JP2021527031A - セピアプテリンの薬学的に許容される塩 - Google Patents
セピアプテリンの薬学的に許容される塩 Download PDFInfo
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- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
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- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- C07C309/01—Sulfonic acids
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- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
- C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
Description
本出願において、文脈から他に明らかでない限り、(i)用語「a」は、「少なくとも1つ」を意味すると理解してもよく、(ii)用語「又は」は、「及び/又は」を意味すると理解してもよく、(iii)用語「含む」及び「包含する」という用語は、それ自体で提示されるか又は1つ以上の追加の構成要素もしくは工程と共に提示されるかにかかわらず、箇条書きされた構成要素又は工程を包含するものと理解してもよく、且つ(iv)「約」及び「およそ」という用語は、当業者によって理解されるように標準的な変形を可能にすると理解してもよく、且つ(v)範囲が提供されている場合は、終点が含まれる。
抗酸化剤
セピアプテリンは、空気にさらされると急速に酸化する傾向がある。従って、本発明の医薬組成物は抗酸化剤を含んでいてもよい。抗酸化剤はセピアプテリンの酸化的分解を最小限に抑えることができる。抗酸化剤の例には、4-クロロ-2, 6-ジ-tert-ブチルフェノール、トコフェロール、α-トコフェロール、アルキル化ジフェニルアミン類、アスコルビン酸、アスコルビルミリステート、アスコルビルパルミテート、アスコルビルステアレート、ベータカロチン、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、クエン酸、システイン、D-α-トコフェリルポリエチレングリコール1000スクシネート、デフェロキサミンメタンスルホネート、ドデシルガレート、エチルパラベン、葉酸、フマル酸、ガリック酸、グルタチオン、レシチン、リンゴ酸、メチルパラベン、モノチオグリセロール、N-アセチルシステイン、ノルジヒドログアヤレト酸、オクチルガレート、p-フェニレンジアミン、アスコルビン酸カリウム、メタ重亜硫酸カリウム、ソルビン酸カリウム、プロピオン酸、プロピルガレート、レチノール、ソルビン酸、アスコルビン酸ナトリウム、重亜硫酸ナトリウム、ハイドロサルファイトナトリウム、イソアスコルビン酸ナトリウム、メタ重亜硫酸ナトリウム、亜硫酸ナトリウム、チオ硫酸ナトリウム、酒石酸、tert-ブチルヒドロキノン、酢酸トコフェリル、ビタミンA、ビタミンB6、ビタミンB12、又はビタミンEを含む。いくつかの実施形態では、本発明の医薬組成物は、アスコルビン酸、トコフェロール、レチノール、アスコルビルパルミテート、N-アセチルシステイン、グルタチオン、ブチル化ヒドロキシトルエン、及び/又はブチル化ヒドロキシアニソールを抗酸化剤として含む。
