JPWO2015133580A1 - Injectable polylactic acid-containing composition - Google Patents
Injectable polylactic acid-containing composition Download PDFInfo
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- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
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- A61K9/0048—Eye, e.g. artificial tears
- A61K9/0051—Ocular inserts, ocular implants
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0085—Brain, e.g. brain implants; Spinal cord
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
Abstract
本発明の組成物は、少なくとも一種のポリ乳酸類及び少なくとも一種のその可溶化溶媒を含有し、ポリ乳酸類が可溶化溶媒に溶解している液状組成物である。本発明の組成物は薬理学的に許容できるため、一般的な注射剤として投与可能である。本発明の組成物に薬物を含ませることにより、投与部位で長時間にわたって薬物を放出できるため、頻回投与せずとも長期的な治療効果が期待できる医薬品を提供できる。また、本発明の組成物は、安全性が高く、最終的にはすべて生体内で消失するので治療後取り出す必要がない医薬品を提供できる。さらに、本発明の組成物は、簡便に、人体に有害な物質を使用せずとも製造でき、多くの薬物に適応可能である。The composition of the present invention is a liquid composition containing at least one polylactic acid and at least one solubilizing solvent thereof, wherein the polylactic acid is dissolved in the solubilizing solvent. Since the composition of the present invention is pharmacologically acceptable, it can be administered as a general injection. By including a drug in the composition of the present invention, the drug can be released over a long period of time at the administration site, so that a pharmaceutical product that can be expected to have a long-term therapeutic effect without frequent administration can be provided. In addition, the composition of the present invention can provide a pharmaceutical product that is highly safe and does not need to be taken out after treatment because it eventually disappears in vivo. Furthermore, the composition of the present invention can be easily produced without using substances harmful to the human body, and can be applied to many drugs.
Description
本発明は、一般的な注射剤として投与可能で、投与部位で長時間にわたり薬物を放出するため頻回投与せずとも長期的な治療効果が期待できる組成物に関する。 The present invention relates to a composition that can be administered as a general injection and can be expected to have a long-term therapeutic effect without frequent administration because it releases the drug over a long period of time at the administration site.
多くの治療薬は、投与後体内で迅速に代謝され、消失するため、適切な治療濃度を維持するには、薬物を頻繁に投与する必要がある。
特許文献１に述べられているように、この頻回投与を避けるために、薬物の放出制御機能を持つインプラントを使用する技術はよく知られている。
いくつかの放出制御インプラントは、「マトリックス」型である。すなわち、薬物が多孔性又は非多孔性タイプのポリマーからなるマトリックスに分散されていて、そのマトリックスは、固体又は半固体であり、かつ、有効成分に対して透過性又は不透過性である。
マトリックスインプラントが、例えばポリ乳酸類のような生分解性物質より形成されている場合には、インプラントの分解とともに薬物が放出されるという利点、さらにインプラント自体も徐々に分解消失するために、薬物が放出された後も取り除く必要がないという利点を有している。
このような生体分解性のインプラントは、薬物の徐放性に優れ、かつ、最終的にデバイスを取り除く必要はないという優れた利点を有している。しかし、生体分解性インプラントを投与するには、投与部位を切開して埋め込む必要があり、患者側の投与時の侵襲が避けられない。そのため、生体分解性のインプラントも、切開することが困難な患部に使用できないという欠点を有している。Many therapeutic agents are rapidly metabolized and disappear in the body after administration, requiring frequent administration of the drug to maintain an appropriate therapeutic concentration.
As described in Patent Document 1, in order to avoid this frequent administration, a technique using an implant having a drug release control function is well known.
Some controlled release implants are of the “matrix” type. That is, the drug is dispersed in a matrix composed of a porous or non-porous type polymer, and the matrix is solid or semi-solid and is permeable or impermeable to the active ingredient.
When the matrix implant is formed of a biodegradable substance such as polylactic acid, for example, the drug is released along with the degradation of the implant, and the implant itself gradually degrades and disappears. It has the advantage that it does not have to be removed after being released.
Such a biodegradable implant has excellent advantages that it is excellent in sustained drug release and does not require the device to be finally removed. However, in order to administer a biodegradable implant, it is necessary to incise and implant the administration site, and invasion at the time of administration on the patient side is inevitable. For this reason, biodegradable implants also have the disadvantage that they cannot be used in affected areas that are difficult to incise.
医学の分野では、治療の安全性や、患者に負担をかけない低侵襲治療の考え方が重視されるようになっている。それに伴い、より安全な材料を設計・合成する技術や、体内に投与する技術が求められている。
特許文献２にはこの点を解決するために、インプラントを微粒子として成型し、患部を切開することなしに注射針などを用いて投与する持続性製剤が提案されている。この方法により、患部を切開することなしに注射によりインプラントを投与できるという利点、薬物の徐放性が得られるという利点、さらに微粒子が生体中で分解するために最終的にインプラントを取り出す必要がないという利点が得られている。しかし、このような微粒子製剤にするためには、毒性を有するジクロロメタンなどの有機溶媒や試薬を使用しなければならず、安全性が懸念される。また、微粒子であるために薬物を保持する容量が限られているという欠点、及び調製で使用したジクロロメタンなどの有機溶媒の除去洗浄中に微粒子から薬物も一緒に排出されてしまうため、微粒子に保持される薬物量が小さくなるという欠点が新たに生じている。In the field of medicine, importance is attached to the safety of treatment and the concept of minimally invasive treatment that does not burden the patient. Accordingly, technology for designing and synthesizing safer materials and technology for administration into the body are required.
In order to solve this point, Patent Document 2 proposes a long-lasting preparation in which an implant is molded as fine particles and administered using an injection needle or the like without incising the affected area. By this method, there is an advantage that the implant can be administered by injection without incising the affected part, an advantage that a sustained release of the drug can be obtained, and there is no need to finally take out the implant because the microparticles are degraded in the living body. The advantage is obtained. However, in order to obtain such a fine particle formulation, a toxic organic solvent or reagent such as dichloromethane must be used, and there is a concern about safety. In addition, because it is a fine particle, the capacity to hold the drug is limited, and since the drug is also discharged from the fine particle during the removal of the organic solvent such as dichloromethane used in the preparation, it is retained in the fine particle. A new drawback has arisen in that the amount of drug applied is reduced.
特許文献３には、薬物と乳酸ベースのポリマーが、エタノール、プロパノール、イソプロパノールなどの低級アルコールに溶解したゲル状組成物が提案されている。このゲル状組成物は、チキソトロピー性が高く、注射針などを通過できるため、シリンジなどで注入投与することができる。投与されたゲル中の乳酸ベースのポリマーが徐々に分解して、それに伴い薬物も徐放される。この組成物であれば、ジクロロメタンなどの有機溶媒を使用する必要がなく、かつ、薬物の保持量も大きい。しかし、エタノールの体内への投与は、刺激、生殖能又は胎児への悪影響、呼吸器への刺激、眠気やめまい、肝臓の障害及び中枢神経系の障害のおそれが指摘されている。 Patent Document 3 proposes a gel composition in which a drug and a lactic acid-based polymer are dissolved in a lower alcohol such as ethanol, propanol, or isopropanol. Since this gel composition has high thixotropic properties and can pass through an injection needle or the like, it can be injected and administered with a syringe or the like. The lactic acid-based polymer in the administered gel gradually degrades, and the drug is gradually released accordingly. With this composition, it is not necessary to use an organic solvent such as dichloromethane, and the amount of drug retained is large. However, it has been pointed out that administration of ethanol into the body may cause irritation, adverse effects on fertility or fetus, respiratory irritation, sleepiness and dizziness, liver damage and central nervous system damage.
特許文献４には、水性媒体またはヒトもしくは動物の体液に不溶性であり、薬学的に許容され、生分解性である熱可塑性ポリマー、薬学的に許容され、生分解性であり、水不溶性または水難溶性である有機溶媒、薬学的に許容され、水溶性であり生体適合性であるアジュバント、および生物活性剤を含む組成物が提案されている。この組成物は、液体組成物としてシリンジにより体内に注入することができ、体液に曝されることにより体内にその場で固体インプラントを形成する。そのため、この組成物は薬物徐放性担体として利用できる。しかし、有機溶媒の種類によっては、安全性の観点から眼組織等における使用には適していないと考えられる。 Patent Document 4 describes thermoplastic polymers that are insoluble in aqueous media or human or animal body fluids, pharmaceutically acceptable and biodegradable, pharmaceutically acceptable and biodegradable, water insoluble or water insoluble. Compositions have been proposed comprising an organic solvent that is soluble, a pharmaceutically acceptable, water-soluble and biocompatible adjuvant, and a bioactive agent. This composition can be injected into the body as a liquid composition with a syringe and forms a solid implant in situ within the body upon exposure to body fluids. Therefore, this composition can be used as a drug sustained-release carrier. However, depending on the type of organic solvent, it is considered that the organic solvent is not suitable for use in eye tissues or the like from the viewpoint of safety.
