CN103768043B - Adopt the method for HP-β-CD preparation tetrahydronaphthalene compounds stable homogeneous solution - Google Patents
Adopt the method for HP-β-CD preparation tetrahydronaphthalene compounds stable homogeneous solution Download PDFInfo
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Abstract
The invention discloses a kind of method adopting HP-β-CD to prepare tetrahydronaphthalene compounds stable homogeneous solution, comprise step: 1) HP-β-CD be dissolved in the water, be mixed with HP-β-CD solution; 2) take tetrahydronaphthalene compounds, be dissolved in HP-β-CD solution, form the tetrahydronaphthalene compounds solution of stable homogeneous.The present invention is simple to operate, and preparation fast, solves the difficult problem that tetrahydronaphthalene compounds dissolubility is not good, can be widely used in the preparation of the tetrahydronaphthalene compounds solution of stable homogeneous.
Description
Technical field
The present invention relates to a kind of method preparing tetrahydronaphthalene compounds stable homogeneous solution, particularly relate to a kind of employing HP-β-CD (HP-β-CD), the method for fast and convenient preparation tetrahydronaphthalene compounds stable homogeneous solution.
Background technology
Tetralin quasi-compound novel structure is a kind of selectivity 5-HTA receptor antagonist.Recently, find that this compounds has remarkable antifungal activity in vitro, have Development volue.The tetrahydronaphthalene compounds gone on the market at present is as NAPHTHOQUINE PHOSPHATE, strain gametocyte is planted to various Plasmodium merozoite and some and organizes phase protozoon to have killing action, antagonism property of medicine plasmodium has good healing effect, has long-acting preventive effect to plasmodium.In addition, other multiple tetrahydronaphthalene compounds such as 8 cyclosubstituted 2-amino-1,2,3,4-tetralins all have certain Development volue.
When carrying out the clinical front developmental research of tetrahydronaphthalene compounds, need the solution of tetrahydronaphthalene compounds preparation stable homogeneous.But, tetrahydronaphthalene compounds poor solubility, multiple conventional solvent dissolves the highly concentrated solution being all difficult to form stable homogeneous, and therefore, the tetrahydronaphthalene compounds solution of the higher concentration of preparation stable homogeneous often becomes one of obstacle of this compounds of exploitation.
At present, by literature search, not finding can the documents and materials of fast and easy preparation tetrahydronaphthalene compounds stable homogeneous solution.
Research proves, adopts following conventional solvent to dissolve tetrahydronaphthalene compounds---during 8 cyclosubstituted 2-amino-1,2,3,4-tetralin, be all difficult to form high concentration stable homogeneous solution:
When being 1, solvent with 0.9% normal saline: be suspension when 50mg/mL, also without dissolving sign during adjustment pH to 7.0.During with normal saline dilution to 12.5mg/mL, 37 DEG C of water-baths remain suspension in 30 minutes, slightly leave standstill and can produce precipitation.
2, use DMA(dimethyl acetylamide): the volume ratio of dehydrated alcohol be 1:9 mixed liquor when being solvent: be suspension when 50mg/mL.When being diluted to 12.5mg/mL with this solvent, 37 DEG C of water-baths remain suspension in 30 minutes, slightly leave standstill and can produce precipitation.
When being 3, solvent with 0.5% (w/v) Tween 80 aqueous solution: be suspension when 50mg/mL, when being diluted to 15mg/mL, 37 DEG C of water-baths remain suspension in 30 minutes, slightly leave standstill and can produce precipitation.
4, DMSO(dimethyl sulfoxide is used): PEG400: the volume ratio of pure water is the mixed liquor of 1:3:1 when being solvent: be suspension when 50mg/mL.When being diluted to 12.5mg/mL with this solvent, 37 DEG C of water-baths remain suspension in 30 minutes, slightly leave standstill and can produce precipitation.
5, with polyoxyethylene ether (35) Oleum Ricini (
eL): dehydrated alcohol: the volume ratio of 0.9% normal saline is the mixed liquor of 1:1:8 when being solvent: be suspension when 50mg/mL.When being diluted to 12.5mg/mL with this solvent, 37 DEG C of water-baths remain suspension in 30 minutes, slightly leave standstill and can produce precipitation.
