CN102151274B - Method for stable light focusing of fasudil hydrochloride and composition obtained using same - Google Patents
Method for stable light focusing of fasudil hydrochloride and composition obtained using same Download PDFInfo
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- CN102151274B CN102151274B CN 201110041003 CN201110041003A CN102151274B CN 102151274 B CN102151274 B CN 102151274B CN 201110041003 CN201110041003 CN 201110041003 CN 201110041003 A CN201110041003 A CN 201110041003A CN 102151274 B CN102151274 B CN 102151274B
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- methyl hydroxybenzoate
- fasudic hydrochloride
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Abstract
The invention deeply and thoroughly researches the light focusing stability of the fasudil water solution so as to take the methylparaben as a stabilizing agent. The fasudil hydrochloride water solution is stable by adjusting the content of the methylparaben, so that the invention is suitable for preparing not only the oral solution but also the injection with higher requirement.
Description
Technical field
A kind of stable method of Fasudic hydrochloride light and compositions of obtaining of method thus of making.
Background technology
Fasudic hydrochloride, chemical name are six hydrogen-1-(5-isoquinolinesulfonylcompounds)-1H-1,4-diazepine hydrochlorate.Fasudic hydrochloride is novel fine macrophages, kinases inhibitor; can come blood vessel dilating by the terminal stage myosin light chain phosphorylation of blocking-up vasoconstriction process; suppress vasospasm; the protection ischemic tissue of brain; thereby control CVS; the effective various ischemic encephalopathys that cause for the treatment of CVS play the protection cranial nerve cell, improve prognosis, reduce the effect of mortality rate.Fasudil hydrochloride injection to treatment SAH after rapid-action, the determined curative effect of CVS, can prevent and alleviate CVS, reduction CVS case fatality rate and disability rate.Result of study shows that Fasudic hydrochloride and nimodipine are all effective to SAH postoperative CVS, but the former curative effect is better.The patient occurs without serious adverse reaction during the treatment, and Blushing, hypotension, slight headache appear in the minority case, ends rear these symptom Lock-outs of transfusion.
Because Fasudic hydrochloride has photo-labile, therefore have in the existing fasudil injection and adopt the listing of brown light resistant container, have also that to adopt wavelength be that the transmitance of the light of 350nm is gone on the market at the coloring container 10% below or by the container package that the light-proofness coating agent applies.Publication application 200580008301.8 discloses a kind of method that solves the Fasudic hydrochloride photolysis, pH can guarantee resolution ratio below 5, and table 1 is resolution and the transmitance situation of Fasudic hydrochloride in the fasudil hydrochloride injection under the 12nd page of disclosed each pH value in this patent application.
Decomposition and the light transmittance situation of fasudil hydrochloride injection under the 12nd page of disclosed each pH value of table 1 patent application 200580008301.8 description:
As can be seen from Table 1, along with the rising resolution ratio increase of pH value, transmitance descends rapidly, and transmitance only has 70% during pH=3.Such result has following deficiency: (1) pH value is 5 when following, and Fasudic hydrochloride is met with photolysis color reaction, yellowly, and this is one of excessively low reason of transmitance, this need not can judge by detecting instrument.(2) Fasudic hydrochloride is yellow after seeing photolysis, is enough to illustrate a small amount of decomposition of Fasudic hydrochloride, still requires to keep in Dark Place, and this is so that the visible foreign matters inspection need to be carried out by means of instrument, and original visible foreign matters inspection only need be estimated.(3) fasudil hydrochloride injection that obtains by the method need to dilute to reduce acid to the zest of human body with sodium chloride or glucose injection when injecting.The stable pH of human body pH and Fasudic hydrochloride is one group of contradiction in the documents 200580008301.8, if want to improve the zest of pH value to reduce near human body pH to bring with the difference between the pH value of human body because of injection of Fasudic hydrochloride aqueous solution, the stability of Fasudic hydrochloride will significantly descend so.
More than 3 deficiencies bring inconvenience for merely preparation technology and safety inspection, main is to bring many hidden danger to safe medication.
Summary of the invention
In order to overcome above some deficiency, the inventor has carried out positive and deep research to the stability of Fasudic hydrochloride, finally found methyl hydroxybenzoate (or methyl hydroxybenzoate sodium, below the content of all methyl hydroxybenzoate sodium all refer in methyl hydroxybenzoate)) when can make Fasudic hydrochloride light stable, pH value there is not special requirement, but in order to adapt to medicinal needs, only need remain on pH value in the scope that approaches with human body pH and get final product.
