JPH06199657A - Sustained release pharmaceutical preparation - Google Patents
Sustained release pharmaceutical preparationInfo
- Publication number
- JPH06199657A JPH06199657A JP4352995A JP35299592A JPH06199657A JP H06199657 A JPH06199657 A JP H06199657A JP 4352995 A JP4352995 A JP 4352995A JP 35299592 A JP35299592 A JP 35299592A JP H06199657 A JPH06199657 A JP H06199657A
- Authority
- JP
- Japan
- Prior art keywords
- sustained
- drug
- methacrylic acid
- hydroxypropylmethylcellulose
- preparation according
- 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.)
- Pending
Links
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は胃液と腸液の中間付近の
ｐＨで溶解度が最大となるような塩基性薬物またはその
塩のｐＨ非依存型徐放性製剤に関するものである。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pH-independent sustained release preparation of a basic drug or a salt thereof, which has a maximum solubility at a pH around the midpoint between gastric juice and intestinal juice.
【０００２】[0002]
【従来の技術】塩基性薬物やその塩の多くは溶出液のｐ
Ｈや液組成に依存して多様な溶解性を示すので、これら
薬物の徐放性製剤を投与すると、消化管内のｐＨ変動や
消化液ｐＨの個体差等により、放出制御が不規則になる
事が多い。かかる問題点を解決するため、これまでに多
くの試みが行われてきた。例えば、胃液ｐＨ付近で溶解
度が高く腸液ｐＨ側へ移行するにつれて溶解度が減少す
るような薬物では、腸溶性成分や酸性成分の添加（特開
平２−２２３５３３号公報、特開平３−２０４８１０号
公報等）等の方法が挙げられる。2. Description of the Related Art Most basic drugs and their salts are p
Since it exhibits various solubilities depending on H and liquid composition, when controlled-release preparations of these drugs are administered, the release control becomes irregular due to pH fluctuations in the digestive tract and individual differences in digestive pH. There are many. Many attempts have been made so far to solve such problems. For example, in the case of a drug having a high solubility near the pH of gastric juice and a decrease in solubility as it shifts to the pH of intestinal juice, addition of an enteric component or an acidic component (JP-A-2-223533, JP-A-3-204810, etc.) ) Etc. are mentioned.
【０００３】[0003]
【発明が解決しようとする課題】しかし、これらの技術
では胃液と腸液の中間付近のｐＨで溶解度が最大となる
ような薬物のｐＨ非依存化を達成するのは困難なことが
多い。実際、薬物の塩酸塩の場合、共通イオン効果によ
り、液組成として塩酸・塩化ナトリウムを含む胃液中で
の溶解が抑制され、胃液中及び腸液中と比べてその間の
ｐＨで溶解度が高い値を示すものも多い。一方、より確
実に広範囲の薬物に適用される方法として、浸透圧ポン
プ装置（特開昭５８−１６２５９号公報）等が知られて
いる。しかし、これらは薬物保持部分と水との接触によ
り浸透圧を発生する部分からなり、さらにその外側を水
難溶性高分子物質の皮膜でコ−ティングしたのち小孔を
設けるものであり、製造上非常に複雑な工程を必要とす
る場合が多い。このような状況から、胃液と腸液の中間
付近のｐＨで溶解度が最大となるような塩基性薬物また
はその塩のｐＨ非依存型徐放性製剤の開発が望まれてい
る。However, it is often difficult with these techniques to achieve pH independence of a drug that maximizes the solubility at a pH around the midpoint between gastric juice and intestinal juice. In fact, in the case of the hydrochloride salt of a drug, the common ionic effect suppresses its dissolution in gastric juice containing hydrochloric acid and sodium chloride as its liquid composition, and it shows a higher solubility at pH between that in gastric juice and intestinal juice. There are many things. On the other hand, an osmotic pump device (Japanese Patent Laid-Open No. 58-16259) and the like are known as a method for more reliably applying to a wide range of drugs. However, these are composed of a drug-retaining part and a part which generates an osmotic pressure by contact with water, and the outside of the drug-retaining part is coated with a film of a poorly water-soluble polymer substance, and then a small hole is provided. Often requires complex steps. Under these circumstances, it is desired to develop a pH-independent sustained-release preparation of a basic drug or a salt thereof that maximizes the solubility at a pH around the midpoint between gastric juice and intestinal juice.
