmer (PLGA). The preferred weight ratio of Compound I to PLGA is 15;S5 to5:95. .As described herein, the compositions of the present invention may be mixed with a pharmaceutically acceptable earner capable of being administered by the preferred route in order to produce a sustained release of Compound L That is (-^)-a-(2,3-dimethoxyphenylVl- [2-(4-tluorophenyl)ethylj-4-piperidinemeihanol, Formula 1 can be supplied to the paiiem over a period of days or weeks. Preferably the sustained release formulation comprises micropanicies of the present invention and a pharmaceutical I y acceptable carrier for parenteral administration as an aqueous suspension, oil solution, oil suspension or emulsion as described hereinabove. More preferably pharmaceutical compositions of the present invention when administered to a patient releases Compound 1 for a period of at least about 2 weeks, and most preferably for a penod of from about 2 weeks to about one month at a dose sufiicieni to antagonize the effects of serotonin ai the 5HT;,A receptor. Since the mi crop articles of the present invention release (T)-a-(23-dimethoxypheny])-l-[2-(4-f]uorophenyl)ethyl]-4-piperidinemethanol ('Active Ingredient") into the patient for the therapeutic effect, the micropartlcles of the present invention are useful for all indications of use for which the Active Ingredient is usen:!. Some of these indications of use have been descnbed in the patent- issued genencally encompassmg the Active Ingredient (U.S. Patent No. 4,7S3,47I) or sDecifically co\'enng the Active Ingredient (U.S. Patent Nos. 5.134,149; 5,561,144; 5,618.824: 5.700,812; 5,700,813; 5,721,249; and PCT/US97/02597}, all incorporated herein by reference. These references disclose uses of psychosis (including schizophrenia), obsessive compulsive disorder, thrombotic illness, coronary vasospasm, intermittent claudication, anorexia ner\'osa, Ravnaud's phenomenon, fibromyalgia, extra¬pyramidal side effects, anxiety, arrhythmia, depression and bipolar disorder, sleep disorder or drug abuse (e.g.. cocaine, nicotine, etc.). Some of these indications have been disclosed in the patents described above and m U.S. Patent Nos. 4,877,798; and 5,021,428; all incorporated herein by reference. Psychoses as used herein are conditions where the patient experiences a major mental disorder of organic and/or emotiona) origin characterized by derangement of the personality and loss of contact with realitv, often with delusions, hallucinations or illusions. Representative examples of psychotic illnesses which can be treated with the compositions of the present invention include schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder not otherwise specified, and substance-induced psychotic disorder. See Diagnostic and Statistical Manual of Mental Disorders, 4th ed., American Psychiatric Association, incorporated herein by reference. The Acrive Ingredient is currently in clinical trials for the treatment of schizophrenia. The Active Ingredient has the proille of an atypical antipsychotic in numerous preclinical neurochemical, electrophysiological and behavioral models of antipsychotic activity. These effects include reduction of MDMA-induced dopamine release in the striatum, selective effects on AlO vs. A9 neuronal activity after chronic administration, blockade of amphetamine-stimulaied locomotion, and reversal of 5-HTT agonist-induced deficits in prepulse inhibition and latent inhibition. See Journal of Pharmacology and Experimental Tnerapeutics. 266: 68^-69! (1993'). S, VI. Sorensen et al.. "Characterization of the 5-HT; receptor antagonist MDL 100.907 as a putative atypical antipsychotic: behavioral, electrophysiological and neurochemical studies"; Journal Pharmacology and txperimenial Therapeutics. 277: 968-981 (1996). J. K. Kshne. "Preclinical characterization of die potential of the putative atNTjical antipsychotic MDL 100.907 as potent S-HT^A antagonist with a favorable CNS safety profile'; and C!\S Drug Reviews, 3(1): 49-67 (1997), C. J. Schmidt et al. 'MDL 100,907: .A seiecii\'e 5-HT2A receptor antagonist for the treatment of schizophrenia": all of these references are incorporated herein by reference. Patients with obsessive-compulsive disorders (OCD) fail to inhibit or "gaie" intrusive, distressing thought or imiages. Since OCD is characterized by deficient 'cognitive gating" and by aberrant meiabolic activity in circuitrv' linking the orbital conex and straitum, it has been predicted that OCD patients might exhibit deficient PPI (prepulse inhibition)- The Active Ingredient has been found to restore disrupted PPI. See Psychopharmacology 124: 107-116 (1996), R. A. Padich- et al. "5HT modulation of auditory and visual sensorimotor gating: II. Effects of 5HT;A antagonist MDL 100,907 on disruption of sound and light prepulse inhibition produced by 5HT agonists in Wistai rats." The Active Ingredient is also effecuve in the prevention of acute thrombosis, especially those of the coronar>' aneriss. This compound decreases the rate at which platelets assregate as the result of minor alterations in the endothelial lining of the vasculature and therefore prevents the foimaiion of acute pathological thrombi. See U.S. Patent No. 5,561.144 for description. Amxiety. vanian! angina, anorexia ner.'osa, Raynaud's phenomenon and coronary vasospams are used in the marmer deilned in the 27ih edition of Dorland's Illustrated Medical Dictionary, incorporated herein by reference. Fibromyalgia is a chronic disease state wherein the patient suffers from