CN105055332A - Hydroxyfasudil composition dry suspension for treating ischemic cerebrovascular diseases - Google Patents
Hydroxyfasudil composition dry suspension for treating ischemic cerebrovascular diseases Download PDFInfo
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- CN105055332A CN105055332A CN201510572425.4A CN201510572425A CN105055332A CN 105055332 A CN105055332 A CN 105055332A CN 201510572425 A CN201510572425 A CN 201510572425A CN 105055332 A CN105055332 A CN 105055332A
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- fasudic hydrochloride
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- dry suspension
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Abstract
The invention relates to a hydroxyfasudil composition dry suspension for treating ischemic cerebrovascular diseases and belongs to the technical field of medicine. The composition dry suspension is prepared from hydroxyfasudil, mannitol, microcrystalline cellulose, calcium sulfate, xanthan gum, hydroxypropyl methylcellulose, steviosin and 95% ethyl alcohol. The hydroxyfasudil is a new crystal form compound, and is hydroxyfasudil different from what is reported in prior art by an X ray power diffraction pattern as shown in picture 1 by using Cu-Kalpha ray measurement, test proves that the new crystal form compound is high in purity, good in mobility and stability, low in impurity content and safe and reliable in clinical use, and does not easily absorb humidity, the dry suspension prepared by the compound is good in stability, high in bioavailability and very suitable for clinical use.
Description
Technical field
The invention belongs to medical art, relate to a kind of medicine Fasudic hydrochloride compositions dry suspension for the treatment of ischemic cerebrovascular.
Background technology
Fasudic hydrochloride (fasudilhydrochloride, 1) is a kind of novel isoquinoline sulphonamide derivatives of Japanese Asahi Kasei Corporation and Nagoya University cooperative development.As Ca in a kind of RHO inhibitors of kinases and novel cell
2+antagonist, this medicine, by increasing the active blood vessel dilating of Myosin light chain phosphatase, reduces the tension force of endotheliocyte, improves cerebral tissue microcirculation, protection ischemic tissue of brain, simultaneously can antagonism inflammatory factor, and neuroprotective anti-apoptotic, promotes neuranagenesis.June nineteen ninety-five is gone on the market by Japanese Asahi Kasei Corporation, and within 2004, in Discussion on Chinese Listed, be mainly used in the improvement of the ischemic cerebrovascular symptom that cerebral vasospasm after subarachnoid hemorrhage etc. causes, its clinical application range also will constantly be expanded, and market prospect is had an optimistic view of.
Draw moist because Fasudic hydrochloride has, the change of the physicochemical properties such as the decline of caking, mobility, deliquescence, crystal formation change can be caused after moisture absorption, thus affect the interior qualities such as product stability, effectiveness, safety.But prior art does not propose corresponding solution, the crystal formation involved by prior art does not also improve this.
Material owing to affecting by various factors, makes in molecule or molecular linkage mode changes when crystallization, cause molecule or atom different in lattice vacancy arrangement, form different crystal structures.Polymorph in pharmaceuticals phenomenon is one of key factor affecting drug quality and clinical efficacy, and therefore in Control of drug quality, crystal formation is one of them important quality control index.The quality of polymorphism on product of medicine has important impact.The compound that crystal structure is different, due to the difference of its molecules align order, be in different energy state respectively, usual unformed medicine has larger potential energy, interparticle bond strength is little compared with crystal formation, total per surface free energy is comparatively large, surface easily aquation between particle, thus causes the difference with crystalline azithromycin dissolubility.In the structure cell of different crystal forms, molecule is different from arrangement in steric configuration, conformation, its dissolubility is made to there is significant difference, preparation is caused to have different dissolution rates in vivo, directly affect preparation absorption in vivo, distribution, excretion and metabolism, finally cause the difference of clinical drug effect because its bioavailability is different.
The present inventor starts with from Fasudic hydrochloride crude drug, has carried out a large amount of tests, surprisingly obtains a kind of Fasudic hydrochloride crystalline compounds being different from prior art, the purity of this fasudil hydrochloride compound is high, good fluidity, good stability, not easily moisture absorption, impurity content is low, and the preparation for preparation brings conveniently, and clinical practice is safe and reliable, utilize the dry suspension that this crystal compound is obtained, good stability, bioavailability is high, is very suitable for clinical practice.
