JP5675758B2 - 安定な結晶性5−メチルテトラヒドロ葉酸塩 - Google Patents
安定な結晶性5−メチルテトラヒドロ葉酸塩 Download PDFInfo
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- JP5675758B2 JP5675758B2 JP2012264084A JP2012264084A JP5675758B2 JP 5675758 B2 JP5675758 B2 JP 5675758B2 JP 2012264084 A JP2012264084 A JP 2012264084A JP 2012264084 A JP2012264084 A JP 2012264084A JP 5675758 B2 JP5675758 B2 JP 5675758B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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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
- A61P3/02—Nutrients, e.g. vitamins, minerals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
Description
例中に記載される5−メチルテトラヒドロ葉酸塩の含有量は、それぞれHPLCによって測定され、そして%−表面で記載される。水分含有量はカールフィシャー法で測定される。
結晶性5−メチルテトラヒドロ葉酸塩の安定性測定のために、この物質を比較試料と一緒に25℃及び相対湿度60%で大気下に保存する。周期的間隔で5−メチルテトラヒドロ葉酸塩の残存含有量を測定し、出発値と比較して記載する。
結晶性5−メチルテトラヒドロ葉酸塩の構造性質(結晶度)を調べるために、これらの物質による粉末X線図(回折スペクトル)を採用する。
5−メチル−(6S)−テトラヒドロ葉酸の結晶性カルシウム塩(タイプI)
回折メーター:透過
モノクロメーター:Curved Ge(111)
波長:1.54098 Cu
検出器:ライナーPSD
スキャンモード:Debye−Scherrer/Moving PSD/Fixed omega
2θスキャン
!ピークサーチパラメーター:期待半値幅 : .150
! 有意水準 : 2.5
! ピーク高さ水準:10
ピークリスト〔範囲1:2θ=5.000 34.980 .020 Imax=765〕
5−メチル−(6S)−テトラヒドロ葉酸の結晶性カルシウム塩(タイプII)
回折メーター:透過
モノクロメーター:Curved Ge(111)
波長:1.54098 Cu
検出器:ライナーPSD
スキャンモード:Debye−Scherrer/Moving PSD/Fixed omega
2θスキャン
!ピークサーチパラメーター:期待半値幅 : .150
! 有意水準 : 2.5
! ピーク高さ水準:10
ピークリスト〔範囲1:2θ=5.000 34.980 .020 Imax=526〕
5−メチル−(6S)−テトラヒドロ葉酸の結晶性カルシウム塩(タイプIII)
回折メーター:透過
モノクロメーター:Curved Ge(111)
波長:1.540598 Cu
検出器:ライナーPSD
スキャンモード:Debye−Scherrer/Moving PSD/Fixed omega
2θスキャン
!ピークサーチパラメーター:期待半値幅 : .150
! 有意水準 : 2.5
! ピーク高さ水準:10
ピークリスト〔範囲1:2θ=5.000 34.980 .020 Imax=817〕
5−メチル−(6S)−テトラヒドロ葉酸の結晶性カルシウム塩(タイプIV)
回折メーター:透過
モノクロメーター:Curved Ge(111)
波長:1.540598 Cu
検出器:ライナーPSD
スキャンモード:Debye−Scherrer/Moving PSD/Fixed omega
2θスキャン
!ピークサーチパラメーター:期待半値幅 : .150
! 有意水準 : 2.5
! ピーク高さ水準:10
ピークリスト〔範囲1:2θ=5.000 34.980 .020 Imax=473〕
タイプ 選択された2θ値
タイプI 6.5、13.3、16.8及び20.1
タイプII 5.3、 6.9、18.7及び21.1
タイプIII 6.8、10.2、15.4及び22.5
タイプIV 6.6、15.9、20.2及び22.5
結晶性5−メチル−(6S)−テトラヒドロ葉酸カルシウム塩の溶解度を次の表に記載する。
タイプ 20℃での溶解度
0.9%NaCl 水
タイプI 1.6% 1.1%
タイプII 5.8% 3.8%
タイプIII 1.5% 1.0%
N2の導入下に室温で水75mlに5−メチル−(6S)−テトラヒドロ葉酸7.5gを添加して、30%水酸化ナトリウム溶液でpH12に調整する。得られた澄明な溶液を37%塩酸でpH7.5に調整し、これに水11.7ml中に塩化カルシウム6H2O7.15gを含有する溶液を加える。得られた白色懸濁液を5時間攪拌して室温で吸引濾取し、水で十分に洗滌して、45℃で減圧乾燥する。
5−メチル−(6R,S)−テトラヒドロ葉酸70gを水780ml中に入れ、30%NaOH45.2gでpH7.5に調整する。澄明な淡い赤色溶液を水140ml中に塩化カルシウム6H2O62.7gを含有する溶液を加え、濾過して、少量の水で十分に洗滌する。得られた粗精製物を水中に懸濁させて、90℃で湿室中で24時間処理する。
5−メチル−(6R)−テトラヒドロ葉酸16.5gを92℃の水100ml及び塩化カルシウム6H2O50g中に入れる。澄明な淡い黄色懸濁液を10分間、91℃で攪拌し、濾過し、少量の水で十分に洗滌して、35℃で減圧乾燥する。
