JP7020915B2 - 抗炎症性、増殖性、保護性及び粘膜付着性の、可溶性且つ安定な医薬組成物、粘膜部位の状態を治療するためのその使用及び取得方法、並びに医薬組成物の調製のための基本医薬組成物及びその取得方法 - Google Patents
抗炎症性、増殖性、保護性及び粘膜付着性の、可溶性且つ安定な医薬組成物、粘膜部位の状態を治療するためのその使用及び取得方法、並びに医薬組成物の調製のための基本医薬組成物及びその取得方法 Download PDFInfo
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
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Description
HIVウイルスは、進行した段階(既にAIDSの基準が存在する時期)及びウイルス感染の急性期において口腔潰瘍を引き起こし得る。小児に非常によくみられるコクサッキーウイルスの感染症(ヘルパンギーナ)は、咽頭炎、発熱、小口腔潰瘍、並びに手のひら及び足裏の病変部をもたらし得る。第一期及び第二期両方の梅毒は、口腔潰瘍をもたらし得る。これらの潰瘍は通常複数であり、第二期には治癒までに長時間を要する。小胞としてみられる口唇ヘルペスは、破裂後に小潰瘍となり得る。外観はあまり咽頭炎のようではないが、一般人は混同し得る。口腔のある種の癌は、最初は一般的な口内炎と混同する、潰瘍として存在する可能性がある。
本発明の液体基本処方の調製物に関連する以下の記載は、本発明の新規要素を構成する処方を表すと共に、不満足な結果であった工程も含み、本発明者らによって成功裏に開発された対象物の、実際の有効性を実証する。
-第1段階-蒸留水又は蒸留水及びプロピレングリコールの1:1v/vの混合物を含有する処方の、室温における機械的撹拌下(500rpm)による調製、
-第2段階-クルクミノイド類を一定の機械的撹拌下で添加し、クルクミノイド類の濃度が2.5mg/mL未満である溶液を得ること、
-第3段階-水と、プロピレングリコールと、クルクミノイドとの混合物にポロクサマーを添加すること、
から構成される。
処方中のクルクミノイド類の溶解度を更に増大させるため、溶媒系の組成に、PEG400を大量に含む(30%、v v)別の改変を加えた。この量の増加により、調製物中の水の量を20%に減らした(v/v)(処方PI03)。この新しい変更により、添加したクルクミノイド類の質量のすべてが可溶化され、2.5mg/mlのクルクミノイド類を含む溶液が得られた。
この基本処方における好ましい溶媒系は以下のように表される:
-(1)45%~55%、好ましくは50%のプロピレングリコール、
-(2)25%~35%、好ましくは30%のポリエチレングリコール400、
-(3)15%~25%、好ましくは20%の精製水。
クルクミノイド類-2.5mg/mL、及び、好ましくは
溶媒-プロピレングリコール 50%v/v
共溶媒-ポリエチレングリコール400 30%v/v
界面活性剤-ポロクサマー 15%w/v
担体-精製水 20%v/v
からなる溶媒系。
最初に、液体基本処方と、ウコン抽出物及びコセンダングサ抽出物との組み合わせを含有する相乗的混合物から調製された液体組成物の調製のため、高濃度のクルクミノイド類(7.5mg/ML)をPI03処方に添加することによって、大量の沈殿物の形成が観察された。これによって、以下に示すように、本発明の組成物の調製技術を変更することとなった。
-(1)PEG400とプロピレングリコールとの混合物を調製し、65℃に維持したホットプレートを用いて、この混合物を加熱した、
-(2)該処方のポロクサマー質量を2つの同等な部分に分け、その部分の1つを、加熱したプロピレングリコールとPEG-400の混合物中に分散させた-段階I、
-(3)次に、30分間の機械的撹拌下(500rpm)に、加熱を続けながら(65℃)、該混合物にクルクミノイド類を加えた、
-(4)ポロクサマー質量の残りの半分を、室温にて水相に加えた-段階II、
-(5)完全に分散させた後、第II相の溶液を、プロピレングリコールとPEG400とを含有する段階Iの混合物中に注いだ。段階III、
-(6)最終的な混合物を、温度が25℃になるまで撹拌した(おおよそ30分間)。
(1)プロピレングリコール、30%(v/v)、
(2)ポリエチレングリコール400、30%(v/v)、
(3)コセンダングサのグリセリン化抽出物、40%(v/v)。
半固体処方の開発は、油相を、油性成分の総処方の10~14.75%w/wの範囲で含有し、以下の成分の優先的な量:
-(1)液体ワセリン(5%、w/w)、
-(2)ステアリン酸(3%、w/w)、
-(3)セチルアルコール(0.4%、w/w)、
-(4)セトステアリルアルコール(0.35%、w/w)、
-(5)モノステアリン酸グリセリン(3%、w/w)、
-(6)ミリスチン酸イソプロピル(1%、w/w)、
を含有する、クリームジェルタイプの基剤の調製を目的として行った。
