JPH04338324A - Multi-reservoir-type sustained release granule and its preparation - Google Patents
Multi-reservoir-type sustained release granule and its preparationInfo
- Publication number
- JPH04338324A JPH04338324A JP13831591A JP13831591A JPH04338324A JP H04338324 A JPH04338324 A JP H04338324A JP 13831591 A JP13831591 A JP 13831591A JP 13831591 A JP13831591 A JP 13831591A JP H04338324 A JPH04338324 A JP H04338324A
- Authority
- JP
- Japan
- Prior art keywords
- layer
- pharmaceutically active
- water
- sustained release
- granules
- 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.)
- Granted
Links
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- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960002422 lomefloxacin Drugs 0.000 description 1
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960002221 methylephedrine Drugs 0.000 description 1
- 229960005195 morphine hydrochloride Drugs 0.000 description 1
- XELXKCKNPPSFNN-BJWPBXOKSA-N morphine hydrochloride trihydrate Chemical compound O.O.O.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O XELXKCKNPPSFNN-BJWPBXOKSA-N 0.000 description 1
- 229960004715 morphine sulfate Drugs 0.000 description 1
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 description 1
- CYGSXDXRHXMAOV-UHFFFAOYSA-N o-cresol hydrogen sulfate Chemical compound CC1=CC=CC=C1OS(O)(=O)=O CYGSXDXRHXMAOV-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- HXNFUBHNUDHIGC-UHFFFAOYSA-N oxypurinol Chemical compound O=C1NC(=O)N=C2NNC=C21 HXNFUBHNUDHIGC-UHFFFAOYSA-N 0.000 description 1
- 229960002305 phenylpropanolamine hydrochloride Drugs 0.000 description 1
- 229960002310 pinacidil Drugs 0.000 description 1
- 229920002239 polyacrylonitrile Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 229920000139 polyethylene terephthalate Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 229960002244 promethazine hydrochloride Drugs 0.000 description 1
- XXPDBLUZJRXNNZ-UHFFFAOYSA-N promethazine hydrochloride Chemical compound Cl.C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 XXPDBLUZJRXNNZ-UHFFFAOYSA-N 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 229960000620 ranitidine Drugs 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 229960000581 salicylamide Drugs 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- 229960000351 terfenadine Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- BFKJFAAPBSQJPD-UHFFFAOYSA-N tetrafluoroethene Chemical group FC(F)=C(F)F BFKJFAAPBSQJPD-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 239000004520 water soluble gel Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
Description
【0001】0001
【産業上の利用分野】本発明は、多層構造の各層の構成
単位が医薬活性成分を含有する粉末コ−ティング薬物層
および該粉末コ−ティング薬物層を被覆する水不溶性フ
ィルム層からなることを特徴とする徐放性顆粒剤および
その製造方法を提供する。よって、本発明は、複数の医
薬活性成分を含有し、それら個別の放出制御を必要とす
る製剤、例えば徐放性総合感冒剤等に適用できる。[Industrial Application Field] The present invention provides that the constituent units of each layer of a multilayer structure consist of a powder-coated drug layer containing a pharmaceutically active ingredient and a water-insoluble film layer covering the powder-coated drug layer. Provided are sustained-release granules and a method for producing the same. Therefore, the present invention can be applied to preparations that contain a plurality of pharmaceutically active ingredients and require individual release control, such as sustained-release general cold preparations.
【0002】0002
【先行技術】医薬活性成分の溶出および吸収を効果的に
制御する徐放化技術は、マトリックス形成法、隔膜分離
法、化学吸着の利用、水溶性ゲルマトリックスの利用等
、多数開示されている。ただし、いずれも単一の医薬活
性成分の徐放化を目的としたものであり、複数種の医薬
活性成分に対して個別に放出制御する試みはなされてい
ない。[Prior Art] Many sustained release techniques for effectively controlling the elution and absorption of pharmaceutically active ingredients have been disclosed, including matrix formation methods, diaphragm separation methods, use of chemical adsorption, and use of water-soluble gel matrices. However, all of these are aimed at sustained release of a single pharmaceutically active ingredient, and no attempt has been made to individually control the release of multiple types of pharmaceutically active ingredients.
【0003】また多層構造を有する徐放性顆粒剤に関す
る技術はいくつか開示されているが、溶出曲線をゼロ次
型とするための技法(特開昭63−27424)や、同
一医薬活性成分の徐放部と速放部を組み合わせた多層構
造製剤のための技法(特開昭60−4120)であって
、複数種の医薬活性成分の溶出特性を個別に制御出来る
徐放化技術に関する記載は見られない。[0003]Also, several techniques regarding sustained release granules having a multilayer structure have been disclosed, including a technique for making the dissolution curve zero-order (Japanese Patent Application Laid-Open No. 63-27424), and There is a description of a technique for a multilayer structure preparation combining a sustained release part and an immediate release part (Japanese Unexamined Patent Publication No. 60-4120), which describes a sustained release technology that can individually control the elution characteristics of multiple types of pharmaceutically active ingredients. can not see.
【0004】0004
【発明が解決すべき課題】前記先行技術に基づいて調製
された複数種の医薬活性成分を含有する徐放性顆粒剤で
は、医薬活性成分間の溶解度、配合量、溶解速度等の相
違により、各医薬活性成分は異なる溶出挙動を示すこと
が多く、すべての医薬活性成分に対して合目的な溶出特
性を同時に与えることは極めて困難である。一方、各医
薬活性成分に対して個別に徐放性顆粒を調製し、これら
を混合して一製剤として使用する場合は、周知の如く混
合時の偏析により、目的とする製剤の医薬活性成分の含
量、溶出特性等を精密に制御し管理するのが困難である
。[Problems to be Solved by the Invention] In the sustained release granules containing multiple types of pharmaceutically active ingredients prepared based on the above-mentioned prior art, due to differences in solubility, blending amount, dissolution rate, etc. between the pharmaceutically active ingredients, Each pharmaceutically active ingredient often exhibits different elution behavior, and it is extremely difficult to simultaneously provide desired elution characteristics to all pharmaceutically active ingredients. On the other hand, when sustained-release granules are prepared individually for each pharmaceutically active ingredient and used as a single preparation by mixing them, as is well known, segregation during mixing may cause the amount of the pharmaceutically active ingredient in the desired preparation to be mixed. It is difficult to precisely control and manage the content, elution characteristics, etc.
【0005】[0005]
【課題を解決するための手段】以上の点に鑑み、本発明
者らは、一顆粒中に医薬活性成分を収納できる複数の薬
物層を設置し、さらに、各薬物層を水不溶性フィルム層
で分離して多層構造とするならば、各医薬活性成分の放
出速度を任意に制御できることを見出し、本発明を完成
した。さらに詳しくは、本発明は、多層構造の各層の構
成単位が医薬活性成分を含有する粉末コ−ティング薬物
層(以下、単に薬物層とも言う)および該粉末コ−ティ
ング薬物層を被覆する水不溶性フィルム層(以下、単に
フィルム層とも言う)からなり、各薬物層がフィルム層
で隔離されたリザ−バ−を形成していることを特徴とす
る徐放性顆粒剤を提供するものである。[Means for Solving the Problems] In view of the above points, the present inventors installed a plurality of drug layers capable of storing pharmaceutically active ingredients in one granule, and further, each drug layer was formed with a water-insoluble film layer. The present invention was completed based on the discovery that the release rate of each pharmaceutically active ingredient can be arbitrarily controlled by separating it into a multilayer structure. More specifically, the present invention provides a powder-coated drug layer (hereinafter also simply referred to as drug layer) in which the constituent units of each layer of a multilayer structure contain a pharmaceutically active ingredient, and a water-insoluble drug layer covering the powder-coated drug layer. The present invention provides a sustained release granule comprising a film layer (hereinafter also simply referred to as a film layer), each drug layer forming a reservoir isolated by the film layer.