In prior art, for the crystal formation of Fasudic hydrochloride, had many research, but the hygroscopicity of impurity content, stability and crystal formation is still undesirable, brings difficulty also to while have impact on self stability the preparation of preparation.
The present invention is through a large amount of experimental studies, and obtained a kind of Fasudic hydrochloride crystalline compounds being different from prior art, the purity of this fasudil hydrochloride compound is high, good fluidity, good stability, not easily moisture absorption, impurity content is low, preparation for preparation brings conveniently, clinical practice is safe and reliable, utilizes the dry suspension that this crystal compound is obtained, good stability, bioavailability is high, is very suitable for clinical practice.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of medicine Fasudic hydrochloride compositions dry suspension for the treatment of ischemic cerebrovascular.
In order to complete object of the present invention, the technical scheme of employing is:
The present invention relates to a kind of medicine Fasudic hydrochloride compositions dry suspension for the treatment of ischemic cerebrovascular, described compositions dry suspension is made up of Fasudic hydrochloride, mannitol, microcrystalline Cellulose, calcium sulfate, xanthan gum, hypromellose, steviosin, 95% ethanol; Described Fasudic hydrochloride is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
First optimal technical scheme of the present invention is: with parts by weight, and described compositions dry suspension is made up of the Fasudic hydrochloride of 1-4 weight portion, the mannitol of 28-30 weight portion, the microcrystalline Cellulose of 11-13 weight portion, the calcium sulfate of 4.2-4.4 weight portion, the xanthan gum of 0.6-0.8 weight portion, the hypromellose of 0.6-0.7 weight portion, the steviosin of 0.2-0.4 weight portion, 95% ethanol of 9-10 weight portion.
Second optimal technical scheme of the present invention is: with parts by weight, and described compositions dry suspension is made up of the Fasudic hydrochloride of 3 weight portions, the mannitol of 29 weight portions, the microcrystalline Cellulose of 12 weight portions, the calcium sulfate of 4.3 weight portions, the xanthan gum of 0.7 weight portion, the hypromellose of 0.65 weight portion, the steviosin of 0.3 weight portion, 95% ethanol of 9.5 weight portions.
3rd optimal technical scheme of the present invention is: the preparation method of described compositions dry suspension comprises the following steps:
1) weigh according to technology preparation amount;
2) supplementary material process: raw material Fasudic hydrochloride is pulverized 100 sieves of looking over so as to check;
3) premixing: the Fasudic hydrochloride of recipe quantity and mannitol are mixed with equal increments method;
4) mixing granulation: the microcrystalline Cellulose of the Fasudic hydrochloride of premixing, mannitol and recipe quantity, calcium sulfate, xanthan gum, hypromellose, steviosin are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add wetting agent 95% ethanol, wet mixing 200-240 soft material second, 18 order nylon wires are arranged in oscillating granulator granulates;
5) dry granulate: arranging boiling drier inlet temperature is 60 DEG C, is dried to moisture < 3.5%, joins 18 order granulate in oscillating granulator by granule after drying;
6) always mix: the dry granule after granulate is joined in three-dimensional motion mixer, motor rotation frequency 200r/min is set, open mixer and mix 5 minutes;
7) pack with particles packing machine, content uniformity controls to meet inner quality standard.
4th optimal technical scheme of the present invention is: the preparation method of the crystal of described Fasudic hydrochloride comprises the following steps:
(1) get Fasudic hydrochloride crude drug, add in deionized water, the volumetric usage of deionized water is 5 times of the quality of Fasudic hydrochloride;
(2) be stirred to whole dissolving, regulate pH to 6-9;
(3) add activated carbon decolorizing, filter, obtain settled solution;
(4) settled solution is moved in pressure vessel, the pressure in pressure vessel is controlled 2.0Mpa and stir condition under drip 2 DEG C 45% isopropanol water solution, speed of agitator controls at 35rmp, and the volumetric usage of isopropanol water solution is 3 times of the volume of deionized water;
(5) bleed off pressure after dripping, with the speed of 10 DEG C/min, solution is cooled to-5 DEG C, leave standstill 2h, filter, washed with diethylether, drying under reduced pressure, obtains Fasudic hydrochloride crystal.
