United States Patent [191
`Kino et al.
`
`lllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll
`US005656299A
`5,656,299
`[11] Patent Number:
`[45] Date of Patent:
`Aug. 12, 1997
`
`[54] SUSTAINED RELEASE MICROSPHERE
`PREPARATION CONTAINING
`ANTIPSYCHOTIC DRUG AND PRODUCTION
`PROCESS THEREOF
`
`[75]
`
`Inventors: Shigemi Kino; Tomonori Osajima;
`Hiroaki Mizuta, all of Fukuoka, Japan
`
`[73] Assignee: Yoshitomi Phannaceutical Industries,
`Ltd .. Osaka, Japan
`
`[21] Appl. No.: 443,021
`[22] Filed:
`May 17,1995
`
`Related U.S. Application Data
`
`[63] Continuation-in-part of PCT/JP93/01673, Nov. 15, 1993.
`[30]
`Foreign Application Priority Data
`Nov. 17, 1m
`[JP]
`Japan .................................... 4-332441
`Int. CI.6
`[51)
`....................................................... A61K 9/50
`[52] U.S. Cl ........................... 424/489; 424/490; 424/497;
`424/426
`[58] Field of Search ..................................... 424/426, 490,
`424/497, 489, 529, 530; 514/938
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`3,713,919 11/1973 Boswell et al ............................ 424/19
`
`4,389,330
`4,940,588
`4,994,281
`5,008,114
`
`6/1983 Tice et al ........................... 4271213.36
`7/1990 Sparks et al. ........................... 424/490
`2/1991 Maranishi et al ....................... 424/497
`4/1991 Lovrecich ............................... 424/484
`OTHER PUBLICATIONS
`
`Microencapsulation And Dissolution Properties Of A Neu-
`roleptic In A Biodegradable Polymer, Poly (d~-lactide),
`Journal of Pharmaceutical Sciences, by Suzuki and Price,
`vol. 74, No.1, 21-24, Jan. 1985.
`Chemical Abstracts, vol. 117, No. 24, 14 Dec. 1992.
`Chemical Abstracts, vol. 102, No. 18, 6 May 1985.
`Chemical Abstracts, vol. 106, No.6, 9 Feb. 1987.
`International Search Report.
`
`Primary Examiner-Thurman K. Page
`Assistant Examiner-Sharon Howard
`Attorney, Agent, or Finn-Sughrue, Mion, Zinn, Macpeak
`& Seas
`ABSTRACT
`[57]
`A sustained release microsphere preparation which is pro-
`duced by including a hydrophobic antipsychotic drug such
`as bromperidol, haloperidol or the like into a base composed
`of a high molecular weight polymer having in vivo histo-
`compatibility such as polylactic acid, poly(lactic-co-
`glycolic)acid or the like, and a process for the production
`thereof.
`
`4 Claims, 4 Drawing Sheets
`
`• EXAMPLE I
`• EXAMPLE 2
`• EXAMPLE 3
`
`5
`
`20
`15
`10
`TIME {DAY)
`
`25
`
`30
`
`-~ 0 ........
`
`w
`~
`0::
`{9 z 50
`-<l.
`z
`40
`~ 30
`w
`0:: 20
`10
`0
`0
`
`LUYE1010
`IPR of Patent No. 6,667,061
`
`

`
`U.S. Patent
`
`Aug. 12, 1997
`
`Sheet 1 of 4
`
`5,656,299
`
`• EXAMPLE I
`• EXAMPLE 2
`• EXAMPLE 3
`
`_.,
`~ 0 .__,;
`
`w ti 0:::
`(.9 z 50
`-z 40
`-<(,
`~ 30
`w
`0::
`
`10
`0
`0
`
`5
`
`20
`15
`10
`TIME (DAY)
`
`25
`
`30
`
`FIG. I
`
`LUYE1010
`IPR of Patent No. 6,667,061
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`

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`U.S. Patent
`
`Aug. 12, 1997
`
`Sheet 2 of 4
`
`5,656,299
`
`-+- EXAMPLE 4
`
`I.OxiO 2'
`......... 5.0xi01
`E
`' Ol c
`..._.
