CA2208571A1

CA2208571A1 - Resin particle, medical material and pharmaceutical preparation containing said resin particle

Info

Publication number: CA2208571A1
Application number: CA002208571A
Authority: CA
Inventors: Yuzo Kimura; Rika Hamamoto; Seiichiro Iguchi; Toshio Nakamura; Shinsuke Nakagawa; Keigo Yamada; Hiroaki Yamamoto; Minoru Yamato
Original assignee: Individual
Current assignee: Otsuka Pharmaceutical Co Ltd; Otsuka Pharmaceutical Factory Inc
Priority date: 1995-01-10
Filing date: 1996-01-04
Publication date: 1996-07-18
Also published as: AU4357096A; CN1168102A; WO1996021448A1; MX9705185A; KR19980701292A; EP0794778A1

Abstract

A resin particle is provided which comprises an ethylene vinyl alcohol copolymer and 5 to 90 % by weight of cilostazol incorporated therein, and has a particle size of not greater than 2,000 µm. The resin particle, upon being administered orally, allows the concentration of cilostazol in blood to be kept constant over an extended period of time and, therefore, remarkably alleviates side effects such as pain and headache which may otherwise be caused by rapid release of cilostazol into a body.

Description

CA 02208~71 1997-06-23 W O96121448 PCTlJr96~00001 DESCRIPTION
RESIN PARTICLE, MEDICAL MATERIAL AND PHARMACEUTICAL
PREPARATION CONTAINING SAID RESIN PARTICLE
TECHNICAL FIELD
The present invention relates to a resin particle containing cilostazol as an active ingredient, a medical material and a pharm~ceutical preparation containing said resin particle, which is particularly used as an oral preparation.
BACKGROUND ART
Cilostazol exhibits a high thrombocyto-aggregation inhibi1ing action as well as a phosphodiesterase inhibiting action, anti-ulcerative action, depression action and resolu1:ion action. Therefore, cilostazol is widely used as an anti-t~lrombotic agen-t, cerebrovascular agent, anti-inflammatory agent, anti-hypertensive agent, anti-asthma agent and phosphodiesterase inhibitor.
Cilostazol is typically ~mi x~d with an excipient and other ingredients and compressed into a tablet form for oral aclministration.
Since the tablet rapidly disintegrates upon being administered orally, an undesirably large amount of cilostazol is released in a body in a short time, thereby causing side effects such as headache, heavy head feeling and pain.
DISCLOSURE OF lNV~N-lION

To solve the aforesaid problem, it is a principal CA 02208~71 1997-06-23 W O96/21448 PCT/J~9~'00004 . 2--~; object of the present invention to provide a resin particle which is capable of continuously releasing a required amount ; o~ cilostazol in a body over an extended period of time.
- The present inventors have been studied the incorporation of cilostazol in a polymer material to solve the aforesaid problem, and found that a resin particle prepared by incorporating 5 to 90% by weight of cilostazol into an -~ ethylene vinyl alcohol copolymer and granulating the resulting resin into a particle size of not greater than 2,000,um can ~ 10 release cilostazol into a body at a controlled rate, thereby -~ ensuring the continuous release of cilostazol into the body :.
' over an extended period of time. Thus, the inventors have . .
achieved the present invention.

~- In accordance with the present invention, there is .
provided a resin particle comprising an ethylene vinyl alcohol copolymer and a cilostazol incorporated therein, the ~- cilostazol being contained in an amount of 5 to 90% by weight ~ for the total amount of the ethylene vinyl alcohol copolymer -- and the cilostazol, the resin particle having particle size of 2~, .
not greater than 2,000~m.
The ethylene vinyl alcohol copolymer is highly ~F ! stable and biologically safe, and is used in various medical materials. Cilostazol is highly dispersible in the ethylene vinyl alcohol copolymer. Therefore, cilostazol is incorporated in the ethylene vinyl alcohol copolymer in a , , -CA 02208571 1997-06-23 .
W~ 96/2~448 PC~JPg6~'CO~

-3- 6~ 073 n~/s~. 24.5a2.l997 desire~l proportion at a high temperature, and then the result:ng resin is cooled into a solid state. Alternatively, cilostc~zol and the ethylene vinyl alcohol copolymer are dissol~ed in a solvent, and then the solvent is removed from the resulting solution to obtain a solid resin.
The medical material of the present invention comprises an ethylene vinyl alcohol copolymer and 60 to 85~ by weight of cilostazol incorporated therein.
The resin particle of the prese~t invention is used singly or in combination with a pharmaceutically available carrier as a pharmaceutical preparation.