水130kgを予め入れ、ついで5−メチル−(6S)−テトラヒドロ葉酸12.8kgを添加する。30%NaOH約9.1kgでpH−値11.6に調整し、ついで37%塩酸約1.9kgで7.6に調整する。澄明な溶液に炭0.3kg及びセルフロック(cellflock)0.3kgを含有する懸濁液を添加し、濾過して、水13Lで十分に洗滌する。濾液に塩化カルシウム・2H2O8.3kgを含有する溶液を添加し、90℃に加熱して、30分間攪拌する。生成物を熱い状態で濾過して、水2×20kgで十分に洗滌する。得られた湿性粗生成物を水115L中に懸濁させ、90℃に加熱して、直ちに熱いうちに濾過し、水2×20kgで十分に洗滌して、40℃で減圧乾燥させる。
水1600mlを予め入れ、ついで5−メチル−(6S)−テトラヒドロ葉酸194kgを添加する。30%NaOH約80mlでpH−値7.0に調整する。澄明な溶液に、水190ml中に炭20kg及びセルフロック20gを含有する懸濁液を添加し、濾過して、水で十分に洗滌する。濾液に5.5M塩化カルシウム溶液950mlを添加し、90℃に加熱して、60分間攪拌する。生成物を熱い状態で濾過して、水で十分に洗滌し、ついで45℃で減圧乾燥させる。
水554gを予め入れ、ついで5−メチル−(6S)−テトラヒドロ葉酸53.1kgを添加する。30%NaOHでpH値を7.5に調整する。澄明な溶液に炭1.3g、セルフロック1.3g及び水19.5gを添加する。懸濁液を濾過して、水55mlで十分に洗滌する。濾液に水84.6g中に塩化カルシウム・6H2O52.0gを含有する溶液を添加し、90℃に加熱して、結晶性5−メチルテトラヒドロ葉カルシウム塩100mgを結晶種として入れる。結晶化させた後に、生成物を90℃の熱い状態で濾過して、水2×103gで十分に洗滌する。得られた湿性粗生成物を90℃で水480ml中に懸濁させ、90℃に加熱して、直ちに熱いうちに濾過し、上述のように十分に洗滌して、45℃で減圧乾燥させる。
5−メチル−(6S)−テトラヒドロ葉酸カルシウム塩15.8gを水140ml中でN2の導入下に95℃に加熱して、95℃で30分後、白色懸濁液を熱い状態で吸引濾取し、水で十分に洗滌して、35℃で減圧乾燥する。
5−メチル−(6S)−テトラヒドロ葉酸カルシウム塩20.0gを水180ml中でN2の導入下に100℃に加熱して、100℃で30分後、白色懸濁液を熱い状態で吸引濾取し、水で十分に洗滌して、25℃で減圧乾燥する。
Claims (1)
- 5−メチル−(6S)−テトラヒドロ葉酸の結晶性カルシウム塩であって、該結晶性塩が2θ値5.3、6.9、18.7及び21.1(タイプII)を示す、上記結晶性カルシウム塩。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH00695/99A CH693905A5 (de) | 1999-04-15 | 1999-04-15 | Stabile kristalline Salze von 5-Methyltetrahydrofolsäure. |
CH19990695/99 | 1999-04-15 |
Related Parent Applications (1)
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JP2000112606A Division JP5202774B2 (ja) | 1999-04-15 | 2000-04-13 | 安定な結晶性5−メチルテトラヒドロ葉酸塩 |
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Publication Number | Publication Date |
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JP2013047278A JP2013047278A (ja) | 2013-03-07 |
JP5675758B2 true JP5675758B2 (ja) | 2015-02-25 |
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JP2000112606A Expired - Lifetime JP5202774B2 (ja) | 1999-04-15 | 2000-04-13 | 安定な結晶性5−メチルテトラヒドロ葉酸塩 |
JP2012264085A Expired - Lifetime JP5675759B2 (ja) | 1999-04-15 | 2012-12-03 | 安定な結晶性5−メチルテトラヒドロ葉酸塩 |
JP2012264086A Expired - Lifetime JP5675760B2 (ja) | 1999-04-15 | 2012-12-03 | 安定な結晶性5−メチルテトラヒドロ葉酸塩 |
JP2012264084A Expired - Lifetime JP5675758B2 (ja) | 1999-04-15 | 2012-12-03 | 安定な結晶性5−メチルテトラヒドロ葉酸塩 |
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JP2000112606A Expired - Lifetime JP5202774B2 (ja) | 1999-04-15 | 2000-04-13 | 安定な結晶性5−メチルテトラヒドロ葉酸塩 |
JP2012264085A Expired - Lifetime JP5675759B2 (ja) | 1999-04-15 | 2012-12-03 | 安定な結晶性5−メチルテトラヒドロ葉酸塩 |
JP2012264086A Expired - Lifetime JP5675760B2 (ja) | 1999-04-15 | 2012-12-03 | 安定な結晶性5−メチルテトラヒドロ葉酸塩 |
Country Status (19)
Country | Link |
---|---|