The polymorphism of solid chemical is the natural phenomena that a kind of general material exists, this phenomenon refers to that a kind of solid chemical can exist 2 kinds or two or more crystal form state, be also called the polymorphic state of material, the polymorphic state of material is also referred to as " allomorphism " phenomenon.Although its chemical nature of allomorphous solid matter is identical, its physicochemical property may be different.For " allomorphism medicine " that physicochemical property is different, also can show the curative effect of different disease preventing and treating clinically, directly affect application and the clinical effectiveness of medicine.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction that the Fasudic hydrochloride crystal of the embodiment of the present invention 1 preparation uses the measurement of Cu-K alpha ray to obtain.
Detailed description of the invention
Below by specific embodiment, summary of the invention of the present invention is described in further detail, but does not therefore limit content of the present invention.
embodiment 1:the preparation of Fasudic hydrochloride crystal
(1) get Fasudic hydrochloride crude drug, add in deionized water, the volumetric usage of deionized water is 5 times of the quality of Fasudic hydrochloride;
(2) be stirred to whole dissolving, regulate pH to 6-9;
(3) add activated carbon decolorizing, filter, obtain settled solution;
(4) settled solution is moved in pressure vessel, the pressure in pressure vessel is controlled 2.0Mpa and stir condition under drip 2 DEG C 45% isopropanol water solution, speed of agitator controls at 35rmp, and the volumetric usage of isopropanol water solution is 3 times of the volume of deionized water;
(5) bleed off pressure after dripping, with the speed of 10 DEG C/min, solution is cooled to-5 DEG C, leave standstill 2h, filter, washed with diethylether, drying under reduced pressure, obtains Fasudic hydrochloride crystal.
As shown in Figure 1, its purity of high-performance liquid chromatogram determination is 99.9% to the X-ray powder diffraction pattern that the Fasudic hydrochloride crystal prepared uses the measurement of Cu-K alpha ray to obtain.
embodiment 2:the preparation of Fasudic hydrochloride dry suspension
Prescription: with parts by weight, Fasudic hydrochloride 3 parts, 28 parts, mannitol, microcrystalline Cellulose 11 parts, 4.2 parts, calcium sulfate, xanthan gum 0.6 part, hypromellose 0.6 part, steviosin 0.2 part, 95% ethanol 9 parts that embodiment 1 is obtained.
Preparation method:
1) weigh according to technology preparation amount;
2) supplementary material process: raw material Fasudic hydrochloride is pulverized 100 sieves of looking over so as to check;
3) premixing: the Fasudic hydrochloride of recipe quantity and mannitol are mixed with equal increments method;
4) mixing granulation: the microcrystalline Cellulose of the Fasudic hydrochloride of premixing, mannitol and recipe quantity, calcium sulfate, xanthan gum, hypromellose, steviosin are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add wetting agent 95% ethanol, wet mixing 200-240 soft material second, 18 order nylon wires are arranged in oscillating granulator granulates;
5) dry granulate: arranging boiling drier inlet temperature is 60 DEG C, is dried to moisture < 3.5%, joins 18 order granulate in oscillating granulator by granule after drying;
6) always mix: the dry granule after granulate is joined in three-dimensional motion mixer, motor rotation frequency 200r/min is set, open mixer and mix 5 minutes;
7) pack with particles packing machine, content uniformity controls to meet inner quality standard.
System meets inner quality standard.
embodiment 3:the preparation of Fasudic hydrochloride dry suspension
Prescription: with parts by weight, Fasudic hydrochloride 3 parts, 29 parts, mannitol, microcrystalline Cellulose 12 parts, 4.3 parts, calcium sulfate, xanthan gum 0.7 part, hypromellose 0.65 part, steviosin 0.3 part, 95% ethanol 9.5 parts that embodiment 1 is obtained.
