JP2021123559A - Agent sustained-release composition - Google Patents
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Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は薬剤徐放性組成物に関する。 The present invention relates to a drug sustained release composition.
外科手術を受けた患者の４１％が術後に深刻な激痛を経験すると言われており、人工膝関節置換術（ＴＫＡ：Total Knee Arthroplasty）を受けた患者はその割合が５０％にのぼると言われている。現在も術前から術中、術後１週間程度までの急性疼痛に対しては消炎鎮痛剤の服用または麻酔等の治療が行われている。しかし、手術直後から約３ヶ月にわたり遷延性の疼痛を感じるという患者も少なくない。このことは、手術の満足度を押し下げる要因となっている。 It is said that 41% of patients who have undergone surgery experience severe severe pain after surgery, and 50% of patients who have undergone total knee arthroplasty (TKA). It has been. Even now, treatments such as taking anti-inflammatory analgesics or anesthesia are being performed for acute pain from preoperative to intraoperative and up to about 1 week after surgery. However, there are many patients who experience persistent pain for about 3 months immediately after surgery. This is a factor that reduces the satisfaction level of surgery.
ところで、生体内に投与される組成物に関する技術として、様々な技術が知られている。例えば、特許文献１では、薬剤化合物、生体内分解性ポリマー、並びに繰り返し単位として酸性アミノ酸および／または酸性アミノ酸の金属塩を有するアミノ酸ポリマーを含有し、生体内分解性ポリマーに対するアミノ酸ポリマーの含有量が特定の範囲である徐放性薬剤組成物が開示されている。 By the way, various techniques are known as techniques for compositions to be administered in vivo. For example, Patent Document 1 contains a drug compound, a biodegradable polymer, and an amino acid polymer having an acidic amino acid and / or a metal salt of an acidic amino acid as a repeating unit, and the content of the amino acid polymer with respect to the biodegradable polymer is A specific range of sustained release drug compositions are disclosed.
また、特許文献２では、生体適合性と柔軟性とを有する材料である非置換アクリレートモノマーと置換アクリレートモノマーとのコポリマーと、生理学的に許容される懸濁化剤とを含んでなる皮膚充填材として使用される注射用アロプラスト懸濁液を含んでなる組成物が開示されている。 Further, in Patent Document 2, a skin filler comprising a copolymer of an unsubstituted acrylate monomer and a substituted acrylate monomer, which are materials having biocompatibility and flexibility, and a physiologically acceptable suspending agent. A composition comprising an injectable alloplast suspension used as is disclosed.
特許文献３では、アクリル酸および／またはメタクリン酸および／または少なくとも一つの該酸の誘導体の重合および架橋により得られる（共）重合体の少なくとも一つのヒドロゲルの粒子を含む組成物が開示されている。 Patent Document 3 discloses a composition containing at least one hydrogel particle of a (co) polymer obtained by polymerization and cross-linking of acrylic acid and / or methacrylic acid and / or at least one derivative of the acid. ..
上述の遷延性の疼痛を緩和するために、本発明者らは独自に、薬剤の徐放に着目した。しかしながら、上述のような従来技術は薬剤徐放性の観点から改善の余地があった。本発明の一態様は、上記問題点を鑑みなされたものであり、その目的は薬剤徐放性に優れた組成物を実現することである。 In order to relieve the above-mentioned persistent pain, the present inventors independently focused on the sustained release of the drug. However, the prior art as described above has room for improvement from the viewpoint of sustained release of the drug. One aspect of the present invention has been made in view of the above problems, and an object of the present invention is to realize a composition excellent in sustained release of a drug.
上記の課題を解決するために、本発明は、以下の態様を含む。 In order to solve the above problems, the present invention includes the following aspects.
＜１＞生体内に投与するための薬剤徐放性組成物であって、連続相と、前記連続相に分散した分散相と、を含み、前記分散相は、生分解性ポリマーと薬剤とを含んでいる、薬剤徐放性組成物。 <1> A drug sustained release composition for administration into a living body, which comprises a continuous phase and a dispersed phase dispersed in the continuous phase, and the dispersed phase contains a biodegradable polymer and a drug. Included, drug sustained release composition.
＜２＞前記分散相は、平均粒径１ｎｍ〜１０００μｍの粒子である、＜１＞に記載の薬剤徐放性組成物。 <2> The drug sustained release composition according to <1>, wherein the dispersed phase is particles having an average particle size of 1 nm to 1000 μm.
