JP5727925B2 - 脂質組成物 - Google Patents
脂質組成物 Download PDFInfo
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- JP5727925B2 JP5727925B2 JP2011506766A JP2011506766A JP5727925B2 JP 5727925 B2 JP5727925 B2 JP 5727925B2 JP 2011506766 A JP2011506766 A JP 2011506766A JP 2011506766 A JP2011506766 A JP 2011506766A JP 5727925 B2 JP5727925 B2 JP 5727925B2
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- Prior art keywords
- testosterone
- acid
- oil
- composition
- lipid
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- A61P5/30—Oestrogens
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Description
ステロイドホルモンと、
脂質系担体であり、前記担体が少なくとも1つのトリグリセライド脂肪酸を含み、該脂肪酸が少なくとも炭素原子10個の長さである脂質系担体と
を含む、ステロイドの経口送達に適合した医薬組成物が提供される。
テストステロンまたはテストステロンの官能性変異体と、
少なくとも1つのトリグリセライド脂肪酸を含む脂質系担体であり、脂肪酸の長さが少なくとも炭素原子10個である脂質系担体と、
組成物中のテストステロンまたは前記官能性変異体の溶解性を促進する少なくとも1つの薬品と
を含む、テストステロンまたはテストステロンの官能性変異体の経口送達に適合した医薬組成物が提供される。
2.5〜7.5%w/wのテストステロン、
少なくとも40%w/wのゴマ油、
少なくとも30%w/wのラウログリコール、
少なくとも5%w/wのエタノール、および
少なくとも15%w/wのベンジルアルコールから成る。
ステロイドと、
脂肪酸が少なくとも炭素原子10個の長さの少なくとも1つのトリグリセライド脂肪酸を含む脂質系担体と、
組成物中のステロイドの溶解性を高める少なくとも1つの薬品と
を含む、ステロイドの経口送達に適合した医薬組成物が提供される。
テストステロンの送達に使用される脂質系は、天然食用油、この特定の蒸留画分、または合成的に修飾した誘導体から選択され得る。そのような系は、
A.植物または動物源から、炭素単位が10を超える(主)鎖長の脂肪酸を含有するトリグリセリドと共に得た食用油、すなわち、アーモンドオイル、アラキス(ラッカセイ)油、菜種油、肝油、コーン(トウモロコシ)油、綿実油、アマニ油、ブドウ種子油、ピーナッツ油、サフラワー油、ゴマ油、大豆油、ひまわり油およびクルミ油(表1参照)と、
B.カプリル酸/カプリン酸トリグリセリド(Migyol810および812)、カプリル酸/カプリン酸/リノール酸トリグリセリド(Miglyol818)、カプリル酸/カプリン酸/ミリスチン酸/ステアリン酸トリグリセリド(Softisan378)、カピル酸(capylic)/カプリン酸/コハク酸トリグリセリド(Miglyol829)、カプリル酸/カプリン酸トリグリセリド(および)ステアラルコニウムベノナイト(benonite)(および)プロピレンカーボネート(Migyol Gel T)、カプリル酸/カプリン酸トリグリセリド(および)ステアラルコニウムヘクトライト(および)プロピレンカーボネート(Migyol Gel B)などの中長鎖のトリグリセリドの蒸留画分(表2参照)と、
C.中長鎖の水素化ココグリセリドの蒸留画分−C10〜C18の脂肪酸のトリグリセリド(Softisan100、133、134、138、142、154)(表3参照)と、
D.個々の脂肪酸の蒸留画分−ミリスチン酸のトリグリセリド(Trimyristin Dynasan1140)、パルミチン酸のトリグリセリド(Tripalmintin Dynasan116)およびステアリン酸のトリグリセリド(Tristearin Dynasan118)(表4参照)と、
E.天然または水素化植物油のトリグリセリドのエステル交換生成物およびポリアルキレンポリオール−ポリオキシエチル化杏仁油(Labrafil M1944CS)、ポリオキシエチル化コーンオイル(Labrafil M2125CS)およびポリエチル化水素化ココナッツ(Gelucire37/06)(表5参照)と、
F.脂肪酸のプロピレングリコールモノおよび/またはジエステル−プロピレングリコールモノラウリン酸(ラウログリコール)、プロピレングリコールモノミリスチン酸(Mipryl)、プロピレングリコールジカプリル酸/ジカプリン酸(Capex200)、プロピレングリコールジカプリル酸/ジカプリン酸(Miglyol840)およびプロピレングリコールジカプリル酸/ジカプリン酸(NeobeeM−20)(表6参照)と
を含む。
表1に列挙した配合物系は、全てがテストステロンに対して顕著な可溶化容量(>50mg/1)を示し、これは、水媒体中で達成可能な可溶化容量(<0.3mg/g1)より少なくとも100倍高く、単一成分の脂質ビヒクル単独中で達成可能な可溶化容量(最大値、<10mg/g)より少なくとも5倍高い。
表1〜3に列挙した配合物系は、下記の方法に従って調製した。
a.液体添加剤は、配合物の各々に規定した重量比で、適当な容器内で混合し、均一なビヒクルを作った。
b.所定量のテストステロンを、完全な溶解を確保するために連続撹拌しながら、適切な場合軽く加熱して、均一なビヒクルに加えた。