Preparation method:
1) weigh according to technology preparation amount;
2) supplementary material process: raw material Fasudic hydrochloride is pulverized 100 sieves of looking over so as to check;
3) premixing: the Fasudic hydrochloride of recipe quantity and mannitol are mixed with equal increments method;
4) mixing granulation: the microcrystalline Cellulose of the Fasudic hydrochloride of premixing, mannitol and recipe quantity, calcium sulfate, xanthan gum, hypromellose, steviosin are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add wetting agent 95% ethanol, wet mixing 200-240 soft material second, 18 order nylon wires are arranged in oscillating granulator granulates;
5) dry granulate: arranging boiling drier inlet temperature is 60 DEG C, is dried to moisture < 3.5%, joins 18 order granulate in oscillating granulator by granule after drying;
6) always mix: the dry granule after granulate is joined in three-dimensional motion mixer, motor rotation frequency 200r/min is set, open mixer and mix 5 minutes;
7) pack with particles packing machine, content uniformity controls to meet inner quality standard.
embodiment 4:the preparation of Fasudic hydrochloride dry suspension
Prescription: with parts by weight, Fasudic hydrochloride 3 parts, 30 parts, mannitol, microcrystalline Cellulose 13 parts, 4.4 parts, calcium sulfate, xanthan gum 0.8 part, hypromellose 0.7 part, steviosin 0.4 part, 95% ethanol 10 parts that embodiment 1 is obtained.
Preparation method:
1) weigh according to technology preparation amount;
2) supplementary material process: raw material Fasudic hydrochloride is pulverized 100 sieves of looking over so as to check;
3) premixing: the Fasudic hydrochloride of recipe quantity and mannitol are mixed with equal increments method;
4) mixing granulation: the microcrystalline Cellulose of the Fasudic hydrochloride of premixing, mannitol and recipe quantity, calcium sulfate, xanthan gum, hypromellose, steviosin are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add wetting agent 95% ethanol, wet mixing 200-240 soft material second, 18 order nylon wires are arranged in oscillating granulator granulates;
5) dry granulate: arranging boiling drier inlet temperature is 60 DEG C, is dried to moisture < 3.5%, joins 18 order granulate in oscillating granulator by granule after drying;
6) always mix: the dry granule after granulate is joined in three-dimensional motion mixer, motor rotation frequency 200r/min is set, open mixer and mix 5 minutes;
7) pack with particles packing machine, content uniformity controls to meet inner quality standard.
experimental example 1: fluidity test
The mobility of this experimental example to the Fasudic hydrochloride crystal that the embodiment of the present invention 1 obtains detects.
Method: according to the embodiment of the present invention 1 method continuous production 6 batches of Fasudic hydrochlorides (batch: 1,2,3,4,5 and 6), sample from 6 batches of obtained Fasudic hydrochlorides respectively, adopt fixed funnel method, funnel is placed in the suitable height on graph paper, Fasudic hydrochloride crystal is freely flowed down from bell mouth, until the cone top formed contacts with bell mouth, measure hypotenuse and the horizontal angle (θ angle of repose) of Fasudic hydrochloride accumulation horizon.The results are shown in Table 1:
The fluidity test result of table 1 Fasudic hydrochloride
From the interpretation of table 1, the mobility of Fasudic hydrochloride crystal of the present invention is fine.
experimental example 2: influence factor tests
1, hot test
The Fasudic hydrochloride crystalline compounds that Example 1 prepares, simulation listing packaging, puts in sealing clean container, place 10 days at 40 ± 2 DEG C of temperature, in the 5th day and sampling in the 10th day, detect by stability high spot reviews project, result of the test compared with 0 day.
2, high humility test
The Fasudic hydrochloride crystalline compounds that Example 1 prepares, simulation listing packaging, put in sealing clean container, place 10 days under the condition of 25 ± 2 DEG C of relative humiditys 90% ± 5%, in the 5th day and sampling in the 10th day, detect by stability high spot reviews project, result of the test compared with 0 day.