US (1) | US6441168B1 (ja) |
EP (5) | EP1044975B1 (ja) |
JP (4) | JP5202774B2 (ja) |
KR (2) | KR100774012B1 (ja) |
CN (1) | CN1154648C (ja) |
AT (2) | ATE496052T1 (ja) |
AU (1) | AU782641B2 (ja) |
CA (1) | CA2305926C (ja) |
CH (1) | CH693905A5 (ja) |
CY (2) | CY1109874T1 (ja) |
DE (2) | DE50015815D1 (ja) |
DK (4) | DK2194057T3 (ja) |
ES (3) | ES2374369T3 (ja) |
HU (1) | HU229423B1 (ja) |
NO (1) | NO325495B1 (ja) |
PT (4) | PT2192120E (ja) |
RU (1) | RU2265605C2 (ja) |
TW (1) | TWI285205B (ja) |
ZA (1) | ZA200001851B (ja) |
Families Citing this family (62)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH693905A5 (de) * | 1999-04-15 | 2004-04-15 | Eprova Ag | Stabile kristalline Salze von 5-Methyltetrahydrofolsäure. |
EP1349554A2 (en) * | 2000-12-14 | 2003-10-08 | Tufts University | Compositions and methods for treating an arthritic condition |
ES2905305T4 (es) | 2003-11-17 | 2022-07-13 | Biomarin Pharm Inc | Tratamiento de la fenilcetonuria con BH4 |
ATE498401T1 (de) * | 2004-09-15 | 2011-03-15 | Nipro Corp | Wässrige, stabile (6s)-folinsäurelösung zur injektion |
WO2006063215A2 (en) * | 2004-12-08 | 2006-06-15 | Biomarin Pharmaceutical Inc. | Methods and compositions for the treatment of pulmonary hypertension of the newborn |
UY29527A1 (es) | 2005-05-13 | 2006-12-29 | Schering Ag | Composicinn farmaccutica que contienen gestrgenos y/o estrngenos y 5-metil - (6s) - tetrhidrofolato. |
CN101489563A (zh) | 2006-07-06 | 2009-07-22 | 拜耳先灵医药股份有限公司 | 用于避孕和预防先天性畸形风险的药物制剂 |
DE112007001600A5 (de) * | 2006-07-06 | 2009-04-30 | Bayer Schering Pharma Aktiengesellschaft | Pharmazeutische Zusammensetzung zur Kontrazeption und zur Verminderung des Risikos angeborener Fehlbildungen |
EP1891959A1 (de) * | 2006-08-14 | 2008-02-27 | Bayer Schering Pharma Aktiengesellschaft | Pharmazeutische Zusammensetzung zur Kontrazeption und zur Verminderung des Risikos angeborener Fehlbildungen |
US8617597B2 (en) * | 2006-07-06 | 2013-12-31 | Bayer Intellectual Property Gmbh | Pharmaceutical composition containing a tetrahydrofolic acid |
CH698729B1 (de) | 2007-05-30 | 2009-10-15 | Cerbios Pharma Sa | Stabile, kristalline (6S)-N(5)-Methyl-5, 6,7,8-tetrahydrofolsäure. |
EP2027855A1 (de) | 2007-08-24 | 2009-02-25 | Bayer Schering Pharma AG | Verwendung von Gestagenen in Kombination mit (6S)5-Methyltetrahydrofolat zur Therapie der Endometriose mit gleichzeitiger Verminderung von Therapie-Nebenwirkungen sowie der Verminderung des Risikos angeborener Fehlbildungen bei Eintritt einer Gravidität |
