JP2006213600A - Sustained release system of medicine - Google Patents
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- JP2006213600A JP2006213600A JP2005025225A JP2005025225A JP2006213600A JP 2006213600 A JP2006213600 A JP 2006213600A JP 2005025225 A JP2005025225 A JP 2005025225A JP 2005025225 A JP2005025225 A JP 2005025225A JP 2006213600 A JP2006213600 A JP 2006213600A
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Abstract
Description
本発明は、生体内に一定期間保持され、内部に担持された生物学的に活性な物質または組成物（以下薬剤）を目的期間にわたり目的生体内濃度で、生体内で徐放させる薬剤徐放システムに関する。さらに詳述すれば、本発明は、１種以上の薬剤を使用環境に徐々に放出またはその放出速度等を制御できる薬剤徐放システムに関する。 The present invention provides a sustained drug release in which a biologically active substance or composition (hereinafter referred to as a drug) held in a living body for a certain period of time is gradually released in vivo at a target in vivo concentration over a target period. About the system. More specifically, the present invention relates to a sustained drug release system capable of gradually releasing one or more kinds of drugs into a use environment or controlling the release rate thereof.
近年、薬剤の開発改良が進み、高分子医薬と呼ばれる高分子化合物を含有する医薬がさまざま上市されている。高分子医薬は主に高分子化合物それ自体が薬理活性を有するものと、薬理活性を有する低分子化合物をキャリヤーと呼ばれる高分子に結合させたものがある。
本発明の属する生体内徐放システムはどちらにも応用可能である。さらに徐放システムとは生体内への薬剤投与を効果的に行い、副作用を抑制する目的で、必要最小限の薬剤を治療すべき局所のみへ運び、さらに必要な時間だけ滞留させるように製剤からの薬剤放出速度と量を制御する方法である。または、薬剤の血中濃度が副作用発現濃度と最低有効濃度との範囲内にある最適治療濃度領域となるように、製剤からの薬剤放出速度と量を制御する方法である。
このような薬剤を制御放出する方法として、現在までのさまざまの薬物徐放システムが考案され、これに適合するための種々の高分子材料が検討されている。
その結果、現在の技術では、生体内の薬剤濃度を比較的一定にすることが可能になりつつあり、薬剤の濃度が急激に上昇し、その後減少するようなことはなくなりつつある。
In recent years, development and improvement of drugs have progressed, and various drugs containing polymer compounds called polymer drugs have been put on the market. There are two types of high molecular drugs, one having a high molecular compound itself having pharmacological activity and the other having a low molecular compound having a pharmacological activity bound to a polymer called a carrier.
The in vivo sustained release system to which the present invention belongs is applicable to both. Furthermore, the sustained-release system effectively administers the drug in vivo and suppresses side effects from the drug product so that the minimum necessary drug is transported only to the area to be treated and is retained for the required time. This is a method for controlling the drug release rate and amount. Alternatively, it is a method of controlling the drug release rate and amount from the preparation so that the blood concentration of the drug falls within the optimum therapeutic concentration range within the range of the side effect expression concentration and the lowest effective concentration.
As a method for controlled release of such a drug, various sustained drug release systems have been devised up to now, and various polymer materials for adapting to this have been studied.
As a result, with the current technology, the concentration of the drug in the living body can be made relatively constant, and the concentration of the drug does not rapidly increase and then decreases.
薬剤の徐放のための各種製剤についてはこれまで様々報告されてきた。これらの製剤のうちのあるものは、それらの効果を出すために拡散現象、薬剤徐放温度によるものが検討され、前者は特許文献１（特公平０７−０５３６７２）、後者は特許文献２（特開平０６−２４７８４１）、特許文献３（特開平１１−９２５５４）に記載されている。
しかしながら、薬剤徐放に関する単位時間当たりの徐放量の制御に関して述べるのであれば、前述の現状技術では、患者の容態に応じた単位時間当たりの薬剤徐放量のコントロールが不十分である。即ち、現状技術ではドラッグデリバリーシステムにおいて重要となる、ターゲティングと徐放という２つのものにたいしての考察が不完全である。敢えて限定的に詳しく述べるのであればターゲティングの技術の進歩は目覚しいものがあるが、その単位時間当たりの徐放速度の制御に関してはいまだに技術課題を残している。詳しく述べると、ターゲティングは薬剤及び担体が生体内に入った際に、その外部環境に応じて、薬剤の放出応答を開始する。この分野に関してはもっぱら前述のような発明、技術ブレイクスルーが生まれつつある。しかし、これだけの技術では薬剤の徐放そのもの、即ち、どれくらいの徐放期間、徐放量、徐放速度で、患者に投与すれば良いかという問題を解決できない。
Various preparations for sustained release of drugs have been reported so far. Some of these preparations have been studied for diffusion phenomenon and drug sustained release temperature in order to exert their effects. The former is Patent Document 1 (Japanese Patent Publication No. 07-053672), and the latter is Patent Document 2 (Japanese Patent Kaihei 06-247841) and Patent Document 3 (Japanese Patent Laid-Open No. 11-92554).
