CA2207334C - Sustained-release granular preparations and production process thereof - Google Patents

Abstract

This invention relates to sustained-release granular preparations obtained by wet-granulating an aqueous suspension, which comprises a medicinal ingredient, a fine particulate polymer having an average particle size not greater than 50 .mu.m and a plasticizer, into granules and treating said granules at a temperature not less than the lower one of a minimum film-forming temperature and glass transition temperature of a mixture of said polymer and said plasticizer. This invention is also concerned with a process for the production of the sustained-release granular preparations. According to the present invention, granular preparations having an excellent sustained-release property and a high safety to the human body can be easily produced in a simple manner.

Description

a .r SUSTAINED-RELEASE GRANULAR PREPARATIONS
AND PRODUCTION PROCESS THEREOF
TECHNICAL FIELD
This invention relates to sustained-release granular preparations permitting control of the release rates of their medicinal ingredients and also to a pro-duction process thereof.
BACKGROUND ART
Sustained release preparations have a function to control the release rate.of its medicinal ingredient, and they can maintain the effective blood level of the medicinal ingredient for a long time following adminis-tration to patients. In addition, it can also reduce the frequency of administration so that the compliance and QOL (quality of life) of the patient can be im-proved. Further, control of a blood level of the medi-cinal ingredient in the range of its minimum effective level to its minimum toxic level can make assure its effectiveness and safety to the human body.
Such sustained release preparations include prep-arations wherein a medicinal ingredient is coated with a film and preparations of matrix type wherein a medi-cinal ingredient is dispersed in a matrix. Illustra-z tive preparation forms include multiple-unit prepara-tions and single unit preparations. These multiple-unit preparations in turn include granules and fine granules, which are composed of a number of subunits, and capsules and tablets containing granules or pellets which promptly disintegrate into subunits in the di-gestive tract after oral administration thereof. On the other hand, such single unit preparations include lion-disintegrative matrix tablets, and tablets coated with a release-controlling film.
Multiple-unit preparations are advantageous over single unit preparations in that they have high reproducibility of movement in the digestive tract, have a lower hazardous problem of local irritation owing to their movement in a wide-spread manner through the digestive tract, and permit administration in por-tions [Isao Sugimoto et al., "(Seizai Kaihatsu No Jis-sai To Kadai (Practice and Pr~hl Pm~ ; n i-hA nP~TAI nmmcnt _ __ _ ___ _ _____ _ _ _____.._ ___ ___~ ............._..r.~«....,~,.
of Dosable Preparations)", Chapter 3, 215-228, 1986, R
& D Planning]. As a production method of multiple-unit preparations, commonly employed is a method in which granules with a medicinal ingredient contained therein are coated with a release-controlling film is commonly employed. Also proposed include a method in which ion-exchange resin beads with a medicinal ingredient bound thereon are coated with a polymer, a method in which granules with a medicinal ingredient dispersed in an enteric solid are prepared by solid dispersion, a meth-od in which matrix-type granules or fine granules with a medicinal ingredient dispersed in a polyglycerin fatty acid ester are formed by spray chilling [Japanese Patent Laid-Open No. 223533/1990], and as a production method of sustained-release granular preparations of a dihydropyridine-type Ca channel blocker, a method in which the sustained-release granular preparations are produced by extrusion granulation while using an enter-is polymer, especially a water-base latex dispersion of a methacrylic acid copolymer LD as a binder (European Patent Application No. 87118948.6 filed on December 21, 19 8'7 ) .
However, the coating method causes a safety prob-lem to the human body because a polymer is dissolved using an organic solvent. Further, there is anothe-r problem that cumbersome control is required because the dissolution rate of a medicinal ingredient varies by a change in the thickness of a coating film or in the size of pores present in the coating film. Moreover, the coating method is accompanied by a further problem that, if a crack is formed in the coating film, the medicinal ingredient is rapidly released. On the other r hand, in the method in which matrix-type granules or fine granules are produced, production procedures and quality control are relatively easy. It is, however, accompanied by a problem that a special apparatus such as a spray-chilling drier has to be used to obtain granular preparations.
Incidentally, Japanese Language Laid-Open Publi-cation (PCT) No. 503315/1990 discloses a process for producing sustained-release dosable preparations by blending a medicinal ingredient and a polymer having a glass transition temperature (Tg) of from 30 to 150°C
into a raw material composition and forming the raw material composition into a predetermined shape, in which the raw material composition is maintained at the glass transition temperature or at a temperature higher than the glass transition temperature for a time suffi-cient to impart a preparation form having sustained-release property. This process, however, requires ad-dition of the polymer after its dissolution in an organic solvent or addition of the polymer as a latex dispersion by dissolving it in an organic solvent and then emulsifying the resulting solution in water.
Regarding preparation forms, its Examples also disclose only tablets. Application of this process for the pro-duction of granular preparations failed to provide the resulting preparations with fully satisfactory sustained-release property.
Accordingly, it has been desired to develop a process which makes it possible to easily produce a sustained-release granular preparations of the matrix type without using any special apparatus.
DISCLOSURE OF THE INVENTION
Under such circumstances as described above, the present inventors have proceeded with an extensive in-vestigation. As a result, it has been found that a granular preparation having excellent sustained-release property can be easily produced by wet-granulating method, which comprises wet-granulating an aqueous suspension, which comprises a medicinal ingredient, a fine particulate polymer having an average particle size not greater than 50 ~m and a plasticizer, into granules and treating said granules at a temperature not less than the lower one of a minimum film-forming temperature and glass transition temperature of a mix-ture of said polymer and said plasticizer, leading to the completion of the present invention.
Namely, the present invention provides a process for the production of sustained-release granular prepa-rations, which comprises wet-granulating an aqueous suspension, which comprises a medicinal ingredient, a fine particulate polymer having an average particle size not greater than 50 ~m and a plasticizer, into granules and treating said granules at a temperature not less than the lower one of a minimum film-forming temperature and a glass transition temperature of a mixture of said polymer and said plasticizer, and also the resulting sustained-release granular preparations produced by the above process.
BEST MODE FOR CARRYING OUT THE INVENTION
No particular limitation is imposed on the medi-cinal ingredient available in the sustained-release granular preparations according to the present inven-tion., As long as medicinal ingredients are orally dosable and are solid at room temperature like tranexamic acid, cetraxate hydrochloride, ticlopidine hydrochloride, ofloxacin, levofloxacin, cephem anti-biotics, theophylline and procainamide hydrochloride, they are all available. Such medicinal ingredients are usually employed in the form of powders, and their par-ticle sizes are preferably 250 ~cm or smaller in gener-al.
The term "polymer" as used herein does not mean an emulsion-like latex polymer or pseudolatex polymer z _ - 7 -but means a solid, specifically powdery high-molecular compound obtained by conducting a polymerization reac-tion, a polymerizing reaction or the like in a usual manner or a powdery high-molecular compound produced by drying a latex polymer or a pseudolatex polymer. I1-lustrative examples include ethylcellulose, cellulose acetate, cellulose acetate phthalate, carboxymethylcel-lulose, methacrylic acid-methyl methacrylate copolymers fmethacrylic acid copolymer L, methacrylic acid copolymer S, etc.), ethyl acrylate-methyl methacrylate-trimethyl ammonioethylmethacrylate chloride copolymers (aminoalkyl methacrylate copolymers RS), hydroxypropyl methylcellulose phthalates (hydroxypropyl methylcel-lulose phthalate 200731, hydroxypropyl methylcellulose phthalate 200824, etc.), hydroxypropyl methylcellulose acetate succinate, ethylene-vinyl acetate copolymer, polyvinyl acetate, shellac, and the like. These nnlvmArc ran ho iicc~i of+her c;,~,..r~<> ~, ~.,i..~....r..:., r.._.~1 ~wvr. yr vuia wm. uvyn a-.y vylG1 W 111 i.Z yr iW W luu.Liict t.tVi1 .
In the present invention, it is preferred from the viewpoint of temperature control to employ a polymer which, when mixed with the plasticizer to be described subsequently herein, gives a minimum film-forming temperature or a glass transition temperature of about 100°C or lower, desirably 90°C or lower. From this standpoint, it is preferred to employ as the polymer s - g _ ethylcellulose, methacrylic acid-methyl methacrylate copolymer, ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl-cellulose, cellulose acetate phthalate or the like.
The term "minimum film-forming temperature (hereinafter abbreviated as "MFT") means a minimum drying temperature at which latex particles undergo deformation and fusion into a continuous film under a capillary attraction produced in inter-particle capil-laries. MFT is determined by properties of a polymer, colloidal property of a latex, environmental condi-tions, etc. Of these, the MFT is dependent especially on the glass transition temperature (Tg) of the polymer and indicates a temperature around the Tg [see Soichi Murai, "Latex No Kagaku (Chemistry of Latex)", Kobunshi Kankokai, Tokyo Japan]. It is not only a latex polymer or a pseudolatex polymer but also a mixture of a fine particulate polymer and a plasticizes, said mixture being useful in the practice of the present invention, that has an MFT. Whichever the case may be, the MFT
