JP6866560B2 - エステトロール成分を含有する口腔内崩壊性投与単位 - Google Patents
エステトロール成分を含有する口腔内崩壊性投与単位 Download PDFInfo
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- JP6866560B2 JP6866560B2 JP2017564402A JP2017564402A JP6866560B2 JP 6866560 B2 JP6866560 B2 JP 6866560B2 JP 2017564402 A JP2017564402 A JP 2017564402A JP 2017564402 A JP2017564402 A JP 2017564402A JP 6866560 B2 JP6866560 B2 JP 6866560B2
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- estetrol
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- DEIYFTQMQPDXOT-UHFFFAOYSA-N sildenafil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 DEIYFTQMQPDXOT-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 238000012306 spectroscopic technique Methods 0.000 description 1
- 235000000891 standard diet Nutrition 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 125000000185 sucrose group Chemical group 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229960003410 testosterone decanoate Drugs 0.000 description 1
- VOCBWIIFXDYGNZ-IXKNJLPQSA-N testosterone enanthate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCCCC)[C@@]1(C)CC2 VOCBWIIFXDYGNZ-IXKNJLPQSA-N 0.000 description 1
- 229960003484 testosterone enanthate Drugs 0.000 description 1
- 229960001712 testosterone propionate Drugs 0.000 description 1
- 229960000746 testosterone undecanoate Drugs 0.000 description 1
- UDSFVOAUHKGBEK-CNQKSJKFSA-N testosterone undecanoate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCCCCCCCC)[C@@]1(C)CC2 UDSFVOAUHKGBEK-CNQKSJKFSA-N 0.000 description 1
- 150000003515 testosterones Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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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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- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
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- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
Description
上記エステトロール成分を少なくとも80重量%含有するエステトロール粒子0.1〜25重量%、及び
1種又は複数の薬学的に許容される成分75〜99.9重量%
から成る。
国際公開第2002/094275号は、女性のリビドーを増強する方法におけるエステトロールの使用について記載されており、前記方法は、前記女性に有効量のエステトロールを投与することを含む。経口投与は適切な投与様式として言及されている。この特許出願は、国際公開第2002/094276号と同じエステトロール錠剤について記載されている。