【０００４】[0004]
【課題を解決するための手段】本発明者らは前記課題を
解決するため鋭意検討を行った結果、徐放性マトリック
ス製剤中に、カルボキシビニルポリマ−、メチルビニ−
ルエ−テル無水マレイン酸コポリマ−、もしくはそれら
の塩、またはそれらの混合物と腸溶性基剤を添加するこ
とによって、塩基性薬物またはその塩の、製剤からの溶
出をｐＨ非依存型に制御できることを見出し本発明を完
成するに至った。即ち、本発明は水溶性高分子を基剤と
するマトリックス中に、(1) 胃液に相当する第十一改正
日本薬局方崩壊試験法第１液（ｐＨ１．２）中及び腸液
に相当する同第２液（ｐＨ６．８）中と比べて前記日本
薬局方記載の酢酸・酢酸ナトリウム緩衝液（ｐＨ４．
０）中で高い溶解度を示す様な塩基性薬物またはその
塩、(2) カルボキシビニルポリマー、メチルビニールエ
ーテル無水マレイン酸コポリマー、もしくはそれらの
塩、またはそれらの混合物、および、(3) 腸溶性基剤、
を含有する事を特徴とする徐放性製剤に関するものであ
る。Means for Solving the Problems As a result of intensive studies for solving the above problems, the present inventors have found that carboxyvinyl polymer and methyl vinyl
It is possible to control the elution of a basic drug or a salt thereof from a preparation in a pH-independent manner by adding a ruthel-maleic anhydride copolymer, or a salt thereof, or a mixture thereof and an enteric base. Heading The present invention has been completed. That is, the present invention provides a matrix based on a water-soluble polymer, which is (1) equivalent to gastric juice in the 11th revised Japanese Pharmacopoeia disintegration test method 1st liquid (pH 1.2) and intestinal juice. Compared to the second solution (pH 6.8), the acetic acid / sodium acetate buffer solution (pH 4.
A basic drug or a salt thereof which exhibits high solubility in 0), (2) a carboxyvinyl polymer, a methyl vinyl ether maleic anhydride copolymer, or a salt thereof, or a mixture thereof, and (3) an enteric group Agent,
The present invention relates to a sustained-release preparation characterized by containing:
【０００５】本発明の徐放性マトリックス製剤で用いら
れる薬物は、第十一改正日本薬局方崩壊試験法第１液
（ｐＨ１．２）中及び同第２液（ｐＨ６．８）中と比べ
て前記日本薬局方記載の酢酸・酢酸ナトリウム緩衝液
（ｐＨ４．０）中で高い溶解度を示すような塩基性薬物
またはその塩であり、経口投与によって消化管内の液体
中で解離または溶解し、何らかの薬効を発現するもので
あれば特に限定するものではない。前記のとおり、塩基
性薬物の塩酸塩にこのような性質を示す薬物が多い。例
としては、シス-2-[4-[4-(1,2-ベンズイソチアゾール-3
- イル)-1-ピペラジニル] ブチル] ヘキサヒドロ-1H-イ
ソインドール-1,3(2H)- ジオンハイドロクロライド・２
水和物（cis-2-[4-[4-(1,2- benzisothiazol-3-yl)-1-p
iperazinyl]butyl]hexahydro-1H-isoindole-1,3(2H)-di
one hydrochloride・2H2 O ）（以下化合物Ａと略
す）、塩酸パパベリン、塩酸ブロムヘキシン、塩酸アロ
チノロ−ル等が挙げられる。本発明の徐放性マトリック
ス製剤で用いられる水溶性高分子としては、通常固形製
剤で用いられているものであれば特に限定はないが、例
えばヒドロキシプロピルメチルセルロース、ヒドロキシ
プロピルセルロース、メチルセルロース、ポリビニルピ
ロリドン、ヒドロキシエチルセルロース等が挙げられ、
特に好ましくはヒドロキシプロピルメチルセルロースが
挙げられる。一般的な知見から、これらの水溶性高分子
は、粘度が高くなる程薬物の溶出速度を抑え、また逆に
乳糖などの通常の低分子賦形剤を添加することにより溶
出速度を速めることができる。The drugs used in the sustained-release matrix preparation of the present invention are compared with those in the 11th revised Japanese Pharmacopoeia disintegration test method liquid 1 (pH 1.2) and liquid 2 (pH 6.8). A basic drug or a salt thereof that exhibits a high solubility in the acetic acid / sodium acetate buffer solution (pH 4.0) described in the Japanese Pharmacopoeia, which dissociates or dissolves in a liquid in the digestive tract upon oral administration, and has some medicinal effect. There is no particular limitation as long as it expresses. As mentioned above, many hydrochlorides of basic drugs exhibit such properties. As an example, cis-2- [4- [4- (1,2-benzisothiazole-3