`z
`0
`-~
`<(
`0::
`1-
`2 w
`(.) z
`0
`(.)
`
`I.Oxi01
`
`S.OxlOO
`
`I.Oxt0° .
`0
`
`5
`
`JO
`
`20
`15
`TIME (DAY)
`
`25
`
`30
`
`FIG .2
`
`LUYE1010
`IPR of Patent No. 6,667,061
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`

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`U.S. Patent
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`Aug. 12, 1997
`
`Sheet 3 of 4
`
`5,656,299
`
`100
`90
`-.. 80
`~ 0 ---
`70-
`w 60
`J--
`<!
`et:
`w 40
`(f)
`<( 30
`w
`_J
`w 20
`0:::
`10
`0
`0
`
`-e- FORMULATION A
`-o- FORMULATION B
`
`5
`
`tO
`
`I
`15 20 25 30 35 40
`TIME (DAY)
`FIG.3
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`LUYE1010
`IPR of Patent No. 6,667,061
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`U.S. Patent
`
`Aug. 12, 1997
`
`Sheet 4 of 4
`
`5,656,299
`
`..._ FORMULATION C
`
`-o- FORMULATION D
`
`-~ 0 -w
`
`......
`<t
`ct:
`w
`(/)
`<! w
`_J w
`0::
`
`0
`
`0
`
`ro
`
`20
`TIME
`
`30
`(DAY)
`
`40
`
`FIG. 4
`
`LUYE1010
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`SUMMARY OF THE INVENTION
`With the aim of improvement in compliance at the time of
`maintenance therapy with hydrophobic antipsychotic drugs,
`
`1
`SUSTAINED RELEASE MICROSPHERE
`PREPARATION CONTAINING
`ANTIPSYCHOTIC DRUG AND PRODUCTION
`PROCESS THEREOF
`
`2
`the present inventors have conducted intensive studies on
`the development of a sustained release pharmaceutical
`preparation in which a drug itself is used as an active
`ingredient without modification. As the result, it was found
`5 that a drug can be released at an almost constant rate
`This is a continuation-in-part application of PCT/JP93/
`extending over 1 week or more by including a hydrophobic
`antipsychotic drug in the fonn of microcrystals having an
`01673, filed Nov. 15. 1993.
`average particle size of 10 JIIn or less, desirably 5 JIIn or less,
`1. Technical Field
`into a base comprising a biodegradable high molecular
`This invention relates to a sustained release micro sphere
`preparation which contains a hydrophobic antipsychotic 10 weight polymer having in vivo histocompatibility to make a
`drug and to a process for producing the preparation.
`sustained release microsphere preparation and adrninistrat-
`2. Background Art
`It is said that, in the drug therapy of mental diseases,
`ing it by subcutaneous or intramuscular injection, hence
`resulting in the accomplishment of the present invention.
`maintenance therapy by continuous administration is effec-
`tive in preventing recidivism of symptoms, whereby it is
`Accordingly, the present invention relates to (1) an antip-
`possible to guide patients in their daily lives. However, since 15 sychotic drug-containing sustained release microsphere
`preparation which is produced by including a hydrophobic
`the current maintenance therapy with antipsychotic drugs is
`antipsychotic drug in the fonn of microcrystals of the
`carried out by orally administering tablets or fine granules
`once a day or dividing the daily dose into several doses per
`above-noted size into a base comprising a high molecular
`day, decreased patient compliance during the maintenance
`weight polymer having in vivo histocompatibility and (2) a
`therapy .ca~ses recidivism of sympt.oms or 20 processforproducinganantipsychoticdrug-containingsus-
`tained release microsphere preparation which comprises
`re-hospttalizatwn. Conse.quently, cm;rent mamtenance
`therapy has a. drawback m ~at certain mean_s. m?st be
`making an oil layer comprising a solution of a high molecu-
`elllJ?loyed to .Impro~e compliance after rehabilitation or
`lar weight polymer having in vivo histocompatibility con-
`dunng outpatient mamte~ance therapy.