いくつかの実施形態では、本発明の医薬組成物は、少なくとも1つの分散剤を含む。分散剤は、製剤中の粒子を分離させてもよく、例えば、水分との接触でその薬効物質を放出させてもよい。分散剤の例としては、架橋ポリビニルピロリドン、カルボキシメチルセルロース(例えば、クロスカルメロース塩、例えば、クロスカルメロースナトリウム)、澱粉(例えば、澱粉グリコール酸ナトリウム)、又はアルギン酸を含むが、これらに限定されない。いくつかの実施形態では、医薬組成物中の分散剤は、クロスカルメロースの薬学的に許容される塩のようなカルボキシメチルセルロースである。いくつかの実施形態では、医薬組成物は、総重量に対して0.1〜1.5%(例えば、0.1%、0.5%、1%、又は1.5%)の分散剤を含んでもよい。いくつかの実施形態では、医薬組成物は、1.5%未満(例えば、1%未満、0.5%未満、又は0.1%未満)の分散剤を含む。
セピアプテリンは、水溶液に添加すると塊になることがわかっている。アンチケーキング剤は、しばしば、例えば、溶液中でのダマの形成を防止するために、医薬組成物に添加される。従って、いくつかの実施形態では、本発明の医薬組成物は、少なくとも1つのアンチケーキング剤を含む。いくつかの実施形態では、本発明の医薬組成物は、少なくとも2つのアンチケーキング剤を含む。例示的なアンチケーキング剤には、コロイダル二酸化ケイ素、微結晶セルロース、リン酸三カルシウム、微結晶セルロース、ステアリン酸マグネシウム、炭酸水素ナトリウム、フェロシアン化ナトリウム、フェロシアン化カリウム、フェロシアン化カルシウム、リン酸カルシウム、ケイ酸ナトリウム、コロイダル二酸化ケイ素、ケイ酸カルシウム、三ケイ酸マグネシウム、タルカムパウダー、アルミノケイ酸ナトリウム、ケイ酸アルミニウムカリウム、アルミノケイ酸カルシウム、ベントナイト、ケイ酸アルミニウム、ステアリン酸、及びポリジメチルシロキサンを含む。いくつかの実施形態では、少なくとも1つのアンチケーキング剤は、コロイダル二酸化ケイ素又は微結晶セルロースである。いくつかの実施形態では、医薬組成物は、総重量に対して65〜75%(例えば、65%、67%、70%、73%、又は75%)のアンチケーキング剤を含んでもよい。いくつかの実施形態では、医薬組成物は、コロイダル二酸化ケイ素及び微結晶セルロースの両方を含む。いくつかの実施形態では、医薬組成物は、総重量に対して60〜65%の微結晶セルロース、及び総重量に対して5〜7%のコロイダル二酸化ケイ素を含む。
いくつかの実施形態では、本発明の医薬組成物は、投与前に投与用ビヒクルと組み合わされる。前記いずれかの組成物のいくつかの実施形態では、組成物は、薬学的組成物の懸濁及び投与を助けるために、例えば、約50〜1750センチポイズ(cP)の粘度を有する投与ビヒクル中で投与されてもよい。使用することができる懸濁剤の1つのタイプは、水中のグリセリンとショ糖の組み合わせである(例えば、2.5%のグリセリン及び27%のショ糖を水中に含むMEDISCA(R) oral mix)。適切な量の組成物を投与ビヒクル混合物に添加し、投与直前に組成物を懸濁させるために撹拌できる。
セピアプテリンの薬学的に許容される塩は、任意の適切な用量で使用できる。適切な用量及び用量レジメンは、従来技術の範囲で決定できる。一般に、治療は、最適な用量よりも小さい用量で開始される。その後、状況下で最適な効果が得られるまで、投与量を小刻みに増加させる。便宜上、1日の総投与量は、所望であれば、1日の間に分割して投与できる。適切な用量及び特定の化合物の適切な投与では、本発明は広い範囲の応答を提供する。典型的には、投与量は、治療される患者の約2.5〜約150mg/kg体重/日の範囲である。例えば、実施形態では、セピアプテリンの薬学的に許容される塩を、所望の治療効果を得るために、約20mg/kg〜約200mg/kg、約40mg/kg〜約150mg/kg、約60mg/kg〜約120mg/kg、約80mg/kg〜約100mg/kg、約40mg/kg〜約60mg/kg、約2.5mg/kg〜約20mg/kg、約2.5mg/kg〜約10mg/kg、約2.5mg/kg〜約5mg/kg対象体重/日で、1日に1回以上投与できる。
担体の選択は、組成物を投与するために使用される特定の方法と同様に、特定の活性剤によって部分的に決定され得る。従って、本発明の医薬組成物の好適な製剤は多様である。経口、エアロゾル、非経口、皮下、静脈内、動脈内、筋肉内、腹腔内、髄腔内、直腸、及び膣の投与のための以下の製剤は、単に例示的なものであり、いかなる意味でも限定するものではない。