3, strong illumination test
The Fasudic hydrochloride crystalline compounds that Example 1 prepares, simulation listing packaging, puts in sealing clean container, being placed in illumination is place 10 days under the condition of 4500lx, in the 5th day and sampling in the 10th day, detect by stability high spot reviews project, result compared with 0 day.The results are shown in Table 2.
Table 2 influence factor result of the test
Result shows: the Fasudic hydrochloride crystalline compounds that the present invention prepares, and its stability is good, and under high temperature, high humidity, high light conditions, equal retention is stablized.
experimental example 3: Acceleration study
The Fasudic hydrochloride crystalline compounds that Example 1 prepares 3 batches and marketable material, simulation listing packaging, put in sealing clean container, in 40 DEG C ± 2 DEG C, place 6 months under relative humidity 70% ± 5% condition, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stability high spot reviews project is tested.The results are shown in Table 3.
Table 3 accelerated test result
Result shows: the Fasudic hydrochloride crystalline compounds that the present invention prepares, known through accelerated test result, its good stability, and total assorted content is low.
experimental example 4: wettability test
1 instrument
PL203 electronic balance, LRH-250-S constant temperature and humidity incubator, HH-400SD testing chamber for medicine stability;
2 methods
Get the glass desicator (for ensureing that saline solution is saturated, excessive salt should be had bottom exsiccator to exist) that bottom fills salt supersaturated solution, the built-in weighing botle of exsiccator, places 48h to constant humidity in calorstat.Sample thief is about 2g, puts in weighing botle, accurately weighed, bottle cap is opened, puts into exsiccator top, put in 25 DEG C of constant temperature and humidity incubators or 20 DEG C of stability test casees by different temperatures requirement and preserve, operation repetitive 3 parts, weighs respectively at different time, calculates the hydroscopicity of different time.
Computing formula: hydroscopicity=(medicated powder weight after moisture absorption-moisture absorption prodrug grain weight amount)/moisture absorption prodrug grain weight amount × 100%.Result is as table 4.
Table 4 hygroscopicity test results
According to above-mentioned experiment, the hygroscopicity of Fasudic hydrochloride crystalline compounds prepared by the present invention is low, good stability.
Claims (5)
1. treat a medicine Fasudic hydrochloride compositions dry suspension for ischemic cerebrovascular, it is characterized in that: described compositions dry suspension is made up of Fasudic hydrochloride, mannitol, microcrystalline Cellulose, calcium sulfate, xanthan gum, hypromellose, steviosin, 95% ethanol; Described Fasudic hydrochloride is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
2. the medicine Fasudic hydrochloride compositions dry suspension for the treatment of ischemic cerebrovascular according to claim 1, it is characterized in that: with parts by weight, described compositions dry suspension is made up of the Fasudic hydrochloride of 1-4 weight portion, the mannitol of 28-30 weight portion, the microcrystalline Cellulose of 11-13 weight portion, the calcium sulfate of 4.2-4.4 weight portion, the xanthan gum of 0.6-0.8 weight portion, the hypromellose of 0.6-0.7 weight portion, the steviosin of 0.2-0.4 weight portion, 95% ethanol of 9-10 weight portion.
3. the medicine Fasudic hydrochloride compositions dry suspension for the treatment of ischemic cerebrovascular according to claim 2, it is characterized in that: with parts by weight, described compositions dry suspension is made up of the Fasudic hydrochloride of 3 weight portions, the mannitol of 29 weight portions, the microcrystalline Cellulose of 12 weight portions, the calcium sulfate of 4.3 weight portions, the xanthan gum of 0.7 weight portion, the hypromellose of 0.65 weight portion, the steviosin of 0.3 weight portion, 95% ethanol of 9.5 weight portions.