-Yl) -1-piperazinyl] butyl] hexahydro-1H-isoindole-1,3 (2H) -dionehydrochloride.2
Hydrate (cis-2- [4- [4- (1,2-benzisothiazol-3-yl) -1-p
iperazinyl] butyl] hexahydro-1H-isoindole-1,3 (2H) -di
One hydrochloride · 2H 2 O) (hereinafter abbreviated as compound A), papaverine hydrochloride, bromhexine hydrochloride, arotinolol hydrochloride and the like. The water-soluble polymer used in the sustained-release matrix preparation of the present invention is not particularly limited as long as it is usually used in a solid preparation, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, Hydroxyethyl cellulose and the like,
Particularly preferred is hydroxypropyl methylcellulose. From the general knowledge, these water-soluble polymers can suppress the dissolution rate of the drug as the viscosity increases, and conversely increase the dissolution rate by adding a normal low molecular weight excipient such as lactose. it can.
【０００６】本発明の徐放性マトリックス製剤で用いら
れる腸溶性基剤としては、通常固形製剤で用いられてい
るものであれば特に限定はないが、例えばヒドロキシプ
ロピルメチルセルロースフタレート、ヒドロキシプロピ
ルメチルセルロースアセテートサクシネート、カルボキ
シメチルエチルセルロース、酢酸フタル酸セルロース、
メタアクリル酸メタアクリル酸メチルコポリマー、メタ
アクリル酸アクリル酸エチルコポリマー等が挙げられ、
特に好ましくはメタアクリル酸メタアクリル酸メチルコ
ポリマーが挙げられる。本発明の構成成分のそれぞれの
割合は、種々の組合せが可能である。例えば、薬物が１
〜９０重量％、水溶性高分子が１０〜９９重量％、カル
ボキシビニルポリマー、メチルビニールエーテル無水マ
レイン酸コポリマー、もしくはそれらの塩、またはそれ
らの混合物が０．１〜５０重量％、腸溶性基剤が０．１
〜５０重量％である。好ましい組合せは、薬物が１〜５
０重量％、水溶性高分子が３０〜９０重量％、カルボキ
シビニルポリマー、メチルビニールエーテル無水マレイ
ン酸コポリマー、もしくはそれらの塩、またはそれらの
混合物が０．５〜２０重量％、腸溶性基剤が０．５〜２
０重量％である。The enteric base used in the sustained-release matrix preparation of the present invention is not particularly limited as long as it is one which is usually used in solid preparations. For example, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate. Nate, carboxymethyl ethyl cellulose, cellulose acetate phthalate,
Methyl methacrylic acid methacrylic acid copolymer, methacrylic acid ethyl acrylate copolymer, and the like,
Particularly preferred is methyl methacrylic acid copolymer. Various combinations of the respective proportions of the constituents of the invention are possible. For example, 1 drug
-90 wt%, water-soluble polymer 10-99 wt%, carboxyvinyl polymer, methyl vinyl ether maleic anhydride copolymer, or salt thereof, or 0.1-50 wt% of a mixture thereof, enteric base Is 0.1
~ 50% by weight. The preferred combination is 1 to 5 drugs.
0% by weight, 30 to 90% by weight of water-soluble polymer, 0.5 to 20% by weight of carboxyvinyl polymer, methyl vinyl ether maleic anhydride copolymer, or a salt thereof, or a mixture thereof, and an enteric base. 0.5-2
It is 0% by weight.