経口使用のための製剤は、非毒性の薬剤学的に許容される賦形剤との混合物中に活性成分を含む粒子を含み、そのような製剤は当業者に知られている(例えば、U.S. Patent Nos.: 5,817,307, 5,824,300, 5,830,456, 5,846,526, 5,882,640, 5,910,304, 6,036,949, 6,036,949, 6,372,218。これらは本明細書に組み込まれる。)。賦形剤は、例えば、不活性希釈剤又は充填剤(例えば、ショ糖、ソルビトール、砂糖、マンニトール、微結晶セルロース、ポテトスターチを含む澱粉、炭酸カルシウム、塩化ナトリウム、乳糖、リン酸カルシウム、硫酸カルシウム、又はリン酸ナトリウム)、造粒・崩壊剤(例えば、微結晶セルロースを含むセルロース誘導体、ポテトスターチを含む澱粉、クロスカルメロースナトリウム、アルギネート類又はアルギン酸)、結合剤(例えば、ショ糖、グルコース、ソルビトール、アカシア、アルギン酸、アルギン酸ナトリウム、ゼラチン、澱粉、プレゼラチン化澱粉、微結晶セルロース、ケイ酸アルミニウムマグネシウム、カルボキシメチルセルロースナトリウム、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、エチルセルロース、ポリビニルピロリドン、又はポリエチレングリコール)、及び潤滑剤、滑剤、付着防止剤(例えば、ステアリン酸マグネシウム、ステアリン酸亜鉛、ステアリン酸、シリカ、水添植物油、又はタルク)、及びアンチケーキング剤(例えば、コロイダル二酸化ケイ素、微結晶セルロース、リン酸三カルシウム、微結晶セルロース、ステアリン酸マグネシウム、炭酸水素ナトリウム、フェロシアン化ナトリウム、フェロシアン化カリウム、フェロシアン化カルシウム、リン酸カルシウム、ケイ酸ナトリウム、コロイダル二酸化ケイ素、ケイ酸カルシウム、三ケイ酸マグネシウム、タルカムパウダー、アルミノケイ酸ナトリウム、ケイ酸アルミニウムカリウム、アルミノケイ酸カルシウム、ベントナイト、ケイ酸アルミニウム、ステアリン酸、ポリジメチルシロキサン)であってもよい。他の薬学的に許容される賦形剤は、着色剤、香料、可塑剤、腐植剤、及び緩衝剤であり得る。いくつかの実施形態では、賦形剤(例えば、香料)は、組成物と共に包装される。いくつかの実施形態では、賦形剤(例えば、香料)は、組成物とは別に包装される(例えば、投与前に組成物と組み合わされる)。
本発明は、例えば、経口許容可能な処方の医薬組成物であって、治療上有効な量のセピアプテリンの製薬学的に許容可能な塩及び/又は共結晶、例えば、及び10%未満の抗酸化剤を含むことによって特徴付けられる。いくつかの実施形態では、医薬組成物は、薬学的に許容される担体中に分散された顆粒状の製剤であり、例えば、組成物は、水に混合され得、且つ患者によって摂取され得る(例えば、5分から10分の間に)。本発明で使用するための好適な製剤は、Remington(The Science and Practice of Pharmacy, (22nd ed.) ed. L.V. Allen, Jr., 2013, Pharmaceutical Press, Philadelphia, PA)に記載されている。活性成分と相容れない場合を除き、医薬組成物中での任意の従来の担体の使用が企図される。さらに、動物(例えば、ヒト)投与のために、調製物は、規制機関によって要求されるように、無菌性、高温性、一般的な安全性及び純度の基準を満たすべきであることが理解される。
いくつかの実施形態では、本発明の医薬組成物は、1つ以上の賦形剤、例えば、分散剤、及び1つ以上のアンチケーキング剤とともに、セピアプテリン又はその薬学的に許容される塩及び/又は共結晶、及び抗酸化剤を混合することによって生産され得る。いくつかの実施形態では、組成物の各成分は、混合する前に、サイズ排除フィルター(例えば、200μm以下のポアを有するフィルター)を通過させる。いくつかの実施形態では、アンチケーキング剤は、組成物の各成分(例えば、セピアプテリン、分散剤、及び抗酸化剤)を添加する前に一緒に混合される。