varies depending on the amount of the plasticizes to be added. In general, MFT goes down by increasing the amount of an added plasticizes. Measurement of such an MFT can be performed by a method known per se in the art, for example, in accordance with the temperature gradient plate method devised by Protzman et al. in J.
Appl. Polymer Sci., 4, 81, 1960 or the method described in the periodical, Chem. Pharm. Bull., 42(3), 656-662, 1994.
Further, "glass transition temperature" (herein-after abbreviated as "Tg") is one of important parame-ters for specifying physical properties of a polymer.
When a polymer in a liquid form is cooled under certain conditions, the polymer is frozen into a glassy state via a supercooled liquid. A phenomenon in which, as mentioned immediately above, a polymer changes into a glassy state without crystallization is called "glass ' transition". The temperature at that polymer's transi-tion phenomenon is called "Tg". In essence, this transition phenomenon is a freezing phenomenon and is a sort of relaxing phenomenon. Described specifically, the liquid state cannot follow the cooling temperature, resulting in a glassy state which can be considered as having frozen during an observation period (segment mo-tion -. micro-Brownian motion -~ freezing). Ac-cordingly, a temperature lower than or equal to Tg causes no micro-Brown motion of molecules, leading to substantial changes in physical properties, especially r to significant changes in the coefficient of expansion, transmission, heat capacity, refractive index and hard-ness [see "Iyakuhin No Kaihatsu (Development of Pharmaceuticals), Vol. 12: Seizai Sozai (Pharmaceutical Necessities)", Hirokawa Publishing Co., Tokyo, Japan;
"Kobunshi Kagaku No Kiso (Fundamental of High Molecular Chemistry)", Tokyo Kagaku Dojin, Tokyo, Japan]. Such Tg also varies by the addition of a plasticizer.
Similarly to MFT, Tg generally tends to go down by in-creasing the amount of an added plasticizer.
The average particle size of the polymer is 50 ~cm or smaller in general. An average particle size not greater than 20 ~cm but not smaller than 1 ~m is partic-ularly preferred from the standpoint of obtaining marked sustained-release property. An average polymer particle size greater than 50 ~cm makes it difficult to obtain a granular preparation having preferred sustained-release property. The term "average particle size" as used herein means a volume mean particle size measured by a laser diffraction particle size distribu-tion measuring instrument.
No particular limitation is imposed on a method which is available for finely grinding the polymer.
Applicable methods include, for example, a method using a grinding machine such as a jet mill or ball mill and to spray-drying a dispersion of a latex of the polymer.
Although no particular limitation is imposed on the amount of the polymer to be added, the polymer can be added generally in an amount 0.001 to 10,000 times by weight as much as the medicinal ingredient. How-ever, from the standpoint of obtaining better sustained-release property as an advantageous effect, it is preferred to add the polymer in an amount 0.001 to 50 times by weight as much as the medicinal in-gredient.
Illustrative examples of the plasticizer employed in the present invention include alkyl citrates such as triethyl citrate, acetyl triethyl citrate, tributyl citrate and acetyl tributyl citrate; sucrose fatty acid esters; glycerin mono-, di- and tri-fatty acid esters such as triacetin, glycerin mono-fatty acid esters, glycerin monostearate and acetylated monoglyceride;
polyglycerin fatty acid esters; polyethylene glycols such as macrogol 400, macrogol 600, macrogol 1500, mac-rogol 4000 and macrogol 6000; tributyl sebacate;
propylene glycol; sesame oil; castor oil; glycerin;
silicone resins; D-sorbitol; phytosterol; alkyl phtha-lates such as diethyl phthalate, dibutyl phthalate and dioctyl phthalate; adipate polyesters; isopropyl myristate; medium chain triglyceride; butyl phthalyl butyl glycolate; and polyoxyethylene polyoxypropylene glycol. They can be used either singly or in combina-tion. Of these, preferred for use in the present in-vention from the stand point of general-purpose ap-plicability and simplicity are alkyl citrates such as triethyl citrate, acetyl triethyl citrate, tributyl citrate and acetyl tributyl citrate; glycerin mono-, di- and tri-fatty acid esters such as triacetin;
polyethylene glycols such as macrogol 400, macrogol 1500 and macrogol 6000; alkyl phthalates such as diethyl phthalate and dibutyl phthalate; and propylene glycol.
The plasticizer can be added in such an amount that the resulting mixture of the plasticizer and the above-described polymer has an MFT or Tg of preferably not more than about 100°C, more preferably not more than 90°C. It is therefore preferred to add the plasticizer in an amount 0.001 to 5 times, notably 0.01 to 1 times by weight parts as much as the polymer.
The granular preparations according to the pres-ent invention can also contain, as needed, one or more of additives generally employed for the production of granular preparations and fine granular preparations, for example, excipients such as lactose, starch and crystalline cellulose; binders such as hydroxypropyl cellulose, polyvinyl pyrrolidone and hydroxypropyl methylcellulose; disintegrators such as calcium car-boxymethylcellulose, low-substituted hydroxypropylcel-lulose and croscarmellose sodium; surfactants such as polysorbate 80, sodium laurylsulfate and "Pluronic"
(trade mark); lubricant such as magnesium stearate;
glidants; wetting agents; coloring matters; and bioad-hesive polymers such as carboxyvinyl polymer, sodium alginate and sodium carboxymethylcellulose. The ex-cipient can be added in a usual amount and regarding its particle size, it is generally sufficient to set it at 600 ~cm or smaller in the case of lactose, at 100 ~cm or smaller in the case of starch, and at 250 ~cm or smaller in the case of crystalline cellulose. Further, the amount of the binder to be added can usually be 1 to 5 wt.% based on the total weight of the granular preparations according to the present invention. As to the~particle size of the binder, it is generally suffi-cient to set it at 500 ~m or smaller in the case of hydroxypropyl cellulose, at 250 ~m or smaller in the case of polyvinyl pyrrolidone, and 180 dam or smaller in the case of hydroxypropyl methylcellulose. The amount of the disintegrator to be added can usually be 1 to 20 wt.% based on the total weight of the granular prepara-tions according to the present invention. With respect to the particle size of the disintegrator, it is gener-ally sufficient to set it at 75 ~m or smaller in the case of calcium carboxymethylcellulose, at 180 ~cm or smaller in the case of low-substituted hydroxypropyl cellulose, and at 75 ~.m or smaller in the case of cros-carmellose sodium. Further, regarding the amounts and particle sizes of the glidant, wetting agent, coloring matter, surfactant and lubricant, those having commercially-available particle sizes can be used in usual amount ranges, specifically in amounts of 1%
based on the total weight of the granular preparations according to the present invention. With respect to particle size of the bioadhesive polymers, commercially available polymer's particle size can be selected in view of availability, and those polymers can be used in an amount of usually from 1 to 20% based on the total weight of the granular preparations according to the present invention. -The granular preparations according to the pres-ent invention can be obtained by wet-granulating an aqueous suspension of the above-described ingredients.
Upon wet granulation, it is preferred to homogeneously suspend the plasticizer in water in advance. Water is generally sufficient when used in an amount of 0.1 to 1 times by weight parts as much as the total weight of solid ingredients employed. In the present invention, an aqueous suspension consisting of ingredients and a binder solution or water is granulated by a wet-granulation method. Usable examples of the wet-s granulation method include (1) the extrusion granula-tion method in which water or the like is added to pow-deny raw materials, the resulting mixture is kneaded, and the mass so kneaded is pressed against a die or a screen for its extrusion therethrough, whereby the kneaded mass is formed, that is, granulated; (2) the mixing and agitating granulation method in which pow-dery raw materials are mixed with a binder solution or water and under mixing and agitation, the resulting mixture is granulated; (3) the high-speed mixing and agitating granulation method, which is to conduct the mixing and agitating granulation method under a high shear force, namely, in which powdery raw materials are added with a binder solution or water and are granu-lated while mixing, agitating and fluidizing the pow-dery raw materials at a high speed; (4) the fluidized bed granulation method in which a fluidized bed of pow-dery raw materials is formed by an air stream and a binder solution of water is sprayed into the fluidized bed under drying conditions so that particles are caused to cohere into grains by liquid linkage; and (5) the rolling granulation method in which rolling raw materials is~~sprayed or coated with a binder or water to form spherical particles [see "Iyakuhin No Kaihatsu (Development of Pharmaceuticals)", Volume 11: "Seizai No Tan-i Sousa To Kikai (Unit Operations and Machines for the Prod~iction of Dosable Preparations)", Hirokawa Publishing Co., Tokyo, Japan]. These methods are all usable in thi present invention.
- The target sustained-release granular prepara-tions can be!,obtained by treatinq the qranules. which have been obtained by the above-described wet granula-tion, at a temperature not less than the lower one of the MFT and ~g of the mixture of the polymer and the plasticizer,~specifically by allowing the granules to stand where the treatment temperature is in the range i of room temperature or by heating the granules where the treatment temperature is higher than room tempera-i ture. In general, however, treatment at a temperature a ual to or hi her than the T of the q I g g polymer can pro-vide granular preparations having sufficient sustained-release effedt. In general, the treatment temperature can be set preferably at a temperature higher from 10 to 50°C than the lower one of the MFT and Tg of the i used polymer.; A treatment time of 1 to 24 hours is !
sufficient. !

