JP2022516099A - 眼科用医薬組成物及び癌表面疾患の処置方法 - Google Patents
眼科用医薬組成物及び癌表面疾患の処置方法 Download PDFInfo
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- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
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Abstract
Description
本出願は、2018年12月27日に出願された米国特許出願第62/785,312号の米国特許法第119条(e)の下での優先権の利益を主張し、この出願の内容全体は、本明細書に参照により組み込まれる。
本発明は、全般的に、眼科の分野、より具体的には哺乳動物における眼表面疾患、例えばドライアイ症候群を処置、軽減及び/又は防止するための組成物及び方法、並びにそのような組成物を調製する方法に関する。
本開示は、非常に低濃度の副腎皮質ステロイド(例えばベタメタゾン)を免疫抑制薬、例えばミコフェノール酸に加えることにより、眼表面疾患、例えばそれらに限定されないが、乾性角結膜炎、突発性ドライアイ疾患、不応性ドライアイ疾患、加齢性ドライアイ、神経障害性眼表面疾患、マイボーム腺疾患及び眼瞼炎を処置、防止及び/又は緩和するための優れたかつ/又は相乗的な有効性が得られることを見出したことに基づく。したがって、本発明は、(i)ミコフェノール酸又はその医薬的に許容される塩、誘導体若しくは類似体と、(ii)副腎皮質ステロイド又はその医薬的に許容される塩、誘導体若しくは類似体との組み合わせを含む第一成分であって、副腎皮質ステロイドが、約0.005重量%から0.05重量%の濃度で存在する第一成分と、脱イオン水及び緩衝塩類溶液からなる群より選択される担体とを含む医薬組成物を提供する。
特に定義しない限り、本明細書に記載する分析化学、合成有機及び無機化学に関連して、またその実験手順及び技術において用いられる術語は、当該分野において知られているものである。標準的な化学記号を、そのような記号により表される完全名称と交換可能に用いる。よって、例えば用語「水素」及び「H」は、同一の意味を有すると理解される。化学合成、化学分析、組成物の処方及びそれらの試験のために、標準的な技術を用いることができる。上記の技術及び手順は、当該技術において公知の従来の方法に従って一般的に行うことができる。
を有する化合物のことをいう。
を有する化合物のことをいう。
を有するコルチコステロンの誘導体であるステロイドの亜属に属する任意のステロイドホルモンのことをいう。
を有する化合物のことをいう。
副腎皮質ステロイド外用薬は、処置ガイドラインに含まれ、ドライアイ疾患の処置に広く用いられているので、非常に低濃度の副腎皮質ステロイド(例えばベタメタゾン)を免疫抑制薬、例えばミコフェノール酸に添加することは、標準的な処置プロトコールと比較して、優れたかつ/又は相乗的な有効性をもたらすことが期待される。このような処置に組込まれる非常に低濃度の副腎皮質ステロイドに鑑みて、安全性に対する負の影響は予期されない。このような組成物は、炎症性眼疾患の処置における使用について承認されている経口CELLCEPT(登録商標)単剤療法で証明されているように、ステロイド減量効果を最終的に導くとも予期される。
HO-(CH2-CH2-O)x-(C3H6-O)y-(CH2-CH2-O)x-H
(式中、xは、少なくとも8の値を有する整数であり、yは、少なくとも38の値を有する整数である)を有する非イオンポリオキシエチレン-ポリオキシプロピレンブロック共重合体であり得る。
(式中、P188について、x及びz=80かつy=27であり、P407について、x及びz=101かつy=56である)を有する。
実施例1 医薬組成物第1号の調製
