Sustained-Release Microsphere Containing Antipsychotic and Process for Producing the Same

Home , Bromperidol, Carpipramine, Mosapramine, Promazine

Eu^^esP— || | MMMMI 1 1 1 1 1 1 1| | || 1 1||| || J European Patent Office « #»0 _ „ © Publication number: 0 669 1 28 A1 Office_„. europeen des brevets

@ Date of filing: 15.11.93

© Priority: 17.11.92 JP 332441/92 Fukuoka 871 (JP) Inventor: OSAJIMA, Tomonorl, YoshltomI @ Date of publication of application: Pharmac. Ind. Ltd. 30.08.95 Bulletin 95/35 Pharmac. Lab., 955, Oaza-kolwal, © Designated Contracting States: Yoshltomlmachl AT BE CH DE DK ES FR GB GR IE IT LI LU MC Chlkujo-gun, NL PT SE Fukuoka 871 (JP) Inventor: MIZUTA, Hlroakl, YoshltomI © Applicant: YOSHITOMI PHARMACEUTICAL Pharmaceutical Ind. Ltd INDUSTRIES, LTD. Pharmac. Lab., 6-9, Hlranomachl 2-chome 955, Oaza-kolwal, Chuo-ku Yoshltomlmachl Osaka-shl Chlkujo-gun, Osaka 541 (JP) Fukuoka 871 (JP)

@ Inventor: KINO, Shlgeml, YoshltomI Pharmaceutical Ind. Ltd. © Representative: Baverstock, Michael George Pharmac. Lab., Douglas et al 955, Oaza-kolwal, BOULT, WADE & TENNANT Yoshltomlmachl 27 Furnlval Street Chlkujo-gun, London, EC4A 1PQ (GB)

SUSTAINED-RELEASE MICROSPHERE CONTAINING ANTIPSYCHOTIC AND PROCESS FOR PRODUCING THE SAME.

00 CM © A sustained-release microsphere produced by the use of the biocompatible polymer serves to enclosing a hydrophobic antipsychotic such as entirely dispense with surgical operations such as o> bromperidol or haloperidol in a base comprising a implantation, facilitates hypodermic and in- CO biocompatible polymer such as polylactic acid or a tramuscular injection just like the case of suspending CO lactic acid/glycolic acid copolymer. It can exhibit a injection, and can dispense with the widrawal of the desired pharmacological effect, where a long-term microsphere. Furthermore, the microsphere can be administration is necessary, by injecting once every administered with little aversion and pain. 1 to 8 weeks instead of every day. As a result, a remarkable improvement can be expected in the compliance during maintenance therapy. In addition,