numerous Evmptoms such as. for examnle. widespread generalized musculoskeletal pams, aching, fatigue, morning stifihess and a sleep disturbance which can be characterized as inadequacy of stage 4 sleep. Extra-pyramidal side effects often accompany the administration of neuroleptic aesnts such as haloperidol and chlorpromazine. Panents often experience a parkinsonian-like svTidrorae, wherein they expenence muscular ngidily' and tremors. Others exoerience akathisia and acute dystonia reactions. The .A.ctive Ingredient increases the duration of the action potential of myocardial tissue producing an increase in the refractory penod of that tissue, which under the classification system of Vaughan Williams, exhibits Class III ami-arrhythmic activiry- The pharmaceutical composition of the present invention may be used to treat drus abuse in the patient. See T. ?. Meert, el al.. European Journal of Phcrmacoiogy 1S3; 1924 where SHTi antagonist abolished preference for both alcohol and cocaine in the rodent model of the drug abuse. Other anima! models such as the rodent self-stimulation mode; described in R. .\. Frank, et. a!.. Behavioral Neurosclence 101: 546-559 (1987) may be used to demonstrate the ability of the sustained release compositions of the present invention to treai arug aDuse. The compositions of the present invention are useful in treating patients with depressive disorders and bipolar disorders. In the Diagnostic and Statistical Manual of Mental Disorders (Third £dition-Re\ised) ("DSM-III-R"), incorporated herein by reference, depressive disorders are defmed as major depression, dysthymla and depressive disorder NOS. We also include in this category major depressive episode including chronic type. melancholia, and seasonal partem. Bipolar disorders include bipolar disorder, cyclothj'mia and bipolar disorder NOS. .A, feature of depressive disorders is one or more periods of depression without a history of either manic or h>pomamc episodes. A feature of bipolar disorders is the presence of one or more manic or hypomanic episodes usually accom.panied by one or more major depressive enisodes. A manic or hypomanic episode is a distinct period during which the predominant mood is either elevated, expansive or irritable and there are associated symptoms of the manic syndrome as defined in DSM-III-R, The disturbance is severe enough to cause marked impairment in occupational or social functioning. Major depression has one or more major depressive episodes. A major depressive episode is characterized bv: (1) at least five of the following: depressed mood, loss of interest in pleasure unhedonia), significant weight loss or weight gain when not dieting, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropnate guilt, diminished ability to think or concenu-ate, or recurrent thouahts of death inciudina suicide; (2) it cannot be established that an organic :acior initiated and maintained the disturbance; (3) there are no delusions or hallucinations for as long as tw-o weeks in the abse^ice of prominent mood symptoms; and (4) it is not superimposed on schizophrenia, schizonhrenifomi disoi"der, delusional disorder, or psvchotic disorder NOS, Dysihvmia has a history of a depressed mood more days than not for at least two vears and during the first two years of the disturbance; the condition does not meet the criteria for a major degressive episode. The depressed mood in children and adolescents can be exhibiied as irritability. Also present is at least TWO of the following: poor appetite or overeaiing, insomnia or nvpersomnia, low energy or fatigue, low self-esteem, poor concentration or difficulty making decisions or feeling of hopelessness. These s>Tnpioms are not superim.posed on a chronic psychotic disorder such as schizophrenia or delusional disorder. Also ii canjiot be determined that an organic facior initiated and maintained the disturbance. Tnere are many ways to show diat the composition of the present invention is useful in ireaiing depressive disorders and bipolar disorders such as in animal models- See for example, ".^jiimal Models as Simulations of Depression" by Paul Willner, TiPS 12:131-136 (Apnl 1991): ".Animal Models of Depression; .An overview" by Paul Wilkier. Pharmac. Ther 45:425-455 (1990). both of which are incorporated herein by reference. 0ns such model is the Chronic Mild Stress Model of Depression ("CMS"). CMS uses mild stressors, such as food and water deprivation, cage tilts, changes of cage males, etc. Over a period of weeks of exposure to the mild stressors, the animals gradually reduce their consum.ption of a highly preferred sucrose solution which persists (in untreated animals) for several weeks following the cessation of stress. This decreased sensitivirv to reward (the sucrose solution) reflects anhedonia, a symptom of a Major Depressive Episode (see for example. Behavioral Pharmacol. 