4. prepare a method for the medicine Fasudic hydrochloride compositions dry suspension for the treatment of ischemic cerebrovascular as claimed in claim 1, it is characterized in that comprising the following steps:
1) weigh according to technology preparation amount;
2) supplementary material process: raw material Fasudic hydrochloride is pulverized 100 sieves of looking over so as to check;
3) premixing: the Fasudic hydrochloride of recipe quantity and mannitol are mixed with equal increments method;
4) mixing granulation: the microcrystalline Cellulose of the Fasudic hydrochloride of premixing, mannitol and recipe quantity, calcium sulfate, xanthan gum, hypromellose, steviosin are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add wetting agent 95% ethanol, wet mixing 200-240 soft material second, 18 order nylon wires are arranged in oscillating granulator granulates;
5) dry granulate: arranging boiling drier inlet temperature is 60 DEG C, is dried to moisture < 3.5%, joins 18 order granulate in oscillating granulator by granule after drying;
6) always mix: the dry granule after granulate is joined in three-dimensional motion mixer, motor rotation frequency 200r/min is set, open mixer and mix 5 minutes;
7) pack with particles packing machine, content uniformity controls to meet inner quality standard.
5. the medicine Fasudic hydrochloride compositions dry suspension for the treatment of ischemic cerebrovascular according to claim 1, it is characterized in that, the preparation method of the crystal of described Fasudic hydrochloride comprises the following steps:
(1) get Fasudic hydrochloride crude drug, add in deionized water, the volumetric usage of deionized water is 5 times of the quality of Fasudic hydrochloride;
(2) be stirred to whole dissolving, regulate pH to 6-9;
(3) add activated carbon decolorizing, filter, obtain settled solution;
(4) settled solution is moved in pressure vessel, the pressure in pressure vessel is controlled 2.0Mpa and stir condition under drip 2 DEG C 45% isopropanol water solution, speed of agitator controls at 35rmp, and the volumetric usage of isopropanol water solution is 3 times of the volume of deionized water;
(5) bleed off pressure after dripping, with the speed of 10 DEG C/min, solution is cooled to-5 DEG C, leave standstill 2h, filter, washed with diethylether, drying under reduced pressure, obtains Fasudic hydrochloride crystal.
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| CN201510572425.4A CN105055332A (en) | 2015-09-10 | 2015-09-10 | Hydroxyfasudil composition dry suspension for treating ischemic cerebrovascular diseases |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0912573A (en) * | 1995-06-29 | 1997-01-14 | Asahi Chem Ind Co Ltd | 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride trihyrate |
| WO2009155777A1 (en) * | 2008-06-26 | 2009-12-30 | 天津红日药业股份有限公司 | The use and method of the compound of fasudil and the pharmaceutical composition thereof |
| CN101985444A (en) * | 2010-08-20 | 2011-03-16 | 天津红日药业股份有限公司 | V crystal form of Fasudil hydrochloride and preparation method and application thereof |
| CN102060844A (en) * | 2010-12-28 | 2011-05-18 | 天津红日药业股份有限公司 | Fasudil crystal formation IV as well as preparation method and application thereof |
| CN102060845A (en) * | 2010-12-28 | 2011-05-18 | 天津红日药业股份有限公司 | Fasudil crystal formation III as well as preparation method and application thereof |
| CN102199123A (en) * | 2010-03-24 | 2011-09-28 | 天津红日药业股份有限公司 | New crystal form and pharmaceutical application of fasudil |
-
2015
- 2015-09-10 CN CN201510572425.4A patent/CN105055332A/en not_active Withdrawn
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0912573A (en) * | 1995-06-29 | 1997-01-14 | Asahi Chem Ind Co Ltd | 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride trihyrate |
| WO2009155777A1 (en) * | 2008-06-26 | 2009-12-30 | 天津红日药业股份有限公司 | The use and method of the compound of fasudil and the pharmaceutical composition thereof |
| CN102199123A (en) * | 2010-03-24 | 2011-09-28 | 天津红日药业股份有限公司 | New crystal form and pharmaceutical application of fasudil |
| CN101985444A (en) * | 2010-08-20 | 2011-03-16 | 天津红日药业股份有限公司 | V crystal form of Fasudil hydrochloride and preparation method and application thereof |
| CN102060844A (en) * | 2010-12-28 | 2011-05-18 | 天津红日药业股份有限公司 | Fasudil crystal formation IV as well as preparation method and application thereof |
| CN102060845A (en) * | 2010-12-28 | 2011-05-18 | 天津红日药业股份有限公司 | Fasudil crystal formation III as well as preparation method and application thereof |
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Application publication date: 20151118 |