JP2011506266A - 眼科用水中油型乳剤を製造する方法 - Google Patents
眼科用水中油型乳剤を製造する方法 Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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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
- A61K9/0048—Eye, e.g. artificial tears
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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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
Abstract
Description
本出願は、2006年12月21日に出願し、「大量の眼科用水中油型乳剤を製造する方法(Process for Manufacturing Large Volumes of an Ophthalmic Oil-in-water Emulsion)」と題する仮特許出願第60/876,200号の優先権を主張するものである。この仮出願は、その全体が参照により本明細書に組み込まれている。
便宜の目的で、本明細書を通して用いる様々な用語の定義を以下に示す。
上述のように、本発明は、眼科での適用における使用に適する乳剤を十分な歩留りと妥当な時間で製造するという利点を有し、小から中バッチサイズの装置を用いて実施することができる、水中油型乳剤の調製の方法に関する。
本発明により提供される方法は、一般的に(1)水中油型乳剤の前濃縮物を製造する工程と(2)工程(1)で得られた前濃縮物を希釈水相で希釈して、眼科での適用で用いることができる水中油型乳剤を得る工程とを含む。
本発明による水中油型乳剤の前濃縮物の製造の方法は、一般的に油相を水相および少なくとも1つの界面活性作用物質で乳化して前濃縮物を得る工程を含む。そのような方法において、油相は、眼への使用に適する少なくとも1つの油を含む。
限定されない。
薬、インターフェロン、オピオイド)、細胞増殖抑制薬(例えば、アルキル化薬、代謝拮抗薬および細胞毒性抗生物質)、抗酸化薬(例えば、α-トコフェロール、アスコルビン酸、レチノイン酸、ルテインおよびそれらの誘導体、前駆体またはプロドラッグ)、UVフィルター化合物(例えば、ベンゾフェノン)、抗潮紅薬(例えば、ナファゾリン、テトラヒドロゾリン、エフェドリンおよびフェニルエフリン)、脂肪酸(例えば、ω-3脂肪酸)、および同様なものならびにその任意の組合せを含むが、これらに限定されない。
本発明はまた、眼科用水中油型乳剤の製造の方法を提供する。そのような方法は、一般的に、上述のように前濃縮物を製造する工程と、1容量の前濃縮物を、2〜50容量、例えば、2〜25容量または2〜10容量の希釈水溶液で希釈する工程とを含む。上で開示したように、そのような方法で用いる前濃縮物は、約3容積/容積%から約50容積/容積%、例えば、約6容積/容積%から約30容積/容積%または約10容積/容積%から約20容積/容積%の油中含量を有し、眼科での適用における使用に適する少なくとも1つの油を含む。
本明細書に記載する眼科用水中油型乳剤は、それ自体で、または医薬組成物の形態で投与することができる。したがって、本発明は、有効な量の本明細書に記載する水中油型乳剤および少なくとも1つの薬学的に許容できる担体、媒体または賦形剤を含む医薬組成物を提供する。当業者により認識されるように、薬学的に許容できる担体または賦形剤は、発明の前濃縮物からの乳剤の調製に用いる希釈水相に含めることができる。
他の態様において、本発明は、眼の疾患または状態の治療の方法に関する。そのような方法は、本明細書に開示する方法により得られた有効な量の眼科用水中油型乳剤をそれを必要とする対象に投与する工程を一般的に含む。
他の態様において、本発明は、医薬品パックまたはキットに関する。本発明による医薬品パックまたはキットは、対象への組成物の投与を可能にする、発明の組成物の1つまたは複数の成分を含む1つまたは複数の容器(例えば、バイアル、アンプル、試験管、フラスコ、びんまたは充填済み注射器)を含む。そのような容器は、ガラス製、プラスチック材料製、樹脂製などであってよい。それらは、透明であってよく、あるいは、有効成分が光に直接曝露するリスクを防止または低減するために着色されているか、または不透明であってよい。特定の実施形態において、容器は、発明の組成物の調節された容積(例えば、液滴)の投与を可能にする形であってよい。他の実施形態において、発明の組成物の調節された容積の投与を可能にするシステム(例えば、点滴注入器)を含む。