5: Suppl.l. p. S6 (1994) where lithium, carbamazepine and ketoconazols were evaluated in CMS; Psvchopharmacologv 93:358-364 (19S7) where a tricyclic antidepressant was evaluated in CMS; Behavioral Pharmacologv: 5:344-350 (1994) where a catechol-0-methyl transferase inhibitor was evaluated in CMS"). The following CMS study was performed using the Active Ingredient of the compositions of the present invention (hereafter "MDL 100,907") in comparison to known anti-depressant compound Im.ipramine. Male Wisiar rats were broueht into the iaboratory two months before the start of the expenmeni at which time they weighed approximately 300 grams. Except as described below, the animais were singly housed, with food and water freely available, and maintained on a 12 hour lighu'daric cycle (lights on at 8AM) at a temperature of about 22 °C. The animals were first trained to consume a 1% sucrose soiution; training consisted of eight 1 hour baseline tests in which sucrose was presented, in the home cage, following 14 hours food and water deprivation; intake was measured by weighing pre-weished bottles containing the sucrose solution at the end of 'he test. Subsequently, sucrose consumption was monitored, under similar conditions, at weekly inten'als throughout the whole experiment. On die basis of their sucrose intakes in the final baseline test, the animals were divided into two matched groups. One group of animals was subjected to a chj-onic mild stress procedure for a period of 9 consecuti\"e weeks. Each week of stress regime consisted of: two penods of food or water deprivation (12 and 14 hour), two periods of 45 degree caas tilt (12 and 14 hour-), two periods of intermittent overnight illumination (lights on and off every 2 hours], two 14 hour penods of soiled cage (200 ml water in sawdust bedding), two 14 hour periods of paired housing, two 14 hour periods of iow intensity stroboscopic iliumination (150 ilashes/min). Stressors were applied continuously throughout the day and night, and scheduled randomly. Control animals were housed in a separate room and had no contract with the stressed animais. They were depnved of food and water for the 14 hours preceding each sucrose test, but otherwise food and water were freely available in the home c&ge. On the basis of their sucrose intake scores following 3 weeks of stress, both stressed and control animals were each divided further into matched subgroups (n=8), and for subsequent five weeks they received daily administrations of vehicle (Iml/kg, mtrapentoneally (ip)) imipramine (10ma'kg, ip) or MDL 100.907 i0,002, 0.02 and 0.2 mg/lcg orally). .MI drug injections were in a volume of Iml/kg body weight. Drugs were administered at lO.'^M and sucrose tests were earned out 24 hours following the last drug treatment. After five weeks, the treatments were terminated and after one week of withdrawal a final sucrose test was carried out. Stress was continued throughout the period of treatment and withdrawal. Results were analyzed by m.ultipie analysis of variance, followed by Fisher's LSD test for post hoc comparisons of means. Chronic m.ild stress caused a gradual decrease in the consumption of 1% sucrose solution, in the ilnai baseline test, sucrose intake was approximately 13 gram in both groups-Followins three weeks of stress (Week 0), intakes remained at 12.4 (±0.4) grams in controls but fell to 7.2 (±0.2) grams in stressed animals (p and stressed animais treated with vehicle, persisted at similar level for the rsmaindsr of the experiment. Imipramine had no significant eiTeci on the 'sucrose intake in control animais [F(1,S4)=0.364; NS]. However, the drug caused a gradual increase of sucrose intake in stressed animals (F(1,S4}=16.776; p MDL 100.907 had no significant effect on the sucrose intake in control animals [Treatment effect: F(:sl6S)=0.S2I: NS Treatment x Weeks interaction: F{15.163=0.499: NS], In stressed animais, fvIDL 100.907 gradually reversed the CMS-inducsd derlcit in sucrose iniake. res'j-ltmg m a significant Treatment effect [F(3 A6S)=22.567; p In stressed animals treated with wo higher doses of MDL 100,907 (0.02 and 0.2 ^g'kg), sucrose intakes were significantly increased from initial scores (Week 0) after r^'o (0.02 mg/lcg) and three (0.2mg'k:g) weeks of treatment (p=0,03 and p=0.04, respectively)-This effect was increased fiirther during next weeks, and at the end of treatment period (Week 5) the amount of sucrose solution drorJ; by these animals was comparable to that of vehicle-treated controls and signiilcantiy higher than that of vehicie-treaied stressed anim.£.:s (0,02 m.g'kg: p At the lowest dose of 0-002mg'l:g., MDL ;00,907 had no significant effect on the sucrose intake ihj-oughout the whole treatment period. In consequence, after live weeks of treatment the sucrose consumotion of stressed animals treated with this dose did not differ from the intakes of the vehicle-treated stressed animjals (p=0.860) and was significantly lower than the intakes of vehicle-treated controls (p Of course, clinical tnals on humans may also be used to show the usefulness of the compositions of the present invention in treating depression such as using the Abbreviated Hamilton Psychiatric Rating Scale for Depression. This compnses a series of 17 categories in which the individual is rated, e.g., for depressed mood, guilt, suicide tendencies, insomnia. anxiety, etc., to reach a score which indicates to the clinician whether or not the patient is suffsnng depression. This invention is further illusiraied by the following examples, which are provided for illustration purposes and in no way jimii lhe scope of the present invention. Examples TGeneral) In the Examples that follow, the following abbreviations are used: PLG.i 50/50 - 50/50 mole ratio of Poly(DL-lac:ide-co-glycolide). DSC - Differenuai Scanning Calonmetry. GPC - Gel Permeation Chromatography. HPLC - High Pressure Liquid Chromatography. IV - Inherent Viscosity. MV - .Melt Viscosir,-. NMR - Kuclear Magnetic Resonance Spectroscopy. SEM - Scanning Electron Microscopy. To - Glass transition lemperamre, Tm - Melting point - the peak melting temperature. Genera! Analytical Techniques used for Lhe