JP2021525729A - セピアプテリン血漿曝露を増加させるための方法 - Google Patents
セピアプテリン血漿曝露を増加させるための方法 Download PDFInfo
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- JP2021525729A JP2021525729A JP2020566655A JP2020566655A JP2021525729A JP 2021525729 A JP2021525729 A JP 2021525729A JP 2020566655 A JP2020566655 A JP 2020566655A JP 2020566655 A JP2020566655 A JP 2020566655A JP 2021525729 A JP2021525729 A JP 2021525729A
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- sepiapterin
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- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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。
セピアプテリンは細胞内へ通過し、セピアプテリン還元酵素によって7,8-ジヒドロビオプテリンに変換される。7,8-ジヒドロビオプテリンは、ジヒドロ葉酸還元酵素による還元を介してBH4に変換される。
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てもよい。抗酸化剤の例としては、限定されないが、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、エチレンジアミン四酢酸、重亜硫酸ナトリウム、メタ重亜硫酸ナトリウム、チオウレア、ブチル化ヒドロキシトルエン、ブチル化ヒドロキシアニソール、及びビタミンEを含む。いくつかの実施形態において、本発明の医薬組成物は、抗酸化剤として、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。
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(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)。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。
セピアプテリン又はそ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500mg/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、又はそ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150mg/kg、約40mg/kg〜約100mg/kg、約100mg/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、又は約2.5mg/kg〜約5mg/kg対象体重/日で、1日に1回以上投与できる。
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。これらは参照として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)。
セピアプテリンは、細胞内BH4レベルの低下に関連した疾患、又はプライマリーBH4欠損症、GTPCH欠損症、6-ピルボイル-テトラヒドロプテリン合成酵素(PTPS)欠損症、DHPR欠損症、セピアプテリン還元酵素欠損症、ドーパミン反応性ジストニア、瀬川症候群、チロシン水酸化酵素欠損症、フェニルケトン尿症、DNAJC12欠損症、パーキンソン病、パーキンソン病によるうつ病、パーキンソン病患者における衝動性、大うつ病、自閉症スペクトラム、ADHD、統合失調症、双極性障害、脳虚血、レストレスレッグシンドローム、強迫性障害、不安障害、アルツハイマー病における攻撃性、脳血管障害、くも膜下出血後の痙攣、心筋炎、コロナリーバソスパズム、心肥大、動脈硬化、高血圧、血栓症、感染症、エンドトキシンショック、肝硬変、肥厚性幽門狭窄症、胃粘膜損傷、肺高血圧症、腎機能障害、インポテンツ、及び低血糖症を含むがこれらに限定されない様々なBH4依存性代謝経路の機能不全に関連した疾患の治療に有用であり得る。そのため、本発明の様々な形態のセピアプテリン、又はその塩は、疾患、障害又は状態の治療又は改善を得るために、有効量で患者に投与できる。
当業者は、本明細書に記載の本発明に基づく特定の実施形態と同等のものを多く認識し、又はルーティン実験のみを使用して確認できる。本発明の範囲は、上記の説明に限定されることを意図したものではなく、むしろ、添付の特許請求の範囲に記載されている通りである。
方法:対象に絶食及び摂食状態で1週間に分けてセピアプテリン(10mg/kg)を2回経口投与した。8日目にセピアプテリンの2回目の経口投与を行う30分前から、標準的な高脂肪(食事の総カロリー量の約50パーセント)及び高カロリー(約800〜1000カロリー)の食事を対象に与えた。
本明細書は、詳細な説明と関連して記載されているが、上記説明は、例示することを意図しており、添付の特許請求の範囲によって定義される本明細書の開示の範囲を限定するものではないことが理解されよう。他の態様、利点、及び変更は、以下の特許請求の範囲の範囲内である。
Claims (13)
- それを必要とする対象におけるBH4関連疾患の治療方法であって、有効量のセピアプテリン又はその薬学的に許容される塩を食品を伴わずに前記対象に投与する工程を含む、方法。
- セピアプテリン治療を受けている対象のセピアプテリン血漿曝露を増加させる方法であって、有効量のセピアプテリン又はその薬学的に許容される塩を食品を伴わずに前記対象に投与する工程を含む、方法。
- セピアプテリン治療を受けている対象のセピアプテリン脳脊髄液(CSF)及び/又は脳曝露を増加させる方法であって、有効量のセピアプテリン又はその薬学的に許容される塩を食品を伴わずに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いて経時的に血漿中に到達したセピアプテリンの濃度によって測定される、セピアプテリン又はその薬学的に許容される塩の経口製剤の吸収速度を増加させる及び/又はBH4への末梢変換を減少させる方法であって、有効量のセピアプテリン又はその薬学的に許容される塩を食品を伴わずに前記対象に投与する工程を含む、方法。
