USOO5871778A United States Patent (19) 11 Patent Number: 5,871,778 Kino et al. (45) Date of Patent: Feb. 16, 1999 54 SUSTAINED RELEASE MICROSPHERE 58 Field of Search ..................................... 424/426, 450, PREPARATION CONTAINING 424/497, 489 ANTIPSYCHOTC DRUG 56) References Cited 75 Inventors: Shigemi Kino; Tomonori Osajima; Hiroaki Mizuta, all of Fukuoka, Japan U.S. PATENT DOCUMENTS 4,994,281 2/1991 Muranishi et al. ..................... 424/497 73 Assignee: Yoshitomi Pharmaceutical Industries, Ltd., Osaka, Japan Primary Examiner Thurman K. Page ASSistant Examiner Sharon Howard Attorney, Agent, or Firm Sughrue, Mion, Zinn, Macpeak 21 Appl. No.: 812,544 & Seas, PLLC 22 Filed: Mar. 7, 1997 57 ABSTRACT Related U.S. Application Data A Sustained release microSphere preparation which is pro 62 Division of Ser. No. 443,021, filed as PCT/JP93/01673 N duced by including a hydrophobic antipsychotic drug Such 1. g EN's 656.299 eaS OW. as bromperidol, haloperidol or the like into a base composed 2 2 u stus i v w8 - 2 -/- /24 - - - of a high molecular weight polymer having in Vivo histo 30 Foreign Application Priority Data compatibility Such as polylactic acid, poly(lactic-co Nov. 17, 1992 JP Japan 4-332441 glycolic)acid or the like, and a process for the production • - 1 a Pall . thereof. (51) Int. Cl." ....................................................... A61K 9/50 52 U.S. Cl. ........................... 424/489: 424/426; 424/497 8 Claims, 4 Drawing Sheets 2O O EXAMPLE O A EXAMPLE 2 EXAMPLE 3 OO SS SO 8O U 7O 6O CD Z 5O 2. 4O 3O O1 2 O O O 5 2O 25 3O TIME (DAY) U.S. Patent Feb. 16, 1999 Sheet 1 of 4 5,871,778 2O O EXAMPLE A EXAMPLE 2 EXAMPLE 3 O 5 O 5 2O 25 3O TIME (DAY) FG. U.S. Patent Feb. 16, 1999 Sheet 2 of 4 5,871,778 Loxof -- EXAMPLE 4 Ó 5 lo 15 20 25 3o TME (DAY) FG.2 U.S. Patent Feb. 16, 1999 Sheet 3 of 4 5,871,778 OO -O- FORMULATION A -O- FORMULATION B s 2 (b. 5 to 15 20 25 3o 35 4o TIME (DAY) FG3 U.S. Patent Feb. 16, 1999 Sheet 4 of 4 5,871,778 -o- FORMULATION C -O FORMULATON D 5 O 3O g O O 2O 3O 4O TIME (DAY) FG4 5,871,778 1 2 SUSTAINED RELEASE MICROSPHERE containing a physiologically active Substance (haloperidol, PREPARATION CONTAINING chlorpromazine, etc.) and having an average particle size of ANTIPSYCHOTC DRUG about 0.1 to 10 um. This is a divisional of application Ser. No. 08/443,021 SUMMARY OF THE INVENTION filed May 17, 1995, now U.S. Pat. No. 5,656,299, which is With the aim of improvement in compliance at the time of a continuation-in-part application of PCT/JP93/01673, filed maintenance therapy with hydrophobic antipsychotic drugs, Nov. 15, 1993. the present inventors have conducted intensive Studies on the development of a Sustained release pharmaceutical TECHNICAL FIELD preparation in which a drug itself is used as an active This invention relates to a Sustained release microSphere ingredient without modification. AS the result, it was found preparation which contains a hydrophobic antipsychotic that a drug can be released at an almost constant rate drug and to a proceSS for producing the preparation. extending over 1 week or more by including a hydrophobic antipsychotic drug in the form of microcrystals having an BACKGROUND ART 15 average particle size of 10 um or less, desirably 5 um or less, It is Said that, in the drug therapy of mental diseases, into a base comprising a biodegradable high molecular maintenance therapy by continuous administration is effec weight polymer having in Vivo histocompatibility to make a tive in preventing recidivism of Symptoms, whereby it is Sustained release microSphere preparation and administrat possible to guide patients in their daily lives. However, Since ing it by Subcutaneous or intramuscular injection, hence the current maintenance therapy with antipsychotic drugs is resulting in the accomplishment of the present invention. carried out by orally administering tablets or fine granules Accordingly, the present invention relates to (1) an antip once a day or dividing the daily dose into Several doses per Sychotic drug-containing Sustained release microSphere day, decreased patient compliance during the maintenance preparation which is produced by including a hydrophobic the rapy cause S recidivism of Symptoms or antipsychotic drug in the form of microcrystals of the re-hospitalization. Consequently, current maintenance 25 above-noted size into a base comprising a high molecular therapy has a drawback in that certain means must be weight polymer having in Vivo histocompatibility and (2) a employed to improve compliance after rehabilitation or process for producing an antipsychotic drug-containing Sus during outpatient maintenance therapy. tained release microSphere preparation which comprises In order to resolve this problem, long acting injections making an oil layer comprising a Solution of a high molecu containing drugs in the form of decanoic acid ester