【０００７】本発明の徐放性マトリックス製剤には、さ
らに上述の成分に加えて、それ以外の医薬品として許容
される添加物を用いることができる。医薬品として許容
される添加物は一般的に固形製剤に用いるものであれば
特に限定されるものではなく、例えば乳糖、トウモロコ
シデンプン等の通常の錠剤用賦形剤などが挙げられる。
本発明の徐放性マトリックス製剤の製造法としては、例
えば(1) 薬物、(2) 水溶性高分子、(3) カルボキシビニ
ルポリマー、メチルビニールエーテル無水マレイン酸コ
ポリマー、もしくはそれらの塩、またはそれらの混合
物、(4) 腸溶性基剤、更に必要に応じて前記添加物をマ
イクロスピードミキサー等の混合機を用いて均一に混合
し、通常の打錠機を用いて直接打錠することにより容易
に調製することができる。In the sustained-release matrix preparation of the present invention, in addition to the above components, other pharmaceutically acceptable additives can be used. The pharmaceutically acceptable additives are not particularly limited as long as they are generally used in solid preparations, and examples thereof include usual tablet excipients such as lactose and corn starch.
The method for producing the sustained-release matrix preparation of the present invention includes, for example, (1) drugs, (2) water-soluble polymers, (3) carboxyvinyl polymers, methyl vinyl ether maleic anhydride copolymers, or salts thereof, or salts thereof. The mixture of (4) enteric base and, if necessary, the above additives are uniformly mixed using a mixer such as a micro speed mixer, and the mixture can be easily tableted directly using an ordinary tableting machine. Can be prepared.
【０００８】本発明におけるｐＨ非依存型の薬物放出は
次のようなメカニズムによると考えられる。本発明で使
用される薬物、すなわち胃液と腸液の中間付近のｐＨ
（ｐＨ４付近）で溶解度が最大となる薬物は、通常はｐ
Ｈ４付近で溶出し易くなる。しかし、本発明徐放性製剤
に含まれるカルボキシビニルポリマーまたはメチルビニ
ールエーテル無水マレイン酸コポリマーは、ｐＨ３付近
よりアルカリ性側で膨潤がおこるため、結果としてｐＨ
４付近の薬物溶出を抑えることになる。一方、腸液中で
は、本発明で使用される薬物の性質、および前記のカル
ボキシビニルポリマーまたはメチルビニールエーテル無
水マレイン酸コポリマーが膨潤しているため、薬物の溶
出が抑えられているが、本発明徐放性製剤に含まれる腸
溶性基剤によって適度な薬物溶出を生じさせるものであ
る。従って、本発明技術は第十一改正日本薬局方崩壊試
験法第１液（ｐＨ１．２）中及び同第２液（ｐＨ６．
８）中の溶解度と比べて前記日本薬局方記載の酢酸・酢
酸ナトリウム緩衝液（ｐＨ４．０）中で高い溶解度を示
す様な塩基性薬物またはその塩全般に適用できると考え
られる。The pH-independent drug release in the present invention is considered to be due to the following mechanism. The drug used in the present invention, that is, the pH near the midpoint between gastric juice and intestinal juice
The drug that has the maximum solubility (at around pH 4) is usually p
Elution becomes easy around H4. However, since the carboxyvinyl polymer or methyl vinyl ether maleic anhydride copolymer contained in the sustained-release preparation of the present invention swells on the alkaline side from around pH 3, it results in pH
The drug elution around 4 will be suppressed. On the other hand, in the intestinal fluid, since the properties of the drug used in the present invention and the carboxyvinyl polymer or methyl vinyl ether maleic anhydride copolymer swelled, the dissolution of the drug is suppressed, but The enteric-coated base contained in the release preparation causes appropriate drug dissolution. Therefore, the technology of the present invention is applied to the 11th revised Japanese Pharmacopoeia disintegration test method liquid 1 (pH 1.2) and liquid 2 (pH 6.
It is considered that the present invention can be applied to all basic drugs or salts thereof that exhibit higher solubility in the acetic acid / sodium acetate buffer solution (pH 4.0) described in the Japanese Pharmacopoeia as compared with the solubility in 8).