Rank Xerox (UK) Business Services (3. 10/3.09/3.3.4) 1 EP 0 669 128 A1 2

Technical Field month and production processes thereof. Also, JP- A-55-33414 discloses a so-called in-water drying This invention relates to a sustained release method in which a hydrophobic drug and polylactic microsphere preparation which contains a hydro- acid are dissolved in a common organic solvent, phobic antipsychotic drug and to a production pro- 5 the resulting solution is emulsified by adding a cess thereof. phase separation agent and then the solvent is removed by evaporation to obtain fine particles. Background Art Disclosure of the Invention It is said that, in the drug therapy of mental 70 diseases, maintenance therapy by continuous ad- With the aim of improvement in compliance at ministration is effective in preventing recidivation of the time of maintenance therapy with hydrophobic symptoms whereby it has come to be possible to antipsychotic drugs, the present inventors have guide patients in their daily life. However, since the conducted intensive studies on the development of current maintenance therapy with antipsychotic 75 a sustained release pharmaceutical preparation in drugs is carried out by orally administering tablets which a drug itself is used as an active ingredient or fine granules once a day or dividing the daily without modification. As the result, it was found that dose into several doses per day, decreased com- a drug can be released at an almost constant rate pliance during the maintenance therapy becomes a extending over 1 week or more by including a cause of recidivation of symptoms or re-hospitaliza- 20 hydrophobic antipsychotic drug into a base com- tion. Consequently, it has a drawback in that cer- prising a biodegradable high molecular weight tain means must be employed to improve compli- polymer having in vivo histocompatibility to make ance after rehabilitation or during outpatient main- a sustained release microsphere preparation and tenance therapy. administrating it by subcutaneous or intramuscular In order to resolve this problem, long acting 25 injection, hence resulting in the accomplishment of injections containing drugs in the form of decanoic the present invention. acid ester or enanthic acid ester have been used. Accordingly, the present invention relates to (1) For example, decanoic acid esters of haloperidol an antipsychotic drug-containing sustained release and bromperidol are disclosed in JP-A-56-8318 microsphere preparation which is produced by in- (the term "JP-A" as used herein means "unex- 30 eluding a hydrophobic antipsychotic drug into a amined published Japanese Patent Application"), base comprising a high molecular weight polymer and decanoic acid ester or enanthic acid ester of having in vivo histocompatibility and (2) a process fluphenazine is also known and used in the thera- for producing an antipsychotic drug-containing sus- peutic field. tained release microsphere preparation which com- However, these prior long acting injections 35 prises making an oil layer comprising a solution of have drawbacks in that their administration route is a high molecular weight polymer having in vivo limited to intramuscular injection, resistance at the histocompatibility containing a hydrophobic anti- time of administration is large because they are oil psychotic drug, adding the oil layer to a water injections while the dispersibility of oil in muscular layer, subjecting the resulting mixture to an emul- is small, and their administration gives patients 40 sification treatment to obtain an O/W type emulsion severe pain. In addition, there is a possibility that and subsequently removing the solvent in the oil their effects may vary depending on individuals layer by in-water drying method. and ages because, though the ester bodies of The hydrophobic antipsychotic drug to be ap- active ingredients show a sustained release effect plied to the present invention is selected from in the living body by gradually releasing their ac- 45 haloperidol, bromperidol, fluphenazine, chlor- tive bodies due to the influence of esterase, re- promazine, sulpiride, carpipramine, clocapramine, lease of drugs in the living body generally depends mosapramine, risperidone, clozapine, oranzapine on their transition rate from the administered part and sertindole and pharmaceutically acceptable into lymphoid system and also on the enzyme acid addition salts thereof, preferably from the activity. Accordingly, it has been demanded to de- 50 group consisting of haloperidol, bromperidol, velop new long acting injections in which original fluphenazine maleate, chlorpromazine, chlor- drugs themselves are used. promazine hibenzoate, sulpiride, carpipramine hy- On the other hand, each of JP-A-62-201816, drochloride, carpipramine maleate, clocapramine JP-B-1 -57087 and JP-B-2-124814 (the term "JP-B" hydrochloride, mosapramine hydrochloride, as used herein means "examined Japanese Patent 55 risperidone, clozapine, oranzapine and sertindole, Publication") discloses sustained release micro- of which haloperidol or bromperidol is particularly capsules which make possible to administrate wa- preferred. ter soluble drugs at an interval of once a week or a