HP-β-CD (HP-β-CD) is as anionic highly-water-soluble cyclodextrin derivative, non-covalent complex can be formed well with drug molecule enclose, improve the stability of medicine, water solublity, safety, reduce nephrotoxicity, relax medicine hemolytic, Drug controlled release speed, cover bad smell, but, the existing report also not having the open HP-β-CD of document can prepare tetrahydronaphthalene compounds stable homogeneous solution.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of method adopting HP-β-CD (HP-β-CD) to prepare tetrahydronaphthalene compounds stable homogeneous solution.By the method, the difficult problem that part tetrahydronaphthalene compounds is difficult to be mixed with quickly and easily higher concentration stable homogeneous solution can be solved.
For solving the problems of the technologies described above, employing HP-β-CD of the present invention (HP-β-CD) prepares the method for tetrahydronaphthalene compounds stable homogeneous solution, comprises step:
1) HP-β-CD is dissolved in water (comprising deionized water), is mixed with HP-β-CD solution;
2) take tetrahydronaphthalene compounds, be dissolved in HP-β-CD solution, form the tetrahydronaphthalene compounds solution of stable homogeneous.
In described step 1), the bulking value concentration of HP-β-CD solution is 10% ~ 30%(w/v), i.e. 10g/100mL ~ 30g/100mL, preferably 20%.Wherein, this HP-β-CD solution can 2 ~ 8 DEG C of preservations.
Described step 2) in, tetrahydronaphthalene compounds comprises: tetrahydronaphthalene or 8 cyclosubstituted 2-amino-1,2,3,4-tetralins etc.
In addition, step 2) in, also can adopt assist in dissolving mode, comprise: heating.Wherein, the temperature range of heating is 35 ~ 39 DEG C.
In the present invention, for most of tetrahydronaphthalene compounds (as tetrahydronaphthalene, 8 cyclosubstituted 2-amino-1,2,3,4-tetralins), the concentration of institute's obtain solution can reach more than 12.5mg/ml.
Method of the present invention, simple to operate, and preparation fast, solve the difficult problem that tetrahydronaphthalene compounds dissolubility is not good, namely a difficult problem for the tetrahydronaphthalene compounds solution of preparation stable homogeneous is solved, the preparation of the higher concentration tetrahydronaphthalene compounds solution of stable homogeneous can be widely used in, be conducive to the exploitation accelerating this compounds.
Detailed description of the invention
In following examples, HP-β-CD adopts commercial reagent, purity: >=98%, and the HP-β-CD solution of preparation can be stored in 2 ~ 8 DEG C.
Embodiment 1
1) be dissolved in deionized water by commercially available HP-β-CD, being mixed with bulking value (w/v) concentration is 10%(and 10g/100mL) HP-β-CD solution.
2) take the cyclosubstituted 2-amino-1,2,3,4-tetralin of 250mg8, be dissolved in the above-mentioned 10%(w/v prepared) in HP-β-CD solution 9ml, and be settled to 10ml, solution is suspension.
3) with 10%(w/v) HP-β-CD solution by the 2nd) step preparation suspension be diluted to 20mg/ml concentration, form half settled solution, leave standstill have a small amount of precipitation after 10 minutes.
4) with 10%(w/v) HP-β-CD solution by the 3rd) step suspension is diluted to 12.5mg/ml concentration, forms even settled solution, leave standstill after 10 minutes without precipitation.
5) the cyclosubstituted 2-amino-1,2,3,4-tetralin solution of the 12.5mg/ml8 prepared, can be directly used in correlation test, also can be diluted to after aimed concn for correlation test.
Embodiment 2
1) be dissolved in deionized water by commercially available HP-β-CD, being mixed with bulking value (w/v) concentration is 20%(and 20g/100mL) HP-β-CD solution;
2) take the cyclosubstituted 2-amino-1,2,3,4-tetralin of 250mg8, be dissolved in the above-mentioned 20%(w/v prepared) in HP-β-CD solution 9ml, and be settled to 10ml, solution is suspension.