本発明は、薬物を含ませた場合にその薬物の徐放性組成物を可能とする、シリンジなどで体内に注入可能であり、注入後、体内で固化する液状組成物を提供することを目的としている。 An object of the present invention is to provide a liquid composition that, when a drug is contained, enables a sustained-release composition of the drug, can be injected into the body with a syringe or the like, and solidifies in the body after the injection. It is said.
本発明により、ポリ乳酸類及びその可溶化溶媒を含み、ポリ乳酸類が可溶化溶媒に溶解しており、室温で液状であるため体内に注入することが可能な組成物及びその調製法を提供する。さらに、薬物とポリ乳酸類をポリエチレングリコール（以降、PEGと称することもある）などの可溶性溶媒に溶解することにより、注入可能な徐放性組成物及びその調製法を提供する。すなわち、本発明により、
＜１＞ 少なくとも一種のポリ乳酸類及び少なくとも一種のその可溶化溶媒を含有し、ポリ乳酸類が可溶化溶媒に溶解している液状組成物；
＜２＞ ポリ乳酸類がL-乳酸、D-乳酸、グリコール酸より選ばれる少なくとも一種をモノマーとする＜１＞に記載の組成物；
＜３＞ 重量平均分子量が5,000〜30,000であるポリ乳酸類の少なくとも一種を含む＜１＞又は＜２＞に記載の組成物；
＜４＞ 可溶化溶媒がプロピレングリコール及びポリエチレングリコールの少なくとも一種を含む＜１＞〜＜３＞のいずれか１項に記載の組成物；
＜５＞ 可溶化溶媒として、重量平均分子量が200〜400であるポリエチレングリコールの少なくとも一種を含む＜４＞に記載の組成物；
＜６＞ 可溶化溶媒とポリ乳酸類の質量比が、可溶化溶媒/ポリ乳酸類=1〜6である＜１＞〜＜５＞のいずれか１項に記載の組成物；
＜７＞ さらに薬物を含有する＜１＞〜＜６＞のいずれか１項に記載の組成物；
＜８＞ 人体に有害な物質を含まない、＜１＞〜＜７＞のいずれか１項に記載の組成物；
＜９＞ 人体に有害な物質が、ジクロロメタン、エタノール、メタノール又はアセトニトリルである＜８＞記載の組成物；及び
＜１０＞ ＜１＞〜＜９＞のいずれか１項記載の組成物を調製する方法であって、ポリ乳酸類及びその可溶化溶媒を混合し、加熱し、ポリ乳酸類を可溶化溶媒中に溶解する工程を含むが、人体に有害な物質を使用する工程を含まない、前記方法；
を提供する。According to the present invention, a composition containing polylactic acid and a solubilizing solvent thereof, the polylactic acid being dissolved in the solubilizing solvent, and being liquid at room temperature, a composition that can be injected into the body and a method for preparing the same are provided. To do. Furthermore, an injectable sustained-release composition and a preparation method thereof are provided by dissolving a drug and polylactic acid in a soluble solvent such as polyethylene glycol (hereinafter sometimes referred to as PEG). That is, according to the present invention,
<1> A liquid composition containing at least one polylactic acid and at least one solubilizing solvent thereof, wherein the polylactic acid is dissolved in the solubilizing solvent;
<2> The composition according to <1>, wherein the polylactic acid has at least one monomer selected from L-lactic acid, D-lactic acid, and glycolic acid as a monomer;
<3> The composition according to <1> or <2>, comprising at least one polylactic acid having a weight average molecular weight of 5,000 to 30,000;
<4> The composition according to any one of <1> to <3>, wherein the solubilizing solvent contains at least one of propylene glycol and polyethylene glycol;
<5> The composition according to <4>, which contains at least one polyethylene glycol having a weight average molecular weight of 200 to 400 as a solubilizing solvent;
<6> The composition according to any one of <1> to <5>, wherein the mass ratio of the solubilizing solvent and the polylactic acid is solubilizing solvent / polylactic acid = 1 to 6;
<7> The composition according to any one of <1> to <6>, further containing a drug;
<8> The composition according to any one of <1> to <7>, which does not contain a substance harmful to the human body;
<9> The composition according to <8>, wherein the substance harmful to the human body is dichloromethane, ethanol, methanol, or acetonitrile; and <10> the composition according to any one of <1> to <9>. A method comprising mixing a polylactic acid and its solubilizing solvent, heating, and dissolving the polylactic acid in the solubilizing solvent, but not using a substance harmful to the human body, Method;
I will provide a.
本発明の組成物は、患部を切開することなしにシリンジなどを用いて投与可能である。投与された組成物は、体内で体液と接触するとその場で固化する。固化した組成物は、投与部位で長期間滞留することができ、その間、徐々に分解し、最後は消失する。したがって、本発明の組成物に薬物を含ませると、長期間に亘って薬物を放出可能な医薬品が得られる。しかも、本発明の組成物は消失するから、薬物をすべて放出し、役割を終えた後に投与部位を再度切開して固化した組成物を取り除く必要がない。さらに、毒性を有するために最終的に除去しなければならないジクロロメタンなどの有機溶媒や試薬を使用しなくとも、加熱するだけで組成物が調製できるので、同類の微粒子製剤に比較して、安全性が高い。その上、毒性のある有機溶媒などを洗浄する際の薬物の流出を防ぐことができるから、組成物中の薬物含有量を高くすることができる。 The composition of the present invention can be administered using a syringe or the like without incising the affected area. The administered composition solidifies in situ upon contact with bodily fluids in the body. The solidified composition can stay for a long time at the site of administration, during which time it gradually decomposes and eventually disappears. Therefore, when a drug is included in the composition of the present invention, a pharmaceutical product capable of releasing the drug over a long period of time can be obtained. In addition, since the composition of the present invention disappears, it is not necessary to release all the drug and remove the solidified composition by incising the administration site again after finishing the role. Furthermore, the composition can be prepared just by heating without using organic solvents and reagents such as dichloromethane, which must be finally removed because they are toxic. Is expensive. In addition, since the outflow of the drug when washing toxic organic solvents and the like can be prevented, the drug content in the composition can be increased.
〔ポリ乳酸類〕
本発明に用いるポリ乳酸類としては、薬理学的に許容できるものであれば、特に制限無く用いることができる。本発明のポリ乳酸類は、乳酸のみを基体とするホモポリマーであってもよいし、グリコール酸のみを基体とするホモポリマーであってもよく、又は乳酸とグリコール酸とを基体とするコポリマーであってもよい。本発明のポリ乳酸類はまた、本発明の効果が損なわれないのであればその他の少量のコモノマー類を含んでもよい。このようなコモノマー類としては、イプシロン−カプロラクトン等があげられる。なお、本明細書において「乳酸」という用語はL-乳酸、D-乳酸、DL-乳酸及びラクチドを指し、「グリコール酸」という用語は、グリコール酸、グリコリドを指す。
本発明に適した乳酸・グリコール酸コポリマーの乳酸：グリコール酸のモル比は、50:50〜85:15であり、特に50:50、75:25、80:20、85:15が好ましい。
本発明に適したポリ乳酸類の重量平均分子量は3,000〜150,000を例示できる。その中でも、重量平均分子量が好ましくは5,000〜100,000、より好ましくは5,000〜30,000のポリ乳酸類を用いた場合、より注入し易い本発明の組成物を形成する。重量平均分子量が5,000〜30,000であるポリ乳酸類の少なくとも一種を含むのが好ましい。とりわけ、重量平均分子量が5000〜20000である、乳酸とグリコール酸の共重合体を基体とするポリ乳酸類が好ましい。
本発明で使用されるポリ乳酸類は本発明の特性が得られるならば、単独で用いても、いくつかのポリ乳酸類を混合して使用しても良い。
医薬品に添加するポリ乳酸類の実例として、医薬品添加物事典2007(日本医薬品添加物協会編集、株式会社薬事日報社発行)に記載の、乳酸・グリコール酸共重合体（１：１）、乳酸・グリコール酸共重合体（95：5）(高分子量共重合体)及び乳酸・グリコール酸共重合体（95：5）(低分子量共重合体)があげられる。[Polylactic acid]
Any polylactic acid can be used without particular limitation as long as it is pharmacologically acceptable. The polylactic acid of the present invention may be a homopolymer based only on lactic acid, a homopolymer based only on glycolic acid, or a copolymer based on lactic acid and glycolic acid. There may be. The polylactic acids of the present invention may also contain a small amount of other comonomers as long as the effects of the present invention are not impaired. Examples of such comonomers include epsilon-caprolactone. In this specification, the term “lactic acid” refers to L-lactic acid, D-lactic acid, DL-lactic acid and lactide, and the term “glycolic acid” refers to glycolic acid and glycolide.