2 3 EP 0 669 128 A1 4

The base that constitutes the sustained release Examples of the solvent include those which microspheres of the present invention should have have a boiling point of about 120°C or lower, do such a function that its concentration in blood plas- not show miscibility with water and can dissolve ma can be maintained at a constant level by a high molecular weight polymers, such as alkane single administration whereby its effects can be 5 halides (dichloromethane, chloroform, chloroethane, obtained stably over a prolonged period of time. A dichloroethane, trichloroethane and the like), ethyl biodegradable high molecular weight polymer hav- acetate, ethyl ether, cyclohexane, benzene, n-hex- ing in vivo histocompatibility is used as a base ane, toluene and the like, which may be used alone having such a function. The sustained release or as a mixture of two or more. microspheres of the present invention are con- io In the production process of the microsphere structed in the manner that the hydrophobic an- preparation, a hydrophobic antipsychotic drug is tipsychotic drug is included therein. Examples of dissolved or dispersed in a solution prepared by such a high molecular weight polymer having in dissolving a in vivo histocompatible high molecular vivo histocompatibility include polymers of fatty weight polymer in a solvent to give an oil layer. acid esters or copolymers thereof, polyacrylic es- is The thus obtained oil layer is added to a water ters, polyhydroxybutyric acids, polyalkylene ox- layer and subjected to an emulsification treatment alates, polyorthoester, polycarbonate and to prepare an O/W type emulsion. Thereafter, the polyamino acids, which may be used alone or as a microsphere preparation is obtained by removing mixture of two or more. Illustrative examples of the the solvent in the oil layer by means of in-water polymers of fatty acid esters or copolymers thereof 20 drying method. include polylactic acid, polyglycolic acid, polycitric When the oil layer is prepared by dispersing a acid, polymalic acid and poly(lactic-co-glycolic)- drug, the drug may be used after making it into acid, which may also be used alone or as a mixture fine particles. By the use of microcrystals, the of two or more. Another useful examples include surface of microspheres becomes smooth and the poly-a-cyanoacrylic ester, poly-/3-hydroxybutyric 25 drug release becomes close to 0 order. Such a acid, polytrimethylene oxalate, polyorthoester, releasing capacity close to 0 order seems to be polyorthocarbonate, polyethylene carbonate, poly accomplished due to decrease in the initial releas- 7-benzyl-L-glutamic acid and poly L-alanine, which ing rate resulting from the increased interaction may be used alone or as a mixture of two or more. between the afore-mentioned high molecular Of these polymers, polylactic acid, polyglycolic 30 weight polymer and the drug effected by the in- acid or poly(lactic-co-glycolic)acid may be used creased contacting area and due to increase in the preferably. releasing rate in the late stage effected by the These in vivo histocompatible high molecular increased surface area of the drug. The finely weight polymers to be used in the present inven- ground drug may have a particle size of preferably tion may have an average molecular weight of 35 within a range of 10 urn or less, more preferably preferably from about 2,000 to about 80,000, more within a range of 5 urn or less (about 0.1 to about preferably from about 5,000 to about 20,000. When 5 urn, preferably 0.5 to 5 urn). Fine particles of the poly(lactic-co-glycolic)acid is used as the in vivo drug can be obtained by usually used means. histocompatible high molecular weight polymer, Examples of such means include jet mill, ball mill, compositional ratio of lactic acid and glycolic acid 40 vibrating mill, hammer mill, colloid mill and the like. may be in the range of from about 100:0 to 50:50, In preparing microspheres of the present inven- preferably at 75:25 and 50:50. tion, it is preferable to add an emulsifying agent to Although the amount of the high molecular the water layer, and examples thereof include weight polymer(s) is decided by the drug-releasing those which are able to form a stable O/W type rate, period and the like, and may be controlled 45 emulsion, such as an anionic surfactant (sodium within in a range of from about 0.2 to about 10,000 oleate, sodium stearate, sodium lauryl sulfate or times by weight of the drug, it is preferred that the the like), a nonionic surfactant (a polyoxyethylene high molecular weight polymer is used as the base sorbitan fatty acid ester, a polyoxyethylene castor of the microsphere preparation of the present in- oil derivative or the like), polyvinyl pyrrolidone, vention in an amount of from 1 to 1,000 times by 50 polyvinyl alcohol, carboxymethylcellulose, lecithin, weight of the drug. gelatin and the like, which may be used alone or as A solution containing the above high molecular a mixture of two or more. These agents may be weight polymer (oil layer) is prepared by dissolving used in a concentration of from about 0.01% to the high molecular weight polymer in a solvent. about 20%, more preferably from about 0.05% to The concentration of the high molecular weight 55 about 10%. polymer in the oil layer may be in the range of Removal of the solvent from the oil layer is preferably from about 0.5 to about 90% (w/w), effected by a conventionally used means (in-water more preferably from about 2 to about 60% (w/w). drying method: Tamotsu Kondo,