国際公開第2003/041718号は、哺乳動物に対するホルモン補充法におけるエステトロールの使用について記載されており、前記方法は、哺乳動物に、低エストロゲン症の症状を予防又は治療するために有効な量のエステトロール及びプロゲストゲン成分を経口投与することを含む。この特許出願は、国際公開第2002/094279号と同じエステトロール錠剤について記載されている。
上記エステトロール成分を少なくとも80重量%含有するエステトロール粒子0.1〜25重量%、及び
1種又は複数の薬学的に許容される成分75〜99.9重量%
から成る。
上記エステトロール成分を少なくとも80重量%含有し、体積中位径が2μm〜50μmであるエステトロール粒子を提供するステップ、
上記エステトロール粒子を1種又は複数の顆粒化賦形剤と混合し、顆粒化混合物を製造するステップ、
上記顆粒化混合物を、液体溶媒を少なくとも60重量%含有する、造粒液と混合し、エステトロール含有顆粒を形成するステップ、
上記エステトロール含有顆粒から液体溶媒を除去し、乾燥したエステトロール含有顆粒を形成するステップ、
任意選択で、上記乾燥した顆粒を1種又は複数の錠剤化賦形剤と混合するステップ、及び
上記乾燥した顆粒又は乾燥した顆粒と1種又は複数の錠剤化賦形剤の上記混合物を固形投与単位に形成するステップ
を含む方法によって入手可能である。
エステトロール、エステトロールエステル、及びその組合せから選択されるエステトロール成分を少なくとも80重量%含有し、体積中位径が2μm〜50μmであるエステトロール粒子を提供するステップ、
上記エステトロール粒子を1種又は複数の顆粒化賦形剤と混合し、顆粒化混合物を製造するステップ、
上記顆粒化混合物を、液体溶媒を少なくとも60重量%含有する、造粒液と混合し、エステトロール含有顆粒を形成するステップ、
上記エステトロール含有顆粒から液体溶媒を除去し、乾燥したエステトロール含有顆粒を形成するステップ、
任意選択で、上記乾燥した顆粒を1種又は複数の薬学的に許容される賦形剤と混合するステップ、及び
上記乾燥した顆粒又は乾燥した顆粒と1種又は複数の錠剤化賦形剤の上記混合物を固形投与単位に形成するステップ
を含む、前記方法をさらに提供する。
エステトロール、エステトロールエステル、及びその組合せから選択されるエステトロール成分を少なくとも80重量%含有するエステトロール粒子0.1〜25重量%、及び
1種又は複数の薬学的に許容される成分75〜99.9重量%
から成る、前記投与単位であって、
上記エステトロール成分を少なくとも100μg含有する上記固形投与単位に関し;
ここで、上記固形投与単位は:
上記エステトロール成分を少なくとも80重量%含有し、体積中位径が2μm〜50μmであるエステトロール粒子を提供するステップ、
上記エステトロール粒子を1種又は複数の顆粒化賦形剤と混合し、顆粒化混合物を製造するステップ、
上記顆粒化混合物を、液体溶媒を少なくとも60重量%含有する、造粒液と混合し、エステトロール含有顆粒を形成するステップ、
上記エステトロール含有顆粒から液体溶媒を除去し、乾燥したエステトロール含有顆粒を形成するステップ、
任意選択で、上記乾燥した顆粒を1種又は複数の錠剤化賦形剤と混合するステップ、及び
上記乾燥した顆粒又は乾燥した顆粒と1種又は複数の錠剤化賦形剤の上記混合物を固形投与単位に形成するステップ
を含む方法によって得られる。
エステトロール、エステトロールエステル、及びその組合せから選択されるエステトロール成分を少なくとも80重量%含有し、体積中位径が2μm〜50μmであるエステトロール粒子を提供するステップ、
上記エステトロール粒子を1種又は複数の顆粒化賦形剤と混合し、顆粒化混合物を製造するステップ、
上記顆粒化混合物を、液体溶媒を少なくとも60重量%含有する、造粒液と混合し、エステトロール含有顆粒を形成するステップ、
上記エステトロール含有顆粒から液体溶媒を除去し、乾燥したエステトロール含有顆粒を形成するステップ、
任意選択で、上記乾燥した顆粒を1種又は複数の錠剤化賦形剤と混合するステップ、及び
上記乾燥した顆粒又は乾燥した顆粒と1種又は複数の錠剤化賦形剤の上記混合物を固形投与単位に形成するステップ
を含む、前記方法に関する。
下記溶出試験は、口腔内崩壊性投与単位の溶出挙動を試験するために適用することができる。
パドル及びバスケット溶出試験器バンケルVK7010(VanKel VK7010)又はVK7025、オートサンプラーVK8000、1000mL溶出試験器用ベッセル、及び多孔性ミクロンフィルター(35ピン)
10,000mLのメスフラスコに脱イオン水(demineralised water)9,000mLを移す。
68.05gのKH2PO4及び8.96gのNaOHを加え、すべてが溶解するまで上記溶液を撹拌する。
上記溶液を混合し、必要であれば、NaOH又はリン酸を用いてpHを6.8に調整し、脱イオン水を用いて体積を調整する。