- 前記有効量が、投与1時間以内に対象の血漿中に少なくとも0.5 ng/mlの濃度を生成するのに十分な量である、請求項1〜4のいずれか1項に記載の方法。
- 前記有効量が、セピアプテプリン又はその薬学的に許容される塩を食品と共に投与後1時間以内に対象の血漿中に少なくとも0.5 ng/mlの最大血漿中濃度(Cmax)を生成するのに十分な量よりも少なくとも20%未満の投与量を含む、請求項5の方法。
- 前記有効量が、投与1回あたり2.5mg/kg〜100mg/kgである、請求項1〜6のいずれか1項に記載の方法。
- 前記対象への投与が、食品を摂取する30分超前又は4時間超後に行われる、請求項1〜7のいずれか1項に記載の方法。
- 前記有効量が、食品を伴う投与の場合と比較して、セピアプテリン又はその薬学的に許容される塩の最大血漿中、CSF中、及び/又は脳内濃度(Cmax)の増加をもたらす、請求項1〜8のいずれか1項の方法。
- 前記BH4関連疾患がCNS障害である、請求項1〜9のいずれかに記載の方法。
- 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、有効量のセピアプテリン又はその薬学的に許容される塩を食品を伴わずに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11の方法。
- 前記対象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11又は12の方法。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010523708A (ja) * | 2007-04-11 | 2010-07-15 | バイオマリン ファーマシューティカル インコーポレイテッド | テトラヒドロビオプテリンを投与する方法、関連する組成物および測定方法 |
WO2011132435A1 (ja) * | 2010-04-22 | 2011-10-27 | 学校法人日本大学 | 脳機能障害予防・改善用の薬剤及び飲食物 |
US20130108694A1 (en) * | 2011-11-02 | 2013-05-02 | Biomarin Pharmaceutical Inc. | Dry blend formulation of tetrahydrobiopterin |
Family Cites Families (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5925323A (ja) | 1982-03-03 | 1984-02-09 | 鐘淵化学工業株式会社 | プテリン誘導体からなる脳内神経伝達物質の関わる疾病の治療剤 |
US5910304A (en) | 1982-12-13 | 1999-06-08 | Texas A&M University System | Low-dose oral administration of interferons |
CA1320905C (en) | 1986-11-06 | 1993-08-03 | Joseph M. Cummins | Treatment of immuno-resistant disease |
US5736343A (en) | 1995-08-18 | 1998-04-07 | Landry; Donald | Detection of organic compounds through regulation of antibody-catalyzed reactions |
US6036949A (en) | 1998-03-05 | 2000-03-14 | Amarillo Biosciences, Inc. | Treatment of fibromyalgia with low doses of interferon |
US8188043B2 (en) | 1999-07-28 | 2012-05-29 | The Board Of Trustees Of The Leland Stanford Jr. University | Nicotine in therapeutic angiogenesis and vasculogenesis |
FR2859996B1 (fr) | 2003-09-19 | 2006-02-03 | Aventis Pharma Sa | Solvat acetonique du dimethoxy docetaxel et son procede de preparation |
AU2004291082A1 (en) * | 2003-11-13 | 2005-06-02 | The General Hospital Corporation | Methods for treating pain |
JP5184783B2 (ja) | 2003-11-17 | 2013-04-17 | バイオマリン ファーマシューティカル インコーポレイテッド | テトラヒドロビオプテリン、及びテトラヒドロビオプテリン類似体の製造方法 |
ES2755334T3 (es) | 2003-11-17 | 2020-04-22 | Merck & Cie | Proceso para la preparación de formas cristalinas B de clorhidrato de (6R)-L-eritro-tetrahidrobiopterina a partir de otras formas cristalinas |
CA2545584C (en) | 2003-11-17 | 2012-10-23 | Biomarin Pharmaceutical Inc. | Methods and compositions for the treatment of metabolic disorders |
BRPI0517088A (pt) | 2004-11-17 | 2008-09-30 | Biomarin Pharm Inc | formulação de comprimido estável |
JP2008523090A (ja) | 2004-12-08 | 2008-07-03 | バイオマリン ファーマシューティカル インコーポレイテッド | 新生児肺高血圧症の治療のための方法および組成物 |
WO2006118322A1 (en) | 2005-04-28 | 2006-11-09 | Shiratori Pharmaceutical Co., Ltd. | Method for producing hydrazone derivatives |