以下の実施例では、本発明を行い、実施する好ましい態様のいくつかを記述する。しかし、これらの実施例は、例示の目的のものにすぎず、本発明の範囲を限定するものではないことが理解されるべきである。さらに、実施例における記述が過去時制で示されていない限り、本明細書の残りのような本文は、実験が実際に実施されたか、またはデータが実際に得られたことを示唆することを意図しない。
シクロスポリンAを含む100kgの乳剤の1バッチの調製
1-組成
以下の表にシクロスポリンA乳剤の組成を示す。
図1に調製に用いた調合方法のスキームを示す。工程1、2および6において、油相中のAPIを含む各相を別個に調製した。工程1および2で得られた水相および油相を次に工程3で希釈して、プレミックス(重量/重量)を得た。得られたプレミックスを高せん断混合に約30分から1時間かけ(工程4)、次いで、高圧下で約5時間ホモジナイズした(工程5)。次いで、2回目の希釈を1重量プレミックス/6重量水相2の比率で行って(工程6および7)、最終乳剤を得た。次いで、これを加熱により滅菌した(工程8)。
以下の表に言及した手順に従って行った部分的管理の結果を示す。
APIを含まない乳剤の500kgの1バッチの調製
1-組成
以下の表にシクロスポリンA乳剤の組成を示す。
図2に調製に用いた調合方法のスキームを示す。工程1、2および6において、各相を別個に調製した。工程1および2で得られた水相および油相を次に工程3で希釈して、プレミックス(重量/重量)を得た。得られたプレミックスを高せん断混合に約1時間かけ(工程4)、次いで、高圧下で約8時間ホモジナイズした(工程5)。次いで、2回目の希釈を1重量プレミックス/10重量水相2の比率で行って(工程6および7)、最終乳剤を得た。次いで、これを加熱により滅菌した(工程8)。
以下の表に言及した手順に従って行った部分的管理の結果を示す。
ナファゾリンを含む乳剤の100kgの1バッチの調製
1-組成
以下の表にナファゾリン乳剤の組成を示す。
図3に調製に用いた調合方法のスキームを示す。工程1、2および6において、各相を別個に調製した。APIを水相に含めた。工程1および2で得られた水相および油相を次に工程3で希釈して、プレミックス(重量/重量)を得た。得られたプレミックスを高せん断混合に約30分かけ(工程4)、次いで、高圧下で約5時間ホモジナイズした(工程5)。次いで、2回目の希釈を1重量プレミックス/25重量水相2の比率で行って(工程6および7)、最終乳剤を得た。次いで、これを加熱により滅菌した(工程8)。
以下の表に言及した手順に従って行った部分的管理の結果を示す。
本発明の他の実施形態は、明細書の考慮または本明細書に開示した発明の実施から当業者には明らかであろう。明細書および実施例は例示にすぎないとみなすものとし、本発明の真の範囲は添付の特許請求の範囲により示されている。
Claims (24)
- 眼科用水中油型乳剤の前濃縮物を製造する方法であって、
水相および少なくとも1つの界面活性作用物質で油相を乳化して前濃縮物を得る工程
を含み、油相が眼への使用に適する少なくとも1つの油を含み、得られた前濃縮物が3容積/容積%から50容積/容積%まで、好ましくは6%から30%まで、より好ましくは10%から20%までの油中含量を有する方法。 - 眼への使用に適する油がヒマシ油、MCT、鉱油、植物油およびそのいずれかの組合せからなる群から選択される、請求項1に記載の方法。
- 油相が少なくとも1つの薬学的に活性な物質をさらに含む、請求項1または2に記載の方法。
- 薬学的に活性な物質が抗生物質、抗ウイルス薬、抗真菌薬、眼圧降下薬、抗炎症薬、ステロイド、抗アレルギー化合物、抗脈管形成化合物、抗体およびそのフラグメント、オリゴアプタマー、アプタマーおよび遺伝子フラグメント、オリゴヌクレオチド、プラスミド、リボザイム、小分子干渉RNA、核酸フラグメント、ペプチドおよびアンチセンス配列、成長因子、免疫調節薬、イムノフィリン作用薬、インターフェロン、オピオイド、細胞増殖抑制薬、抗酸化薬、UVフィルター化合物、抗潮紅薬、ω-3脂肪酸、そのプロドラッグならびにそのいずれか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。