＜３＞前記薬剤は、固体である、＜１＞または＜２＞に記載の薬剤徐放性組成物。 <3> The drug sustained release composition according to <1> or <2>, wherein the drug is a solid.
＜４＞３５℃以上では粘度が１００ｍＰａ・ｓ以上である、＜１＞〜＜３＞のいずれか１つに記載の薬剤徐放性組成物。 <4> The drug sustained release composition according to any one of <1> to <3>, which has a viscosity of 100 mPa · s or more at 35 ° C. or higher.
＜５＞前記薬剤は、局所麻酔薬および消炎鎮痛薬の少なくともいずれか一方である、＜１＞〜＜４＞のいずれか１つに記載の薬剤徐放性組成物。 <5> The drug sustained release composition according to any one of <1> to <4>, wherein the drug is at least one of a local anesthetic and an anti-inflammatory analgesic.
＜６＞前記生分解性ポリマーは、脂肪酸ポリエステル、ポリオール、ポリカーボネート；乳酸、グリコール酸、カプロラクタン、ウレタンの重合体または共重合体；多糖類、タンパク質、ゼラチン、キチン、キトサンからなる群より選択される少なくとも１種を含む、＜１＞〜＜５＞のいずれか１つに記載の薬剤徐放性組成物。 <6> The biodegradable polymer is selected from the group consisting of fatty acid polyesters, polyols, polycarbonates; polymers or copolymers of lactic acid, glycolic acid, caprolactane and urethane; polysaccharides, proteins, gelatin, chitin and chitosan. The drug sustained-release composition according to any one of <1> to <5>, which comprises at least one.
＜７＞前記分散相は、生体内に留置した日から１年以内に分解される、＜１＞〜＜６＞のいずれか１つに記載の薬剤徐放性組成物。 <7> The drug sustained release composition according to any one of <1> to <6>, wherein the dispersed phase is decomposed within one year from the date of indwelling in vivo.
＜８＞前記分散相において、前記薬剤は前記生分解性ポリマーに包まれている、＜１＞〜＜７＞のいずれか１つに記載の薬剤徐放性組成物。 <8> The drug sustained release composition according to any one of <1> to <7>, wherein in the dispersed phase, the drug is wrapped in the biodegradable polymer.
＜９＞前記連続相は、脂肪酸ポリエステル、ポリオール、ポリカーボネート；乳酸、グリコール酸、カプロラクタン、ウレタンの重合体または共重合体；多糖類、タンパク質、ゼラチン、キチン、キトサン、ポリアクリル酸、ポリアクリル酸の誘導体、ポリサイラミン、アクリルアミド誘導体、ポリビニルエーテル、ポリデプシペプチド；ポリエチレンオキシドとポリプロピレンオキシドとの共重合体、ウレイド基含有モノマーと架橋剤モノマーとの共重合体、メタクリル酸とアクリルアミド誘導体との共重合体、ポリエチレンオキシドとポリ乳酸とのトリブロック共重合体、乳酸−グリコール酸共重合体とポリエチレングリコールとのトリブロック共重合体からなる群より選択される少なくとも１種を含む、＜１＞〜＜８＞のいずれか１つに記載の薬剤徐放性組成物。 <9> The continuous phase is a polymer or copolymer of fatty acid polyester, polyol, polycarbonate; lactic acid, glycolic acid, caprolactane, urethane; polysaccharide, protein, gelatin, chitin, chitosan, polyacrylic acid, polyacrylic acid. Derivatives, polycyramine, acrylamide derivatives, polyvinyl ethers, polydepsipeptides; copolymers of polyethylene oxide and polypropylene oxide, copolymers of ureido group-containing monomers and cross-linking agent monomers, copolymers of methacrylic acid and acrylamide derivatives, poly <1> to <8>, which comprises at least one selected from the group consisting of a triblock copolymer of ethylene oxide and polylactic acid, and a triblock copolymer of a lactic acid-glycolic acid copolymer and polyethylene glycol. The drug sustained-release composition according to any one.
＜１０＞前記連続相は、生分解性ポリマーを含む、＜１＞〜＜８＞のいずれか１つに記載の薬剤徐放性組成物。 <10> The drug sustained release composition according to any one of <1> to <8>, wherein the continuous phase contains a biodegradable polymer.