Characterization: .A variety of analytical techniques were used to characterize the pharmaceutical compositions of die present invention, which included the following: NMR; NMR analysis was conducted using a 200 MHz spectrometer for the determmation of the loading levels of phaimaceuiicaily active compounds, i.e., the drugs used in the present invention. A 500 MHz spectrometer was used for the quantification of transestenncation levels. Samples were prepared as ! weight percent solutions in CDCI;- DSC: Thermal transitions were measured using a T.A. Instnimenis model 3200 calorimeter. Thermal scans from 0 !o 200°C were prepared in a nitrogen atmosphere using a scan rale of 1 O^C/minute, The DSC curves obtained from the first heating run were taken for analysis. GPC: PoKTner molecular weights were analN^ied using a Vi'aters 20] ins:nirnent equipped ^^■ith refractive index and UV deteciors, A soiution of 2.0 mg'rai of polvmsr in THF was prepared for analysis. HPLC; Drug conieni was measured by HPLC using a Hewlett-Packard 1090 system. The samples were prepared in an aqueous CH;,CN solution. I\": The soludon viscosirs-. inherent v!3cosi!>\ of the polymer samples was measured at 25"C in a concentration of 0,5 weight percent solution of polymer in chloroform, MV: The melt viscosity of PLG.^ wzs e\'a!uaied using a Kayeness capillar.- rheometer, Tne rheomete: chamber temperature was maintained at 125=C and viscosity calculations were based on a die measuring 0,6" length and 0,04" diameter, SEM: Samples for SEM were prepared by freeze ftactunng under liquid nitrogen to reveal the internal structure. SEM micrographs of the fractured samples were taien after coatins with gold at a magniilcation of 5,000 to 10. 000 X. Example 1 This Example 1 demonstrates that excellent dispersions of pharmaceutically active molecule in a oolymer matrix (i,e,, a solid solution) can be obtained by melt mixing m a Kaake System 90 meh mixer. The poN-mer used in this example was PLG.\ 50/50 having an IV of 0." dL'2, The pharmaceutically active molecule used in this example was ComtDound I. (-)-a-(2.3-dimethoxv-phenyl)-l-i2-(4-fluorophenyI)ethyl]-4-pipendinemiethanol (Formula I). The Haake System 90 was equipped with a heated mixing bowl having thj"ee zones of temperature control. Contained within the mixing bow! were two counter-rotating mixing blades w^-hich draw the fed material into the bowl. The speed (RPVI) of the mixing blades was controlled by the operator depending upon the desired level of mixing. The Haake System 90 was also eauipped with a computer control unit which regulated the temperature of the bowl and the iensth of a mixing run. Since moisture gain was a concern in the storage of the materials, all maienals w^-ere stored in a freezer with desiccant. .Ml transponing of materials v,'as done m a desiccator. A:; materials were weiahed in a glove box m a dry. nitrogen atmosphere. Once the matenais were weighed, their respective jars were sealed, placed into 'Jie desiccator and transporled into the Haake System 90 melt mixer. In four separate runs, mixing of PLGA 50/50 with compound of Formula I was carried out as follows. 56 grams of PLGA and 14 grams of Compound ! were weighed in a sieve box in each of these mns and sealed in separate containers. The Haake melt mixer was heated to the desired temperature, and the mixing blades were set to the desired rotation speed. First, about half of the PLGA pol%Tner was fed into the mixing bow] followed by half of the Compound 1, Then the remainder of the ?LG.\ was fed into the mixing bowl followed by the rest of the Compound L rnroughout this feeding step of the materials into the mixing bowl a blanket of nitrogen was maintained over the mixing bow] in order to minimize any degradation of the PLGA polymer due to moismre. Ones ail of the materia! had been fed into the m.ixing bowl, the run timer was started. The run was allowed to go to comDletion. 'when the run was completed, the bowl was immediately disassembled and the material was removed usmg copper knives. Tne removed maiena] was placed in a jar and sealed under nitrosen atmosphere. The run number, ratio of PLG.A/Compound of Formula L time needed to completion of mixing, run temperature, and the speed of the blades (RPM) are tabulated in Table I. .A.lso listed in Table I is a control run wherein only PLGA polymer was used in the mixing run. Table 1 Run Number Materials 1 ime Temoerature RPM Control 100% PLGA 3 min 105°C 60 1 SO/20 PLGA7ComDOUnd ■ of Fomiula I 5 min 105=C 60 -^ 80/20 PLG.VCompound of Formula I 5 min 1I5=C 60 —1 80/20 PLGA7Compound of Formula I 4 min 11SX 60 4 80/20 PLG.A/Compound of Formula 1 5 mm 123=C 60 The meil blended materials from all of the runs as set forth in Table 1 were analyzed by DSC, All of the samples from Run Numbers ; to 4 as set forth in Table 1 exhibited a single T. at around 34 to 37"C, whereas Lhe original T| of the PLG.A polymer was around 47°C, This cleariv suggests that substantial amounts of the compound of Formula I is dissolved in the PLGA polymer matnx. The DSC analysis also showed a small melting peak due to the meiiing of the compound of Fomiuia 1 around 120'^C. Tliis melting peak corresponded to the compound of Formula i, which is not dissolved in PLGA. Amounis of compoLind of Formula I which is not dissolved in PLGA from the Run Numbers 3 to 5 are shown in Table 2. In each of these runs three samples from different areas of the blend was analyzed by DSC. Table 2 BJend Run Number w eight percent crystalline drug (undissolved