JP6104390B2 - ミクロスフェアを含む改良された創傷治癒用組成物 - Google Patents
ミクロスフェアを含む改良された創傷治癒用組成物 Download PDFInfo
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/745—Polymers of hydrocarbons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0014—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Inorganic Chemistry (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
比重とは、同体積の水の重量に対する、ある物質の重量を表す。典型的に、比重は25℃で測定される。例えば、水の比重は1である。本発明のいくつかの実施形態において、増粘剤を水担体に溶解して、好適な比重を持つ溶液を作成する。いくつかの特定の実施形態において、好適な比重は、本発明の組成物中のミクロスフェアの比重と同様である。ポリスチレンミクロスフェアの比重は、通常1.05の範囲である。いくつかの特定の実施形態において、水溶性増粘剤は、溶液安定化効果を有する。用語「溶液安定化効果」は、かなり長期間、懸濁液/分散液に残る(即ち、凝固しない)ミクロスフェアことを言うものとする。ここで使用される「かなり長期間」は、増粘剤を含まないミクロスフェアを含む組成物より少なくとも10%、少なくとも15%、少なくとも20%、少なくとも30%、少なくとも40%または少なくとも50%長い期間と関連する。ここで開示される前記溶液安定化効果は、少なくとも3か月間保たれる。
本発明の組成物中のミクロスフェアは、いかなる薬剤または治療用物質をさらに添加または包含することなく、創傷の治癒を促進することができる。該ミクロスフェアは、治療効果を生み出すために、変質やその他の化学変化をせず、他の異なる有効成分の担体として単に機能するというよりはむしろ、本発明の組成物の有効成分であると考えられる。
いくつかの特定の実施形態において、本発明の医薬組成物は、それを必要とする被検者の創傷の治療に有用である。
材料と方法
動物:11匹のスプレーグ・ドーリーラット(雌、250〜300g、ハーランラボラトリーズ(Harlan Laboratories)、エルサレム、イスラエル)
試験品目:0.025%ポリスチレンミクロスフェア注射用水(WFI)。
材料
麻酔混合物:1mLのケタミン(100mg/ml、フォート・ドッジアニマルヘルス(Fort Dodge Animal Health)、フォート・ドッジ、米国)、1mLのキシラジン(20mg/ml、ユーロペット(Europet))、および13mLの0.9%NaClの混合物。
無痛化剤:ブプリノルフィン(Buprinorphine)(0.3mg/ml、ベットマーケット(VetMarket)、ペタク・チクヴァ、イスラエル)。3.3mlのブプリノルフィンを1リットルの飲用水で希釈した。
0.025%ポリスチレンビーズの塩水。治療溶液を同じ白色のポリプロピレン点耳液15mL容器に供給した。
ラットに番号を付し、別々のケージに入れ、食餌と水を自由摂取させた。ラットに麻酔をかけて、ドレッシングを交換した。
麻酔をかけたラットの背部を剃り、EtOH(70%)で滅菌した。その皮膚を伸ばし、ラットの背部側の2箇所に1×2cmの創傷を付けた。外科用メスとハサミで、筋膜(含まず)まで伸びる全層創傷を切開により作った。
各ラットの左右の創傷を、符号を付けた溶液(創傷部位を完全に覆うように4滴)で治療した。創傷をドレッシングした。実験中、ラットは、飲用水(ブプリノルフィン)で無痛状態にした。
各ドレッシングを除去後、0日目および一日おきに創傷の写真を撮った。
画像分析ソフトを用いて創傷面積を測定した。各創傷の創傷治癒速度を下記式:
により計算した。
ポリスチレンミクロスフェアの注射用水(WFI)または塩水で治療した創傷の創傷閉鎖速度
塩水またはミクロスフェアの塩水溶液で治療した創傷の創傷閉鎖速度と、ポリスチレンミクロスフェアのWFIで治療した創傷とを比較した。実験は、上記詳述した手順に従い、ソロカ医療センター(Soroka Medical Center)で行った。
ラットに麻酔をかけ、背部側に全層創傷を作製した(0日目)。各動物に対して、左側創傷に、5μmの、負に帯電したミクロスフェアを懸濁させたWFIを適用し、右側創傷に塩水を適用した。第2の試験セットでは、左側創傷に、5μmの、ポリスチレンミクロスフェアを懸濁させた塩水を適用し、右側創傷に、5μmの、ポリスチレンミクロスフェアを懸濁させたWFIを適用した。創傷をガーゼ、Kerlexロール、およびドレッシングネットでドレッシングした。一日おきにラットに麻酔をかけ、写真を撮り、治療し、ドレッシングした。Xは、ラットが死んだことを示す。
ポリスチレンミクロスフェア水溶液をベースとした製剤の適用後の創傷閉鎖速度のin vivo評価
この研究の目的は、ポリスチレンミクロスフェアを懸濁させたWFI(0.025%)および22%グリセロールの3つの別個の製剤:(i)pHを調節していない製剤;ii)pH5に調節した製剤;および(iii)pH7に調節した製剤の多数回適用後の創傷閉鎖速度を評価することであった。ダルベッコ改変イーグル培地(DMEM)に懸濁させた負に帯電したミクロスフェア(5μm)を含む製剤を陽性対照として使用した。
Claims (9)
- 負に帯電したポリスチレンミクロスフェア、水、および増粘剤を含む、創傷を治療するための医薬組成物であって、前記増粘剤が、前記組成物の22体積%存在するグリセロールであり、ポリスチレンミクロスフェアとほぼ同様の比重である1.05±0.04の比重を持つ溶液を形成する、医薬組成物。
- 前記ポリスチレンミクロスフェアが、約0.02μm〜約20μmの範囲の直径をもつ、請求項1記載の医薬組成物。
- 前記ポリスチレンミクロスフェアが、前記組成物の約0.001重量%〜約10重量%を構成する、請求項1記載の医薬組成物。
- 前記ポリスチレンミクロスフェアが、治療期間中は生分解性でない、請求項1記載の医薬組成物。
- 前記組成物が、約4.5〜約7.5のpHを有する、請求項1記載の医薬組成物。
- 創傷の治療において使用するための請求項1記載の医薬組成物。
- 前記創傷が、治癒困難な熱傷、外傷、および慢性創傷から選択される、請求項6記載の医薬組成物。
- 前記慢性創傷が、糖尿病性潰瘍、圧迫潰瘍、動脈性潰瘍、静脈性潰瘍、深刻な創傷、外傷後および外科手術による創傷からなる群から選択される、請求項7記載の医薬組成物。
- 前記増粘剤が、約1.05の比重を持つ溶液を形成する、請求項1記載の医薬組成物。
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