JPH0260643B2 - - Google Patents
Info
- Publication number
- JPH0260643B2 JPH0260643B2 JP15607382A JP15607382A JPH0260643B2 JP H0260643 B2 JPH0260643 B2 JP H0260643B2 JP 15607382 A JP15607382 A JP 15607382A JP 15607382 A JP15607382 A JP 15607382A JP H0260643 B2 JPH0260643 B2 JP H0260643B2
- Authority
- JP
- Japan
- Prior art keywords
- granules
- osmotic pressure
- coating
- pharmaceutical
- excipient
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 239000008187 granular material Substances 0.000 claims description 66
- 239000011248 coating agent Substances 0.000 claims description 31
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 29
- 239000003814 drug Substances 0.000 claims description 23
- 238000000576 coating method Methods 0.000 claims description 22
- 230000003204 osmotic effect Effects 0.000 claims description 22
- 238000004519 manufacturing process Methods 0.000 claims description 21
- 229940079593 drug Drugs 0.000 claims description 16
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 16
- 238000013268 sustained release Methods 0.000 claims description 13
- 239000012730 sustained-release form Substances 0.000 claims description 13
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 9
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000012530 fluid Substances 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 5
- 230000002496 gastric effect Effects 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 239000011230 binding agent Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 12
- 239000008101 lactose Substances 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 229940126062 Compound A Drugs 0.000 description 10
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 10
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 10
- 239000000306 component Substances 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 10
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 10
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 10
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 8
- 239000011824 nuclear material Substances 0.000 description 8
- 239000000843 powder Substances 0.000 description 7
- 239000008358 core component Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 229960001270 d- tartaric acid Drugs 0.000 description 5
- 239000001087 glyceryl triacetate Substances 0.000 description 5
- 235000013773 glyceryl triacetate Nutrition 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000002075 main ingredient Substances 0.000 description 5
- 239000004014 plasticizer Substances 0.000 description 5
- 238000007873 sieving Methods 0.000 description 5
- 229960002622 triacetin Drugs 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 229920003137 Eudragit® S polymer Polymers 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000000968 intestinal effect Effects 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 238000007922 dissolution test Methods 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- 239000001384 succinic acid Substances 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- 229920003151 Eudragit® RL polymer Polymers 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 210000000941 bile Anatomy 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- DNKKLDKIFMDAPT-UHFFFAOYSA-N n,n-dimethylmethanamine;2-methylprop-2-enoic acid Chemical compound CN(C)C.CC(=C)C(O)=O.CC(=C)C(O)=O DNKKLDKIFMDAPT-UHFFFAOYSA-N 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- BSHDUMDXSRLRBI-JOYOIKCWSA-N rentiapril Chemical compound SCCC(=O)N1[C@H](C(=O)O)CS[C@@H]1C1=CC=CC=C1O BSHDUMDXSRLRBI-JOYOIKCWSA-N 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- VUAFHZCUKUDDBC-BYPYZUCNSA-N Bucillamine Chemical compound CC(C)(S)C(=O)N[C@@H](CS)C(O)=O VUAFHZCUKUDDBC-BYPYZUCNSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 229920003136 Eudragit® L polymer Polymers 0.000 description 1
- 229920003152 Eudragit® RS polymer Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229940125708 antidiabetic agent Drugs 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 229940075522 antidotes Drugs 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 229940125716 antipyretic agent Drugs 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000000496 cardiotonic agent Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Natural products CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- FSXVSUSRJXIJHB-UHFFFAOYSA-M ethyl prop-2-enoate;methyl 2-methylprop-2-enoate;trimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]azanium;chloride Chemical compound [Cl-].CCOC(=O)C=C.COC(=O)C(C)=C.CC(=C)C(=O)OCC[N+](C)(C)C FSXVSUSRJXIJHB-UHFFFAOYSA-M 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- -1 hydroxypropyl Chemical group 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 1
- XDEPVFFKOVDUNO-UHFFFAOYSA-N pentafluorobenzyl bromide Chemical compound FC1=C(F)C(F)=C(CBr)C(F)=C1F XDEPVFFKOVDUNO-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Description
【発明の詳細な説明】
本発明は医薬品を持続的に放出する顆粒剤に関
する。本発明の目的は医薬品が胃から腸管にわた
り徐々に放出されることによつて医薬品の有効血
中濃度を長時間維持すること、および胆汁成分が
腸液などにより分解または不活性化させる恐れの
ある医薬品を浸透圧調節剤を加えることにより安
定化させることにある。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to granules for sustained release of pharmaceuticals. The purpose of the present invention is to maintain the effective blood concentration of pharmaceuticals for a long time by gradually releasing the pharmaceuticals from the stomach to the intestinal tract, and to prevent pharmaceuticals whose bile components may be degraded or inactivated by intestinal fluids, etc. The aim is to stabilize this by adding an osmotic pressure regulator.