CH-A-0 ~,83 673 relates to an antithrombotic resin containing a polyuret:hane or polyurethane urea and an antithrombotic agent (e g c lostazol) in an amount of 0.1-50~ by weight with respect to the polyurethane or polyurethane urea.
BEST MODE FOR CARRYING OUT THE INVENTION
The ethylene content in the ethylene vinyl alcohol copolymer is appropriately determined depending on the processing method of the resin particle, but may be s2nerally 27 to 7~ mol.%, preferably 38 to 47 mol.%, most preferably 44 to 47 mol.%. An ethylene content of less than 27 mol.% will result in a poor processibility of the ethylene vinyl alcohol copolymer by a melting method which will be described later.
On the other hand, an ethylene content of greater than 70 mol.~ w:ll result in a poor miscibility of cilostazol with the ethylene vinyl alcohol copolymer.
The ethylene vinyl alcohol copolymer has a number-average degree of polymerization of 5,000 to lOO,OOO, prefera}~ly lO,OOO to 50,000, more preferably 12,000 to 40,000.

A7~E~D ~

CA 02208~71 1997-06-23 WO 96121448 PCT~J~96~0000 1 As required, any of various biologically safe plasticizers, stabilizers, secondary plasticizers, lubricants and like additives may be added to the ethylene vinyl alcohol copolymer.
The ethylene vinyl alcohol copolymer generally has a melting point of 120 to 200~C, preferably 140 to 191~C, most preferably 160 to 175~C. A melting point of lower than 120~C
will r~!sult in a poo~ solubility and dispersibility of cilostcazol in the ethylene vinyl alcohol copolymer. A melting point of higher than 200~C will cause the decomposition of cilostazol, resulting in a poor processibility of the ethylene vinyl alcohol copolyrner and the coloration of the ethylene vinyl alcohol copoly~er during the melting process.
The content of cilostazol is generally about 5 to 90~ by weight, preferably 20 to 85~ by weight, more preferably 30 to ~5~ by weight, where 40 to 85~ by weight is preferred and 60 to 85~ by weiyht is most preferred. If the content of cilostazol is less than 5~ by weight, desired absorption of cilostazol through oral administration cannot be expected because of excessive release of cilostazol. If the content of cilostazol is greater than 90~ by weight, the sustained-release effect is not: recognized so that suppression of side effects such as h~che cannot be expected.
The particle size of the resin particle containing cilostazol is not greater than 2,000,um, preferably not greater CA 02208~71 1997-06-23 W O 96/21448 PCT/JlJG~00001 than l OOO~m, most preferably not greater than 600,um. More specif~cally, the particle size is in a range of 75 to 250~m, wherein 75 to 150~m is preferred and 75 to 105,um is most preferred. A particle size of greater than 2,000~m is inappropriate, because the release of cilostazol from the inside of particles is excessively suppressed, failing to obtain a desired absorption of cilostazol through oral a~m; n; stration.
To prepare ~he resin particle of the present invention, the melting method is preferably employed in which cilostazol is admixed with the ethylene vinyl alcohol copolyner in a molten state and the resulting melt is formed into a predetermined form. Cilostazol should be homogeneously dispersed in the ethylene vinyl alcohol copolymer without being decomposed during the melting process. For this, the ethylene vinyl alcohol copolymer is melted at a temperature lower than the decomposition point of cilostazol (about 240~C), generally 140 to 210~C, preferably 160 to 185~C, most preferably 165 to 180~C. As required, the melting and forming process~s are performed in an oxygen-free atmosphere to prevent the cilostazol and the copolymer from being oxidized.
Moistur~ contained in the ethylene vinyl alcohol copolymer is preferably removed as much as possible to ensure the stability of the cilostazol and the copolymer and the integrity of the ~ 25 formed resin particle.

