JP2016500095A - テトラサイクリン局所製剤、その調製及び使用 - Google Patents
テトラサイクリン局所製剤、その調製及び使用 Download PDFInfo
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- JP2016500095A JP2016500095A JP2015543515A JP2015543515A JP2016500095A JP 2016500095 A JP2016500095 A JP 2016500095A JP 2015543515 A JP2015543515 A JP 2015543515A JP 2015543515 A JP2015543515 A JP 2015543515A JP 2016500095 A JP2016500095 A JP 2016500095A
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- minocycline
- tetracycline
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- suspension formulation
- topical
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Abstract
Description
本発明は、一般に医薬組成物、及びそれを調製する方法、並びに様々な疾患の治療における、その使用に関する。より詳細には、本発明は、テトラサイクリン化合物群、具体的には、ミノサイクリンの安定な製剤に関し、かつ感染症又は炎症の治療における局所使用のために該製剤を投与すること、及び皮膚疾患、眼疾患又は神経系疾患の治療のために該製剤を投与することに関する。
ざ瘡は、皮膚科の診療で観察される最もよく見られる病状の1つである。ざ瘡は、ほとんど全ての若者及び若年成人に、ある程度の影響を及ぼす。Anthony Manciniによって示唆されているように、ざ瘡の影響は皮膚に限定されない。つまり、若者及び若年成人の間で、ざ瘡病変は一般に情緒的な感受性が高められているときに起こり、かつ著しい精神的苦悩、落ち込みの一因となり得、かつ自殺の危険性さえも増加させ得る(Anthony Manciniの文献「ざ瘡の罹患率、有病率、及び病理生理学(Incidence, prevalence, and pathophysiology of acne)」(Johns Hopkins Adv Stud Med, volume 8 (4), 100-105 (2008))。
該製剤中に懸濁した形態の、テトラサイクリン、又はその医薬として許容し得る塩、水和物、若しくは多形体と;
テトラサイクリンを溶解しない、又は実質的に最小に溶解する液状媒体と;
高分子炭化水素ゲル化剤とを含む、局所懸濁製剤を提供する。
前記疎水性液状媒体は、(a)室温で2時間後に、該媒体に溶解しているテトラサイクリン活性成分が、HPLCで測定して5%未満であること、及び/又は(b)室温で1か月間保管したときに、4-エピ-ミノサイクリン(ミノサイクリンが活性成分として使用されたとき)が、HPLCで測定して4%未満であることを特徴とする。
製剤中に懸濁した形態の、テトラサイクリン、又はその医薬として許容し得る塩、水和物、若しくは異形態と;
テトラサイクリンを溶解しない、又は実質的に最小に溶解する面皰を生じにくい疎水性液状媒体と;
懸濁液を濃くするための高分子炭化水素ゲル化剤とを含む、局所懸濁製剤を提供する。
本発明は、局所投与のためのテトラサイクリン懸濁製剤であって、テトラサイクリン群の化合物、又はその医薬として許容し得る塩、若しくは水和物、若しくは多形体に属する活性化合物を含み、適切な液状媒体の懸濁物として実質的に安定化され、該テトラサイクリンは、該液体媒体に溶解性を有さない、又は実質的に最小の溶解性を有し、かつ感染症、又は炎症、又は皮膚疾患、又は眼疾患に対する治療を必要とするヒトへの局所適用に適している、前記懸濁製剤に関する。懸濁媒体は、例えば、アメリカのFDAの非活性成分ガイドの一覧から選択され、局所適用に適した面皰を生じにくい液体からなることが好ましい。特に好ましい実施態様において、該懸濁媒体は、鉱油又は類似の油から選択される。より好ましい実施態様において、該懸濁媒体は、市販のVersagel(登録商標)M (Versagel(登録商標)M750は、例えば、白色鉱油(90%〜100%)+エチレン/プロピレン/スチレンコポリマー(2.5〜10%)+ブチレン/エチレン/スチレンコポリマー(1〜2.5%)、及びブチル化ヒドロキシトルエン(<0.1%)の混合物を含む。)などのゲル状鉱油を含むゲル化剤と混合される。