セピアプテリンと塩酸、メタンスルホン酸、トルエンスルホン酸、ベンゼンスルホン酸、ニコチン酸、硫酸、リン酸、マロン酸、L-酒石酸、フマル酸、ゲンチシン酸、グリコール酸の塩及び/又は共結晶を、セピアプテリンのフリーベースと酸をアセトン/水(9/1、v/v)又はメタノール中で2〜17日間スラリー化して製造した。
調製した塩及び/又は共結晶の安定性を、25℃及び相対湿度60%の環境下及び40℃及び相対湿度75%の環境下で1及び2週間後に分析した。結果は以下の表16にまとめられている。驚くべきことに、試験した全ての塩及び/又は共結晶のうち、リン酸塩及び/又は共結晶、酒石酸塩及び/又は共結晶、ニコチン酸塩及び/又は共結晶は、他の塩及び/又は共結晶よりも顕著に安定であった。リン酸塩、酒石酸塩、又はニコチン酸塩及び/又は共結晶のいずれも、安定性試験中に形態変化を起こしておらず、それぞれが試験の2週間にわたって97%以上の純度を保持していた。実際、酒石酸塩とニコチン酸塩は両方とも99%以上の純度を保持していた。
セピアプテリンのニコチン酸塩、リン酸塩、L-酒石酸塩、フマル酸塩及び/又は共結晶について、水中及びMedisca Oral Mixでの動的溶解性を評価した。粉末X線回折(XRPD)を形態変化/不均化(form change/disproportionation)を確認するために残留固形物について実施した。固形物を〜7 mg/ml(フリーベースで計算)の目標濃度でメディアに懸濁した。懸濁液をローリングインキュベーターで25rpmで1、4、及び24時間撹拌した。各タイムポイントで、懸濁液の1mLをピペッティングし、10000rpm(2分間)で遠心分離し、0.45μmの膜を介してろ過し、HPLC溶解性とpHテストのための上清を得、残留固形物をXRPDによって分析した。溶解性の結果を表17〜20にまとめた。
本発明は、その特定の実施形態に関連して記載されてきたが、さらなる変更が可能であり、本願は、典型的には、本発明の原理に従う本発明のあらゆる変形、使用、又は適応をカバーすることを意図しており、本明細書の開示からのそのような展開は、本発明が属する技術分野において既知又は慣習的プラクティスの範囲内にあり、本明細書に記載されている本質的な特徴に適用され得るものである。
Claims (36)
- セピアプテリンの薬学的に許容される塩及び/又は共結晶であって、メタンスルホン酸塩及び/又は共結晶、ニコチン酸塩及び/又は共結晶、トルエンスルホン酸塩及び/又は共結晶、ベンゼンスルホン酸塩及び/又は共結晶、硫酸塩及び/又は共結晶、リン酸塩及び/又は共結晶、マロン酸塩及び/又は共結晶、酒石酸塩及び/又は共結晶、フマル酸塩及び/又は共結晶、ゲンチセート塩及び/又は共結晶、又はグリコール酸塩及び/又は共結晶である、薬学的に許容される塩及び/又は共結晶。
- リン酸塩及び/又は共結晶、酒石酸塩及び/又は共結晶、グリコール酸塩及び/又は共結晶、フマル酸塩及び/又は共結晶、ゲンチセート塩及び/又は共結晶、マロン酸塩及び/又は共結晶、又はニコチン酸塩及び/又は共結晶である、請求項1の薬学的に許容される塩及び/又は共結晶。
- ニコチン酸、リン酸、又は酒石酸塩及び/又は共結晶である、請求項1又は2の薬学的に許容される塩及び/又は共結晶。
- ニコチン酸塩及び/又は共結晶である、請求項1の薬学的に許容される塩及び/又は共結晶。
- リン酸塩及び/又は共結晶である、請求項1の薬学的に許容される塩及び/又は共結晶。
- 酒石酸塩及び/又は共結晶である、請求項1の薬学的に許容される塩及び/又は共結晶。
- メタンスルホン酸塩及び/又は共結晶である、請求項1の薬学的に許容される塩及び/又は共結晶。
- トルエンスルホン酸塩及び/又は共結晶である、請求項1の薬学的に許容される塩及び/又は共結晶。
- ベンゼンスルホン酸塩及び/又は共結晶である、請求項1の薬学的に許容される塩及び/又は共結晶。