溶出媒体900mLをパドル装置の各ベッセルに移す。
装置を組み立て、上記媒体を37±0.5℃に加温し、温度計を取り外す。
パドルの回転を開始する前に6個のベッセルの底にそれぞれ1個の錠剤を置く。
直ちにパドルの回転を開始する。
50rpmの撹拌速度を用いる。
1.15gのNH4H2PO4(10mM)を脱イオン水1,000mLに移して溶解し、リン酸を用いてpHを3.0に調整する。
クォータナリ溶媒送達システム、容量可変インジェクター、温度制御オートサンプラー、カラム恒温槽、及びフォトダイオードアレイ検出器2996(すべてWaters)から成るアライアンス2695(Alliance2695)分離モジュール
分析カラム:シンメトリーC18(Symmetry C18)、3.9×150mm、dp=5μm(Waters製)
ガードカラム:セキュリティーガード(Security guard)カラムC18、4x3mm(Phenomenex)
流量:1.0mL/分
検出:UV@280nm
カラム温度:30℃
オートサンプラー温度:10℃
注入量:100μL
実行時間:12分
溶出試験は3回実施する。
エステトロール一水和物の粒径分布は、マルバーンマスターサイザーマイクロプラス(MALVERN MASTERSIZER MICROPLUS)レーザー粒径分析器を用いて実施する。
エステトロール一水和物1g及びトリオレイン酸ソルビタン1gをフラスコ内に量り取る。
n−ヘキサン1Lを加え、室温で少なくとも1時間混合する。
0.45μmフィルターを通して濾過する。
サンプル100mgを25mLビーカーに入れる。
分散媒を数滴加える。
ガラス棒で慎重に混合し、粉末を十分に懸濁させる。
分散媒10mLを加える。
サンプル分散ユニットの速度3000〜3500rpmで分析を実施する。
粒径測定は、同じ分散を用いて3回実施する。最終的な結果は、3回の検出結果を平均して得られる。
舌下錠は、下記の手順によって調製する。
舌下錠は、下記の手順によって調製する。
舌下錠は、下記の手順によって調製する。
7種の異なる舌下錠のセット(製剤処方A〜G)は、下記の手順及び図1に示される手順によって調製した。
無作為化、非盲検、二期間、クロスオーバー、薬物動態試験を実施し、80mgの錠剤(実施例4の製剤処方Eに記載の錠剤として同組成物を含有)1個で投与されたエステトロール10mgの舌下バイオアベイラビリティと、エステトロール10mgを含有する83mgの錠剤に含有されたエステトロールの経口アベイラビリティを比較した。これらの錠剤は、絶食状態の女性健常者に舌下及び経口投与された。
Claims (28)
- 重量が30〜1,000mgの間である口腔内崩壊性固形医薬剤形であって:
エステトロール、エステトロールエステル、及びその組合せから選択されるエステトロール成分を少なくとも90重量%含有するエステトロール粒子0.1〜25重量%、及び
1種又は複数の薬学的に許容される成分75〜99.9重量%
から成り、
前記エステトロール粒子が、1種又は複数の顆粒化賦形剤をさらに含有する顆粒の成分として前記剤形中に存在し、
前記エステトロール成分を少なくとも100μg含有し;
前記エステトロール成分を少なくとも90重量%含有し、体積中位径が2μm〜50μmであるエステトロール粒子を提供するステップ、
前記エステトロール粒子を1種又は複数の顆粒化賦形剤と混合し、顆粒化混合物を製造するステップ、
前記顆粒化混合物を、液体溶媒を少なくとも60重量%含有する、造粒液と混合し、エステトロール含有顆粒を形成するステップ、
前記エステトロール含有顆粒から液体溶媒を除去し、乾燥したエステトロール含有顆粒を形成するステップ、
任意選択で、前記乾燥した顆粒を1種又は複数の錠剤化賦形剤と混合するステップ、及び
前記乾燥した顆粒又は乾燥した顆粒と1種又は複数の錠剤化賦形剤の前記混合物を固形剤形に形成するステップ
を含む方法によって得られる、口腔内崩壊性固形医薬剤形。 - 前記剤形の重量が40〜500mgの間である、請求項1に記載の口腔内崩壊性固形医薬剤形。
- エステトロール成分を0.5〜25重量%含有する、請求項1又は2に記載の口腔内崩壊性固形医薬剤形。
- 前記エステトロール成分を0.3〜100mg含有する、請求項1〜3のいずれか一項に記載の口腔内崩壊性固形医薬剤形。
- 前記エステトロール成分がエステトロールである、請求項1〜4のいずれか一項に記載の口腔内崩壊性固形医薬剤形。
- 前記エステトロール粒子の体積中位径が3〜35μmである、請求項1〜5のいずれか一項に記載の口腔内崩壊性固形医薬剤形。
- マルトース、フルクトース、スクロース、ラクトース、グルコース、ガラクトース、トレハロース、キシリトール、ソルビトール、エリスリトール、マルチトール、マンニトール、イソマルト、及びその組合せから選択される水溶性炭水化物を50〜99.9重量%含有する、請求項1〜6のいずれか一項に記載の口腔内崩壊性固形医薬剤形。