Particularly, the invention provides a kind of Fasudic hydrochloride that makes to the stable method of light, wherein: with methyl hydroxybenzoate or its sodium salt as stabilizing agent, make the Fasudic hydrochloride aqueous solution stable to light, wherein, the content of methyl hydroxybenzoate is 0.05%-0.25% (W/V) in the described Fasudic hydrochloride aqueous solution.Preferably, the content of described methyl hydroxybenzoate is 0.1%-0.2% (W/V).More preferably, the content of methyl hydroxybenzoate is 0.1% (W/V).
The present invention also provides a kind of compositions that is made by said method, and wherein, said composition contains fasudil, methyl hydroxybenzoate or its sodium salt and water; The oral liquid of wherein said compositions for being made by fasudil, methyl hydroxybenzoate or its sodium salt, water and correctives; It perhaps is the injection of being made by fasudil, methyl hydroxybenzoate or its sodium salt and water for injection.
Such innovation and creation have not only overcome above deficiency and defective, also enlarged the dosage form scope of Fasudic hydrochloride preparation, for example, because pH value is too strong in 3 following acidity, zest to human body is excessive, heavy dose of injection and directly oral requirement can not be satisfied, and more dosage form can be developed with convenient clinical use to the reduction of pH value requirement after adding light stabilizer.
Specific embodiment
The comparative example
Above-mentioned Fasudic hydrochloride solution is put in the lighting box, under the condition of illumination 4500 ± 5001x, placed 10 days, in the 5th day and sampling investigation in the 10th day.This product check result sees Table 2, and the inspection condition of transmitance is: ultraviolet-uisible spectrophotometer TU-1800 (Beijing Puxi General Instrument Co., Ltd); Measure wavelength 400nm; The pond, quartzy system; Contrast solution: water for injection.
Impurity content detects and adopts HPLC detection method, testing conditions: test column, octadecylsilane chemically bonded silica post; Mobile phase is with 1.0% triethylamine aqueous solution (regulating pH value to 7.0 with phosphoric acid)-methanol (50: 50); The detection wavelength is 275nm.
Every testing result of table 2 comparative example resulting composition
Total impurities content is along with the increase of irradiation natural law significantly increases as can be seen from Table 2, and this explanation is kept in Dark Place to unsettled needs only.
Embodiment 1 adds 0.05% light stabilizer methyl hydroxybenzoate on comparative example's basis
Detection method is equal to the comparative example, and acquired results sees Table 3
Every testing result of table 3 embodiment 1 resulting composition
As can be seen from Table 3, total impurities content does not have significant change, and transmitance does not have significant change yet, and this illustrates that this compositions is stable to illumination, does not need to keep in Dark Place.
Embodiment 2 adds 0.15% light stabilizer on comparative example's basis
Detection method is equal to the comparative example, and acquired results sees Table 4:
Every testing result of table 4 embodiment 2 resulting compositions
As can be seen from Table 4, total impurities content does not have significant change, and transmitance does not have significant change yet, and this illustrates that this compositions is stable to illumination, does not need to keep in Dark Place.
Embodiment 3 adds 0.25% light stabilizer methyl hydroxybenzoate on comparative example's basis
Detection method is equal to the comparative example, and acquired results sees Table 5
Every testing result of table 5 embodiment 3 resulting compositions
As can be seen from Table 5, total impurities content does not have significant change, and transmitance does not have significant change yet, and this illustrates that this compositions is stable to illumination, does not need to keep in Dark Place.
The content that we have also investigated methyl hydroxybenzoate sodium (in methyl hydroxybenzoate) is the stability under each pH value (regulating with hydrochloric acid or sodium hydroxide) from 0.05%～0.25% the time, the result shows all stable, and there is not significant difference, below enumerate again methyl hydroxybenzoate content and be respectively 0.05,0.15 and 0.25, and pH is respectively 1 and every check result of recording at 9 o'clock, our experimental data is not limited to these, enumerates no longer one by one at this and gives unnecessary details.The adding methyl hydroxybenzoate can make Fasudic hydrochloride stable to light in the Fasudic hydrochloride aqueous solution in a word, and pH value is not required, and can make to be suitable for the various composition of liquid medicine that human body needs.