- CA 02208~71 1997-06-23 j W 096/21448 PCT/Jr~/OC~~I

=o---~ Any of various melt forming methods can be employed.
~
- For example, the melt is formed into a bar shape, drop shape .- or sheet form by extrusion. Injection molding may otherwise be employed.
i -~- 5 After the forming, the resin particle is ground by a grinder and, as required, the resulting particles are sieved ', to obtain a predetermined particle size. The grinder and ~-- grinding conditions to be employed may be appropriately determined dep~nA~ ng on a desired particle size and the like.
The release of cilostazol from the resin particle formed through the melt forming process can be controlled by ~- appropriately adjusting the content of cilostazol in the resin particle, and the saponification value of and the ethylene -~ content in the ethylene vinyl alcohol copolymer. The release of cilostazol can otherwise be controlled by ~AA;ng, as _s .
~= re~uired, a plasticizer, stabilizer, secondary plasticizer, lubricant and a like additive to the ethylene vinyl alcohol . .
copolymer.
Instead of the melt method, a solution method may be employed. In the solution method, the ethylene vinyl alcohol .~ .
-~ copolymer and cilostazol are homogeneously dissolved in a solvent, and then the solvent is removed ~rom the solution.
- The resulting resin is ground in the same m~nnPr as described above to obtain the resin particle of the present invention.
.
~ 25 Examples of the solvent include dimethylformamide, ~1 .
., -CA 02208~71 1997-06-23 W O96121448 rCT~JP~.~J~DC~1 dimethylacetamide, dimethyl sulfoxide, cycloh~x~non~, ~ tetrah~drofuran, chloroform, dichloromethane, acetone and l,l,l,~,3,3-hexafluoro-2-propanol. The aforesaid solvents are used either alone or in combination. Among the aforesaid solvents, l,l,l,3,3,3-hexafluoro-2-propanol and dimethyl sulfoxide are particularly preferable because the ethylene vinyl alcohol copolymer is highly soluble therein and these solvents can be easily removed by evaporation.
Cont~;n~nt:s in the ethylene vinyl alcohol copolymer to be used are preferably pr~ ;narily removed therefrom through sufficient cl~ning by means of Soxhlet's extractor.
Further, moisture in the copolymer is preferably perfectly removed therefrom by sufficient drying.
The solution cont~; n; ng the aforesaid ingredients dissolv~d therein is spread onto a glass plate or extruded in a bar form, and then the solvent is removed from the solution.
Thus, the resin particle can be obtained in a film form or bar form. lrhe .el,.~val of the solvent is achieved by, for example, air drying, heat drying under a reduced pressure, or phase separation by adding a solidifying agent to the solution.
Example:j of the solidifying àgent include poor solvents for the ethylene vinyl alcohol copolymer, for example, water, alcohols such as methanol, ethanol, propanol and butanol, and ketones such as acetone. In this case, the diffusion of cilosta:~ol into the solidifying agent during the ~c :
. CA 02208~71 1997-06-23 ~ .

~ -8-- ~;
solidification process should be prevented as much as : possible. Therefore, where the solubility of cilostazol in such a poor solvent is high, another solvent is preferably added to the poor solvent to reduce the solubility of cilostazol in the solidifying agent.
The release of cilostazol from the resin particle ; formed by the solution method can be controlled by appropriately adjusting the amount of cilostazol to be incorporated in the ethylene vinyl alcohol copolymer and the ethylene content in the ethylene vinyl alcohol copolymer, and by appropriately selecting the solvent removing method (e.g., drying under atmospheric pressure or under reduced pressure, ' or solidification using the solidifying agent). The release -~ - rate of cilostazol can otherwise be controlled by adding, as re~uired, a plasticizer, stabilizer, secondary plasticizer, ~~ lubricant and a like additive to the ethylene vinyl alcohol copolymer.
The resin particle containing cilostazol can be -= orally administered to a~; m~ 1 ." or human beings directly or in , 20 any of various formulations such as capsule, tablet, granules -and suspension which are obtained by mixing the resin particle ~-~ with a pharmaceutically available carrier. The resin particle . ~ .
may otherwise be ,~m; ni stered in a suppository formulation.

- Formulations such as tablet and capsule for oral -~ 25 a~m; n; ~tration are prepared in a conventional manner. More ' .