`.
`. .
`.
`taining said hydrophobic antipsychotic drug microcrystals,
`In. o:der to res~lve this problem, long ~cling lDJections 25 adding the oil layer to a water layer, subjecting the resulting
`enanthic acid ester have been used. For example, decanoic = . e 0 an emu 8 ca on ea ~n ° 0
`0/Wtyp
`contailling drugs m the form of decan01c. acid ester or
`. tur t
`tr
`tm tt btai
`1 iii ti
`nan .
`.e
`acid esters of haloperidol and bromperidol are disclosed in
`· emulston an~ subsequen~y removmg the solvent m the oil
`JP-A-56-8318 (the term "JP-A" as used herein means "unex-
`layer by the m-water drymg method.
`Xn another and preferred embodiment of the present
`arnined published Japanese Patent Application"), and
`decanoic acid ester or enanthic acid ester of fluphenazine is 30 invention, the resulting microspheres, following any neces-
`sary size screening, have an average particle size of about
`also known and used in this therapeutic field.
`0.5 to 400 J!In, more preferably about 0.5 to 200 fll11, most
`However, these prior art long acting injections have
`preferably about 15 to 50 flllL
`drawbacks in that their administration route is limited to
`intramuscular injection, resistance at the time of adminis-
`DErAll.ED DESCRIPTION OF THE
`tration is large because they are oil injections while the 35
`INVENTION
`dispersibility of oil in muscular tissue is low, and their
`.
`.
`administration gives patients severe pain. In addition, there
`The hydrophobic antipsychotic drug to be applied to the
`is a possibility that their effects may vary depending on
`individuals and their ages because, though the esters of
`present invention is selected from haloperidol, bromperidol,
`active ingredients show a sustained release effect in the 40 fluphenazine, chlorpromazine, sulpirlde, carpipramine,
`living body by gradually releasing their active moieties due
`clocaprarnine, mosapramine, risperidone, clozapine, oranza-
`to the influence of esterase, release of drugs in the living
`pine and sertindole and pharmaceutically acceptable acid
`body generally depends on their transition rate from, the
`addition salts thereof, preferably from the group consisting
`of haloperidol, bromperidol, fluphenazine maleate,
`administered site into the lymphoid system and also on
`enzyme ~ctiv~~· A~cordfngly, !tis desirable to develop new 45 chlorpromazine, chlorpromazine hibenzoate, sulpiride,
`carpiprarnine hydrochloride, carpiprarnine maleate, cloca-
`long acting m~ectwns m which the drugs themselves as
`pramine hydrochloride, mosaprarnine hydrochloride,
`opposed to therr esters can be used.
`On the other hand, each of JP-~-62-~?1816, JP-B-~-
`risperidone, clozapine, oranzapine and sertindole, of which
`57087 and JP:B-2-124814 (the term JP:B .as use~ herem
`haloperidol or bromperidol is particularly preferred.
`means "exarnmed Japanese Patent Publication") discloses
`.
`.
`.
`sustained release microcapsules which make possible the so
`The base that con~titut~ the sustained release rmc:o-
`administration of water soluble drugs at an interval of once
`sphe:es of the pre~ent ~vention should have such .a ~nction
`a week or once a month, and production processes therefor.
