JPWO2020225395A5 - - Google Patents
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- JPWO2020225395A5 JPWO2020225395A5 JP2021565869A JP2021565869A JPWO2020225395A5 JP WO2020225395 A5 JPWO2020225395 A5 JP WO2020225395A5 JP 2021565869 A JP2021565869 A JP 2021565869A JP 2021565869 A JP2021565869 A JP 2021565869A JP WO2020225395 A5 JPWO2020225395 A5 JP WO2020225395A5
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- methylnaltrexone
- docusate
- polyoxyl
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Description
図6は、メチルナルトレキソンの平均血漿中濃度と、上記セクション2.4に従い調製したメチルナルトレキソン-ドキュセートを含む自己乳化薬物送達システムの投与後の時間とを対比したものを示す。メチルナルトレキソンの最も高い血漿中濃度約8,000ng/mLがイヌ5において投与の1時間以内に観察された。
本発明は、以下の実施形態を包含する。
（実施形態１）
(a)式:
(b)油、界面活性剤、共溶媒、又はこれらの組合せ
を含む液体経口投与剤形の医薬組成物。
（実施形態２）
R
-
がラウリル硫酸である、実施形態1に記載の医薬組成物。
（実施形態３）
R
-
がドキュセートである、実施形態1に記載の医薬組成物。
（実施形態４）
約1重量%～約75重量%、約10重量%～約60重量%、約15重量%～約50重量%、又は約20重量%～約40重量%の前記イオン対を含む、実施形態1から3のいずれか一項に記載の医薬組成物。
（実施形態５）
前記油が、モノオレイン酸グリセリル、モノリノール酸グリセリル、ジカプリル酸/ジカプリン酸プロピレングリコール、ダイズ油、ジオレイン酸ポリグリセリル-3、オレイン酸、カプリル酸グリセリル、中間鎖トリグリセリド、及びこれらの組合せのうちの少なくとも1つを含む、実施形態1から4のいずれか一項に記載の医薬組成物。
（実施形態６）
前記油がモノリノール酸グリセリルを含む、実施形態1から5のいずれか一項に記載の医薬組成物。
（実施形態７）
前記油がオレイン酸を含む、実施形態1から6のいずれか一項に記載の医薬組成物。
（実施形態８）
前記油がカプリル酸グリセリルを含む、実施形態1から7のいずれか一項に記載の医薬組成物。
（実施形態９）
前記油が中間鎖トリグリセリドを含む、実施形態1から8のいずれか一項に記載の医薬組成物。
（実施形態１０）
前記油がカプリル酸グリセリル及び中間鎖トリグリセリドを含む、実施形態1から9のいずれか一項に記載の医薬組成物。
（実施形態１１）
少なくとも2種の油を含む、実施形態1から10のいずれか一項に記載の医薬組成物。
（実施形態１２）
前記医薬組成物の全油含有量が、約10重量%～約80重量%、約10重量%～約20重量%、約20重量%～約50重量%、又は約50重量%～約70重量%である、実施形態1から11のいずれか一項に記載の医薬組成物。
（実施形態１３）
少なくとも2種の界面活性剤を含む、実施形態1から12のいずれか一項に記載の医薬組成物。
（実施形態１４）
前記界面活性剤が、オレオイルポリオキシル-6グリセリド、リノレオイルポリオキシル-6グリセリド、カプリロカプロイルポリオキシル-8グリセリド、ポリソルベート80、ポリオキシル40硬化ヒマシ油、ヒドロキシステアリン酸ポリオキシル15、ラウロイルポリオキシル-32グリセリド、及びこれらの組合せからなる群から選択される、実施形態1から13のいずれか一項に記載の医薬組成物。
（実施形態１５）
前記界面活性剤がカプリロカプロイルポリオキシル-8グリセリドを含む、実施形態13又は14に記載の医薬組成物。
（実施形態１６）
前記界面活性剤がポリソルベート80を含む、実施形態13又は14に記載の医薬組成物。
（実施形態１７）
前記界面活性剤がリノレオイルポリオキシル-6グリセリドを含む、実施形態13又は14に記載の医薬組成物。
（実施形態１８）
約10重量%～約70重量%、約15重量%～約40重量%、又は約20重量%～約35重量%の前記界面活性剤を含む、実施形態1から17のいずれか一項に記載の医薬組成物。
（実施形態１９）
約1mg～約100mg、約50mg～約900mg、約75mg～約850mg、約100mg～約850mg、約150mg～約850mg、約200mg～約800mg、又は約200mg～約700mgの前記イオン対を含む、実施形態1から18のいずれか一項に記載の医薬組成物。