以下に記載するようにして、医薬組成物を調製した。以下の成分を、記載する量で用いた:
(a)約0.321gのミコフェノール酸ナトリウム;
(b)約0.05%のシクロスポリン;
(c)約0.25gのコンドロイチン硫酸(ウシ);
(d)約0.10gの粉末エデト酸二ナトリウム二水和物;
(e)約0.2gのPLURONIC(登録商標)F-127;
(f)約1.0mLのグリセロール;
(g)約0.2%のポリソルベート-80;
(h)約0.125gのMETHOCEL(登録商標)E4M;及び
(i)約100mLの緩衝塩類溶液。
以下に記載するようにして、医薬組成物を調製した。以下の成分を、記載する量で用いた:
(a)約0.321gのミコフェノール酸ナトリウム粉末;
(b)約0.2gのロテプレドノールエタボン酸エステル;
(c)約0.25gのコンドロイチン硫酸(ウシ);
(d)約0.10gの粉末エデト酸二ナトリウム二水和物;
(e)約0.2gのPLURONIC(登録商標)F-127;
(f)約1.0mLのグリセロール;
(g)約0.1gのポリソルベート-80;
(h)約1gのポリビニルピロリドン;
(i)約0.125gのMETHOCEL(登録商標)E4M;及び
(j)約100mLの緩衝塩類溶液。
以下に記載するようにして、医薬組成物を調製した。以下の成分を、記載する量で用いた:
(a)約0.321gのミコフェノール酸ナトリウム粉末;
(b)約0.01gのリン酸ベタメタゾンナトリウム粉末;
(c)約0.25gのコンドロイチン硫酸(ウシ);
(d)約0.25の粉末デキストラン70,000;
(e)約0.30gの粉末チオ硫酸ナトリウム五水和物;
(f)約0.20gのPLURONIC(登録商標)F-127;
(g)約1.0mLのグリセロール;
(h)約1.17gの無水リン酸二ナトリウム;
(i)約0.4gの無水リン酸一ナトリウム;
(j)約0.10gのMETHOCEL(登録商標)E4M;
(k)約40mLの緩衝塩類溶液;及び
(l)約100mLの滅菌注射用水。
以下に記載するようにして、医薬組成物を調製した。以下の製品を、記載する量で用いた:
(a)約0.321gのミコフェノール酸ナトリウム粉末;
(b)約0.0255gのタクロリムス一水和物粉末;
(c)約0.25gのコンドロイチン硫酸(ウシ);
(d)約0.25の粉末デキストラン70,000;
(e)約0.1gのエデト酸二ナトリウム粉末;
(f)約0.30gの粉末チオ硫酸ナトリウム五水和物;
(g)約0.20gのPLURONIC(登録商標)F-127;
(h)約1.0mLのポリソルベート-80;
(i)約4.0mLのポリエチレングリコール400MW;
(j)約1.0mLのグリセロール;
(k)約1.17gの無水リン酸二ナトリウム;
(l)約0.14gの無水リン酸一ナトリウム;
(m)約0.10gのMETHOCEL(登録商標)E4M;
(n)約40mLの緩衝塩類溶液;及び
(o)約100mLの滅菌注射用水。
実施例5~12 ミコフェノール酸及びリン酸ベタメタゾンナトリウムの注射用医薬製剤の調製
Claims (30)
- (a)(i)ミコフェノール酸又はその医薬的に許容される塩、誘導体若しくは類似体と、(ii)副腎皮質ステロイド又はその医薬的に許容される塩、誘導体若しくは類似体との組み合わせを含む第一成分であって、副腎皮質ステロイドが、約0.005重量%~0.05重量%の濃度で存在する第一成分と、
(b)脱イオン水及び緩衝塩類溶液からなる群より選択される担体と
を含む、医薬組成物。 - ミコフェノール酸の医薬的に許容される塩が、ミコフェノール酸ナトリウム又はミコフェノール酸モフェチルである、請求項1に記載の医薬組成物。
- 副腎皮質ステロイドが、ベタメタゾンである、請求項1に記載の医薬組成物。
- ベタメタゾンの塩、誘導体又は類似体が、酢酸ベタメタゾン、リン酸ベタメタゾンナトリウム、吉草酸ベタメタゾン及びジプロピオン酸ベタメタゾンからなる群より選択される、請求項3に記載の医薬組成物。