- 前記剤形がマンニトールを少なくとも20重量%含有する、請求項7に記載の口腔内崩壊性固形医薬剤形。
- 前記剤形が、加工デンプン、架橋ポリビニルピロリドン、クロスカルメロース、及びその組合せから選択される崩壊剤を0.1〜20重量%含有する、請求項1〜8のいずれか一項に記載の口腔内崩壊性固形医薬剤形。
- 医学的治療における使用又は女性ホルモン補充療法における使用であって、前記剤形を舌下、頬側、又は唇下投与することを含む前記使用のための、請求項1〜9のいずれか一項に記載の口腔内崩壊性固形医薬剤形。
- 前記使用が、少なくとも1週間の期間に1日1回投与することを含む、請求項10に記載の口腔内崩壊性固形医薬剤形。
- 女性の避妊の方法における使用であって、前記剤形を舌下、頬側、又は唇下投与することを含む前記使用のための、請求項1〜9のいずれか一項に記載の口腔内崩壊性固形医薬剤形。
- 前記使用が、少なくとも1週間の期間に1日1回投与することを含む、請求項12に記載の口腔内崩壊性固形医薬剤形。
- 請求項1〜13のいずれか一項に記載の口腔内崩壊性固形医薬剤形を製造する方法であって:
エステトロール、エステトロールエステル、及びその組合せから選択されるエステトロール成分を少なくとも90重量%含有し、体積中位径が2μm〜50μmであるエステトロール粒子を形成するステップ、
前記エステトロール粒子を1種又は複数の顆粒化賦形剤と混合し、顆粒化混合物を製造するステップ、
前記顆粒化混合物を、液体溶媒を少なくとも60重量%含有する、造粒液と混合し、エステトロール含有顆粒を形成するステップ、
前記エステトロール含有顆粒から液体溶媒を除去し、乾燥したエステトロール含有顆粒を形成するステップ、
任意選択で、前記乾燥した顆粒を1種又は複数の錠剤化賦形剤と混合するステップ、及び
前記乾燥した顆粒又は乾燥した顆粒と1種又は複数の錠剤化賦形剤の前記混合物を固形剤形に形成するステップ
を含む、方法。 - 前記エステトロール粒子の体積中位径が3〜35μmである、請求項14に記載の方法。
- 前記顆粒化混合物が、加工デンプン、架橋PVP、クロスカルメロース、及びその組合せから選択される崩壊剤を0.1〜20重量%含有する、請求項14又は15に記載の方法。
- 前記顆粒化混合物が、前記エステトロール粒子と前記1種又は複数の顆粒化賦形剤を、1:4〜1:1,000の範囲内の重量比で組み合わせることによって製造される、請求項14〜16のいずれか一項に記載の方法。
- 前記エステトロール含有顆粒が、前記顆粒化混合物と前記造粒液を、0.5:1〜20:1の範囲内の重量比で混合することによって製造される、請求項14〜17のいずれか一項に記載の方法。
- 前記エステトロール含有顆粒が、高剪断造粒機、低剪断造粒機、又は流動層造粒機で、前記顆粒化混合物を前記造粒液と混合することによって製造される、請求項14〜18のいずれか一項に記載の方法。
- 前記造粒液が、水、メタノール、エタノール、イソプロパノール、アセトン、及びその組合せから選択される極性溶媒を少なくとも60重量%含有する、請求項14〜19のいずれか一項に記載の方法。
- 前記造粒液が、水、エタノール、及びその組合せから選択される極性溶媒を少なくとも60重量%含有する、請求項20に記載の方法。
- 前記極性溶媒が水を少なくとも80重量%含有する、請求項20又は21に記載の方法。
- 前記造粒液が、セルロース誘導体、デンプン及びデンプン誘導体、ポリビニルアルコール、ポリビニルピロリドン、寒天、ゼラチン、グアーガム、アラビアゴム、アルギン酸塩、ポリエチレングリコール、グルコース、スクロース、ソルビトール及びその組合せから選択される結合剤を0.5〜40重量%含有する、請求項14〜22のいずれか一項に記載の方法。
- 前記結合剤が、セルロース誘導体、アルファ化デンプン、ポリビニルピロリドン、及びその組合せから選択される、請求項23に記載の方法。
- 前記セルロース誘導体が、ヒドロキシプロピルセルロース、ヒドロキシエチルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、エチルセルロース、カルボキシメチルセルロース、及びその組合せから選択される、請求項23又は24に記載の方法。
- 前記乾燥したエステトロール含有顆粒の体積中位径が100〜4,000μmの範囲内である、請求項14〜25のいずれか一項に記載の方法。
- 前記1種又は複数の錠剤化賦形剤が、ラクトース、マンニトール、キシリトール、微結晶セルロース、デンプン、クロスカルメロースナトリウム、ポリビニルピロリドン、及びその組合せを含む、請求項14〜26のいずれか一項に記載の方法。
- 前記口腔内崩壊性固形医薬剤形が直接圧縮又は圧縮成形によって形成される、請求項14〜27のいずれか一項に記載の方法。
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