本発明の一態様によれば、薬剤徐放性に優れた組成物を提供することができる。 According to one aspect of the present invention, it is possible to provide a composition excellent in sustained release of a drug.
以下、本発明の一実施形態について、詳細に説明する。なお、本明細書において特記しない限り、数値範囲を表す「Ａ〜Ｂ」は、「Ａ以上Ｂ以下」を意味する。 Hereinafter, one embodiment of the present invention will be described in detail. Unless otherwise specified in the present specification, "A to B" representing a numerical range means "A or more and B or less".
〔１．薬剤徐放性組成物〕
本発明の一実施形態に係る薬剤徐放性組成物は、生体内に投与するための薬剤徐放性組成物であって、連続相と、前記連続相に分散した分散相と、を含み、前記分散相は、生分解性ポリマーと薬剤とを含んでいる。なお、以下では「本発明の一実施形態に係る薬剤徐放性組成物」を単に「組成物」とも称する。
[1. Drug Sustained Release Composition]
The drug sustained release composition according to one embodiment of the present invention is a drug sustained release composition for administration in vivo, and includes a continuous phase and a dispersed phase dispersed in the continuous phase. The dispersed phase contains a biodegradable polymer and a drug. In the following, the "drug-release composition according to one embodiment of the present invention" will also be simply referred to as "composition".
前記組成物では、分散相が生分解性ポリマーと薬剤とを含んでいるため、分散相が分解されながら薬剤を徐放することができる。前記組成物によれば、連続相および分散相の二相の形態をとらずに連続相中に直接的に薬剤を含んでいるのみの組成物に比べて、連続相および分散相の組成等を調整することにより薬剤の放出期間を制御しやすい。よって、前記組成物は、優れた薬剤徐放性を示す。 In the above composition, since the dispersed phase contains the biodegradable polymer and the drug, the drug can be slowly released while the dispersed phase is decomposed. According to the composition, the composition of the continuous phase and the dispersed phase and the like can be compared with the composition which does not take the form of two phases of the continuous phase and the dispersed phase and only contains the drug directly in the continuous phase. It is easy to control the release period of the drug by adjusting. Therefore, the composition exhibits excellent sustained release drug.
上述の特許文献１に記載の徐放性薬剤組成物は、連続相と分散相という二相を有する形態ではない。また、特許文献２に記載の組成物および特許文献３に記載の組成物は、主にシワなどの改善のために皮膚に充填される充填材を意図しており、薬剤の送達については何ら検討されていない。さらに、特許文献２に記載の組成物および特許文献３に記載の組成物は、あくまで充填材として生体内に残存する必要があるため、生体適合性については検討されているものの生分解性については検討されていない。 The sustained release drug composition described in Patent Document 1 described above does not have a form having two phases, a continuous phase and a dispersed phase. Further, the composition described in Patent Document 2 and the composition described in Patent Document 3 are intended to be a filler to be filled in the skin mainly for the improvement of wrinkles and the like. It has not been. Further, since the composition described in Patent Document 2 and the composition described in Patent Document 3 need to remain in the living body as a filler to the last, biocompatibility has been investigated, but biodegradability has been investigated. Not considered.
前記組成物は、生体内に投与することができる。生体内に投与する方法は限定されず、生体内に注入する方法、皮膚を切開して生体内にスプレーまたは塗布する方法などが挙げられる。例えば手術の前、手術中、または手術後に前記組成物を患部近傍に投与すれば、生体内で組成物が分解されて薬剤が徐放され、長期にわたって患部に対して薬剤を作用させることができる。なお、本明細書において、「患部」とは、生体内において治療対象となる領域または疼痛を生じ得る領域を意味する。 The composition can be administered in vivo. The method of administration into the living body is not limited, and examples thereof include a method of injecting into the living body, a method of incising the skin and spraying or applying it into the living body. For example, if the composition is administered to the vicinity of the affected area before, during, or after the operation, the composition is decomposed in vivo and the drug is slowly released, so that the drug can act on the affected area for a long period of time. .. In addition, in this specification, "affected part" means the area to be treated or the area which can cause pain in a living body.