- グリセロール、ポリビニルピロリドン、ソルビトール、ポリエチレングリコール、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース及びポリ酢酸ビニルからなる群より選択される少なくとも1つの第二成分をさらに含む、請求項1に記載の医薬組成物。
- 第二成分の濃度が、約0.1重量%と約5.0重量%の間である、請求項5に記載の医薬組成物。
- グリコサミノグリカン、コンドロイチン、コンドロイチン硫酸、デルマタン硫酸、デルマチン硫酸、ヘパリン硫酸、ヘパラン硫酸、ケラチン硫酸、ケラタン硫酸及びヒアルロン酸からなる群より選択される少なくとも1つの第三成分をさらに含む、請求項5に記載の医薬組成物。
- 第三成分の濃度が、約0.1重量%と約5.0重量%の間である、請求項7に記載の医薬組成物。
- デキストラン、デキストラン硫酸、塩化ナトリウム、デキストロース及びスクロースからなる群より選択される少なくとも1つの第四成分をさらに含む、請求項7に記載の医薬組成物。
- 第四成分の濃度が、約0.1重量%と約5.0重量%の間である、請求項9に記載の医薬組成物。
- タクロリムス、リフィテグラスト、シクロスポリン、ベタメタゾン以外の副腎皮質ステロイド、任意のそれらの医薬的に許容される塩若しくは類似体、アルブミン、血漿、多血小板血漿及び血清からなる群より選択される少なくとも1つのさらなる化合物をさらに含む、請求項1に記載の医薬組成物。
- ベタメタゾン以外の副腎皮質ステロイドが、ロテプレドノール、トリアムシノロン、トリアムシノロンアセトニド、酢酸トリアムシノロン、トリアムシノロンベネトニド、トリアムシノロンフレトニド、トリアムシノロンヘキサアセトニド、デキサメタゾン、フルオロメトロン、フルオシノロンアセトニド、プレドニゾン、プレドニゾロン、メチルプレドニゾン、コルチコール、コルチゾン、フルオロコルチゾン、酢酸デオキシコルチコステロン、アルドステロン及びブデソニドからなる群より選択される、請求項11に記載の医薬組成物。
- アスコルビン酸、エリソルビン酸、アスコルビン酸ナトリウム、チオグリセロール、システイン、アセチルシステイン、シスチン、ジチオエリトレイトール、ジチオトレイトール、グルタチオン、トコフェロール類、ブチル化ヒドロキシアニソール、ブチル化ヒドロキシトルエン、硫酸ナトリウム、重亜硫酸ナトリウム、アセトン重亜硫酸ナトリウム、メタ重亜硫酸ナトリウム、亜硫酸ナトリウム、ホルムアルデヒドスルホキシラートナトリウム、チオ硫酸ナトリウム及びノルジヒドログアヤレチン酸からなる群より選択される少なくとも1つの抗酸化剤をさらに含む、請求項1に記載の医薬組成物。
- ミコフェノール酸が、約0.05重量%から約1.0重量%の濃度で存在する、請求項1に記載の医薬組成物。
- 第一成分が、0.3重量%のミコフェノール酸と、0.03重量%のベタメタゾンとを含む、請求項14に記載の医薬組成物。
- 第一成分の濃度が、約0.001重量%と約75.0重量%の間である、請求項1に記載の医薬組成物。
- 非イオンポリオキシエチレン-ポリオキシプロピレンブロック共重合体、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重合体、ポリカルボフィル重合体、エデト酸二ナトリウム二水和物(EDTA)、ポリソルベート-80、チオ硫酸ナトリウム、チオ硫酸ナトリウム五水和物、リン酸ナトリウム、無水リン酸二ナトリウム及び無水リン酸一ナトリウムからなる群より選択される少なくとも1つの賦形剤又は界面活性剤をさらに含む、請求項1に記載の医薬組成物。
- 賦形剤又は界面活性剤の濃度が、約0.1重量%と約4.0重量%の間である、請求項17に記載の医薬組成物。
- 副腎皮質ステロイドが、シクロスポリンであり、組成物が、