c.テストステロン溶液の一定分量を、適切な用量強度を提供するために適当なサイズのカプセル(名目上のカプセルサイズ00)に充填した。
d.適当な粘度を有するゼラチン溶液を用いて、カプセル蓋でカプセル本体に封をし、密封(漏れのない)した。
表2〜4に記載したテストステロンの脂質配合物の分散安定性を、模擬胃内条件(pH1)および模擬腸内条件(pH6.8)の下で評価した。サンプルは、(ゼラチンカプセル中に充填した)テストステロン配合物を、Caleva溶解槽において37℃に維持した媒体250ml中に設置することにより評価した。パドル装置を用いて50rpmで穏やかに撹拌した。沈殿物に関して分散性を視覚的に観察し、形成物が溶液中に残留した時間を記録した。溶液系は、15、30および60分の時点において観察し、いくらかの沈殿が起こった場合、さらに試験することを中止した。変化が観察されない場合、試験を継続し、1時間毎に最大7時間監視し、その後24時間夜通し放置した。
表2〜3に記載したテストステロンの脂質配合物の物理的安定性を、室温(20〜25℃)において、および促進させた温度条件下(50℃)で、2週間にわたり評価した。テストステロンの脂質配合物は、サイズ00のゼラチンカプセル中に充填し、規定した各々の保存条件において安定性試験を行った。カプセルは、ガラスバイアル中に直立状態で(および水平に)保存した。全てのサンプルは、変色、沈殿、分離および(カプセルからの)漏出に関して、2週間にわたり毎日観察した。
脂質配合物B2およびB3の吸収挙動は、雌のビーグル犬において、投与間に少なくとも6日のウォッシュアウト期間をおき6相において評価した。給餌条件下の動物に全ての配合物を服用させ、1つの配合物(B2)は、絶食条件下でも服用させた。ゴマ油中のテストステロン懸濁液を含む対照配合物を、対照として含めた。試験品目の詳細および投薬シーケンスは、表4に示されている。
配合物の重要な生体外性能のデータセットの概要は、表5に提供されている。全ての非配合物系は、内容物を胃内環境へ放出するゼラチンカプセルの迅速な溶解を示した。テストステロン溶液の放出に続き、全ての配合物は、充填濃度依存性の分散安定性プロファイルを示した。非常に高いテストステロン充填濃度(配合物B1、>10mg/g)の安定性は、微細な(および限定された)沈殿の徴候があるまで最大10分間維持された。より低い濃度では、配合物系(B2、B3およびB4)は、最大1時間安定で、1時間を超えても胃腸管から生じる吸収には十分であった。
Claims (7)
- テストステロンの経口送達に適合した医薬組成物であって、
2.5〜7.5%w/wの天然のテストステロンと、
少なくとも40%w/wのゴマ油と、
少なくとも30%w/wのラウログリコールと、
少なくとも5%w/wのエタノールと、
少なくとも15%w/wのベンジルアルコール
とを含有する組成物。 - 5.46%w/wの天然のテストステロン、41.51%w/wのゴマ油、31.80%w/wのラウログリコール、5.3%w/wのエタノールおよび、15.93%w/wのベンジルアルコールからなる、請求項1に記載の組成物。
- 2.73%w/wの天然のテストステロン、42.7%w/wのゴマ油、32.72%w/wのラウログリコール、5.46%w/wのエタノールおよび、16.39%w/wのベンジルアルコールからなる、請求項1に記載の組成物。
- テストステロン補充療法において使用するための、請求項1から3のいずれか一項に記載の組成物。
- テストステロン療法が、男性の性腺機能低下症の治療である、請求項4に記載の組成物。
- テストステロン補充療法において使用するための組成物であって、テストステロンを生理的に補充するためにテストステロンの日周性分泌に従って被検体に有効量で投与される、請求項4又は5に記載の組成物。
- 前記組成物が、20時から24時の間に投与される、請求項6に記載の組成物。
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GB0807605.1 | 2008-04-28 | ||
GBGB0807605.1A GB0807605D0 (en) | 2008-04-28 | 2008-04-28 | Lipid composition |
PCT/GB2009/001068 WO2009133352A2 (en) | 2008-04-28 | 2009-04-27 | Lipid composition |
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GB0000313D0 (en) * | 2000-01-10 | 2000-03-01 | Astrazeneca Uk Ltd | Formulation |
EP1260225A1 (en) * | 2001-05-18 | 2002-11-27 | Pantarhei Bioscience B.V. | A pharmaceutical composition for use in hormone replacement therapy |
JO2505B1 (en) * | 2003-03-14 | 2009-10-05 | باير شيرنغ فارما اكتنجيسيلشافت | Pharmacy methods and formulations for obtaining acceptable serum testosterone levels |
US7138389B2 (en) * | 2004-02-09 | 2006-11-21 | University Of Washington | Oral androgen therapy using modulators of testosterone bioavailability |