前記組成物、並びに連続相および分散相は、固形であってもよく、液状、ゾル状、クリーム状またはゲル状であってもよい。例えば、前記組成物は、粉末が液体に分散された形態であってもよい。なお、注入、スプレーまたは塗布などの様々な投与方法を採用可能であり、投与が容易であるという観点から前記組成物は固形ではないことが好ましい。また、生体内へ投与した後、組成物の形態が変化してもよい。例えば、前記組成物は生体外ではゾル状であって、生体内へ投与した後はゲル状であってもよい。 The composition and the continuous phase and the dispersed phase may be solid, liquid, sol-like, cream-like or gel-like. For example, the composition may be in the form of powder dispersed in a liquid. It should be noted that various administration methods such as injection, spraying and coating can be adopted, and it is preferable that the composition is not solid from the viewpoint of easy administration. In addition, the morphology of the composition may change after administration into the living body. For example, the composition may be in the form of a sol in vitro and in the form of a gel after being administered in vivo.
前記組成物は、３５℃以上では粘度が１００ｍＰａ・ｓ以上であることが好ましい。このことは、体温付近で組成物が特定の粘度を示すことを表している。これにより、生体内に投与された組成物は特定の粘度を示し、生体内の所望の領域にとどまることができる。また、前記組成物は体内で固化しないことが好ましく、粘度の上限は例えば５００００ｍＰａ・ｓ以下であることが好ましい。本明細書において、前記粘度は細管式粘度計、落球式粘度計、回転式粘度計等によって測定された値を意味する。 The composition preferably has a viscosity of 100 mPa · s or more at 35 ° C. or higher. This indicates that the composition exhibits a specific viscosity near body temperature. As a result, the composition administered in vivo exhibits a specific viscosity and can stay in a desired region in vivo. Further, it is preferable that the composition does not solidify in the body, and the upper limit of the viscosity is preferably, for example, 50,000 mPa · s or less. In the present specification, the viscosity means a value measured by a thin tube viscometer, a falling ball viscometer, a rotary viscometer, or the like.
連続相および分散相の少なくともいずれか一方、特に連続相の組成を調整することにより、前記粘度を制御することができる。例えば、連続相が温度応答性ポリマー、ゾル−ゲル相転移ポリマー、ｐＨ応答性ポリマー、硬化剤を使用することで粘度変化を起こす生分解性ポリマーなどを含むことにより、生体内に投与された組成物の粘度を上述の範囲に調整することができる。具体例として、前記連続相は、脂肪酸ポリエステル、ポリオール、ポリカーボネート；乳酸、グリコール酸、カプロラクタン、ウレタンの重合体または共重合体；多糖類、タンパク質、ゼラチン、キチン、キトサン、ポリアクリル酸、ポリアクリル酸の誘導体、ポリサイラミン、アクリルアミド誘導体、ポリビニルエーテル、ポリデプシペプチド；ポリエチレンオキシドとポリプロピレンオキシドとの共重合体、ウレイド基含有モノマーと架橋剤モノマーとの共重合体、メタクリル酸とアクリルアミド誘導体との共重合体、ポリエチレンオキシドとポリ乳酸とのトリブロック共重合体、乳酸−グリコール酸共重合体（ＰＬＧＡ）とポリエチレングリコールとのトリブロック共重合体からなる群より選択される少なくとも１種を含んでいてもよい。 The viscosity can be controlled by adjusting the composition of at least one of the continuous phase and the dispersed phase, particularly the continuous phase. For example, a composition administered in vivo by a continuous phase containing a temperature-responsive polymer, a sol-gel phase transition polymer, a pH-responsive polymer, a biodegradable polymer whose viscosity is changed by using a curing agent, and the like. The viscosity of the object can be adjusted within the above range. As a specific example, the continuous phase is a polymer or copolymer of fatty acid polyester, polyol, polycarbonate; lactic acid, glycolic acid, caprolactane, urethane; polysaccharide, protein, gelatin, chitin, chitosan, polyacrylic acid, polyacrylic acid. Derivatives of, polycyramine, acrylamide derivatives, polyvinyl ethers, polydepsipeptides; copolymers of polyethylene oxide and polypropylene oxide, copolymers of ureido group-containing monomers and cross-linking agent monomers, copolymers of methacrylic acid and acrylamide derivatives, It may contain at least one selected from the group consisting of a triblock copolymer of polyethylene oxide and polylactic acid, and a triblock copolymer of lactic acid-glycolic acid copolymer (PLGA) and polyethylene glycol.
