JP5932829B2 - 経口活性ヌクレオチドアナログ又は経口活性ヌクレオチドアナログプロドラッグの高度に安定な組成物 - Google Patents
経口活性ヌクレオチドアナログ又は経口活性ヌクレオチドアナログプロドラッグの高度に安定な組成物 Download PDFInfo
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Classifications
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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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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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
- A61K9/20—Pills, tablets, discs, rods
-
- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Description
[0074]この実施例は、本発明の一実施形態による組成物を調製及び特徴付けする方法を示すものである。
[0078]この実施例は、実施例1で説明した本発明の一実施形態によって調製された組成物の保存安定性を示すものである。
(a)40℃かつ75%RHで3ヶ月間保存されたときに、分解して生じる組成物に含有される経口生物学的利用能がより低いアデホビルのモノエステル(すなわちモノ−(POM)PMEA)の量は、初期製品の各単位用量中に最初に含有されていたADの量に対して2.0%w/w以下、好ましくは1.5%w/w、より好ましくは1.0%w/w、さらにより好ましくは0.75%w/w以下である。
(b)40℃かつ75%RHで2ヶ月間保存されたときに、分解して生じる組成物に含有される経口生物学的利用能がより低いアデホビルのモノエステル(すなわちモノ−(POM)PMEA)の量は、初期製品の各単位用量中に最初に含有されていたADの量に対して1.75%w/w以下、好ましくは1.5%w/w、より好ましくは1.0%w/w、さらにより好ましくは0.6%w/w以下である。
(c)40℃かつ75%RHで1ヶ月間保存されたときに、分解して生じる組成物に含有される経口生物学的利用能がより低いアデホビルのモノエステル(すなわちモノ(POM)−PMEA)の量は、初期製品の各単位用量中に最初に含有されていたADの量に対して1.5%w/w以下、好ましくは1.0%w/w、より好ましくは0.75%w/w、最も好ましくは0.5%w/w以下である。
(d)60℃かつ75%RHで5日間保存されたときに、分解して生じる組成物に含有される経口生物学的利用能がより低いアデホビルのモノエステル(すなわちモノ(POM)PMEA)の量は、初期製品の各単位用量中に最初に含有されていたADの量に対して2.5%w/w以下、好ましくは2.0%w/w、より好ましくは1.5%w/w、最も好ましくは1.0%w/w、さらに最も好ましくは0.7%w/w以下である。
(a)25℃かつ60%RHで24ヶ月間保存されたときに、該医薬製品が分解して生じる組成物に含有される経口生物学的利用能がより低いアデホビルのモノエステル(すなわちモノ−(POM)PMEA)の量は、初期製品の各単位用量中に最初に含有されていたADの量に対して1.5%w/w以下、好ましくは1.2%w/w、より好ましくは1.0%w/w、さらにより好ましくは0.8%w/w以下と予測される。
(b)25℃かつ60%RHで12ヶ月間保存されたときに、該医薬製品が分解して生じる組成物に含有される経口生物学的利用能がより低いアデホビルのモノエステル(すなわちモノ−(POM)PMEA)の量は、初期製品の各単位用量中に最初に含有されていたADの量に対して1.2%w/w以下、好ましくは1.0%w/w、より好ましくは0.8%w/w、さらにより好ましくは0.6%w/w以下である。
[0088]この実施例は、実施例1で説明した本発明の一実施形態によって調製された組成物の水性環境中への溶解中の薬物分解に対する抵抗性を示すものである。
(a)1時間の溶解の後に、各錠剤中に最初に含有されていたADの量に対して10.5%w/w以下、好ましくは8.5%w/w以下、より好ましくは6.0%w/w以下、さらにより好ましくは4.0%w/w以下の、経口生物学的利用能がより低いアデホビルのモノエステル