医薬品の徐放化に関する報告は数多くなされて
いるが、それらの報告は製剤の崩壊、溶解速度の
差または製剤中の拡散速度の差を利用したもので
あり、生理的条件（消化管内のPH等）に徐放効果
が大きく影響をうけ、又、製剤のロツト間によつ
ても徐放効果が異なりやすい等の欠点があつた。
本発明者らは鋭意研究の結果、顆粒剤内部に少量
で高い浸透圧を与える物質を添加し、外壁に腸溶
性物質、腸液および胃液不溶性物質（以下不溶性
物質と略す）、即ち胃液に対して不溶性の物質で
コーテイングすることによりこれらの欠点を解決
した。尚、本発明に係る製剤の徐放効果に実質上
影響を与えない程度の量の胃溶性物質を含むこと
を妨げるものではない。 There have been many reports on sustained release of pharmaceuticals, but these reports utilize disintegration of the formulation, differences in dissolution rate, or differences in diffusion rate within the formulation, and they are based on physiological conditions (PH in the gastrointestinal tract, etc.). ), the sustained release effect was greatly affected, and the sustained release effect also tended to vary between different formulation lots.
As a result of intensive research, the present inventors added a substance that gives a high osmotic pressure in a small amount to the inside of the granule, and added to the outer wall an enteric substance, an intestinal fluid, and a substance insoluble in gastric juice (hereinafter referred to as insoluble substance), that is, a substance that is resistant to gastric juice. These drawbacks were overcome by coating with insoluble substances. Note that this does not preclude the formulation from containing a gastrosoluble substance in an amount that does not substantially affect the sustained release effect of the formulation according to the present invention.
次に本発明の顆粒剤の効果について説明する。
本顆粒剤を経口投与すると、まず低PH領域の胃内
では顆粒の皮膜を通つて顆粒内に侵入した水が顆
粒中の浸透圧調節剤を溶解することにより顆粒内
部の浸透圧が上昇し、その浸透圧ポンプ的作用の
結果、顆粒から医薬品を徐々に溶出させる。次に
顆粒が腸管へ移行したとき、皮膜が徐々に溶解し
て医薬品を放出するか、または皮膜の細孔を通つ
て医薬品徐々に放出される。上記の徐放効果と同
時に、胆汁成分、高いPHの腸液または腸管内酵素
等で不活性化されやすい医薬品の顆粒剤の場合に
は、顆粒内部の低PH環境により医薬品を安定化さ
せる効果も有する。 Next, the effects of the granules of the present invention will be explained.
When this granule is orally administered, water enters the granule through the granule coating in the stomach in the low pH range and dissolves the osmotic pressure regulator in the granule, increasing the osmotic pressure inside the granule. As a result of its osmotic pump action, the drug is gradually eluted from the granules. When the granules then pass into the intestinal tract, the coating either gradually dissolves and releases the drug, or the drug is gradually released through the pores of the coating. At the same time as the above-mentioned sustained release effect, in the case of pharmaceutical granules that are easily inactivated by bile components, high pH intestinal fluids, or intestinal enzymes, the low pH environment inside the granules also has the effect of stabilizing the drug. .
本発明の徐放性顆粒剤の非常に大きな特徴とし
ては、従来の徐放性製剤が異なる性質を有する顆
粒の混合によつて始めて効果を発揮するのに対し
て、１種類の顆粒で上記の特筆すべき効果を示す
ことである。 A very significant feature of the sustained-release granules of the present invention is that while conventional sustained-release preparations exhibit their effects only by mixing granules with different properties, one type of granules can achieve the above-mentioned effects. The purpose is to demonstrate noteworthy effects.
本発明の徐放性顆粒に含有させる浸透圧調節剤
としては、少量で高い浸透圧を有し、顆粒内部に
低PH環境を提供する物質が好ましく、その浸透圧
調節剤としては水溶性有機酸が適しており、例え
ば、酒石酸、コハク酸、クエン酸、フマル酸、マ
レイン酸、アスコルビン酸等をあげることができ
る。その浸透圧調節剤の含有量は顆粒全体の重量
の30〜70％である。 The osmotic pressure regulator to be contained in the sustained release granules of the present invention is preferably a substance that has high osmotic pressure in a small amount and provides a low pH environment inside the granules. Suitable examples include tartaric acid, succinic acid, citric acid, fumaric acid, maleic acid, and ascorbic acid. The content of the osmotic pressure regulator is 30-70% of the total weight of the granules.