3 5 EP 0 669 128 A1 6

"Maikurokapuseru-sono kinou to ouyou (Microcaps- adult per administration. Since the pharmaceutical ules, Their Functions And Applications)", p.78, Jap- preparation of the present invention releases its anese Standards Association, March 20, 1991). In active ingredient depending on the hydrolysis of this method, a solvent is removed by gradually the high molecular weight polymer by water, it reducing pressure while stirring using a propeller 5 shows less individual difference and can be admin- mixer, a magnetic stirrer or the like or by control- istered by not only intramuscular injection but also ling the degree of vacuum using a rotary evapora- subcutaneous injection. tor or the like. The thus obtained microspheres are collected BRIEF DESCRIPTION OF THE DRAWINGS by centrifugation or filtration, washed several times 10 with distilled water to remove free drug, the emul- Fig. 1 is a graph showing remaining amount of sifying agent and the like adhered to the surface of bromperidol in the administered area of rat after the microspheres and then treated under a reduced intramuscular injection of each of the microsphere pressure, if necessary, with heating, to perfect re- preparations obtained in Examples 1 to 3. moval of water and solvent in the microspheres. is Fig. 2 is a graph showing periodical changes in If necessary, the thus obtained microspheres the drug concentration in blood plasma of rat after are gently ground and screened to remove over- intramuscular injection of the haloperidol-containing sized microspheres. When used as suspensions for microsphere preparation obtained in Example 4. injection use, the particle size of the microspheres Fig. 3 is a graph showing results of an in vitro may be a range which can satisfy their disper- 20 drug release test of the microsphere preparation sibility and needle-passing property, for example, obtained in Test Example 3. in the range of from about 0.5 to about 400 urn, more preferably from about 0.5 to about 200 urn, BEST MODE OF CARRYING OUT THE INVEN- as an average particle size. TION The microspheres of the present invention can 25 be made into sustained release injections by pre- The following Examples and Test Examples paring an aqueous suspension together with a dis- are provided to illustrate the present invention fur- persing agent (polysorbate 80, sodium carbox- ther in detail. ymethylcellulose, sodium alginate or the like), a preservative (methylparaben, propylparaben, ben- 30 EXAMPLE 1 zyl alcohol, chlorobutanol or the like) and an isotonic agent (sodium chloride, glycerol, sorbitol, Poly(lactic-co-glycolic)acid (50:50) (molecular glucose or the like) or by preparing an oily suspen- weight: about 20,000) was dissolved in 3 ml of sion by dispersing the microspheres in a plant oil dichloromethane to prepare a 40% solution. In this such as olive oil, sesame oil, peanut oil, cotton oil, 35 was dissolved 190 mg of bromperidol (average corn oil or the like or in propylene glycol or the particle size: 13.0 urn) to prepare a mixed solution. like. In this instance, in order to lessen resisting This was poured into 1,000 ml of 0.5% polyvinyl feeling at the time of injection, the sustained re- alcohol (Gosenol EG-40, manufactured by The Nip- lease microsphere preparation of the present inven- pon Synthetic Chemical Industry) and dispersed tion may be used preferably in the form of aqueous 40 using a homogenizer (manufactured by Tokushu suspension. Kika Kogyo) to prepare an O/W type emulsion. In addition, sustained release injections of Thereafter, the O/W type emulsion was gently microspheres of the present invention can be made stirred using a conventional mixer to effect evap- into more stable sustained release injections by oration of dichloromethane and solidification of further mixing the above composition with a filler 45 microspheres which were subsequently collected (mannitol, sorbitol, lactose, glucose or the like), by centrifugation, simultaneously washing with dis- dispersing the mixture and then subjecting the re- tilled water. The thus recovered microspheres were sulting dispersion to freeze drying or spray drying made into a powder preparation by freeze drying. to obtain a solid preparation which is used by adding distilled water for injection use or an appro- 50 EXAMPLE 2 priate dispersion medium at the time of injection. Dose of a hydrophobic antipsychotic drug as c//-Polylactic acid (molecular weight: about the active ingredient of the sustained release 10,000) was dissolved in 3 ml of dichloromethane microsphere preparation of the present invention to prepare a 20% solution. In this was suspended can be decided depending on each disease to be 55 190 mg of bromperidol (average particle size: 2.5 treated, symptoms and age of each patient and the linn) to obtain a mixed solution. Thereafter, a brom- like, and it may be in the range of generally from 5 peridol-containing microsphere preparation was ob- to 5,000 mg, preferably from 10 to 2,000 mg, per tained in the same manner as described in Exam-