_ 17 -Although no particular limitation is imposed on the particle size of the sustained-release granular preparations, the particle size can generally range from 10 ~cm to 170 Vim. In the case of fine granules, however, it is preferred to control the content of granules smaller than 75 ~cm at 10 wt.% or less, the content of granules equal to and greater than 75 um but smaller than 500 um at 85 wt.% or more, and the content of granules equal to and greater than 500 ~cm but small-er than 850 um at 5 wt.% or less. In the case of a granular preparation, on the other hand, it is preferred to control the content of granules smaller than 355 ~Cm at 15 wt.% or less, the content of granules equal to and greater than 355 ~m but smaller than 1,400 ~m at 80 wt.% or more, and the content of granules equal to and greater than 1,400 ~m but smaller than 1,700 ~m at 5 wt.% or less.
The granular preparations according to the pres-ent invention can be formed into capsules by filling it in capsules in a manner known per se in the art. It can also be compressed into tablets together with an ex-cipient, a disintegrator and a lubricant, as needed.
The present invention will hereinafter be de-scribed in further detail by the following Examples.
It is however be borne in mind that the present inven-tion is not limited to the following Examples.
Example 1 and Comparative Example 1 In accordance with the formulas shown in Table 1, granular preparations were produced as will be de-scribed below. By conducting the following dissolution test, an investigation was carried out about any dif-ference in sustained release property depending on whether the plasticizer was contained or not.
(-Dissolution test) The dissolution test was conducted following Method 2 (the paddle method) described under General Tests, Processes and Apparatus in The Pharmacopoeia of Japan, Twelfth Edition (JPXII). Described specifical-ly, the preparation in an amount equivalent to 100 mg in terms of theophylline was immersed in 900 m2 of water, followed by rotation of a stirring wing at 100 rpm to cause dissolution of the medicinal ingredient from the preparation. The dissolved solution was peri-odically sampled and filtered. The absorption of each filtrate so obtained was measured, and a dissolution rate was calculated from the absorption.