- 薬学的に活性な物質がシクロスポリンA、ラタノプロスト、パルミチン酸デキサメタゾンおよびフルビプロフェンからなる群から選択される、請求項3に記載の方法。
- 得られた前濃縮物が約10nmを超え、約500nm未満、好ましくは約10nmを超え、約300nm未満、最も好ましくは約10nmを超え、約200nm未満の平均サイズを有する小滴を含む、請求項1から5のいずれか一項に記載の方法。
- 前濃縮物が少なくとも24時間、好ましくは少なくとも3日、最も好ましくは少なくとも7日を超える期間安定である、請求項1から6のいずれか一項に記載の方法。
- 前濃縮物がカチオン性乳剤、アニオン性乳剤または非アニオン性乳剤の形態である、請求項1から7のいずれか一項に記載の方法。
- 前濃縮物がカチオン性乳剤の形態である、請求項8に記載の方法。
- 眼科用水中油型乳剤を製造する方法であって、
眼科用水中油型乳剤の前濃縮物を製造する工程と、
1容量の前濃縮物を2容量から50容量の希釈水溶液で希釈する工程と
を含み、前濃縮物が3容積/容積%から50容積/容積%まで、好ましくは6容積/容積%から30容積/容積%まで、より好ましくは10容積/容積%から20容積/容積%までの油中含量を有する方法。 - 希釈水溶液が等張化剤、粘稠化剤、緩衝剤、保存剤、抗酸化剤、着色剤、ミセル溶液およびその組合せからなる群から選択される添加剤を含む、請求項10に記載の方法。
- 希釈水溶液が塩化ベンザルコニウムを含む、請求項10または11に記載の方法。
- 希釈水溶液が少なくとも1つの水溶性治療薬を含む、請求項10から12のいずれか一項に記載の方法。
- 水溶性治療薬が鎮痛薬、麻酔薬、弛緩薬、ホルモン、抗炎症薬、ビタミン、ミネラル、抗脈管形成薬、創傷治癒薬、サイトカイン、成長因子、抗ヒスタミン薬、抗菌薬、抗ウイルス薬、抗生物質、かゆみ止め薬、解熱薬などからなる群の水溶性メンバーである、請求項13に記載の方法。
- 眼科用水中油型乳剤の前濃縮物の製造を請求項1から9のいずれか一項に記載の方法を用いて実施する、請求項10から14のいずれか一項に記載の方法。
- 水中油型乳剤が約10nmを超え、約500nm未満、好ましくは約10nmを超え、約300nm未満、最も好ましくは約10nmを超え、約200nm未満の平均サイズを有する小滴を含む、請求項1から15のいずれか一項に記載の方法。
- 水中油型乳剤が少なくとも12カ月、好ましくは少なくとも24カ月、最も好ましくは少なくとも36カ月を超える期間安定である、請求項1から16のいずれか一項に記載の方法。
- 水中油型乳剤がカチオン性乳剤、アニオン性乳剤または非アニオン性乳剤の形態である、請求項1から17のいずれか一項に記載の方法。
- 水中油型乳剤がカチオン性乳剤の形態である、請求項8に記載の方法。
- 請求項1から9のいずれか一項に記載の方法により得られる眼科用水中油型乳剤の前濃縮物。
- 請求項10から19のいずれか一項に記載の方法により得られる眼科用水中油型乳剤。
- 眼の疾患または状態の治療用の薬剤の製造のための、請求項21に記載の眼科用水中油型乳剤の使用。
- 眼の疾患または状態の治療に有効な量の請求項21に記載の眼科用水中油型乳剤を含む薬剤。
- 眼の疾患または状態が、炎症、アレルギー、乾燥眼、網膜疾患、感染症、緑内障および眼圧上昇からなる群のメンバーである、請求項22に記載の使用または請求項23に記載の薬剤。
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AU2007336206A1 (en) | 2008-06-26 |
EP2129364A2 (en) | 2009-12-09 |
ES2796116T3 (es) | 2020-11-25 |
JP5850602B2 (ja) | 2016-02-03 |
US20080181867A1 (en) | 2008-07-31 |
AU2007336206B2 (en) | 2014-02-20 |
IL199458A (en) | 2015-04-30 |
CA2672973C (en) | 2016-03-08 |
EP2129364B1 (en) | 2020-04-15 |
US9364461B2 (en) | 2016-06-14 |
WO2008074885A3 (en) | 2008-10-09 |
WO2008074885A2 (en) | 2008-06-26 |
CA2672973A1 (en) | 2008-06-26 |
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