WO2012126363A1 - 一种无定型积雪草酸氨丁三醇盐及其制备方法 - Google Patents
一种无定型积雪草酸氨丁三醇盐及其制备方法 Download PDFInfo
- Publication number
- WO2012126363A1 WO2012126363A1 PCT/CN2012/072690 CN2012072690W WO2012126363A1 WO 2012126363 A1 WO2012126363 A1 WO 2012126363A1 CN 2012072690 W CN2012072690 W CN 2012072690W WO 2012126363 A1 WO2012126363 A1 WO 2012126363A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- asiatic acid
- amorphous
- organic solvent
- tromethamine
- tromethamine salt
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
Definitions
- the invention relates to an amorphous asiatic acid tromethamine salt and a preparation method thereof. Background technique
- hydrophilic groups three alcoholic hydroxyl groups and one carboxyl group
- it has poor wettability and is almost insoluble in water, and its physical and chemical properties require configuration suitable for local use.
- Formulations, especially hydrophilic formulations require the use of unique methods and special excipients.
- skin absorption is mainly carried out in an epidermal manner (intracellular and through cells) and is mainly controlled by the action of an effective component on the stratum corneum composed mainly of keratin and water. Therefore, in addition to the configuration problems, the problem of the appropriate bioavailability of asiatic acid at the epidermal level has still not been solved.
- Snow oxalate is a protonated salt formed by the combination of asiatic acid and a medically acceptable base.
- the water solubility of asiatic oxalate is greater than that of asiatic acid, which makes the development of asiatic acid oxalate very important.
- snow oxalates that have been reported in the patents include the asiatic acid succinic acid and hemisuccinates disclosed in USP 3. 3,366,669, and the decylamino chain sterols and dimethylamino chain sterols of asiatic acid. salt.
- a salt such as ethylenediamine, ethanolamine, diethanolamine, lysine, benzyltrimethylamine hydroxide or tetramethylammonium hydroxide of asiatic acid is disclosed in CN1238330C.
- Ammonium, sodium, potassium, sodium carbonate, sodium phosphate, triacetate amino and tromethamine salts of asiatic acid are disclosed in WO 2009/089365. All of the above compounds can be used in the preparation of aqueous solutions for topical administration.
- the technical problem to be solved by the present invention is to overcome the defects of the existing asiatic acid free acid or asiatic acid tromethamine salt solubility and the difficulty in simultaneously improving the bioavailability, and provide an amorphous snow oxalate Triol salt and its preparation method.
- the invention finds another way to prepare the amorphous asiatic acid tromethamine salt in a simple and effective manner, and the solubility and bioavailability of the thus obtained succinic acid tromethamine salt are compared.
- the technology has been greatly improved, the application range of the salt has been broadened, and it has broad application prospects.
- the present invention provides an amorphous asiatic acid tromethamine salt.
- the amorphous asiatic acid tromethamine salt is preferably obtained by the following method: Step (1) dissolving asiatic acid in an organic solvent; and step (2) mixing with tromethamine; Step (3) Stir and carry out a salt formation reaction to remove the organic solvent.
- the molar ratio of the asiatic acid to the tromethamine can be selected according to a conventional method in the art, generally to make an excess of tromethamine, and the molar ratio of the asiatic acid to the tromethamine The good land is 0.8: 1 ⁇ 1: 1.5.
- the organic solvent may be an organic solvent capable of dissolving asiatic acid, which is conventionally used in the art, preferably an alcohol solvent, more preferably a saturated monohydric alcohol having 1-5 carbon atoms. And one or more of aromatic alcohols having 7-8 carbon atoms, more preferably one of methanol, absolute ethanol, isopropanol, n-butanol, n-pentanol, benzyl alcohol and n-propanol Or more, preferably one or more of methanol, absolute ethanol, and isopropanol.
- an organic solvent capable of dissolving asiatic acid, which is conventionally used in the art, preferably an alcohol solvent, more preferably a saturated monohydric alcohol having 1-5 carbon atoms.
- aromatic alcohols having 7-8 carbon atoms more preferably one of methanol, absolute ethanol, isopropanol, n-butanol, n-pentanol, benzyl alcohol and n-propanol Or more
- the dissolving is preferably carried out under heating conditions, and the heating strip is The part is generally the reflux temperature of the organic solvent.
- the amount of the organic solvent may be selected according to a conventional method in the art, preferably in the case of dissolving asiatic acid, and is usually 50 to 150 ml/g of asiatic acid.
- the temperature of the mixing is preferably from 50 to 100 °C.
- the reaction temperature of the salt-forming reaction can be selected according to a conventional method of such a reaction in the art, preferably from 50 to 100 °C.
- the reaction time of the salt-forming reaction can be selected according to a conventional method of such a reaction in the art, preferably from 0.5 to 9 hours.
- the method for removing the organic solvent is a conventional organic solvent removal method in the art, and is usually carried out under a pressure of 0.05 MP to 0.1 MP, for example, by rotary evaporation.
- the evaporation temperature is preferably from 50 to 100 °C.
- drying is also carried out after the completion of step (3).