However, if the control of the sustained release amount per unit time relating to the sustained release of the drug is described, the current state-of-the-art technique is insufficient to control the sustained release amount of the drug per unit time according to the patient's condition. In other words, in the current technology, the two considerations of targeting and sustained release, which are important in drug delivery systems, are incomplete. Although the progress of targeting technology is remarkable if it is described in detail in a limited manner, there are still technical issues regarding the control of the sustained release rate per unit time. More specifically, targeting initiates a drug release response depending on its external environment when the drug and carrier enter the body. In this field, the above-mentioned inventions and technological breakthroughs are being born. However, such a technique cannot solve the problem of the sustained release of the drug itself, that is, how long the sustained release period, the sustained release amount, and the sustained release rate should be administered to the patient.
また、特許文献４（特開平１０−２９８１０８）には水溶性ポリマー繊維、生分解性ポリマー及びリン酸カルシウム系化合物からなる複合体に薬剤を含ませることにより薬剤の徐放速度を制御すること述べられている。しかしながら、この技術では水溶性ポリマーの溶出を薬剤徐放に利用しており、本質的に分解吸収速度の異なる生体吸収性高分子より形成されているわけではない。そのため、分解吸収性によって薬剤の徐放がコントロールされているとは言えず、特許文献１と同様に、単に水溶性高分子よりの薬剤を拡散しているにすぎないので、十分な薬剤の徐放コントロールが可能であるとは考えにくい。
Patent Document 4 (Japanese Patent Laid-Open No. 10-298108) states that the drug sustained release rate is controlled by including a drug in a complex composed of a water-soluble polymer fiber, a biodegradable polymer, and a calcium phosphate compound. Yes. However, in this technique, elution of a water-soluble polymer is used for drug sustained release, and it is not formed from bioabsorbable polymers having essentially different degradation and absorption rates. Therefore, it cannot be said that the sustained release of the drug is controlled by the decomposition and absorbability, and as in
本発明が解決しようとする問題点は、従来の徐放薬剤製剤では、患者に投与する際に、薬剤の徐放期間、量、速度等をコントロールしにくい点である。 The problem to be solved by the present invention is that it is difficult to control the sustained release period, amount, rate, and the like of a drug in a conventional sustained-release drug formulation when administered to a patient.
本発明の目的は、１種類以上の生理活性を有する有効剤を使用環境に徐放する製剤を提供することであり、使用環境に徐放する際には、至適濃度、至適期間徐放するような製剤を提供することである。
［１］本発明は、二種類以上の薬剤担体を有し、当該薬剤担体を相互に分解吸収速度の異なる分解吸収性高分子より形成し、安定した薬剤の単位時間当たりの徐放速度を制御可能にした薬剤徐放システムを提供する。
［２］本発明は、前記単位時間当たりの徐放速度の制御は、二種類以上の薬剤担体として構成されるそれぞれの分解吸収性高分子の分解吸収速度の差により制御している［１］に記載の薬剤徐放システムを提供する。
［３］本発明は、前記それぞれの分解吸収性高分子の分解吸収速度の差は、それぞれ分解されるまでの期間が１２時間以上異なる［１］ないし［２］に記載の薬剤徐放システムを提供する。
［４］本発明は、前記薬剤担体が、粒状、微粉末状、シート状、層状、コロイド状、ゲル状の中から選ばれる少なくとも一種類以上の組み合わせである［１］ないし［３］に記載の薬剤徐放システムを提供する。
［５］本発明は、第一の薬剤担体を第二の薬剤担体で段階構造となし、及び／又は前記第二の薬剤担体を第三の薬剤担体で段階構造となし、錠剤、微粉末状、コロイド状、シート状、ゲル状、チューブ状、ストランド状、またはそれらの多孔体のいずれかに形成した［１］ないし［４］に記載の薬剤徐放システムを提供する。
［６］本発明は、前記薬剤担体としての分解吸収性高分子は、脂肪族エステル化合物及びその誘導体、共重合体である［１］ないし［５］に記載の薬剤徐放システムを提供する。
［７］本発明は、前記薬剤担体としての分解吸収性高分子である脂肪族エステル化合物及びその誘導体、共重合体が、その共重合比で分解吸収性をコントロールしている［１］ないし［６］に記載の薬剤除放システムを提供する。
［８］本発明は、前記薬剤担体としての分解吸収性高分子が、その分子量で分解吸収性をコントロールしている［１］ないし［７］に記載の薬剤徐放システムを提供する。
［９］本発明は、前記薬剤担体としての脂肪族ポリエステルが、ポリ乳酸、ポリグリコール酸、ポリ−ε−カプロラクトンのいずれかを含む［１］ないし［８］に記載の薬剤徐放システムを提供する。
［１０］本発明は、前記薬剤担体としての脂肪族エステルがポリ乳酸、ポリグリコール酸、ポリ−ε−カプロラクトンのうち、２種あるいは３種を共重合させたものである［１］ないし［９］に記載の薬剤徐放システムを提供する。
［１１］本発明は、前記薬剤が、抗炎症剤、抗生物質、アルキル化剤、制癌剤、免疫抑制剤、免疫刺激剤、血圧降下剤、ホルモン、神経成長因子、成長分化因子、軟骨由来成長因子、骨盤成長因子、上皮成長因子、線維牙細胞由来成長因子、血小板由来成長因子、コロニー刺激因子、エリスロポエチン、インターロイキン１，２，３，インターフェロンα，β，γ，トランスフォーミング成長因子、インシュリン、カルシトニン、プロスタグランジンの中から選ばれる少なくとも一種類以上である［１］ないし［１０］に記載の薬剤徐放システムを提供する。
It is an object of the present invention to provide a preparation for slowly releasing one or more types of active agents having physiological activity to the use environment. Is to provide such a formulation.