【０００９】[0009]
【発明の効果】このようにして得られる本発明徐放性マ
トリックス製剤は、ｐＨ依存性の溶解度を示す薬物をｐ
Ｈに依存することなく溶出させるものである。これによ
り薬物の溶出は溶出液性の影響を受けにくくなり、患者
に投与した際には、その消化管内で消化液の液性によっ
て薬物の溶出速度が変化せず、血中薬物濃度の個体内及
び個体間でのバラツキを最小限にすることができる。従
って、本発明は、ｐＨ依存性の溶解度を示す薬物につい
て、ｐＨ非依存化を図ることによってバイオアベイラビ
リティーの向上した安全かつ有用な徐放性マトリックス
製剤の提供を可能にしたものである。INDUSTRIAL APPLICABILITY The sustained-release matrix preparation of the present invention thus obtained contains a drug exhibiting pH-dependent solubility
It elutes without depending on H. As a result, the dissolution of the drug is less likely to be affected by the eluate property, and when administered to a patient, the dissolution rate of the drug does not change due to the liquid property of the digestive fluid in the digestive tract, and the drug concentration in the individual And the variation between individuals can be minimized. Therefore, the present invention makes it possible to provide a safe and useful sustained-release matrix preparation having improved bioavailability by achieving pH independence of a drug exhibiting pH-dependent solubility.
【００１０】[0010]
【実施例】以下に比較例及び本発明の実施例を挙げて具
体的に説明するが、本発明を何ら限定するものではな
い。 比較例１ 本発明の徐放性マトリックス製剤と比較するため、従来
より公知の技術である水溶性高分子物質と滑沢剤を用い
た前記化合物Ａの徐放性マトリックス製剤を調製した。EXAMPLES The present invention will be specifically described below with reference to comparative examples and examples of the present invention, but the present invention is not limited thereto. Comparative Example 1 In order to compare with the sustained-release matrix preparation of the present invention, a sustained-release matrix preparation of Compound A using a water-soluble polymer substance and a lubricant, which are conventionally known techniques, was prepared.
【表１】 ─────────────────────────── 処方 化合物Ａ ２４ｇ ヒドロキシプロピルメチルセルロース （分子量約３００００） ３７４ｇ ステアリン酸マグネシウム ２ｇ ─────────────────────────── 合計 ４００ｇ ─────────────────────────── 上記処方に基づき、化合物Ａ及びヒドロキシプロピルメ
チルセルロースをマイクロスピードミキサーで混合後、
更にステアリン酸マグネシウムを添加混合して得た粉末
をストークス打錠機で圧縮成形し、１錠２００ｍｇの錠
剤を得た。[Table 1] ─────────────────────────── Formulation Compound A 24 g Hydroxypropylmethylcellulose (molecular weight about 30,000) 374 g Magnesium stearate 2 g ── ───────────────────────── Total 400g ──────────────────────── ──── Based on the above formulation, after mixing Compound A and hydroxypropylmethylcellulose with a microspeed mixer,
Further, magnesium stearate was added and mixed, and the obtained powder was compression-molded with a Stokes tableting machine to obtain 200 mg tablets.
【００１１】この徐放性マトリックス錠剤について、化
合物Ａの溶出試験を行ったところ図１の結果を得た。但
し試験条件は、次のとおりである。 試験液：第十一改正日本薬局方崩壊試験法第１液９００
ｍｌ、同第２液９００ｍｌ、または同記載の酢酸・酢酸
ナトリウム緩衝液（ｐＨ４．０）９００ｍｌ パドル法回転数：１００ｒｐｍ この比較例１では、第十一改正日本薬局方崩壊試験法第
１液、同第２液、及び同記載の酢酸・酢酸ナトリウム緩
衝液（ｐＨ４．０）中での溶出速度に大きな差が認めら
れた。第十一改正日本薬局方崩壊試験法第１液は塩酸及
び塩化ナトリウムを含むｐＨ約１．２の水溶液であり、
第２液はリン酸二水素カリウム及び水酸化ナトリウムを
含むｐＨ約６．８の水溶液である。従って図１の結果
は、本比較例の徐放性マトリックス製剤からの化合物Ａ
の溶出が、溶出環境の液体の組成、液性等により、大き
く影響されることを示している。When a dissolution test of Compound A was carried out on the sustained-release matrix tablet, the results shown in FIG. 1 were obtained. However, the test conditions are as follows. Test liquid: 11th revised Japanese Pharmacopoeia disintegration test method No. 1 liquid 900
ml, 900 ml of the second liquid, or 900 ml of the acetic acid / sodium acetate buffer solution (pH 4.0) described above Paddle method rotation speed: 100 rpm In this Comparative Example 1, the 11th revised Japanese Pharmacopoeia disintegration test method first liquid, A large difference was observed in the elution rate in the second liquid and the acetic acid / sodium acetate buffer solution (pH 4.0) described above. The 11th revised Japanese Pharmacopoeia disintegration test method first liquid is an aqueous solution containing hydrochloric acid and sodium chloride and having a pH of about 1.2,
The second liquid is an aqueous solution containing potassium dihydrogen phosphate and sodium hydroxide and having a pH of about 6.8. Therefore, the results in FIG. 1 show that Compound A from the sustained release matrix formulation of this comparative example.