（実施形態２０）
少なくとも約1mg、約10mg、約25mg、約50mg、約75mg、約100mg、約150mg、約200mg、約250mg、約300mg、約350mg、約400mg、約450mg、約500mg、約550mg、約600mg、約650mg、約700mg、約750mg、約800mg、約850mg又は約900mgの前記イオン対を含む、実施形態1から19のいずれか一項に記載の医薬組成物。
（実施形態２１）
水をさらに含み、液体組成物がエマルジョンを含む、実施形態13から20のいずれか一項に記載の医薬組成物。
（実施形態２２）
前記組成物が水性液体との接触によりエマルジョンを形成する、実施形態13から20のいずれか一項に記載の医薬組成物。
（実施形態２３）
(a)式:
を含む、液体経口投与剤形の医薬組成物。
（実施形態２４）
R
-
がラウリル硫酸である、実施形態23に記載の医薬組成物。
（実施形態２５）
R
-
がドキュセートである、実施形態24に記載の医薬組成物。
（実施形態２６）
(i)メチルナルトレキソン、(ii)ラウリル硫酸又はドキュセート及び(iii)油、界面活性剤、及び共溶媒のうちの1つ以上を含む液体経口投与剤形の医薬組成物であって、前記メチルナルトレキソン及びラウリル硫酸又はドキュセートが実質的に等モル量で存在する、液体経口投与剤形の医薬組成物。
（実施形態２７）
ラウリル硫酸を含む、実施形態26に記載の医薬組成物。
（実施形態２８）
ドキュセートを含む、実施形態26に記載の医薬組成物。
（実施形態２９）
約1重量%～約75重量%、約10重量%～約60重量%、約15重量%～約50重量%、又は約20重量%～約40重量%の前記メチルナルトレキソン及びラウリル硫酸を含む、実施形態26又は27のいずれか一項に記載の医薬組成物。
（実施形態３０）
約1重量%～約75重量%、約10重量%～約60重量%、約15重量%～約50重量%、又は約20重量%～約40重量%の前記メチルナルトレキソン及びドキュセートを含む、実施形態26又は28のいずれか一項に記載の医薬組成物。
（実施形態３１）
前記油が、モノオレイン酸グリセリル、モノリノール酸グリセリル、ジカプリル酸/ジカプリン酸プロピレングリコール、ダイズ油、ジオレイン酸ポリグリセリル-3、オレイン酸、カプリル酸グリセリル、中間鎖トリグリセリド、及びこれらの組合せのうちの少なくとも1つを含む、実施形態26から30のいずれか一項に記載の医薬組成物。
（実施形態３２）
前記油がモノリノール酸グリセリルを含む、実施形態26から31のいずれか一項に記載の医薬組成物。
（実施形態３３）
前記油がオレイン酸を含む、実施形態26から32のいずれか一項に記載の医薬組成物。
（実施形態３４）
前記油がカプリル酸グリセリルを含む、実施形態26から33のいずれか一項に記載の医薬組成物。
（実施形態３５）
前記油が中間鎖トリグリセリドを含む、実施形態26から34のいずれか一項に記載の医薬組成物。
（実施形態３６）
前記組成物が少なくとも2種の油を含む、実施形態26から35のいずれか一項に記載の医薬組成物。
（実施形態３７）
前記2種の油が、カプリル酸グリセリル及び中間鎖トリグリセリドを含む、実施形態36に記載の医薬組成物。
（実施形態３８）
前記医薬組成物の全油含有量が、約10重量%～約80重量%、約10重量%～約20重量%、約20重量%～約50重量%、又は約50重量%～約70重量%である、実施形態26から37のいずれか一項に記載の医薬組成物。
（実施形態３９）
少なくとも2種の界面活性剤を含む、実施形態26から38のいずれか一項に記載の医薬組成物。
（実施形態４０）
前記界面活性剤が、オレオイルポリオキシル-6グリセリド、リノレオイルポリオキシル-6グリセリド、カプリロカプロイルポリオキシル-8グリセリド、ポリソルベート80、ポリオキシル40硬化ヒマシ油、ヒドロキシステアリン酸ポリオキシル15、ラウロイルポリオキシル-32グリセリド、及びこれらの組合せからなる群から選択される、実施形態26から39のいずれか一項に記載の医薬組成物。
（実施形態４１）
前記界面活性剤が、カプリロカプロイルポリオキシル-8グリセリドを含む、実施形態39又は40に記載の医薬組成物。
（実施形態４２）
前記界面活性剤が、ポリソルベート80を含む、実施形態39又は40に記載の医薬組成物。
（実施形態４３）
前記界面活性剤が、リノレオイルポリオキシル-6グリセリドを含む、実施形態39又は40に記載の医薬組成物。
（実施形態４４）
約10重量%～約70重量%、約15重量%～約40重量%、又は約20重量%～約35重量の前記界面活性剤を含む、実施形態1から43のいずれか一項に記載の医薬組成物。
（実施形態４５）