[1] The present invention has two or more kinds of drug carriers, and the drug carriers are formed from degradable and absorbable polymers having different decomposable absorption rates, and the controlled sustained release rate per unit time of the drug is controlled. Provided is a drug sustained release system.
[2] In the present invention, the controlled release rate per unit time is controlled by the difference in the decomposition and absorption rates of the respective decomposition and absorption polymers configured as two or more kinds of drug carriers [1]. A sustained drug release system described in 1. is provided.
[3] The present invention relates to the sustained release system of medicine according to [1] or [2], wherein the difference in the rate of degradation and absorption of each of the degradation and absorption polymers is different in a period until degradation by 12 hours or more. provide.
[4] The present invention according to [1] to [3], wherein the drug carrier is at least one combination selected from a granular form, a fine powder form, a sheet form, a layer form, a colloid form, and a gel form. To provide a sustained drug release system.
[5] In the present invention, the first drug carrier has a step structure with a second drug carrier, and / or the second drug carrier has a step structure with a third drug carrier. The drug sustained-release system according to [1] to [4], which is formed in any one of a colloidal shape, a sheet shape, a gel shape, a tube shape, a strand shape, or a porous body thereof.
[6] The present invention provides the sustained drug release system according to any one of [1] to [5], wherein the decomposition and absorption polymer as the drug carrier is an aliphatic ester compound, a derivative or a copolymer thereof.
[7] In the present invention, the aliphatic ester compound, which is a degradation / absorption polymer as a drug carrier, and derivatives and copolymers thereof control the degradation / absorption by the copolymerization ratio [1] to [ [6] A drug release system as described in [6].
[8] The present invention provides the drug sustained-release system according to [1] to [7], wherein the decomposition / absorption polymer as the drug carrier controls the decomposition / absorption by the molecular weight.
[9] The drug sustained-release system according to [1] to [8], wherein the aliphatic polyester as the drug carrier includes any of polylactic acid, polyglycolic acid, and poly-ε-caprolactone. To do.
[10] In the present invention, the aliphatic ester as the drug carrier is obtained by copolymerizing two or three of polylactic acid, polyglycolic acid, and poly-ε-caprolactone [1] to [9]. ] The medicine sustained-release system described in the above.
[11] In the present invention, the drug is an anti-inflammatory agent, antibiotic, alkylating agent, anticancer agent, immunosuppressive agent, immunostimulant, antihypertensive agent, hormone, nerve growth factor, growth differentiation factor, cartilage-derived growth factor , Pelvic growth factor, epidermal growth factor, fibroblast-derived growth factor, platelet-derived growth factor, colony stimulating factor, erythropoietin,
本発明により、（１）薬剤の徐放が、分解吸収性の異なる高分子の複合体により制御可能である。（２）（１）により、至適濃度、至適期間生体内の薬物濃度を制御できる。（３）また本発明では、患者に薬剤を投与するに際し、どれくらいの徐放期間、徐放量、徐放速度で、患者に投与すれば良いかという問題にたいして、単位時間当たりの徐放速度を制御することにより、より明確な技術ブレイクスルーとなりうる。 According to the present invention, (1) sustained release of a drug can be controlled by a polymer complex having different decomposition and absorbability. (2) By (1), the optimal concentration and the drug concentration in the living body can be controlled. (3) Further, in the present invention, when a drug is administered to a patient, the sustained release rate per unit time is controlled for the problem of how long the sustained release period, sustained release amount, and sustained release rate should be administered to the patient. By doing so, it can be a clearer technology breakthrough.
以下に本発明を実施するための薬剤徐放システムの原理、材料、形態を詳細に説明する。
［本発明の原理］
本発明の薬剤徐放システムは、二種類以上の薬剤担体を有し、当該薬剤担体を相互に分解吸収速度の異なる分解吸収性高分子より形成し、安定した薬剤の単位時間当たりの徐放速度を制御可能にしたものである。
前記単位時間当たりの徐放速度の制御は、薬剤担体として使用される分解吸収性高分子の分解吸収速度の差により制御している。
The principle, material, and form of the sustained drug release system for carrying out the present invention will be described in detail below.
[Principle of the present invention]
The drug sustained-release system of the present invention has two or more types of drug carriers, the drug carriers are formed from degradable and absorbable polymers having different decomposable absorption rates, and a stable sustained release rate per unit time of the drug Can be controlled.
The controlled release rate per unit time is controlled by the difference in the decomposition and absorption rate of the decomposition and absorption polymer used as the drug carrier.