`that 1ts concentration m b!ood plas~. can ?e mamtained .at
`a constant level by a smgle administration whereby 1ts
`Also JP-A-55-33414 discloses a so-called in-water drying
`effects ca.n be obtained. stably over a pr~longed period of
`method in which a hydrophobic drug and a polylactic acid
`are dissolved in a common organic solvent, the resulting 55 ~~·A ~10d~gJ:adable !J!g.h. m~lecular we1ght pol~er hav-
`mg m v1vo histocompatibility IS used as a base havmg such
`solution is emulsified by adding a phase separation agent
`a function. The sustained release micro spheres of the present
`and then the solvent is removed by evaporation to obtain fine
`inv;ntion ar.e constf?c~ed in the man~er that the hydrophobic
`particles.
`U.S. Pat. No. 4,994,281 discloses polylactic acid
`~tipsychotic drug ~s mcluded therem. ~a.mrles of such a
`microspheres, prepared by the in-water drying method, 60 hi~ ,n;ol~cular wetght polymer hav~g m v1vo hlstocom-
`patibility mclude ~olymers of fatty aCid esters ?r copolymers
`containing a physiologically active substance (haloperidol,
`chlorpromazine, etc.) and having an average particle size of
`thereof, polyacrylic esters, poly hydroxybutyric actds, poly-
`about 0.1 to 10 J.lm.
`alkylene oxalates, polyorthoesters, polycarbonates and
`polyamine acids, which may be used alone or as a mixture
`65 of two or more. illustrative examples of the polymers fatty
`acid esters or copolymers thereof include poly lactic acid,
`polyglycolic acid, polycitric acid, polymalic acid and poly
`
`LUYE1010
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`5,656,299
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`3
`(lactic-co-glycolic )acid, which may also be used alone or as
`a mixture of two or more. Other useful examples include
`poly-a-cyanoacrylic ester, poly-p-hydroxybutyric acid,
`polytrimethylene oxalate, polyorthoester,
`polyorthocarbonate, polyethylene carbonate, poly y-benzyl-
`L-glumatic acid and poly L-alanine, which may be used
`alone or as a mixture of two or more. Of these polymers
`poly lactic acid, polyglycolic acid or poly(lactic-co-glycolic)
`acid may be preferred.
`These in vivo histocompatibility high molecular weight
`polymers to be used in the present invention may have an
`average molecular weight of preferably from about 2,000 to
`about 80,000, more preferably from about 5,000 to about
`20,000. When poly(lactic-co-glycolic)acid is used as the in
`vivo histocompatibility high molecular weight polymer,
`compositional ratio of lactic acid and glycolic acid may be
`in the range of from about 100:0 to 50:50, preferably at
`75:25 and 50:50.
`Although the amount of the high molecular weight
`polymer(s) is decided by the drug-releasing rate, period and
`the like, and may be controlled within in a range of from
`about 0.2 to about 10,000 times by weight of the drug, it is
`preferred that the high molecular weight polymer is used as
`the base of the microsphere preparation of the present
`invention in an amount of from 1 to 1,000 times by weight
`of the drug.
`A solution containing the above high molecular weight
`polymer (oil layer) is prepared by dissolving the high
`molecular weight polymer in a solvent. The concentration of 30
`the high molecular weight polymer in the oil layer may be
`in the range of preferably from about 0.5 to about 90%
`(w/w), more preferably from about 2 to about 60% (w/w).
`Examples of the solvent include those which have a
`boiling point of about 120° C. or lower, do not show 35
`miscibility with water and can dissolve high molecular
`weight polymers, such as alkane halides (dichloromethane,
`chloroform, chloroethane, dichloroethane, trichloroethane
`and the like), ethyl acetate, ethyl ether, cyclohexane,
`benzene, n-hexane, toluene and the like, which may be used 40
`alone or as a mixture of two or more.
`In the production process of the micro sphere preparation,
`a hydrophobic antipsychotic drug is dissolved or dispersed
`in a solution prepared by disso~ving an in vivo histocom-
`patible high molecular weight polymer in a solvent to give 45
`an oil layer. The thus obtained oil layer is added to a water
`layer and subjected to an emulsification treatment to prepare
`an 0/W type emulsion. Thereafter, the microsphere prepa-
`ration is obtained by removing the solvent in the oil layer by
`means of an in-water drying method.