粒子径分布は、以下の通りであった:
実施例1及び2で調製したミノサイクリン懸濁製剤の、安定性についての試験を、ミノサイクリン及び4-エピ-ミノサイクリンを測定することにより行った。実施例1からのサンプルは、ミノサイクリンが40℃で6か月にわたり安定なままであったことを示している一方で、実施例2からのサンプルは、色の変化を示し、分解産物の形成を示した。さらに、実施例2からのサンプルは、40℃で3か月後に沈殿物を示した。ミノサイクリンのC-4におけるエピメリ化の程度は、不純物を表す重要な安定性の1つであり;実施例1からのサンプルは、40℃で6か月にわたり1%未満の4-エピミノサイクリンを示した。
上記実施例1のミノサイクリン懸濁製剤を、皮膚浸透性(フランツ細胞及びヒトの皮膚)に関して、生体外で評価した。実施例1に記載のミノサイクリン懸濁製剤(20μL、1%懸濁ゲル)を、2cm2の皮膚表面に適用し、48時間にわたって浸透性を検討した。結果は、レセプターチャンバーと比較して、約5倍のミノサイクリンが、表皮及び真皮に存在することを示した(表皮及び真皮における約530ng対レセプターチャンバーにおける約100ng)。つまり、これは実施例1に記載のミノサイクリン製剤が、局所投与において、より低い全身曝露、及び表皮及び真皮における(全身よりも)比較的高い濃度を潜在的にもたらし得ることを示唆する。この生体外浸透検討において、ミノサイクリンの大部分は、吸収されず、表面洗浄(surface wash)において測定された(表4)。
Claims (42)
- 局所懸濁製剤であって:
該製剤中に懸濁した形態の、テトラサイクリン、又はその医薬として許容し得る塩、水和物、若しくは多形体と;
該テトラサイクリンを溶解しないか、又は、実質的に最小に溶解する、液状媒体と;
高分子炭化水素ゲル化剤とを含み、
該テトラサイクリンの粒子径が、20ミクロン以下である、前記局所懸濁製剤。 - 前記テトラサイクリンが、約4ミクロン〜約10ミクロンである値を有するD90粒子径を有する、請求項1記載の局所懸濁製剤。
- 前記テトラサイクリンが、約4ミクロン〜約10ミクロンである値を有するD90粒子径を有し、かつ約1ミクロン〜約5ミクロンである値を有するD50粒子径を有する、請求項1記載の局所懸濁製剤。
- 前記テトラサイクリンが、約4ミクロン〜約10ミクロンである値を有するD90粒子径を有し、約1ミクロン〜約5ミクロンである値を有するD50粒子径を有し、かつ約0.5ミクロン〜約1.5ミクロンである値を有するD10粒子径を有する、請求項1記載の局所懸濁製剤。
- 前記テトラサイクリンが、ミノサイクリン若しくはドキシサイクリン、又はそれらの医薬として許容し得る塩、水和物、若しくは多形体である、請求項1〜4のいずれか一項記載の局所懸濁製剤。
- 前記ミノサイクリンの濃度が、約0.05%〜約10%である、請求項5記載の局所懸濁製剤。
- 実時間(25℃/60%相対湿度(RH))及び促進(40℃/75%RH)安定性条件で6か月間保管後に、4-エピミノサイクリンの濃度が、HPLC分析で測定して4%以下である、請求項1〜6のいずれか一項記載の、ミノサイクリンを含む、局所懸濁製剤。
- 40℃/75%RHで1か月間保管した場合、ミノサイクリン懸濁製剤中の前記4-エピミノサイクリンの濃度が、HPLC分析で測定して3%未満の4-エピ-ミノサイクリンをもたらす、請求項1〜7のいずれか一項記載の、ミノサイクリンを含む、局所懸濁製剤。
- 40℃/75%RHで3か月間保管した場合、ミノサイクリン懸濁製剤中の前記4-エピミノサイクリンの濃度が、HPLC分析で測定して4%未満の4-エピ-ミノサイクリンをもたらす、請求項1〜8のいずれか一項記載の、ミノサイクリンを含む、局所懸濁製剤。
- 実時間(25℃/60%RH)安定性条件で12か月間保管後に、前記4-エピミノサイクリンの濃度が、HPLC分析で測定して4%以下である、請求項1〜9のいずれか一項記載の、ミノサイクリンを含む、局所懸濁製剤。
- 前記液状媒体が、面皰を生じにくい液状媒体である、請求項1〜10のいずれか一項記載の局所懸濁製剤。
- 前記面皰を生じにくい液状媒体が、鉱油、軽油、最小に面皰を生じやすい油、及び付加的な面皰を生じにくい油の1種以上である、請求項11記載の局所懸濁製剤。