CA 02208~71 1997-06-23 W096121448 PCT/~96JOOOOJ

specif:cally, the resin particle of the present invention is m; x~ ~Tith an excipient such as gelatin, starch, lactose, magnesium stearate, -talc or gum arabic, and the resulting mixture is compresse(~ into a tablet form. Alternatively, the resin Elarticle is mixed with an inert filler, diluent or the like, and the resulting mixture is filled in a hard gelatin capsul~ or soft capsule.
The amount of the resin particle to be administered is not particularly limited, but may be appropriately selected from a wide range. To produce a primary effect of cilostazol, the dose of cilostazol is preferably 0.06 ~o lOmg/lkg-weight per day. The formulation preferably contains l to 500mg of the resin particle and may be administered once a day.
The medical material of the present invention is suitabl~ for use as, for example, materials for pharmaceutical preparation or medical device which are capable of continuously releasing cilostazol in an effective concent:-ation. The medical material can also be provided in medical devices (e.g., platelet bags, extracorporeal ~0 circula.ion circuits) to achieve antiplatelet action.
FIELD OF lN~uS-~IAL APPLICABILITY
The resin particle of the present invention comprises particles oE an ethylene vinyl alcohol copolymer and cilostaz,ol incorporated therein in a predetermined proportion, and has a predetermined particle size. The release of .

. .
- cilostazol into a body is suppressed to keep the cilostazol co~c~ntration in blood constant over an extended period of time. Therefore, side effects such as pain and headache can - be remarkably alleviated which may otherwise be caused by rapid release of cilostazol into the body.
-- The medical material of the present contributes to -~ the continuous release of cilostazol in an effective ,on~ ntratiOn.
~;: E~MPLES
, 10 F~XAMP~
~~ A mixture of 60g of cilostazol and 60g of an ethylene vinyl alcohol copolymer (EVAL ES-G llOA available - from Kuraray Co., Ltd., ethylene content: 47 mol.%) in a ~ ground form (sieved with a 28-mesh) was melted and extruded at an extruding temperature of 165~C by means of a ~;x;ng extruder (CS-194A available from Custom Scientific Instruments .~ .
. Inc.). The extruded resin particle was ground by means of a 5: small-scale grinder (SM-l available from Iuchiseieido). Thus, particles cont~; n; ng 50~ by weight of cilostazol were -l- 20 obtained.
;, .
~XAI~qPT.F~ ?~
The particles (containing 50% by weight of - cilostazol) obt~;ne~ in EXAMPLE 1 were classified into ~ -~ particle size ranges of 355 to SOO~m, 250 to 355~m, 150 to -~ 25 250,um, 105 to 150~m, 75 to 105~m, less than 75~m, and the , . .
, WO 96121448 ~CTJJF~6JO'~

other ~ly using sieves specified by JIS (Japanese Industrial St~n~ds).
r~x~MPrr~- 3 Particles cont~;n;ng 40% by weight of cilostazol were o~tained in substantially the same manner as in EXAMPLE
1, except that a mixture of 48g of cilostazol and 72g of an ethylene vinyl alcohol copolymer (EVAL ES-G llOA available from Kuraray Co., Ltcl., ethylene content: 47 mol.~) in a ground form (sieved with a 28-mesh) was melted and extruded at an extruding temperature of 165~C.
r~MPr.r~ _~
The particles (containing 40~ by weight of cilostazol) obtained in EXAMPLE 3 were classified into particl~ size ranges of 105 to 150,um, 75 to 105;um, less than 75~m, and the other.
r~ MpT~r~_~
Particles cont~;n; ng 30~ by weight of cilostazol were ob~; ne~ in substantially the same m~nner as in EXAMPLE
1, except that a mixture of 36g of cilostazol and 84g of an ethylene vinyl alcohol copolymer (EVAL ES-G llOA available from Kuraray Co., Ltd., ethylene content: 47 mol.%) in a ground :-orm (sieved with a 28-mesh) was melted and extruded at an extr~ding temperature of 165~C.
r~AMPrr~ 6 The particles (containing 30~ by weight of CA 02208~71 1997-06-23 W O96/21448 PCT/JP~G/0000 - cilostazol) obtained in EXAMPLE 5 were classified into particle size ranges of 105 to 150~m, 75 to 105~m, less than 75~m, and the other.
- r~X~MPT.r~ 7 , . .
~ 5 Particles cont~;n;ng 20% by weight of cilostazol ~-~ were obt~;ne~ in substantially the same manner as in EXAMPLE

~ 1, except that a mixture of 24g of cilostazol and 96g of an .. ...
-- ethylene vinyl alcohol copolymer (EVAL ES-G llOA available from Kuraray Co., Ltd., ethylene content: 47 mol.%) in a -, 10 ground form (sieved with a 28-mesh) was melted and extruded at ~ an extruding temperature of 165~C.
, . .
r~x~MPTr~ 8 Particles containing 10% by weight of cilostazol were obtained in substantially the same manner as in EXAMPLE
1, except that a mixture of 12g of cilostazol and 108g of an ethylene vinyl alcohol copolymer (EVAL ES-G llOA available from Kuraray Co., Ltd., ethylene content: 47 mol.%) in a - ground form (sieved with a 28-mesh) was melted and extruded at .
~ an extruding temperature of 165~C.