The lactic acid / glycolic acid molar ratio of the lactic acid / glycolic acid copolymer suitable for the present invention is 50:50 to 85:15, and 50:50, 75:25, 80:20, and 85:15 are particularly preferable.
Examples of the weight average molecular weight of the polylactic acid suitable for the present invention include 3,000 to 150,000. Among them, when a polylactic acid having a weight average molecular weight of preferably 5,000 to 100,000, more preferably 5,000 to 30,000 is used, the composition of the present invention that is more easily injected is formed. It is preferable to contain at least one polylactic acid having a weight average molecular weight of 5,000 to 30,000. In particular, polylactic acids based on a copolymer of lactic acid and glycolic acid having a weight average molecular weight of 5000 to 20000 are preferred.
The polylactic acid used in the present invention may be used alone or in combination with several polylactic acids as long as the characteristics of the present invention are obtained.
Examples of polylactic acids added to pharmaceuticals include lactic acid / glycolic acid copolymers (1: 1), lactic acid / glycolic acid copolymers (1: 1) described in Pharmaceutical Additives Encyclopedia 2007 (edited by the Japan Pharmaceutical Additives Association, published by Yakuji Nippo Inc.) And glycolic acid copolymer (95: 5) (high molecular weight copolymer) and lactic acid / glycolic acid copolymer (95: 5) (low molecular weight copolymer).
ポリ乳酸類は、一般的に、加熱により加水分解を起こしやすいため、本発明の組成物を調製する際に、本発明で用いるポリ乳酸類をあまり高温にしない方が好ましい。また、通常の製造設備で使用できる水浴でも調製できるよう、本発明で用いる可溶化溶媒としては、ポリ乳酸類を１００℃以下で均一に溶解できるものが好ましい。また、本発明の組成物を体内又は水に注入したときに、本発明の組成物中の可溶化溶媒と水分（体液に含まれる水分を含む）との置換が起こることにより、ポリ乳酸類がその場で固まることが本発明の組成物の特性であるため、本発明に用いる可溶化溶媒は、水分と置換され得る特性を持つ必要がある。
〔可溶化溶媒〕
本発明の可溶化溶媒としては、本発明の特性が得られるならば特に制限はないが、好ましくはポリエチレングリコールやプロピレングリコールを例示できる。可溶化溶媒がプロピレングリコール及びポリエチレングリコールの少なくとも一種を含むのが好ましい。可溶化溶媒が、プロピレングリコール及びポリエチレングリコール以外の溶媒を含む場合、人体に悪影響を与えないものであるのが好ましい。本発明の可溶化溶媒としては、ポリエチレングリコールのみを用いるのが好ましい。Since polylactic acids generally tend to be hydrolyzed by heating, it is preferable not to make the polylactic acids used in the present invention too high when preparing the composition of the present invention. Moreover, as the solubilizing solvent used in the present invention, a solvent capable of uniformly dissolving polylactic acids at 100 ° C. or lower is preferable so that it can be prepared in a water bath that can be used in ordinary production equipment. In addition, when the composition of the present invention is injected into the body or water, substitution of the solubilizing solvent and water (including water contained in body fluid) in the composition of the present invention causes polylactic acids to Since it is a property of the composition of the present invention to solidify in-situ, the solubilizing solvent used in the present invention needs to have a property that can be replaced with moisture.
[Solubilizing solvent]
The solubilizing solvent of the present invention is not particularly limited as long as the characteristics of the present invention are obtained, but preferably, polyethylene glycol and propylene glycol can be exemplified. The solubilizing solvent preferably contains at least one of propylene glycol and polyethylene glycol. When the solubilizing solvent contains a solvent other than propylene glycol and polyethylene glycol, it is preferably one that does not adversely affect the human body. As the solubilizing solvent of the present invention, it is preferable to use only polyethylene glycol.
本発明に用いられるポリエチレングリコールは、第十六改正日本薬局方に収載されているものを好適に用いることができる。例えば、PEG-200、PEG-300、PEG-400、PEG-600、PEG-1000、PEG-1540、PEG-2000、PEG-4000、PEG-6000、PEG-20000、PEG-50000、PEG-500000、PEG-2000000及びPEG-4000000の商品名で、和光純薬工業株式会社から販売されている。また、マクロゴール-200、マクロゴール-300、マクロゴール-400、マクロゴール-600、マクロゴール-1000、マクロゴール-1540、マクロゴール-4000、マクロゴール-6000及びマクロゴール-20000の商品名で日本油脂株式会社から販売されている。
本発明に用いられるポリエチレングリコールの重量平均分子量は、本発明の特性が得られるならば特に制限はないが、200〜600が好ましく、200〜400が特に好ましい。重量平均分子量が600以下の場合は、室温で液状になり注入し易いため好ましい。
また、本発明の特性が得られるならば、2種以上のPEGを混合して使用することも可能である。PEGの概要、規格、用途、使用量及び商品名などについては、医薬品添加物事典2007（日本医薬品添加物協会編集、株式会社薬事日報社発行）にも詳細に記載されている。As the polyethylene glycol used in the present invention, those listed in the 16th revision Japanese Pharmacopoeia can be suitably used. For example, PEG-200, PEG-300, PEG-400, PEG-600, PEG-1000, PEG-1540, PEG-2000, PEG-4000, PEG-6000, PEG-20000, PEG-50000, PEG-500000, They are sold by Wako Pure Chemical Industries, Ltd. under the trade names PEG-2000000 and PEG-4000000. Also, under the names of Macrogoal-200, Macrogoal-300, Macrogoal-400, Macrogoal-600, Macrogoal-1000, Macrogoal-1540, Macrogoal-4000, Macrogoal-6000 and Macrogoal-20000 It is sold by Nippon Oil & Fat Co., Ltd.
The weight average molecular weight of the polyethylene glycol used in the present invention is not particularly limited as long as the characteristics of the present invention can be obtained, but is preferably 200 to 600, particularly preferably 200 to 400. A weight average molecular weight of 600 or less is preferable because it becomes liquid at room temperature and can be easily injected.
If the characteristics of the present invention can be obtained, a mixture of two or more PEGs can be used. The outline of PEG, specifications, usage, usage amount and product name are also described in detail in Pharmaceutical Additives Encyclopedia 2007 (edited by Japan Pharmaceutical Additives Association, published by Yakuji Nippo Co., Ltd.).
本発明の組成物におけるポリ乳酸類及び可溶化溶媒の含有量は、本発明の組成物を液体状態とし、本発明に期待される効果が得られるのであれば特に制限はない。本発明の組成物におけるポリ乳酸類の含有量は、通常20〜75質量%、好ましくは25〜65質量％、最も好ましくは33〜50質量％である。本発明の組成物における可溶化溶媒の含有量は、使用するポリ乳酸類の重量平均分子量及び配合量によるが、通常25〜80質量%、好ましくは30〜70質量%、最も好ましくは50〜67質量％である。また、本発明の組成物における可溶化溶媒/ポリ乳酸類の質量比は、通常0.3〜10、好ましくは1〜6、より好ましくは2〜5、最も好ましくは2〜4である。
本発明の組成物は、少なくとも25℃において液状である。The content of the polylactic acid and the solubilizing solvent in the composition of the present invention is not particularly limited as long as the effect of the present invention can be obtained by making the composition of the present invention into a liquid state. The content of polylactic acids in the composition of the present invention is usually 20 to 75% by mass, preferably 25 to 65% by mass, and most preferably 33 to 50% by mass. The content of the solubilizing solvent in the composition of the present invention depends on the weight average molecular weight and blending amount of the polylactic acid used, but is usually 25 to 80% by mass, preferably 30 to 70% by mass, and most preferably 50 to 67%. % By mass. The mass ratio of the solubilizing solvent / polylactic acid in the composition of the present invention is usually 0.3 to 10, preferably 1 to 6, more preferably 2 to 5, and most preferably 2 to 4.
The composition of the present invention is liquid at least at 25 ° C.
