JP5707405B2 - ナノ粒子を含有する経口固体剤形、および魚ゼラチンを使用して同剤形を製剤化する方法 - Google Patents
ナノ粒子を含有する経口固体剤形、および魚ゼラチンを使用して同剤形を製剤化する方法 Download PDFInfo
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- JP5707405B2 JP5707405B2 JP2012529814A JP2012529814A JP5707405B2 JP 5707405 B2 JP5707405 B2 JP 5707405B2 JP 2012529814 A JP2012529814 A JP 2012529814A JP 2012529814 A JP2012529814 A JP 2012529814A JP 5707405 B2 JP5707405 B2 JP 5707405B2
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- fish gelatin
- solid dosage
- oral solid
- nanosuspension
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Classifications
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5169—Proteins, e.g. albumin, gelatin
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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- Biomedical Technology (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
ナノ懸濁液を、予め冷却した凍結乾燥機に移すことができる。本発明に適した凍結乾燥機の例は、FTS Lyostar II(SP Industries、Warminster、PA)またはUsifroid SMH90(Usifroid、Paris、France)であるが、例えば氷昇華を引き起こすように、時間と共に棚温度およびチャンバー圧力を調節する能力を有するいかなる凍結乾燥機もこの目的に好適であろう。装置が、必要とされる速度で必要とされる温度まで生成物を凍らせる機能性を有する限りは、FTS Lyostar IIまたはUsifroid SMH90などの凍結乾燥機のみを使用して、凍結工程および乾燥工程の双方を行うことも可能である。本発明のために、別個のフリーザーおよび凍結乾燥機の使用または凍結乾燥機単独での使用のいずれの選択も可能である。
(実施例1Aおよび1B)
有効成分ナプロキセンと、ナノ安定剤として添加剤魚ゼラチン(Norland Products社製のSMW魚ゼラチングレード-実施例1A;およびNorland Products社製のDFGグレード-実施例1B)と、増量剤としてマンニトールとを含む経口固体剤形を調製した。5%魚ゼラチンおよび3%マンニトールの水溶液を調製した;次いで、ナプロキセンをこの溶液に添加して、懸濁スラリーを生成した。この懸濁スラリーを、ジルコニウム粉砕媒体を含有する、600ccのチャンバーサイズのDyno(登録商標)粉砕機に入れた。粉砕スラリー中のナプロキセン濃度は、15重量%であった。この装置の初期設定の粉砕条件を使用して、再循環させている懸濁液において1.5時間粉砕を行った。結果として生じたバルクのナノ懸濁液を粉砕機から出し、Digispenseユニットを使用して調節されたIVEKポンプを使用して、250mgの単位用量を0.25mL容量のブリスターポケット内に正確に分注した。ブリスターポケットを、冷却剤として液体窒素を使用して3分間の凍結時間でAir Products CM2000フリーザー内で凍結させて、その後、予め冷却したフリーズドライヤーの棚に移すまでフリーザー内に保存した。Lyostar IIフリーズドライヤー内で、500mTorr未満の真空を使用して乾燥を行った。調製した経口固体剤形は、以下のTable 1(表1)に記載の粒径パラメータを有するナプロキセン粒子を含有していた。この実施例および全ての実施例では、NIST標準をサブミクロン範囲で使用して同じ日に較正を行う、Malvern Mastersizer 2000を使用して粒径データを作製した。全てのナノ懸濁液の解析および固体経口剤形試験のために、水性分散剤を超音波処理様式で使用した。