-- 20 r~AMpr~r~ 9 Particles cont~; ni ng 5% by weight of cilostazol were . ~
-= obtained in substantially the same manner as in EXAMPLE 1, except that a mixture of 6g of cilostazol and 114g of an ethylene vinyl alcohol copolymer (EVAL ES-G llOA available from Kuraray Co., Ltd., ethylene content: 47 mol.%) in a , ....r ' W O 96121448 PCT~JF9~/O0001 ground form (sieved with a 28-mesh) was melted and extruded at ~ an extruding temperature of 165~C.
F~XAMPT.~, 1 0 Particles cont~; n; ng 60% by weight of cilostazol were o~t~ in substantially the same manner as in EXAMPLE
1, exc~!pt that a mixture of 72g of cilostazol and 48g of an ethylene vinyl alcohol copolymer ( EVAL ES-G llOA available from Kuraray Co., Ltd., ethylene content: 47 mol.%) in a ground form (sieved with a 28-mesh) was melted and extruded at an extruding temperature of 165~C.
~XAMPT.E 11 The particles (containing 60~ by weight of cilostcLzol) obt~; n~A in EXAMPLE 10 were classified into partic].e size ranges of 75 to 105~m, less than 75,um, and the other.
~XAMPT.F: 1 ~
Particles containing 70% by weight of cilostazol were o~t~; n~ in substantially the same manner as in EXAMPLE
1, except that a mixture of 84g of cilostazol and 36g of an ethylene vinyl alcohol copolymer (EVAL ES-G llOA available from Kuraray Co., Ltd., ethylene content: 47 mol.~) in a ground form (sieved with a 28-mesh) was melted and extruded at an extruding temperature of 170~C.

F~X AMP T .~ i 13 The particles (containing 70% by weight of -,~ W O 96/21448 PCTlJr~6/0~~~

.
-- cilostazol) obtained in EXAMPLE 12 were classified into - particle size ranges of 75 to 105~m, less than 75~m, and the other.
., ~.
~xAMpr~ 14 Particles cont~;n;ng 80~ by weight of cilostazol were obt~; n~ in substantially the same manner as in EXAMPLE
l, except that a mixture of 96g of cilostazol and 24g of an ethylene vinyl alcohol copolymer (EVAL ES-G llOA available from Kuraray Co., Ltd., ethylene content: 47 mol.%) in a '- 10 ground form (sieved with a 28-mesh) was melted and extruded at ~, an extruding temperature of 170~C.
: ~AMPT~ 15 The particles (containing 80~ by weight of ~. cilostazol) obtained in EXAMPLE 14 were classified into -~ 15 particle size ranges of 75 to 105~m, less than 75~m, and the ~.
~i other.
. ~ .
- ~AMPT~ 16 ~ Particles cont~;ning 90% by weight of cilostazol r -~ ~ were obtained in substantially the same m~nn~ as in EXAMPLE
-~ 20 1, except that a mixture of 108g of cilostazol and 12g of an . ~ .
~i~ ethylene vinyl alcohol copolymer (EVAL ES-G llOA available :
-~- from Kuraray Co., Ltd., ethylene content: 47 mol.%) in a = ~ ground form (sieved with a 28-mesh) was melted and extruded at .- ~
~ an extruding temperature of 170~C.
.
- 25 ~X~MPT.~ 17 ~' .
,, ~

~ ~R
.... .
. .
_r -W O 96121448 PCT/JP9~ CJ

The particles (containing 90% by weight of cilostazol) obtained in EXAMPLE 16 were classified into particla size ranges of less than 75~m and the other.
~X~MPT.~ lR
Particles cont~;n;~g 40~ by weight of cilostazol were obt~;~P~ in substantially the same manner as in EXAMPLE
1, except that a mixture of 48g of cilostazol and 72g of an ethylene vinyl alcohol copolymer (EVAL EP-E 105A available from Ku:--aray Co., Ltd., ethylene content: 44 mol.%) in a ground :-orm (sieved with a 28-mesh) was melted and extruded at an extruding temperature of 170~C.