【0006】本製剤の製造方法について以下に説明する
。本製剤は、下記の2工程を一単位とする操作を複数回
行なうことにより、製造することができる。
a工程:医薬活性成分を含有する粉末の粉末コ−ティン
グ工程
b工程:ひき続き行なう水不溶性フィルムコ−ティング
工程各工程について、以下に説明する。[0006] The method for producing this preparation will be explained below. This preparation can be manufactured by performing the following two steps multiple times as one unit. Step a: Powder coating step of powder containing a pharmaceutically active ingredient Step b: Subsequent water-insoluble film coating step Each step will be explained below.
【0007】(a工程)本工程は、結合剤存在下、芯物
質または本製法のb工程完了後に得られる粒子の表面に
、医薬活性成分を含有する粉末を、粉末コ−ティング法
によりコ−ティングして、薬物層を形成する工程である
。(Step a) In this step, in the presence of a binder, a powder containing a pharmaceutically active ingredient is coated on the core material or on the surface of the particles obtained after completion of Step b of the present manufacturing method using a powder coating method. This step is to form a drug layer.
【0008】結合剤としては、水不溶性または難溶性の
ものであれば、医薬活性成分およびその溶出性に悪影響
を与えないものである限り幅広く使用可能であり、メチ
ルセルロ−ス、エチルセルロ−ス、ヒドロキシエチルセ
ルロ−ス、ヒドロキシプロピルセルロ−ス、キサンタン
ガム等が例示される。A wide variety of binders can be used as long as they are water-insoluble or poorly soluble, as long as they do not adversely affect the pharmaceutically active ingredients and their dissolution properties, such as methylcellulose, ethylcellulose, hydroxy Examples include ethyl cellulose, hydroxypropyl cellulose, and xanthan gum.
【0009】芯物質としては、薬理学的に不活性であり
使用する医薬活性成分となんら相互作用のない物質であ
れば使用可能であり、しょ糖、乳糖、マンニト−ル、果
糖、等の糖類、セルロ−ス類、デンプン類、糖脂肪酸エ
ステル類などが例示され、これらを単独、その結晶、ま
たは混合物として使用すればよい。ただし、水不溶性フ
ィルム基剤によるコ−ティングを、水系のスプレ−を使
用して行なう場合は、芯物質が膨潤して崩壊しやすくな
るので、膨潤による崩壊のない結晶セルロ−ス粒等を使
用するのが好ましい。使用量は、目的とする顆粒の大き
さにより任意に選べる。[0009] As the core substance, any substance can be used as long as it is pharmacologically inactive and has no interaction with the pharmaceutically active ingredients used, such as sugars such as sucrose, lactose, mannitol, fructose, etc. Examples include celluloses, starches, sugar fatty acid esters, etc., and these may be used alone, as crystals, or as a mixture. However, when coating with a water-insoluble film base using a water-based spray, the core material swells and disintegrates easily, so crystalline cellulose particles, etc., which do not disintegrate due to swelling, are used. It is preferable to do so. The amount used can be arbitrarily selected depending on the desired size of the granules.
【0010】医薬活性成分を含有する粉末とは、コ−テ
ィングの操作性を向上させるための適当な賦形剤やその
他の添加剤と医薬活性成分との混合末である。Powder containing a pharmaceutically active ingredient is a mixed powder of the pharmaceutically active ingredient and suitable excipients and other additives for improving the operability of coating.
【0011】医薬活性成分としては、水溶解性のもので
あれば特に限定されないが、例えばマレイン酸クロルフ
ェニラミン、d−マレイン酸クロルフェニラミン、フマ
ル酸クレマスチン、マレイン酸カルビノキサミン、塩酸
プロメタジン、ジフェンヒドラミン、テルフェナジン等
の抗ヒスタミン剤、アスピリン、サルチルアミド、エテ
ンザミド、アセトアミノフェン、ジクロフェナクナトリ
ウム、リン酸ジヒドロコデイン、硫酸モルヒネ、塩酸モ
ルヒネ、リン酸コデイン等の解熱鎮痛または鎮痛剤、メ
シル酸ビトルテロ−ル等の気管支拡張剤、臭化水素酸デ
キストロメトルファン、塩酸クロペラスチン、塩酸フェ
ニルプロパノ−ルアミン、メチルエフェドリン、硫酸カ
リウムクレゾ−ル、ベラドンナ総アルカロイド等の鎮咳
去痰剤、セトラキサ−ト、ラニチジン、ファモチジン等
の抗潰瘍剤、ピンドロ−ル、プロプラノロ−ル、アルプ
レノロ−ル、オキシプリノ−ル、ジルチアゼム、ピナシ
ジル等の循環器系薬剤、5−フルオロウラシル、テガフ
−ル等の抗腫瘍剤、シノキサシン、エノキサシン、ロメ
フロキサシン等の抗菌剤、セファレキシン、セファクロ
ル等の抗生物質等が例示される。賦形剤は特に限定され
ず、乳糖やコ−ンスタ−チ等の有機物、リン酸カルシウ
ム等の無機物等一般的に使用されるものならば幅広く使
用可能である。使用量も必ずしも限定されないが、配合
量が少なくかつ溶解度の大きな医薬活性成分即ち中心部
近くに配合される医薬活性成分については、出来るだけ
使用量を減ずることが好ましい。The pharmaceutically active ingredients are not particularly limited as long as they are water-soluble, but examples include chlorpheniramine maleate, chlorpheniramine d-maleate, clemastine fumarate, carbinoxamine maleate, promethazine hydrochloride, diphenhydramine, Antihistamines such as terfenadine, antipyretic analgesics or analgesics such as aspirin, salicylamide, ethenzamide, acetaminophen, diclofenac sodium, dihydrocodeine phosphate, morphine sulfate, morphine hydrochloride, codeine phosphate, and bronchodilators such as bitolterol mesylate. , dextromethorphan hydrobromide, cloperastine hydrochloride, phenylpropanolamine hydrochloride, methylephedrine, potassium cresol sulfate, antitussive expectorants such as belladonna total alkaloids, anti-ulcer agents such as cetraxate, ranitidine, famotidine, pindro Circulatory system drugs such as alcohol, propranolol, alprenolol, oxypurinol, diltiazem, pinacidil, antitumor agents such as 5-fluorouracil and tegafur, antibacterial agents such as cinoxacin, enoxacin, lomefloxacin, cephalexin, Examples include antibiotics such as cefaclor. The excipient is not particularly limited, and a wide variety of commonly used excipients can be used, such as organic substances such as lactose and cornstarch, and inorganic substances such as calcium phosphate. Although the amount used is not necessarily limited, it is preferable to reduce the amount used as much as possible for pharmaceutical active ingredients that are blended in small amounts and have high solubility, that is, pharmaceutical active ingredients that are blended near the center.