> >

Table 1 Formula (g) Example Comp. Ex.

Theophylline (THEO) 15 15 Ethyl cellulose (EC)*1 110 110 Triethyl citrate (TEC) 25 -Polysolbate 80 (Tween 80) Trace Trace Total 150 125 Tg ( C) 36*2 ,130*3 MFT (C) 65*2 -*1: Fine particle grade (volume mean particle size:
10.0 dam); N-10-F, Shin-Etsu Chemical Co., Ltd.
*2: Estimated from the data shown in Chem. Pharm.
Bull., 42(3), 656-662(1994) *3: Int. J. Pharm. 27, 267-277(1985) Int. J. Pharm. 34, 93-103(1986) J. Pharm. Pharmacol., 31, 269-277(1979) First, polysorbate 80 was dissolved in 75 mB of water, in which triethyl citrate was homogeneously suspended to obtain a binder suspension. After -theophylline and ethyl cellulose were mixed in a high-speed agitating granulation machine, the resulting mix-ture was granulated while slowly dropping the above-described binder suspension thereto. A portion of the granules so obtained was dried at 80°C for 4 hours, whereby a granular preparation was obtained. Prepara-tions obtained by drying another portion of the a granules at room temperature were provided as a con-trol. A dissolution test was conducted using granules of 500 to 1,400 um in particle size in each of the thus-obtained preparations. The results are presented in Table 2.

O N O O

O

d' O O O O

In O 01 O O

~i O In O O 111 pp d' a1 CO O 01 O1 CO O a1 O d' l~ O Ln N

d' a1 In O a1 ~i O t0 ~-IO r1 M CO M O a1 ri O lfl N a1 111 O

M t0 O CO CO

o\o a1 pp v ~ O O ~-I01 O

td N CO lp CD CO

~-1 01 I~ 61 Ol O O 01 r-I01 N

'I 00 a-1 e-1lfl e-~CO t~

01 t~ 01 01 N
O

O Ul O O1 al l~ In UI N

ri ed Ln M I~ l0 A

N

M N r1 L(7 O

N N l0 l0 M M M In O

M 111 O l0 ~0 d' 01 al In l~ N 01 CO

O O O O

O

O O O O

O O

~

O 1-1~ O F-I

~

N S-a O '~ ~
O

U U ~ U
U

~

A .1-~ co A +~ co U7 v-1 a c ~C O ~C

W W U W

i ' - 22 -From Table 2, it has been confirmed that granules added with a plasticizer (Example 1) can be formed into a preparation having marked sustained release property when heated but that a preparation free of a plasticiz-er (Comparative Example 1) does not have any sustained release property.
Examples 2-3 In each example, granules were formed as in Exam-ple 1. Portions of the granules were dried at 40, 60 and 80°C for 4 hours or 12 hours to obtain prepara-tions, respectively. Further, a portion of the granules was dried at room temperature for a day to ob-taro a preparation as a control. Using granules of 500 to 1,400 ~m in particle size in each of the thus-obtained preparations, a dissolution test was conducted as in Example 1. An investigation was carried out to check any influence by the drying temperature. The results are presented in Table 3. -O O O N O O O

O

d' O O O O O O O

O Ln In L~ O In l~ N

d' 01 01 d1 CO 01 a1 CO

a1 d1 01 CO 01 d1 a1 O d' N l0 I~ In l0 N

N

d' 01 01 00 Ln d1 CO lfl 01 01 O1 CO O1 01 a1 O CO M O u-ICO O r-1 M 00 CO GO M 00 CO d' O1 al O1 00 O1 O1 dl O ~ I~ 00 N M 00 N