- 前記面皰を生じにくい液状媒体が鉱油である、請求項11記載の局所懸濁製剤。
- 前記面皰を生じにくい液状媒体が、(a)室温で2時間後に、該液状媒体に溶解しているテトラサイクリン活性成分が、HPLCで測定して5%未満となること、及び/又は(b)ミノサイクリンが活性成分として使用された場合、室温で1か月間保管すると、HPLCで測定して4%未満の4-エピ-ミノサイクリンをもたらすことを特徴とする、請求項1〜13のいずれか一項記載の局所懸濁製剤。
- 前記鉱油が、前記懸濁製剤の少なくとも約70%を構成する、請求項1〜14のいずれか一項記載の局所懸濁製剤。
- 前記高分子炭化水素ゲル化剤が、アルケンモノマー、特に、C1〜C10若しくはC1〜C6若しくはC2〜C4のアルケンモノマー、及び、フェニルアルケンモノマー、特に、C1〜C10若しくはC1〜C6若しくはC2〜C4のフェニルアルケンモノマーから選択される1種以上のモノマーに基づく、1種以上のコポリマーと鉱油との混合物であるか、又は、油と1種以上のゲル化ポリマーとを含むゲルである、請求項1〜15のいずれか一項記載の局所懸濁製剤。
- 前記1種以上のコポリマーが、エチレン/プロピレン/スチレンコポリマーを含む、請求項16記載の局所懸濁製剤。
- 前記1種以上のコポリマーが、ブチレン/エチレン/スチレンコポリマーを含む、請求項16又は17記載の局所懸濁製剤。
- 前記懸濁剤が、抗酸化剤、特に、ブチル化ヒドロキシトルエンをさらに含む、請求項16、17、又は18記載の局所懸濁製剤。
- 前記高分子ゲル化剤が、エチレン/プロピレン/スチレンコポリマー、及びブチレン/エチレン/スチレンコポリマー、及び任意の抗酸化剤としてのブチル化ヒドロキシトルエンを含む、請求項16記載の局所懸濁製剤。
- 前記製剤が、皮膚浸透促進剤、又は、主として若しくは単独で皮膚浸透促進剤として作用する賦形剤を含まない、請求項1〜20のいずれか一項記載の局所懸濁製剤。
- 前記製剤が、テトラサイクリン活性成分の溶解をもたらす化合物を含まない、請求項1〜21のいずれか一項記載の局所懸濁製剤。
- 前記テトラサイクリン活性成分の溶解をもたらす化合物が、水、親水性溶媒、及びエモリエントエステルの1種以上を含む、請求項22記載の局所懸濁製剤。
- 前記液状媒体が、面皰を生じにくい媒体と面皰を生じやすい媒体との混合物を含み、かつ該面皰を生じにくい媒体が、該面皰を生じやすい媒体よりも多い量で存在する、請求項1〜23のいずれか一項記載の局所懸濁製剤。
- 前記組成物が、本質的に、医薬として有効な量のミノサイクリンと、テトラサイクリンを溶解しないか、又は最小に溶解する面皰を生じにくい液状媒体と、該組成物を濃くするための高分子炭化水素ゲル化剤と、任意に、4-エピミノサイクリン、着色剤、染料、芳香剤、並びに日焼け止め物質の1種以上とからなる、請求項1〜24のいずれか一項記載の局所懸濁製剤。
- 前記組成物が、医薬として有効な量のミノサイクリンと、テトラサイクリンを溶解しないか、又は最小に溶解する面皰を生じにくい液状媒体と、該組成物を濃くするための高分子炭化水素ゲル化剤とからなる、請求項1〜25のいずれか一項記載の局所懸濁製剤。
- 前記組成物が、医薬として有効な量のミノサイクリンと、テトラサイクリンを溶解しないか、又は最小に溶解する、面皰を生じにくい液状媒体と、該組成物を濃くするためのゲル化剤と、4-エピミノサイクリンと、任意に、該面皰を生じにくい液状媒体よりも少ない量で存在する面皰を生じやすい液状媒体、着色剤、染料、芳香剤、及び日焼け止め物質の1種以上とからなる、請求項1〜26のいずれか一項記載の局所懸濁製剤。
- 前記組成物が、非発泡性であり、かつ発泡助剤を含まない、請求項1〜27のいずれか一項記載の局所懸濁製剤。
- 皮膚の感染症又は炎症を治療する方法であって、請求項1〜28のいずれか一項記載の懸濁製剤を、そのような治療を必要とする対象に局所的に投与することを含む、前記方法。
- 前記疾患が、ざ瘡又は酒さと特徴付けられる、請求項29記載の皮膚の感染症又は炎症を治療する方法。
- 眼疾患又は眼症状を治療する方法であって、請求項1〜30のいずれか一項記載の懸濁製剤を、そのような治療を必要とする対象の眼の表面に局所的に投与することを含む、前記方法。
- 前記テトラサイクリンが、結晶性ミノサイクリン遊離塩基である、請求項1〜28のいずれか一項記載の局所懸濁製剤。
- さらに、日焼け止め剤、芳香剤、及び着色剤、又は染料の1種以上を含む、請求項1〜28又は32のいずれか一項記載の局所懸濁組成物。
