JP2019194248A - 近視の治療用の治療キット、および、近視の治療のための薬剤の製造におけるアトロピンの使用 - Google Patents
近視の治療用の治療キット、および、近視の治療のための薬剤の製造におけるアトロピンの使用 Download PDFInfo
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- JP2019194248A JP2019194248A JP2019129405A JP2019129405A JP2019194248A JP 2019194248 A JP2019194248 A JP 2019194248A JP 2019129405 A JP2019129405 A JP 2019129405A JP 2019129405 A JP2019129405 A JP 2019129405A JP 2019194248 A JP2019194248 A JP 2019194248A
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- Prior art keywords
- atropine
- ophthalmic
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- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940069078 citric acid / sodium citrate Drugs 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229960000958 deferoxamine Drugs 0.000 description 1
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- 239000008121 dextrose Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
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- 230000005750 disease progression Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000010894 electron beam technology Methods 0.000 description 1
- 230000004890 epithelial barrier function Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
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- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
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- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 230000002911 mydriatic effect Effects 0.000 description 1
- FARKARKUKMFYQQ-UHFFFAOYSA-N n-[5-[acetyl(hydroxy)amino]pentyl]-n'-[5-[5-aminopentyl-[4-(hydroxyamino)-4-oxobutanoyl]amino]pentyl]-n'-hydroxybutanediamide Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN(CCCCCN)C(=O)CCC(=O)NO FARKARKUKMFYQQ-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- RARSHUDCJQSEFJ-UHFFFAOYSA-N p-Hydroxypropiophenone Chemical compound CCC(=O)C1=CC=C(O)C=C1 RARSHUDCJQSEFJ-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- DCNLOVYDMCVNRZ-UHFFFAOYSA-N phenylmercury(.) Chemical class [Hg]C1=CC=CC=C1 DCNLOVYDMCVNRZ-UHFFFAOYSA-N 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
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- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
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- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
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- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000003786 sclera Anatomy 0.000 description 1
- 229950003422 sepazonium chloride Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 235000019832 sodium triphosphate Nutrition 0.000 description 1
- 229940063675 spermine Drugs 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 238000009283 thermal hydrolysis Methods 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940035024 thioglycerol Drugs 0.000 description 1
- 229960004906 thiomersal Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- CYHOMWAPJJPNMW-JIGDXULJSA-N tropine Chemical compound C1[C@@H](O)C[C@H]2CC[C@@H]1N2C CYHOMWAPJJPNMW-JIGDXULJSA-N 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