本発明顆粒剤の腸溶性皮膜剤としてはEudrgit
−ＳおよびＬ（商品名、ローム・フアーマ社製、
一般名：メタアクリル酸コポリマー）HP−50、
55および55S（商品名、信越化学社製、一般名：
ヒドロキシプロピルメチルセルロースフタレー
ト）、セルロースアセテートフタレート（CAP）
などが使用でき、また不溶性物質としては
Eudragit−RSおよび−RL（商品名、ローム・フ
アーマ社製、一般名：アミノアルキルメタアクリ
レートコポリマー）、エチルセルロースなどが使
用できる。本顆粒の皮膜には上記物質を単独で用
いても混合して用いてもよい。 As the enteric coating agent for the granules of the present invention, Eudrgit
-S and L (product name, manufactured by Rohm Pharma Co., Ltd.,
Generic name: methacrylic acid copolymer) HP-50,
55 and 55S (product name, manufactured by Shin-Etsu Chemical Co., Ltd., general name:
hydroxypropyl methylcellulose phthalate), cellulose acetate phthalate (CAP)
etc. can be used, and as an insoluble substance
Eudragit-RS and -RL (trade name, manufactured by Rohm Pharma Co., Ltd., general name: aminoalkyl methacrylate copolymer), ethyl cellulose, etc. can be used. The above substances may be used alone or in combination for the coating of the present granules.
本発明顆粒はほとんどの医薬品に利用すること
ができるので、主薬となる医薬品について制限さ
れることはなく、降圧剤、解熱鎭痛消炎剤、免疫
調節剤、副腎ホルモン、糖尿病用剤、血管拡張
剤、強心剤、不整脈用剤、動脈硬化用剤、解毒剤
等様々な薬効分野の医薬品に利用できる。 Since the granules of the present invention can be used for most pharmaceuticals, there are no restrictions on the main pharmaceuticals, such as antihypertensive agents, antipyretic and antiinflammatory agents, immunomodulators, adrenal hormones, antidiabetic agents, and vasodilators. It can be used in various medicinal products such as cardiotonic agents, arrhythmia agents, arteriosclerotic agents, and antidotes.
本顆粒剤の特徴的な組成物は、まず浸透圧調節
作用を有する物質を主体とする球型核（メツシユ
は顆粒の大きさにより任意に選べるが、20〜40メ
ツシユが好ましい。）を作り、その周囲に主薬、
賦形剤および必要に応じて浸透圧調節剤を付結合
せしめて得られる素顆粒に胃液不溶性の皮膜剤を
コーテイングして得られるものである。 The characteristic composition of this granule is to first create a spherical nucleus (the mesh can be arbitrarily selected depending on the size of the granule, but preferably 20 to 40 mesh), which is mainly composed of a substance that has an osmotic pressure regulating effect. Around it, the main drug,
It is obtained by coating elementary granules obtained by binding excipients and, if necessary, an osmotic pressure regulator, with a coating agent insoluble in gastric fluid.
主薬と球型核形成成分との間の相互作用があ
り、変色、吸湿等の理由で製剤的に通常配合不適
と考えられる場合においても、本顆粒剤の場合は
球型核に速溶性皮膜、即ち胃溶性皮膜（例えば
TC−５（商品名、信越化学社製、一般名：ヒドロ
キシプロピルメチルセルロース））を球型核の重
量の数パーセントコーテイングするか、あるいは
相互作用のない賦形剤を球型核に球型核の重量の
数パーセント付着結合させる事により、配合可能
となる。本顆粒の製造において、医薬品と賦形剤
の粉末を付着結合せしめる際の結合剤としては、
ポリビニルピロリドン、ヒドロキシプロピルセル
ロース等の低級アルコール溶液など公知の結合剤
を使用できる。 Even if there is an interaction between the active ingredient and the spherical nucleus-forming component, which would normally be considered unsuitable for formulation due to discoloration, moisture absorption, etc., in the case of this granule, the spherical nucleus has a fast-dissolving coating, That is, gastric soluble coatings (e.g.
Either coat the spherical core with TC-5 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd., generic name: hydroxypropyl methyl cellulose) by several percent of the weight of the spherical core, or coat the spherical core with a non-interacting excipient. It can be blended by adhering and bonding several percent of the weight. In the production of this granule, the binder used to adhere and bond the pharmaceutical and excipient powders is as follows:
Known binders such as lower alcohol solutions such as polyvinylpyrrolidone and hydroxypropylcellulose can be used.
本顆粒剤の徐放効果の例として、降圧剤である
（2R、4R）−２−（２−ヒドロキシフエニル）−３
−（３−メルカプトプロピオニル）−４−チアゾリ
ジカルボン酸を主薬とする顆粒剤の効果を第１図
及び第２図に示した。顆粒は実施例１で製造した
ものを用い、対照製剤として同一薬物を主薬とす
る素錠を用いた。素錠の処方を下記に示す。 As an example of the sustained release effect of this granule, (2R, 4R)-2-(2-hydroxyphenyl)-3, which is an antihypertensive agent,
The effects of granules containing -(3-mercaptopropionyl)-4-thiazolidicarboxylic acid as the main ingredient are shown in Figures 1 and 2. The granules produced in Example 1 were used, and uncoated tablets containing the same drug as the active ingredient were used as control preparations. The prescription for uncoated tablets is shown below.