4 7 EP 0 669 128 A1 8 pie 1. cally collected from ophthalmic veins to measure concentration of the drug in blood plasma. As the EXAMPLE 3 result, sustained concentration of haloperidol in blood plasma was confirmed as shown in Fig. 2. c//-Polylactic acid (molecular weight: about 5 20,000) was dissolved in 3 ml of dichloromethane TEST EXAMPLE 3 to prepare a 20% solution. In this was dissolved 85 mg of bromperidol (average particle size, 13.0 urn) A 25 mg portion of each of the bromperidol- to obtain a mixed solution. Thereafter, a brom- containing microsphere preparations obtained from peridol-containing microsphere preparation was ob- io the following formulations A and B was dispersed tained in the same manner as described in Inven- in 20 ml of physiological saline and shaken at tive Example 1 . 37 °C and at 80 revolutions per minute using a constant temperature shaker (manufactured by EXAMPLE 4 Yamato Kagaku). Thereafter, samples were periodi- 15 cally collected to calculate drug releasing ratio by c//-Polylactic acid (molecular weight, about ultraviolet absorption photometry (245 nm). As 10,000) was dissolved in 4 ml of dichloromethane shown in Fig. 3, it was confirmed that the micro- to prepare a 30% solution. In this was suspended sphere preparation of formulation A which com- 380 mg of haloperidol (average particle size: 3.0 prises finely ground bromperidol can release the linn) to obtain a mixed solution. Thereafter, a 20 drug at a rate of almost 0 order. haloperidol-containing microsphere preparation was obtained in the same manner as described in Ex- FORMULATION A ample 1 . c//-Polylactic acid (molecular weight: about EXAMPLE 5 25 5,000) was dissolved in 3 ml of dichloromethane to prepare a 12% solution. In this was suspended 190 A microsphere preparation is obtained in the mg of bromperidol (average particle size: 2.5 urn) same manner as described in the above Examples to obtain a mixed solution. Thereafter, a brom- using fluphenazine maleate, chlorpromazine, chlor- peridol-containing microsphere preparation was ob- promazine hibenzoate, sulpiride, carpipramine hy- 30 tained in the same manner as described in Exam- drochloride, carpipramine maleate, clocapramine ple 1. hydrochloride, mosapramine hydrochloride, risperidone, clozapine, oranzapine or sertindole as FORMULATION B the drug. 35 Bromperidol with no grinding (average particle TEST EXAMPLE 1 size: 13.0 urn) was used in stead of the bromperidol of Formulation A having an average particle Each of the bromperidol-containing micro- size of 2.5 urn. sphere preparations obtained in Examples 1 to 3 was suspended in physiological saline and admin- 40 INDUSTRIAL APPLICABILITY istered into the femoral muscle of male SD rats (15 weeks of age) in a dose of 12.5 mg as brom- According to the hydrophobic antipsychotic peridol. After a predetermined period of time, drug-containing sustained release microsphere microspheres remained in the administered area preparation of the present invention, considerable were periodically recovered to measure remaining 45 improvement in compliance in maintenance ther- amount of bromperidol. As the result, release of the apy of mentally deranged persons can be expected drug at an almost constant rate was confirmed as because of the following features of the preparation shown in Fig. 1 . of the present invention. (1) When a long-term administration is required, TEST EXAMPLE 2 50 desired pharmacological effects can be obtained continuously by one injection per 1 to 8 weeks, The haloperidol-containing microsphere prep- in stead of daily administration. aration obtained in Example 4 was suspended in a (2) Since a biodegradable high molecular weight 0.5% sodium carboxymethylcellulose solution polymer is used, surgical operations such as isotonized with mannitol and administered into the 55 embedding and the like are not required at all, femoral muscle of male SD rats (13 weeks of age) and subcutaneous and intramuscular administra- in a dose of 25 mg as haloperidol. After a predeter- tions can be made easily absolutely in the same mined period of time, blood samples were periodi- manner as the case of conventional suspension