約1mg～約100mg、約50mg～約800mg、約100mg～約750mg、約150mg～約750mg、又は約200mg～約700mgの前記メチルナルトレキソン及びラウリル硫酸を含む、実施形態26、27、29、又は31から44のいずれか一項に記載の医薬組成物。
（実施形態４６）
約1mg～約100mg、約50mg～約900mg、約100mg～約900mg、約150mg～約850mg、又は約200mg～約800mgの前記メチルナルトレキソン及びドキュセートを含む、実施形態26、28、又は30から44のいずれか一項に記載の医薬組成物。
（実施形態４７）
少なくとも約1mg、約10mg、約25mg、約50mg、約75mg、約100mg、約150mg、約200mg、約250mg、約300mg、約350mg、約400mg、約450mg、約500mg、約550mg、約600mg、約650mg又は約700mgの前記メチルナルトレキソン及びラウリル硫酸を含む、実施形態26、27、29、又は31から44のいずれか一項に記載の医薬組成物。
（実施形態４８）
少なくとも約1mg、約10mg、約25mg、約50mg、約75mg、約100mg、約150mg、約200mg、約250mg、約300mg、約350mg、約400mg、約450mg、約500mg、約550mg、約600mg、約650mg、約700mg、約750mg、約800mg、約850mg又は約900mgの前記メチルナルトレキソン及びドキュセートを含む、実施形態26、28、又は30から44のいずれか一項に記載の医薬組成物。
（実施形態４９）
水をさらに含み、液体組成物がエマルジョンを含む、実施形態39から48のいずれか一項に記載の医薬組成物。
（実施形態５０）
前記組成物が水性液体との接触によりエマルジョンを形成する、実施形態39から48のいずれか一項に記載の医薬組成物。
（実施形態５１）
界面活性剤及び共溶媒を含む、実施形態1から50のいずれか一項に記載の医薬組成物。
（実施形態５２）
前記共溶媒が、トリアセチン、エタノール、グリセロール、プロピレングリコール、及びポリエチレングリコールからなる群から選択される、実施形態1から51のいずれか一項に記載の医薬組成物。
（実施形態５３）
安定剤をさらに含む、実施形態1から52のいずれか一項に記載の医薬組成物。
（実施形態５４）
前記安定剤が、ブチル化ヒドロキシトルエン(BHT)、ブチル化ヒドロキシアニソール(BHA)、没食子酸プロピル、アスコルビン酸-6-パルミテート、アルファトコフェロール、ビタミンE TPGS及びこれらの組合せからなる群から選択される、実施形態53に記載の医薬組成物。
（実施形態５５）
前記安定剤が、前記組成物の少なくとも約0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1、2、3、4、5、6、7、8、9、又は10重量%の量で存在する、実施形態54に記載の医薬組成物。
（実施形態５６）
式
（実施形態５７）
実施形態56に記載の塩を含む医薬組成物。
（実施形態５８）
経口投与のための液体組成物である、実施形態56に記載の医薬組成物。
（実施形態５９）
油をさらに含む、実施形態57又は58に記載の医薬組成物。
（実施形態６０）
界面活性剤及び共溶媒のうちの1つ以上をさらに含む、実施形態57から59のいずれか一項に記載の医薬組成物。
（実施形態６１）
カプセル剤である、実施形態1から55又は57から60のいずれか一項に記載の医薬組成物。
（実施形態６２）
それを必要とする対象においてオピオイド誘発性便秘を処置する方法であって、前記対象に実施形態1から55又は57から61のいずれか一項に記載の医薬組成物を経口投与することを含む、方法。
（実施形態６３）
前記対象への前記医薬組成物の経口投与が、約50ng/mL～約200ng/mLの範囲のメチルナルトレキソンのC
max
をもたらす、実施形態62に記載の方法。
（実施形態６４）
前記対象への前記医薬組成物の経口投与が、約4時間未満、約2時間未満、約1時間未満、約30分間未満、約15分間未満、又は約10分間未満である、メチルナルトレキソンのT
max
をもたらす、実施形態62又は63に記載の方法。
Figure 6 shows mean plasma concentrations of methylnaltrexone versus time after administration of a self-emulsifying drug delivery system containing methylnaltrexone-docusate prepared according to Section 2.4 above. The highest plasma concentration of methylnaltrexone of approximately 8,000 ng/mL was observed in dog 5 within 1 hour of dosing.