It is shown that the elution of is greatly affected by the composition and liquid properties of the liquid in the elution environment.
【００１２】実施例１ 本発明の徐放性マトリックス製剤を、化合物Ａを用いて
以下のよう調製した。Example 1 A sustained release matrix preparation of the present invention was prepared using compound A as follows.
【表２】 ─────────────────────────── 処方 ─────────────────────────── 化合物Ａ ２４ｇ ヒドロキシプロピルメチルセルロース （分子量約３００００） ３７０ｇ メタアクリル酸メタアクリル酸メチル コポリマー ２ｇ カルボキシビニルポリマー ２ｇ ステアリン酸マグネシウム ２ｇ ─────────────────────────── 合計 ４００ｇ ─────────────────────────── 上記処方に基づき、化合物Ａ、ヒドロキシプロピルメチ
ルセルロース、メタアクリル酸メタアクリル酸メチルコ
ポリマー、カルボキシビニルポリマーをマイクロスピー
ドミキサーで混合後、更にステアリン酸マグネシウムを
添加混合して得た粉末をストークス打錠機で圧縮成形
し、１錠２００ｍｇの錠剤を得た。この徐放性マトリッ
クス錠剤について、前記と同様に化合物Ａの溶出試験を
行ったところ図２の結果を得た。この実施例では、第十
一改正日本薬局方崩壊試験法第１液、同第２液、及び同
記載の酢酸・酢酸ナトリウム緩衝液（ｐＨ４．０）中で
の溶出速度に殆ど差が認められなかった。従って図２の
結果は、本実施例の徐放性マトリックス製剤からの化合
物Ａの溶出が、溶出環境の液体の組成、液性等により影
響されないことを示している。[Table 2] ─────────────────────────── Prescription ────────────────── ────────── Compound A 24g Hydroxypropylmethylcellulose (Molecular weight about 30000) 370g Methyl methacrylate methyl methacrylate copolymer 2g Carboxyvinyl polymer 2g Magnesium stearate 2g ───────────── ─────────────── Total 400g ─────────────────────────── Compound based on the above formulation Stoke the powder obtained by mixing A, hydroxypropylmethyl cellulose, methacrylic acid methyl methacrylic acid copolymer, and carboxyvinyl polymer with a micro speed mixer and then adding and mixing magnesium stearate. Compression molded on a tablet machine to yield tablets each weighing 200 mg. When the dissolution test of Compound A was carried out on the sustained-release matrix tablet in the same manner as described above, the results shown in FIG. 2 were obtained. In this example, almost no difference was observed in the dissolution rates in the 11th revised Japanese Pharmacopoeia disintegration test method No. 1 solution, No. 2 solution, and the acetic acid / sodium acetate buffer solution (pH 4.0) described therein. There wasn't. Therefore, the results in FIG. 2 indicate that the elution of Compound A from the sustained-release matrix preparation of this Example is not affected by the composition and liquidity of the liquid in the elution environment.
【００１３】実施例２ 実施例１の処方中、水溶性高分子のヒドロキシプロピル
メチルセルロースとして、より粘度の高いグレードのも
の（分子量約１０００００）を使用し、更にその一部を
乳糖に置き換えて同様に調製した。Example 2 In the formulation of Example 1, as the water-soluble polymer hydroxypropylmethylcellulose, one having a higher viscosity grade (molecular weight about 100,000) was used, and a part thereof was replaced with lactose. Prepared.
