JP2013500995A - 結晶化方法および生物学的利用能 - Google Patents
結晶化方法および生物学的利用能 Download PDFInfo
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- JP2013500995A JP2013500995A JP2012523084A JP2012523084A JP2013500995A JP 2013500995 A JP2013500995 A JP 2013500995A JP 2012523084 A JP2012523084 A JP 2012523084A JP 2012523084 A JP2012523084 A JP 2012523084A JP 2013500995 A JP2013500995 A JP 2013500995A
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- JP
- Japan
- Prior art keywords
- zoledronic acid
- acid
- complex
- water
- lysine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 108
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 85
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Classifications
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
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Abstract
Description
本願は、2009年7月31日出願の米国特許出願第61/230,222号、2009年12月18日出願の米国特許出願第61/288,036号、2010年2月6日出願の米国特許出願第61/302,110号、2010年3月11日出願の米国特許出願第61/312,879号、2010年3月29日出願の米国特許出願第61/318,503号、および2010年6月29日出願の米国特許出願第61/359,544号(参照により本明細書に組み込まれる)の優先権を請求するものである。
固相特性評価
i.IV投与:IV投与のためのゾレドロン酸の用量は、0.5mg/kgであった。各ラットの用量は、ラット当たりベースで計算された(ロット内の全ラットの平均重量ではなく)。
ii.経口強制投与:固体懸濁液が投与された。各ラットの用量は、ラット当たりベースで計算された(ロット内の全ラットの平均重量ではなく)。固体懸濁液の場合、動物は、5mg/kgのゾレドロン酸またはPEG400の懸濁液中に含有されるゾレドロン酸錯体中5mg/kgのゾレドロン酸を投与された。
iii.十二指腸カニューレ投与:固体懸濁液が投与された。各ラットの用量は、ラット当たりベースで計算された(ロット内の全ラットの平均重量ではなく)。固体懸濁液の場合、動物は、5mg/kgのゾレドロン酸またはPEG400の懸濁液中に含有されるゾレドロン酸錯体中5mg/kgのゾレドロン酸を投与された。
i.IV投与:各イヌの用量体積が、イヌの平均重量に基づいて調節された。
ii.経口投与:ゾレドロン酸およびそのゾレドロン酸錯体製剤の等量が、イヌの平均重量に基づいて、サイズ0ゼラチンカプセルを通して投与された。
iii.腸溶性被覆されたカプセルによる経口投与:ゾレドロン酸およびそのゾレドロン酸錯体製剤の等量が、イヌの平均重量に基づいて、サイズ0腸溶性被覆されたゼラチンカプセル投与された。
iv.付加的共形成体との分子錯体の経口投与:付加的共形成体とのゾレドロン酸錯体の物理的混合物が、サイズ0ゼラチンカプセルを通して投与された。
群1:4つの亜群(I−IV)から成る、ラットであって、PKプロファイルグラフ上の各データ点の結果は、3匹のラットの血漿中の平均薬物濃度である。
群2:イヌPK試験は、亜群(A、B、C、D、E、およびF)を伴う、3つの群を含み、PKプロファイルグラフ上の各データ点の結果は、5匹のイヌの血清の平均薬物濃度である。
Claims (29)
- ビスホスホン酸またはその塩と、少なくとも1種の共形成体と、を含む、分子錯体であって、前記分子錯体由来ビスホスホン酸またはその塩の生物学的利用能は、前記共形成体なしでの、前記ビスホスホン酸またはその塩の生物学的利用能を上回る、分子錯体。
- 前記ビスホスホン酸は、ゾレドロン酸、クロドロン酸、チルドロン酸、パミドロン酸、アレンドロン酸、リセドロン酸、およびイバンドロン酸から成る群から選択される、請求項1に記載の分子錯体。
- 少なくとも1種の共形成体は、アミノ酸である、請求項1に記載の分子錯体。
- 前記ビスホスホン酸は、ゾレドロン酸であって、少なくとも1種の共形成体は、アミノ酸である、請求項1に記載の分子錯体。
- 少なくとも1種の共形成体は、リシンである、請求項1−4のいずれかに記載の分子錯体。
- 請求項1−4のいずれかに記載の分子錯体と、過剰量の少なくとも1種の共形成体と、を含む、組成物。
- 前記過剰共形成体は、前記分子錯体の質量の最大100倍の量で存在する、請求項6に記載の組成物。
- 請求項7に記載の組成物と、薬学的に許容される賦形剤と、を含む、医薬組成物。
- 請求項6に記載の組成物と、薬学的に許容される賦形剤と、を含む、医薬組成物。
- 前記医薬組成物は、経口投薬形態である、請求項8に記載の医薬組成物。
- 前記医薬組成物は、経口投薬形態である、請求項9に記載の医薬組成物。
- 前記分子錯体は、結晶性である、請求項1−4のいずれかに記載の分子錯体。