【0012】添加剤としては、増粘剤、滑沢剤、保水剤
等が使用される。滑沢剤としては、ステアリン酸マグネ
シウム、グリセリン脂肪酸エステル等が例示される。保
水剤としては、コ−ンスタ−チ、結晶セルロ−ス、部分
アルファ−化デンプン等が例示される。ただし、いずれ
の添加剤の場合も、医薬活性成分を含有する粉末の粉末
コ−ティングの操作性を高めるために使用されるので、
種類や使用量は必ずしも限定されない。[0012] As additives, thickeners, lubricants, water retention agents, etc. are used. Examples of the lubricant include magnesium stearate and glycerin fatty acid ester. Examples of water retention agents include corn starch, crystalline cellulose, and partially pregelatinized starch. However, in the case of both additives, they are used to improve the operability of powder coating of powders containing pharmaceutically active ingredients;
The type and amount used are not necessarily limited.
【0013】(b工程)本工程は、a工程で得られる粒
子(以下、素顆粒という)の表面に水不溶性フィルムコ
−ティング基剤をコ−ティングして、フィルム層を形成
する工程である。所望により、腸溶性コ−ティング基剤
、水溶性コ−ティング基剤、滑沢剤、増量剤、可塑剤等
の添加剤を添加して使用してもよい。(Step b) This step is a step of coating the surface of the particles obtained in step a (hereinafter referred to as elementary granules) with a water-insoluble film coating base to form a film layer. . If desired, additives such as an enteric coating base, a water-soluble coating base, a lubricant, a filler, a plasticizer, and the like may be added.
【0014】本工程で使用され得る水不溶性フィルムコ
−ティング基剤としては、エチルセルロ−ス、メタアク
リル酸エチル・メタアクリル酸塩化トリメチルアンモニ
ウム共重合体、アクリル酸エチル・メタアクリル酸メチ
ル共重合体の乳濁液(オイドラギットNE30D、30
%水エマルジョン、樋口商会(株))、セラック、高重
合度ポリビニルアルコ−ル、水不溶性ポリビニルピロリ
ドン、ポリ塩化ビニル、セルロ−スアセテ−ト、ポリウ
レタン、テトラフルオロエチレン、ポリスチレン、ポリ
プロピレン、乳酸重合体、ヒドロキシエチルメタアクリ
レ−ト、グルコ−ル酸重合体、ポリエチレンテレフタレ
−ト、ポリエチレン、ポリアミド、ポリアクリロニトリ
ル、ポリカルボン酸、シアノアクリレ−ト重合体等が例
示される。Water-insoluble film coating bases that can be used in this step include ethyl cellulose, ethyl methacrylate/trimethylammonium methacrylate copolymer, and ethyl acrylate/methyl methacrylate copolymer. emulsion (Eudragit NE30D, 30
% water emulsion, Higuchi Shokai Co., Ltd., shellac, highly polymerized polyvinyl alcohol, water-insoluble polyvinylpyrrolidone, polyvinyl chloride, cellulose acetate, polyurethane, tetrafluoroethylene, polystyrene, polypropylene, lactic acid polymer, Examples include hydroxyethyl methacrylate, glycolic acid polymer, polyethylene terephthalate, polyethylene, polyamide, polyacrylonitrile, polycarboxylic acid, and cyanoacrylate polymer.
【0015】本発明では、特に水浸透性が高く、薄膜で
緻密なフィルムが要求されるので、可塑性に富みシ−ム
レス化が容易でかつ水浸透性が高い前記オイドラギット
NE30Dが好ましい。また、水不溶性フィルムコ−テ
ィング基剤には、必要により添加剤を加えても良いが、
上記の理由により造膜性や、水の浸透性に悪影響を及ぼ
さない範囲で極力使用量を減ずるのが好ましい。In the present invention, a thin and dense film with particularly high water permeability is required, so the Eudragit NE30D, which is rich in plasticity, can be easily made seamless, and has high water permeability, is preferred. Additionally, additives may be added to the water-insoluble film coating base if necessary.
For the above reasons, it is preferable to reduce the amount used as much as possible without adversely affecting film forming properties and water permeability.
【0016】水不溶性フィルムコ−ティング基剤の被覆
量は、該基剤の種類、薬物層中の医薬活性成分の配合量
、溶解度、裸顆粒の表面積および目的とする溶出特性等
によって変化するので一概には規定できないが、一般的
には素顆粒に対して1〜50%重量増、好ましくは1〜
20%重量増の範囲である。上限以上では、中心部に近
い薬物層に配合された医薬活性成分の放出制御に著しい
悪影響を及ぼし、下限以下では、フィルム層は放出制御
膜として有効ではなく、含有医薬活性成分の徐放化が十
分に達成されない。尚、各工程で得られた粒子に対して
、若干の乾燥を行なった後、次の工程へ進むのが望まし
い。[0016] The amount of water-insoluble film coating base coated varies depending on the type of base, the amount of pharmaceutically active ingredient in the drug layer, solubility, surface area of bare granules, desired elution characteristics, etc. Although it cannot be absolutely defined, the weight increase is generally 1 to 50% compared to the elementary granules, preferably 1 to 50%.
The range is 20% weight increase. Above the upper limit, it will have a significant negative effect on the release control of the pharmaceutically active ingredient contained in the drug layer near the center, and below the lower limit, the film layer will not be effective as a release control membrane, and the sustained release of the contained pharmaceutical active ingredient will not be achieved. Not enough is achieved. Note that it is desirable to proceed to the next step after slightly drying the particles obtained in each step.
【0017】腸溶性コ−ティング基剤としてはヒドロキ
シプロピルメチルセルロ−スフタレ−ト(HPMCP)
、ヒドロキシプロピルメチルセルロ−スアセテ−トサク
シネ−ト(HPMC−AS)、メタアクリル酸・メタア
クリル酸メチル共重合体、セルロ−スアセテ−トフタレ
−ト(CAP)などが例示される。水溶性コ−ティング
基剤としては、メチルセルロ−ス(MC)、ヒドロキシ
プロピルセルロ−ス(HPC)、ポリビニルピロリドン
(PVP)、ポリビニルアルコ−ル(PVA)、ゼラチ
ン、ヒドロキシプロピルメチルセルロ−ス(HPMC)
、ポリカルボン酸、澱粉、アルギン酸ナトリウムなどが
例示される。滑沢剤としては、ステアリン酸マグネシウ
ム、ステアリン酸等が例示される。増量剤としては、タ
ルク、炭酸カルシウム等が例示される。可塑剤としては
、トリアセチン、クエン酸トリエチル等が例示される。Hydroxypropylmethylcellulose phthalate (HPMCP) is used as the enteric coating base.
, hydroxypropylmethylcellulose acetate succinate (HPMC-AS), methacrylic acid/methyl methacrylate copolymer, cellulose acetate phthalate (CAP), and the like. Examples of water-soluble coating bases include methylcellulose (MC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), gelatin, and hydroxypropylmethylcellulose (HPMC). )
, polycarboxylic acid, starch, sodium alginate, etc. Examples of the lubricant include magnesium stearate and stearic acid. Examples of the filler include talc, calcium carbonate, and the like. Examples of the plasticizer include triacetin and triethyl citrate.