【表３】 ─────────────────────────── 処方 ─────────────────────────── 化合物Ａ ２４ｇ ヒドロキシプロピルメチルセルロース （分子量約１０００００） ２００ｇ 乳糖 １７０ｇ メタアクリル酸メタアクリル酸メチル コポリマー ２ｇ カルボキシビニルポリマー ２ｇ ステアリン酸マグネシウム ２ｇ ─────────────────────────── 合計 ４００ｇ ─────────────────────────── この徐放性マトリックス錠剤について、前記と同様に化
合物Ａの溶出試験を行ったところ図３の結果を得た。こ
の実施例でも、第十一改正日本薬局方崩壊試験法第１
液、同第２液、及び同記載の酢酸・酢酸ナトリウム緩衝
液（ｐＨ４．０）での溶出速度に殆ど差が認められなか
った。また、実施例２の全体的な溶出時間が実施例１
（Ｔ50% ＝２hr）に比べてＴ50% ＝３hrと延長された。
従って図３の結果は、水溶性高分子の粘度グレード及び
低粘性賦形剤（乳糖）との配合比率を調整することによ
り、化合物Ａの溶出速度を制御可能であることも示して
いる。[Table 3] ─────────────────────────── Prescription ────────────────── ───────── Compound A 24g Hydroxypropylmethylcellulose (Molecular weight about 100,000) 200g Lactose 170g Methyl methacrylate methyl methacrylate copolymer 2g Carboxyvinyl polymer 2g Magnesium stearate 2g ─────────── ───────────────── Total 400g ─────────────────────────── This sustained release When the matrix A was subjected to the dissolution test of compound A in the same manner as above, the results shown in FIG. 3 were obtained. Also in this example, the 11th revised Japanese Pharmacopoeia disintegration test method No. 1
Almost no difference was observed in the elution rates of the solution, the second solution, and the acetic acid / sodium acetate buffer solution (pH 4.0) described above. Also, the overall elution time of Example 2 was
It was extended to T50% = 3 hr compared to (T50% = 2 hr).
Therefore, the results in FIG. 3 also show that the dissolution rate of Compound A can be controlled by adjusting the viscosity grade of the water-soluble polymer and the mixing ratio with the low-viscosity excipient (lactose).
【００１４】[0014]
【図１】図１は、比較例１で得た製剤の、第十一改正日
本薬局方溶出試験法第２法（パドル法）による溶出試験
の結果を示すものである。FIG. 1 shows the results of the dissolution test of the preparation obtained in Comparative Example 1 according to the 11th revised Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method).
【図２】図２は、実施例１で得た製剤の、第十一改正日
本薬局方溶出試験法第２法（パドル法）による溶出試験
の結果を示すものである。FIG. 2 shows the results of the dissolution test of the preparation obtained in Example 1 by the 11th revised Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method).
【図３】図３は、実施例２で得た製剤の、第十一改正日
本薬局方溶出試験法第２法（パドル法）による溶出試験
の結果を示すものである。FIG. 3 shows the results of the dissolution test of the preparation obtained in Example 2 by the 11th revised Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method).
フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ａ６１Ｋ 31/44 ＡＡＹ 7431−4Ｃ 47/32 Ｃ 7433−4Ｃ 47/38 Ｂ 7433−4Ｃ Ｃ 7433−4Ｃ Ｃ０７Ｄ 417/14 //(Ｃ０７Ｄ 417/14 209:00 211:00 9165−4Ｃ 275:00） 9051−4Ｃ Continuation of front page (51) Int.Cl. 5 Identification code Office reference number FI Technical indication location A61K 31/44 AAY 7431-4C 47/32 C 7433-4C 47/38 B 7433-4C C 7433-4C C07D 417 / 14 // (C07D 417/14 209: 00 211: 00 9165-4C 275: 00) 9051-4C
Claims (6)
に、(1) 第十一改正日本薬局方崩壊試験法第１液（ｐＨ
１．２）中及び同第２液（ｐＨ６．８）中の溶解度に対
して、前記日本薬局方記載の酢酸・酢酸ナトリウム緩衝
液（ｐＨ４．０）中で高い溶解度を示す様な塩基性薬物
またはその塩、(2) カルボキシビニルポリマー、メチル
ビニールエーテル無水マレイン酸コポリマー、もしくは
それらの塩、またはそれらの混合物、および、(3) 腸溶
性基剤、を含有する事を特徴とする徐放性製剤。1. In a matrix based on a water-soluble polymer, (1) 1st liquid (pH) of the 11th revised Japanese Pharmacopoeia disintegration test method
1.2) and the second drug (pH 6.8), the basic drug has a high solubility in the acetic acid / sodium acetate buffer (pH 4.0) described in the Japanese Pharmacopoeia. Or a salt thereof, (2) carboxyvinyl polymer, methyl vinyl ether maleic anhydride copolymer, or a salt thereof, or a mixture thereof, and (3) an enteric base, which is a sustained release property. Formulation.