- the drying may be carried out by a conventional method in the art, and may be atmospheric drying or vacuum drying, and the drying temperature is preferably 50 to 80 °C.
- the present invention also provides a method for preparing an amorphous asiatic acid tromethamine salt, wherein the amorphous asiatic acid tromethamine salt is preferably obtained by the following method: (1) The asiatic acid is dissolved in an organic solvent; (2) mixed with tromethamine; (3) stirred and subjected to a salt formation reaction, and the organic solvent is removed.
- the molar ratio of the asiatic acid to the tromethamine can be selected according to a conventional method in the art, generally to make an excess of tromethamine, and the molar ratio of the asiatic acid to the tromethamine The good land is 0.8: 1 ⁇ 1: 1.5.
- the organic solvent may be selected from an organic solvent capable of dissolving asiatic acid, which is conventionally used in the art, preferably an alcohol solvent, more preferably a saturated monohydric alcohol having a carbon number of 1-5.
- an alcohol solvent more preferably a saturated monohydric alcohol having a carbon number of 1-5.
- aromatic alcohols having 7-8 carbon atoms more preferably one of methanol, absolute ethanol, isopropanol, n-butanol, n-pentanol, benzyl alcohol and n-propanol or A plurality of, most preferably one or more of methanol, absolute ethanol, and isopropanol.
- the dissolving is preferably carried out under heating, and the heating temperature is such that the asiatic acid is completely dissolved, and is generally the reflux temperature of the organic solvent.
- the amount of the organic solvent may be selected according to a conventional method in the art, preferably in the case of dissolving asiatic acid, and is usually 50 to 150 ml/g of asiatic acid.
- the temperature of the mixing is preferably from 50 to 100 °C.
- the reaction temperature of the salt-forming reaction can be selected according to a conventional method of such a reaction in the art, preferably from 50 to 100 °C.
- the reaction time of the salt-forming reaction can be selected according to a conventional method of such a reaction in the art to clarify the reaction system, preferably from 0.5 to 9 hours.
- the method for removing the organic solvent is a conventional organic solvent removal method in the art, and is generally carried out under a pressure of 0.05 MP to 0.1 MP, and the evaporation temperature is preferably 50. ⁇ 100 °C.
- drying is also carried out after the completion of step (3).
- the drying may be carried out by a conventional method in the art, and may be atmospheric drying or vacuum drying, and the drying temperature is preferably 50 to 80 °C.
- the starting materials and reagents of the present invention are commercially available.
- the positive progress of the present invention is as follows:
- the present invention produces an amorphous asiatic acid tromethamine salt by a simple method, and the amorphous asiatic acid tromethamine salt has a compound compared to a crystalline compound. Better water solubility and bioavailability have broader application prospects.
- Figure 1 is an X-ray powder diffraction pattern of amorphous stearoxylate tromethamine salt.
- Figure 2 is an X-ray powder diffraction pattern of the crystalline form of asiatic acid tromethamine salt obtained in the patent WO 2009/089365.
- Figure 3 is a bioavailability map of amorphous and crystalline asiatic acid tromethamine salt. detailed description
- Comparative Sample The product of this patent was prepared according to the process disclosed in the patent WO 2009/089365 as a comparative sample with this patent.
- the pulverized and sieved amorphous asiatic acid tromethamine salt and the comparative sample were uniformly mixed with microcrystalline cellulose, crosslinked polyvinylpyrrolidone and pregelatinized starch, respectively, and then respectively Mix 5% ethanol solution, granulate, dry, and then mix with magnesium stearate separately, then compress.
- the asiatic acid tromethamine salt is pulverized and sieved to a 60 mesh sieve; the microcrystalline cellulose and the crosslinked polyvinylpyrrolidone are pulverized and sieved to pass through a 80 mesh sieve;
- the particle size of the granules is 20 mesh;
- the drying temperature is preferably within 3% of the controlled moisture content of 90 °C.