（2R，4R）−２−（２−ヒドロキシフエニル）−
３−（３−メルカプトプロピオニル）−４−チアゾ
リジンカルボン酸 10mg
ダアラクトース（商品名、フロイント産業製、一
般名：乳糖） 63mg
アビセル301（商品名、旭化成工業製、一般名：結
晶セルロース） 15mg
ヒドロキシプロピルセルロース １mg
ステアリン酸マグネシウム １mg
計 90mg
上記処方のものを混合し、直接打錠法により素
錠とした。(2R,4R)-2-(2-hydroxyphenyl)-
3-(3-Mercaptopropionyl)-4-thiazolidinecarboxylic acid 10mg Dallactose (trade name, Freund Sangyo Co., Ltd., generic name: lactose) 63mg Avicel 301 (trade name, Asahi Kasei Corporation, generic name: crystalline cellulose) 15mg Hydroxypropyl cellulose 1 mg Magnesium stearate 1 mg Total 90 mg The above formulations were mixed and made into uncoated tablets by direct compression.
尚、試験においては、本顆粒中の主薬の量と対
照の素錠中の主薬の量が同一となるようにして行
つた。 The test was conducted so that the amount of the active ingredient in the present granules was the same as the amount of active ingredient in the control uncoated tablet.
第１図は日本薬局方第10改正（以下第10局と略
す）の溶出試験器を用い第10局の溶出試験法第１
法の回転バスケツト（100rpm）法により、溶出
試験を行ない、縦軸を溶出率（％）、横軸を時間
とし溶出曲線を示した。溶出液は最初の２時間ま
では第10局の第１液（PH1.2）を用い、２時間以
後は第10局の第２液（PH6.8）を用いた。定量は
高速液体クロマトグラフ法（検出波長286nｍ）
で行つた。１は本発明の顆粒剤、２は対照素錠で
ある。第１図より明らかな如く本発明顆粒剤は対
照素錠よりはるかに徐々に主薬が溶出している。 Figure 1 shows the dissolution test method 1 of the Japanese Pharmacopoeia, 10th revision (hereinafter referred to as the 10th Bureau) using a dissolution tester.
A dissolution test was conducted using a rotating basket (100 rpm) method, and a dissolution curve is shown, with the vertical axis representing the dissolution rate (%) and the horizontal axis representing time. As the eluate, the 1st solution (PH 1.2) from the 10th station was used for the first 2 hours, and the 2nd solution (PH 6.8) from the 10th station was used after 2 hours. Quantification is by high performance liquid chromatography (detection wavelength 286nm)
I went there. 1 is a granule of the present invention, and 2 is a control uncoated tablet. As is clear from FIG. 1, the active ingredient in the granules of the present invention dissolves much more gradually than in the control plain tablet.
第２図は本発明顆粒剤及び対照素錠を健康人に
軽食後投与（主薬として50mg／人）し、血中濃度
の経時的推移を示した。縦軸は血中濃度（ng／
ml）、横軸は時間である。定量はペンタフルオロ
ベンジルブロマイドでSH基を保護し、ジアゾメ
タンでエステル化した後ガスクロマトグラフ法で
行つた。１は本発明顆粒剤、２は対照素錠であ
る。第２図より明らかな如く本発明顆粒剤は対照
素よりはるかに長時間主薬の血中濃度が維持され
ている。 FIG. 2 shows the time course of the blood concentration of the granules of the present invention and control uncoated tablets administered to healthy people after a light meal (50 mg/person as the main drug). The vertical axis is the blood concentration (ng/
ml), and the horizontal axis is time. Quantification was performed by gas chromatography after protecting the SH group with pentafluorobenzyl bromide and esterifying it with diazomethane. 1 is a granule of the present invention, and 2 is a control uncoated tablet. As is clear from FIG. 2, the granules of the present invention maintain the blood concentration of the active ingredient for a much longer time than the control substance.
以下に実施例を示すが、本発明は実施例に限定
されるものではない。 Examples are shown below, but the present invention is not limited to the examples.