これらのうち、温度応答性ポリマーとしては、アクリルアミド誘導体およびそれを含む共重合体、多糖類、タンパク質などが挙げられる。ゾル−ゲル相転移ポリマーとしては、アクリルアミド誘導体およびそれを含む共重合体、多糖類、ゼラチンなどが挙げられる。ｐＨ応答性ポリマーとしては、多糖類、タンパク質、ゼラチン、キチン、キトサンなどが挙げられる。硬化剤を使用することで粘度変化を起こす生分解性ポリマーとしては、脂肪酸ポリエステル、ポリオール、ポリカーボネート；乳酸、グリコール酸、カプロラクタン、ウレタンの重合体または共重合体；多糖類、タンパク質、ゼラチン、キチン、キトサンなどが挙げられる。なお、粘度を変化させるための硬化剤としては、アミン系硬化剤、ポリアミド系硬化剤、有機過酸化物などが挙げられる。 Among these, examples of the temperature-responsive polymer include acrylamide derivatives and copolymers containing them, polysaccharides, proteins and the like. Examples of the sol-gel phase transition polymer include acrylamide derivatives and copolymers containing them, polysaccharides, gelatin and the like. Examples of the pH-responsive polymer include polysaccharides, proteins, gelatin, chitin, chitosan and the like. Biodegradable polymers that change viscosity with the use of hardeners include fatty acid polyesters, polyols, polycarbonates; lactic acid, glycolic acid, caprolactane, urethane polymers or copolymers; polysaccharides, proteins, gelatin, chitin, Examples include chitosan. Examples of the curing agent for changing the viscosity include amine-based curing agents, polyamide-based curing agents, and organic peroxides.
中でも、前記連続相は、生分解性ポリマーを含むことが好ましい。これにより、連続相が分解されるとともに分散相が分解されながら薬剤を徐放することができる。生分解性ポリマーの例としては、上述の脂肪酸ポリエステル、ポリオール、ポリカーボネート；乳酸、グリコール酸、カプロラクタン、ウレタンの重合体または共重合体；多糖類、タンパク質、ゼラチン、キチン、キトサンが挙げられる。これらの生分解性ポリマーの組み合わせを調整することにより、分解速度を制御することができる。 Above all, the continuous phase preferably contains a biodegradable polymer. As a result, the drug can be slowly released while the continuous phase is decomposed and the dispersed phase is decomposed. Examples of biodegradable polymers include the above-mentioned fatty acid polyesters, polyols, polycarbonates; lactic acid, glycolic acid, caprolactane, urethane polymers or copolymers; polysaccharides, proteins, gelatin, chitin, chitosan. By adjusting the combination of these biodegradable polymers, the decomposition rate can be controlled.
連続相に含まれる生分解性ポリマーの種類は、分散相に含まれる生分解性ポリマーと同じであってもよいし、異なる種類であってもよい。 The type of biodegradable polymer contained in the continuous phase may be the same as that of the biodegradable polymer contained in the dispersed phase, or may be a different type.
なお、生分解性ポリマーは、生体内において、一般に加水分解または酵素分解によって分解される。体外に塗布するための組成物は一般的にこのように加水分解または酵素分解される必要がないため、本発明の一実施形態に係る組成物とは異なる。 The biodegradable polymer is generally decomposed in vivo by hydrolysis or enzymatic decomposition. The composition for application outside the body is different from the composition according to one embodiment of the present invention because it generally does not need to be hydrolyzed or enzymatically decomposed in this way.
前記連続相は、薬剤を含まなくてもよい。薬剤を含む分散相が薬剤を含まない連続相中に分散していることにより、薬剤が連続相中に直接含まれている場合に比べて薬剤の放出を遅らせることができる。 The continuous phase may be drug-free. Since the dispersed phase containing the drug is dispersed in the continuous phase containing no drug, the release of the drug can be delayed as compared with the case where the drug is directly contained in the continuous phase.
前記分散相に含まれる生分解性ポリマーは、脂肪酸ポリエステル、ポリオール、ポリカーボネート；乳酸、グリコール酸、カプロラクタン、ウレタンの重合体または共重合体；多糖類、タンパク質、ゼラチン、キチン、キトサンからなる群より選択される少なくとも１種を含むことが好ましい。これにより分散相が生体内で好適に分解される。また、これらの生分解性ポリマーの組み合わせを調整することにより、分解速度を制御することができる。 The biodegradable polymer contained in the dispersed phase is selected from the group consisting of fatty acid polyester, polyol, polycarbonate; lactic acid, glycolic acid, caprolactane, urethane polymer or copolymer; polysaccharide, protein, gelatin, chitin, and chitosan. It is preferable to contain at least one type of lactic acid. As a result, the dispersed phase is suitably decomposed in vivo. In addition, the decomposition rate can be controlled by adjusting the combination of these biodegradable polymers.