- 尋常性ざ瘡に悩む個人を治療するための局所ミノサイクリン懸濁製剤であって、該組成物が、本質的に、医薬として有効な量のミノサイクリンと、テトラサイクリンを溶解しないか、又は最小に溶解する、疎水性液状媒体と、該組成物を濃くするための高分子炭化水素ゲル化剤とからなり:
該疎水性液状媒体が(a)室温で2時間後に、該媒体に溶解しているテトラサイクリン活性成分がHPLCで測定して5%未満となること、及び/又は(b)室温で1か月間保管した場合、HPLCで測定して4%未満の4-エピ-ミノサイクリン(ミノサイクリンが該活性成分として使用される場合)をもたらすことを特徴とする、前記局所ミノサイクリン懸濁製剤。 - 局所懸濁製剤であって:
該製剤中に懸濁した形態の、テトラサイクリン、又はその医薬として許容し得る塩、水和物、若しくは異形態と;
該テトラサイクリンを溶解しないか、又は、実質的に最小に溶解する、面皰を生じにくい疎水性液状媒体と;
該懸濁剤を濃くするための高分子炭化水素ゲル化剤とを含む、前記局所懸濁製剤。 - 前記製剤が、請求項1〜28又は32〜33のいずれか一項においてさらに定義した通りである、請求項34又は35記載の製剤。
- 医薬として使用するための、請求項1〜28、又は32〜36のいずれか一項記載の製剤。
- 皮膚の感染症又は炎症の治療に使用するための、請求項37記載の製剤。
- ざ瘡又は酒さの治療に使用するための、請求項38記載の製剤。
- 眼疾患又は眼病状の治療に使用するための、請求項37記載の製剤。
- 別の抗ざ瘡剤をさらに含む、請求項1〜36のいずれか一項記載の製剤、又は請求項37〜40のいずれか一項記載の、使用するための製剤。
- 前記抗ざ瘡剤が、トレチノイン、アダパレン、又はタザロテンなどのレチノイドである、請求項41記載の製剤又は使用するための製剤。
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EP2925293B1 (en) | 2017-08-02 |
PL2925293T3 (pl) | 2017-12-29 |
ES2645449T3 (es) | 2017-12-05 |
KR20150104102A (ko) | 2015-09-14 |
US10213443B2 (en) | 2019-02-26 |
US9592246B2 (en) | 2017-03-14 |
KR102235922B1 (ko) | 2021-04-05 |
BR112015012162B1 (pt) | 2021-02-23 |
CN104902875B (zh) | 2018-04-03 |
JP6444308B2 (ja) | 2018-12-26 |
RU2015122786A (ru) | 2017-01-10 |
US20140147504A1 (en) | 2014-05-29 |
NZ708824A (en) | 2019-01-25 |
RU2639591C2 (ru) | 2017-12-21 |
DK2925293T3 (da) | 2017-11-06 |
AU2013350941B2 (en) | 2018-04-26 |
PT106679B (pt) | 2015-03-25 |
MX355174B (es) | 2018-04-09 |
EP2925293A1 (en) | 2015-10-07 |
ZA201504369B (en) | 2017-01-25 |
CA2895395C (en) | 2021-04-06 |
US20170182071A1 (en) | 2017-06-29 |
SG11201504145PA (en) | 2015-07-30 |
IL239022B (en) | 2020-11-30 |
MX2015006632A (es) | 2016-02-17 |
AU2013350941A1 (en) | 2015-07-16 |
PT106679A (pt) | 2014-05-27 |
CA2895395A1 (en) | 2014-06-05 |
IL239022A0 (en) | 2015-07-30 |
WO2014083311A1 (en) | 2014-06-05 |
HUE034932T2 (en) | 2018-03-28 |
NO2925293T3 (ja) | 2017-12-30 |
CN104902875A (zh) | 2015-09-09 |
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