The present invention includes the following embodiments.
(Embodiment 1)
(a) Formula:
(b) oils, surfactants, co-solvents, or combinations thereof;
A pharmaceutical composition in liquid oral dosage form comprising:
(Embodiment 2)
The pharmaceutical composition according to embodiment 1, wherein R - is lauryl sulfate.
(Embodiment 3)
The pharmaceutical composition according to embodiment 1, wherein R - is docusate.
(Embodiment 4)
from about 1% to about 75%, from about 10% to about 60%, from about 15% to about 50%, or from about 20% to about 40% by weight of said ion pair, Embodiment 1 4. The pharmaceutical composition according to any one of 3 to 3.
(Embodiment 5)
The oil comprises at least glyceryl monooleate, glyceryl monolinoleate, propylene glycol dicaprylate/dicaprate, soybean oil, polyglyceryl-3 dioleate, oleic acid, glyceryl caprylate, medium chain triglycerides, and combinations thereof. 5. The pharmaceutical composition according to any one of embodiments 1-4, comprising one.
(Embodiment 6)
6. The pharmaceutical composition according to any one of embodiments 1-5, wherein said oil comprises glyceryl monolinoleate.
(Embodiment 7)
7. The pharmaceutical composition according to any one of embodiments 1-6, wherein said oil comprises oleic acid.
(Embodiment 8)
8. The pharmaceutical composition according to any one of embodiments 1-7, wherein said oil comprises glyceryl caprylate.
(Embodiment 9)
9. The pharmaceutical composition according to any one of embodiments 1-8, wherein said oil comprises medium chain triglycerides.
(Embodiment 10)
10. The pharmaceutical composition according to any one of embodiments 1-9, wherein said oil comprises glyceryl caprylate and medium chain triglycerides.
(Embodiment 11)
11. The pharmaceutical composition according to any one of embodiments 1-10, comprising at least two oils.
(Embodiment 12)
The total oil content of the pharmaceutical composition is from about 10% to about 80%, from about 10% to about 20%, from about 20% to about 50%, or from about 50% to about 70% by weight. %. The pharmaceutical composition according to any one of embodiments 1-11, wherein
(Embodiment 13)
13. The pharmaceutical composition according to any one of embodiments 1-12, comprising at least two surfactants.
(Embodiment 14)
The surfactant is oleoyl polyoxyl-6 glyceride, linoleoyl polyoxyl-6 glyceride, caprylocaproyl polyoxyl-8 glyceride, polysorbate 80, polyoxyl 40 hydrogenated castor oil, polyoxyl 15 hydroxystearate, lauroyl polyoxyl 14. The pharmaceutical composition according to any one of embodiments 1-13, which is selected from the group consisting of xyl-32 glycerides, and combinations thereof.
(Embodiment 15)
15. The pharmaceutical composition according to embodiment 13 or 14, wherein said surfactant comprises caprylocaproyl polyoxyl-8 glycerides.
(Embodiment 16)
15. The pharmaceutical composition according to embodiment 13 or 14, wherein said surfactant comprises polysorbate 80.
(Embodiment 17)
15. The pharmaceutical composition according to embodiment 13 or 14, wherein said surfactant comprises linoleoyl polyoxyl-6 glycerides.
(Embodiment 18)
18. Any one of embodiments 1-17, comprising from about 10% to about 70%, from about 15% to about 40%, or from about 20% to about 35% by weight of said surfactant. pharmaceutical composition of
(Embodiment 19)
about 1 mg to about 100 mg, about 50 mg to about 900 mg, about 75 mg to about 850 mg, about 100 mg to about 850 mg, about 150 mg to about 850 mg, about 200 mg to about 800 mg, or about 200 mg to about 700 mg of said ion pair. 19. A pharmaceutical composition according to any one of Forms 1-18.
(Embodiment 20)
at least about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 20. The pharmaceutical composition according to any one of embodiments 1-19, comprising 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg or about 900 mg of said ion pair.
(Embodiment 21)
21. The pharmaceutical composition according to any one of embodiments 13-20, further comprising water and wherein the liquid composition comprises an emulsion.
(Embodiment 22)
21. The pharmaceutical composition according to any one of embodiments 13-20, wherein said composition forms an emulsion upon contact with an aqueous liquid.
(Embodiment 23)
(a) Formula:
A pharmaceutical composition in liquid oral dosage form comprising:
(Embodiment 24)
24. The pharmaceutical composition according to embodiment 23, wherein R - is lauryl sulfate.
(Embodiment 25)
25. The pharmaceutical composition according to embodiment 24, wherein R - is docusate.
(Embodiment 26)
A pharmaceutical composition in a liquid oral dosage form comprising one or more of (i) methylnaltrexone, (ii) lauryl sulfate or docusate, and (iii) oils, surfactants, and co-solvents, said methylnaltrexone and lauryl sulfate or docusate are present in substantially equimolar amounts.