求項１記載の徐放性製剤。2. The sustained-release preparation according to claim 1, wherein a hydrochloride of a basic drug is used as the drug.
チアゾール-3- イル)-1-ピペラジニル] ブチル] ヘキサ
ヒドロ-1H-イソインドール-1,3(2H)- ジオンハイドロク
ロライド・２水和物(cis-2-[4-[4-(1,2- benzisothiazo
l-3-yl)-1-piperazinyl] butyl]hexahydro-1H-isoindol
e-1,3(2H)-dione hydrochloride ・2H2 O ) （以下、化
合物Ａと略す。）を用いた請求項１記載の徐放性製剤。3. As a drug, cis-2- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] hexahydro-1H-isoindole-1,3 (2H) -Dione hydrochloride dihydrate (cis-2- [4- [4- (1,2-benzisothiazo
l-3-yl) -1-piperazinyl] butyl] hexahydro-1H-isoindol
The sustained-release preparation according to claim 1, wherein e-1,3 (2H) -dione hydrochloride.2H 2 O) (hereinafter abbreviated as compound A) is used.
チルセルロース、ヒドロキシプロピルセルロース、メチ
ルセルロース、ポリビニルピロリドン、またはヒドロキ
シエチルセルロースを用いた請求項１記載の徐放性製
剤。4. The sustained-release preparation according to claim 1, wherein hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone or hydroxyethylcellulose is used as the water-soluble polymer.
ルセルロースフタレート、ヒドロキシプロピルメチルセ
ルロースアセテートサクシネート、カルボキシメチルエ
チルセルロース、酢酸フタル酸セルロース、メタアクリ
ル酸メタアクリル酸メチルコポリマー、メタアクリル酸
アクリル酸エチルコポリマーもしくはそれらの塩、また
はそれらの混合物を用いた請求項１記載の徐放性製剤。5. As an enteric base, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, methacrylic acid methyl methacrylic acid copolymer, ethyl methacrylic acid ethyl acrylate copolymer or theirs. The sustained-release preparation according to claim 1, wherein a salt or a mixture thereof is used.
セルロース、メタアクリル酸メタアクリル酸メチルコポ
リマーおよびカルボキシビニルポリマーからなる請求項
１記載の徐放性製剤。6. The sustained-release preparation according to claim 1, which comprises the compound A, hydroxypropylmethylcellulose, a methylmethacrylate methacrylic acid copolymer and a carboxyvinyl polymer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4352995A JPH06199657A (en) | 1992-12-10 | 1992-12-10 | Sustained release pharmaceutical preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4352995A JPH06199657A (en) | 1992-12-10 | 1992-12-10 | Sustained release pharmaceutical preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06199657A true JPH06199657A (en) | 1994-07-19 |
Family
ID=18427856
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4352995A Pending JPH06199657A (en) | 1992-12-10 | 1992-12-10 | Sustained release pharmaceutical preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH06199657A (en) |
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| JP2006096757A (en) * | 1998-09-10 | 2006-04-13 | Cv Therapeutics Inc | Sustained-release ranolazine formulation |
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1992
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| KR20100087011A (en) | 2007-10-19 | 2010-08-02 | 오츠카 세이야쿠 가부시키가이샤 | Matrix-type pharmaceutical solid preparation |
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