`When the oil layer is prepared by dispersing a drug, the
`drug may be used as fine particles. By the use of
`microcrystals, the surface of microspheres becomes smooth
`and the drug release becomes close to 0 order. Such a
`releasing capacity close to 0 order seems to be accomplished 55
`due to decrease in the initial releasing rate resulting from the
`increased interaction between the aforemeJ;ttioned high
`molecular weight polymer and the drug effected by the
`increased contacting area and due to an increase in the
`releasing rate in the late stage effected by the increased 60
`surface area of the drug. The finely ground drug may have
`a particle size of preferably within a range of 10 fUll or less,
`more preferably within a range of 5 J.Imor less (about 0.1 to
`about 5 fUU, preferably 0.5 to 5 Jllll). Fine particles of the
`drug can be obtained by known means, such as use of jet 65
`mill, ball mill, vibrating mill, hammer mill, colloid mill and
`the like.
`
`4
`In preparing microspheres of the present invention, it is
`preferable to add an emulsifying agent to the water layer,
`and examples thereof include those which are able to form
`a stable 0/W type emulsion, such as an anionic surfactant
`5 (sodium oleate, sodium stearate, sodiumlauryl sulfate or the
`like), a nonionic surfactant (a polyoxyethylene sorbitan fatty
`acid ester, a polyoxyethylene castor oil derivative or the
`like), polyvinyl pyrrolidone, polyvinyl alcohol,
`carboxymethylcellulose, lecithin, gelatin and the like, which
`10 may be used alone or as a mixture of two or more. These
`agents may be used in a concentration of from about 0.01%
`to about 20%, more preferably from about 0.05% to about
`10%.
`Removal of the solvent from the oil layer is effected by a
`15 conventionally used means [in-water drying method:
`Tamotsu Kondo, "Maikurokapuseru-sono kinou to ouyou
`(Microcapsules, Their Functions And Applications)" ,_page
`78, Japanese Standards Association, Mar. 20, 1991]. In this
`method, a solvent is removed by gradually reducing pressure
`20 while stirring using a propeller mixer, a magnetic stirrer or
`the like or by controlling the degree of vacuum using a
`rotary evaporator or the like.
`The thus obtained microspheres are collected by centrifu-
`gation or filtration, washed several times with distilled water
`25 to remove free drug, the emulsifying agent and the like
`adhered to the surface of the microspheres and then treated
`under a reduced pressure, if necessary, with heating, to
`perfect removal of water and solvent in the microspheres.
`If necessary, the thus obtained microspheres are gently
`ground and screened to remove oversized microspheres.
`When used as suspensions for injection use, the particle size
`of the microspheres may be a range which can satisfy their
`dispersibility and needle-passing property, for example, in
`the range of from about 0.5 to about 400 J-liil, more prefer-
`ably from about 0.5 to about 200 fUU, most preferably from
`about 15 to 50 J.Im as an average particle size.
`The microspheres of the present invention can be made
`into sustained release injections by preparing an aqueous
`suspension together with a dispersing agent (polysorbate 80,
`sodium carboxymethylcellulose, sodium alginate or the
`like), a preservative (methylparaben, propylparaben, benzyl
`alcohol, chlorobutanol or the like) and an isotonic agent
`(sodium chloride, glycerol, sorbitol, glucose or the like) or
`by preparing an oily suspension by dispersing the micro-
`spheres in a plant oil such as olive oil, sesame oil, peanut oil,
`cotton oil, corn oil or the like or propyleneglycol or the like.
`In this instance, in order to lessen resistance at the time of
`injection, the sustained release microsphere preparation of
`50 the present invention may be used preferably in the form of
`an aqueous suspension.