RU2429850C2 (ru) | 2005-04-15 | 2011-09-27 | Кларус Терапьютикс, Инк. | Фармацевтические системы доставки для гидрофобных лекарственных средств и композиций, их содержащих |
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2008
- 2008-04-28 GB GBGB0807605.1A patent/GB0807605D0/en not_active Ceased
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2009
- 2009-04-27 CA CA2722408A patent/CA2722408C/en active Active
- 2009-04-27 EP EP09738382.2A patent/EP2273984B1/en active Active
- 2009-04-27 JP JP2011506766A patent/JP5727925B2/ja active Active
- 2009-04-27 KR KR1020107025087A patent/KR101617811B1/ko active IP Right Grant
- 2009-04-27 PT PT97383822T patent/PT2273984E/pt unknown
- 2009-04-27 AU AU2009241910A patent/AU2009241910B2/en active Active
- 2009-04-27 WO PCT/GB2009/001068 patent/WO2009133352A2/en active Application Filing
- 2009-04-27 DK DK09738382.2T patent/DK2273984T3/da active
- 2009-04-27 PL PL09738382T patent/PL2273984T3/pl unknown
- 2009-04-27 CN CN2009801149913A patent/CN102083421B/zh active Active
- 2009-04-27 US US12/989,948 patent/US9012436B2/en active Active
- 2009-04-27 EP EP13186572.7A patent/EP2722038A3/en not_active Withdrawn
- 2009-04-27 ES ES09738382.2T patent/ES2502242T3/es active Active
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- 2010-10-25 ZA ZA2010/07612A patent/ZA201007612B/en unknown
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- 2014-12-22 IL IL236400A patent/IL236400A/en active IP Right Grant
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Also Published As
Publication number | Publication date |
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AU2009241910B2 (en) | 2013-10-24 |
WO2009133352A3 (en) | 2010-10-28 |
EP2722038A3 (en) | 2014-06-18 |
US20110039814A1 (en) | 2011-02-17 |
GB0807605D0 (en) | 2008-06-04 |
CN102083421A (zh) | 2011-06-01 |
AU2009241910A1 (en) | 2009-11-05 |
ES2502242T3 (es) | 2014-10-03 |
KR20110007169A (ko) | 2011-01-21 |
IL208612A (en) | 2015-03-31 |
CN102083421B (zh) | 2012-12-12 |
ZA201007612B (en) | 2011-07-27 |
WO2009133352A2 (en) | 2009-11-05 |
IL236400A (en) | 2016-06-30 |
EP2273984A2 (en) | 2011-01-19 |
IL208612A0 (en) | 2010-12-30 |
PL2273984T3 (pl) | 2015-04-30 |
EP2722038A2 (en) | 2014-04-23 |
KR101617811B1 (ko) | 2016-05-03 |
DK2273984T3 (da) | 2014-08-25 |
CA2722408C (en) | 2018-01-30 |
PT2273984E (pt) | 2014-11-03 |
US9012436B2 (en) | 2015-04-21 |
JP2011519846A (ja) | 2011-07-14 |
EP2273984B1 (en) | 2014-07-30 |
CA2722408A1 (en) | 2009-11-05 |
IL236400A0 (en) | 2015-01-29 |
US20150133417A1 (en) | 2015-05-14 |
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