【0018】本発明製剤は、上記2工程を一単位とする
操作(以下、単にコ−ティング操作という)を複数回行
なうことにより製造出来る。よって、例えば2層構造よ
りなる製剤は、コ−ティング操作を2回行なうことによ
り、3層構造よりなる製剤であれば、3回行なうことに
より製造でき、さらに4層、5層構造の製剤も同様の方
法により製造可能である。つまり、目的とする薬物層の
数に応じて、コ−ティング操作を反復すれば、さらに多
層の構造を有する製剤も製造可能である。The preparation of the present invention can be produced by performing the above two steps as one unit (hereinafter simply referred to as coating operation) multiple times. Therefore, for example, a formulation with a two-layer structure can be manufactured by performing the coating operation twice, a formulation with a three-layer structure can be manufactured by performing the coating operation three times, and formulations with a four-layer or five-layer structure can also be manufactured. It can be manufactured by a similar method. That is, by repeating the coating operation depending on the desired number of drug layers, it is possible to produce a preparation having a multilayer structure.
【0019】本発明製剤は、複数の医薬活性成分の個別
の放出制御を可能とする。この作用機構は以下のように
説明される。投与された製剤が胃内に到達した後、胃内
の水分は最外層のフィルム層を通過して内部へ浸透し、
各薬物層中に充満する。薬物層中に充満した水は、薬物
層中の各医薬活性成分の一部を溶解した後、各フィルム
層を拡散透過しつつ放出される。[0019] The formulation of the present invention allows for individual controlled release of a plurality of pharmaceutically active ingredients. This mechanism of action is explained as follows. After the administered preparation reaches the stomach, the water in the stomach passes through the outermost film layer and penetrates into the inside.
Fill each drug layer. The water filled in the drug layer dissolves a portion of each pharmaceutically active ingredient in the drug layer and is then released while diffusing through each film layer.
【0020】この時、溶出の律速段階になるのは、医薬
活性成分の溶解およびフィルム層における拡散透過であ
る。よって、溶解速度および拡散透過速度を制御するこ
とにより、該医薬活性成分に目的とする溶出特性を与え
ることができる。溶解速度は、各医薬活性成分の薬物層
の容積を変化させることにより、また拡散透過速度は、
フィルム層の組成および厚さを変化させることによりそ
れぞれ制御可能である。At this time, the rate-determining steps for elution are the dissolution of the pharmaceutically active ingredient and its diffusion through the film layer. Therefore, by controlling the dissolution rate and the diffusion permeation rate, the pharmaceutically active ingredient can be given desired elution characteristics. The dissolution rate can be determined by changing the volume of the drug layer of each pharmaceutical active ingredient, and the diffusive permeation rate can be determined by changing the volume of the drug layer of each pharmaceutical active ingredient.
Each can be controlled by changing the composition and thickness of the film layer.
【0021】一般的に、医薬活性成分を溶解律速によっ
て徐放化するためには、その医薬活性成分のリザ−バ中
の配合密度を高くする方が望ましいことが知られている
。よって、溶解度が大きくかつ配合量が少ない医薬活性
成分ほど、顆粒の中心部近くに配合しかつ薬物層の容積
を小さくするのが好ましく、このためには医薬活性成分
以外の添加剤を出来るだけ減ずることが好ましい。[0021] Generally, it is known that in order to achieve sustained release of a pharmaceutically active ingredient by dissolution rate limiting, it is desirable to increase the compounding density of the pharmaceutically active ingredient in the reservoir. Therefore, it is preferable that the higher the solubility of the pharmaceutically active ingredient and the smaller the amount of the pharmaceutically active ingredient to be blended, the closer to the center of the granule it is and the smaller the volume of the drug layer.For this purpose, the amount of additives other than the pharmaceutically active ingredient should be reduced as much as possible. It is preferable.
【0022】また、各医薬活性成分の溶出特性が各薬物
層を直接被覆するフィルム層のみに依存し、これより外
部のフィルム層には実質的に影響されないことが好まし
い。このためには、各フィルム層が出来るだけ薄く、緻
密でかつ水浸透性が良好である方が好ましいので、水不
溶性フィルムコ−ティング基剤にタルク等の増量剤を添
加しない方が望ましい。[0022] Furthermore, it is preferable that the elution characteristics of each pharmaceutically active ingredient depend only on the film layer directly covering each drug layer, and are not substantially influenced by film layers outside this. For this purpose, it is preferable that each film layer be as thin as possible, dense, and have good water permeability, so it is preferable not to add an extender such as talc to the water-insoluble film coating base.
【0023】本発明により、目的とする徐放化に応じて
、各医薬活性成分の溶出特性を各個にかつ任意に制御す
ることができる。また、医薬活性成分の溶解度または配
合量等を考慮すれば、例えば、各医薬活性成分の溶出特
性をほぼ同一にすることも可能である。なお、各薬物層
中の医薬活性成分は、必ずしもすべて異種のものである
必要はなく、徐放化剤の目的に応じて、一部またはすべ
て同種のものであっても、何等不都合は生じない。According to the present invention, the elution characteristics of each pharmaceutically active ingredient can be individually and arbitrarily controlled depending on the desired sustained release. Furthermore, if the solubility or blending amount of the pharmaceutically active ingredients is considered, it is possible, for example, to make the elution characteristics of each pharmaceutically active ingredient almost the same. It should be noted that the pharmaceutical active ingredients in each drug layer do not necessarily all have to be of different types, and depending on the purpose of the sustained release agent, some or all of them may be of the same type without causing any inconvenience. .
【0024】以下に、本発明をさらに詳細に説明するた
めに各実施例および各参考例を示すが、これらは何等本
発明を制限するものではない。Examples and reference examples are shown below to explain the present invention in more detail, but these are not intended to limit the present invention in any way.
【0025】(本発明製剤の一般的調製法)遠心転動造
粒機(CF−360,フロイント産業(株))を使用し
、転動を止めずに前記a工程およびb工程を以下のよう
に繰り返して被覆操作を行なう。(General method for preparing the preparation of the present invention) Using a centrifugal rolling granulator (CF-360, Freund Sangyo Co., Ltd.), the steps a and b are carried out as follows without stopping the rolling. Repeat the coating operation.
【0026】a工程:粉末コ−ティング工程50%平均
粒子径が320μmφである結晶セルロ−ス粒(アビセ
ルSP,旭化成(株))または、b工程完了後に得られ
る粒子を中心核となりうる物質とし、結合剤スプレ−液
を噴霧しつつ、粉末コ−ティング薬物第n層(以下、単
に薬物第n層という,nは1以上の整数を表わす)を形
成する混合末を中心核となりうる物質の表面にコ−ティ
ングする。次いで、約50℃、約300NL/minの
空気を底部より約15分間送風して、若干の乾燥を行な
う。Step a: Powder coating step 50% Crystalline cellulose grains (Avicel SP, Asahi Kasei Corporation) having an average particle diameter of 320 μmφ or particles obtained after completion of step b are used as a material that can serve as the central core. While spraying the binder spray liquid, the mixed powder forming the powder coating drug nth layer (hereinafter simply referred to as drug nth layer, n represents an integer of 1 or more) is mixed with a substance that can serve as a core. Coat the surface. Next, air is blown at about 50° C. and about 300 NL/min from the bottom for about 15 minutes to dry it slightly.