O

.-. M CO I~ l0 O CO l0 c-1 0\0 01 al Ol 00 dl Ol Ol v - N O O O ~ ~ [w M

td N CO l~ In l0 l~ In ~-I 01 a1 O1 l~ 01 01 CO

O O 01 M c~ e- W M N

'r-I00 M e-It~ M N

01 01 01 l~ 01 01 00 M

O

O U1 O 01 N r1 01 01 c~ N

wi e-ILn M O M LL1 O d~

N

M N CO N d' M L~

O

N lflc-1 N N c-IO

01 CO CO Ilk01 00 l0 M In N M l0 M lid O

M lf~ d' 01 O l0 d1 I~

CO l~ lfl d' CO l0 In e-1CO 01 O 00 d' e-Ie-i l~ M CO l0 M Ln ~1 ~ N l~ tf)M

O O O O O O O

O

O O O O O O O

~r O

O
N

r1 ~-I ~-I ~-1,~-1 ~d d' d' d' ri ri r1 ~

O

~ U U U U U U
t1, .r-I~~ o o o o o ~ o 0 0 0 0 0 N

d' ~ ~ d~

N M

r1 td .f".., O

r1 O 'k,' ',x', ~I

W U W W

From Table 3, it has been confirmed that a prepa-ration having more prominent sustained-release property can be obtained as the drying temperature for granules becomes higher. On the other hand, it is also observed from the table that there is no difference in sustained release property between drying for 4 hours and drying for 12 hours.
Example 4 - Granules were formed as in Example 1. Portions of the granules were dried at 80°C for 1, 2 or 3 hours to obtain preparations, respectively. Further, a por-tion of the granules was dried at room temperature to obtain a preparation as a control. Using granules of 500 to 1,400 um in particle size in each of the thus-obtained preparations, a dissolution test was conducted as in Example 1. An investigation was carried out to check any influence by the drying temperature. The results are presented in Table 4. -o ,~ ,-i o ~O t~ M ri ,-i O ~ ~ ~ O

to IW -I O O

O ~O N ~ O

~O O O~ O~

O v--I v0 O W
I

N

n d, n d>

O ~O O~ N fi M ~O t~ ~O tf1 O O v-IO~ O~

O

cY~ M i0 ~O M N

O

h BLS O v0 N I~

N u1 M O O~

D\ ~ ~ n O

r-I

l~

O r1 i.nt~ tf1 r-1 O r1 lf1 W O tI1 n n ri ri O Ov O ri v-1 n O

M M O I~

O~ lD l0 tn u1 M v0 O~

O

M O r-1OW f~

N ~' w1' r-I~ ~ o0 W

OJ M M M

O O O O

O

O O O O

O

O

~ N

- M
--I

N S-i U U U

'LS O O O
N

N O O O

r-I 00 ~ N
~

~
N

A

~. ~
r~

G
o r-iO DC
,4 W U W

r From Table 4, it is observed that desired sustained-release property was substantially achieved by drying for 1 hour and that in drying for 1 to 4 hours, sustained release property slightly increased with the drying time.
Example 5 In accordance with the formula shown in Table 5, granular preparations were produced as in Example 1.
using granules of 500 to 1,400 ~m in particle size in the thus-obtained preparation, a dissolution test was conducted as in Example 1. An investigation was carried out to check any difference in the sustained release property of the preparations in which the plasticizer (TEC) had been increased relative to the polymer (EC). The results are presented in Table 6.
Table 5 Formula (g) Example 5 Theophylline (THEO) 15 Ethyl cellulose (EC)*1 100 Triethyl citrate (TEC) 35 Polysolbate 80 (Tween 80) Trace Total 150 Tg ( C) 34*2 MFT (C) 55*2 _ 2~ _ *1: Fine particle grade (volume mean particle size:
10.0 Vim) *2: Estimated from the data shown in Chem. Pharm.
Bull., 42(3), 656-662(1994) o ~D o0 M

D\

O I~ 01 u7 I~

O ~O ~-i p~

w1't~ O

Q\

O v-I 00 N

n O v0 M v0 tf1 O I~

O

dP M u'1 N

d1 O

l~

cd O 00 N

S-I ~' N ~ O~

O

1~

O O wt r-1 O v-1M tt1 r1 0 0~ N

o, o o ~O M M

e0 M

n O

M tf1 t I~ N

N

~O N

O O

O

O O

O

F'.O N >-t ~

O ~' v j~ a..1 S-i U
~

'C3 O
~ O

N P. O
U

d.~.ri 00 ~ ~

S-i N

b O +~

.

~d W W

From Table 6, it has been confirmed that sustained release property becomes more prominent by an increase in the amount of a plasticizer. This appears to be attributable to retarded release of the medicinal ingredient due to formation of the polymer into a homogeneous matrix under the influence of the plasticizer.
Examples 6-8 - In each example, granular preparations were pro-duced in accordance with the formula shown in Table 7 by following the procedures of Example 1. Using granules of 500 to 1,400 ~m in particle size in'the thus-obtained preparation, a dissolution test was con-ducted as in Example 1. An investigation was carried out to check any influence by the ratio of the polymer to the medicinal ingredient. The results are presented in Table 8.

' - 30 -Table 7 Formula (g) Ex. 6 Ex. 7 Ex. 8 Theophylline (THEO) 15 15 15 Ethyl cellulose (EC)*1 55 30 15 Triethyl citrate (TEC) 12.5 6.8 3.4 Polysolbate 80 Trace Trace Trace (Tween 80) Total 82.5 51.8 33.4 Tg (C~ 36*2 36*2 36*2 MFT (C) 65*2 65*2 65*2 *1: Fine particle grade (volume mean particle size:
10.0 Vim) *2: Estimated from the data shown in Chem. Pharm.
Bull., 42(3), 656-662(1994) 0 0 ,-ar~ o r~ 00 Q

a\

a' ~ ~ ~ a, O~ M M 00 \p Op O~ O~ O~ 01 01 O I~ \O M M M

pp M n n I~ n O~ O~ O~ O\ O\

O I~ ~' O ~ N N

00 N (W O I~ 1~

01 O~ O\ O~ O~ 01 O o~ O I~ M O O

M I~ O l0 \O I~ I~

a> ~ ~ Q\

O M ~ N vf1W O~

~ O

- dP M I~ t W O ~f1v0 v0 --O~ 00 O~ O~ Q1 Q~

U

l~

cd O o0 .-iO~ O tt1 ~O

S-i~' N l0 ~' tI1 ~' tD vD

d\ d>

~ O N ~O M

r-100 O v-I~O ~ tfW -I v0 n ~ Q1 r~

r-I

O

o ~ o N a. o o W o ~o ~n a, ~ ~ ~ a' M OO v-I ~' N \O

Q . . . , v0 N u1 N ~ ~ ,-I

n ~ a>

n O . . . . , M f~ N c0 ~ ,-~I N

\O v-i~' \D ~ O

r-1OO N v--I M N ~p i~ M CO ~ 00 v0 O O O O O O

O

O O O O O O

~ O O O

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.~ .. ..