本発明の組成物に、薬物をさらに含有させることができる。このような薬物としては、例えば、アムホテリシンＢ、フルコナゾール、硝酸ミコナゾール、コリスチンメタンスルホン酸ナトリウム、カルベニシリンナトリウム、硫酸ゲンタマイシン、エリスロマイシン、アジスロマイシン、トブラマイシン、カナマイシン、塩酸シプロフロキサシン、塩酸ロメフロキサシン、オフロキサシン、レボフロキサシン、トシル酸パズフロキサシン、ガチフロキサシン、塩酸モキシフロキサシン、アシクロビル、ガンシクロビル、シドフォビル、ソリブジン、トリフルオロチミジン、ドキシサイクリンなどのテトラサイクリン類などの抗感染剤、アシタザノラスト、塩酸レボカバスチン、フマル酸ケトチフェン、クロモグリク酸ナトリウム、トラニラストなどの抗アレルギー薬、リン酸ベタメタゾン、デキサメタゾン、ヒドロコルチゾン、ジクロフェナクナトリウ厶、プラノプロフェン、トリアムシノロンアセトニド、インドメタシン、ブロムフェナックナトリウム、メロキシカム、ロルノキシカム、シクロスポリン、タクロリムスなどの抗炎症剤、マレイン酸チモロール、塩酸ブナゾシン、ラタノプロスト、ニプラジロール、塩酸カルテオロール、イソプロピルウノプロストン、塩酸ドルゾラミド、ブリンゾラミドなどの緑内障治療薬、アミノエチルスルホン酸、アミノ酸、コンドロイチン硫酸ナトリウム、ヒアルロン酸ナトリウム、イルソグラジン、ドキシサイクリンなどのテトラサイクリン類などの角膜障害あるいはドライアイ治療剤、のペガプタニブナトリウム、ラニビズマブ、アフリベルセプト、ベバシズマブなどの抗VEGF薬、カンデサルタン、アジルサルタン、テルミサルタン、ロサルタン、アジルサルタンなどのアンジオテンシンII受容体拮抗薬などを挙げることができる。これら薬物の本発明の組成物における含有量は、期待される薬効が得られる濃度であれば特に制限はない。例えば、組成物中、0.01〜10質量％程度である。 The composition of the present invention can further contain a drug. Examples of such drugs include amphotericin B, fluconazole, miconazole nitrate, sodium colistin methanesulfonate, carbenicillin sodium, gentamicin sulfate, erythromycin, azithromycin, tobramycin, kanamycin, ciprofloxacin hydrochloride, romefloxacin hydrochloride, ofloxacin, levofloxacin, Anti-infectives such as tetracyclines such as pazufloxacin, gatifloxacin tosilate, moxifloxacin hydrochloride, acyclovir, ganciclovir, cidofovir, sorivudine, trifluorothymidine, doxycycline, acitazanolast, levocabastine hydrochloride, ketotifen fumarate, cromoglycic acid Antiallergic drugs such as sodium and tranilast, betamethasone phosphate, dexamethas , Hydrocortisone, diclofenac natripodium, pranoprofen, triamcinolone acetonide, indomethacin, bromfenac sodium, meloxicam, lornoxicam, cyclosporine, tacrolimus and other anti-inflammatory agents, timolol maleate, bunazosin hydrochloride, latanoprost, nipradilol hydrochloride, carteolol hydrochloride Pega, a therapeutic agent for glaucoma, such as isopropyl unoprostone, dorzolamide hydrochloride, brinzolamide, a therapeutic agent for corneal disorders such as aminoethyl sulfonic acid, amino acid, sodium chondroitin sulfate, sodium hyaluronate, irsogladine, doxycycline, etc. Candesartan, an anti-VEGF drug such as ptanib sodium, ranibizumab, aflibercept, bevacizumab Azilsartan can include telmisartan, losartan, and the like angiotensin II receptor antagonists such as azilsartan. The content of these drugs in the composition of the present invention is not particularly limited as long as it is a concentration at which an expected medicinal effect is obtained. For example, it is about 0.01-10 mass% in a composition.
本発明の組成物には、このほか必要に応じて緩衝剤、等張化剤、ｐＨ調整剤、安定化剤、防腐剤、可溶化剤及び増粘剤等の添加剤を、本発明の効果を損なわない範囲で加えることができる。 In addition to the composition of the present invention, additives such as buffers, isotonic agents, pH adjusters, stabilizers, preservatives, solubilizers, thickeners and the like are added as necessary. Can be added to the extent that does not impair.
本発明の組成物は、人体に有害な物質を使用することなく調製することができる。人体に有害な物質としては、例えば、ジクロロメタン、エタノール、メタノール又はアセトニトリル等があげられる。 The composition of the present invention can be prepared without using substances harmful to the human body. Examples of substances harmful to the human body include dichloromethane, ethanol, methanol, and acetonitrile.
次に、本発明の組成物の製造法の一例を記述する。所定量のポリ乳酸類をビーカーに秤量し、ここに所定量の可溶化溶媒を加える。水浴中で加温し（好ましくは100℃以下）、ポリ乳酸類を溶解させ、均一になるまで撹拌し、本発明の組成物を得る。本発明の組成物にさらに薬物を含有させる場合、薬物はポリ乳酸と一緒に添加しても又はポリ乳酸類の溶解後に添加してもよく、溶解又は分散させ、均一になるまで撹拌し、本発明の組成物を得る。本発明の組成物を所定量バイアルに充填し、オートクレーブで滅菌することで製品とすることもできる。 Next, an example of a method for producing the composition of the present invention will be described. A predetermined amount of polylactic acid is weighed into a beaker, and a predetermined amount of solubilizing solvent is added thereto. Heat in a water bath (preferably 100 ° C. or less) to dissolve the polylactic acid and stir until uniform to obtain the composition of the present invention. When the composition of the present invention further contains a drug, the drug may be added together with the polylactic acid or after the polylactic acid is dissolved, dissolved or dispersed, stirred until uniform, An inventive composition is obtained. A predetermined amount of the composition of the present invention can be filled into a vial and sterilized with an autoclave to obtain a product.
本発明の組成物の使用方法は、特に制限はないが、例えば、筋肉内注射、関節腔内注射、軟組織内注射、腱内注射、滑液嚢内注入、硬膜外注射、腹腔内注入、局所皮内注射、結膜下注射、鼻腔内注入、副鼻腔内注入、鼻甲介内注射、鼻茸内注射、中耳腔内注入、皮下注射、硝子体内注射、強膜内注入、テノン嚢内注入又は涙点内注入などが挙げられる。本発明の組成物はまた、水中で成型した後、体内に埋め込むことにより使用することもできる。 The method of using the composition of the present invention is not particularly limited. For example, intramuscular injection, intraarticular injection, soft tissue injection, intratendon injection, intrasynovial injection, epidural injection, intraperitoneal injection, local injection Intradermal injection, subconjunctival injection, intranasal injection, intranasal injection, intranasal turbinate injection, intranasal injection, intraauricular injection, subcutaneous injection, intravitreal injection, intrascleral injection, intratenon injection or punctum Internal injection etc. are mentioned. The composition of the present invention can also be used by molding in water and then implanting it in the body.
以下に、本発明を具体的に説明するが、本発明はこれらのみに限定されるものではない。 The present invention will be specifically described below, but the present invention is not limited to these.
実施例1〜12
ポリ乳酸類として、以下に示す多木化学株式会社製の製品を使用した。
・DLG-80 DL-乳酸-グリコール酸共重合体
(D−乳酸とL-乳酸のモル比が１：１で、乳酸含有量は80mol%)
重量平均分子量 0.5万、1万、2万、3万、5万
・DLG-50 DL-乳酸-グリコール酸共重合体
(D−乳酸とL-乳酸のモル比が１：１で、乳酸含有量は50mol%)
重量平均分子量 1万
・L-100-100 L-乳酸100%ポリマー 重量平均分子量 10万
可溶化溶媒として、以下に示す製品を使用した。
・PEG300、400 和光純薬製ポリエチレングリコール300、400Examples 1-12
The following products manufactured by Taki Chemical Co., Ltd. were used as polylactic acids.
・ DLG-80 DL-lactic acid-glycolic acid copolymer
(The molar ratio of D-lactic acid and L-lactic acid is 1: 1, and the lactic acid content is 80 mol%)
Weight average molecular weight: 5,000, 10,000, 20,000, 30,000, 50,000 DLG-50 DL-lactic acid-glycolic acid copolymer
(The molar ratio of D-lactic acid and L-lactic acid is 1: 1, and the lactic acid content is 50 mol%)
Weight average molecular weight 10,000 / L-100-100 L-lactic acid 100% polymer Weight average molecular weight 100,000 The following products were used as solubilizing solvents.