(Embodiment 27)
27. The pharmaceutical composition according to embodiment 26, comprising lauryl sulfate.
(Embodiment 28)
27. A pharmaceutical composition according to embodiment 26, comprising docusate.
(Embodiment 29)
about 1% to about 75%, about 10% to about 60%, about 15% to about 50%, or about 20% to about 40% by weight of said methylnaltrexone and lauryl sulfate; 28. The pharmaceutical composition according to any one of embodiments 26 or 27.
(Embodiment 30)
about 1% to about 75%, about 10% to about 60%, about 15% to about 50%, or about 20% to about 40% by weight of said methylnaltrexone and docusate. 29. A pharmaceutical composition according to any one of Forms 26 or 28.
(Embodiment 31)
The oil comprises at least glyceryl monooleate, glyceryl monolinoleate, propylene glycol dicaprylate/dicaprate, soybean oil, polyglyceryl-3 dioleate, oleic acid, glyceryl caprylate, medium chain triglycerides, and combinations thereof. 31. The pharmaceutical composition according to any one of embodiments 26-30, comprising one.
(Embodiment 32)
32. The pharmaceutical composition according to any one of embodiments 26-31, wherein said oil comprises glyceryl monolinoleate.
(Embodiment 33)
33. The pharmaceutical composition according to any one of embodiments 26-32, wherein said oil comprises oleic acid.
(Embodiment 34)
34. The pharmaceutical composition according to any one of embodiments 26-33, wherein said oil comprises glyceryl caprylate.
(Embodiment 35)
35. The pharmaceutical composition according to any one of embodiments 26-34, wherein said oil comprises medium chain triglycerides.
(Embodiment 36)
36. The pharmaceutical composition according to any one of embodiments 26-35, wherein said composition comprises at least two oils.
(Embodiment 37)
37. The pharmaceutical composition according to embodiment 36, wherein said two oils comprise glyceryl caprylate and medium chain triglycerides.
(Embodiment 38)
The total oil content of the pharmaceutical composition is from about 10% to about 80%, from about 10% to about 20%, from about 20% to about 50%, or from about 50% to about 70% by weight. %. The pharmaceutical composition according to any one of embodiments 26-37.
(Embodiment 39)
39. The pharmaceutical composition according to any one of embodiments 26-38, comprising at least two surfactants.
(Embodiment 40)
The surfactant is oleoyl polyoxyl-6 glyceride, linoleoyl polyoxyl-6 glyceride, caprylocaproyl polyoxyl-8 glyceride, polysorbate 80, polyoxyl 40 hydrogenated castor oil, polyoxyl 15 hydroxystearate, lauroyl polyoxyl 40. The pharmaceutical composition according to any one of embodiments 26-39, which is selected from the group consisting of xyl-32 glycerides, and combinations thereof.
(Embodiment 41)
41. The pharmaceutical composition according to embodiment 39 or 40, wherein said surfactant comprises caprylocaproyl polyoxyl-8 glycerides.
(Embodiment 42)
41. The pharmaceutical composition according to embodiment 39 or 40, wherein said surfactant comprises polysorbate 80.
(Embodiment 43)
41. The pharmaceutical composition according to embodiment 39 or 40, wherein said surfactant comprises linoleoyl polyoxyl-6 glycerides.
(Embodiment 44)
44. Any one of embodiments 1-43, comprising from about 10% to about 70%, from about 15% to about 40%, or from about 20% to about 35% by weight of said surfactant. pharmaceutical composition.
(Embodiment 45)
Embodiments 26, 27, 29, or 31 comprising about 1 mg to about 100 mg, about 50 mg to about 800 mg, about 100 mg to about 750 mg, about 150 mg to about 750 mg, or about 200 mg to about 700 mg of said methylnaltrexone and lauryl sulfate. 45. The pharmaceutical composition according to any one of 44.
(Embodiment 46)
of embodiment 26, 28, or 30-44, comprising from about 1 mg to about 100 mg, from about 50 mg to about 900 mg, from about 100 mg to about 900 mg, from about 150 mg to about 850 mg, or from about 200 mg to about 800 mg of said methylnaltrexone and docusate. A pharmaceutical composition according to any one of claims.
(Embodiment 47)
at least about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 45. The pharmaceutical composition of any one of embodiments 26, 27, 29, or 31-44, comprising 650 mg or about 700 mg of said methylnaltrexone and lauryl sulfate.