錠剤、錠剤、又はカプセル剤、更に好ましくは錠剤の形態である固体処方を、希釈剤としてマンニトール、及び粘膜付着性薬剤としてポロクサマーを用いて開発した。使用した造粒液は、35~45%w/vの比率の、コセンダングサ抽出物自体であった。混合物の各成分の質量を以下のように表す:(1)クルクミノイド類(1錠剤あたり25~200mg)、マンニトール(1錠剤あたり250~350mg)、ポロクサマー(1錠剤あたり100~140mg)、結晶セルロース(200~400mg)、メタ重亜硫酸ナトリウム(5~15mg)、及びクエン酸(20~40mg)。
本発明者らによって行った試験により、クルクミノイド類含有量が5%を超えるウコン画分と、Bdのグリセリン化抽出物との組み合わせは、5-フルオロウラシルに曝露された動物を別々に評価した際、これらの物質による効果よりも優れた、重要な過剰増殖性及び抗炎症性効果を示したことが実証された。5-フルオロウラシル(5-FU)誘導性粘膜炎に対する防御効果は、クルクミノイド類又はBdに対して別々に評価した防御効果よりも、予防的及び治療的両方において優れていることが観察された。
a)クルクミノイド類による防御効果の評価、
b)Bdによる防御効果の評価、
c)クルクミノイド類とBDとの組み合わせによる防御効果の評価。
群I:3.7mg/kgのクルクミノイド+5-FU、
群II:7.5mg/kgのクルクミノイド+5-FU、
群III:15mg/kgのクルクミノイド+5-FU、
群IV:陽性対照(5-FU)、
群V:陰性対照(水)。
群I:75mg/kgのBd+5-FU、
群II:100mg/kgのBd+5-FU、
群III:125mg/kgのBd+5-FU、
群IV:陽性対照(5-FU)、
群V:陰性対照(水)。
群I:CBd+5-FU、
群II:CBd+5-FU、
群III:CBd+5-FU、
群IV:陽性対照(5-FU)、
群V:陰性対照(水)。
1. Armstrong JA, McCaffrey R. The effects of mucositis on quality of life in patients with head and neck cancer. Clin J Oncol Nurs. 2006;10(1):53-6.
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Claims (4)
- 抗炎症性、増殖性、保護性及び粘膜付着性の、可溶性かつ安定な医薬組成物を得るための方法であって、前記医薬組成物が15~25mg/mLまでのクルクミノイド類、40%(v/v)のコセンダングサのグリセロール抽出物、30%(v/v)のプロピレングリコール、30%(v/v)のポリエチレングリコール400、及び15%(w/v)のポロクサマー407を含み、以下の段階、
-(1)30%(v/v)のPEG400と30%(v/v)のプロピレングリコールとの混合物を調製し、この混合物を65℃にて加熱すること、
-(2)該処方に導入されるポロクサマー407の量を2つの同等な部分に分け、一方の部分を、加熱した工程(1)のプロピレングリコールとPEG400の混合物中に分散させること、
-(3)30分間の機械的撹拌下(500rpm)に、加熱を続けながら(65℃)、工程(2)の混合物に25mg/mLまでのクルクミノイド類を加えること、
-(4)ポロクサマー407の量の残りの半分を、40%(v/v)のコセンダングサのグリセロール抽出物に加えること、
-(5)工程(4)の溶液を工程(3)の混合物に注いで、最終的な混合物を調製すること、並びに、
-(6)前記最終的な混合物を、温度が25℃になるまで撹拌し、前記最終的な混合物を完全に溶解させ、室温下で長時間安定にすること、
を経ることにより得られる、方法。 - 請求項1に記載の方法であって、更に、0.01~1%(v/v)の、亜硫酸水素ナトリウム及びブチルヒドロキシトルエンを含有させる、方法。
- クルクミノイド類を15~25mg/mL;
コセンダングサのグリセロール抽出物を40%(v/v);
プロピレングリコールを30%(v/v);
ポリエチレングリコール400を30%(v/v);並びに
ポロクサマー407を15%(w/v);
を含む、請求項1記載の方法により調製される抗炎症性、増殖性、保護性及び粘膜付着性の、可溶性且つ安定な医薬組成物。 - 異なった病因による、粘膜炎、皮膚疾患、及び口内炎の状態の治療のための薬剤を調製するための、請求項3に記載の組成物の使用。
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PCT/BR2014/050002 WO2016065442A1 (pt) | 2014-10-27 | 2014-10-27 | Composições farmacêuticas antiinflamatórias, proliferativas, protetoras e mucoadesivas, solúveis e estáveis; seu uso no tratamento dos quadros de mucosite e processo de obtenção; composição farmacêutica de base para o preparo das composições farmacêuticas e seu processo de obtenção |
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