~ o ~ ~ ~

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O O O

.-IO p. O N p., O N p, O
U U U

~ ~ N

N S-i S-a N

'b Ca l~ l~ l~

N

GL

~d x W W W W

From Table 8, it has been confirmed that sustained release property is exhibited more prominent-ly as the ratio of the polymer (EC) to the medicinal ingredient (theophylline) increases.
Examples 9-10 and Comparative Example 2 In each example, granular preparations were pro-duced as in Example 1 except that the ingredients in the formula shown in Table 1 were mixed with the parti-cle size of the polymer changed. Using granules of 500 to 1,400 um in particle size in the thus-obtained nrPn-_ _ _ __-_____ r--r aration, a dissolution test was conducted as in Example 1. An investigation was carried out about any in-fluence by the particle size of the polymer. The results are presented in Table 9.

_ - 33 -O O N O~ tD I~ p tf1 O O O~ tT ~ O

O O\ 01 O\ 01 O

O u'1 O u1 01 a1 O ~ I~ M N O tit N

01 tf'7Ov O~ 01 O~

Q\

O ~ ~-I01 r-Iov 01 M c0 M ~ Iw o0 00 O ~O N u1 O~

O

M a0 O o0 u1 ~ op O O r1 N O ~O O

o~ N CO ~O ~ ~' t~ a0 01 I~ d> 01 01 O~

N

O O~ r1 ,-a O ri tT I~ O~ O~ 01 h O ~ O~ ~' M O~ ~O

O ~-I tr1 M IW p ~ tt~

r1 M N 00 O o0 M

H O

v0 N N W u0 N r1 tn ~ n d1 M M \O O~ O~ M

O

M ~ O ri M I~ M

n M

v-I .-i OO M 01 O O~

i~ N 00 ~ 00 v0 O O O O O O

O

O O O O O O

O O O

O O ~ O N ~-tO O ~-t ~ ~ ~

~ ~ ~

O ~ O ~ ~ O

d-~ ~..t 1~ .4.~
h ~ 1~ Sa ~.I

~ ~ ~

N ~ 7-t U 7-a U ~ ~ U
~ ~

u7 N 2S N O d N O 'd O O
~ O O O

P.. O G1, O O p., O N , O
~ r1 U U U

(I~ .,...~ O~ r1 ~ pp r1 ~ O~
'-I ~ ~ v v ~

O

O

r-I

~ O 1~

r-i N ~

O N Ov v S

-1 V7 r-1 N tr1 rd W

O

p., N

W U W

r ' - 34 -From Table 9, it is observed that the sustained release property of a granular preparation becomes more prominent as the average particle size of the added polymer becomes smaller and that the addition of the polymer of 59.7 ~cm in average particle size failed to provide any granular preparation having sustained release property.
Examples 11-12 - In each example, granular preparations of the formulation shown in Table 10 were produced in a manner similar to Example 1. Using granules of 500 to 1,400 ~cm in particle size in the thus-obtained prepara-tion, a dissolution test was conducted as in Example 1.
An investigation was carried out to check its sustained release property. The results are presented in Table 11.

i ~ 1 ' - 35 -Table 10 Formula (g) Example 11 Example 12 Theophylline (THEO) 15 15 Ethyl cellulose (EC)*1 110 -Hydroxypropylmethyl-cellulose acetate - 110 succinate (HPMCAS)*2 Triethyl citrate (TEC) - 25 Triacetone 25 -Polysorbate 80 (Tween 80) Trace Trace Total 150 150 Tg ( C ) - -MFT (C) 35-40*3 15-20*3 *1: Fine particle grade (volume mean particle size:
10.0 ~cm) *2: Fine particle grade (volume mean particle size:
8.1 ~cm); AS-HF, Shin-Etsu Chemical Co., Ltd.
*3: Portions of a suspension of the polymer in an aqueous solution of the plasticizer were added to Petridishesand stored at--different-temperatures, respectively. About 48 hours later, the Petri dishes were taken out and observed to determine whether or not a film had been formed. An MFT was considered to exist between a lowest temperature at which a transparent film was formed and a highest temperature at which a transparent film was not formed.

- 3c~ _ O O ~ ~ N

O

O ~ N M

O O~ t~ 1~

O O O~ O~ O~

~f1O M O~ O

O O~ ~O t~

O O M N o0 pp ~t O M t~ n O ~ ~O ~p r-1 O 00 M N O~

N

O~ N vy' a\ d\ ~O tD

O o0 ~ M O

O t~ tf1M a0 n O

op M 01 O ~O ~D

N

y0 v-1tn U~

N 01 O W -1 c-i ~. 01 0~ u1 W

O

l~

O M M ~ Ov - p0 O r-iOv I~ u~

r-I ,-i ~f O v0 ~' .-1 Ov N

O~ OJ M M

OJ \O M 1w p lD I~ O O~ ~O

O~ c0 N N

f~ r-II~ N

p M t11 ~O O O

(~ N N

Ov N u'1 O~

u1 ~-1O O~ u'1 ~f1 O O O O

O

O O O O

O O

O N 7-aO O ?-a ~ ~

~

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1-.~
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O O

v d-~'r1 00 r1 ~ o0 ~ ~

b p .I-~ C~ 1~

O

N

W W W

' - 37 -From Table 11, it has been confirmed that the use of triacetin as a plasticizes for ethylcellulose (Exam-ple 11) and the use of HPMCAS as a polymer (Example 12) both provided preparations having sustained release property, respectively.
Example 13 Preparations of the formula shown in Table 1 were produced by a granulation method different from that employed in Example 1, and its sustained release prop-erty was investigated. First, polysorbate 80 was dis-solved in 75 mZ of water, in which triethyl citrate was homogeneously suspended to obtain a suspension.
After theophylline and ethyl cellulose were mixed in a high-speed agitating granulation machine, the resulting mixture was kneaded while slowly dropping the above-described suspension thereto. A portion of the mass so kneaded was granulated through an extruding granulation machine (which was equipped with a screen of 0.5 mm-in opening) and then processed in a "Marumerizer" (trade mark; manufactured by Fuji Pandal Co., Ltd.), whereby granules were obtained. A portion of the granules were dried at 80°C for 4 hours so that a granular prepara-tion was obtained. Another portion of the granules was dried at room temperature to provide a control. A dis-solution test was conducted using granules of 355 to ' - 38 -500 ~m in particle size in each of the thus-obtained preparations. The results are presented in Table 12.