・ PEG300, 400 Wako Pure Chemicals Polyethylene Glycol 300, 400
所定量のポリ乳酸類をビーカーに入れ、ここに所定量の可溶化溶媒を添加した。これを80〜90℃の水浴中で加温し、ポリ乳酸類が可溶化溶媒に溶解し、均一になるまでマグネチックスターラーで撹拌した。そして、室温まで放冷し、本発明の組成物(実施例1〜10)を得た。 A predetermined amount of polylactic acid was put in a beaker, and a predetermined amount of solubilizing solvent was added thereto. This was heated in a water bath at 80 to 90 ° C., and the polylactic acid was dissolved in the solubilizing solvent and stirred with a magnetic stirrer until uniform. And it stood to cool to room temperature, and obtained the composition (Examples 1-10) of this invention.
試験例1 (本発明の組成物のリン酸緩衝食塩水（PBS）中への注入性とPBS中での滞留性の評価)
実施例1〜10で得られた本発明の組成物を、2.5mLのロック式プラスチックシリンジに0.5mL充填した。そして、所定の注射針(21、27又は30ゲ−ジ)を装着し、5mLのPBSが入ったネジ口バイアル瓶に、注射針をPBSに浸しながら、本発明の組成物0.1mLをゆっくりと注入した。PBS中に注入した本発明の組成物は、直ちに乳白色に固化し、リボン状又は塊状になり、バイアル瓶の底部に沈降した。そして、バイアル瓶に蓋をして、37℃で保管した。24時間後、バイアル瓶中のPBSを、固化した本発明の組成物が流失しないように注意しながら、全量廃棄した。ここに、別途37℃に加温しておいたフレッシュなPBS 5mLを追加した。PBSの廃棄及び追加を、バイアル瓶中で固化した本発明の組成物が完全に分解消失するまで２４時間毎に繰り返し、消失までに要した月数を0.5箇月単位で記録した。Test Example 1 (Evaluation of Injectability of the Composition of the Present Invention into Phosphate Buffered Saline (PBS) and Retention in PBS)
0.5 mL of a 2.5 mL locking plastic syringe was filled with the composition of the present invention obtained in Examples 1-10. Then, a predetermined injection needle (21, 27 or 30 gauge) is attached, and 0.1 mL of the composition of the present invention is slowly added while the injection needle is immersed in PBS in a screw-mouth vial containing 5 mL of PBS. Injected. The composition of the present invention injected into PBS immediately solidified to milky white, became a ribbon or a lump, and settled to the bottom of the vial. The vial was capped and stored at 37 ° C. After 24 hours, all of the PBS in the vial was discarded, taking care not to wash away the solidified composition of the invention. To this, 5 mL of fresh PBS that had been separately heated to 37 ° C. was added. The disposal and addition of PBS was repeated every 24 hours until the composition of the present invention solidified in the vial was completely decomposed and disappeared, and the number of months required for disappearance was recorded in units of 0.5 months.
表1に、本発明の組成物の組成、PBSに注入時に使用した注射針のゲージ、37℃のPBS中から本発明の組成物が分解消失するまでの期間を示した。
本発明の組成物の調製に用いたポリ乳酸類は、いずれも100℃以下の温度で可溶化溶媒に溶解することが示された。また、いずれの組成物も注射針を通過し、注入可能なことが示された。さらに、本発明の組成物をPBS中に注入した場合、水分と可溶化溶媒の置換により、組成物中のポリ乳酸類が固化することが示された。そして、固化した組成物は37℃のPBS中で徐々に分解し、0.5〜2箇月の長期間滞留した後、完全に消失することが示された。Table 1 shows the composition of the composition of the present invention, the gauge of the injection needle used at the time of injection into PBS, and the period until the composition of the present invention decomposes and disappears from PBS at 37 ° C.
All of the polylactic acids used for the preparation of the composition of the present invention were shown to dissolve in the solubilizing solvent at a temperature of 100 ° C. or lower. Moreover, it was shown that any composition can be injected through the injection needle. Furthermore, when the composition of the present invention was injected into PBS, it was shown that the polylactic acids in the composition were solidified by substitution of moisture and solubilizing solvent. It was shown that the solidified composition gradually decomposed in PBS at 37 ° C. and disappeared completely after a long-term residence of 0.5 to 2 months.
実施例11
ビーカーに、DLG-50(重量平均分子量 1万)0.6gを、イルソグラジン0.03gをいれた。ここに、PEG-400を0.5g添加した。これを80〜90℃の水浴に浸け加温し、DLG-50とイルソグラジンがPEG-400に溶解し、均一になるまでマグネチックスターラーで撹拌した。そして、室温まで放冷し、本発明の組成物(実施例11)を得た。Example 11
In a beaker, 0.6 g of DLG-50 (weight average molecular weight 10,000) and 0.03 g of irsogladine were added. Here, 0.5 g of PEG-400 was added. This was immersed in an 80-90 ° C. water bath and heated, and DLG-50 and irsogladine were dissolved in PEG-400 and stirred with a magnetic stirrer until uniform. Then, it was allowed to cool to room temperature to obtain the composition of the present invention (Example 11).
試験例2 (本発明の組成物のPBS中への薬物放出の持続性評価)
実施例11で得られた本発明の組成物を2.5mLのロック式プラスチックシリンジに0.5mL充填した。そして、そのシリンジに23ゲージの注射針を装着し、5mLのPBSが入ったネジ口バイアル瓶に、注射針をPBSに浸しながら、本発明の組成物を0.1mLゆっくりと注入した。PBS中に注入した本発明の組成物は直ちに乳白色に固化し、バイアル瓶の底部に沈降した。そして、バイアル瓶に蓋をして、37℃で保管した。1週間後、バイアル瓶中のPBSを、固化した本発明の組成物が流失しないように注意しながら、1mL採取した。バイアル瓶に、別途37℃に加温しておいたフレッシュなPBS 1mLを追加した。PBSの採取及び追加を１週間毎に16週間繰り返した。採取した1mLのPBS中のイルソグラジン濃度をHPLCで測定した。Test Example 2 (Evaluation of persistence of drug release into the PBS of the composition of the present invention)
0.5 mL of a 2.5 mL lock plastic syringe was filled with the composition of the present invention obtained in Example 11. Then, a 23-gauge injection needle was attached to the syringe, and 0.1 mL of the composition of the present invention was slowly injected into a screw-mouth vial containing 5 mL of PBS while the injection needle was immersed in PBS. The composition of the invention injected into PBS immediately solidified to milky white and settled to the bottom of the vial. The vial was capped and stored at 37 ° C. After 1 week, 1 mL of PBS in the vial was collected taking care not to wash away the solidified composition of the invention. To the vial, 1 mL of fresh PBS that had been separately heated to 37 ° C. was added. PBS collection and addition was repeated every week for 16 weeks. The irsogladine concentration in 1 mL of collected PBS was measured by HPLC.
図1に、PBS中のイルソグラジンの濃度推移を示した。初期から14週間までほぼ一定の薬物濃度を示した。毎週PBSを採取しているにもかかわらず薬物濃度が一定なのは、PBSの採取によりバイアル瓶中のPBSから取り除いた薬物量だけ、固化した組成物からPBS中に薬物が徐々に放出されたことを示している。 FIG. 1 shows the change in the concentration of irsogladine in PBS. The drug concentration was almost constant from the beginning to 14 weeks. The drug concentration is constant despite the fact that PBS is collected every week because the drug was gradually released into the PBS from the solidified composition by the amount of drug removed from the PBS in the vial by collecting PBS. Show.
実施例12
ビーカーに、DLG-80(重量平均分子量 1万)3gをいれた。ここにPEG-300を6g添加した。これを80〜90℃の水浴に浸け加温し、DLG-80がPEG-300に溶解し、均一になるまでマグネチックスターラーで撹拌した。そして、室温まで放冷し、本発明の組成物を得た。これを20mLのバイアルに充填した。密栓後、オートクレーブ滅菌を実施し、放冷した。
これを2.5mLのロック式プラスチックシリンジに2.5mL無菌的に充填した。そして、そのシリンジに21ゲージの注射針を装着した。Example 12
In a beaker, 3 g of DLG-80 (weight average molecular weight 10,000) was placed. 6g of PEG-300 was added here. This was immersed in a water bath at 80 to 90 ° C. and heated, and DLG-80 was dissolved in PEG-300 and stirred with a magnetic stirrer until uniform. And it stood to cool to room temperature, and obtained the composition of this invention. This was filled into 20 mL vials. After sealing, autoclave sterilization was performed and the mixture was allowed to cool.