さらに詳述すれば、生体内での分解吸収速度の異なる高分子の分解吸収され、或いは分解され薬剤を坦持できなくなる、このような高分子を用いることによって、１種類以上の薬剤を、生体内生理的液体に徐々に放出し、且つ、薬剤を投与される患者の必要度合いに応じて必要期間（至適期間）、必要濃度（至適濃度）徐放することが可能になる。
また本発明における「分解吸収速度が異なる」（分解吸収速度の差）とは、生理学的液体内にて薬剤を含有できなくなる強度に達するまでの期間が１２時間以上、好ましくは２４時間以上が良い。１２時間未満の分解吸収性の差異は、薬剤を投与する患者にとって有効になる可能性は低い。
More specifically, one or more kinds of drugs can be produced by using such a polymer that is decomposed and absorbed by a polymer having a different rate of decomposition and absorption in a living body or cannot be supported by a drug. It is possible to gradually release into the physiological fluid in the body and to release the required concentration (optimum concentration) and the required concentration (optimum concentration) gradually according to the degree of necessity of the patient to whom the drug is administered.
In the present invention, “degradation / absorption rate is different” (difference in decomposition / absorption rate) is 12 hours or more, preferably 24 hours or more until reaching a strength at which no drug can be contained in a physiological fluid. . Differences in degradation absorbency of less than 12 hours are unlikely to be effective for the patient receiving the drug.
［材料：生体内分解吸収性高分子］
本発明は、薬剤担体として生体内分解吸収性高分子（分解吸収性高分子ともいう）が使用される。分解吸収性高分子とは、生体内で分解吸収され、分解吸収の段階においては、加水分解や酵素分解されて最終的には代謝されて生体内より排出される高分子である。
本発明に使用する前記薬剤担体としての分解吸収性高分子は、特に限定するものではないが、例えば生体内で加水分解ないし吸収される、脂肪族エステル化合物及びその誘導体、共重合体等であって、その中でも乳酸、グリコール酸、ポリ−ε−カプロラクトン等の脂肪族のポリエステル化合物等が好適である。
前記脂肪族のポリエステル化合物は、ポリ乳酸、ポリグリコール酸、ポリ−εカプロラクトンのいずれかを含み、好ましくは、これらのうち、２種あるいは３種を共重合させたものが好適である。特にこれらの脂肪族のポリエステル化合物は、前記乳酸、グリコール酸、ポリ−ε−カプロラクトンをそれぞれを重合単位として、単独重合や共重合が可能であり、且つ共重合単位で分解吸収速度（分解吸収性）が異なるため、それぞれの共重合比、分子量での分解吸収性が制御可能であるために好適である。
さらにそれぞれの薬剤担体を形成する際の、それぞれの共重合モル比及びその分子量（モル平均）は、それぞれの分解期間を考慮した範囲であれば如何なる制約も受けることなく使用可能である。使用範囲をあえて論ずるのであれば、薬剤担体の分解期間を考慮して、薬剤担体内層及び薬剤担体外層の分解吸収性（分解吸収性とは単体が薬剤を坦持できなくなる期間をいう）の速度の異なる高分子を用いることであり、それら分解吸収性の速度は各高分子の共重合比あるいは分子量によって推測、考慮できるために、その処方する患者の様態に適合した担体設計が望まれる。
[Material: Biodegradable absorbable polymer]
In the present invention, a biodegradable / absorbable polymer (also referred to as a degradable / absorbable polymer) is used as a drug carrier. The degradable and absorbable polymer is a polymer that is decomposed and absorbed in a living body, and is hydrolyzed or enzymatically decomposed and finally metabolized and discharged from the living body at the stage of decomposing and absorbing.
The decomposition-absorbing polymer as the drug carrier used in the present invention is not particularly limited, and examples thereof include aliphatic ester compounds and derivatives, copolymers, and the like that are hydrolyzed or absorbed in vivo. Of these, aliphatic polyester compounds such as lactic acid, glycolic acid and poly-ε-caprolactone are preferred.
The aliphatic polyester compound contains any one of polylactic acid, polyglycolic acid, and poly-ε-caprolactone, and preferably a copolymer obtained by copolymerizing two or three of these. In particular, these aliphatic polyester compounds can be homopolymerized or copolymerized with each of the lactic acid, glycolic acid, and poly-ε-caprolactone as polymerized units, and the decomposition / absorption rate (decomposition / absorbability) of the copolymerized units. ) Are different from each other, it is preferable because the decomposition and absorption at each copolymerization ratio and molecular weight can be controlled.
Furthermore, the copolymerization molar ratio and the molecular weight (molar average) in forming each drug carrier can be used without any limitation as long as each decomposition period is taken into consideration. If the range of use is deliberately discussed, the rate of decomposition / absorption of the drug carrier inner layer and the drug carrier outer layer (decomposition / absorption refers to the period during which a single substance can no longer carry a drug) in consideration of the decomposition period of the drug carrier. Since the rate of decomposition and absorption can be estimated and taken into consideration by the copolymerization ratio or molecular weight of each polymer, a carrier design suitable for the condition of the patient to be prescribed is desired.