【0027】b工程:水不溶性フィルムコ−ティング工
程
a工程で得られた素顆粒に対して、約40℃、約200
NL/minの空気を送風しつつ、アクリル酸エチル・
メタアクリル酸メチル共重合体乳濁液(オイドラギット
NE30D,30%水エマルジョン,樋口商会(株))
を、約10g/minの速度で所定量コ−ティングする
。次いで少量のタルクを散布して水不溶性フィルム第n
層(以下、単にフィルム第n層という,nは1以上の整
数を表わす)を形成させた後、約50℃、約300NL
/minの空気を送風して若干の乾燥を行なう。Step b: Water-insoluble film coating step The elementary granules obtained in step a are heated at about 40°C and about 200℃.
Ethyl acrylate while blowing air at NL/min.
Methyl methacrylate copolymer emulsion (Eudragit NE30D, 30% water emulsion, Higuchi Shokai Co., Ltd.)
A predetermined amount of is coated at a rate of about 10 g/min. Then, sprinkle a small amount of talc to form a water-insoluble film.
After forming a layer (hereinafter simply referred to as the n-th film layer, n represents an integer of 1 or more), about 50°C and about 300NL
Blow air at a rate of /min for some drying.
【0028】例えば、3層構造よりなる本発明製剤を製
造する場合には、下記の6工程を行なう。第一工程:薬
物第一層形成
前記結晶セルロ−ス粒を芯物質として、a工程を行ない
薬物第一層を形成する。第二工程:フィルム第一層形成
第一工程で得られた素顆粒に対して、b工程を行ないフ
ィルム第一層を形成する。For example, when producing a preparation of the present invention having a three-layer structure, the following six steps are carried out. First step: Formation of drug first layer Using the crystalline cellulose grains as a core material, step a is performed to form a drug first layer. Second step: Formation of first layer of film The elementary granules obtained in the first step are subjected to step b to form a first layer of film.
【0029】第三工程:薬物第二層形成第二工程で得ら
れた粒子に対して、a工程を行ない薬物第二層を形成す
る。
第四工程:フィルム第二層形成
第三工程で得られた素顆粒に対して、b工程を行ないフ
ィルム第二層を形成する。Third step: Formation of second drug layer The particles obtained in the second step are subjected to step a to form a second drug layer. Fourth step: Formation of second film layer The elementary granules obtained in the third step are subjected to step b to form a second film layer.
【0030】第五工程:薬物第三層形成第四工程で得ら
れた粒子に対して、a工程を行ない薬物第三層を形成す
る。
第六工程:フィルム第三層形成
第五工程で得られた素顆粒に対して、b工程を行ないフ
ィルム第三層を形成させた後、転動を中止し、得られる
粒子を取りだす。Fifth step: Formation of third drug layer The particles obtained in the fourth step are subjected to step a to form a third drug layer. Sixth step: Formation of third layer of film After performing step b on the elementary granules obtained in the fifth step to form a third layer of film, rolling is stopped and the resulting particles are taken out.
【0031】なお、最終工程で得られた粒子を流動乾燥
機(WSG5型,グラット社)により約50℃で約1h
r乾燥させることにより、目的のマルチリザ−バ−型徐
放性顆粒剤を得る。次に、使用した各医薬活性成分の水
溶解度を表1に示す。[0031] The particles obtained in the final step were dried at about 50°C for about 1 hour in a fluidized dryer (WSG5 type, Glatt Co., Ltd.).
By drying, the desired multi-reservoir sustained release granules are obtained. Next, Table 1 shows the water solubility of each pharmaceutical active ingredient used.
【表1】[Table 1]
【0032】実施例1
一般的調製法に準じ、下記の工程により2層構造の顆粒
を調製した。第一工程:薬物第一層形成芯物質として、
50%平均粒子径が320μmΦである結晶セルロ−ス
粒(アビセルSP,旭化成(株))を1000g使用し
、その表面に、結合剤として2%メチルセルロ−ス25
cps 15%エタノ−ル水溶液340gを噴霧しつつ
、臭化水素酸デキストロメトルファン88.8g、ステ
アリン酸マグネシウム4.4gからなる混合末を粉末コ
−ティングし、薬物第一層を形成する。
次いで、約50℃、約300NL/minの空気を底部
より約15分間送風して、若干の乾燥を行なう。Example 1 Granules having a two-layer structure were prepared according to a general preparation method by the following steps. First step: As the core material for forming the drug first layer,
1000 g of crystalline cellulose grains (Avicel SP, Asahi Kasei Corporation) with a 50% average particle diameter of 320 μmΦ were used, and 2% methylcellulose 25% was applied as a binder on the surface.
A mixed powder consisting of 88.8 g of dextromethorphan hydrobromide and 4.4 g of magnesium stearate is powder coated while spraying 340 g of a 15% cps ethanol aqueous solution to form a first drug layer. Next, air is blown at about 50° C. and about 300 NL/min from the bottom for about 15 minutes to dry it slightly.
【0033】第二工程:フィルム第二層形成第一工程で
得られた素顆粒に対して、約40℃、約200NL/m
inの空気を送風しつつ、オイドラギットNE30D
740gを、約10g/minの速度で所定量コ−ティ
ングする。次いでタルク74gを散布してフィルム第二
層を形成させた後、約50℃、約300NL/minの
空気を送風して若干の乾燥を行なう。Second step: Formation of second film layer The elementary granules obtained in the first step are heated at about 40° C. and about 200 NL/m.
Eudragit NE30D while blowing air inside
A predetermined amount of 740 g is coated at a rate of about 10 g/min. Next, 74 g of talc is sprinkled to form a second film layer, and then air is blown at about 50° C. and about 300 NL/min to perform some drying.
【0034】第三工程:薬物第二層形成第二工程で得ら
れた粒子に対して、その表面に、結合剤として2%メチ
ルセルロ−ス25cps 15%エタノ−ル水溶液61
6gを噴霧しつつ、アセトアミノフェン1665g、ス
テアリン酸マグネシウム10.0g、メチルセルロ−ス
25cps 14.0gからなる混合末を粉末コ−ティ
ングし、薬物第二層を形成する。次いで、約50℃、約
300NL/minの空気を底部より約15分間送風し
て、若干の乾燥を行なう。Third step: Formation of drug second layer. 2% methylcellulose 25cps 15% ethanol aqueous solution 61 as a binder is applied to the surface of the particles obtained in the second step.
A mixed powder consisting of 1665 g of acetaminophen, 10.0 g of magnesium stearate, and 14.0 g of 25 cps of methylcellulose is powder coated while spraying 6 g of the drug to form a second drug layer. Next, air is blown at about 50° C. and about 300 NL/min from the bottom for about 15 minutes to dry it slightly.