in PLGA) '^ 2 to 6.5 ■n J 3,5 10 15 A -T L5 to 7 The melt blended samples were analyzed by KPLC to determine the amount of compound of Formula I in the sample. Tne results showed that all of the samples contained 19 weight percent of me compound of Formula I. The samples from run numbers 2 to 4 were further analvzed bv SEM. The SEM micrographs showed uniform distribution of the compound of Formula I in me PLGA poKiner matrix. The NMR analyses of the blended samples indicated the degree of transesterification was below the quantifiable limits. Comparative Example 1 This Comparative Example 1 illustrates that dry mixing of the PLGA polymer with compound of Formula i does not afford a miscible blend of the drug molecule in the polymer miatrix, A 20:S0 weight ratio of compound or Fomiula 1 and PLGA poKoner powders were blended together by hand. The blended powders were then anah-zed by DSC. The first heating cur\'e showed the T^, the melting peak of the compound of Formula 1 at 120'C and the Te of the polvmer at 51 ^C. as expected. The second heating cun'e. after cooling from 130=C. showed two separate glass transitions of the drug and poKmer at 47°C and 23'C, respectively. If the two components had formed a miscible blend, only a single To is expected. Therei"ore. this result indicates that the melted drug is not fully dissolved in the DoivTner melt. example 2 Ttiis example illustrates the preparaiion of phamiaceutical compositions containing the biodegradable polvxQer and a phannaceuticaUy active molecule using a twin screw extruder. The melt extrusion experiments in this example was carried out using an 18 mm twin screw extruder, manufactured by Leistniz, which was operated in.the co-rotating mode. The poi>'mer used in this example was PLGA 50/50 having an Fv' of 0.76 dlVg. The pharmaceutically active molecule used :n this example was compound of Formula I, (^Va-(23-dimethoxypherLyl)-l-[Z-(4-fluQrophenyiiei:hyl]-4-p!peridtnemethanol. Tne raw materials were metered into the extruder using an Accurate SOOO for PLGA and a K-Tron T-20 for the compound of Formula I. PLGA polymer and the compound were dried for 48 hours under vacuum pnor to compounding. The feeders were blanketed wiih nitrogen during processmg to minimize exposure of the raw materials to moisture. The screw was configured to generate a moderate ieve! of mixing without excessive shear. The extradate exited the die onto a conveyor belt and was allowed to slowly cool before being pelletized in a Conair pelietizer. The exrrudates obtained at various melt temperatures and screw speed were analyzed for weight ratio of PLGA and the compound of Formula I by HPLC and NMR, The extrudate samples obtained at these various conditions were also analyzed for weight average molecular weight (M^), inherent viscosity (JV), thermal transitions, Tg and Tm, by DSC and mole percent of transesterification by NMR. The results are summarized in Table 3. Table 3 Sample No. Melt temp Screw i-peea (rpm) Niw (g'mol) Inherent Viscosity Compound I (wt %) HPLC NMR Thermal Tg 1 m Transest, (mol %) !50 158 200 33.000 0.40 25.0 1 22.6 57.3 112.9 5,1 160 135 300 31.S00 0.37 15,0 15.7 36,6 4,7 170 138 400 32.300 0.38 22,0 22,1 36.1 7.4 180 138 200 34.700 0,40 14,0 15,8 41,9 9,5 190 116 300 42.300 0,44 11.0 14.4 40,4 4.7 200 113 200 44,700 0,45 10,0 7,8 43,0 5,5 As shown in Table 3. the Tg of the pharmacemical composition decreases with the increasing weight percent levels of compotmd of Formuia I. This suggests that the compound of Formula I dissolves in the PLGA matrix. This is runner confirmed fay SEM analyses of these samples, which showed a single phase system. The extrudate samples were further micronized in a hammer mill. Trie micronizins was performed under various different process variables, which included the rotor spesd (varying from 4500 to 7200 rpm). screen size, and cryogenic conditions. Particle size anaivsis was conducted either using a Coulter iaser analyzer or optical mdcroscocy combined with image anah^-zer. Various conditions used and ihe results obtained in these milling expenments are summarized in Table 4. Table 4 Sample No. 160 170 180 Screen size (in) 0.020 0.012 0.012 Rotor speed ("rpm) 6000 4500 6000 — - — Njtrosen assist / / y ; Mean panicle size (um) 196.S 223,7 230.9 D75 particle size (|im) 272,6 253.2 300,7 D10 particle size (jim) 55,9 42.3 50.6 The milled panicles were then classified using stainless steel sieves stacked in a rntsch vibratory shaker. Samples of panicles with a size distribution ranging from 45 microns lo 106 microns were separated and tested for the release rate of the compound of Formula 1. tLxample j This example illustrates that lowering of.melt temperature in the extruder lowers the level of transesienficahon. This example funher illustrates that use of compound of Formula I below 20 weight percent in a PLGA matrix results in a composition m which compound of Formula 1 is totally miscible in the PLGA matrix. Example 2 was substantially repeated in Example 3 with the exception that the PLGA 50/50 havms an IV of 0.44 dL/g was used with the following modifications in the extrusion experiment, .