前記分散相に含まれる薬剤は、固体であることが好ましい。薬剤が固体であることにより、扱い易く、連続相中に好適に分散させることができる。また、連続相が分解されても薬剤が液体のように漏れることがなく、薬剤の効果を発揮するため、徐放特性を制御しやすい。 The drug contained in the dispersed phase is preferably a solid. Since the drug is solid, it is easy to handle and can be suitably dispersed in the continuous phase. Further, even if the continuous phase is decomposed, the drug does not leak like a liquid, and the effect of the drug is exhibited, so that the sustained release characteristic can be easily controlled.
前記薬剤としては、局所麻酔剤、消炎鎮痛剤、抗菌剤、抗アレルギー剤、種々の治療薬などが挙げられる。中でも、前記薬剤は、局所麻酔薬および消炎鎮痛薬の少なくともいずれか一方であることが好ましい。これにより、例えば人工関節置換手術前後の疼痛などの緩和または除去に好適に利用できる。また、前記薬剤は、少なくとも局所麻酔剤を含むことが好ましく、複数の種類の局所麻酔剤を含むことがより好ましい。薬剤が複数の種類の局所麻酔剤を含む場合、多角的な疼痛管理を可能とするだけでなく、１種類毎の薬剤の量を減らすことができるため、局所麻酔中毒などの副作用を低減する効果が期待できる。局所麻酔剤としては、リドカイン、ブピバカイン、キシロカインなどが挙げられる。消炎鎮痛剤としては、アスピリン、インドメタシン、ジクロフェナクナトリウムなどが挙げられる。 Examples of the drug include local anesthetics, anti-inflammatory analgesics, antibacterial agents, antiallergic agents, various therapeutic agents and the like. Above all, the drug is preferably at least one of a local anesthetic and an anti-inflammatory analgesic. Thereby, for example, it can be suitably used for alleviating or eliminating pain before and after artificial joint replacement surgery. In addition, the drug preferably contains at least a local anesthetic, and more preferably contains a plurality of types of local anesthetic. When a drug contains multiple types of local anesthetics, not only is it possible to manage pain from multiple angles, but also the amount of each drug can be reduced, which has the effect of reducing side effects such as local anesthetic poisoning. Can be expected. Examples of local anesthetics include lidocaine, bupivacaine, xylocaine and the like. Examples of anti-inflammatory analgesics include aspirin, indomethacin, diclofenac sodium and the like.
前記分散相は、平均粒径１ｎｍ〜１０００μｍの粒子であることが好ましい。分散相の平均粒径が特定の範囲であることにより、分散相を扱い易く、連続相中に好適に分散させることができる。 The dispersed phase is preferably particles having an average particle size of 1 nm to 1000 μm. When the average particle size of the dispersed phase is in a specific range, the dispersed phase can be easily handled and can be suitably dispersed in the continuous phase.
前記分散相は、生体内に留置した日から１年以内に分解されることが好ましい。これにより、１年以内の長期にわたって薬剤の放出を制御することができる。また、分散相は生体内に留置した日から１週間未満の期間では分解されてしまわないことが好ましい。 The dispersed phase is preferably decomposed within one year from the date of indwelling in vivo. This makes it possible to control the release of the drug over a long period of up to one year. Further, it is preferable that the dispersed phase is not decomposed within a period of less than one week from the day of indwelling in the living body.
なお、生体内において、本発明の一実施形態に係る薬剤徐放性組成物は、最初に連続相が生体組織および体液と接触するため、連続相の生体内における分解および／または体液への拡散は、分散相の分解よりも早期に生じる。 In the living body, in the drug sustained release composition according to the embodiment of the present invention, since the continuous phase first comes into contact with the living tissue and the body fluid, the continuous phase is decomposed in the living body and / or diffused into the body fluid. Occurs earlier than the decomposition of the dispersed phase.