【0035】第四工程:フィルム第二層形成第三工程で
得られた素顆粒に対して、約40℃、約200NL/m
inの空気を送風しつつ、オイドラギットNE30D
1000gを、約10g/minの速度で所定量コ−テ
ィングする。次いでタルク110gを散布してフィルム
第二層を形成させた後、約50℃、約300NL/mi
nの空気を送風して若干の乾燥を行なう。Fourth step: Formation of second layer of film The elementary granules obtained in the third step are heated at about 40° C. and about 200 NL/m.
Eudragit NE30D while blowing air inside
A predetermined amount of 1000 g is coated at a rate of about 10 g/min. Next, 110 g of talc was sprinkled to form a second film layer, and then heated at about 50°C and about 300 NL/mi.
Slight drying is performed by blowing n air.
【0036】転動を中止し、得られる粒子を取りだして
流動乾燥機(WSG5型,グラット社)により約50℃
で約1hr乾燥させる。このようにして、1服用単位
1038mg中に臭化水素酸デキストロメトルファン2
4mg、アセトアミノフェン450mgを含有し、50
%平均粒子径約620μmφの顆粒を得る。[0036] The rolling was stopped, and the obtained particles were taken out and dried at about 50°C in a fluidized fluid dryer (WSG5 type, Glatt Co., Ltd.).
Let dry for about 1 hour. In this way, one dose unit
Dextromethorphan hydrobromide 2 in 1038mg
Contains 4mg, acetaminophen 450mg, 50
Granules with a % average particle diameter of about 620 μmφ are obtained.
【0037】実施例2〜3および参考例1〜5前記一般
調製法に準じ、各工程共、表2に示す配合量に基づいて
調製した。Examples 2 to 3 and Reference Examples 1 to 5 Each step was prepared based on the amounts shown in Table 2 according to the general preparation method described above.
【表2】
実施例2〜3は、実施例1と同様の2層構造の顆粒であ
り、参考例1〜5は、通常の隔膜分離型の顆粒(以下、
シングルリザ−バ−型顆粒と言う)である。なお、いず
れの場合も芯物質には前記結晶セルロ−ス粒を1000
g使用した。[Table 2] Examples 2 to 3 are granules with a two-layer structure similar to Example 1, and Reference Examples 1 to 5 are ordinary diaphragm-separated granules (hereinafter referred to as
(referred to as single reservoir type granules). In both cases, the core material contains 1000 of the crystalline cellulose grains.
g was used.
【0038】また、各使用物質を以下の略記号で表わす
こともある。結晶セルロ−ス粒:a,臭化水素酸デキス
トロメトルファン:b,アセトアミノフェン:c,エテ
ンザミド:d,ステアリン酸マグネシウム:e,メチル
セルロ−ス25cps:f,2%メチルセルロ−ス25
cps 15%エタノ−ル水溶液:g,オイドラギット
NE30D:h,タルク:i[0038] Each substance used may also be represented by the following abbreviations. Crystalline cellulose grains: a, dextromethorphan hydrobromide: b, acetaminophen: c, ethenzamide: d, magnesium stearate: e, methylcellulose 25cps: f, 2% methylcellulose 25
cps 15% ethanol aqueous solution: g, Eudragit NE30D: h, talc: i
【0039】各実施例および各参考例で得られた各顆粒
中の医薬活性成分の組成を表3に示す。Table 3 shows the composition of the pharmaceutically active ingredient in each granule obtained in each Example and each Reference Example.
【表3】
各実施例で得られた各顆粒の粒度分布、収量、および収
率を表4に示す。[Table 3] Table 4 shows the particle size distribution, yield, and yield of each granule obtained in each example.
【表4】[Table 4]
【0040】実施例4〜7
実施例1の第四工程で水不溶性フィルムコ−ティング基
剤に使用したオイドラギットNE30D(h)の被覆量
を、表5に示す通り変化させて調製した。Examples 4 to 7 Films were prepared by varying the coating amount of Eudragit NE30D (h) used as the water-insoluble film coating base in the fourth step of Example 1, as shown in Table 5.
【表5】[Table 5]
【0041】実施例8〜11実施例2の第四工程で水不
溶性フィルムコ−ティング基剤に使用したオイドラギッ
トNE30D(h)の被覆量を、表6に示す通り変化さ
せて調製した。Examples 8 to 11 The coating amount of Eudragit NE30D (h) used as the water-insoluble film coating base in the fourth step of Example 2 was varied as shown in Table 6.
【表6】[Table 6]
【0042】(溶出試験)試験方法
試験は、第11改正日本薬局方の一般試験法、溶出試験
の項に準じ、パドル法(100rpm)により行ない、
試験液には第1液(Fluid)、第2液(Fluid
)、または水を使用した。(Dissolution test) Test method The test was conducted using the paddle method (100 rpm) in accordance with the 11th revised Japanese Pharmacopoeia, General Test Methods, Dissolution Test section.
The test liquid includes the first liquid (Fluid) and the second liquid (Fluid).
), or using water.
【0043】実験例1
実施例1のマルチリザ−バ−型徐放性顆粒に関して、上
記溶出試験を行なった。試験液には、第1液(Flui
d)、第2液(Fluid)を使用し、顆粒は、臭化水
素酸デキストロメトルファン(b)24mg、アセトア
ミノフェン(c)450mg相当量のものを使用した。
結果を図1に示す。いずれの医薬活性成分もほぼ同程度
の溶出特性を示し、pH依存性はほとんど見られなかっ
た。Experimental Example 1 The above dissolution test was conducted on the multi-reservoir sustained release granules of Example 1. The test liquid includes the first liquid (Flui
d), a second liquid (Fluid) was used, and the granules used were equivalent to 24 mg of dextromethorphan hydrobromide (b) and 450 mg of acetaminophen (c). The results are shown in Figure 1. All pharmaceutical active ingredients showed approximately the same elution characteristics, and almost no pH dependence was observed.
【0044】実験例2
実施例2のマルチリザ−バ−型徐放性顆粒に関して、上
記溶出試験を行なった。試験液には、第1液、第2液を
使用し、顆粒は、アセトアミノフェン125mg、エテ
ンザミド375mg相当量のものを使用した。結果を図
2に示す。いずれの医薬活性成分もほぼ同程度の溶出特
性を示し、pH依存性はほとんど見られなかった。Experimental Example 2 The above dissolution test was conducted on the multi-reservoir sustained release granules of Example 2. The test solutions used were the first and second solutions, and the granules used were equivalent to 125 mg of acetaminophen and 375 mg of ethenzamide. The results are shown in Figure 2. All pharmaceutical active ingredients showed approximately the same elution characteristics, and almost no pH dependence was observed.
【0045】実験例3
実施例3のマルチリザ−バ−型徐放性顆粒に関して、上
記溶出試験を行なった。試験液には、水を使用し、顆粒
は、臭化水素酸デキストロメトルファン24mg、アセ
トアミノフェン125mg、エテンザミド375mg相
当量のものを使用した。結果を図3に示す。いずれの医
薬活性成分もほぼ同程度の溶出特性を示した。Experimental Example 3 The above dissolution test was conducted on the multi-reservoir sustained release granules of Example 3. Water was used as the test solution, and granules were used in amounts equivalent to 24 mg of dextromethorphan hydrobromide, 125 mg of acetaminophen, and 375 mg of ethenzamide. The results are shown in Figure 3. All pharmaceutical active ingredients showed approximately the same elution characteristics.