- 硫酸塩及び/又は共結晶である、請求項1の薬学的に許容される塩及び/又は共結晶。
- マロン酸塩及び/又は共結晶である、請求項1の薬学的に許容される塩及び/又は共結晶。
- フマル酸塩及び/又は共結晶である、請求項1の薬学的に許容される塩及び/又は共結晶。
- フマル酸塩及び/又は共結晶が2:1フマル酸塩及び/又は共結晶である、請求項12の薬学的に許容される塩及び/又は共結晶。
- ゲンチセート塩及び/又は共結晶である、請求項1の薬学的に許容される塩及び/又は共結晶。
- グリコール酸塩及び/又は共結晶である、請求項1の薬学的に許容される塩及び/又は共結晶。
- 結晶である、請求項1〜15のいずれか1項の薬学的に許容される塩及び/又は共結晶。
- 40重量%未満のアモルファス化合物を含む、請求項16の薬学的に許容される塩及び/又は共結晶。
- 請求項1〜17のいずれか1項の薬学的に許容される塩及び/又は共結晶、及び薬学的に許容される賦形剤を含む、医薬組成物。
- それを必要とする対象におけるテトラヒドロビオプテリン関連障害の治療方法であって、有効量の請求項1〜17のいずれか1項の薬学的に許容される塩及び/又は共結晶、又は請求項18の医薬組成物を前記対象に投与する工程を含む、方法。
- 前記テトラヒドロビオプテリン関連障害が、フェニルケトン尿症又はテトラヒドロビオプテリン欠損症である、請求項19の方法。
- それを必要とする対象におけるテトラヒドロビオプテリンレベルを増加させる方法であって、有効量の請求項1〜17のいずれかの薬学的に許容される塩及び/又は共結晶、又は請求項18の医薬組成物を前記対象に投与する工程を含む、方法。
- それを必要とする対象におけるフェニルアラニンレベルを低下させる方法であって、有効量の請求項1〜17のいずれか1項の薬学的に許容される塩及び/又は共結晶、又は請求項18の医薬組成物を前記対象に投与する工程を含む、方法。
- 対象におけるフェニルアラニン水酸化酵素の活性を高める方法であって、有効量の請求項1〜17のいずれか1項の薬学的に許容される塩及び/又は共結晶、又は請求項18の医薬組成物を前記対象に投与する工程を含む、方法。
- それを必要とする対象におけるフェニルケトン尿症の治療方法であって、有効量の請求項1〜17のいずれか1項の薬学的に許容される塩及び/又は共結晶、又は請求項18の医薬組成物を前記対象に投与する工程を含む、方法。
- それを必要とする対象におけるセロトニンレベルを増加させる方法であって、有効量の請求項1〜17のいずれか1項の薬学的に許容される塩及び/又は共結晶、又は請求項18の医薬組成物を前記対象に投与する工程を含む、方法。
- 対象におけるトリプトファン水酸化酵素の活性を増加させる方法であって、有効量の請求項1〜17のいずれか1項の薬学的に許容される塩及び/又は共結晶、又は請求項18の医薬組成物を前記対象に投与する工程を含む、方法。
- それを必要とする対象におけるドーパミンレベルを増加させる方法であって、有効量の請求項1〜17のいずれか1項の薬学的に許容される塩及び/又は共結晶、又は請求項18の医薬組成物を前記対象に投与する工程を含む、方法。
- 対象のチロシン水酸化酵素の活性を高める方法であって、有効量の請求項1〜17のいずれか1項の薬学的に許容される塩及び/又は共結晶、又は請求項18の医薬組成物を前記対象に投与する工程を含む、方法。
- 対象における一酸化窒素合成酵素の活性を高める方法であって、有効量の請求項1〜17のいずれか1項の薬学的に許容される塩及び/又は共結晶、又は請求項18の医薬組成物を前記対象に投与する工程を含む、方法。
- 対象におけるアルキルグリセロールモノオキシゲナーゼの活性を高める方法であって、有効量の請求項1〜17のいずれか1項の薬学的に許容される塩及び/又は共結晶、又は請求項18の医薬組成物を前記対象に投与する工程を含む、方法。
