JPWO2019167983A1 - 医薬組成物、包装体及びその製造方法 - Google Patents
医薬組成物、包装体及びその製造方法 Download PDFInfo
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- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
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- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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- 239000004328 sodium tetraborate Substances 0.000 description 1
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- 239000007787 solid Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
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- 230000019635 sulfation Effects 0.000 description 1
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- 230000001629 suppression Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
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- 239000012929 tonicity agent Substances 0.000 description 1
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/51—Lyases (4)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
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- A—HUMAN NECESSITIES
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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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- 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
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y402/00—Carbon-oxygen lyases (4.2)
- C12Y402/02—Carbon-oxygen lyases (4.2) acting on polysaccharides (4.2.2)
- C12Y402/0202—Chondroitin-sulfate-ABC endolyase (4.2.2.20)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y402/00—Carbon-oxygen lyases (4.2)
- C12Y402/02—Carbon-oxygen lyases (4.2) acting on polysaccharides (4.2.2)
- C12Y402/02021—Chondroitin-sulfate-ABC exolyase (4.2.2.21)
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y402/00—Carbon-oxygen lyases (4.2)
- C12Y402/02—Carbon-oxygen lyases (4.2) acting on polysaccharides (4.2.2)
- C12Y402/02004—Chondroitin ABC lyase (4.2.2.4), i.e. chondroitinase
Abstract
Description
医薬組成物は、糖分解酵素を有効成分として含む凍結乾燥製剤である。医薬組成物は、力価が0.3ユニット/μg以上である凍結乾燥された糖分解酵素を有効成分として含み、前記糖分解酵素量が2μg以上8μg以下の単位用量製剤である。本明細書において「単位用量」は、1回の投薬のために用意される必要量であり、単位用量製剤は医薬組成物が単位用量で製剤化されてなる。単位用量は、有効量に加えて、1回の投与液調製のために必要な増仕込み量を含み得る。
有効成分: コンドロイチナーゼABC
単位用量あたりの酵素量: 2μg以上7μg以下
酵素力価: 0.36(ユニット/μg)以上1(ユニット/μg)以下
単位用量あたりの酵素活性: 0.9ユニット以上3ユニット以下
適用: 椎間板ヘルニア
有効成分: コンドロイチナーゼABC
単位用量あたりの酵素量: 2μg以上5μg以下
酵素力価: 0.36(ユニット/μg)以上0.5(ユニット/μg)以下
単位用量あたりの酵素活性: 0.9ユニット以上2.5ユニット以下
適用: 椎間板ヘルニア
有効成分: コンドロイチナーゼABC
単位用量あたりの酵素量: 2μg以上5μg以下
酵素力価: 0.36(ユニット/μg)以上0.5(ユニット/μg)以下
単位用量あたりの酵素活性: 0.9ユニット以上2ユニット以下
適用: 椎間板ヘルニア
有効成分: コンドロイチナーゼABC