^ homogeneous dr>' nowder blend of PLGA and the Compound of Formuia I m the weight ratio of S5::5 (PLGA;Compoiind I) was prepared. Prior io dr>' blending, the Compound ! was micronized in ajst m:iil to a mean panicle size of IS microns. The dry blend of PLG.VCompound 1 was tumbled for about an hour'using a mechanical roller. The dr%' blend was then dried at room temperamre under vacuum for a minimum of about 16 hours. The dried dry blend was metered into the twin screw extruder usmg a K-Tron twin screw feeder. The barrel lem.peratures of the Leisiritz twin screw eximder were adjusted to maintain ihe melt lemperamres of the blend between !04'=C and 116T. Two exuudaie samples of the PLG.VCompound I melt blends were prepared at screw speeds of 200 rpm (Sample No. 110) and 150 rpm (Sample No. 120). The samples were analv'zed for inherent viscosity, weight percent of Compound I, level of transesteriilcation (mole percent), glass transition temperature (T^. °C) and the fraction of Compound L if any. Fne results are summarized in Table 5. Table 5 Samoie Iniierent Weishi Psrcsni Transesier- Glass transition Fraction of No. Viscosin' Comoound I i location tsmo crystalline HPLC NT^IR (mol %) (T„ °C) Compound I. "% 110 0.30 14.9 ! 15.3 1.3 3S.0 0 120 0.31 !5.2 i 14.7 1.5 39.5 0 The level of transesterificaiion was quantified by integration of a new peak appearing at 6.0 ppm in the 'H NMR spectra. As indicated in Table 5, the level of transesterificaiion is significantly reduced to 1.3 to 1.5 mol percent. Also, as shown in Table 5, there is no crystalline Compound 1 in ihe pharmaceuticai composiuon, suggesting that Compound I is lOtally dissolved in the PLGA poh-mer m.atrix. The extrudates of PLGAyCompound 1 compositions were milled using a fluidized bed jet mill. The mill used for this purpose was an Alpine .AJGIOO fluidized bed jet mill Since micronization in the iluidized bed jet miill occurs by panicle-particle contact rather than by impact against a blade, the panicles tend to be more spherical. The optical micrographs confirmed the increased spherical shape of jet milled particles relative to the hammer milled particles. -\ range of conditions was employed to evaluate the effect of classifier speed and grind air pressure on panicle size distribution. Table 6 summanzes the milling conditions and resulting panicle sizes. Particle sizes were measured using a Coulter LS 230 analyzer in a solution of distilled water and TWEEN 80® surfactant. Samples compounded with lower molecular weight PLGA were micromsed lo smaller panicle sizes due to the more briule nature of the polymer. The use ot'the larger diameter nozzles reduced the air pressure in the grmd chamber, effecting a larger panicle size disinbution. Table 6 Test No. 1 2 ■^ J i Material 110 120 120 120 Nozzle diameter, in. 1.9 1,9 5.0 3.0 Classiiler speed, rpm 7000 4500 3000 5000 Grind .A.ir pressure, bar S 8 5 5 Mean parade size, microns ■ ' 20 37 Example 4 Example 3 was substantially repeated in this example except iTiat me PLGA 54-'4-6 polymer used was of slightly higher molecular weight having an IV of 0.66 dL/g and also contained a residual monomer amount cf about 1 mole percent. The pellets of PLGA polymer were milled to a panicle size of less than !25 microns using a hammer mil! before dry blending with the Compound I. Two samples of extmdates cf PLG-VCompound I were formed following the procedures of Example 3 at a screw speed of 200 rpm and melt temperatures of 113^0 (Sample No. 210) and 116'C (Sample No. 2). The samples were analyzed as in Example 3 for inherent viscosity, weight percent of Compound I, level of transestenfication (mOie percent), glass transition temperamre (T=, ~C) and the fraction of Compound I, if any. The results are siim.manzed m Table 7. Table 7 Sample No. Liherent Viscosity ! Weight Percent : Compound I ! HPLC KMR Transester-incation (mol %) Glass transition temi: (T=, °C> Fraction of crystalline Compound I, 210 0.35 : 15.0 15.0 3.7 35.0 0 220 0.38 \ 14,1 i U.9 ■ 2.6 35.0 0 The miilins, of the extrudates were earned out as set fonh m Example 3, Table S summarizes the miliina conditions and resulting particle sizes. Table 8 Tesi No- ! 1 i 2 1 3 Material i 210 ; 210 i 220 Nozzle diameter, in- | 1.9 1.9 3.0 Classifier speed, rpm 3900 5000 5000 Grind Air pressure, bar 6 s 8 Mean particle size, microns 38 ! 32 38- r-xample D This example demonstrates the slow release of the phaimaceutically active compound n-om the pharmaceutical compositions of the present invention. Two samples of PLCVCompound I of Example !, Rim Nos. 2 and 4 were used in this dissoiuiion study. The samples from Example 1, Run Nos. 2 and 4 were milled and sieved to a panicie size distribution of 50 to 150 ,um. The dissolution of so formed micropanicles was conducted in an USP apparatus ?=2 at 37°C using 900 mL of 0.02M phosphate buffer at a pH of about 6-5. 500 mg of m.icropanicles from Example 1, Run Nos. 2 and 4 were used in each of these vessels. Tne amount of Compound I dissolved in the phosphate bufier was measured by UV spectroscopy at 272 nm. Tne percent Compound I released was calculated by dividing the Compound 1 content in solution by the theoretical concentration at 100 percent release based on 20 weight percent loading of Compoimd 1 in the microparticles of Example 1. The dissolution pro tile was followed for 5 days. The results of dissolution studies are summanzed in Table 9. Table 9 ; Percent Compound I Released T;me (hours) Example L Run No. 2 Example 1. Run No. 4 4 2 2 24 115 1 23 48 1 28 i 72 37 40 96 -11 45 120 1 46 i 5,1 Example 6 This e>;ampie 6 illustrates the sjow reisase of ihe pharmaceuticaily a.c:jve compound from the compositions of the present invention at a steady rate over a period of 30 davs. Example 5 was substamiaily repeated in this example except thai the micropanicies fonned from Example 2, Sample Nos. 170 and ISO were used. The results from the dissolution