This was aseptically filled into a 2.5 mL locking plastic syringe. A 21-gauge needle was attached to the syringe.
試験例3 (ラットを用いた皮下投与による本発明の組成物の滞留性と刺激性評価)
実施例12で得られた本発明の組成物0.5mLを、ラット(BN/CrlCrlj系統、雄性)の頚部皮下に投与した。投与1日後及び14日後に、投与部位の頚部皮膚を切開し、固化した実施例12の組成物の残存の程度、形状及び皮下の炎症の有無を肉眼で確認した。また、投与14日後にラットの採血を行い、血清中のアルカリフォスファターゼ、ロイシンアミノペプチターゼ及びクレアチンフォスフォキナーゼについて血液生化学的検査を実施した。Test Example 3 (Evaluation of retention and irritation of the composition of the present invention by subcutaneous administration using rats)
0.5 mL of the composition of the present invention obtained in Example 12 was administered subcutaneously to the neck of a rat (BN / CrlCrlj strain, male). One day and 14 days after administration, the cervical skin at the administration site was incised, and the degree and shape of the solidified composition of Example 12 and the presence or absence of subcutaneous inflammation were confirmed with the naked eye. Further, 14 days after administration, blood was collected from rats, and blood biochemical tests were performed for alkaline phosphatase, leucine aminopeptidase and creatine phosphokinase in serum.
図2に、投与1日後及び14日後の投与部位における本発明の組成物の形状について示した。本発明の組成物は、皮下投与後固化し、投与部位に滞留することが示された。投与1日後と投与14日後における本発明の組成物の大きさは、見かけ上大きな差は見受けられなかった。このことから、本発明の組成物は投与後長期間にわたって投与部位に留まることが示された。また、見かけ上、炎症などの有害な事象は観察されなかった。さらに、投与14日後の血液生化学的検査結果においても、対照とした無投与群に比較して差はなく、本発明の組成物は安全であることが示された。
以上の結果より、本発明の組成物は、注射による投与が可能なこと、投与後投与部位で固化すること、投与部位に長時間滞留すること、及び安全性が非常に高いことが示された。図２を参照。FIG. 2 shows the shape of the composition of the present invention at the administration site 1 day and 14 days after administration. The composition of the invention has been shown to solidify after subcutaneous administration and remain at the site of administration. There was no apparent difference in the size of the composition of the present invention 1 day after administration and 14 days after administration. From this, it was shown that the composition of the present invention stays at the administration site for a long period after administration. Apparently, no adverse events such as inflammation were observed. Furthermore, the results of blood biochemical examination 14 days after administration were not different from the non-administration group as a control, indicating that the composition of the present invention was safe.
From the above results, it was shown that the composition of the present invention can be administered by injection, solidifies at the administration site after administration, stays at the administration site for a long time, and is very safe. . See FIG.
製剤例1(涙点内注入剤)
実施例11と同様にして調製したイルソグラジンを含む本発明の組成物1mLを10mLのバイアルに充填した。密栓後、オートクレーブ滅菌を実施し、放冷し、涙点内注入剤とした。
涙点内への投与に当たっては、バイアルからシリンジなどに本発明の組成物を無菌的に移して使用される。Formulation Example 1 (Intrapunctum injection)
A 10 mL vial was filled with 1 mL of the composition of the invention containing irsogladine prepared as in Example 11. After sealing, autoclave sterilization was performed and the mixture was allowed to cool to obtain an intrapunctum injection.
For administration into the punctum, the composition of the present invention is aseptically transferred from a vial to a syringe or the like.
製剤例2(筋肉内注射剤、関節腔内注射剤、軟組織内注射剤、腱内注射剤、滑液嚢内注入剤、硬膜外注射剤、腹腔内注入剤、局所皮内注射剤、結膜下注射剤、鼻腔内注入剤、副鼻腔内注入剤、鼻甲介内注射剤、鼻茸内注射剤、中耳腔内注入剤、皮下注射剤)
DLG-80(重量平均分子量 1万)3g及びデキサメタゾン0.1gに、PEG-300 6gを添加した。これを80〜90℃の水浴に浸け加温し、DLG-80とデキサメタゾンがPEG-300に溶解し、均一になるまでマグネチックスターラーで撹拌した。そして、室温まで放冷し、本発明の組成物を得た。この2mLを10mLのバイアルに充填した。密栓後、オートクレーブ滅菌を実施し、放冷し、筋肉内注射剤、関節腔内注射剤、軟組織内注射剤、腱内注射剤、滑液嚢内注入剤、硬膜外注射剤、腹腔内注入剤、局所皮内注射剤、結膜下注射剤、鼻腔内注入剤、副鼻腔内注入剤、鼻甲介内注射剤、鼻茸内注射剤、中耳腔内注入剤又は皮下注射剤とした。
投与に当たっては、バイアルからシリンジなどに本発明の組成物を無菌的に移して使用される。Formulation Example 2 (Intramuscular injection, intraarticular injection, soft tissue injection, intratendon injection, synovial capsule injection, epidural injection, intraperitoneal injection, local intradermal injection, subconjunctival Injection, intranasal injection, intranasal injection, intranasal injection, intranasal injection, intraauricular injection, subcutaneous injection)
6 g of PEG-300 was added to 3 g of DLG-80 (weight average molecular weight 10,000) and 0.1 g of dexamethasone. This was immersed in a water bath at 80 to 90 ° C. and heated, and DLG-80 and dexamethasone were dissolved in PEG-300 and stirred with a magnetic stirrer until uniform. And it stood to cool to room temperature, and obtained the composition of this invention. 2 mL of this was filled into a 10 mL vial. After sealing, autoclave sterilization is performed, and then allowed to cool. Intramuscular injection, intraarticular injection, soft tissue injection, intratendon injection, synovial sac injection, epidural injection, intraperitoneal injection Local intradermal injections, subconjunctival injections, intranasal injections, intranasal injections, intranasal injections, intranasal injections, intraauricular injections or subcutaneous injections.
For administration, the composition of the present invention is aseptically transferred from a vial to a syringe or the like.
製剤例3(硝子体注射剤、強膜内注入剤、テノン嚢内注入剤)
DLG-80(重量平均分子量 2万)1g、DLG-50(重量平均分子量 1万)2g及びトリアムシノロンアセトニド0.1gに、PEG-300 6gを添加した。これを80〜90℃の水浴に浸け加温し、DLG-80及びDLG-50とトリアムシノロンアセトニドがPEG-300に溶解し、均一になるまでマグネチックスターラーで撹拌した。そして、室温まで放冷し、本発明の組成物を得た。この2mLを10mLのバイアルに充填した。密栓後、オートクレーブ滅菌を実施し、放冷し、硝子体注射剤、強膜内注入剤又はテノン嚢内注入剤とした。
投与に当たっては、バイアルからシリンジなどに本発明の組成物を無菌的に移して使用される。Formulation Example 3 (Vitreous injection, intrascleral injection, intratenon injection)
6 g of PEG-300 was added to 1 g of DLG-80 (weight average molecular weight 20,000), 2 g of DLG-50 (weight average molecular weight 10,000), and 0.1 g of triamcinolone acetonide. This was immersed in a water bath of 80 to 90 ° C. and heated, and DLG-80, DLG-50 and triamcinolone acetonide were dissolved in PEG-300 and stirred with a magnetic stirrer until uniform. And it stood to cool to room temperature, and obtained the composition of this invention. 2 mL of this was filled into a 10 mL vial. After sealing, autoclave sterilization was performed and the mixture was allowed to cool to obtain a vitreous injection, an intrascleral injection, or a Tenon sac injection.
For administration, the composition of the present invention is aseptically transferred from a vial to a syringe or the like.