(Embodiment 48)
at least about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 45. The pharmaceutical composition of any one of embodiments 26, 28, or 30-44, comprising 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, or about 900 mg of said methylnaltrexone and docusate.
(Embodiment 49)
49. The pharmaceutical composition according to any one of embodiments 39-48, further comprising water, wherein the liquid composition comprises an emulsion.
(Embodiment 50)
49. The pharmaceutical composition according to any one of embodiments 39-48, wherein said composition forms an emulsion upon contact with an aqueous liquid.
(Embodiment 51)
51. The pharmaceutical composition according to any one of embodiments 1-50, comprising a surfactant and a co-solvent.
(Embodiment 52)
52. The pharmaceutical composition according to any one of embodiments 1-51, wherein said co-solvent is selected from the group consisting of triacetin, ethanol, glycerol, propylene glycol, and polyethylene glycol.
(Embodiment 53)
53. The pharmaceutical composition according to any one of embodiments 1-52, further comprising a stabilizer.
(Embodiment 54)
said stabilizer is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, ascorbate-6-palmitate, alpha tocopherol, vitamin E TPGS and combinations thereof; A pharmaceutical composition according to embodiment 53.
(Embodiment 55)
The stabilizer is at least about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2 , 3, 4, 5, 6, 7, 8, 9, or 10% by weight.
(Embodiment 56)
formula
(Embodiment 57)
A pharmaceutical composition comprising a salt according to embodiment 56.
(Embodiment 58)
57. A pharmaceutical composition according to embodiment 56, which is a liquid composition for oral administration.
(Embodiment 59)
59. The pharmaceutical composition according to embodiment 57 or 58, further comprising an oil.
(Embodiment 60)
60. The pharmaceutical composition according to any one of embodiments 57-59, further comprising one or more of surfactants and co-solvents.
(Embodiment 61)
The pharmaceutical composition according to any one of embodiments 1-55 or 57-60, which is a capsule.
(Embodiment 62)
A method of treating opioid-induced constipation in a subject in need thereof, comprising orally administering to said subject a pharmaceutical composition according to any one of embodiments 1-55 or 57-61, Method.
(Embodiment 63)
63. The method of embodiment 62, wherein oral administration of said pharmaceutical composition to said subject results in a C max of methylnaltrexone ranging from about 50 ng/mL to about 200 ng/mL.
(Embodiment 64)
T of methylnaltrexone, wherein oral administration of the pharmaceutical composition to the subject is less than about 4 hours, less than about 2 hours, less than about 1 hour, less than about 30 minutes, less than about 15 minutes, or less than about 10 minutes 64. The method of embodiment 62 or 63, which results in max .
Claims (12)
を含む液体経口投与剤形の医薬組成物。 (a) Formula:
A pharmaceutical composition in liquid oral dosage form comprising :
をさらに含む、請求項1に記載の医薬組成物。2. The pharmaceutical composition of claim 1, further comprising
（ii）約1mg～約100mg、約50mg～約900mg、約75mg～約850mg、約100mg～約850mg、約150mg～約850mg、約200mg～約800mg、又は約200mg～約700mgの前記イオン対を含む、及び／又は
（iii）少なくとも約1mg、約10mg、約25mg、約50mg、約75mg、約100mg、約150mg、約200mg、約250mg、約300mg、約350mg、約400mg、約450mg、約500mg、約550mg、約600mg、約650mg、約700mg、約750mg、約800mg、約850mg又は約900mgの前記イオン対を含む、
請求項1又は2に記載の医薬組成物。 (i) from about 1% to about 75%, from about 10% to about 60%, from about 15% to about 50%, or from about 20% to about 40% by weight of said ion pair;
(ii) about 1 mg to about 100 mg, about 50 mg to about 900 mg, about 75 mg to about 850 mg, about 100 mg to about 850 mg, about 150 mg to about 850 mg, about 200 mg to about 800 mg, or about 200 mg to about 700 mg of the ion pair; includes and/or
(iii) at least about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg or about 900 mg of said ion pair;