［形態］
本発明の薬剤徐放システムは、前記薬剤担体として、例えば、錠剤、微粉末状、コロイド状、シート状、ゲル状、チューブ状、ストランド状、またはそれらの多孔体から選ばれる少なくとも一種類以上の組み合わせて使用することができる。
本発明の薬剤徐放システムの好ましい形態は、第一の薬剤担体を第二の薬剤担体で段階構造となし、及び／又はさらに前記第二の薬剤担体を第三の薬剤担体で段階構造となす。
すなわち相互に分解吸収速度（生体吸収性）の異なる生体吸収性高分子を段階構造とし、それぞれの生理学的溶液内、或いは生体内においての分解性を制御することによって薬剤の徐放をコントロールすることができる。段階構造とは、固体を液体で積層（コーテイング）（積層）する手段、粒状等の固体（またはコロイド）を同固体（またはコロイド）で積層する手段等も含む。
前記薬剤担体の各形態を組み合わせて、錠剤、微粉末状、コロイド状、シート状、ゲル状、チューブ状、ストランド状、またはそれらの多孔体のいずれかに形成する。
（１）錠剤
前記第一の薬剤担体は、薬剤を含有した第二及び／又は第三の薬剤担体の内部に存在し内層を形成する。前記第二及び／又は第三の薬剤担体は、薬剤の含有した第一の薬剤担体の外部に存在して外層を形成する。
前記第一の薬剤担体（分解吸収性高分子）は、ゲル状または固体であり薬剤を徐放するのに好適な形態を有する。その形態は第二及び／又は第三の薬剤担体内部に存在するのであれば如何なる形状でもかまわないが薬剤を徐放するその性質より、安定した形態を維持しておいたほうがより好ましい。
[Form]
In the drug sustained release system of the present invention, the drug carrier is, for example, at least one or more selected from tablets, fine powders, colloids, sheets, gels, tubes, strands, or porous bodies thereof. Can be used in combination.
In a preferred form of the sustained drug release system of the present invention, the first drug carrier has a stage structure with the second drug carrier, and / or the second drug carrier has a stage structure with the third drug carrier. .
That is, controlling the sustained release of drugs by making bioabsorbable polymers with different degradation and absorption rates (bioabsorbability) from each other into a step structure and controlling the degradability in each physiological solution or in vivo. Can do. The staged structure includes means for laminating (coating) (stacking) a solid with a liquid, means for laminating a solid (or colloid) such as a granular form with the same solid (or colloid), and the like.
Each form of the drug carrier is combined to form a tablet, a fine powder, a colloid, a sheet, a gel, a tube, a strand, or a porous body thereof.
(1) Tablet The first drug carrier is present inside the second and / or third drug carrier containing the drug and forms an inner layer. The second and / or third drug carrier is present outside the first drug carrier containing the drug to form an outer layer.
The first drug carrier (degradable and absorbable polymer) is in a gel or solid form and has a form suitable for sustained release of the drug. The form may be any shape as long as it exists inside the second and / or third drug carrier, but it is more preferable to maintain a stable form from the property of sustained release of the drug.
（２）コロイド状
本発明の薬剤徐放システムの好ましい形態は、第一の薬剤担体及び第二の薬剤担体、及び／又は第三の薬剤担体が水分散性の高分子である。
すなわち相互に分解吸収速度（生体吸収性）の異なる高分子コロイドを形成することによって、高分子コロイドの内部あるいは、高分子コロイド自体に含有させた薬剤を、前記高分子の分解性を制御することによって薬剤の徐放をコントロールすることができる。
(2) Colloidal In a preferred form of the drug sustained-release system of the present invention, the first drug carrier, the second drug carrier, and / or the third drug carrier are water-dispersible polymers.
That is, by forming polymer colloids with different degradation absorption rates (bioabsorbability) from each other, the degradability of the polymer can be controlled by the drug contained in the polymer colloid or in the polymer colloid itself. Can control the sustained release of the drug.
［薬剤徐放の制御方法］
本発明の分解吸収性高分子を利用した薬剤徐放の制御は、分解性高分子の分解速度差を利用したものである。詳しくは分解性高分子が分解して、薬剤を含有できなるまでの時間差を利用したものである。
また、薬剤を含有できなくなるまでの時間差は、製造者の意図する期間に設定可能である。例えば、本発明の含まれる分解吸収性高分子の中には、ポリ乳酸、ポリグリコール酸、ポリε−カプロラクトン、などの脂肪族炭化水素は、その分子構造によって分解期間が異なることは周知の事実である。さらに、われわれが鋭意検討した結果、それらの共重合体などは、それらの構成される脂肪族炭化水素に依存した分解吸収性を示し、かつ、より精密な分解期間の設定が可能あることが分かっている。さらにそれらの脂肪族炭化水素は分子量、分子量分布により制御可能であることも分かっており、これらによって分解期間の設定は可能である。
［薬剤］
また、本発明は１種類以上の有効な生理学的活性を有する薬剤を、人間のような哺乳動物を含めた、全ての生理学的液体を有する生物に対応するものである。
本発明で使用される薬剤として、例えば、抗炎症剤、抗生物質、アルキル化剤、制癌剤、免疫抑制剤、免疫刺激剤、血圧降下剤、ホルモン、神経成長因子、成長分化因子、軟骨由来成長因子、骨盤成長因子、上皮成長因子、線維牙細胞由来成長因子、血小板由来成長因子、コロニー刺激因子、エリスロポエチン、インターロイキン１，２，３，インターフェロンα，β，γ，トランスフォーミング成長因子、インシュリン、カルシトニン、プロスタグランジンの中から選ばれる少なくとも一種類以上である。
[Control method of sustained drug release]
Control of sustained drug release using the degradable and absorbable polymer of the present invention utilizes the difference in the degradation rate of the degradable polymer. Specifically, the time difference from when the degradable polymer is decomposed until it can contain the drug is used.