US20080075666A1 (en) | 2006-08-25 | 2008-03-27 | Dudley Samuel C Jr | Methods and compositions for treating diastolic dysfunction |
WO2010017570A2 (de) | 2008-08-12 | 2010-02-18 | Orpha Swiss Gmbh | Pharmazeutische darreichungsform enthaltend tetrahydrobiopterin |
US9884909B2 (en) | 2010-12-01 | 2018-02-06 | Alderbio Holdings Llc | Anti-NGF compositions and use thereof |
RU2017134002A (ru) | 2011-03-01 | 2019-02-07 | Дифарма С.А. | Стабильные композиции тетрагидробиоптерина |
IN2014DN09053A (ja) | 2012-05-07 | 2015-05-22 | Shiratori Pharm | |
EP3213062B1 (en) * | 2014-10-31 | 2020-02-12 | Children's Medical Center Corporation | Methods and assays relating to sepiapterin reductase inhibition |
KR102561697B1 (ko) | 2016-11-29 | 2023-07-28 | 피티씨 테라퓨틱스 엠피, 인크. | 세피아프테린의 다형체 및 그의 염 |
JP7148532B2 (ja) | 2016-11-29 | 2022-10-05 | 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 | セピプテリンの多形 |
JP2020532535A (ja) | 2017-09-01 | 2020-11-12 | 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 | セピアプテリンを含む医薬組成物及びその使用 |
KR20240028571A (ko) * | 2017-11-23 | 2024-03-05 | 가부시키가이샤 한도오따이 에네루기 켄큐쇼 | 표시 장치 및 전자 기기 |
KR20210038848A (ko) | 2018-05-30 | 2021-04-08 | 피티씨 테라퓨틱스 엠피, 인크. | 세피아프테린의 제약상 허용되는 염 |
CA3102105A1 (en) * | 2018-05-30 | 2019-12-05 | Ptc Therapeutics Mp, Inc. | Compositions and methods for increasing tetrahydrobiopterin plasma exposure |
AU2020324435A1 (en) | 2019-08-05 | 2022-02-24 | Ptc Therapeutics Mp, Inc. | Use of sepiapterin and metabolites thereof to treat radiation exposure |
WO2021062264A1 (en) | 2019-09-25 | 2021-04-01 | Ptc Therapeutics Mp, Inc. | Methods for treating hyperphenylalaninemia |
-
2019
- 2019-05-30 AU AU2019277382A patent/AU2019277382A1/en active Pending
- 2019-05-30 WO PCT/US2019/034523 patent/WO2019232130A1/en unknown
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- 2019-05-30 MX MX2020012979A patent/MX2020012979A/es unknown
- 2019-05-30 US US17/059,719 patent/US11617752B2/en active Active
- 2019-05-30 EP EP19811888.7A patent/EP3801536A4/en active Pending
-
2023
- 2023-03-31 US US18/129,177 patent/US20230381181A1/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010523708A (ja) * | 2007-04-11 | 2010-07-15 | バイオマリン ファーマシューティカル インコーポレイテッド | テトラヒドロビオプテリンを投与する方法、関連する組成物および測定方法 |
WO2011132435A1 (ja) * | 2010-04-22 | 2011-10-27 | 学校法人日本大学 | 脳機能障害予防・改善用の薬剤及び飲食物 |
US20130108694A1 (en) * | 2011-11-02 | 2013-05-02 | Biomarin Pharmaceutical Inc. | Dry blend formulation of tetrahydrobiopterin |
Non-Patent Citations (1)
Title |
---|
CLINICA CHIMICA ACTA, vol. 93, JPN6023012295, 1979, pages 251 - 262, ISSN: 0005028255 * |
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US20210220363A1 (en) | 2021-07-22 |
WO2019232130A1 (en) | 2019-12-05 |
MX2020012979A (es) | 2021-04-29 |
CN112703002A (zh) | 2021-04-23 |
CA3102106A1 (en) | 2019-12-05 |
US11617752B2 (en) | 2023-04-04 |
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