`In addition, sustained release injections of microspheres
`of the present invention can be made into more stable
`sustained release injections by further mixing the above
`composition with a filler (mannitol, sorbitol, lactose, glucose
`or the like), dispersing the mixture and then subjecting the
`resulting dispersion to freeze drying or spray drying to
`obtain a solid preparation which can be used by adding
`distilled water for injection or an appropriate dispersion
`medium at the time of injection.
`Dose of a hydrophobic antipsychotic drug as the active
`ingredient of the sustained release microsphere preparation
`of the present invention can be decided depending on each
`disease to be treated, symptoms and age of each patient and
`the like, and it may be in the range of generally from 5 to
`5,000 mg, preferably from 10 to 2,000 mg. per adult per
`administration. Since the pharmaceutical preparation of the
`
`LUYE1010
`IPR of Patent No. 6,667,061
`
`

`
`5
`present invention releases its active ingredient depending on
`the hydrolysis of the high molecular weight polymer by
`water, it shows less difference per individual and can be
`administered by not only intramuscular injection but also
`subcutaneous injection.
`
`5,656,299
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`6
`Thereafter, a powder preparation was obtained in the same
`manner as described in Example 1. The haloperidol-
`containing freeze dried microspheres had an average particle
`size of 25.4 J.Un.
`
`5
`
`10
`
`EXAMPLES
`A micro sphere preparation is obtained in the same manner
`as described in the above Examples using fluphenazine
`maleate, chlorpromazine, chlorpromazine hibenzoate,
`sulpiride, carpiprarnlne hydrochloride, carpiprarnlne
`maleate, clocaprarnine hydrochloride, mosaprarnine
`hydrochloride, risperidone, clozapine, oranzapine or sertin-
`dole as the drug.
`
`BR1EF DESCRIPTION OF THE DRAWINGS
`FIG. 1 is a graph showing remaining amount of bromp-
`eridol in the administered area of rat after intramuscular
`injection of each of the rnicrosphere preparations obtained in
`Examples 1 to 3.
`FIG. 2 is a graph showing periodical changes in the drug
`concentration in blood plasma of rat after intramuscular
`injection of the haloperidol-containing rnlcrosphere prepa- 15
`TEST EXAMPLE 1
`ration obtained in Example 4.
`Each of the bromperidol-containing rnicrosphere prepa-
`FIGS. 3 and 4 are graphs showing results of an in vitro
`rations obtained in Examples 1 to 3 was suspended in
`drug release test of the microsphere preparation obtained in
`physiological saline and administered into the femoral
`Test Example 3 and Test Example 4, respectively.
`The following Examples and Test Examples are provided 20 muscle of male SD rats (15 weeks of age) in a dose of 12.5
`to illustrate the present invention in further detail.
`mg as bromperidol. After a predetermined period of time,
`micro spheres which remained in the administered area were
`periodically recovered to measure remaining amount of
`bromperidol. As the result, release of the drug at an almost
`constant rate was confirmed as shown in FIG. 1.
`
`EXAMPLE 1
`Poly(lactic-co-glycolic)acid (50:50) (molecular weight: 25
`about 20,000) was dissolved in 3 rnl of dichloromethane to
`prepare a 40% solution. In this was dissolved 190 mg of
`bromperidol (average particle size: 13.0 Jllll) to prepare a
`mixed solution. This was poured into 1,000 m1 of 0.5%
`polyvinyl alcohol (Gosenol EG-40, manufactured by The 30
`Nippon Synthetic Chemical Industry) and dispersed using a
`homogenizer (manufactured by Tokushu Kika Kogyo) to
`prepare an 0/W type emulsion. Thereafter, the 0/W type
`emulsion was gently stirred using a conventional mixer to
`effect evaporation of dichloromethane and solidification of 35
`rnicrospheres which were subsequently collected by
`centrifugation, simultaneously washing with distilled water.