3) with 20%(w/v) HP-β-CD solution by the 2nd) step preparation suspension be diluted to 15mg/ml concentration, form even settled solution, leave standstill after 10 minutes without precipitation.
4) the cyclosubstituted 2-amino-1,2,3,4-tetralin solution of the 15mg/ml8 prepared, can be directly used in correlation test, also can be diluted to after aimed concn for correlation test.
Embodiment 3
1) be dissolved in deionized water by commercially available HP-β-CD, being mixed with bulking value (w/v) concentration is 30%(and 30g/100mL) HP-β-CD solution;
2) take the cyclosubstituted 2-amino-1,2,3,4-tetralin of 250mg8, be dissolved in the above-mentioned 30%(w/v prepared) in HP-β-CD solution 9ml, and be settled to 10ml, solution is suspension.
3) with 30%(w/v) HP-β-CD solution by the 2nd) step preparation suspension be diluted to 15mg/ml concentration, form even settled solution, leave standstill after 10 minutes without precipitation.
4) the cyclosubstituted 2-amino-1,2,3,4-tetralin solution of the 15mg/ml8 prepared, can be directly used in correlation test, also can be diluted to after aimed concn for correlation test.
Claims (6)
1. adopt HP-β-CD to prepare a method for tetrahydronaphthalene compounds stable homogeneous solution, it is characterized in that, comprise step:
1) HP-β-CD be dissolved in the water, be mixed with HP-β-CD solution, its bulking value concentration is 10%-30%;
2) take tetrahydronaphthalene compounds, be dissolved in HP-β-CD solution, form the tetrahydronaphthalene compounds solution of stable homogeneous, its concentration reaches more than 12.5mg/mL;
Described tetrahydronaphthalene compounds comprises: tetrahydronaphthalene or 8 cyclosubstituted 2-amino-1,2,3,4-tetralins.
2. the method for claim 1, is characterized in that: described step 1) in, water comprises: deionized water.
3. the method for claim 1, is characterized in that: described step 1) in, the bulking value concentration of HP-β-CD solution is 20%.
4. the method for claim 1, is characterized in that: described step 1) in, HP-β-CD solution is 2-8 DEG C of preservation.
5. the method for claim 1, is characterized in that: described step 2) in, also adopt assist in dissolving mode, comprising: heating.
6. method as claimed in claim 5, is characterized in that: described heating-up temperature is 35 ~ 39 DEG C.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001038321A1 (en) * | 1999-11-23 | 2001-05-31 | Aderis Pharmaceuticals, Inc. | Improved process for preparing nitrogen-substituted aminotetralins |
| CN1777422A (en) * | 2003-12-23 | 2006-05-24 | 施瓦茨制药股份公司 | Intranasal formulation of rotigotine |
| CN1832734A (en) * | 2003-07-26 | 2006-09-13 | 施瓦茨制药有限公司 | Substituted 2-amino-1,2,3,4-tetrahydronaphthalene of depression |
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- 2012-10-22 CN CN201210402979.6A patent/CN103768043B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001038321A1 (en) * | 1999-11-23 | 2001-05-31 | Aderis Pharmaceuticals, Inc. | Improved process for preparing nitrogen-substituted aminotetralins |
| CN1832734A (en) * | 2003-07-26 | 2006-09-13 | 施瓦茨制药有限公司 | Substituted 2-amino-1,2,3,4-tetrahydronaphthalene of depression |
| CN1777422A (en) * | 2003-12-23 | 2006-05-24 | 施瓦茨制药股份公司 | Intranasal formulation of rotigotine |
Non-Patent Citations (1)
| Title |
|---|
| 羟丙基-β-环糊精增溶难溶性药物研究进展;刘鄂湖，等;《中国药业》;20071231;第16卷(第8期);25-27 * |
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Address after: 215104 No. 1318 Wuzhong Avenue, Wuzhong District, Suzhou City, Jiangsu Province Patentee after: Suzhou AppTec Co., Ltd. Address before: 215104 No. 1318 Wuzhong Avenue, Wuzhong District, Suzhou City, Jiangsu Province Patentee before: Suzhou medicine bright Kant's new drug development limited company |