5 9 EP 0 669 128 A1 10

injections so that recovery of the material is not co-glycolic)acid. required. (3) Pain and resistance at the time of administra- 7. The antipsychotic drug-containing sustained tion are small. release microsphere preparation according to 5 any one of claims 1 to 6, wherein said high Claims molecular weight polymer having in vivo histocompatibility is one or more compounds 1. An antipsychotic drug-containing sustained re- selected from polylactic acid, polyglycolic acid, lease microsphere preparation which is pro- polycitric acid, polymalic acid, poly(lactic-co- duced by including a hydrophobic anti- io glycolic)acid, poly-a-cyanoacrylic ester, poly- psychotic drug into a base comprising a high /3-hydroxybutyric acid, polytrimethylene ox- molecular weight polymer having in vivo alate, polyorthoester, polyorthocarbonate, poly- histocompatibility. ethylene carbonate, poly-7-benzyl-L-glutamic acid and poly-L-alanine. 2. The antipsychotic drug-containing sustained 15 release microsphere preparation according to 8. The antipsychotic drug-containing sustained claim 1 wherein said hydrophobic anti- release microsphere preparation according to psychotic drug is selected from haloperidol, any one of claims 1 to 7, wherein said hy- bromperidol, fluphenazine, chlorpromazine, sul- drophobic antipsychotic drug is in the form of piride, carpipramine, clocapramine, 20 microcrystals having an average particle size mosapramine, risperidone, clozapine, oran- of 5 urn or less. zapine and sertindole and pharmaceutically acceptable acid addition salts thereof. 9. The antipsychotic drug-containing sustained release microsphere preparation according to 3. The antipsychotic drug-containing sustained 25 any one of claims 1 to 8, wherein said an- release microsphere preparation according to tipsychotic drug-containing sustained release claim 1 or 2, wherein said hydrophobic an- microsphere preparation is an aqueous sus- tipsychotic drug is selected from haloperidol, pension. bromperidol, fluphenazine maleate, chlorpromazine, chlorpromazine hibenzoate, sul- 30 10. A process for producing an antipsychotic drug- piride, carpipramine hydrochloride, car- containing sustained release microsphere pipramine maleate, clocapramine hydrochlo- preparation which comprises making an oil lay- ride, mosapramine hydrochloride, risperidone, er comprising a high molecular weight polymer clozapine, oranzapine and sertindole. having in vivo histocompatibility containing a 35 hydrophobic antipsychotic drug, adding the oil 4. The antipsychotic drug-containing sustained layer to a water layer, subjecting the resulting release microsphere preparation according to mixture to an emulsification treatment to obtain claim 1, wherein said hydrophobic anti- an O/W type emulsion and subsequently re- psychotic drug is selected from haloperidol moving the solvent in the oil layer by in-water and bromperidol. 40 drying method.

5. The antipsychotic drug-containing sustained 11. The process for producing an antipsychotic release microsphere preparation according to drug-containing sustained release microsphere claim 1, wherein said high molecular weight preparation according to claim 10, wherein polymer having in vivo histocompatibility is 45 said hydrophobic antipsychotic drug is select- one or more compounds selected from poly- ed from haloperidol, bromperidol, fluphenazine, mers of fatty acid esters or copolymers there- chlorpromazine, sulpiride, carpipramine, of, polyacrylic esters, polyhydroxybutyric ac- clocapramine, mosapramine, risperidone, ids, polyalkylene oxalates, polyorthoester, clozapine, oranzapine and sertindole and phar- polycarbonate and polyamino acids. 50 maceutically acceptable acid addition salts thereof. 6. The antipsychotic drug-containing sustained release microsphere preparation according to 12. The process for producing an antipsychotic any one of claims 1 to 5, wherein said high drug-containing sustained release microsphere molecular weight polymer having in vivo 55 preparation according to claim 10 or 11, histocompatibility is one or more compounds wherein said hydrophobic antipsychotic drug is selected from polylactic acid, polyglycolic acid, selected from haloperidol, bromperidol, polycitric acid, polymalic acid and poly(lactic- fluphenazine maleate, chlorpromazine, chlor-

6 11 EP 0 669 128 A1 12

promazine hibenzoate, sulpiride, carpipramine histocompatibility is a solvent which has a boil- hydrochloride, carpipramine maleate, ing point of 120° C or less and does not admix clocapramine hydrochloride, mosapramine hy- with water. drochloride, risperidone, clozapine, oranzapine and sertindole. 5 19. The process for producing an antipsychotic drug-containing sustained release microsphere 13. The process for producing an antipsychotic preparation according to any one of claims 10 drug-containing sustained release microsphere to 18, wherein one or more compounds se- preparation according to claim 10, wherein lected from anionic surfactants, nonionic sur- said hydrophobic antipsychotic drug is select- 10 factants, polyvinyl pyrrolidone, polyvinyl alco- ed from haloperidol and bromperidol. hol, carboxymethylcellulose, lecithin and gelatin are added as emulsifying agents to said 14. The process for producing an antipsychotic water layer. drug-containing sustained release microsphere preparation according to claim 10, wherein 15 20. The process for producing an antipsychotic said high molecular weight polymer having in drug-containing sustained release microsphere vivo histocompatibility is one or more com- preparation according to any one of claims 10 pounds selected from polymers of fatty acid to 19, wherein said antipsychotic drug-contain- esters or copolymers thereof, polyacrylic es- ing sustained release microsphere preparation ters, polyhydroxybutyric acids, polyalkylene 20 is an aqueous suspension. oxalates, polyorthoester, polycarbonate and polyamino acids.