or lar weight polymer having in Vivo histocompatibility con enanthic acid ester have been used. For example, decanoic taining Said hydrophobic antipsychotic drug microcrystals, acid esters of haloperidol and bromperidol are disclosed in adding the oil layer to a water layer, Subjecting the resulting JP-A-56-8318 (the term “JP-A” as used herein means “unex mixture to an emulsification treatment to obtain an O/W type amined published Japanese Patent Application”), and emulsion and Subsequently removing the Solvent in the oil decanoic acid ester or enanthic acid ester of fluphenazine is 35 layer by the in-water drying method. also known and used in this therapeutic field. In another and preferred embodiment of the present However, these prior art long acting injections have invention, the resulting microSpheres, following any neces drawbacks in that their administration route is limited to Sary Size Screening, have an average particle size of about intramuscular injection, resistance at the time of adminis 40 0.5 to 400 um, more preferably about 0.5 to 200 um, most tration is large because they are oil injections while the preferably about 15 to 50 lum. dispersibility of oil in muscular tissue is low, and their administration gives patients Severe pain. In addition, there DETAILED DESCRIPTION OF THE is a possibility that their effects may vary depending on INVENTION individuals and their ages because, though the esters of 45 The hydrophobic antipsychotic drug to be applied to the active ingredients show a Sustained release effect in the present invention is Selected from haloperidol, bromperidol, living body by gradually releasing their active moieties due flu phenazine, chlorpromazine, Sulpiride, carpipramine, to the influence of esterase, release of drugs in the living clocapramine, mosapramine, risperidone, clozapine, oranza body generally depends on their transition rate from, the pine and Sertindole and pharmaceutically acceptable acid administered Site into the lymphoid System and also on 50 addition Salts thereof, preferably from the group consisting enzyme activity. Accordingly, it is desirable to develop new of haloperidol, bromperidol, flu phenazine male ate, long acting injections in which the drugs themselves as chlorpromazine, chlorpromazine hibenzoate, Sulpiride, opposed to their esters can be used. carpipramine hydrochloride, carpipramine maleate, cloca On the other hand, each of JP-A-62-201816, JP-B-1- pramine hydrochloride, mosapramine hydrochloride, 57087 and JP-B-2-124814 (the term “JP-B” as used herein 55 risperidone, clozapine, oranzapine and Sertindole, of which means “examined Japanese Patent Publication') discloses haloperidol or bromperidol is particularly preferred. Sustained release microcapsules which make possible the The base that constitutes the Sustained release micro administration of water Soluble drugs at an interval of once Spheres of the present invention should have Such a function a week or once a month, and production processes therefor. that its concentration in blood plasma can be maintained at Also, JP-A-55-33414 discloses a so-called in-water drying 60 a constant level by a single administration whereby its method in which a hydrophobic drug and a polylactic acid effects can be obtained Stably over a prolonged period of are dissolved in a common organic Solvent, the resulting time. A biodegradable high molecular weight polymer hav Solution is emulsified by adding a phase Separation agent ing in Vivo histocompatibility is used as a base having Such and then the solvent is removed by evaporation to obtain fine a function. The Sustained release microSpheres of the present particles. 65 invention are constructed in the manner that the hydrophobic U.S. Pat. No. 4,994,281 discloses polylactic acid antipsychotic drug is included therein. Examples of Such a microSpheres, prepared by the in-water drying method, high molecular weight polymer having in Vivo histocom 5,871,778 3 4 patibility include polymers of fatty acid esters or copolymers Surface area of the drug. The finely ground drug may have thereof, polyacrylic esters, polyhydroxybutyric acids, poly a particle size of preferably within a range of 10 um or less, alkylene oxalates, poly orthoesters, polycarbonates and more preferably within a range of 5um or less (about 0.1 to polyamino acids, which may be used alone or as a mixture about 5 um, preferably 0.5 to 5 um). Fine particles of the of two or more. Illustrative examples of the polymers fatty drug can be obtained by known means, Such as use of jet acid esters or copolymers thereof include polylactic acid, mill, ball mill, vibrating mill, hammer mill, colloid mill and polyglycolic acid, polycitric acid, polymalic acid and poly the like. (lactic-co-glycolic) acid, which may also be used alone or as In preparing microSpheres of the present invention, it is a mixture of two or more.