(b)30分の溶解の後に、各錠剤中に最初に含有されていたADの量に対して6.5%w/w以下、好ましくは5.5%w/w以下、より好ましくは4.3%w/w以下、さらにより好ましくは3.0%w/w以下の、経口生物学的利用能がより低いアデホビルのモノエステル
(a)2時間の溶解の後に、各錠剤中に最初に含有されていたADの量に対して6.4%w/w以下、好ましくは5.6%w/w以下、より好ましくは4.8%w/w以下、さらにより好ましくは4.1%w/w以下の、経口生物学的利用能がより低いアデホビルのモノエステル
(b)1時間の溶解の後に、各錠剤中に最初に含有されていたADの量に対して4.2%w/w以下、好ましくは3.6%w/w以下、より好ましくは3.0%w/w以下、さらにより好ましくは2.5%w/w以下の、経口生物学的利用能がより低いアデホビルのモノエステル
(c)30分の溶解の後に、各錠剤中に最初に含有されていたADの量に対して3.0%w/w以下、好ましくは2.5%w/w以下、より好ましくは2.0%w/w以下、さらにより好ましくは1.5%w/w以下の経口生物学的利用能がより低いアデホビルのモノエステル
Claims (10)
- (i)増量剤、賦形剤、結合剤、崩壊剤、流動促進剤、滑沢剤、及びマトリックス形成材料からなる群から選択される少なくとも1種の薬学的に許容される不活性な成分と、
(ii)9−[2−[ビス[(ピバロイルオキシ)−メトキシ]ホスフィニル]メトキシ]エチル]アデニン(AD)及びビニルピロリドン−酢酸ビニルコポリマーからなるアモルファス固溶体と、
を含む医薬組成物を製造する方法であって、
前記医薬組成物は固体剤形であり、
前記医薬組成物が温度40℃かつ相対湿度(RH)75%に3ヶ月間保持されるときに、ADが分解して生じる組成物に含有される、生物学的利用能がより低い不純物の量は、ADの当初の量に対して0.75重量%以下であり、
前記生物学的利用能がより低い不純物は9−[2−(ピバロイルオキシ)−メトキシホスフィニル]メトキシ]エチル]アデニンであり、
該方法は、
(i)ADとビニルピロリドン−酢酸ビニルコポリマーとを液体有機溶媒中に溶解し、液体有機溶媒を蒸発させることによって、前記アモルファス固溶体を調製するステップと、
(ii)得られたアモルファス固溶体を前記少なくとも1種の薬学的に許容される不活性な成分と乾燥混合させるステップと、
を含み、
前記液体有機溶媒は、揮発性ケトン、揮発性ハロカーボン、及びそれらの組み合わせからなる群から選択される、
方法。 - 前記液体有機溶媒は揮発性ケトンである、請求項1に記載の方法。
- 前記揮発性ケトンはアセトンである、請求項2に記載の方法。
- 前記医薬組成物が温度40℃かつRH75%に1ヶ月間保持されるときに、ADが分解して生じる組成物に含有される、前記生物学的利用能がより低い不純物の量は、ADの当初の量に対して0.5重量%以下である、請求項1〜3のいずれか一項に記載の方法。
- 前記医薬組成物が温度40℃かつRH75%に2ヶ月間保持されるときに、ADが分解して生じる組成物に含有される、前記生物学的利用能がより低い不純物の量は、ADの当初の量に対して0.6重量%以下である、請求項1〜4のいずれか一項に記載の方法。
- 前記少なくとも1種の薬学的に許容される不活性な成分は、無水ラクトース、微結晶性セルロース、二酸化ケイ素、及びステアリン酸マグネシウムからなる群から選択される、請求項1〜5のいずれか一項に記載の方法。
- 前記固体剤形は錠剤、カプセル剤又は散剤である、請求項1〜6のいずれか一項に記載の方法。
- 調製直後に前記医薬組成物中に存在する、前記生物学的利用能がより低い不純物の量は、ADの当初の量に対して0.15重量%以下である、請求項1〜7のいずれか一項に記載の方法。
- ADの当初の量は10mgである、請求項1〜8のいずれか一項に記載の方法。
- 前記医薬組成物は、ウイルス感染症又は腫瘍の治療のための医薬組成物である、請求項1〜9のいずれか一項に記載の方法。
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CN104688747B (zh) * | 2013-12-04 | 2019-04-12 | 重庆药友制药有限责任公司 | 包含富马酸替诺福韦二吡呋酯的药物组合物 |
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