実施例 １
（2R，4R）−２−（２−ヒドロキシフエニル）
−３−（３−メルカプトプロピオニル）−４−チ
アゾリジンカルボン酸（以下化合物Ａと略す）
を主薬とする顆粒剤Ａの製造
●核物質の製造工程
遠心流動装置を用いて、ｄ−酒石酸の結晶
（核成分1*500ｇに７％（Ｗ／Ｖ、以下同じ）ヒ
ドロキシプロピルセルロース−エタノール溶液
（結合剤１）を噴霧しながら、ｄ−酒石酸の粉
末（核成分2*）を900ｇと粉末乳糖（賦形剤）
300ｇの混合粉砕品を徐々に散布し付着結合さ
せる。乾燥後、篩過により24〜32メツシユの球
型酒石酸核を得る。Example 1 (2R,4R)-2-(2-hydroxyphenyl)
-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid (hereinafter abbreviated as compound A)
Manufacture of granules A with the main ingredient ● Manufacturing process of nuclear material Using a centrifugal flow device, add a 7% (W/V, same below) hydroxypropylcellulose-ethanol solution to d-tartaric acid crystals (core component 1 * 500 g). While spraying (binder 1), add 900 g of d-tartaric acid powder (core component 2 * ) and powdered lactose (excipient).
Gradually sprinkle 300g of the mixed pulverized product to adhere and bond. After drying, 24 to 32 mesh spherical tartaric acid nuclei are obtained by sieving.
●素顆粒の製造工程
上記球型酒石酸核500ｇに７％ヒドロキシプ
ロピルセルロースエタノール溶液（結合剤２）
400mlを噴霧しながら、ｄ−酒石酸（浸透圧調
節剤）300ｇおよび粉末乳糖（賦形剤）500ｇの
混合粉砕物に化合物Ａ（主薬）30ｇを配合した
微粉末を付着結合させる。乾燥後篩過により16
〜28メツシユの素顆粒を得る。Manufacturing process of elementary granules 7% hydroxypropyl cellulose ethanol solution (binder 2) in 500 g of the above spherical tartrate nuclei
While spraying 400 ml, a fine powder prepared by blending 30 g of Compound A (main drug) with a pulverized mixture of 300 g of d-tartaric acid (osmotic pressure regulator) and 500 g of powdered lactose (excipient) is bonded. 16 by sieving after drying
Obtain ~28 mesh elementary granules.
●皮膜剤のコーテイング工程
上記素顆粒500ｇにトリアセチン（可塑剤）
４ｇ、Eudragit Ｓ（皮膜剤１）50ｇおよびHP
−55（皮膜剤２）50ｇのアセトン−イソプロピ
ルアルコール（皮膜液）１：１混合液1000mlの
溶液を、遠心流動層内でコーテイングする。乾
燥後篩過により20〜28メツシユの顆粒415ｇを
得る。●Coating process of film agent Add triacetin (plasticizer) to 500g of the above elementary granules.
4g, Eudragit S (filming agent 1) 50g and HP
-55 (Coating agent 2) A solution of 1000 ml of a 1:1 mixture of 50 g of acetone and isopropyl alcohol (coating solution) is coated in a centrifugal fluidized bed. After drying, 415 g of 20-28 mesh granules were obtained by sieving.
*核成分１および２は浸透圧調節作用を有す
る（以下の実施例についても同じ）。 * Nuclear components 1 and 2 have an osmotic pressure regulating effect (the same applies to the following examples).
実施例 ２
化合物Ａを主薬とする顆粒剤Ｂの製造
下記処方を用い、実施例１と同様の操作で20〜
58メツシユの標記顆粒550ｇを得る。Example 2 Production of granules B containing Compound A as the main drug Using the following formulation, 20 to
550 g of the title granules of 58 mesh were obtained.
●核物質製造工程
核成分１ ｄ−酒石酸結晶 500ｇ
核成分２ ｄ−酒石酸粉末 900ｇ
賦形剤 乳糖 300ｇ
結合剤１ ７％ヒドロキシプロピルセルロース
エタノール溶液 600ml
●顆粒製造工程
核物質 ｄ−酒石酸核 500ｇ
主薬 化合物Ａ 30ｇ
浸透圧調節剤 ｄ−酒石酸粉末 300ｇ
結合剤２ ７％ヒドロキシプロピルセルロース
−エタノール溶液 400ml
賦形剤 乳糖 500
●皮膜剤コーテイング工程
素顆粒 700ｇ
皮膜剤１ Eudragit Ｓ 35ｇ
皮膜剤２ HP−55 35ｇ
皮膜液 アセトン−イソプロピルアルコール
（１：１） 800ml
可塑剤 トリアセチン ４ｇ
実施例 ３
化合物Ａを主薬とする顆粒剤Ｃの製造
下記処方を用い、実施例１と同様の操作で20〜
28メツシユの標記顆粒380ｇを得る。●Nuclear material manufacturing process Nucleic component 1 d-tartrate crystals 500g Nuclear component 2 d-tartaric acid powder 900g Excipient Lactose 300g Binder 1 7% hydroxypropyl cellulose ethanol solution 600ml ●Grane manufacturing process Nuclear material d-tartrate nuclei 500g Main drug Compound A 30g Osmotic pressure regulator d-tartaric acid powder 300g Binder 2 7% hydroxypropyl cellulose-ethanol solution 400ml Excipient Lactose 500 ●Coating agent Coating process raw granules 700g Coating agent 1 Eudragit S 35g Coating agent 2 HP-55 35g Coating Liquid: Acetone-isopropyl alcohol (1:1) 800ml Plasticizer: Triacetin 4g Example 3 Production of granules C containing Compound A as the main ingredient Using the following formulation, 20~
380 g of the title granules of 28 mesh were obtained.