`The thus recovered microspheres, after being made into a
`powder preparation by freeze drying, had an average particle
`size of 36.4 Jllll·
`
`TEST EXAMPLE 2
`The haloperidol-containing microsphere preparation
`obtained in Example 4 was suspended in a 0.5% sodium
`carboxymethyl-cellulose solution isotonized with mannitol
`and administered into the femoral muscle of male SD rats
`(13 weeks of age) in a dose of 25 mg as haloperidol. After
`a predetermined period of time, blood samples were peri-
`odically collected from ophthalmic veins to measure con-
`centration of the drug in blood plasma. As the result,
`sustained concentration of haloperidol in blood plasma was
`confirmed as shown in FIG. 2.
`
`40
`
`TEST EXAMPLE 3
`A 25 mg portion of each of the bromperidol-containing
`EXAMPLE 2
`microsphere preparations obtained from the following For-
`mulations A and B was dispersed in 20 m1 of physiological
`dl-Polylactic acid (molecular weight: about 10,000) was
`dissolved in 3 m1 of dichloromethane to prepare a 20%
`saline and shaken at 37° C. and at 80 revolutions per minute
`solution. In this was suspended 190 mg of bromperidol 45 using a constant temperature shaker (manufactured by
`Yarnato Kagaku). Thereafter, samples were periodically
`(average particle size: 2.5 Jllll) to obtain a mixed solution.
`Thereafter, a powder preparation was obtained in the same
`collected to calculate drug releasing ratio by ultraviolet
`manner as described in Example 1. The bromperidol-
`absorption photometry (245 nm). As shown in FIG. 3, it was
`confirmed that the microsphere preparation of Formulation
`containing freeze dried micro spheres had an average particle
`size of 21.4 Jllll.
`50 A which comprises finely ground bromperidol can release
`the drug at a rate of almost 0 order.
`
`EXAMPLE3
`dl-Polylactic acid (molecular weight: about 20,000) was
`dissolved in 3 m1 of dichloromethane to prepare a 20%
`solution. In this was dissolved 85 mg of bromperidol
`(average particle size, 13.0 Jllll) to obtain a mixed solution.
`Thereafter, a powder preparation was obtained in the same
`manner as described in Example 1. The bromperidol-
`containing freeze dried microspheres had an average particle
`size of 25.5 Jllll.
`
`55
`
`FORMUL!ITION A
`dl-Polylactic acid (molecular weight: about 5,000) was
`dissolved in 3 m1 of dichloromethane to prepare a 12%
`solution. In this was suspended 190 mg of bromperidol
`(average particle size: 2.5 Jllll) to obtain a mixed solution.
`Thereafter, a bromperidol-containing microsphere prepara-
`60 tion was obtained in the same manner as described in
`Example 1. The freeze dried powder had an average particle
`size of 19.6 J.Un.
`
`FORMUL!ITION B
`Bromperidol with no grinding (average particle size: 13.0
`Jllll) was used instead of the bromperidol of Formulation A
`having an average particle size of 2.5 Jllll· The freeze dried
`
`EXAMPLE4
`dl-Polylactic acid (molecular weight about 10,000) was
`dissolved in 4 m1 of dichloromethane to prepare a 30% 6S
`solution. In this was suspended 380 mg of haloperidol
`(average particle size: 3.0 Jllll) to obtain a mixed solution.
`
`LUYE1010
`IPR of Patent No. 6,667,061
`
`

`
`7
`powder, obtained as described in Example 1. had an average
`particle size of 21.0 J.1111.
`
`5,656,299
`
`TEST EXAMPLE 4
`A 15 mg portion of each of the haloperidol-containing
`rnicrosphere preparations obtained from the following For-
`mulations C and D was dispersed in 20 m1 of physiological
`saline and shaken at 37° C. and at 80 revolutions per minute
`using a constant temperature shaker (manufactured by
`Taitech), and samples were periodically collected to calcu-
`late drug releasing ratio by ultraviolet absorption photom-
`etry (245 nm). As shown in the FIG. 4, it was confirmed that
`the rnicrosphere preparation of Formulation C which com-
`prises finely ground haloperidol can release the drug at a rate
`of almost 0 order.