r 0 0 .fl ~o 0 0 0, O O M

tr1O M

O O~

r-1 O O~ ,-I

O~ N

O \D M

N

O

O tI1 '-I

M O~ 07 O N tf1 O

dP M OW 1 v p1 CO

O

dS O O I~

~-t ~' N Ov ,-I

a>

O

l~

N ~ O o0 ir1 r--Ic0 O r1 00 vD

n m r1 r-I

O W O

N

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tf1 M

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.I-.>

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O

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U

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b ~1 J~

U

Aa ~d r-1 W W

' - 40 -From Table 12, it is observed that a preparation having sustained release property can be obtained even when granulation is conducted in a manner different from that employed in Example 1 and the resultant granules are heat-treated as in Example 1.
Example 14 Preparations of the formula shown in Example 12 (Table 10) were produced by a granulation method dif-ferent from that employed in Example 12, and its sustained release property was investigated. First, polysorbate 80 was dissolved in 50 me of water, in which triethyl citrate was homogeneously suspended to obtain a suspension. After theophylline and hydroxy-propyl methylcellulose acetate succinate were mixed in a high-speed agitating granulation machine, the result-ing mixture was kneaded while slowly dropping the above-described suspension thereto. Next, the mass so kneaded and 10 mE of water were placed in a kneader-and kneaded there. The thus-obtained kneaded mass was granulated through an extruding granulation machine (which was equipped with a screen of 0.5 mm in opening) and then processed in a "Marumerizer" (trade mark;
manufactured by Fuji Pandal Co., Ltd.), whereby granules were obtained. A portion of the granules were dried at 80°C for 4 hours so that a granular prepara-tion was obtained. Another portion of the granules was dried at room temperature to provide a control. A dis-solution test similar to that conducted in Example 1 was conducted on the granules of the entire particle size range in the preparation so obtained. The results are presented in Tables 13 and 14.
Table 13 Particle (o) size 850 ~Cm and greater 6.2 850 - 500 ~Cm 73.7 500 - 355 ~Cm 14.3 355 - 250 ~m 4.6 250 ~Cm and smaller 1.2 100.0 c O O M

O

O W p O n o~

O

O ,-I Iw N

M

O M

M M N

Q\ 01 O N

O

dP M N O

O

~d O n n N O t~

O

r-1 ~1' ~ O ~t m CO

O ~--Io0 M

W OO op r~

O N M

M O

O

M

O

M l f1 N

N N

r~ ~O ~p O O

O

O O

O

--f.O O ?.a n O ~' E 'd a~ O
O

N p. O
U

v ~p 'b C.~
~

O

td r-1 W W

. r ' - 43 -Like the granules produced by the agitating granulation method in Example 12, similar sustained release property was observed on both granules of a preparation dried under heat and those of a preparation dried at room temperature. The dissolution test in this Example showed somewhat faster dissolution proper-ty than that in Example 12 probably because the dis-solution test in this Example was conducted using the granules of the entire particle size range obtained.
Example 15 Following the formula shown in Table 1, prepara-tions were produced by slightly changing the production process of Example 13. The sustained release property of the preparation was investigated. Further, polysor-bate 80 was dissolved in 50 me of water, in which triethyl citrate was homogeneously suspended to obtain a suspension. After theophylline and ethylcellulose were mixed in a high-speed agitating granulation ma-chine, the resulting mixture was kneaded while slowly dropping the above-described suspension thereto. Next, the mass so kneaded and 30 mB of water were placed in a kneader and kneaded there. The thus-obtained kneaded mass was granulated through an extruding granulation machine (which was equipped with a screen of 0.8 mm in opening) and then processed in a "Marumerizer" (trade mark; manufactured by Fuji Pandal Co., Ltd.), whereby granules were obtained. A portion of the granules were dried at 80°C for 4 hours so that a granular prepara-tion was obtained. Another portion of the granules was dried at room temperature to provide a control. A dis-solution test similar to that conducted in Example 1 was conducted on granules of 500 to 850 um in particle size in each of the preparations so obtained. The results are presented in Table 15.

O ~D N

O

O ~t r1 O M I~

O O

N

op M

O O N

M ~ O

O 1~

O

dP M IW p v N

1~

~3 O v0 CO

N i~ O

O

In ~ O ~ M

-~ pp O ~-It~

r-~ r-1 A

0 o M

a, o ~f1 N

O

M v0 ,-I

O~ M

M

N

N

O O

O

O O

O

O N ~.I
n O ~' v ~ 1-1 ~1 ~d ~d J..~

'd U O
O

r1 N p. O
U

1-~ra ~ c0 ~

~ U

b Ca l~

N

x W W

' - 46 -As the granules obtained by conducting the extru sion granulation through the 0.8 mm screen were greater in particle size than those obtained through the 0.5 mm screen in Example 13, marked sustained-release property was exhibited.
Examples 16 and 17 In each example, granular preparations of the formula shown in Table 16 were produced as will be de-scribed below and its sustained release property was investigated. First, polysorbate 80 was dissolved in 50 mE of water, in which triethyl citrate was homogeneously suspended to obtain a suspension. Fur-they, hydroxypropyl cellulose was dissolved in 30 mE
of water and the solution so prepared was mixed with the suspension. After theophylline and ethylcellulose were mixed in a high-speed agitating granulation ma-chine, the resulting mixture was kneaded while slowly dropping the above-described suspension thereto. Next, the mass so kneaded was placed in a kneader and kneaded there. The thus-obtained kneaded mass was granulated through an extruding granulation machine (which was equipped with a screen of 0.5 mm in opening) and then processed in a "Marumerizer" (trade mark; manufactured by Fuji Pandal Co., Ltd.), whereby granules were ob-tamed. A portion of the granules were dried at 80°C

