JP5173832B2 - 濃縮液体甲状腺ホルモン組成物 - Google Patents
濃縮液体甲状腺ホルモン組成物 Download PDFInfo
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- JP5173832B2 JP5173832B2 JP2008549014A JP2008549014A JP5173832B2 JP 5173832 B2 JP5173832 B2 JP 5173832B2 JP 2008549014 A JP2008549014 A JP 2008549014A JP 2008549014 A JP2008549014 A JP 2008549014A JP 5173832 B2 JP5173832 B2 JP 5173832B2
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- buffer
- sodium
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Classifications
-
- 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
- A61K9/08—Solutions
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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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
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
Description
本発明は、医薬として許容できる溶媒中において可溶化される甲状腺ホルモンを含む液体医薬組成物を提供する。これらの組成物は、通常の保存温度で安定である傾向があり、特に、経口投与に有用である。
好ましい実施形態のこの詳細な記載は、本出願人らの発明、この原理、およびこの実際の適用を当分野における他の技術者に紹介し、当分野における他の技術者が、特定の使用の必要条件に最適であると思われるような多数の形態において本発明を応用および適用させ得ることを意図しているにすぎない。この詳細な記載および具体的な実施例は、本発明の好ましい実施形態を示す一方、例示の目的を意図しているにすぎない。したがって、本発明は、この明細書において記載する好ましい実施形態に限定されることなく、様々に変更してよい。
実施例
下記組成物を調製した。
レボチロキシンナトリウムは、3つのpKa、2.2、6.7および10.1を持つ三塩基酸である。この溶解性はpHの変化により影響され、中間pHのほうが低い(例えば、pH7.3で28μg/ml)。レボチロキシンナトリウムの溶解性は、9.4のpHで7倍、10.45のpHで11倍、pH7.3より高い。許容できる生理学的pHを有し、レボチロキシンの溶解性を向上させるため、pHは少なくとも約8、または少なくとも約9が好ましい。
超微粉砕化したレボチロキシンナトリウム(D99<13μm)、および超微粉砕化していないレボチロキシンナトリウム(D99<125μm)のバッチの溶解性を調べた。一定容量の水中における各種の量の活性成分を有する調製物を、24時間後に観察した。両者において、水1ml当たり100μg未満のレボチロキシンナトリウムが溶解した。したがって、超微粉砕化だけでは、溶解性、または水における溶解時間は改善しなかった。
30(w/w)%HPBCD(Kleptose HPB、Roquette、France)の水溶液中において、レボチロキシンナトリウム1000μg/mlが溶解した。本出願人らにより、同様のレボチロキシンナトリウム溶解性が、例えば、カルボキシメチルセルロースナトリウム(「CMC」)、ヒドロキシプロピルメチルセルロース4000(「HPMC」)、および/またはポビドン12PFなどのコポリマー(複数可)を付加することによって、低濃のHPBCDで達成できることが認められた。より具体的には、本出願人らにより、1000μg/mlのレボチロキシンナトリウムが、コポリマー/HPBCDの下記濃度のいずれかを有する水溶液中において達成することが認められた。
0.5w/w%のCCMおよび15(w/w)%のHPBCD、
0.5w/w%のHPMCおよび20(w/w)%のHPBCD、または
2w/w%のポビドン12PFおよび20(w/w)%のHPBCD。
実施例1の第一製剤におけるレボチロキシンの安定性を、30ml密閉I型ガラス瓶中で試験した。2−8℃で6カ月後、有意な変化は外観上、レボチロキシン含有量(+3.1%)、リオチロニンナトリウム、エタノール含有量、またはpHにおいて全く認められなかった。これは、レボチロキシン含有量が、密閉した30mlI型ガラス瓶中、2−8℃で、9カ月を超えて安定(−4.2%)なままであると認められた異なる実験の結果と一致する。23−27℃および55−65%RHで6カ月後、レボチロキシン含有量(−6.7%)およびpHの軽度の低下が認められた。調製物は、いずれの例においても清澄なままであった。
安定化した、または安定化しないHPBCDの水溶液におけるレボチロキシンナトリウムの安定性を調べた。結果を表2−4に示す。
本出願人らによって、10.2のpHで20%HPBCDの水溶液にレボチロキシンナトリウムを添加した直後、溶液のpHが、約0.07から1.11単位低下することが認められた。本出願人らの知見を、表5において下記に要約する。
本出願人らは、20(w/v)%HPBCD水溶液中に溶解している0.1(w/v)%レボチロキシンナトリウムを含有する最終生成物における炭酸水素ナトリウムの緩衝能を、pHを0.1および1.0低下させるのに必要な0.5(v/v)%HCl溶液の量を測定することにより評価した。本出願人らの知見を、表8において下記に要約する。
本出願人らは、密閉容器中において、リン酸緩衝液およびカーボネート緩衝液を有するHPBCD水溶液中におけるレボチロキシンナトリウムの安定性を調べた。結果を表9において下記に要約する。
Claims (17)
- 少なくとも1種の甲状腺ホルモン、
1(重量)%超のヒドロキシプロピル−β−シクロデキストリン、
少なくとも1種の緩衝液、および
少なくとも5(重量)%の水
を含み、pHが8から12である液体医薬組成物。 - pHが9から10.5である、請求項1に記載の組成物。
- pHが10.1から10.3である、請求項2に記載の組成物。
- 甲状腺ホルモンが、レボチロキシンまたは医薬として許容できるこの塩を含む、請求項1から3のいずれか一項に記載の組成物。
- ヒドロキシプロピル−β−シクロデキストリン濃度が10(重量)%から50(重量)%である、請求項1から4のいずれか一項に記載の組成物。
- NaOHをさらに含む、請求項1から5のいずれか一項に記載の組成物。
- 緩衝液が少なくとも9.5のpKaを有する、請求項1から6のいずれか一項に記載の組成物。
- 緩衝液が、10.0から10.5のpHでpH安定性をもたらす、請求項1から7のいずれか一項に記載の組成物。
- 緩衝液が炭酸水素ナトリウムを含む、請求項1から8のいずれか一項に記載の組成物。
- 防腐剤を30(重量)%以下の濃度でさらに含む、請求項1から9のいずれか一項に記載の組成物。
- 5(重量)%から30(重量)%のエタノールをさらに含む、請求項1から10のいずれか一項に記載の組成物。
- 5(重量)%から20(重量)%のエタノールをさらに含む、請求項1から11のいずれか一項に記載の組成物。