~XP~MPT,Fi~ 1 9 The particles (containing 40~ by weight of cilostaz;ol) obt~ ~A in EXAMPLE 18 were classified into particl~ size ranges of 75 to 105~m and the other.
r~xAMPT~ 20 Particles cont~;n;ng 50~ by weight of cilostazol were obtained in subs~antially the same ~nn~r as in EXAMPLE
1, exceFt that a mixture of 60g of cilostazol and 60g of an ethylene vinyl alcohol copolymer (EVAL EP-E 105A available from Kuraray Co., Ltd., ethylene content: 44 mol.~) in a ground form (sieved with a 28-mesh) was melted and extruded at an extruding temperature of 170~C.

~XAMPr.r~
The particles (cont~; n; ng 50~ by weight of '- CA 02208571 1997-06-23 .
-; W O 96121448 PCT/JP96/00004 . -16-.
' ';
cilostazol) obtained in EXAMPLE 20 were classified into particle size ranges of 75 to 105~m and the other.
-- T;~2~PT.F~
Particles cont~; n; ng 60% by weight of cilostazol were obtA; n~ in substantially the same manner as in EXAMPLE
1, except that a mixture of 72g of cilostazol and 48g of an -~ ethylene vinyl alcohol copolymer (EVAL EP-E 105A available . . .
: from Kuraray Co... Ltd., ethylene content: 44 mol.%) in a ~: ground form (sieved with a 28-mesh) was melted and extruded at ~-- 10 an extruding temperature of 170~C.
XAMPr.~ ~.~
The particles (containing 60~ by weight of cilostazol) obt~;~e~ in EXAMPLE 22 were classified into = . .
; particle size ranges of 75 to 105,um and the other.
5 ~Xz~MPT.F: ~;>. 4 Particles containing 70% by weight of cilostazol .
~- were obtained in substantially the same manner as in EXAMPLE
1, except that a mixture of 84g of cilostazol and 36g of an ethylene vinyl alcohol copolymer (EVAL EP-E 105A available from Kuraray Co., Ltd., ethylene content: 44 mol.~) in a ground form (sieved with a 28-mesh) was melted and extruded at .
an extruding temperature of 175~C.
T;~XAMPT.l;~ ~:7.5 . . . ~
'- The particles (containing 70% by weight of -~t 25 cilostazol) obt~;n~ in EXAMPLE 24 were classified into ~ .
. ~
- ~
: .

~ 5. .

WO 96121448 PCT/Jr~;/WCC4 particLe size ranges of 75 to 105~m and the other.
~Mprl~ ~6 Particles cont~i n; ng 80% by weight of cilostazol were obt~ine~ in substantially the same r-nner as in EXAMPLE
1, exce;~pt that a mixture of 96g of cilostazol and 24g of an ethylene vinyl alcohol copolymer (EVAL EP-E 105A available from Kuraray Co., Ltd., ethylene content: 44 mol.~) in a ground form (sieved with a 28-mesh) was melted and extruded at an e~truding temperature of 175~C.

0 ~XAMPT.F ~.7 The particles (containing 80~ by weight of cilostazol) obt~; n~ in EXAMPLE 26 were classified into particle size ranges of 75 to 105~m and the other.

~MPT.T; ~7.8 Particles cont~; ni ng 90% by weight of cilostazol were obt~; n~ in substantially the same manner as in EXAMPLE
1, except that a mixture of 108g of cilostazol and 12g of an ethylene vinyl alcohol copolymer (EVAL EP-E 105A available from Ku~aray Co., Ltd., ethylene content: 44 mol.%) in a ground form (sieved with a 28-mesh) was melted and extruded at an extrllding temperature of i750C.
F~XAMPT.~ 29 The particles (containing 90~ by weight of cilosta2;01) obt~;n~ :in EXAMPLE 28 were classified into ~ 25 particle size ranges of 75 to 105~m and the other.

.~ CA 02208571 1997-06-23 RT~T.F~A~F~ TF~:;T
The particles obtained in each of EXAMPLES 1 to 29 in an amount equivalent to a cilostazol conten~ of 50mg were , .. immersed in a 500-ml test solution (0.3% sodium lauryl sulfate ~- 5 solution), and the amount of cilostazol released into the test .~ solution was determined by the absorption photometry at predetermined time intervals. The results are shown in Table ,- 10 -.

~- 15 ~ ~ ~

. .
: 20 , , . .
'~

~ - 25 ' .