Table 6a methyl hydroxybenzoate content is 0.05%, and pH value is the every result of 1 gained
Table 6b methyl hydroxybenzoate content is 0.05%, and pH value is the every results of 9 gained
Table 7a methyl hydroxybenzoate content is 0.15%, and pH value is the every result of 1 gained
Table 7b methyl hydroxybenzoate content is 0.15%, and pH value is the every results of 9 gained
Table 8a methyl hydroxybenzoate content is 0.25%, and pH value is the every result of 1 gained
Table 8b methyl hydroxybenzoate content is 0.25%, and pH value is the every results of 9 gained
Claims (5)
1. one kind makes Fasudic hydrochloride to the stable method of light, it is characterized in that: with methyl hydroxybenzoate or its sodium salt as stabilizing agent, make the Fasudic hydrochloride aqueous solution stable to light, wherein, in the described Fasudic hydrochloride aqueous solution methyl hydroxybenzoate or its sodium salt take the content of methyl hydroxybenzoate as 0.05%-0.25% (W/V).
2. the Fasudic hydrochloride that makes claimed in claim 1 is characterized in that the stable method of light: methyl hydroxybenzoate or its sodium salt are take the content of methyl hydroxybenzoate as 0.1%-0.2% (W/V) in the described Fasudic hydrochloride aqueous solution.
3. the Fasudic hydrochloride that makes claimed in claim 1 is characterized in that the stable method of light: methyl hydroxybenzoate or its sodium salt are take the content of methyl hydroxybenzoate as 0.1% (W/V) in the described Fasudic hydrochloride aqueous solution.
4. compositions that is made by described any one method of claims 1 to 3, it is characterized in that: said composition contains Fasudic hydrochloride, methyl hydroxybenzoate or its sodium salt and water; Wherein, in the described compositions methyl hydroxybenzoate or its sodium salt take the content of methyl hydroxybenzoate as 0.05%-0.25% (W/V).
5. the compositions that is made by any one method of claims 1 to 3 according to claim 4 is characterized in that: the injection of said composition for being made by Fasudic hydrochloride, methyl hydroxybenzoate or its sodium salt and water for injection.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110041003 CN102151274B (en) | 2011-02-21 | 2011-02-21 | Method for stable light focusing of fasudil hydrochloride and composition obtained using same |
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| CN 201110041003 CN102151274B (en) | 2011-02-21 | 2011-02-21 | Method for stable light focusing of fasudil hydrochloride and composition obtained using same |
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| CN102151274A CN102151274A (en) | 2011-08-17 |
| CN102151274B true CN102151274B (en) | 2013-04-03 |
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| CN103385852B (en) * | 2013-08-06 | 2015-03-11 | 南京正大天晴制药有限公司 | Hydroxyfasudil injection and preparation method thereof |
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| EP1726306B1 (en) * | 2004-03-16 | 2013-10-30 | Asahi Kasei Pharma Corporation | Fasudil-containing preparation and method of improving stability thereof |
| CN101092413B (en) * | 2006-06-23 | 2011-05-18 | 山东轩竹医药科技有限公司 | Hydrate of medicinal salt of Fasudil |
| CN101507707B (en) * | 2009-04-08 | 2011-01-19 | 邓菊娟 | Fasudil hydrochloride lipo-microballoons carrier preparation and preparation method thereof |
| CN102028694B (en) * | 2010-11-12 | 2012-03-14 | 天津红日药业股份有限公司 | Application of Fasudil in preparing medicaments for treating glaucoma through ophthalmic drug delivery |
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Address after: Lanyuan road 300384 Tianjin Huayuan new technology industrial park, 9 No. 2 Room 401 Patentee after: Nankai Yungong Pharmaceutical Science-Technology Co., Ltd., Tianjin Patentee after: Tongliao Huabang Pharmaceutical Co Ltd Address before: Lanyuan road 300384 Tianjin Huayuan new technology industrial park, 9 No. 2 Room 401 Patentee before: Nankai Yungong Pharmaceutical Science-Technology Co., Ltd., Tianjin Patentee before: Naikai Share Pharmaceutical Co., Ltd. |
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Effective date of registration: 20190521 Address after: 028100 Tiedong, Ganqika Town, Kezuo Houqi, Tongliao City, Inner Mongolia Autonomous Region Patentee after: Tongliao Huabang Pharmaceutical Co Ltd Address before: Room 401, No. 2 Gate, No. 9 Lanyuan Road, Huayuan New Technology Industrial Park, Tianjin 300384 Co-patentee before: Tongliao Huabang Pharmaceutical Co Ltd Patentee before: Nankai Yungong Pharmaceutical Science-Technology Co., Ltd., Tianjin |
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