studies are shown in Table 10. Example 7 Tnis example demousirates that '.he release rate of the pharmaceuticaily active compound deoends upon the panicle size of the microparticles formed according to the process of the oresent invention. Exarripls 5 was substamiaily repeated in ;his example except for the following-, the microparticles produced fron Example 4, Sample No. 210 was used in this example. The extrudates from. Example ■^. Sample No, 210 was milled and sieved into particles having a size distribution in the range of 37 to 53 to 74 to 150 microns. These microparticles were then used in the dissolution studies following the procedures as set forth in Example 5, The results from the dissolution studies are shown in Table 11. Aithoiigh ihe inveniion has besn illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the invention encompasses Ihe generic area as hereinbefore disclosed. Various modir~cadons and embodiments can be made without departing from the spirit and scope thereof. We claim: I. A method for the production of a pharmaceutical composition comprising the steps of: a) mixing a suitable amount of pharmaceutically active compound of Formula I; or a pharmaceulically acceptable salt thereof with a suitable amount of biodegradable polymer for a sufficient period of time and at suitable temperature and pressure conditions to form a dry mixture of said pharmaceulically active compound and said polymer, wherein said biodegradable polymer has a glass transition temperature (Tg) of less than 60 °C; b) subjecting said dry mixture to a suitable shear mixing using a single screw extruder under suitable temperature and pressure conditions for a sufficient period of time such that said polymer softens to form a fluidized medium and said pharmaceutically active compound is sufficiently dissolved to form a solid solution having substantially homogeneously dispersed mixture of said pharmaceutically active compound and said polymer, and said homogeneous mixture is formed into a strand; c) pelletizing said strand; and d) pulverizing said pellets to form sustained release microparticles of said biodegradable polymer and said pharmaceutically active compound, wherein said microparticles are having a size distribution in the range of from 10 to 200 \xm such thai said microparticles are suitable for forming an injectable formulation. 2. The method as claimed m claim ! wherein said polymer is selected from the group consisting of polyester, polyamide. polyanhydrides, polyorthoesters. polycarbonates, poly(phosphoesters), poly(phosphazenes). poly(iminocarbonales). and mixtures thereof 3. The method as claimed in claim I wherein said polymer is selected from the group consisting of polylactide, polyglycoMde, polylactide-co-glycolide, polyhydroxybutyrate, polycaprolactone. polytarlarate. and mixtures thereof 4. The method as claimedin claim I wherein said polymer is polylactide-co-glycolide. 5. The method as claimed in claim 4 wherein said polylactide-co-glycolide has a weight average molecular weight of from 20.000 to 100.000. 6. The method as claimed in claim 4 wherein said polylactide-co-glycolide has a weight average molecular weight of from 30,000 to 45.000. 7. The method as Claimedin claim 4 wherein said polylactide-co-glycolide contains 45 to 90 mole percent of lactide and 10 to 55 mole percent of glycolide units respectively. 8. The method as claimerfn claim ! wherein said mixing in step (a) is carried out at ambient temperature. 9. The method as claimed in claim I wherein said mixing in step (a) is carried out al a temperature in the range of from 20 °C to 30 °C. 10. The method as Claimed in claim I wherein said shear mixing in step (b) is carried out al a temperature in the range of from 60 °C to 140 °C. 11. The method as claimedin claim 1 wherein said shear mixing in step (b) is carried out at a temperature in the range of from 80 °C to 120 °C. 12. The method as claimed in claim i wherein said shear mixing in step (b) is carried oul at u temperature in the range of from 95 °C to 115 °C. 13. The method as claimed in claim 1 wherein weight ratio of said pharmaceutically active compound to said polymer is in the range of from 5:95 to 25:75. 14. The method as claimed in claim I wherein weight ratio of said pharmaceutically active compound to said polymer is in the range of from 10:90 to 20:80. 15. The method as claimed in claim I wherein said pharmaceutically active compound is dissolved in said polymer at least to an extent of 50 weight percent based on the total weight of said pharmaceutically active compound present in said composition. 16. The method as claimedin claim I wherein said pharmaceutically active compound is dissolved in said polymer at least to an extent of 90 weight percent based on the total weight of said pharmaceutically active compound present in said composition. 17. The method as claimed indaim 1 wherein said microparlicles are added to a pharmaceutically acceptable solution to form an injectable suspension. 18. The method as claimed in claim 1 7 wherein said suspension when administered to a patient releases said pharmaceutically active molecule for a period of at least 2 weeks at a dose sufficient to antagonize the effects of serotonin at the SHTIA receptor. 19. The method as claimedin claim 17 wherein said suspension when administered to a patient releases said pharmaceutically active molecule for a period of from 2 weeks to one month at a dose sufficient to antagonize the effects of serotonin at the SHT^A receptor. 