●核物質製造工程
核成分１ コハク酸結晶 500ｇ
核成分２ コハク酸粉末 900ｇ
賦形剤 乳糖 300ｇ
結合剤１ ５％ポリビニルピロリドン−エタノ
ール溶液 450ml
●素顆粒製造工程
核物質 コハク酸核 500ｇ
主 薬 化合物Ａ 30ｇ
浸透圧調節剤 コハク酸粉末 300ｇ
結合剤２ ７％ポリビニルピロリドン−エタノ
ール溶液 400ml
賦形剤 乳糖 500ｇ
●皮膜剤コーテイング工程
素顆粒 500ｇ
皮膜剤１ Eudragit Ｓ 50ｇ
皮膜剤２ HP−55 50ｇ
皮膜液 アセトン−イソピロピルアルコール
（１：１） 1000ml
可塑剤 トリアセチン ４ｇ
実施例 ４
化合物Ａを主薬とする顆粒剤Ｄの製造
下記処方を用い、実施例１と同様の操作で20〜
28メツシユの標記顆粒1100ｇを得る。●Nuclear material manufacturing process Core component 1 Succinic acid crystal 500g Core component 2 Succinic acid powder 900g Excipient Lactose 300g Binder 1 5% polyvinylpyrrolidone-ethanol solution 450ml ●Particle manufacturing process Nucleic material Succinic acid nucleus 500g Main drug Compound A 30g Osmotic pressure regulator Succinic acid powder 300g Binder 2 7% polyvinylpyrrolidone-ethanol solution 400ml Excipient Lactose 500g ●Coating process granules 500g Coating agent 1 Eudragit S 50g Coating agent 2 HP-55 50g Coating liquid Acetone- Isopropyl alcohol (1:1) 1000ml Plasticizer Triacetin 4g Example 4 Production of granules D containing Compound A as the main ingredient Using the following formulation, 20~
1100 g of the title granules of 28 mesh were obtained.
●核物質製造工程
核成分１ クエン酸結晶 500ｇ
核成分２ クエン酸粉末 900ｇ
賦形剤 乳糖 300ｇ
結合剤１ ７％ヒドロキシプロピルセルロース
エタノール溶液 420ml
●素顆粒製造工程
核物質 クエン酸核 500ｇ
主 薬 化合物Ａ 30ｇ
浸透圧調節剤 クエン酸粉末 300ｇ
結合剤２ ７％ヒドロキシプロピルセルロース
エタノール溶液 400ml
賦形剤 乳糖 500ｇ
●皮膜剤コーテイング工程
素顆粒 1300ｇ
皮膜剤１ Eudragit Ｓ 130ｇ
皮膜剤２ HP−55 130ｇ
皮膜液 アセトン−イソプロピルアルコール
（１：１） 2100ml
可塑剤 トリアセチン 11ｇ
実施例 ５
Ｎ−（２−メルカプト−２−メチルプロパノイ
ル）−Ｌ−システイン（以下化合物Ｂと略す）
を主薬とする顆粒剤Ｅの製造
下記処方を用い、実施例１と同様の操作で20〜
28メツシユの標記顆粒400ｇを得る。●Nuclear material manufacturing process Nucleic component 1 Citric acid crystals 500g Nuclear component 2 Citric acid powder 900g Excipient Lactose 300g Binder 1 7% hydroxypropyl cellulose ethanol solution 420ml ●Particle manufacturing process Nucleic material Citric acid nuclei 500g Main drug Compound A 30g Osmotic pressure regulator Citric acid powder 300g Binder 2 7% hydroxypropyl cellulose ethanol solution 400ml Excipient Lactose 500g ●Coating agent coating process raw granules 1300g Coating agent 1 Eudragit S 130g Coating agent 2 HP-55 130g Coating liquid Acetone- Isopropyl alcohol (1:1) 2100ml Plasticizer Triacetin 11g Example 5 N-(2-mercapto-2-methylpropanoyl)-L-cysteine (hereinafter abbreviated as compound B)
Production of granules E containing as the main drug 20~
400 g of the title granules of 28 mesh were obtained.