単位用量あたりの酵素量: 2μg以上5μg以下
酵素力価: 0.36(ユニット/μg)以上0.5(ユニット/μg)以下
単位用量あたりの酵素活性: 1.25以上2ユニット以下
適用: 椎間板ヘルニア
有効成分: コンドロイチナーゼABC
単位用量あたりの酵素量: 3μg以上5μg以下
酵素力価: 0.36(ユニット/μg)以上0.5(ユニット/μg)以下
単位用量あたりの酵素活性: 1.5ユニット
適用: 椎間板ヘルニア
一実施形態では、前記医薬組成物が容器に収容されてなる包装体、およびヘルニア症、リソソーム病、ケロイド、肥厚性瘢痕、筋ジストロフィー、または脊髄損傷の治療のための前記医薬組成物の使用を説明する添付文書又はラベルを含むキットが提供される。
本発明の一側面は、医薬組成物が容器に収容されてなる包装体の製造方法であり、2μg以上8μg以下の糖分解酵素を含む溶液を容器に収容する第1工程と、前記溶液を凍結乾燥して単位用量の医薬組成物を得る第2工程とを含む、製造方法に関する。
1)コンドロイチナーゼABCの調製
コンドロイチナーゼABCは、特開平6−153947号公報に記載の方法に準じて調製した。すなわち、プロテウス・ブルガリスの培養上清から精製することによって製造した。得られたコンドロイチナーゼABCの力価は、0.4U/μgであった。
コンドロイチナーゼABCの酵素活性は以下の方法で測定した。
酵素試料(コンドロイチナーゼABC)を0.01%(w/v)カゼイン試薬(20mMリン酸緩衝液)で4000倍希釈した。この希釈された酵素試料100μLに基質溶液400μL(3mg/mlコンドロイチン硫酸エステルナトリウム(日本薬局方外医薬品規格)、50mM 2−アミノ−2−ヒドロキシメチル−1,3−プロパンジオール、50mM酢酸ナトリウム、pH8)を加えて混和した。溶液を37℃で20分間反応させた後、100℃の水浴中で1分間加熱した。室温まで冷却後、0.05M 塩酸を5.0mL加え、試料溶液を調製した。コンドロイチナーゼABC標準物質を0.01%(w/v)カゼイン試薬で400倍希釈した。この希釈されたコンドロイチナーゼABC標準物質の溶液100μLに対し、試料溶液の調製と同様の操作を行い、標準溶液を調製した。また、0.01%(w/v)カゼイン試薬100μLに対し、試料溶液の調製と同様の操作を行い、対照溶液を調製した。試料溶液、標準溶液並びに対照溶液につき、紫外可視吸光度測定法により、波長232nmにおける吸光度AT、AS、およびABを測定し、下記式により酵素溶液活性(U/mL)を求めた。ここで酵素溶液活性は、単位液量当たりの酵素活性である。
AT:試料溶液の吸光度
AB:対照溶液の吸光度
AS:標準溶液の吸光度
Us:コンドロチナーゼABC標準物質の酵素溶液活性(U/mL)
以下の組成となるよう、酵素用緩衝液を用意した。
(組成;注射用蒸留水1L中)
リン酸水素ナトリウム水和物(リン酸水素ニナトリウム) 1.125mg
リン酸ニ水素ナトリウム 0.3mg
スクロース 5mg
ポリエチレングリコール3350 10mg
pH:6.5以上7.5以下。
酵素用緩衝液を用いて調製したコンドロチナーゼABC溶液を、酵素量が以下になるように3mlサイズのガラスバイアル(SCHOTT社製)に収容した:
試料1: 1.3μg/バイアル(0.5U/バイアル)
試料2: 2.5μg/バイアル(1.00U/バイアル)
試料3: 5.0μg/バイアル(2.00U/バイアル)
試料4: 9.1μg/バイアル(3.63U/バイアル)
工程1:常圧下で、温度を室温からマイナス35℃に冷却させ、試料を凍結させた。
工程2:温度マイナス35℃、常圧の状態を30分間維持した。
工程3:温度マイナス35℃、真空度13.3Paの状態を5時間維持した。
工程4:真空度を13.3Paに維持したまま、温度をマイナス35℃から25℃に昇温させた。
工程5:温度25℃、真空度13.3Paの状態を5時間維持した。
酵素用緩衝液を用いてコンドロチナーゼABC溶液を調製した。この調製した酵素溶液を、酵素量が1.5U/バイアルとなるように試験例1と同様にガラスバイアルに収容し、凍結乾燥した(水分含量2%(w/w)以下)。凍結乾燥後、窒素ガスでバイアル内を復圧し、ゴム栓を打栓し、単位用量製剤を得た。
試験例1の方法に準じて単位用量製剤(1.5U/バイアル)を得た。得られた単位用量製剤を、以下の条件1又は2で貯蔵した。各貯蔵期間後の酵素の力価を求めた。
条件2):5℃±3℃、遮光
本出願は、2018年2月28日付で日本国特許庁に出願された特願2018−35884号に基づく優先権を主張し、その内容は参照によって全体として本出願に組み込まれる。本明細書に記載された全ての文献、特許出願、及び技術規格は、個々の文献、特許出願、及び技術規格が参照により取り込まれることが具体的かつ個々に記された場合と同程度に、本明細書に参照により取り込まれる。
Claims (7)
- 力価が0.3ユニット/μg以上である凍結乾燥された糖分解酵素を有効成分として含み、
前記糖分解酵素量が2μg以上8μg以下の単位用量製剤である、医薬組成物。 - 酵素活性が4ユニット以下である、請求項1に記載の医薬組成物。
- 5℃±3℃で12ヶ月以上の貯蔵安定性を有する、請求項1または請求項2に記載の医薬組成物。
- 請求項1から請求項3のいずれか1項に記載の医薬組成物が容器に収容されてなる、包装体。
- 医薬組成物が容器に収容されてなる包装体の製造方法であり、
2μg以上8μg以下の糖分解酵素を含む溶液を容器に収容する工程と、
前記溶液を凍結乾燥して単位用量の医薬組成物を得る工程とを含む、製造方法。 - 前記医薬組成物は、力価が0.3ユニット/μg以上の糖分解酵素を含む、請求項5に記載の製造方法。
- 前記容器に収容される溶液の酵素活性が4ユニット以下である、請求項5または請求項6に記載の製造方法。
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