15. The process for producing an antipsychotic drug-containing sustained release microsphere 25 preparation according to any one of claims 10 to 14, wherein said high molecular weight polymer having in vivo histocompatibility is one or more compounds selected from polylactic acid, polyglycolic acid, polycitric acid, poly- 30 malic acid and poly(lactic-co-glycolic)acid.

16. The process for producing an antipsychotic drug-containing sustained release microsphere preparation according to any one of claims 10 35 to 15, wherein said high molecular weight polymer having in vivo histocompatibility is one or more compounds selected from polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly(lactic-co-glycolic)acid, poly-a- 40 cyanoacrylic ester, poly-/3-hydroxybutyric acid, polytrimethylene oxalate, polyorthoester, polyorthocarbonate, polyethylene carbonate, poly-7-benzyl-L-glutamic acid and poly-L-alanine.

17. The process for producing an antipsychotic drug-containing sustained release microsphere preparation according to any one of claims 10 to 16, wherein said hydrophobic antipsychotic 50 drug is in the form of microcrystals having an average particle size of 5 urn or less.

18. The process for producing an antipsychotic drug-containing sustained release microsphere 55 preparation according to any one of claims 10 to 17, wherein a solvent of said solution of high molecular weight polymer having in vivo

7 EP 0 669 128 A1

Fig. 1

Time (day)

EP 0 669 128 A1

Fig. 3

100 }■

0 5 10 15 20 25 30 35 40

Time (day)

10 INTERNATIONAL SEARCH REPORT International application No. PCT/JP93/G1673 A. CLASSIFICATION OF SUBJECT MATTER Int. CI5 A61K9/16, A61K31/445 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) Int. CI5 A61K9/14-9/16 , 9/20-26, 9/50-9/52, A61K47/34, A61K31/445, 31/40 Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)

C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. Y JP, A, 63-122620 (Sanraku Inc. and another) , 1-20 May 26, 1988 (26. 05. 88), Claim; lines 6 to 13, upper right column, lines 10 to 12, lower right column, page 2, lines 8 to 15, upper right column, page 4 & EP, A, 269921 & US, A, 4994281

A JP, A, 56-8318 (Junssen Pharmaceutica N.V.), 1-9 January 28, 1981 (28. 01. 81) & DE, A, 3024305 & GB , A, 2054371

A JP, A, 59-130211 (Ralurre Clord) , 1-9 July 26, 1984 (26. 07. 84) & EP, A, 107557 & GB, A, 2129301

| [ Further documents are listed in the continuation of Box C. | | See patent family annex. * "T* lalerdocumentpublishedaftertbcinttrnadoiiainiiiigialeorpriority Special categories of cited documents: but cited understand Aj .I documentj definingj r • thei.. general state of,v the an which is not considereda a dale and not in conflict with the application to to be of parncular relevance ^ principler r or theory/ underlying• the invention "E" earlier document but after the international dale "X" document of particular relevance; the claimed invention cannot be published on or filing considered novel or cannot be considered to involve an inventive "L" document which may throw doubts on priority claimfs) or which.. L is. wbcn the document is taken alone cited to establish the publication dale of another citation or other step special reason (as specified) "Y" document of particular relevance; the claimed invention cannot be «nsidered to involve an inventive step when the document is "O" document referring to an oral disclosure, use, exhibition or other combined with one or more other such documents, such combination means obvious to a skilled in the art "P" document published prior to the international filing date but later than being person the priori ry date claimed "Sc " document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report January 31, 1994 (31. 01. 94) February 22, 1994 (22. 02. 94) Name and mailing address of the ISA/ Authorized officer Japanese Patent Office Facsimile No. Telephone No. Fnrm PCT/ISA^IO Orrond sheets Oulv 10021