,' ~

CA 02208~71 1997-06-23 W O 9612t448 PCT/JP96100004 Table1 Releaseofcilostazol(~t.X) Timelapse(hr) Example 1 2 3 4 6 .8 10 12 355-500~mp.s. 9 14 16 18 22 26 29 31 250-355ump.s. 13 18 23 25 29 32 36 39 150-250~mp.s. 19 27 33 37 42 49 53 57 105-150ump..c. 31 42 48 53 61 67 71 75 75-105~mp.s. 42 54 60 66 74 78 84 84 < 75~mp.~. 67 79 85 89 94 97 99 lO0 ~ 10 14 17 19 24 27 29 33 105-150ump.s. 17 22 27 31 36 40 45 49 475-105ump.s. 21 29 34 40 46 51 56 61 < 75ump.s. 35 44 52 58 66 70 75 80 105-150~mp.s. 16 22 28 31 38 43 47 52 6 75-105~mp.s. 21 31 37 42 49 57 60 66 < 75~mp.s. 36 49 56 66 72 79 84 86 7 7 8 10 11 14 15 18 l9 1 75-105~mp.s. 26 36 42 47 55 59 63 67 -< 75~mp.s. 48 60 66 71 78 83 86 89 13 75-105ump.s. 39 53 61 67 76 83 86 89 < 75~mp.s. 73 83 88 91 95 97 98 lO0 l:i75-105~mp.s. 52 70 79 86 93 98 lO0 102 < 75~mp.s. 81 9297 97 101 102 103 104 1'' < 75ump.s. 81 89 91 92 93 94 95 95 Itl 75-105~mp.s. 25 33 39 43 50 55 58 61 21 75-105ump.s. 31 41 47 52 59 64 69 72 23 75-105~mp.s. 27 37 45 50 59 65 69 72 2'j 75-105~mp.s. 38 51 62 66 75 82 86 88 - 25 2l75-105~mp.s. 50 70 79 87 93 97 99 99 2~1 75-105~mp.s. 64 83 93 100 99 102 102 lO0 llp.S. n means"particlesize"

- CA 02208~71 1997-06-23 . ., '-~' , .
- As can be seen from Table 1, the release of , cilostazol can be controlled as desired by appropriately 4 ; selecting the cilostazol content and particle size.
. .
~R~ORPTTON T~T
An absorption test was carried out on the following ; test preparations and control preparation.
Test preparation 1: Particles having a particle size range of 75 to 105,um obtained in EXAMPLE 2 - Test preparation 2: Particles having a particle size range of 75 to 105~m obtained in EXAMPLE 4 ,~ 10 Test preparation 3: Particles having a particle size range of , 75 to 105~m obtained in EXAMPLE 19 Test preparation 4: Particles having a particle size range of 75 to 105,um obtained in EXAMPLE 21 ~''t. Control preparation: Hydroxypropyl methyl cellulose (HPMC) ~ suspension containing lOmg of cilostazol --' The test preparations and the control preparation each cont~ ng lOmg of cilostazol were respectively ~illed in -~ minicapsules for rats to be used in the absorption test. The preparations were orally administered to rats (32 rats for - each test group), and blood was sampled from inferior vena cava of each rat after 0.5, 1, 2, 3, 4, 6, 8, 10 hours (n=4).
~- 20 Then, cilostazol concentrations in sera of the respective blood samples were determined by the rapid liquid .
.~- chromatography, and the degrees of cilostazol absorption were compared with each other. The results are shown in Table 2.

:~ 25 . .
'-.

,:, -' :.
,~.

CA 0220857l l997-06-23 W O 96/21448 PCT~J~9f'000CI

Table 2 Cilostazol concentration in blood serum (ng/ml) T; mF~ 1 ~p~ ( h~ ) J 0.5 1 2 3 4 6 8 10 Test Preparation 1 14 25 53 48 49 40 15 18 Test Preparation 2 16 23 46 75 32 60 32 30 Test Preparation 3 7 6 11 80 38 48 40 19 Test Preparation 4 12 11 35 21 51 55 41 30 Control Preparation73 96 148107 83 30 6 11 As can be seen from Table 2, a rapid increase in the cilostazol concentration in blood serum ;mme.~iately after the admini-~tration of each of the test preparations is suppressed in comEarison with the control preparation. The cilostazol concent-ration is kept high even after six hours. This indicates that the m~; mllm cilostazol concentration in blood serum (Cmax) can be lowered and, at the same time, the serum cilost2zol co~c~ntration is maintained in a desired range over an ext~nded period of time.