3. The pharmaceutical composition according to claim 1 or 2 .
（ii）約1重量%～約75重量%、約10重量%～約60重量%、約15重量%～約50重量%、又は約20重量%～約40重量%の前記メチルナルトレキソン及びドキュセートを含む、
（iii）約1mg～約100mg、約50mg～約800mg、約100mg～約750mg、約150mg～約750mg、又は約200mg～約700mgの前記メチルナルトレキソン及びラウリル硫酸を含む、
（iv）約1mg～約100mg、約50mg～約900mg、約100mg～約900mg、約150mg～約850mg、又は約200mg～約800mgの前記メチルナルトレキソン及びドキュセートを含む、
（v）少なくとも約1mg、約10mg、約25mg、約50mg、約75mg、約100mg、約150mg、約200mg、約250mg、約300mg、約350mg、約400mg、約450mg、約500mg、約550mg、約600mg、約650mg又は約700mgの前記メチルナルトレキソン及びラウリル硫酸を含む、及び／又は
（vi）少なくとも約1mg、約10mg、約25mg、約50mg、約75mg、約100mg、約150mg、約200mg、約250mg、約300mg、約350mg、約400mg、約450mg、約500mg、約550mg、約600mg、約650mg、約700mg、約750mg、約800mg、約850mg又は約900mgの前記メチルナルトレキソン及びドキュセートを含む、
請求項4に記載の医薬組成物。 (i) from about 1% to about 75%, from about 10% to about 60%, from about 15% to about 50%, or from about 20% to about 40% by weight of said methylnaltrexone and lauryl sulfate; including,
(ii) from about 1% to about 75%, from about 10% to about 60%, from about 15% to about 50%, or from about 20% to about 40% by weight of said methylnaltrexone and docusate; include,
(iii) about 1 mg to about 100 mg, about 50 mg to about 800 mg, about 100 mg to about 750 mg, about 150 mg to about 750 mg, or about 200 mg to about 700 mg of said methylnaltrexone and lauryl sulfate;
(iv) about 1 mg to about 100 mg, about 50 mg to about 900 mg, about 100 mg to about 900 mg, about 150 mg to about 850 mg, or about 200 mg to about 800 mg of said methylnaltrexone and docusate;
(v) at least about 1 mg, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, about 650 mg, or about 700 mg of said methylnaltrexone and lauryl sulfate; and/or
(vi) at least about 1 mg, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg or about 900 mg of said methylnaltrexone and docusate;
5. A pharmaceutical composition according to claim 4 .
（ii）少なくとも2種の界面活性剤を含む、
（iii）前記界面活性剤が、オレオイルポリオキシル-6グリセリド、リノレオイルポリオキシル-6グリセリド、カプリロカプロイルポリオキシル-8グリセリド、ポリソルベート80、ポリオキシル40硬化ヒマシ油、ヒドロキシステアリン酸ポリオキシル15、ラウロイルポリオキシル-32グリセリド、及びこれらの組合せからなる群から選択される、
（iv）約10重量%～約70重量%、約15重量%～約40重量%、又は約20重量%～約35重量の前記界面活性剤を含む、及び／又は
（v）界面活性剤及び共溶媒を含む、好ましくは前記共溶媒が、トリアセチン、エタノール、グリセロール、プロピレングリコール、及びポリエチレングリコールからなる群から選択される、
請求項1から5のいずれか一項に記載の医薬組成物。 (i) the oil is glyceryl monooleate, glyceryl monolinoleate, propylene glycol dicaprylate/dicaprate, soybean oil, polyglyceryl-3 dioleate, oleic acid, glyceryl caprylate, medium chain triglycerides, and combinations thereof; preferably said composition comprises at least two oils, more preferably said two oils comprise glyceryl caprylate and medium chain triglycerides,
(ii) comprising at least two surfactants;
(iii) the surfactant is oleoyl polyoxyl-6 glyceride, linoleoyl polyoxyl-6 glyceride, caprylocaproyl polyoxyl-8 glyceride, polysorbate 80, polyoxyl 40 hydrogenated castor oil, polyoxyl hydroxystearate 15 , lauroyl polyoxyl-32 glycerides, and combinations thereof;
(iv) from about 10% to about 70%, from about 15% to about 40%, or from about 20% to about 35% by weight of said surfactant, and/or
(v) a surfactant and a co-solvent, preferably said co-solvent is selected from the group consisting of triacetin, ethanol, glycerol, propylene glycol and polyethylene glycol;
6. A pharmaceutical composition according to any one of claims 1-5 .
（ii）安定剤をさらに含む、好ましくは
-前記安定剤が、ブチル化ヒドロキシトルエン(BHT)、ブチル化ヒドロキシアニソール(BHA)、没食子酸プロピル、アスコルビン酸-6-パルミテート、アルファトコフェロール、ビタミンE TPGS及びこれらの組合せからなる群から選択される、及び／又は
-前記安定剤が、前記組成物の少なくとも約0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1、2、3、4、5、6、7、8、9、又は10重量%の量で存在する、
請求項1から7のいずれか一項に記載の医薬組成物。 (i) a surfactant and a co-solvent, preferably said co-solvent is selected from the group consisting of triacetin, ethanol, glycerol, propylene glycol and polyethylene glycol;
(ii) further comprising a stabilizer, preferably
- said stabilizer is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, ascorbic acid-6-palmitate, alpha tocopherol, vitamin E TPGS and combinations thereof , and/or
- said stabilizer is at least about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 of said composition; present in an amount of 2, 3, 4, 5, 6, 7, 8, 9, or 10% by weight;