- ビスホスホン酸またはその塩の生物学的利用能または浸透性を向上させるための方法であって、それを必要とする患者に、治療上有効量のビスホスホン酸を請求項1−4のいずれかに記載の分子錯体の形態で投与するステップを含む、方法。
- ビスホスホン酸またはその塩の生物学的利用能または浸透性を向上させるための方法であって、それを必要とする患者に、治療上有効量のビスホスホン酸を請求項5に記載の組成物の形態で投与するステップを含む、方法。
- ビスホスホン酸またはその塩の生物学的利用能または浸透性を向上させるための方法であって、それを必要とする患者に、治療上有効量のビスホスホン酸を請求項6に記載の組成物の形態で投与するステップを含む、方法。
- 骨粗しょう症、高カルシウム血症、癌誘発性骨転移、パジェット病の疾患状態の治療および/または予防、あるいはアジュバントまたはネオアジュバント癌療法のための方法であって、それを必要とする患者に、治療上有効量のビスホスホン酸またはその塩を請求項5に記載の組成物の形態で投与するステップを含む、方法。
- 骨粗しょう症、高カルシウム血症、癌誘発性骨転移、パジェット病に関連する疾患状態の治療および/または予防、あるいはアジュバントまたはネオアジュバント癌療法のための方法であって、それを必要とする患者に、治療上有効量のビスホスホン酸またはその塩を請求項6に記載の組成物の形態で投与するステップを含む、方法。
- ゾレドロン酸と、水と、L−リシン、DL−リシン、ニコチンアミド、アデニン、およびゾレドロン酸塩から選択される化合物と、を含む、ゾレドロン酸の結晶性形態。
- 前記結晶性形態は、
約8.1、13.3、21.5、24.6、および25.6±0.2°2θにピークを有する、X線粉末回折パターンを特徴とする結晶性ゾレドロン酸、ゾレドロン酸ナトリウム、および水錯体、
約11.0、14.6、15.4、19.9、および29.4±0.2°2θに強いピークを有する、X線粉末回折パターンを特徴とする結晶性ゾレドロン酸アンモニウムおよび水錯体、
約12.2、13.0、14.1、17.1、および19.3±0.2°2θに強いピークを有する、X線粉末回折パターンを特徴とするゾレドロン酸ジアンモニウム水錯体、
約9.0、14.4、18.1、26.0、および29.6±0.2°2θにピークを有する、X線粉末回折パターンを特徴とする結晶性ゾレドロン酸、L−リシン、および水錯体、
約9.6、10.7、14.3、21.4、23.5±0.2°2θにピークを有する、X線粉末回折パターンを特徴とする結晶性ゾレドロン酸、L−リシン、および水錯体、
約8.3、11.8、12.3、15.8、および20.8±0.2°2θにピークを有する、X線粉末回折パターンを特徴とする結晶性ゾレドロン酸、DL−リシン、および水錯体、
約9.1、14.7、18.0、21.2、および26.0±0.2°2θにピークを有する、X線粉末回折パターンを特徴とする結晶性ゾレドロン酸、DL−リシン、および水錯体、
約9.7、10.8、14.4、18.9、21.4±0.2°2θにピークを有する、X線粉末回折パターンを特徴とする結晶性ゾレドロン酸、DL−リシン、および水錯体、
約8.8、9.7、17.6、23.1、および26.5±0.2°2θにピークを有する、X線粉末回折パターンを特徴とする結晶性ゾレドロン酸、ゾレドロン酸塩、DL−リシン、エタノール、および水錯体、
約13.6、15.9、19.7、27.9、および29.5±0.2°2θにピークを有する、X線粉末回折パターンを特徴とする結晶性ゾレドロン酸、アデニン、および水錯体、または
約13.1、15.2、21.0、23.9、および26.5±0.2°2θに強いピークを有する、X線粉末回折パターンを特徴とする結晶性ゾレドロン酸、ニコチンアミド、および水錯体、
である、請求項18に記載のゾレドロン酸の結晶性形態。 - ゾレドロン酸と、グリシンと、を含む、ゾレドロン酸の結晶性形態。
- ゾレドロン酸と、グリシンと、を含む、ゾレドロン酸の分子錯体。
- 前記結晶性形態は、約10.2、17.8、19.9、22.9、および28.1±0.2°2θにピークを有する、X線粉末回折パターンを特徴とする結晶性ゾレドロン酸およびグリシン錯体である、請求項20に記載のゾレドロン酸の結晶性形態。
- ゾレドロン酸と、水と、L−リシン、DL−リシン、ニコチンアミド、アデニン、およびゾレドロン酸塩から選択される、化合物と、を含む、またはゾレドロン酸と、グリシンと、を含む、ゾレドロン酸の分子錯体。
- ゾレドロン酸、ゾレドロン酸ナトリウムおよび水錯体、
ゾレドロン酸アンモニウムおよび水錯体、
ゾレドロン酸ジアンモニア水錯体、
ゾレドロン酸、L−リシン、および水錯体、
ゾレドロン酸、DL−リシン、および水錯体、
ゾレドロン酸、ゾレドロン酸塩、DL−リシン、エタノール、および水錯体、
ゾレドロン酸、アデニン、および水錯体、
ゾレドロン酸、ニコチンアミド、および水錯体、または
ゾレドロン酸グリシン錯体、
から成る群から選択される、請求項23に記載のゾレドロン酸の分子錯体。 - ゾレドロン酸と、リシンと、を含む、分子錯体。
- ゾレドロン酸と、リシンと、を含む、結晶性形態。
- 請求項18−26のいずれかに記載の錯体と、薬学的に許容される賦形剤と、を含む、医薬組成物。
- 前記組成物は、経口固体投薬形態である、請求項27に記載の医薬組成物。
- 骨粗しょう症、高カルシウム血症、癌誘発性骨転移、パジェット病に関連する疾患状態の治療および/または予防、あるいはアジュバントまたはネオアジュバント癌療法のための方法であって、それを必要とする患者に、治療上有効量の請求項27に記載の医薬組成物を投与するステップを含む、方法。
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