US20090060997A1 (en) * | 2007-08-27 | 2009-03-05 | Christian Seitz | Process for producing a pharmaceutical preparation for therapeutic treatment of endometriosis containing a combination of a gestagen and (6s)-5-methyltetrahydrofolate |
WO2009101021A2 (en) * | 2008-02-13 | 2009-08-20 | Bayer Schering Pharma Aktiengesellschaft | Estradiol-containing drug delivery system |
JP2011511816A (ja) * | 2008-02-13 | 2011-04-14 | バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト | 安定化効果を有する薬物送達システム |
PL2245032T3 (pl) * | 2008-02-20 | 2015-08-31 | Gnosis Spa | Foliany, ich kompozycje i zastosowania |
AU2010271178B2 (en) | 2009-07-10 | 2015-10-22 | Linzy O. Scott Iii | Methods and compositions for treating thyroid-related medical conditions with reduced folates |
UY32836A (es) | 2009-08-12 | 2011-03-31 | Bayer Schering Pharma Ag | Partículas estabilizadas que comprenden 5-metil-(6s)-tetrahidrofolato |
AU2011215669B2 (en) | 2010-02-12 | 2015-06-04 | HedoniaUSA, Inc. | Compositions and methods for treating depression |
WO2012074496A1 (en) * | 2010-12-03 | 2012-06-07 | Kocak Farma Ilac Ve Kimya San. A.S | A new method for producing antifolate agents having glutamic acid part in their structure |
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EP2502625A1 (en) | 2011-03-21 | 2012-09-26 | GMT Fine Chemicals SA | Process for the preparation of crystalline levofolinic acid |
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IN2014DN06942A (ja) * | 2012-01-20 | 2015-04-10 | Lianyungang Jinkang Hexin Pharmaceutical Co Ltd | |
CN102775407B (zh) * | 2012-01-20 | 2015-08-05 | 连云港金康医药科技有限公司 | 稳定的无定型5-甲基四氢叶酸盐及其制备方法 |
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EP2781214A1 (en) * | 2013-03-22 | 2014-09-24 | Chemo Research, S.L. | Formulation of amorphous calcium L-5-methyltetrahydrofolate (L-5-MTHF-Ca) |
JP2016525576A (ja) * | 2013-07-29 | 2016-08-25 | アデア ファーマシューティカルズ,インコーポレイテッド | 安定化された修飾放出型葉酸誘導体組成物、その治療用途および製造方法 |
US20160053281A1 (en) | 2013-08-15 | 2016-02-25 | The University Court Of The University Of Edinburgh | Enhanced Expression Of RNA Vectors |
US9629846B1 (en) | 2013-11-14 | 2017-04-25 | Argent Development Group, Llc | Nutritional supplements for women desiring to become pregnant, and pregnant and nursing women |
US9492421B1 (en) | 2013-11-14 | 2016-11-15 | Argent Development Group, Llc | Nutritional supplements for treatment of iron deficiency anemia |
EP2878600B1 (en) | 2013-12-02 | 2018-06-27 | Cerbios-Pharma S.A. | Stable complexes of an alkaline earth metal salt of N5-methyl-tetrahydrofolic acid and a polyol |
CN103980279B (zh) * | 2014-04-16 | 2016-07-06 | 悦康药业集团有限公司 | 一种甲氨蝶呤化合物及注射用甲氨蝶呤 |
WO2015193778A1 (en) | 2014-06-16 | 2015-12-23 | Mylan Laboratories Ltd. | Crystalline form of levomefolate calcium |