(a)グリセロール、ポリビニルピロリドン、ソルビトール、ポリエチレングリコール、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース及びポリ酢酸ビニルからなる群より選択される少なくとも1つの第二成分と;
(b)グリコサミノグリカン、コンドロイチン、コンドロイチン硫酸、デルマタン硫酸、デルマチン硫酸、ヘパリン硫酸、ヘパラン硫酸、ケラチン硫酸、ケラタン硫酸及びヒアルロン酸からなる群より選択される少なくとも1つの第三成分と;
(c)非イオンポリオキシエチレン-ポリオキシプロピレンブロック共重合体、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重合体、ポリカルボフィル重合体、エデト酸二ナトリウム二水和物(EDTA)、ポリソルベート-80、チオ硫酸ナトリウム、チオ硫酸ナトリウム五水和物、リン酸ナトリウム、無水リン酸二ナトリウム及び無水リン酸一ナトリウムからなる群より選択される少なくとも1つの賦形剤又は界面活性剤と
をさらに含む、請求項1に記載の医薬組成物。 - ミコフェノール酸の医薬的に許容される塩が、ミコフェノール酸ナトリウムであり、副腎皮質ステロイドが、ロテプレドノールエタボン酸エステルであり、組成物が、
(a)グリセロール、ポリビニルピロリドン、ソルビトール、ポリエチレングリコール、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース及びポリ酢酸ビニルからなる群より選択される少なくとも1つの第二成分と;
(b)グリコサミノグリカン、コンドロイチン、コンドロイチン硫酸、デルマタン硫酸、デルマチン硫酸、ヘパリン硫酸、ヘパラン硫酸、ケラチン硫酸、ケラタン硫酸及びヒアルロン酸からなる群より選択される少なくとも1つの第三成分と;
(c)非イオンポリオキシエチレン-ポリオキシプロピレンブロック共重合体、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重合体、ポリカルボフィル重合体、エデト酸二ナトリウム二水和物(EDTA)、ポリソルベート-80、チオ硫酸ナトリウム、チオ硫酸ナトリウム五水和物、リン酸ナトリウム、無水リン酸二ナトリウム及び無水リン酸一ナトリウムからなる群より選択される少なくとも1つの賦形剤又は界面活性剤と
をさらに含む、請求項2に記載の医薬組成物。 - ミコフェノール酸の医薬的に許容される塩が、ミコフェノール酸ナトリウムであり、副腎皮質ステロイドの誘導体又は類似体が、リン酸ベタメタゾンナトリウムであり、組成物が、
(a)グリセロール、ポリビニルピロリドン、ソルビトール、ポリエチレングリコール、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース及びポリ酢酸ビニルからなる群より選択される少なくとも1つの第二成分と;
(b)グリコサミノグリカン、コンドロイチン、コンドロイチン硫酸、デルマタン硫酸、デルマチン硫酸、ヘパリン硫酸、ヘパラン硫酸、ケラチン硫酸、ケラタン硫酸及びヒアルロン酸からなる群より選択される少なくとも1つの第三成分と;
(c)デキストラン、デキストラン硫酸、塩化ナトリウム、デキストロース及びスクロースからなる群より選択される少なくとも1つの第四成分と;
(d)非イオンポリオキシエチレン-ポリオキシプロピレンブロック共重合体、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重合体、ポリカルボフィル重合体、エデト酸二ナトリウム二水和物(EDTA)、ポリソルベート-80、チオ硫酸ナトリウム、チオ硫酸ナトリウム五水和物、リン酸ナトリウム、無水リン酸二ナトリウム及び無水リン酸一ナトリウムからなる群より選択される少なくとも1つの賦形剤又は界面活性剤と
をさらに含む、請求項2に記載の医薬組成物。 - ミコフェノール酸の医薬的に許容される塩が、ミコフェノール酸ナトリウムであり、副腎皮質ステロイドの誘導体又は類似体が、タクロリムス一水和物であり、組成物が、