有効成分インドメタシンと、ナノ安定剤として添加剤魚ゼラチン(Norland Products社製のDFGグレード)と、増量剤としてマンニトールとを含む経口固体剤形を調製した。5%魚ゼラチンおよび3%マンニトールの水溶液を調製した;次いで、インドメタシンをこの溶液に添加して、懸濁スラリーを生成した。この懸濁スラリーを、ジルコニウム粉砕媒体を含有する、600ccのチャンバーサイズのDyno(登録商標)粉砕機に入れた。粉砕スラリー中のインドメタシン濃度は、15重量%であった。この装置の初期設定の粉砕条件を使用して、再循環させている懸濁液において1.5時間粉砕を行った。結果として生じたバルクのナノ懸濁液を粉砕機から出し、Digispenseユニットを使用して調節されたIVEKポンプを使用して、250mgの単位用量を0.25mL容量のブリスターポケット内に正確に分注した。ブリスターポケットを、冷却剤として液体窒素を使用して3分間の凍結時間でAir Products CM2000フリーザー内で凍結させて、その後、予め冷却したフリーズドライヤーの棚に移すまでフリーザー内に保存した。Lyostar IIフリーズドライヤー内で、500mTorr未満の真空を使用して乾燥を行った。調製した経口固体剤形は、以下のTable 2(表2)に記載の粒径パラメータを有するインドメタシン粒子を含有していた。
有効成分フェナセチンと、添加剤魚ゼラチン(Norland Products社製のSMW魚ゼラチングレード)と、マンニトールとを含む経口固体剤形を調製した。5%魚ゼラチンおよび3%マンニトールの水溶液を調製した;次いで、フェナセチンをこの溶液に添加して、懸濁スラリーを生成した。この懸濁スラリーを、ジルコニウム粉砕媒体を含有する、600ccのチャンバーサイズのDyno(登録商標)粉砕機に入れた。粉砕スラリー中のフェナセチン濃度は、15重量%であった。この装置の初期設定の粉砕条件を使用して、再循環させている懸濁液において1.5時間粉砕を行った。結果として生じたバルクのナノ懸濁液を粉砕機から出し、Digispenseユニットを使用して調節されたIVEKポンプを使用して、250mgの単位用量を0.25mL容量のブリスターポケット内に正確に分注した。ブリスターポケットを、冷却剤として液体窒素を使用して3分間の凍結時間でAir Products CM2000フリーザー内で凍結させて、その後、予め冷却したフリーズドライヤーの棚に移すまでフリーザー内に保存した。Lyostar IIフリーズドライヤー内で、500mTorr未満の真空を使用して乾燥を行った。調製した経口固体剤形は、以下のTable 3(表3)に記載の粒径パラメータを有するフェナセチン粒子を含有していた。
有効成分フェノフィブラートと、ナノ安定剤として魚ゼラチン(Norland Products社製のDFGグレード)とを、さらなる医薬添加剤と共に含む経口固体剤形を調製した。5%魚ゼラチン、3%マンニトール、0.5%スクラロースおよび0.5%ミント香味剤の水溶液を調製した;次いで、インドメタシンをこの溶液に添加して、懸濁スラリーを生成した。この懸濁スラリーを、ジルコニウム粉砕媒体を含有する、600ccのチャンバーサイズのDyno(登録商標)粉砕機に入れた。粉砕スラリー中のフェノフィブラート濃度は、14.5重量%であった。この装置の初期設定の粉砕条件を使用して、再循環させている懸濁液において2.5時間粉砕を行った。結果として生じたバルクのナノ懸濁液を粉砕機から出し、Digispenseユニットを使用して調節されたIVEKポンプを使用して、250mgの単位用量を0.25mL容量のブリスターポケット内に正確に分注した。ブリスターポケットを、冷却剤として液体窒素を使用して3分間の凍結時間でAir Products CM2000フリーザー内で凍結させて、その後、予め冷却したフリーズドライヤーの棚に移すまでフリーザー内に保存した。Lyostar IIフリーズドライヤー内で、500mTorr未満の真空を使用して乾燥を行った。調製した経口固体剤形は、以下のTable 4(表4)に記載の粒径パラメータを有するフェノフィブラート粒子を含有していた。