CN104490887A (zh) * | 2014-09-04 | 2015-04-08 | 连云港金康和信药业有限公司 | (6s)-5-甲基-四氢叶酸钙盐的稳定药物组合物 |
CN105524066B (zh) | 2014-09-04 | 2017-06-27 | 连云港金康和信药业有限公司 | (6s)‑5‑甲基四氢叶酸或其盐组合物及其制备和应用 |
CN104225609B (zh) | 2014-09-20 | 2018-05-18 | 中国药科大学 | 一种炎症靶向的中性粒细胞递药系统及其应用 |
WO2016135707A1 (en) | 2015-02-27 | 2016-09-01 | Nestec S.A. | Diagnosis of major depressive disorder, mild cognitive impairment, and alzheimer's disease and other neurologic and psychiatric disorders |
WO2016185413A1 (en) | 2015-05-20 | 2016-11-24 | Nestec S.A. | Modified release formulations |
CN107698591A (zh) * | 2015-09-25 | 2018-02-16 | 上海华理生物医药有限公司 | (6s)-5-甲基四氢叶酸锌盐晶型及其制备方法 |
DE202015105351U1 (de) | 2015-10-09 | 2016-01-07 | Apotheke am Schlossplatz Inh. Mario Ganster e.K. | Diätetische Zusammensetzung |
KR101712807B1 (ko) | 2015-10-19 | 2017-03-07 | 오인숙 | 스테인레스 빔 제조장치 |
CN105237539A (zh) * | 2015-10-29 | 2016-01-13 | 上海应用技术学院 | A晶型(6s)-5-甲基四氢叶酸锌盐及其制备方法 |
CN107304212A (zh) * | 2016-04-21 | 2017-10-31 | 常州爱诺新睿医药技术有限公司 | 一种无定型l-5-甲基四氢叶酸氨基酸盐及其制备方法 |
WO2018144088A1 (en) | 2016-11-03 | 2018-08-09 | Alexander Vuckovic, M.D., Llc | Compositions and methods for treating depression |
US11185545B2 (en) | 2017-03-31 | 2021-11-30 | Merck Patent Gmbh | Crystalline monosodium salt of 5-methyl-(6S)-tetrahydrofolic acid |
EP3601289A1 (en) | 2017-03-31 | 2020-02-05 | Merck Patent GmbH | Crystalline binary sodium salts of 5-methyl-(6s)-tetrahydrofolic acid with organic bases |
EP3609895A1 (en) * | 2017-03-31 | 2020-02-19 | Merck Patent GmbH | Crystalline sodium salt of 5-methyl-(6s)-tetrahydrofolic acid |
EP3461826A1 (en) | 2017-09-29 | 2019-04-03 | Aprofol AG | Multifunctional folate salts |
EP3818048B1 (en) * | 2018-07-06 | 2023-09-20 | Merck Patent GmbH | Crystalline salt comprising 5-methyl-(6s)-tetrahydrofolic acid and 4-(2-hydroxyethyl)-morpholine |
US20210277006A1 (en) * | 2018-07-06 | 2021-09-09 | Merck Patent Gmbh | Crystalline salts of 5-methyl-(6s)-tetrahydrofolic acid and amino ethyl esters |
EP3817813B1 (en) * | 2018-07-06 | 2023-09-20 | Merck Patent GmbH | Crystalline salts of 5-methyl-(6s)-tetrahydrofolic acid and l-leucine ethyl ester |
US20210269444A1 (en) * | 2018-07-06 | 2021-09-02 | Merck Patent Gmbh | Crystalline salt of 5-methyl-(6S)-tetrahydrofolic acid and L-isoleucine ethyl ester |
EP3817814B1 (en) * | 2018-07-06 | 2023-09-20 | Merck Patent GmbH | Crystalline salts of 5-methyl-(6s)-tetrahydrofolic acid and l-valine ethyl ester |
EP3646873A1 (en) | 2018-10-31 | 2020-05-06 | Aprofol AG | Folate salts |