前記分散相において薬剤は生分解性ポリマー中に均一に分散されていてもよく、薬剤は生分解性ポリマーに包まれていてもよい。好ましくは、分散相において、薬剤は生分解性ポリマーに包まれている。これにより、薬剤の放出をさらに遅らせることができる。例えば、分散相は、薬剤を生分解性ポリマーで包んだマイクロカプセルの形態であってもよい。また、前記分散相は内部から表面に向かって層状構造を有していてもよく、層状構造を有していなくてもよい。例えば、分散相は、薬剤を含まない第一層を最外層に有し、薬剤を含む第二層を第一層の内側に有していてもよい。 In the dispersed phase, the drug may be uniformly dispersed in the biodegradable polymer, and the drug may be wrapped in the biodegradable polymer. Preferably, in the dispersed phase, the drug is wrapped in a biodegradable polymer. This can further delay the release of the drug. For example, the dispersed phase may be in the form of microcapsules in which the drug is wrapped in a biodegradable polymer. Further, the dispersed phase may or may not have a layered structure from the inside toward the surface. For example, the dispersed phase may have a drug-free first layer on the outermost layer and a drug-containing second layer inside the first layer.
前記組成物は、リン脂質、ポリイソシアネートおよび／またはポリフッ化ビニリデンを含まなくてもよい。分子量の観点から前記組成物はリン脂質を含まないことが好ましい。また、生体親和性の観点から前記組成物はポリイソシアネートおよび／またはポリフッ化ビニリデンを含まないことが好ましい。 The composition may be free of phospholipids, polyisocyanates and / or polyvinylidene fluoride. From the viewpoint of molecular weight, it is preferable that the composition does not contain phospholipids. Further, from the viewpoint of biocompatibility, it is preferable that the composition does not contain polyisocyanate and / or polyvinylidene fluoride.
また、薬剤は、生分解性ポリマーと共有結合していないことが好ましい。これにより、多様な薬剤を利用することができる。また、薬剤の放出速度の制御も容易である。 Further, it is preferable that the drug is not covalently bonded to the biodegradable polymer. As a result, various drugs can be used. In addition, it is easy to control the release rate of the drug.
〔２．薬剤徐放性組成物の製造方法〕
前記組成物の製造方法は、例えば、連続相中に分散相を分散させる工程を含む。前記分散相は、生分解性ポリマー中に薬剤を混合する方法などによって得ることができる。例えば、生分解性ポリマーを含む溶液中に薬剤を分散させ、次いで溶媒を揮発し、さらに得られた固形物を粉砕することにより、分散相を得てもよい。または薬剤を生分解性ポリマーによって被覆することにより、分散相を得てもよい。あるいは、薬剤を含む水溶液と生分解性ポリマーを含む有機溶剤溶液からＷ／Ｏ(Water in Oil)エマルションを得る工程と、次いで当該Ｗ／Ｏエマルションを水と混合してＷ／Ｏ／Ｗ(Water in Oil in Water)エマルションを得る工程と、有機溶剤を除去して生分解性ポリマーを析出する工程とを含む方法から、分散相を得てもよい。または薬剤および生分解性ポリマーを含む有機溶剤溶液を水と混合してＯ／Ｗ(Oil in Water)エマルションを得る工程と、有機溶剤を除去して生分解性ポリマーを固化する工程とを含む方法から、分散相を得てもよい。
[2. Method for producing sustained release composition]
The method for producing the composition includes, for example, a step of dispersing the dispersed phase in the continuous phase. The dispersed phase can be obtained by a method of mixing a drug in a biodegradable polymer or the like. For example, a dispersed phase may be obtained by dispersing the drug in a solution containing a biodegradable polymer, then volatilizing the solvent, and pulverizing the obtained solid substance. Alternatively, a dispersed phase may be obtained by coating the drug with a biodegradable polymer. Alternatively, a step of obtaining a W / O (Water in Oil) emulsion from an aqueous solution containing a drug and an organic solvent solution containing a biodegradable polymer, and then mixing the W / O emulsion with water to make W / O / W (Water). In Oil in Water) A dispersed phase may be obtained from a method including a step of obtaining an emulsion and a step of removing an organic solvent to precipitate a biodegradable polymer. Alternatively, a method including a step of mixing an organic solvent solution containing a drug and a biodegradable polymer with water to obtain an O / W (Oil in Water) emulsion, and a step of removing the organic solvent to solidify the biodegradable polymer. The dispersed phase may be obtained from.