有効成分ナプロキセンと、添加剤魚ゼラチン(Norland Products社製のDFGグレード)とを含む経口固体剤形を調製した。5%魚ゼラチンの水溶液を調製した;次いで、ナプロキセンをこの溶液に添加して、懸濁スラリーを生成した。この懸濁スラリーを、ジルコニウム粉砕媒体を含有する、600ccのチャンバーサイズのDyno(登録商標)粉砕機に入れた。粉砕スラリー中のナプロキセン濃度は、15重量%であった。この装置の初期設定の粉砕条件を使用して、再循環させている懸濁液において1.5時間粉砕を行った。結果として生じたバルクのナノ懸濁液を粉砕機から出し、Digispenseユニットを使用して調節されたIVEKポンプを使用して、250mgの単位用量を0.25mL容量のブリスターポケット内に正確に分注した。ブリスターポケットを、冷却剤として液体窒素を使用して3分間の凍結時間でAir Products CM2000フリーザー内で凍結させて、その後、予め冷却したフリーズドライヤーの棚に移すまでフリーザー内に保存した。Lyostar IIフリーズドライヤー内で、500mTorr未満の真空を使用して乾燥を行った。調製した経口固体剤形は、以下のTable 5(表5)に記載の粒径パラメータを有するナプロキセン粒子を含有していた。
有効成分ナプロキセンと、ナノ安定剤として添加剤魚ゼラチン(Norland Products社製のDFGグレード)と、増量剤としてマンニトールとを含む経口固体剤形を調製した。3%魚ゼラチンおよび2%マンニトールの水溶液を調製した;次いで、ナプロキセンをこの溶液に添加して、懸濁スラリーを生成した。この懸濁スラリーを、ジルコニウム粉砕媒体を含有する、600ccのチャンバーサイズのDyno(登録商標)粉砕機に入れた。粉砕スラリー中のナプロキセン濃度は、15重量%であった。この装置の初期設定の粉砕条件を使用して、再循環させている懸濁液において1.5時間粉砕を行った。結果として生じたバルクのナノ懸濁液を粉砕機から出し、Digispenseユニットを使用して調節されたIVEKポンプを使用して、250mgの単位用量を0.25mL容量のブリスターポケット内に正確に分注した。ブリスターポケットを、冷却剤として液体窒素を使用して3分間の凍結時間でAir Products CM2000フリーザー内で凍結させて、その後、予め冷却したフリーズドライヤーの棚に移すまでフリーザー内に保存した。Lyostar IIフリーズドライヤー内で、500mTorr未満の真空を使用して乾燥を行った。調製した経口固体剤形は、以下のTable 6(表6)に記載の粒径パラメータを有するナプロキセン粒子を含有していた。
有効成分ナプロキセンと、添加剤牛ゼラチン(Gelitaにより提供された低ブルームグレードの酸性皮ゼラチン-1A;Weishardtから供給された低ブルームグレードの酸性皮ゼラチン-1B)とを含む経口固体剤形を調製した。3%牛ゼラチンおよび2%マンニトールの水溶液を調製した;次いで、ナプロキセンをこの溶液に添加して、懸濁スラリーを生成した。この懸濁スラリーを、ジルコニウム粉砕媒体を含有する、600ccのチャンバーサイズのDyno(登録商標)粉砕機に入れた。粉砕スラリー中のナプロキセン濃度は、15重量%であった。この装置の初期設定の粉砕条件を使用して、再循環させている懸濁液において1.5時間粉砕を行った。結果として生じたバルクのナノ懸濁液を粉砕機から出し、Digispenseユニットを使用して調節されたIVEKポンプを使用して、250mgの単位用量を0.25mL容量のブリスターポケット内に正確に分注した。ブリスターポケットを、冷却剤として液体窒素を使用して3分間の凍結時間でAir Products CM2000フリーザー内で凍結させて、その後、予め冷却したフリーズドライヤーの棚に移すまでフリーザー内に保存した。Lyostar IIフリーズドライヤー内で、500mTorr未満の真空を使用して乾燥を行った。調製した経口固体剤形は、以下のTable 7(表7)に記載の粒径パラメータを有するナプロキセン粒子を含有していた。