製剤例4(硝子体注射剤、テノン嚢内注入剤)
DLG-80(重量平均分子量 1万)1g及びDLG-50(重量平均分子量 1万)1g、カンデサルタンシレキセチル0.2gに、PEG-300 4gを添加した。これを80〜90℃の水浴に浸け加温し、DLG-80とカンデサルタンシレキセチルがPEG-300に溶解し、均一になるまでマグネチックスターラーで撹拌した。そして、室温まで放冷し、本発明の組成物を得た。この1mLを10mLのバイアルに充填した。密栓後、オートクレーブ滅菌を実施し、放冷し、硝子体注射剤及びテノン嚢内注入剤とした。
投与に当たっては、バイアルからシリンジなどに本発明の組成物を無菌的に移して使用される。Formulation Example 4 (vitreous injection, intratenon injection)
To 1 g of DLG-80 (weight average molecular weight 10,000) and 1 g of DLG-50 (weight average molecular weight 10,000) and 0.2 g of candesartan cilexetil were added 4 g of PEG-300. This was immersed in a water bath at 80 to 90 ° C. and heated, and DLG-80 and candesartan cilexetil were dissolved in PEG-300 and stirred with a magnetic stirrer until uniform. And it stood to cool to room temperature, and obtained the composition of this invention. This 1 mL was filled into a 10 mL vial. After sealing, autoclave sterilization was performed and the mixture was allowed to cool to obtain a vitreous injection and a Tenon sac injection.
For administration, the composition of the present invention is aseptically transferred from a vial to a syringe or the like.
製剤例5(筋肉内注射剤、関節腔内注射剤、硝子体注射剤、テノン嚢内注入剤)
DLG-80(重量平均分子量 1万)2g及びジクロフェナクナトリウム0.2gに、PEG-300 4gを添加した。これを80〜90℃の水浴に浸け加温し、DLG-80とジクロフェナクナトリウムがPEG-300に溶解し、均一になるまでマグネチックスターラーで撹拌した。そして、室温まで放冷し、本発明の組成物を得た。この1mLを10mLのバイアルに充填した。密栓後、オートクレーブ滅菌を実施し、放冷し、筋肉内注射剤、関節腔内注射剤、硝子体注射剤又はテノン嚢内注入剤とした。
投与に当たっては、バイアルからシリンジなどに本発明の組成物を無菌的に移して使用される。Formulation Example 5 (Intramuscular injection, intraarticular injection, vitreous injection, intratenon injection)
4 g of PEG-300 was added to 2 g of DLG-80 (10,000 weight average molecular weight) and 0.2 g of diclofenac sodium. This was immersed in an 80-90 ° C. water bath and heated, and DLG-80 and diclofenac sodium were dissolved in PEG-300 and stirred with a magnetic stirrer until uniform. And it stood to cool to room temperature, and obtained the composition of this invention. This 1 mL was filled into a 10 mL vial. After sealing, autoclave sterilization was performed and the mixture was allowed to cool to obtain an intramuscular injection, an intraarticular injection, a vitreous injection or an intratenon injection.
For administration, the composition of the present invention is aseptically transferred from a vial to a syringe or the like.
実施例13〜52
ポリ乳酸類として、以下に示す多木化学株式会社製の製品を使用した。
・DLG-80 DL-乳酸-グリコール酸共重合体
(D−乳酸とL-乳酸のモル比が１：１で、乳酸含有量は80mol%)
重量平均分子量 0.5万、1万、2万
・DLG-50 DL-乳酸-グリコール酸共重合体
(D−乳酸とL-乳酸のモル比が１：１で、乳酸含有量は50mol%)
重量平均分子量 1万
・DG-80 D-乳酸-グリコール酸共重合体(乳酸はD−乳酸だけからなり、
L-乳酸を含まない。
乳酸含有量は80mol%)
重量平均分子量 1万
・LG-80 L-乳酸-グリコール酸共重合体(乳酸はL−乳酸だけからなり、
D-乳酸を含まない。
乳酸含有量は80mol%)
重量平均分子量 1万Examples 13-52
The following products manufactured by Taki Chemical Co., Ltd. were used as polylactic acids.
・ DLG-80 DL-lactic acid-glycolic acid copolymer
(The molar ratio of D-lactic acid and L-lactic acid is 1: 1, and the lactic acid content is 80 mol%)
Weight average molecular weight: 5,000, 10,000, 20,000DLG-50 DL-lactic acid-glycolic acid copolymer
(The molar ratio of D-lactic acid and L-lactic acid is 1: 1, and the lactic acid content is 50 mol%)
Weight average molecular weight 10,000 ・ DG-80 D-lactic acid-glycolic acid copolymer (lactic acid consists only of D-lactic acid,
Does not contain L-lactic acid.
(Lactic acid content is 80mol%)
Weight average molecular weight 10,000 ・ LG-80 L-lactic acid-glycolic acid copolymer (lactic acid consists only of L-lactic acid,
Does not contain D-lactic acid.
(Lactic acid content is 80mol%)
Weight average molecular weight 10,000
可溶化溶媒として、以下に示す製品を使用した。
・PEG300、400 和光純薬製ポリエチレングリコール300、400The following products were used as solubilizing solvents.
・ PEG300, 400 Wako Pure Chemicals Polyethylene Glycol 300, 400
所定量のポリ乳酸類をビーカーに入れ、ここに所定量の可溶化溶媒を添加した。これを80〜90℃の水浴中で加温し、ポリ乳酸類が可溶化溶媒に溶解し、均一になるまでマグネチックスターラーで撹拌した。そして、室温まで放冷し、本発明の組成物(実施例13〜54)を得た。 A predetermined amount of polylactic acid was put in a beaker, and a predetermined amount of solubilizing solvent was added thereto. This was heated in a water bath at 80 to 90 ° C., and the polylactic acid was dissolved in the solubilizing solvent and stirred with a magnetic stirrer until uniform. And it stood to cool to room temperature, and obtained the composition (Examples 13-54) of this invention.
試験例4 (本発明の組成物のPBS中への注入性とPBS中での滞留性の評価)
実施例13〜51で得られた本発明の組成物を2.5mLのロック式プラスチックシリンジに0.5mL充填した。そして、そのシリンジに18ゲージの注射針を装着し、5mLのPBSが入ったネジ口バイアル瓶に、注射針をPBSに浸さずに、本発明の組成物を1滴ゆっくりと滴下した。PBS中に滴下した本発明の組成物は直ちに乳白色に固化し、塊状になり、バイアル瓶の底部に沈降した。
そして、バイアル瓶に蓋をして、37℃で保管した。1週間に5回(最低24時間以上の間隔をあけて)、固化した本発明の組成物が流失しないように注意しながら、バイアル瓶中のPBSを4mL廃棄した。バイアル瓶に、別途37℃に加温しておいたフレッシュなPBS 4mLを追加した。PBSの廃棄及び追加を、バイアル瓶中の本発明の組成物が完全に分解消失するまで繰り返し、分解消失までに要した時間を週単位で記録した。Test Example 4 (Evaluation of injectability of the composition of the present invention into PBS and retention in PBS)
0.5 mL of a 2.5 mL locking plastic syringe was filled with the composition of the present invention obtained in Examples 13-51. Then, an 18-gauge injection needle was attached to the syringe, and one drop of the composition of the present invention was slowly dropped into a screw-mouth vial containing 5 mL of PBS without immersing the injection needle in PBS. The composition of the present invention dripped into PBS immediately solidified to milky white, became a mass and settled to the bottom of the vial.
The vial was capped and stored at 37 ° C. Five times a week (at least 24 hours apart), 4 mL of PBS in the vial was discarded, taking care not to wash away the solidified composition of the invention. To the vial, 4 mL of fresh PBS that had been separately heated to 37 ° C. was added. The disposal and addition of PBS was repeated until the composition of the present invention in the vial was completely decomposed and the time taken to disappear was recorded in weeks.
表2〜8に、実施例13〜51で得られた本発明の組成物の組成、37℃のPBS中から本発明の組成物が分解消失するまでの時間を示した。
本発明の組成物の調製に用いたポリ乳酸類は、いずれも100℃以下の温度で可溶化溶媒に溶解することが示された。また、いずれの組成物も注射針を通過し、注入可能なことが示された。さらに、本発明の組成物をPBS中に滴下した場合、PBS中の水分と本発明の組成物中の可溶化溶媒の置換により、本発明の組成物中のポリ乳酸類が固化することが示された。そして、固化した本発明の組成物は37℃のPBS中で徐々に分解し、2〜9週間の長期間滞留した後、完全に消失することが示された。
また、本発明の組成物の組成とPBS中での分解速度について概ね次のような傾向があることが示された。
・ポリ乳酸類の乳酸の光学活性について
D-乳酸の分解が遅く、次にL-乳酸、D-乳酸とL-乳酸の混在物の分解が速かった。
・乳酸とグリコール酸のモル比について
乳酸のモル比が高いほど分解が遅かった。
・ポリ乳酸類の分子量について
ポリ乳酸類の重量平均分子量が高いほど分解が遅かった。
・ポリ乳酸類とPEG(可溶化溶媒)の質量比について
ポリ乳酸類の含有量が多いほど分解が遅かった。
以上のように、用いるポリ乳酸類の種類と可溶化溶媒の質量比等を調製することで、ポリ乳酸類の分解速度を制御することが可能であることが示された。これより、本発明の組成物に薬物を配合した場合には、薬物の徐放性がポリ乳酸類の分解に依存すると考えられるため、薬物の放出速度も制御することが可能である。Tables 2 to 8 show the compositions of the compositions of the present invention obtained in Examples 13 to 51 and the time until the composition of the present invention decomposes and disappears from PBS at 37 ° C.