- 医薬として許容できる抗酸化剤を5(重量)%以下の濃度でさらに含む、請求項1から12のいずれか一項に記載の組成物。
- ヒトではない動物における甲状腺ホルモン機能障害に伴う障害を治療する方法であり、請求項1から13のいずれか一項に記載の組成物の治療有効量を前記動物に投与することを含む方法。
- 前記動物がイヌである、請求項14に記載の方法。
- 前記状態が甲状腺機能低下症を含む、請求項14または15に記載の方法。
- 動物における甲状腺ホルモン機能障害に伴う障害の治療用薬物を製造するための、請求項1から13のいずれか一項に記載の組成物の使用。
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US75677706P | 2006-01-06 | 2006-01-06 | |
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EP06100133 | 2006-01-06 | ||
PCT/EP2007/050107 WO2007077252A1 (en) | 2006-01-06 | 2007-01-05 | Concentrated liquid thyroid hormone composition |
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IT1395454B1 (it) * | 2009-03-24 | 2012-09-21 | Altergon Sa | Composizioni e forme farmaceutiche per somministrazione orale di ormoni tiroidei in grado di contrastare l'azione di agenti sequestranti nel tratto gastrointestinale |
WO2012120338A1 (en) * | 2011-03-10 | 2012-09-13 | Emp Pharma Gmbh | Method for the preparaton of a levothyroxine solution |
US10328152B2 (en) | 2011-06-16 | 2019-06-25 | Nayan Patel | Method for stabilization and delivery of therapeutic molecules |
US9006289B2 (en) | 2011-08-30 | 2015-04-14 | Fresenius Kabi Usa, Llc | Levothyroxine formulations |
DE102013017917A1 (de) * | 2013-10-26 | 2015-04-30 | Michael Raschke | L-Thyrogal |
EP3315966A4 (en) * | 2015-06-29 | 2018-11-14 | Fujirebio Inc. | Standard thyroid gland hormone solution |
WO2017013591A1 (en) | 2015-07-22 | 2017-01-26 | Leiutis Pharmaceuticals Pvt Ltd | Stabilized liquid formulation of levothyroxine |
GB2558498B (en) | 2015-11-04 | 2020-10-14 | Leiutis Pharm Pvt Ltd | Novel levothyroxine formulations for oral use |
NL2017110B1 (en) | 2016-07-05 | 2018-01-12 | Emp Levo Gmbh | Methods for the preparation of a levothyroxine solution |
EP3311844A1 (en) | 2016-10-18 | 2018-04-25 | Altergon S.A. | High-stability packaged solutions of t4 thyroid hormone |
US9782376B1 (en) | 2016-12-01 | 2017-10-10 | Fresenius Kabi Usa Llc | Levothyroxine liquid formulations |
WO2019023791A1 (en) * | 2017-07-31 | 2019-02-07 | Apollo Pharmaceuticals Inc. | LEVOTHYROXIN FORMULATIONS |
US11241382B2 (en) | 2019-03-01 | 2022-02-08 | Altergon Sa | Administration regimen of compositions of T4 thyroid hormone with high oral absorption |
US20230338320A1 (en) | 2019-11-22 | 2023-10-26 | Wockhardt Limited | Oral film composition comprising levothyroxine |
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US5002935A (en) * | 1987-12-30 | 1991-03-26 | University Of Florida | Improvements in redox systems for brain-targeted drug delivery |
IE62095B1 (en) * | 1988-03-29 | 1994-12-14 | Univ Florida | Pharmaceutical formulations for parenteral use |
GB9012663D0 (en) * | 1990-06-07 | 1990-08-01 | Erba Carlo Spa | Galenic formulations containing cyclodextrins |
GB9401891D0 (en) | 1994-02-01 | 1994-03-30 | Boots Co Plc | Therapeutic agents |
WO1997017951A1 (en) * | 1995-11-14 | 1997-05-22 | Knoll Pharmaceutical Company | Stabilized thyroid hormone preparations and methods of making same |
HUT75956A (en) * | 1995-11-29 | 1997-05-28 | Cyclolab | Pharmaceutical composition containing thyroxine |
RU2359698C2 (ru) * | 2002-09-13 | 2009-06-27 | Сайдекс, Инк. | Капсулы, содержащие водные наполняющие композиции, стабилизированные производным циклодекстрина |
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WO2007077252A1 (en) | 2007-07-12 |
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