分散相を構成する粒子の平均粒径は、光散乱法、光子相関法、沈降法等を用いて測定できる。また、光学顕微鏡、走査型電子顕微鏡等を用いて試料の拡大画像を取得し、画像解析により個々の粒子の径を求め、その平均値を計算してもよい。 The average particle size of the particles constituting the dispersed phase can be measured by using a light scattering method, a photon correlation method, a precipitation method, or the like. Alternatively, a magnified image of the sample may be acquired using an optical microscope, a scanning electron microscope, or the like, the diameter of each particle may be obtained by image analysis, and the average value thereof may be calculated.
〔３．薬剤徐放性組成物の用途〕
前記組成物は、薬剤を体内に送達するために広く使用することができる。前記組成物は、薬剤を長期にわたって徐放することができるため、種々の治療に用いることができる。特に薬剤として局所麻酔剤および任意で消炎鎮痛剤を含む組成物は、手術前後の疼痛、中でも術後の遷延性の疼痛を緩和または除去するために用いられ得る。前記組成物は、局所麻酔剤および任意で消炎鎮痛剤を長期にわたって徐放することができるため、術後の遷延性の疼痛を緩和または除去するために好適である。そのような遷延性の疼痛が懸念される手術としては、例えば人工関節置換手術などが挙げられる。
[3. Uses of drug sustained release composition]
The composition can be widely used to deliver the drug into the body. The composition can be used for various treatments because the drug can be slowly released over a long period of time. In particular, compositions containing local anesthetics and optionally anti-inflammatory analgesics as agents can be used to relieve or eliminate pre- and post-surgery pain, especially postoperative persistent pain. The composition is suitable for relieving or eliminating postoperative persistent pain, as it allows for long-term sustained release of local anesthetics and optionally anti-inflammatory analgesics. Examples of the surgery in which such persistent pain is a concern include artificial joint replacement surgery.
例えば、本発明の一実施形態に係るキットは、前記組成物を封入したパッケージを備えていてもよい。また、前記キットは、薬剤を含む組成物を封入したパッケージと、薬剤を含まない組成物を封入したパッケージとを備えていてもよい。また、前記キットは、それぞれ薬剤の濃度が異なる組成物を封入した複数のパッケージを備えていてもよい。このような複数のパッケージを順番に投与することにより薬剤投与量を制御してもよい。 For example, the kit according to one embodiment of the present invention may include a package containing the composition. In addition, the kit may include a package containing a composition containing a drug and a package containing a composition containing no drug. In addition, the kit may include a plurality of packages containing compositions having different drug concentrations. The drug dose may be controlled by sequentially administering the plurality of such packages.
例えば、本発明の一実施形態に係る治療方法は、手術の前、手術中、または手術後に前記組成物を、患者の患部近傍に投与する工程を含んでいてもよい。患者はヒトであってもよく、非ヒトの動物であってもよい。前記組成物は、注射器等を用いて生体内に注入されてもよく、皮膚を切開して生体内にスプレーまたは塗布されてもよい。 For example, the treatment method according to one embodiment of the present invention may include a step of administering the composition to the vicinity of the affected area of a patient before, during, or after surgery. The patient may be a human or a non-human animal. The composition may be injected into a living body using a syringe or the like, or the skin may be incised and sprayed or applied into the living body.
また、本発明の一実施形態は、前記組成物を製造するための薬剤の使用も包含する。 In addition, one embodiment of the present invention also includes the use of an agent for producing the composition.
本発明は上述した各実施形態に限定されるものではなく、請求項に示した範囲で種々の変更が可能であり、異なる実施形態にそれぞれ開示された技術的手段を適宜組み合わせて得られる実施形態についても本発明の技術的範囲に含まれる。 The present invention is not limited to the above-described embodiments, and various modifications can be made within the scope of the claims, and the embodiments obtained by appropriately combining the technical means disclosed in the different embodiments. Is also included in the technical scope of the present invention.
本発明の一態様は、薬剤を生体内に送達するために好適に利用することができる。 One aspect of the present invention can be suitably used for delivering a drug in vivo.
Claims (10)
連続相と、
前記連続相に分散した分散相と、を含み、
前記分散相は、生分解性ポリマーと薬剤とを含んでいる、薬剤徐放性組成物。 A drug sustained release composition for administration in vivo.
Continuous phase and
Including the dispersed phase dispersed in the continuous phase,
The dispersed phase is a drug sustained release composition containing a biodegradable polymer and a drug.
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