20. A method for the preparation of a pharmaceutical composition comprising the steps of: a) mixing a pharmaceutically active compound of Formula I Formula I or a pharmaceiilicady acceptable salt thereof and a polylactide-co-ylycolide polymer at a temperature of 25 °C and atmospheric pressure conditions for a sufficient period oftime to form a mixture of said compound and said polymer, wherein weight ratio of said compound to said polymer is in the range of from 10:90 to 15:85, and wherein said polymer has a glass transition temperature (Tg) of less than 60 °C; b) drying said mixture under vacuum at a temperature of 25 °C for a sufficient period oftime such that moisture content of said mixture is less than 0.02 weight percent: c) passing said dry mixture through a heated twin screw extruder having at least one left handed element at a sufficient shear rate and at teinperature of from 95 °C to 115 °C for a sufficient period of lime such that said polymer is allowed to soften to form a Huidized medium and said compound is allowed to substantially dissolve in said polymer to form a solid solution having a substantially homogeneously dispersed mixture of said compound in said polymer matrix and extruding said homogeneous mixture into a strand, wherein said shearing conditions are maintained in such a way that less than one weight percent of said compound reacts with said polymer: d) pelletizing said strand; and e) pulverizing and sieving said pellets to form injectable microparticles having a size distribution in the range of from 10 to 100 |im of the pharmaceutical composllion. A pharmaceutical composition comprising: microparticles having a size distribution in the range of from 10 to ) 00 ^xm formed of a) a biodegradable polymer in an amount of 80 to 95 percerit by weight, wherein said polymer has a glass transition temperature (Tg) of less than 60 °C: and b) a pharmaceutically active compound of Formula I or a pharmaceutically acceptable salt thereof in an amount of 5 to 20 percent by weight; Formula I wherein said compound is a SHTIA receptor antagonist which is substantially dissolved and substantially uniformly dispersed in said polymer. 22. The composition as Claimed in claim 21 wherein said polymer is polylactide-co-glycolide. 23. The composition as claimed jn claim 2i wherein said polylactide-co-glycolide has a weight average molecular weight of from 20,000 to 100,000. 24. The composition as claimed in claim 21 whereiri said polylactide-co-ylycolide has a weight average molecular weight of from 30,000 to 45,000. 25. The composition as claimed in claim 21 wherein said polylactide-co-glycolide contains 45 to 90 mole percent of lactide and 10 to 55 mole percent of glycol ide units respectively. 26. The composition as claimedin claim 2! wherein said pharmaceutically active moiecuie is dissolved in said polymer at least to an extent of 50 weight percent based on the total weight of said pharmaceuticaify active molecule present in said coin posit ion. 27. The composition as claimed'i claim 21 wherein said pharmaceutically active molecule is dissolved in said polymer at least to an extent of 90 weight percent based on the total weight of said pharmaceutically active molecule present in said composition. 28. The composition as claimed in claim 21 wherein said microparticles are added to a pharmaceutically acceplabJe soliiiion to form an injeclabJe suspension. 29. The composition as claimed in claim 28 wherein said suspension when administered to a patient releases said pharmaceutically active molecule for a period of at least 2 weeks at a dose sufficient to antagonize the effects of serotonin at the SHTZA receptor. 30. The pharmaceutical composition as claimed in claim 21 useful for antagonizing the effects of serotonin receptor. 31. The pharmaceutical composition as claimed In claim 30 useful for antagonizing the effects of serotonin receptor for a period from 2 weeks to one month. 32. The pharmaceutical composition as claimed in claim 21 useful for antagonizing the effects of serotonin at the 5HT2A receptor. 33. The pharmaceutical composition as claimed in claim 32 useiul for antagonizing the effects of serotonin at the 5HT2A receptor for a period from 2 weeks to one month. 34. The pharmaceutical composition as claimed in claim 21 useful in inhibiting psychoses. 35. The pharmaceutical composition as claimed in claim 21 useful in the treatment of obsessive compulsive disorder. 36. The pharmaceutical composition as claimed in claim 21 useful in the treatment of drug addiction. 37. The pharmaceutical composition as claimed in claim 21 useful in the treatment of coronary vasospasms. 38. The pharmaceutical composition as claimed in claim 21 useful in the treatment of angina. 39. The pharmaceutical composition as claimed in claim 21 useful in the treatment of thrombotic illness. 40. The pharmaceutical composition as claimed in claim 21 useful in the treatment of sleep disorder.

Documents:

in-pct-2001-0825-che abstract.pdf

in-pct-2001-0825-che claims-duplicate.pdf

in-pct-2001-0825-che claims.pdf

in-pct-2001-0825-che correspondnece-others.pdf

in-pct-2001-0825-che correspondnece-po.pdf

in-pct-2001-0825-che description(complete)-duplicate.pdf

in-pct-2001-0825-che description(complete).pdf

in-pct-2001-0825-che form-1.pdf

in-pct-2001-0825-che form-13.pdf

in-pct-2001-0825-che form-19.pdf

in-pct-2001-0825-che form-3.pdf

in-pct-2001-0825-che form-5.pdf

in-pct-2001-0825-che other.pdf

in-pct-2001-0825-che others.pdf

in-pct-2001-0825-che petition.pdf