`
`8
`(2) Since a biodegradable high molecular weight polymer
`is used, surgical operations such as embedding and the like
`are not required at all, and subcutaneous and intramuscular
`administrations can be made easily absolutely in the same
`5 manner as the case of conventional suspension injections so
`that recovery of the material is not required.
`(3) Pain and resistance at the time of administration are
`small.
`Variations of the invention will be apparent to the skilled
`10 artisan.
`What is claimed is:
`1. An antipsychotic drug-containing sustained release
`rnicrosphere preparation having an almost zero order rate of
`release when administered to a patient in need thereof and
`15 having an average particle size of about 15 to 50 fJ1U,
`wherein a drug bromperidol or haloperidol is in a form of
`microcrystals having an average particle size of about 0.5 to
`5 Jlffi and is included in a base comprising a high molecular
`weight polymer having in vivo histocompatibility selected
`20 from the group consisting of polylactic acid and poly(lactic-
`co glycolic )acid.
`2. The antipsychotic drug-containing sustained release
`rnicrosphere preparation according to claim 1, wherein said
`antipsychotic drug-containing sustained release micro sphere
`25 preparation is an aqueous suspension.
`3. The antipsychotic drug-containing sustained release
`rnicrosphere preparation according to claim 1, wherein said
`antipsychotic drug-containing sustained release rnicrosphere
`preparation is intramuscularly or subcutaneously adminis-
`30 tered to a patient in need thereof.
`4. A process for producing an antipsychotic drug-
`containing sustained release rnicrosphere preparation having
`an almost zero order rate of release when administered to a
`patient in need thereof and having an average particle size of
`INDUSTRIAL APPliCABILITY
`35 about 15 to 50 Jlffi which comprises making an oil layer
`According to the hydrophobic antipsychotic drug-
`comprising a high molecular weight polymer having in vivo
`containing sustained release rnicrosphere preparation of the
`histocompatibility selected from the group consisting of
`present invention, considerable improvement in compliance
`polylacti~ acid and pol~(lac~c-co-glycolic)acid. containing
`bro~endol or halo~ndo~ m the form of Inlcrocrys~s
`in maintenance therapy of mentally deranged persons can be
`expected because of the following features of the prepara- 40 ha~g an average particle stze ~f a?out 0.5 to 5 pro. a~ding
`tion of the present invention.
`the oillayer.to a water layer, subjectm~ the resulting JnlXture
`. d de . d
`to an emulsification treatment to obtain an 0/W type ernul-
`.
`dmi · tr ti
`1
`(1) Wh
`t
`en a ong- erm a ms a on 1s requrre ,
`.
`·
`· h
`ill
`srre
`~on a~d su~seque~tly rem~v~ng the solvent m t e o
`pharmacological effects can be obtained continuously by
`ayer
`Y an m-wa er drymg me 0 •
`one injection per 1 to 8 weeks, instead of daily administra-
`* * * * *
`tion.
`
`FORMULiiTION C
`dl-Polylactic acid (molecular weight: 5,000) was dis-
`solved in 3 ml of dichloromethane to prepare a 12% solu-
`tion. In this was suspended 190 mg of haloperidol (average
`particle size: 3.0 J!ffi) to obtain a mixed solution. Thereafter,
`a freeze dried haloperidol-containing rnicrosphere powder
`preparation (average particle size: 24.8 Jlill) was obtained in
`the same manner as described in Example 1.
`
`FORMULiiTION D
`Haloperidol with no grinding (average particle size: 13.7
`Jlill) was used instead of the haloperidol of Formulation C
`having an average particle size of 3.0 Jlffi to obtain a freeze
`dried haloperidol-containing rnicrosphere powder prepara-
`tion (average particle size: 24.3 J!ffi).
`
`LUYE1010
`IPR of Patent No. 6,667,061