●核物質製造工程
核成分１ クエン酸結晶 500ｇ
核成分２ クエン酸粉末 1000ｇ
賦形剤 粉末乳糖 300ｇ
結合剤１ ７％ヒドロキシプロピルセルロース
エタノール溶液 600ml
●素顆粒製造工程
核物質 クエン酸核 500ｇ
主 薬 化合物Ｂ 200ｇ
浸透圧調節剤 クエン酸粉末 500ｇ
結合剤２ ７％ヒドロキシプロピルセルロース
エタノール溶液 500ml
賦形剤 粉末乳糖 300ｇ
●皮膜剤コーテイング工程
素顆粒 500ｇ
皮膜剤 Eudragit RL 100ｇ
皮膜液 アセトン−イソプロピルアルコール
（２：１） 1200ml
可塑剤 トリアセチン ５ｇ
実施例 ６
化合物Ａを主薬とする顆粒剤Ｆの製造
●核物質製造工程
遠心流動装置を用いて、クエン酸結晶（核成
分１）500ｇに７％ヒドロキシプロピル−セル
ロースエタノール溶液（結合剤）600mlを噴霧
しながら、クエン酸粉末（核成分２）1200ｇを
徐々に散布し付着結合させる。乾燥後篩過によ
り24〜34メツシユの球型クエン酸核を得る。次
いで、この核500ｇにTC−５（速溶性皮膜）の
５％（Ｘ／Ｖ）塩化メチレン−メタノール
（１：１）溶液500mlを遠心流動層装置内で噴霧
しコーテイングした後乾燥する。篩過により20
〜28メツシユの球型核を得る。以下、下記の処
方を用い、実施例１と同様の操作にて20〜58メ
ツシユの標記顆粒410ｇ得る。●Nuclear material manufacturing process Nucleic component 1 Citric acid crystals 500g Nuclear component 2 Citric acid powder 1000g Excipient Powdered lactose 300g Binder 1 7% hydroxypropyl cellulose ethanol solution 600ml ●Particle manufacturing process Nucleic material Citric acid nuclei 500g Main Drug Compound B 200g Osmotic pressure regulator Citric acid powder 500g Binder 2 7% hydroxypropyl cellulose ethanol solution 500ml Excipient Powdered lactose 300g ●Coating agent Coating process raw granules 500g Coating agent Eudragit RL 100g Coating liquid Acetone-isopropyl alcohol (2:1 ) 1200ml Plasticizer Triacetin 5g Example 6 Production of granules F containing Compound A as the main ingredient ●Nuclear material production process Using a centrifugal flow device, add 7% hydroxypropyl-cellulose ethanol solution to 500g of citric acid crystals (core component 1). While spraying 600ml (binder), gradually sprinkle 1200g of citric acid powder (core component 2) to adhere and bond. After drying, 24 to 34 mesh spherical citric acid nuclei are obtained by sieving. Next, 500 g of this core was coated with 500 ml of a 5% (X/V) methylene chloride-methanol (1:1) solution of TC-5 (fast-dissolving coating) in a centrifugal fluidized bed apparatus, and then dried. 20 by sieving
Obtain ~28 mesh spherical nuclei. Thereafter, 410 g of the title granules of 20 to 58 meshes were obtained using the following recipe and the same procedure as in Example 1.
●素顆粒製造工程
核物質 球型核 700ｇ
主 薬 化合物Ａ 25ｇ
結合剤２ ７％ヒドロキシプロピルセルロース
エタノール溶液 250ml
賦形剤 粉末乳糖 400ｇ
●皮膜剤コーテイング工程
素顆粒 500ｇ
皮膜剤 Eudragit Ｌ 100ｇ
皮膜液 アセトン−イソピロピルアルコール
（３：１） 1600ml●Nuclear material for the granule manufacturing process: Spherical core 700g Main drug Compound A 25g Binder 2 7% hydroxypropyl cellulose ethanol solution 250ml Excipient Powdered lactose 400g ●Coating agent Coating process Elementary granules 500g Coating agent Eudragit L 100g Coating liquid Acetone Isopropyl alcohol (3:1) 1600ml
第１図および第２図は夫々本発明顆粒剤および
対照素錠の主薬溶出試験結果および経口投与後の
主薬血中濃度測定結果を示すグラフである。図に
おいて１は本発明顆粒剤、２は対照素錠である。
FIGS. 1 and 2 are graphs showing the results of the active ingredient dissolution test and the results of measuring the active ingredient blood concentration after oral administration for the granules of the present invention and control uncoated tablets, respectively. In the figure, 1 is a granule of the present invention, and 2 is a control uncoated tablet.