【0046】実験例4
参考例1、2、4のシングルリザ−バ−型顆粒に関して
、上記溶出試験を行なった。試験液には、水を使用し、
顆粒は、臭化水素酸デキストロメトルファン24mg、
アセトアミノフェン450mg相当量のものを使用した
。結果を図4に示す。シングルリザ−バ−内に単一の医
薬活性成分を含有する参考例1、2の顆粒の場合には、
それぞれ合目的な溶出特性が得られた。これに対して、
シングルリザ−バ−内に、溶解度はほぼ同程度であるが
配合量が大きく異なる2種の医薬活性成分を含有する参
考例4の場合には、それぞれは全く異なる溶出挙動を示
し、個別の溶出制御は達成できなかった。Experimental Example 4 The above dissolution test was conducted on the single reservoir type granules of Reference Examples 1, 2, and 4. Water is used as the test liquid,
The granules are dextromethorphan hydrobromide 24mg,
An amount equivalent to 450 mg of acetaminophen was used. The results are shown in Figure 4. In the case of the granules of Reference Examples 1 and 2 containing a single pharmaceutically active ingredient in a single reservoir,
The desired elution characteristics were obtained for each. On the contrary,
In the case of Reference Example 4, in which a single reservoir contains two types of pharmaceutically active ingredients with approximately the same level of solubility but greatly different amounts, each of them exhibits completely different elution behavior, resulting in individual elution. Control could not be achieved.
【0047】実験例5
参考例2、3、5のシングルリザ−バ−型顆粒に関して
、上記溶出試験を行なった。試験液には、水を使用し、
顆粒は、アセトアミノフェン125mg、エテンザミド
375mg相当量のものを使用した。結果を図5に示す
。シングルリザ−バ−内に単一の医薬活性成分を含有す
る参考例2,3の顆粒の場合には、それぞれ合目的な溶
出特性が得られた。これに対して、シングルリザ−バ−
内に、溶解度および配合量が異なる2種の医薬活性成分
を含有する参考例5の場合には、それぞれは全く異なる
溶出挙動を示し、個別の溶出制御は達成できなかった。Experimental Example 5 The above dissolution test was conducted on the single reservoir type granules of Reference Examples 2, 3, and 5. Water is used as the test liquid,
The granules used were equivalent to 125 mg of acetaminophen and 375 mg of ethenzamide. The results are shown in Figure 5. In the case of the granules of Reference Examples 2 and 3 containing a single pharmaceutically active ingredient in a single reservoir, appropriate elution characteristics were obtained. In contrast, single reservoir
In the case of Reference Example 5, which contained two types of pharmaceutically active ingredients with different solubility and blending amounts, each exhibited completely different elution behavior, and individual elution control could not be achieved.
【0048】実験例6
実施例1、4、5、6、7のマルチリザ−バ−型徐放性
顆粒に関して、上記溶出試験を行ない、約3時間後の溶
出率を求めて、フィルム第二層の被覆率による影響を調
べた。試験液には、水を使用し、顆粒は、臭化水素酸デ
キストロメトルファン24mg、アセトアミノフェン4
50mg相当量のものを使用した。結果を図6に示す。
フィルム第二層の被覆率の増大に伴い、薬物第二層(以
下、外部層とも言う)に配合されたアセトアミノフェン
の溶出率はなめらかに減少する。一方、薬物第一層(以
下、内部層とも言う)に配合された臭化水素酸デキスト
ロメトルファンの溶出率は、該被覆率が10.9%以下
の場合は、フィルム第一層によって制御された値にほぼ
等しい値を示すが、同値を越えると減少傾向を示す。よ
って、フィルム第二層の被覆率を0〜10.9%の間で
任意に変化させることにより、内部層の臭化水素酸デキ
ストロメトルファンの溶出特性に影響を及ぼすことなく
、外部層のアセトアミノフェンの溶出制御が行なえる。Experimental Example 6 The multi-reservoir sustained release granules of Examples 1, 4, 5, 6, and 7 were subjected to the dissolution test described above, and the dissolution rate after about 3 hours was determined. The influence of the coverage rate was investigated. Water was used as the test solution, and the granules contained 24 mg of dextromethorphan hydrobromide and 4 mg of acetaminophen.
An amount equivalent to 50 mg was used. The results are shown in FIG. As the coverage of the second layer of the film increases, the dissolution rate of acetaminophen blended into the second drug layer (hereinafter also referred to as outer layer) smoothly decreases. On the other hand, the elution rate of dextromethorphan hydrobromide blended in the drug first layer (hereinafter also referred to as inner layer) is controlled by the first film layer when the coverage is 10.9% or less. However, when the value exceeds the same value, it shows a decreasing tendency. Therefore, by arbitrarily changing the coverage of the second layer of the film between 0 and 10.9%, the acetate in the outer layer can be reduced without affecting the elution characteristics of dextromethorphan hydrobromide in the inner layer. Aminophen elution can be controlled.
【0049】実験例7
実施例2、8、9、10、11のマルチリザ−バ−型徐
放性顆粒に関して、上記溶出試験を行ない、約3時間後
の溶出率を求めて、フィルム第二層の被覆率による影響
を調べた。試験液には、水を使用し、顆粒はアセトアミ
ノフェン125mg、エテンザミド375mg相当量の
ものを使用した。結果を図7に示す。フィルム第二層の
被覆率の増大に伴い、外部層に配合されたエテンザミド
の溶出率はなめらかに減少する。一方、内部層に配合さ
れたアセトアミノフェンの溶出率は、該被覆率が10.
8%以下の場合は、フィルム第一層によって制御された
値にほぼ等しい値を示すが、同値を越えると減少傾向を
示す。よって、フィルム第二層の被覆率を0〜10.8
%の間で任意に変化させることにより、内部層のアセト
アミノフェンの溶出特性に影響を及ぼすことなく、外部
層のエテンザミドの溶出制御が行なえる。Experimental Example 7 The multi-reservoir sustained release granules of Examples 2, 8, 9, 10, and 11 were subjected to the dissolution test described above, and the dissolution rate after about 3 hours was determined. The influence of the coverage rate was investigated. Water was used as the test liquid, and granules were used in amounts equivalent to 125 mg of acetaminophen and 375 mg of ethenzamide. The results are shown in FIG. As the coverage of the second layer of the film increases, the elution rate of ethenzamide blended into the outer layer decreases smoothly. On the other hand, the elution rate of acetaminophen blended into the inner layer is 10.
When it is 8% or less, it shows a value almost equal to the value controlled by the first layer of the film, but when it exceeds the same value, it shows a decreasing tendency. Therefore, the coverage rate of the second layer of the film is 0 to 10.8.
By arbitrarily changing the amount between % and %, the elution of ethenzamide in the outer layer can be controlled without affecting the elution characteristics of acetaminophen in the inner layer.