- 前記有効量の請求項1〜17のいずれか1項の薬学的に許容される塩及び/又は共結晶、又は請求項18の医薬組成物が、投与前のテトラヒドロビオプテリンのレベルと比較して、前記対象の血漿中のテトラヒドロビオプテリンのレベルを少なくとも2倍増加させるのに十分な量を含む、請求項19〜30のいずれか1項の方法。
- 前記有効量の請求項1〜17のいずれか1項の薬学的に許容される塩及び/又は共結晶、又は請求項18の医薬組成物が、投与前のテトラヒドロビオプテリンのレベルと比較して、前記対象のCSF及び/又は脳中のテトラヒドロビオプテリンのレベルを少なくとも2倍増加させるのに十分な量を含む、請求項19〜30のいずれか1項の方法。
- 対象におけるホモバニリン酸及び/又は5-ヒドロキシインドール酢酸のレベルを増加させる方法であって、有効量の請求項1〜17のいずれか1項の薬学的に許容される塩及び/又は共結晶、又は請求項18の医薬組成物を投与する工程を含む、方法。
- 前記対象のCSF中のホモバニリン酸及び/又は5-ヒドロキシインドール酢酸のレベルが増加する、請求項33の方法。
- 前記対象中のホモバニリン酸及び/又は5-ヒドロキシインドール酢酸のレベルが、投与前のレベルと比較して少なくとも100%増加する、請求項33又は34の方法。
- 前記対象がヒトである、請求項19〜35のいずれか1項の方法。
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WO2018102315A1 (en) | 2016-11-29 | 2018-06-07 | Censa Pharmaceuticals Inc. | Polymoprhs of sepiapterin and salts thereof |
EP3675863A4 (en) | 2017-09-01 | 2021-01-27 | PTC Therapeutics MP, Inc. | PHARMACEUTICAL COMPOSITION CONSISTING OF SEPIAPTERIN AND ITS USES |
WO2019232130A1 (en) | 2018-05-30 | 2019-12-05 | Censa Pharmaceuticals Inc. | Methods for increasing sepiapterin plasma exposure |
BR112022002029A2 (pt) | 2019-08-05 | 2022-06-07 | Ptc Therapeutics Mp Inc | Uso de sepiapterina e seus metabólitos para tratar exposição à radiação |
JP2022549834A (ja) | 2019-09-25 | 2022-11-29 | ピーティーシー セラピューティクス エムピー,インコーポレイテッド | 高フェニルアラニン血症の治療方法 |
WO2021150983A1 (en) | 2020-01-24 | 2021-07-29 | Ptc Therapeutics Mp, Inc. | Methods for treating parkinson's disease with sepiapterin |
CN114621198A (zh) * | 2020-12-11 | 2022-06-14 | 北京夏禾科技有限公司 | 有机电致发光材料及其器件 |
WO2022173834A1 (en) | 2021-02-09 | 2022-08-18 | Ptc Therapeutics Mp, Inc. | Methods for treating glioblastomas with sepiapterin |
US20240122931A1 (en) | 2021-02-09 | 2024-04-18 | Ptc Therapeutics Mp, Inc. | Methods for treating covid-19 with sepiapterin |
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