8. A pharmaceutical composition according to any one of claims 1-7 .
-約50ng/mL～約200ng/mLの範囲のメチルナルトレキソンのC max をもたらす、及び／又は
-約4時間未満、約2時間未満、約1時間未満、約30分間未満、約15分間未満、又は約10分間未満である、メチルナルトレキソンのT max をもたらす、
前記医薬組成物。 12. A pharmaceutical composition according to any one of claims 1 to 11 for use in treating opioid- induced constipation in a subject in need thereof, said pharmaceutical composition being orally administered to said subject. optionally orally administering said pharmaceutical composition to said subject comprising
- results in a Cmax of methylnaltrexone in the range of about 50 ng/mL to about 200 ng/mL , and/or
- results in a T max of methylnaltrexone that is less than about 4 hours, less than about 2 hours, less than about 1 hour, less than about 30 minutes, less than about 15 minutes, or less than about 10 minutes,
Said pharmaceutical composition .
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| US201962844613P | 2019-05-07 | 2019-05-07 | |
| US62/844,613 | 2019-05-07 | ||
| US202063010528P | 2020-04-15 | 2020-04-15 | |
| US63/010,528 | 2020-04-15 | ||
| PCT/EP2020/062794 WO2020225395A1 (en) | 2019-05-07 | 2020-05-07 | Liquid oral dosage formulations of methylnaltrexone |
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| US4518433A (en) | 1982-11-08 | 1985-05-21 | Fmc Corporation | Enteric coating for pharmaceutical dosage forms |
| US4719215A (en) | 1986-03-07 | 1988-01-12 | University Of Chicago | Quaternary derivatives of noroxymorphone which relieve nausea and emesis |
| US4861781A (en) | 1986-03-07 | 1989-08-29 | The University Of Chicago | Quaternary derivatives of noroxymorphone which relieve nausea and emesis |
| US4816259A (en) | 1987-02-12 | 1989-03-28 | Chase Chemical Company, L.P. | Process for coating gelatin capsules |
| US5102887A (en) | 1989-02-17 | 1992-04-07 | Arch Development Corporation | Method for reducing emesis and nausea induced by the administration of an emesis causing agent |
| US5330759A (en) | 1992-08-26 | 1994-07-19 | Sterling Winthrop Inc. | Enteric coated soft capsules and method of preparation thereof |
| DE19651551C2 (en) | 1996-12-11 | 2000-02-03 | Klinge Co Chem Pharm Fab | Opioid antagonist-containing galenic formulation |
| US6559158B1 (en) | 1997-11-03 | 2003-05-06 | Ur Labs, Inc. | Use of methylnaltrexone and related compounds to treat chronic opioid use side affects |
| US5972954A (en) | 1997-11-03 | 1999-10-26 | Arch Development Corporation | Use of methylnaltrexone and related compounds |
| US6274591B1 (en) | 1997-11-03 | 2001-08-14 | Joseph F. Foss | Use of methylnaltrexone and related compounds |
| ES2500316T3 (en) | 2002-10-01 | 2014-09-30 | Banner Pharmacaps, Inc. | Enteric composition for the manufacture of a soft capsule shell |
| US8946262B2 (en) | 2003-12-04 | 2015-02-03 | Adolor Corporation | Methods of preventing and treating gastrointestinal dysfunction |
| AR057035A1 (en) | 2005-05-25 | 2007-11-14 | Progenics Pharm Inc | SYNTHESIS OF (R) -N-METHYLNTREXONE, PHARMACEUTICAL COMPOSITIONS AND USES |
| MX368805B (en) | 2010-03-11 | 2019-10-17 | Wyeth Llc | Oral formulations and lipophilic salts of methylnaltrexone. |
| JP6397813B2 (en) | 2012-05-02 | 2018-09-26 | キャプシュゲル・ベルジウム・エヌ・ヴィ | Hydroxypropyl methylcellulose acetate succinate (HPMCAS) aqueous dispersion |
| US10485798B2 (en) * | 2012-08-22 | 2019-11-26 | Aptapharma Inc. | Methylnaltrexone nasal formulations, methods of making, and use thereof |
| WO2016061531A1 (en) * | 2014-10-17 | 2016-04-21 | Salix Pharmaceuticals, Inc. | Use of methylnaltrexone to attenuate tumor progression |
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