' - 47 -for 4 hours so that a granular preparation was ob-tamed. Another portion of the granules was dried at room temperature to provide a control. A dissolution test similar to that conducted in Example 1 was con-ducted on granules of 355 to 500 ~cm in particle size in each of the preparations so obtained. The results are presented in Table 17.
Table 16 Formula (g) Example Example Theophylline (THEO) 15 15 Ethyl cellulose (EC) 110 110 Triethyl citrate (TEC) 25 25 Hydroxypropyl cellulose 3 8 (HPC-L) Polysorbate 80 (Tween 80) Trace Trace Total 153 158 O M M M r1 O

d\

O r1 O N I~

u1 e0 ~O o0 n O 1~ \O O tf1 n ~ ~ n a, O W -I O~ N

N

n ~ ~ n O i0 tf1I~ Q~

M t~ ~' I~ ~O

d1 O M M M M

n O

do M ~ M IW p 1~

~d O O W N I~

,L1 ~

N (W -I t~ u1 O

.,.a O O I~ 00 W

O ~-II~ 00 v0 N

ri ,-I

A

O t~ 00 vp M

N

~-I\O N \O N

D\

n O .

O\ v--1O ~O

O

M tf1 tn \O M

tf1 t~ O M

tI~

v-1N N tn W

O~ M OW f1 O O O O

O

O O O O

O O

O N ~-IO N
n n ~

O d' ~ O

1-~ 1-1 .t~ 1~
Sa ~.I

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'd N O 'd N O
O O

a ~ a0 .-I op ~

'b p 1-~ C~ 1~

O

GL v-I r-1 ~d W W W

' - 49 -It has been confirmed that addition of hydroxy-propyl cellulose, a water-soluble substance, into granules makes it possible to control the release rate.
Example 18 Following the formula shown in Table 18, granular preparations were produced as will be described below, and its sustained release property was investigated.
First, triethyl citrate was dissolved in 60 mB of water to obtain a suspension. After theophylline and ethylcellulose were mixed in a high-speed agitating granulation machine, the resulting mixture was kneaded while slowly dropping the above-described suspension thereto. Next, the mass so kneaded and 40 me of water were placed in a kneader and kneaded there. The thus-obtained kneaded mass was granulated through an extrud-ing granulation machine (which was equipped with a screen of 0.5 mm in opening) and then processed in a "Marumerizer" (trade mark; manufactured by Fuji Pandal Co., Ltd.), whereby granules were obtained. A portion of the granules were dried at 80°C for 4 hours so that a granular preparation was obtained. Another portion of the granules was dried at room temperature to pro-vide a control. A dissolution test similar to that conducted in Example 1 was conducted on granules of 355 to 500 ~cm in particle size in each of the preparations so obtained. The results are presented in Table 19.
Table 18 Formula (g) Example 18 Theophylline (THEO) 15 Ethyl cellulose (EC) 110 Triethyl citrate (TEC) 25 Total 150 ~9w o O, o o' O u1 N

tf1I~ N

O

c0 n O ~ Ov N

n O O m1 M I~ Lf1 O

dP M I~ N

v O

1~

~TJ O ~O ~O

~I ~-N ~O O~

OW O

O

01 ~ O tI1 M

CO

O r1 ~O ~p r1 .r-I

A

O N N

N

r-1v0 N

O

O

N

O

M ~ O

r1 O ~l1 O O

O

O O

O

G O U S-I
n O ~i' N ~d 1~

U S-i U
~

'd O O
O

~i N p. O
U

j~ ,~ ~ pp v S-i N

'b ~1 1.~

N

N

ra W W

a . .w"

w ' - 52 -Sustained release property similar to that shown in Example 13 was also exhibited without addition of polysorbate 80.
CAPABILITY OF EXPLOITATION IN INDUSTRY
According to the present invention, granular preparations having excellent sustained release proper-ty and high safety to the human body can be easily ob--wined in a simple manner.

Claims (11)

1. Sustained-release granular preparations ob-tained by wet-granulating an aqueous suspension, which comprises a medicinal ingredient, a fine particulate polymer having an average particle size not greater than 50 µm and a plasticizer, into granules and treat-ing said granules at a temperature not less than the lower one of a minimum film-forming temperature and glass transition temperature of a mixture of said polymer and said plasticizer.

2. Sustained-release granular preparations ac-cording to claim 1, wherein said average particle size of said fine particulate polymer is from 1 µm to 20 µm.

3. Sustained-release granular preparations ac-cording to claim 1, wherein said plasticizer is an alkyl citrate.

4. Sustained-release granular preparations ac-cording to claim 1, wherein said plasticizer is a poly-ethylene glycol.

5. Sustained-release granular preparations ac-cording to claim 1, wherein said plasticizer is propylene glycol.

6. Sustained-release granular preparations ac-cording to claim 1, wherein said plasticizer is a glycerin mono-, di- or tri-fatty acid ester.

7. Sustained-release granular preparations ac-cording to claim 1, wherein said plasticizer is an alkyl phthalate.

8. Sustained-release granular preparations ac-cording to claim 1, obtained by treating said granules at a temperataure not less than said glass transition temperature.

9. Sustained-release granular preparations ac-cording to any one of claims 1 to 7, wherein said polymer is ethylcellulose.

10. Sustained-release granular preparations ac-cording to any one of claims 1 to 7, wherein said polymer is hydroxypropyl methylcellulose acetate suc-cinate.

11. A process for the production of sustained-release granular preparations, which comprises wet-granulating an aqueous suspension, which comprises a medicinal ingredient, a fine particulate polymer having an average particle size not greater than 50 µm and a plasticizer, into granules and treating said granules at a temperature not less than the lower one of a mini-mum film-forming temperature and glass transition temperature of a mixture of said polymer and said plasticizer.