- the bioavailability of the above samples is shown in Figure 3. As can be seen from Figure 3, the bioavailability of the amorphous salt obtained in this patent (about 10.4%) is significantly higher than the bioavailability of the comparative sample (about 7.6%).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/006,198 US8962880B2 (en) | 2011-03-22 | 2012-03-21 | Amorphous asiatic tromethamine salt and preparation method thereof |
EP12760240.7A EP2711373B1 (en) | 2011-03-22 | 2012-03-21 | Amorphous asiatic acid tromethamine salt and preparation method thereof |
JP2014500240A JP2014519475A (ja) | 2011-03-22 | 2012-03-21 | 非晶質アシアト酸トロメタミン塩及びその調製方法 |
Applications Claiming Priority (2)
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---|---|---|---|
CN201110069862.6 | 2011-03-22 | ||
CN201110069862.6A CN102690314B (zh) | 2011-03-22 | 2011-03-22 | 一种无定型积雪草酸氨丁三醇盐及其制备方法 |
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WO2012126363A1 true WO2012126363A1 (zh) | 2012-09-27 |
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PCT/CN2012/072690 WO2012126363A1 (zh) | 2011-03-22 | 2012-03-21 | 一种无定型积雪草酸氨丁三醇盐及其制备方法 |
Country Status (5)
Country | Link |
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US (1) | US8962880B2 (zh) |
EP (1) | EP2711373B1 (zh) |
JP (1) | JP2014519475A (zh) |
CN (1) | CN102690314B (zh) |
WO (1) | WO2012126363A1 (zh) |
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EP2344330A4 (en) * | 2008-10-28 | 2016-07-13 | Madico Inc | SUN-CONTROLLED WINDOW FILMS WITH INFRARED REFLECTION LAYERS |
CN102690314B (zh) | 2011-03-22 | 2015-06-10 | 上海医药工业研究院 | 一种无定型积雪草酸氨丁三醇盐及其制备方法 |
CN104829678B (zh) * | 2014-02-10 | 2017-01-11 | 上海医药工业研究院 | 积雪草酸盐及其制备方法和用途 |
CN104829677B (zh) * | 2014-02-10 | 2017-06-06 | 上海医药工业研究院 | 一种羟基积雪草酸盐及其制备方法和用途 |
AU2017364349A1 (en) | 2016-11-28 | 2019-07-11 | Sarin PARAYIL | Novel organic crystalline salt of haloacetic acid |
CN115381729B (zh) * | 2022-09-02 | 2023-10-10 | 广东领康日用品有限公司 | 一种具有美白去渍及减轻牙龈炎症功效的牙膏及制备方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3366669A (en) | 1963-08-28 | 1968-01-30 | Ratsimamanga Albert Rakoto | Hemisuccinates and salts of the hemisuccinates of asiatic acid |
CN1347398A (zh) * | 1999-04-21 | 2002-05-01 | 欧洲制药集团有限责任公司 | 适用于制备药物和化妆品组合物的亚细亚酸盐和羟基积雪草酸盐 |
WO2009089365A2 (en) | 2008-01-11 | 2009-07-16 | Shanghai Institute Of Pharmaceutical Industry (Sipi) | Therapeutic formulations based on asiatic acid and selected salts thereof |
Family Cites Families (6)
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JPH0710722B2 (ja) * | 1987-11-04 | 1995-02-08 | 小野田セメント株式会社 | 珪酸カルシウムおよびその製造方法 |
JPH0710722A (ja) * | 1993-06-25 | 1995-01-13 | Kotaku Rin | 育毛剤 |
JP2001504514A (ja) * | 1996-11-27 | 2001-04-03 | ドング クック ファーマシューティカル シーオー.,エルティーディー. | アシアト酸誘導体を有効成分とする痴呆及び認識障害治療剤 |
CN1256090C (zh) * | 2003-11-25 | 2006-05-17 | 中国人民解放军第二军医大学 | 积雪草酸及其衍生物在制备抗抑郁药物中的应用 |
CN1943579A (zh) * | 2006-09-30 | 2007-04-11 | 佛山市第一人民医院 | 积雪草酸在制备药物方面的用途 |
CN102690314B (zh) | 2011-03-22 | 2015-06-10 | 上海医药工业研究院 | 一种无定型积雪草酸氨丁三醇盐及其制备方法 |
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2011
- 2011-03-22 CN CN201110069862.6A patent/CN102690314B/zh active Active
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2012
- 2012-03-21 WO PCT/CN2012/072690 patent/WO2012126363A1/zh active Application Filing
- 2012-03-21 EP EP12760240.7A patent/EP2711373B1/en active Active
- 2012-03-21 US US14/006,198 patent/US8962880B2/en active Active
- 2012-03-21 JP JP2014500240A patent/JP2014519475A/ja active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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US3366669A (en) | 1963-08-28 | 1968-01-30 | Ratsimamanga Albert Rakoto | Hemisuccinates and salts of the hemisuccinates of asiatic acid |
CN1347398A (zh) * | 1999-04-21 | 2002-05-01 | 欧洲制药集团有限责任公司 | 适用于制备药物和化妆品组合物的亚细亚酸盐和羟基积雪草酸盐 |
CN1238330C (zh) | 1999-04-21 | 2006-01-25 | 欧洲制药集团有限责任公司 | 适用于制备药物和化妆品组合物的亚细亚酸盐和羟基积雪草酸盐 |
WO2009089365A2 (en) | 2008-01-11 | 2009-07-16 | Shanghai Institute Of Pharmaceutical Industry (Sipi) | Therapeutic formulations based on asiatic acid and selected salts thereof |
CN101969942A (zh) * | 2008-01-11 | 2011-02-09 | 上海医药工业研究院 | 基于积雪草酸及其特定盐的治疗剂 |
Non-Patent Citations (1)
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See also references of EP2711373A4 |
Also Published As
Publication number | Publication date |
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EP2711373A4 (en) | 2014-10-29 |
US20140243553A1 (en) | 2014-08-28 |
US8962880B2 (en) | 2015-02-24 |
EP2711373B1 (en) | 2017-11-01 |
CN102690314A (zh) | 2012-09-26 |
EP2711373A1 (en) | 2014-03-26 |
CN102690314B (zh) | 2015-06-10 |
JP2014519475A (ja) | 2014-08-14 |
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