All of the polylactic acids used for the preparation of the composition of the present invention were shown to dissolve in the solubilizing solvent at a temperature of 100 ° C. or lower. Moreover, it was shown that any composition can be injected through the injection needle. Furthermore, it is shown that when the composition of the present invention is dropped into PBS, the polylactic acids in the composition of the present invention are solidified by replacing the water in PBS with the solubilizing solvent in the composition of the present invention. It was done. And it was shown that the solidified composition of the present invention gradually decomposes in PBS at 37 ° C. and disappears completely after a long-term residence of 2 to 9 weeks.
Further, it was shown that the composition of the present invention and the degradation rate in PBS generally have the following tendencies.
・ About the optical activity of polylactic acid
Decomposition of D-lactic acid was slow, followed by decomposition of L-lactic acid and a mixture of D-lactic acid and L-lactic acid.
-About the molar ratio of lactic acid and glycolic acid The higher the molar ratio of lactic acid, the slower the decomposition.
・ Molecular weight of polylactic acid The higher the weight average molecular weight of polylactic acid, the slower the degradation.
-Mass ratio of polylactic acid to PEG (solubilizing solvent) The higher the polylactic acid content, the slower the degradation.
As described above, it was shown that the degradation rate of polylactic acids can be controlled by adjusting the types of polylactic acids used and the mass ratio of the solubilizing solvent. Thus, when a drug is added to the composition of the present invention, it is considered that the sustained release of the drug depends on the degradation of the polylactic acid, and therefore the drug release rate can be controlled.
実施例52 DLG-80(重量平均分子量 1万)0.2g及び塩酸モキシフロキサシン（以下、MFLXと略称する）0.02gに、PEG300 0.4gを添加した。これを80〜90℃の水浴に浸け加温し、DLG-80とMFLXがPEG-300に溶解し、均一になるまでマグネチックスターラーで撹拌した。そして、室温まで放冷し、本発明の組成物(実施例52)を得た。 Example 52 0.4 g of PEG300 was added to 0.2 g of DLG-80 (weight average molecular weight 10,000) and 0.02 g of moxifloxacin hydrochloride (hereinafter abbreviated as MFLX). This was immersed in an 80-90 ° C. water bath and heated, and DLG-80 and MFLX were dissolved in PEG-300 and stirred with a magnetic stirrer until uniform. And it stood to cool to room temperature, and obtained the composition (Example 52) of this invention.
試験例5 (本発明の組成物のPBS中への薬物放出の持続性評価)
実施例52で得られた本発明の組成物を2.5mLのロック式プラスチックシリンジに充填した。そして、そのシリンジに21ゲージの注射針を装着し、5mLのPBSが入ったネジ口バイアル瓶に、注射針をPBSに浸しながら、本発明の組成物を0.1mLゆっくりと注入した。PBS中に注入した本発明の組成物は、直ちに乳淡黄色に固化し、バイアル瓶の底部に沈降した。そして、バイアル瓶に蓋をして、37℃で保管した。保管1、3、8、14、21、28、35、42及び49日後に、バイアル瓶中のPBSを、固化した本発明の組成物が流失しないように注意しながら4mL採取した。バイアル瓶に、別途37℃に加温しておいたフレッシュなPBS 4mLを追加した。採取した4mLのPBS中のMFLX濃度をHPLCで測定した。
図3にPBS中へのMFLXの放出率の経時変化を示す。放出率は次のように求めた。
放出率(%) =（PBS中に放出されたMFLX総量 / 初めにPBS中に注入したMFLX量）×100
注入1日後までに、添加したMFLXの約半分量がPBS中に放出された。これは本発明の組成物の可溶化溶媒(PEG-300)とPBSが置換するときに、MFLXの一部が可溶化溶媒とともにPBS中に放出されたものと考えられる。その後は、注入49日後までほぼ一定の速度でMFLXが放出され、長期間にわたり薬物が徐放されることが示された。Test Example 5 (Evaluation of drug release persistence in PBS of the composition of the present invention)
The composition of the present invention obtained in Example 52 was filled into a 2.5 mL locking plastic syringe. Then, a 21-gauge injection needle was attached to the syringe, and 0.1 mL of the composition of the present invention was slowly injected into a screw-mouth vial containing 5 mL of PBS while the injection needle was immersed in PBS. The composition of the invention injected into PBS immediately solidified to a pale yellow color and settled to the bottom of the vial. The vial was capped and stored at 37 ° C. After storage 1, 3, 8, 14, 21, 28, 35, 42, and 49 days, 4 mL of PBS in the vial was collected, taking care not to wash away the solidified composition of the invention. To the vial, 4 mL of fresh PBS that had been separately heated to 37 ° C. was added. MFLX concentration in 4 mL of collected PBS was measured by HPLC.
FIG. 3 shows the change over time in the release rate of MFLX into PBS. The release rate was determined as follows.
Release rate (%) = (total amount of MFLX released in PBS / amount of MFLX initially injected into PBS) x 100
By one day after injection, approximately half of the added MFLX was released in PBS. This is considered that a part of MFLX was released into PBS together with the solubilizing solvent when the solubilizing solvent (PEG-300) of the composition of the present invention and PBS were substituted. Thereafter, MFLX was released at a substantially constant rate until 49 days after injection, indicating that the drug was released gradually over a long period of time.
本発明の組成物は、薬物を含有した場合には、医薬品として利用できる。一般的な注射剤として投与可能で、投与部位で長時間にわたり薬物を放出することが可能であるため、頻回投与せずとも長期的な治療効果が期待できる医薬品である。また、安全性が高く、最終的にはすべて生体内で消失するので治療後取り出す必要がない医薬品である。さらに、製造が簡便で、有害な物質を製造に使用せず、多くの薬物に適応可能で、薬物保持量も大きい医薬品である。 The composition of the present invention can be used as a pharmaceutical product when it contains a drug. Since it can be administered as a general injection and can release the drug over a long period of time at the site of administration, it is a pharmaceutical product that can be expected to have a long-term therapeutic effect without frequent administration. In addition, it is a pharmaceutical product that is highly safe and does not need to be taken out after treatment because it eventually disappears in vivo. Furthermore, it is a pharmaceutical product that is easy to manufacture, does not use harmful substances for manufacturing, can be applied to many drugs, and has a large drug retention.
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| US5607686A (en) * | 1994-11-22 | 1997-03-04 | United States Surgical Corporation | Polymeric composition |
| WO1999021908A1 (en) * | 1997-10-29 | 1999-05-06 | Angiotech Pharmaceuticals, Inc. | Polymeric systems for drug delivery and uses thereof |
| JP2003517886A (en) * | 1999-12-22 | 2003-06-03 | サムヤン コーポレイション | Liquid composition of biodegradable block copolymer for drug delivery system and method for producing the same |
| JP2008501757A (en) * | 2004-06-09 | 2008-01-24 | ノバルティス アクチエンゲゼルシャフト | A pharmaceutical composition comprising polyethylene glycol having a molecular weight of less than 600 Daltons |
| JP2011530568A (en) * | 2008-08-12 | 2011-12-22 | ノバルティス アーゲー | Pharmaceutical composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5607686A (en) * | 1994-11-22 | 1997-03-04 | United States Surgical Corporation | Polymeric composition |
| WO1999021908A1 (en) * | 1997-10-29 | 1999-05-06 | Angiotech Pharmaceuticals, Inc. | Polymeric systems for drug delivery and uses thereof |
| JP2003517886A (en) * | 1999-12-22 | 2003-06-03 | サムヤン コーポレイション | Liquid composition of biodegradable block copolymer for drug delivery system and method for producing the same |
| JP2008501757A (en) * | 2004-06-09 | 2008-01-24 | ノバルティス アクチエンゲゼルシャフト | A pharmaceutical composition comprising polyethylene glycol having a molecular weight of less than 600 Daltons |
| JP2011530568A (en) * | 2008-08-12 | 2011-12-22 | ノバルティス アーゲー | Pharmaceutical composition |
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