(a)グリセロール、ポリビニルピロリドン、ソルビトール、ポリエチレングリコール、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース及びポリ酢酸ビニルからなる群より選択される少なくとも1つの第二成分と;
(b)グリコサミノグリカン、コンドロイチン、コンドロイチン硫酸、デルマタン硫酸、デルマチン硫酸、ヘパリン硫酸、ヘパラン硫酸、ケラチン硫酸、ケラタン硫酸及びヒアルロン酸からなる群より選択される少なくとも1つの第三成分と;
(c)デキストラン、デキストラン硫酸、塩化ナトリウム、デキストロース及びスクロースからなる群より選択される少なくとも1つの第四成分と;
(d)アスコルビン酸、エリソルビン酸、アスコルビン酸ナトリウム、チオグリセロール、システイン、アセチルシステイン、シスチン、ジチオエリトレイトール、ジチオトレイトール、グルタチオン、トコフェロール類、ブチル化ヒドロキシアニソール、ブチル化ヒドロキシトルエン、硫酸ナトリウム、重亜硫酸ナトリウム、アセトン重亜硫酸ナトリウム、メタ重亜硫酸ナトリウム、亜硫酸ナトリウム、ホルムアルデヒドスルホキシラートナトリウム、チオ硫酸ナトリウム及びノルジヒドログアヤレチン酸からなる群より選択される少なくとも1つの抗酸化剤と;
(e)非イオンポリオキシエチレン-ポリオキシプロピレンブロック共重合体、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重合体、ポリカルボフィル重合体、エデト酸二ナトリウム二水和物(EDTA)、ポリソルベート-80、チオ硫酸ナトリウム、チオ硫酸ナトリウム五水和物、リン酸ナトリウム、無水リン酸二ナトリウム及び無水リン酸一ナトリウムからなる群より選択される少なくとも1つの賦形剤又は界面活性剤と
をさらに含む、請求項2に記載の医薬組成物。 - 必要とする哺乳動物対象における眼表面疾患を処置、防止及び/又は緩和する方法であって、前記対象に、治療有効量の請求項1又は9に記載の組成物を投与することを含む、方法。
- 投与が、対象の目への局所滴下又は直接注入による、請求項23に記載の方法。
- 眼表面疾患が、乾性角結膜炎、突発性ドライアイ疾患、不応性ドライアイ疾患、加齢性ドライアイ、神経障害性眼表面疾患、マイボーム腺疾患及び眼瞼炎からなる群より選択される、請求項23に記載の方法。
- 眼表面疾患が、乾性角結膜炎である、請求項25に記載の方法。
- 必要とする哺乳動物対象における眼表面疾患を処置、防止及び/又は緩和する方法であって、前記対象に、治療有効量の請求項19~22のいずれか一項に記載の組成物を投与することを含む、方法。
- 投与が、対象の目への局所滴下又は直接注入による、請求項27に記載の方法。
- 眼表面疾患が、乾性角結膜炎、突発性ドライアイ疾患、不応性ドライアイ疾患、加齢性ドライアイ、神経障害性眼表面疾患、マイボーム腺疾患及び眼瞼炎からなる群より選択される、請求項27に記載の方法。
- 眼表面疾患が、乾性角結膜炎である、請求項29に記載の方法。
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EP3902525A1 (en) | 2021-11-03 |
CA3124945A1 (en) | 2020-07-02 |
US20220071945A1 (en) | 2022-03-10 |
KR20210141448A (ko) | 2021-11-23 |
AU2019417161A1 (en) | 2021-07-15 |
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MX2021007709A (es) | 2021-12-15 |
CN113473970A (zh) | 2021-10-01 |
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