Moreover, the time difference until it becomes impossible to contain a chemical | medical agent can be set to the period which a manufacturer intends. For example, among the degradation-absorbing polymers included in the present invention, it is a well-known fact that aliphatic hydrocarbons such as polylactic acid, polyglycolic acid, and poly-ε-caprolactone have different degradation periods depending on their molecular structures. It is. Furthermore, as a result of our intensive studies, it has been found that these copolymers exhibit decomposition absorbability that depends on their constituent aliphatic hydrocarbons and that a more precise decomposition period can be set. ing. Furthermore, it has been found that these aliphatic hydrocarbons can be controlled by molecular weight and molecular weight distribution, and the decomposition period can be set by these.
[Drug]
The present invention also addresses one or more agents with effective physiological activity to organisms having all physiological fluids, including mammals such as humans.
Examples of the drug used in the present invention include anti-inflammatory agents, antibiotics, alkylating agents, anticancer agents, immunosuppressive agents, immunostimulants, antihypertensive agents, hormones, nerve growth factors, growth differentiation factors, and cartilage-derived growth factors. , Pelvic growth factor, epidermal growth factor, fibroblast-derived growth factor, platelet-derived growth factor, colony stimulating factor, erythropoietin,
本実施例と比較例で使用した薬剤担体、製剤（薬剤徐放システム）の形態、薬剤を表１に記載した。製剤（薬剤徐放システム）の形態を図１に記載した。
実施例１
重量平均分子量が４０万の乳酸／グリコール酸／ε−カプロラクトンの三元共重合体（１）（モル費７２：５：２３）をアセトン１００ｇに５ｗｔ％となるように溶解した。その後、溶液に５０ｍｇのアセチルサリチル酸を混合した。その後、溶媒を減圧下で除去し、薬剤Ａを得た。
さらに重量平均分子量が１０万のグリコール酸／ε−カプロラクトンの共重合体（２）（モル比６８：３２）をアセトン１００ｇに１０ｗｔ％となるように溶解し、溶液に５ｇのアセチルサリチル酸を混合した。これを薬剤Bとした。
薬剤Ａを直径１０ｍｍのタブレット粒子になるように２００度のプレス成形機で成形した。その後、薬剤Ｂをディッピングにより積層した。ディッピングは計５回行い、その都度減圧下にて溶媒（アセトン）を乾燥させた。ディッピングした厚みは約５ｍｍであった。
薬剤Ａに薬剤Ｂがコーティングされた薬剤ＡＢを得た。
尚、事前に薬剤ＡＢは外層の高分子の分解が開始後１０〜２０日であると予測されその時期に薬剤の大量徐放が起こるものと予測された。
Table 1 shows the drug carrier, the form of the drug product (drug sustained release system), and the drug used in this example and the comparative example. The form of the preparation (drug sustained release system) is shown in FIG.
Example 1
A terpolymer (1) (molar cost 72: 5: 23) of lactic acid / glycolic acid / ε-caprolactone having a weight average molecular weight of 400,000 was dissolved in 100 g of acetone so as to be 5 wt%. Thereafter, 50 mg of acetylsalicylic acid was mixed into the solution. Thereafter, the solvent was removed under reduced pressure to obtain Drug A.
Furthermore, a glycolic acid / ε-caprolactone copolymer (2) (molar ratio 68:32) having a weight average molecular weight of 100,000 was dissolved in 100 g of acetone so as to be 10 wt%, and 5 g of acetylsalicylic acid was mixed with the solution. . This was designated as Drug B.
The drug A was molded by a 200 ° press molding machine so as to be tablet particles having a diameter of 10 mm. Then, the medicine B was laminated by dipping. Dipping was performed 5 times in total, and the solvent (acetone) was dried under reduced pressure each time. The dipped thickness was about 5 mm.
The drug AB in which the drug A was coated with the drug B was obtained.
The drug AB was predicted in advance to be 10 to 20 days after the start of the degradation of the polymer in the outer layer, and a large amount of drug release was predicted to occur at that time.