Claims (1)
る浸透圧調節剤を主体とする球型核の周囲に、医
薬品、賦形剤および必要に応じて前記規定の浸透
圧調節剤を付着結合させた素顆粒を胃液不溶性皮
膜剤でコーテイングした、該浸透圧調節剤の総重
量が顆粒全体の重量の30〜70％であることを特徴
とする徐放性顆粒剤。 ２ 有機酸が酒石酸、コハク酸またはクエン酸で
ある特許請求の範囲第１項記載の徐放性顆粒剤。 ３ 医薬として許容される水溶性の有機酸からな
る浸透圧調節剤を主体とする球型核の周囲に、医
薬品、賦形剤および必要に応じて前記規定の浸透
圧調節剤を付着結合させ、得られた素顆粒を胃液
不溶性皮膜剤でコーテイングし徐放性顆粒剤を得
る製法であつて、該浸透圧調節剤の総重量が顆粒
全体の重量の30〜70％であることを特徴とする徐
放性顆粒剤の製法。[Scope of Claims] 1. Around a spherical core mainly consisting of an osmotic pressure regulator made of a water-soluble organic acid that is acceptable as a pharmaceutical, a pharmaceutical, an excipient, and, if necessary, the above-described osmotic pressure regulating agent. 1. A sustained-release granule comprising elementary granules to which a drug is adhered and bonded and coated with a coating agent insoluble in gastric fluid, wherein the total weight of the osmotic pressure regulator is 30 to 70% of the total weight of the granules. 2. The sustained release granules according to claim 1, wherein the organic acid is tartaric acid, succinic acid, or citric acid. 3. Adhesively bonding the pharmaceutical, excipient, and if necessary the above-specified osmotic pressure regulating agent around a spherical core mainly composed of an osmotic pressure regulating agent made of a water-soluble organic acid that is acceptable as a pharmaceutical; A manufacturing method for obtaining sustained-release granules by coating the obtained elementary granules with a coating agent insoluble in gastric fluid, characterized in that the total weight of the osmotic pressure regulator is 30 to 70% of the weight of the entire granules. Manufacturing method for sustained release granules.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57156073A JPS5944311A (en) | 1982-09-07 | 1982-09-07 | Slow-releasing granule and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57156073A JPS5944311A (en) | 1982-09-07 | 1982-09-07 | Slow-releasing granule and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5944311A JPS5944311A (en) | 1984-03-12 |
| JPH0260643B2 true JPH0260643B2 (en) | 1990-12-17 |
Family
ID=15619707
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57156073A Granted JPS5944311A (en) | 1982-09-07 | 1982-09-07 | Slow-releasing granule and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5944311A (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH666405A5 (en) * | 1985-06-24 | 1988-07-29 | Ciba Geigy Ag | SOLID, DURABLE PHARMACEUTICAL FORMS WITH ELASTIC FILM COVER. |
| IL86462A (en) * | 1987-05-29 | 1992-12-01 | Fujisawa Pharmaceutical Co | Alkanesulfonanilide derivatives, processes for preparation thereof and pharmaceutical compositions comprising the same |
| JPH02138168A (en) * | 1988-11-18 | 1990-05-28 | Hisamitsu Pharmaceut Co Inc | Sulfonanilide derivative |
| JP2558396B2 (en) * | 1990-06-28 | 1996-11-27 | 田辺製薬株式会社 | Controlled release formulation |
| US5382435A (en) * | 1993-03-24 | 1995-01-17 | Southwest Research Institute | Microparticulate pharmaceutical delivery system |
| US7316819B2 (en) * | 2001-03-08 | 2008-01-08 | Unigene Laboratories, Inc. | Oral peptide pharmaceutical dosage form and method of production |
| JP4848101B2 (en) * | 2001-08-17 | 2011-12-28 | 株式会社フジモト・コーポレーション | Sustained release micropellet |
| RU2311906C2 (en) * | 2001-11-21 | 2007-12-10 | Эйсай Ар Энд Ди Менеджмент Ко., Лтд. | Composition of sustained-release preparation for releasing of acid secretion inhibitor in stomach and method for production thereof |
| AU2004208512B2 (en) * | 2003-01-30 | 2009-01-29 | Ethypharm | Taste-masking coated particles, process for the preparation thereof and orodispersible tablets containing said coated particles |
| FR2850577B1 (en) * | 2003-02-03 | 2005-04-15 | Ethypharm Sa | MASK TASTE ENRICHED PARTICLES, PROCESS FOR THEIR PREPARATION AND ORODISPERSIBLE COMPRESSES CONTAINING SAID PARTICLES |
| JP6251946B2 (en) * | 2012-10-14 | 2017-12-27 | 富田製薬株式会社 | Composite core particle and pharmaceutical composition containing the same |
-
1982
- 1982-09-07 JP JP57156073A patent/JPS5944311A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5944311A (en) | 1984-03-12 |
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