EP3666260A1 (en) | 2018-12-13 | 2020-06-17 | Laboratorios Leon Farma SA | Ethinyl estradiol-beta-cyclodextrin complex and process for preparing thereof |
US20230162351A1 (en) | 2020-04-23 | 2023-05-25 | National University Corporation Shiga University Of Medical Science | Diagnosis assistance device, machine learning device, diagnosis assistance method, machine learning method, machine learning program, and alzheimers prediction program |
EP4149437A1 (en) | 2020-05-15 | 2023-03-22 | Alfasigma S.p.A. | Composition comprising methylfolate |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1572137A (en) | 1977-02-22 | 1980-07-23 | Bioresearch Sas Del Dr Livio C | Stable compositions for therapeutic use based on d,1-5-methyltetrahydrofolic acid and its salts |
US5223500A (en) * | 1977-02-22 | 1993-06-29 | Bioresearch S.P.A. | Stable pharmaceutical composition of alkaline or alkaline earth 5-methyl tetrahydrofolate |
DE3821875C1 (ja) | 1988-06-29 | 1990-02-15 | Eprova Ag, Forschungsinstitut, Schaffhausen, Ch | |
CH680731A5 (ja) * | 1990-04-12 | 1992-10-30 | Sapec Fine Chemicals | |
CH681303A5 (ja) | 1991-01-16 | 1993-02-26 | Eprova Ag | |
CH684270A5 (de) | 1991-10-04 | 1994-08-15 | Sapec Fine Chemicals | Verfahren zur Herstellung von Erdalkalimetallsalzen von (6R)-N(10)-Formyl-5,6,7,8-tetrahydrofolsäure. |
CH683261A5 (it) * | 1991-10-10 | 1994-02-15 | Applied Pharma Res | Procedimento per la preparazione dell'acido metiltetraidrofolico nella forma (6(R,S)(-))N-5 e separazione del diastereoisomero attivo (6(S)(-))N-5) sotto forma di sali. |
CH682664A5 (en) | 1991-10-15 | 1993-10-29 | Eprova Ag | Stable salts of 5,10-methylene tetrahydrofolate. |
CH682665A5 (de) | 1991-10-29 | 1993-10-29 | Sapec Fine Chemicals | Verfahren zur Reinigung von rohen Erdalkalimetallsalzen von N(5)-Methyl-5,6,7,8-tetrahydrofolsäure. |
DE4136921A1 (de) * | 1991-11-11 | 1993-05-13 | Knoll Ag | Verfahren zur trennung von 5-methyl-tetrahydrofolsaeure |
CH686672A5 (de) * | 1992-12-01 | 1996-05-31 | Cerbios Pharma Sa | Verfahren zur Herstellung von (6S)-5,6,7,8-Tetrahydrofolsaeure. |
CH686369A5 (de) * | 1994-05-09 | 1996-03-15 | Eprova Ag | Stabile kristalline (6S)- und (6R)-Tetrahydrofolseure. |
CH689831A5 (de) * | 1995-11-07 | 1999-12-15 | Eprova Ag | Stabile kristalline Tetrahydrofolsaeure-Salze. |
DK0877563T3 (da) | 1996-01-31 | 2004-07-26 | Univ South Alabama | Levnedsmiddel- og vitaminpræparater, der indeholder den naturlige isomer af reducerede folater |
CH693905A5 (de) * | 1999-04-15 | 2004-04-15 | Eprova Ag | Stabile kristalline Salze von 5-Methyltetrahydrofolsäure. |
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