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Abstract
Description
本発明の分野は、近視の治療用の治療キット、および、近視の治療のための薬剤の製造におけるアトロピンの使用であり、特に、種々の貯蔵安定性で使用準備済みの防腐剤を含まない液体貯蔵安定性低用量アトロピン眼科用製剤を含む近視の治療用の治療キット、および、近視の治療のための薬剤の製造におけるアトロピンの使用に関する。
本発明の主題は、改善された安定性および生理学的に許容されるpHを有する使用準備済みのアトロピン組成物に関する。最も好ましくは、そのような組成物は、実質的に防腐剤をも含まない。
さらなる例示的な実施形態において、企図されるアトロピン製剤中のアトロピンの濃度は、約0.005%〜約0.015%(w/w)、または約0.015%〜約0.025%(w/w)、または約0.01%(w/w)、または約0.02%(w/w)、または0.005%〜0.015%(w/w)、または0.015%〜0.025%(w/w)、または0.01%(w/w)、または0.02%(w/w)、または約0.001%(w/w)〜約0.01%(w/w)、または約0.005%(w/w)〜約0.02%(w/w)、または約0.008%(w/w)〜約0.012%(w/w)である。
以下の実施例は、本発明の主題による製剤をもたらすいくつかの実験を説明するが、決して特許請求の範囲を限定すると解釈されるべきではない。
Ultra Performance Liquid Chromatography(UPLC)に基づく複合試験法を開発し、関連する化合物の同定、検査および決定を1回の操作で実行した。これは、UV吸収スペクトルのオンライン取得を含むUV検出を伴う逆相勾配UPLCを使用することによって達成された。2μm未満の粒子を有するオクタデシルシリル官能化シリカをクロマトグラフィー分析用の固定相として使用した。移動相は、酸性pHの水性緩衝溶液をアセトニトリル−水混合物と混合することによって調製される。活性成分および関連化合物の定量は、試料溶液からの対応するピーク応答を、標準溶液からのアトロピンピーク応答と比較することによって行う。応答に対する化学構造の影響を補正するために、相対的応答係数が使用される。この試験方法には2つの識別方法が組み込まれる。アトロピンは、試料溶液クロマトグラムにおける主要なピークの保持時間およびこのピーク内に取得されたUV吸収スペクトルに基づいて同定される。
すぐに使える低用量の眼科用アトロピン製剤を、実質的に図1に示すような2段階プロセスを用いて調製した。
ことが、データから容易に理解できる。24ヶ月の終わりに回帰分析を利用して分解水準を外挿した。当技術分野で一般的に使用されている外挿法に基づくと、50mMおよび緩衝されていない濃厚物は18〜24ヶ月の貯蔵可能期間を有し、それは100mM組成物の外挿貯蔵可能期間15ヶ月を3〜9ヶ月超えている。
Claims (20)
- 近視の治療用の治療キットであって、
液体貯蔵安定性低用量アトロピン眼科用製剤を含有する第1の容器を含み、前記第1の容器は、使い捨ての1回使用の容器または複数回投与容器として構成され、
前記第1の容器を囲む第2の容器を含み、
前記液体貯蔵安定低用量アトロピン眼科用製剤は、緩衝液、等張化剤、粘度調整剤、および、アトロピンまたは薬学的に許容されるその塩を含む水溶液を含み、
前記アトロピンまたはその薬学的に許容される塩は、前記アトロピン眼科用製剤中に0.05重量%またはそれ未満の量で存在し、
前記緩衝液は75mMまたはそれ未満の濃度を有し、前記アトロピン眼科用製剤は5.0〜6.0のpHを有し、
前記アトロピン眼科用製剤は、25℃、相対湿度60%で少なくとも2ヶ月間貯蔵した後、アトロピンの分解により、0.35%またはそれ未満のトロパ酸を含む、キット。 - 前記第1の容器はブロー・フィル・シール(BSF)容器であり、または、第2の容器は積層金属化ポーチである請求項1に記載のキット。
- 前記アトロピンまたはその薬学的に許容される塩は、前記アトロピン眼科用製剤中に0.01重量%〜0.05重量%の量で存在する請求項1のキット。
- 前記緩衝液は、一塩基性および二塩基性リン酸ナトリウムを含む請求項1に記載のキット。
- 前記緩衝液は、75mMまたはそれ未満の濃度を有する請求項1に記載のキット。
- 前記緩衝液は、50mMまたはそれ未満の濃度を有する請求項1に記載のキット。
- 前記近視の治療は、小児の近視の治療である請求項1に記載のキット。
- ビカルボン酸、トリカルボン酸、および、アミノポリカルボン酸からなるグループから選択されるキレート剤をさらに含む請求項1に記載のキット。
- 前記キレート剤は、前記アトロピン眼科用製剤中に0.01重量%またはそれ未満の量で存在する請求項8に記載のキット。
- 前記アトロピン眼科用製剤は、5.5(+/−0.2)のpHを有する請求項1に記載のキット。
- 前記等張化剤は薬学的に許容される塩であり、前記薬学的に許容される塩は前記アトロピン眼科用製剤中に0.2重量%〜0.8重量%の量で存在する請求項1に記載のキット。
- 前記粘度調整剤は、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、および、ヒドロキシプロピルメチルセルロースからなるグループから選択される変性セルロースである請求項1に記載のキット。
- 前記アトロピン眼科用製剤は、防腐剤を実質的に含まない請求項1に記載のキット。
- 近視の治療のための薬剤の製造におけるアトロピンの使用であって、前記薬剤は、眼科用アトロピン組成物であり、
前記眼科用アトロピン組成物は、
(a)0.05重量%またはそれ未満の量でアトロピンまたはその薬学的に許容される塩を含み、
(b)75mMまたはそれ未満の濃度で緩衝液を含み、前記眼科用アトロピン組成物は5.0〜6.0のpHを有し、
(c)等張化剤、粘度調整剤を含み、
(d)25℃、相対湿度60%で少なくとも2ヶ月間貯蔵した後、アトロピンの分解により、0.35%またはそれ未満のトロパ酸を含み、
(e)前記眼科用アトロピン組成物は、D2Oを含まず、
前記眼科用アトロピン組成物は、眼の適用用に調製される、使用。 - 前記近視は、小児の近視である請求項14に記載の使用。
- 前記アトロピンまたはその薬学的に許容される塩は、前記眼科用アトロピン組成物中に0.01重量%〜0.02重量%の量で存在する、請求項14に記載の使用。
- 前記緩衝液は、50mMまたはそれ未満の濃度を有する請求項14に記載の使用。
- 前記眼科用アトロピン組成物は、ビカルボン酸、トリカルボン酸、および、アミノポリカルボン酸からなるグループから選択されるキレート剤をさらに含み、前記キレート剤は、前記眼科用アトロピン組成物中に0.01重量%またはそれ未満の量で存在する請求項14に記載の使用。
- 前記眼科用アトロピン組成物は、5.5(+/−0.2)のpHを有する請求項14に記載の使用。
- 前記眼科用アトロピン組成物は、防腐剤を実質的に含まない請求項14に記載の使用。
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