W O 96121448 PCT/JP9GJC~~~I

- ~ Ph~rm~ t; cc~l ~x~mpl ~
'- A 200mg of the particles obtained in EXAMPLE 2 'r,~= ( which contains 50% by weight of cilostazol and has a particle size of 75 to 105~m) were filled in a capsule to give a capsule cont~ining lOOmg of cilostazol.
.
.
~ - Ph~r~llti~l ~x~m~l~. ~.
. .
- - A 125g of the particles obtained in EXAMPLE 27 (COnt~;n;ng 80% by weight of cilostazol, particle size of 75 --~ 10 to 105~m), 40g of crystal cellulose, 34g of corn starch and lg of magnesium stearate were milled together. The resulting mixture was tableted by means of an R 9-mm punch to give a - 200mg tablet containing lOOmg of cilostazol.

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Claims

1. A resin particle comprising an ethylene vinyl alcohol copolymer and a cilostazol incorporated therein, an ethylene content in the ethylene vinyl alcohol copolymer being 27 to 70 mol% and a melting point of the ethylene vinyl alcohol copolymer being 120 to 200°C, the cilostazol being contained in an amount of 5 to 90% for the total amount of the ethylene vinyl alcohol copolymer and the cilostazol, and the resin particle having particle size of not greater than 2,000µm.

2. A resin particle as set forth in claim 1, wherein cilostazol is contained in an amount of 20 to 85% by weight.

3. A resin particle as set forth in claim 2, wherein cilostazol is contained in an amount of 30 to 85% by weight.

4. A resin particle as set forth in claim 3, wherein cilostazol is contained in an amount of 40 to 85% by weight.

5. A resin particle as set forth in claim 4, wherein cilostazol is contained in an amount of 60 to 85% by weight.

6. A resin particle as set forth in claim 5, wherein a particle size of the resin particle is not greater than 600µm.

7. A resin particle as set forth in claim 6, wherein a particle size of the resin particle is in a range of 75 to 250µm.

8. A resin particle as set forth in claim 7, wherein a particle size of the resin particle is in a range of 75 to 150µm.

9. A resin particle as set forth in claim 8, wherein a particle size of the resin particle is in a range of 75 to 105µm.

10. A resin particle as set forth in claim 4, wherein a particle size of the resin particle is not greater than 600µm.

11. A resin particle as set forth in claim 10, wherein a particle size of the resin particle is in a range of 75 to 250µm.

12. A resin particle as set forth in claim 11, wherein a particle size of the resin particle is in a range of 75 to 105µm.

13. A resin particle as set forth in claim 1, wherein cilostazol and ethylene vinyl alcohol copolymer are blended in a molten state.

14. A resin particle as set forth in claim 13, wherein cilostazol and ethylene vinyl alcohol copolymer are blended at a molten state of 165 to 180°C.

15. A resin particle as set forth in claim 14, wherein cilostazol is contained in an amount of 60 to 85% by weight.

16. A resin particle as set forth in claim 15, wherein ethylene is contained in an amount of 44 to 47 mol.% in the ethylene vinyl alcohol copolymer.

17. A resin particle as set forth in claim 16, wherein a number-average degree of polymerization of the ethylene vinyl alcohol copolymer is in a range of 12,000 to 40,000.

18. A medical material comprising an ethylene vinyl alcohol copolymer and a cilostazol incorporated therein, the cilostazol being contained in an amount of 60 to 85% by weight for the total amount of the ethylene vinyl alcohol copolymer and the cilostazol.

19. A medical material as set forth in claim 18, wherein cilostazol and ethylene vinyl alcohol copolymer are blended at a melting temperature of 165 to 180°C.

20. A medical material as set forth in claim 19, wherein ethylene is contained in an amount of 44 to 47 mol % in the ethylene vinyl alcohol copolymer.

21. A medical material as set forth in claim 20, wherein a number-average degree to polymerization of the ethylene vinyl alcohol copolymer is in a range of 12,000 to 40,000.

22. A medical material as set forth in claim 21, wherein ethylene is contained in a range of 38 to 47 mol.% in the ethylene vinyl alcohol copolymer.

23. A medical material as set forth in claim 22, wherein a number-average degree of polymerization of the ethylene vinyl alcohol copolymer is in a range of 12,000 to 40,000.

24. A pharmaceutical preparation comprising a resin particle as set forth in claim 1, or a mixture of the resin particle and a pharmaceutically available carrier.