有効成分インドメタシンと、添加剤牛ゼラチン(Gelitaにより提供された低ブルームグレードの酸性皮ゼラチン)とを含む経口固体剤形を調製した。3%牛ゼラチンおよび2%マンニトールの水溶液を調製した;次いで、ナプロキセンをこの溶液に添加して、懸濁スラリーを生成した。この懸濁スラリーを、ジルコニウム粉砕媒体を含有する、600ccのチャンバーサイズのDyno(登録商標)粉砕機に入れた。粉砕スラリー中のインドメタシン濃度は、15重量%であった。この装置の初期設定の粉砕条件を使用して、再循環させている懸濁液において1.5時間粉砕を行った。結果として生じたバルクのナノ懸濁液を粉砕機から出し、Digispenseユニットを使用して調節されたIVEKポンプを使用して、250mgの単位用量を0.25mL容量のブリスターポケット内に正確に分注した。ブリスターポケットを、冷却剤として液体窒素を使用して3分間の凍結時間でAir Products CM2000フリーザー内で凍結させて、その後、予め冷却したフリーズドライヤーの棚に移すまでフリーザー内に保存した。Lyostar IIフリーズドライヤー内で、500mTorr未満の真空を使用して乾燥を行った。調製した経口固体剤形は、以下のTable 8(表8)に記載の粒径パラメータを有するナプロキセン粒子を含有していた。
特定の条件下における、本実施例の経口固体剤形の崩壊時間の比較を、以下のTable 9(表9)に記載している。
Claims (10)
- ナノ粒子を含有する経口固体剤形を調製する方法であって、
(a)少なくとも1種の固体状態の医薬有効成分を、魚ゼラチンを含有する溶液に添加する工程と
(b)前記医薬有効成分を前記溶液中に分散させて、前記医薬有効成分の粒径を小さくしてナノ懸濁液を生成する工程と、
(c)工程(b)のナノ懸濁液を凍結乾燥して前記経口固体剤形を生成する工程と
を含む方法。 - 前記魚ゼラチンが、ゲル化していない、加水分解されていない魚ゼラチンであるか、またはゲル化していない、加水分解されていない複数の魚ゼラチンの組合せである、請求項1に記載の方法。
- 前記ナノ懸濁液が、少なくとも1種の医薬添加剤をさらに含む、請求項1に記載の方法。
- 少なくとも1種の前記医薬添加剤が、増量剤、化学的安定性促進剤、崩壊剤、粘度調整剤、甘味剤、香味剤、着色剤、pH調節剤、およびこれらの組合せからなる群から選択される、請求項3に記載の方法。
- 少なくとも1種の前記医薬有効成分が、1mg/mL未満の測定された溶解度を有する、請求項1に記載の方法。
- ナノ粒子を含有する経口固体剤形であって、
(a)少なくとも1種の固体状態の医薬有効成分を、魚ゼラチンを含有する溶液に添加する工程と、
(b)前記医薬有効成分を前記溶液中に分散させて、前記医薬有効成分の粒径を小さくしてナノ懸濁液を生成する工程と、
(c)工程(b)のナノ懸濁液を凍結乾燥して前記経口固体剤形を生成する工程と
を含む方法によって作製される、経口固体剤形。 - 前記魚ゼラチンが、ゲル化していない、加水分解されていない魚ゼラチンであるか、またはゲル化していない、加水分解されていない複数の魚ゼラチンの組合せである、請求項6に記載の経口固体剤形。
- 前記ナノ懸濁液が、少なくとも1種の医薬添加剤をさらに含む、請求項6に記載の経口固体剤形。
- 前記少なくとも1種の医薬添加剤が、増量剤、化学的安定性促進剤、崩壊剤、粘度調整剤、甘味剤、香味剤、着色剤、pH調節剤、およびこれらの組合せからなる群から選択される、請求項8に記載の経口固体剤形。
- 前記少なくとも1種の医薬有効成分が、1mg/mL未満の測定された溶解度を有する、請求項6に記載の経口固体剤形。
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