実施例２
重量平均分子量が４０万の乳酸/グリコール酸／ε−カプロラクトンの共重合体（３）（モル比７５：８：１７）をアセトン１００ｇに１０ｗｔ％となるように溶解し、溶液に５ｇのアセチルサリチル酸を混合した。これを薬剤Cとした。
さらに重量平均分子量が１０万のグリコール酸／ε−カプロラクトンの二元共重合体（２）（モル比４４：５６）をアセトン１００ｇに５ｗｔ％となるように溶解した。その後、溶液に５０ｍｇのアセチルサリチル酸を混合した。その後、溶媒を減圧下で除去し、薬剤Ｄを得た。
薬剤Ｄを直径１０ｍｍのタブレット粒子になるように１００度のプレス成形機で成形した。その後、薬剤Ｃをディッピングにより積層した。ディッピングは計５回行い、その都度減圧下にて溶媒（アセトン）を乾燥させた。ディッピングした厚みは約５ｍｍであった。
薬剤Ｄに薬剤Cがコーティングされた薬剤ＣＤを得た。
尚、事前に薬剤ＣＤは内層の高分子の分解が外層の高分子の分解に先駆けて開始後２０〜３０日後に行われると予測され、内層の徐放と合わせるように錠剤形状を失うものと想定した。
Example 2
A copolymer of lactic acid / glycolic acid / ε-caprolactone (3) (molar ratio 75: 8: 17) having a weight average molecular weight of 400,000 is dissolved in 100 g of acetone so as to be 10 wt%, and 5 g of acetylsalicylic acid is dissolved in the solution. Were mixed. This was designated as Drug C.
Further, a glycolic acid / ε-caprolactone binary copolymer (2) (molar ratio 44:56) having a weight average molecular weight of 100,000 was dissolved in 100 g of acetone so as to be 5 wt%. Thereafter, 50 mg of acetylsalicylic acid was mixed into the solution. Thereafter, the solvent was removed under reduced pressure to obtain Drug D.
The drug D was molded by a press molding machine at 100 degrees so as to be tablet particles having a diameter of 10 mm. Then, the medicine C was laminated by dipping. Dipping was performed 5 times in total, and the solvent (acetone) was dried under reduced pressure each time. The dipped thickness was about 5 mm.
A drug CD obtained by coating drug D with drug C was obtained.
In addition, it is predicted that the medicine CD will be decomposed in advance 20-30 days after the start of the decomposition of the polymer in the inner layer before the decomposition of the polymer in the outer layer, and loses the tablet shape to match the sustained release of the inner layer. Assumed.
実施例３
重量平均分子量が４０万の乳酸／グリコール酸／ε−カプロラクトンの三元共重合体（３）（モル比７５：８：１７）をアセトン１００ｇに５ｗｔ％となるように溶解した。その後、溶液に５０ｍｇのアセチルサリチル酸を混合した。その後、溶媒を減圧下で除去し、薬剤Ｅを得た。
さらに重量平均分子量が３万のグリコール酸／ε−カプロラクトンの共重合体（４）（モル比６８：３２）をアセトン１００ｇに１０ｗｔ％となるように溶解し、溶液に５ｇのアセチルサリチル酸を混合した。これを薬剤Fとした。
薬剤Ｅを直径１０ｍｍのタブレット粒子になるように２００度のプレス成形機で成形した。その後、薬剤Ｆをディッピングにより積層した。ディッピングは計５回行い、その都度減圧下にて溶媒（アセトン）を乾燥させた。ディッピングした厚みは約５ｍｍであった。
薬剤Ｅに薬剤Ｆがコーティングされた薬剤ＥＦを得た。
尚、事前に１０日以内に外層の薬剤の徐放が開始されるものと想定した。
Example 3
A terpolymer (3) (molar ratio 75: 8: 17) of lactic acid / glycolic acid / ε-caprolactone having a weight average molecular weight of 400,000 was dissolved in 100 g of acetone so as to be 5 wt%. Thereafter, 50 mg of acetylsalicylic acid was mixed into the solution. Thereafter, the solvent was removed under reduced pressure to obtain Drug E.
Further, a glycolic acid / ε-caprolactone copolymer (4) (molar ratio 68:32) having a weight average molecular weight of 30,000 was dissolved in 100 g of acetone so as to be 10 wt%, and 5 g of acetylsalicylic acid was mixed with the solution. . This was designated as Drug F.
The medicine E was molded by a 200 ° press molding machine so as to be tablet particles having a diameter of 10 mm. Then, the medicine F was laminated by dipping. Dipping was performed 5 times in total, and the solvent (acetone) was dried under reduced pressure each time. The dipped thickness was about 5 mm.
A drug EF obtained by coating the drug E with the drug F was obtained.
It was assumed that the sustained release of the outer layer drug was started within 10 days in advance.