【0050】[0050]
【発明の効果】本発明により、単一顆粒中に、複数の医
薬活性成分を収納させ、各活性成分の放出速度を任意に
制御することが可能である。よって、本製剤は徐放性総
合感冒剤等、複数種の医薬活性成分の徐放化を必要とす
る徐放性顆粒剤に好適である。また、本製剤は、徐放化
剤として水不溶性フィルムコ−ティング基剤を使用して
いるので、pH非依存性の溶出特性を示し、老人や低酸
、無酸症の人に対しても、通常の健常者に投与した場合
と同様の徐放化が期待される。According to the present invention, it is possible to contain a plurality of pharmaceutically active ingredients in a single granule and to arbitrarily control the release rate of each active ingredient. Therefore, this preparation is suitable for sustained-release granules that require sustained release of multiple types of pharmaceutically active ingredients, such as sustained-release general cold preparations. In addition, since this formulation uses a water-insoluble film coating base as a sustained release agent, it exhibits pH-independent dissolution characteristics, making it suitable for the elderly, hypoacidemia, and achlorhydria. , the same sustained release as when administered to normal healthy individuals is expected.
【図1】図1は、実施例1より得られた顆粒に含有され
る医薬活性成分の溶出試験の結果を示す。縦軸は、溶出
率(%)、横軸は、時間(hr)を表わす。FIG. 1 shows the results of a dissolution test of the pharmaceutically active ingredient contained in the granules obtained in Example 1. The vertical axis represents dissolution rate (%), and the horizontal axis represents time (hr).
【図2】図2は、実施例2より得られた顆粒に含有され
る医薬活性成分の溶出試験の結果を示す。縦軸は、溶出
率(%)、横軸は、時間(hr)を表わす。FIG. 2 shows the results of a dissolution test of the pharmaceutically active ingredient contained in the granules obtained in Example 2. The vertical axis represents dissolution rate (%), and the horizontal axis represents time (hr).
【図3】図3は、実施例3より得られた顆粒に含有され
る医薬活性成分の溶出試験の結果を示す。縦軸は、溶出
率(%)、横軸は、時間(hr)を表わす。FIG. 3 shows the results of a dissolution test of the pharmaceutically active ingredient contained in the granules obtained in Example 3. The vertical axis represents dissolution rate (%), and the horizontal axis represents time (hr).
【図4】図4は、参考例1、2、4より得られた顆粒に
含有される医薬活性成分の溶出試験の結果を示す。縦軸
は、溶出率(%)、横軸は、時間(hr)を表わす。FIG. 4 shows the results of a dissolution test of pharmaceutically active ingredients contained in the granules obtained from Reference Examples 1, 2, and 4. The vertical axis represents dissolution rate (%), and the horizontal axis represents time (hr).
【図5】図5は、参考例2、3、5より得られた顆粒に
含有される医薬活性成分の溶出試験の結果を示す。縦軸
は、溶出率(%)、横軸は、時間(hr)を表わす。FIG. 5 shows the results of a dissolution test of the pharmaceutically active ingredients contained in the granules obtained from Reference Examples 2, 3, and 5. The vertical axis represents dissolution rate (%), and the horizontal axis represents time (hr).
【図6】図6は、実施例1、4、5、6、7より得られ
た顆粒に含有される医薬活性成分の溶出試験の結果を示
す。縦軸は、溶出率(%)、横軸は、水不溶性フィルム
第二層の被覆率(%)を表わす。FIG. 6 shows the results of a dissolution test of the pharmaceutically active ingredients contained in the granules obtained in Examples 1, 4, 5, 6, and 7. The vertical axis represents the elution rate (%), and the horizontal axis represents the coverage rate (%) of the second layer of the water-insoluble film.
【図7】図7は、実施例2、7、8、9、10より得ら
れた顆粒に含有される医薬活性成分の溶出試験の結果を
示す。縦軸は、溶出率(%)、横軸は、水不溶性フィル
ム第二層の被覆率(%)を表わす。FIG. 7 shows the results of a dissolution test of the pharmaceutically active ingredients contained in the granules obtained in Examples 2, 7, 8, 9, and 10. The vertical axis represents the elution rate (%), and the horizontal axis represents the coverage rate (%) of the second layer of the water-insoluble film.
Claims (6)
を含有する粉末コ−ティング薬物層および該粉末コ−テ
ィング薬物層を被覆する水不溶性フィルム層からなるこ
とを特徴とする徐放性顆粒剤。[Claim 1] A sustained release drug characterized in that the constituent units of each layer of the multilayer structure are a powder-coated drug layer containing a pharmaceutically active ingredient and a water-insoluble film layer covering the powder-coated drug layer. Granules.
徐放性顆粒剤。2. The sustained release granule according to claim 1, wherein the multilayer structure is a two-layer structure.
徐放性顆粒剤。3. The sustained release granule according to claim 1, wherein the multilayer structure is a three-layer structure.
・メタアクリル酸メチル共重合体よりなる請求項1〜3
のいずれかに記載の徐放性顆粒剤。4. Claims 1 to 3 in which the water-insoluble film layer comprises an ethyl acrylate/methyl methacrylate copolymer.
The sustained release granule according to any one of the above.
行なうことを特徴とする徐放性顆粒剤の製造方法。 a工程:医薬活性成分を含有する粉末の粉末コ−ティン
グ工程 b工程:ひき続き行なう水不溶性フィルムコ−ティング
工程5. A method for producing sustained release granules, which comprises performing the following two steps multiple times as one unit. Step a: Powder coating step of powder containing pharmaceutically active ingredients Step b: Subsequent water-insoluble film coating step
酸メチル共重合体を水不溶性フィルムコ−ティング基剤
として使用する請求項5記載の方法。6. The method according to claim 5, wherein in step b, an ethyl acrylate/methyl methacrylate copolymer is used as a water-insoluble film coating base.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP03138315A JP3090975B2 (en) | 1991-05-13 | 1991-05-13 | Multi-reservoir type sustained release granule and method for producing the same |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP03138315A JP3090975B2 (en) | 1991-05-13 | 1991-05-13 | Multi-reservoir type sustained release granule and method for producing the same |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH04338324A true JPH04338324A (en) | 1992-11-25 |
JP3090975B2 JP3090975B2 (en) | 2000-09-25 |
Family
ID=15219024
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP03138315A Expired - Lifetime JP3090975B2 (en) | 1991-05-13 | 1991-05-13 | Multi-reservoir type sustained release granule and method for producing the same |
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Country | Link |
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JP (1) | JP3090975B2 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH09510709A (en) * | 1994-03-23 | 1997-10-28 | オーソ・フアーマシユーチカル・コーポレーシヨン | Multilayer modified release pharmaceutical dosage form |
WO2020045456A1 (en) * | 2018-08-28 | 2020-03-05 | 東和薬品株式会社 | Drug-containing particle |
-
1991
- 1991-05-13 JP JP03138315A patent/JP3090975B2/en not_active Expired - Lifetime
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH09510709A (en) * | 1994-03-23 | 1997-10-28 | オーソ・フアーマシユーチカル・コーポレーシヨン | Multilayer modified release pharmaceutical dosage form |
WO2020045456A1 (en) * | 2018-08-28 | 2020-03-05 | 東和薬品株式会社 | Drug-containing particle |
JPWO2020045456A1 (en) * | 2018-08-28 | 2021-08-10 | 東和薬品株式会社 | Drug-containing particles |
EP3845219A4 (en) * | 2018-08-28 | 2022-06-08 | Towa Pharmaceutical Co., Ltd. | Drug-containing particle |
Also Published As
Publication number | Publication date |
---|---|
JP3090975B2 (en) | 2000-09-25 |
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