実施例４
重量平均分子量が４０万の乳酸／グリコール酸／ε−カプロラクトンの三元共重合体（３）（モル比７５：８：１７）をアセトン１００ｇに５ｗｔ％となるように溶解した。その後、溶液に５０ｍｇのアセチルサリチル酸を混合した。その後、溶媒を減圧下で除去し、薬剤Ｇを得た。
さらに重量平均分子量が２０万の乳酸／グリコール酸／ε−カプロラクトンの共重合体（５）（モル比２０：５０：３０）をアセトン１００ｇに１０ｗｔ％となるように溶解し、溶液に５ｇのアセチルサリチル酸を混合した。これを薬剤Hとした。
さらに重量平均分子量が７万のグリコール酸／ε−カプロラクトンの共重合体（６）（モル比６８：３２）をアセトン１００ｇに１０ｗｔ％となるように溶解し、溶液に５ｇのアセチルサリチル酸を混合した。これを薬剤Ｉとした。
薬剤Ｇを直径５ｍｍのタブレット粒子になるように２００度のプレス成形機で成形した。その後、薬剤Ｈをディッピングにより積層した。ディッピングは５回行い、その都度減圧下にて溶媒（アセトン）を乾燥させた。その際のディピング層の厚みは約５ｍｍであった。また、その後にも薬剤Ｉをディッピングにより積層した。ディッピングは５回行い、その都度減圧下にて溶媒（アセトン）を乾燥させた。ディッピングの厚みは５ｍｍであった。
薬剤Ｇに薬剤Ｈ及び薬剤Ｉがコーティングされた薬剤ＧＨＩを得た。
尚、事前に最外層の高分子が開始後１０日以内、中間層が２０日以内で薬剤の徐放を開始することを想定した。
Example 4
A terpolymer (3) (molar ratio 75: 8: 17) of lactic acid / glycolic acid / ε-caprolactone having a weight average molecular weight of 400,000 was dissolved in 100 g of acetone so as to be 5 wt%. Thereafter, 50 mg of acetylsalicylic acid was mixed into the solution. Thereafter, the solvent was removed under reduced pressure to obtain Drug G.
Further, a lactic acid / glycolic acid / ε-caprolactone copolymer (5) (molar ratio 20:50:30) having a weight average molecular weight of 200,000 was dissolved in 100 g of acetone so as to be 10 wt%, and 5 g of acetyl was dissolved in the solution. Salicylic acid was mixed. This was designated as Drug H.
Further, a glycolic acid / ε-caprolactone copolymer (6) (molar ratio 68:32) having a weight average molecular weight of 70,000 was dissolved in 100 g of acetone so as to be 10 wt%, and 5 g of acetylsalicylic acid was mixed with the solution. . This was designated as Drug I.
The drug G was molded by a 200 ° press molding machine so as to be tablet particles having a diameter of 5 mm. Thereafter, the drug H was laminated by dipping. Dipping was performed 5 times, and the solvent (acetone) was dried under reduced pressure each time. The thickness of the dipping layer at that time was about 5 mm. Further, after that, the drug I was laminated by dipping. Dipping was performed 5 times, and the solvent (acetone) was dried under reduced pressure each time. The dipping thickness was 5 mm.
A drug GHI obtained by coating drug G with drug H and drug I was obtained.
In addition, it was assumed in advance that the polymer of the outermost layer starts the sustained release of the drug within 10 days after the start and the intermediate layer starts within 20 days.
比較例１
重量平均分子量が４０万の乳酸／グリコール酸／ε−カプロラクトンの三元共重合体（１）（モル比７２：５：２３）をアセトン１００ｇに５ｗｔ％となるように溶解した。その後、溶液に５０ｍｇのアセチルサリチル酸を混合した。その後、溶媒を減圧下で除去し、薬剤Jを得た。
Comparative Example 1
A terpolymer (1) (molar ratio 72: 5: 23) of lactic acid / glycolic acid / ε-caprolactone having a weight average molecular weight of 400,000 was dissolved in 100 g of acetone to 5 wt%. Thereafter, 50 mg of acetylsalicylic acid was mixed into the solution. Thereafter, the solvent was removed under reduced pressure to obtain Drug J.
比較例２
重量平均分子量が１０万のグリコール酸／ε−カプロラクトンの二元共重合体（２）（モル比６８：３２）をアセトン１００ｇに５ｗｔ％となるように溶解した。その後、溶液に５０ｍｇのアセチルサリチル酸を混合した。その後、溶媒を減圧下で除去し、薬剤Ｋを得た。
＜薬剤放出試験＞
実施例１〜４及び比較例１〜２で得られた本発明の徐放性製剤をリン酸緩衝生理食塩水（ｐＨ７．４）に浸漬し、アセチルサリチル酸の経時毎の生理食塩水中への溶出量を分光光度計により測定した。
薬剤放出試験の結果を表２と図２に、試験結果のまとめを表３に示す。
Comparative Example 2
A glycolic acid / ε-caprolactone binary copolymer (2) (molar ratio 68:32) having a weight average molecular weight of 100,000 was dissolved in 100 g of acetone so as to be 5 wt%. Thereafter, 50 mg of acetylsalicylic acid was mixed into the solution. Thereafter, the solvent was removed under reduced pressure to obtain Drug K.
<Drug release test>
The sustained-release preparations of the present invention obtained in Examples 1 to 4 and Comparative Examples 1 and 2 were immersed in phosphate buffered saline (pH 7.4), and elution of acetylsalicylic acid into physiological saline over time The quantity was measured with a spectrophotometer.
The results of the drug release test are shown in Table 2 and FIG. 2, and the summary of the test results is shown in Table 3.
ＡＢ、ＣＤ、ＥＦ、ＧＨＩ、Ｊ、Ｋ 薬剤 AB, CD, EF, GHI, J, K
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| JP2017533796A (en) * | 2014-12-29 | 2017-11-16 | ボストン サイエンティフィック サイムド，インコーポレイテッドＢｏｓｔｏｎ Ｓｃｉｅｎｔｉｆｉｃ Ｓｃｉｍｅｄ，Ｉｎｃ． | Compositions, devices, and methods for multi-stage release of chemotherapeutic agents |
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