CN105125496A - Medicinal fasudil hydrochloride composition for treating ischemic cerebrovascular diseases - Google Patents

Abstract

The invention discloses a medicinal fasudil hydrochloride composition for treating ischemic cerebrovascular diseases, which belongs to the technical field of medicines. The composition is prepared from fasudil hydrochloride and arginine, wherein the fasudil hydrochloride is a crystal, and an X-ray powder diffraction pattern, which is obtained by measurement of Cu-Kalpha rays, of the crystal, is as shown in figure 1. The new crystalline form of the fasudil hydrochloride provided by the invention is different from a crystalline structure in the prior art; by experimental verification, the medicinal fasudil hydrochloride composition is pleasantly found to have the advantages of high purity, good flowability, good stability, low content of impurities, low possibility of moisture absorption, and safety and reliability in clinical application; a power injection prepared from the new crystalline compound is good in stability, is good in stability after being matched with a solvent, is extremely low in content of insoluble particles, and is very suitable for clinical application.

Description

A kind of medicine Fasudic hydrochloride compositions for the treatment of ischemic cerebrovascular

Technical field

The invention belongs to medical art, relate to a kind of medicine Fasudic hydrochloride compositions 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 fasudil hydrochloride compound being different from prior art, compared with prior art, purity is high for this compound, good fluidity, good stability, impurity content is low, not easily moisture absorption, clinical practice is safe and reliable, utilize the injectable powder that this crystal compound is obtained, good stability, good with solvent compatibility rear stability, particulate matter content is extremely low, 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, through a large amount of experimental studies, has obtained a kind of Fasudic hydrochloride crystalline compounds being different from prior art, has passed through verification experimental verification, surprisingly find that this crystal compound purity is high, good fluidity, good stability, impurity content is low, not easily moisture absorption, clinical practice is safe and reliable, utilizes the injectable powder that this crystal compound is obtained, good stability, good with solvent compatibility rear stability, particulate matter content is extremely low, 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 for the treatment of ischemic cerebrovascular.

In order to complete object of the present invention, the technical scheme of employing is:

Treat a medicine Fasudic hydrochloride compositions for ischemic cerebrovascular, consisting of of described compositions: Fasudic hydrochloride 1 weight portion, arginine 0.001-0.003 weight portion; 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.

Preferably, consisting of of described compositions: Fasudic hydrochloride 1 weight portion, arginine 0.002 weight portion.

Preferably, the dosage form of described compositions is injection, and the preparation method of described injection comprises the following steps:

(1) take Fasudic hydrochloride crystal and arginine in proportion, fully mix;

(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.

The preparation method of the Fasudic hydrochloride crystal in described compositions comprises the following steps:

Volume Fasudic hydrochloride being dissolved in 35 DEG C is in the methanol of 10 times of Fasudic hydrochloride weight and the mixed solvent of acetonitrile, the volume ratio of methanol and acetonitrile is 3:1, after having dissolved, adds the ether solvent that volume is 6 times of Fasudic hydrochloride weight, room temperature is reduced the temperature in 1-2 hour, keep 3 hours in room temperature, then, then be cooled to 0-5 DEG C further, then, place 2-3 hour at 0-5 DEG C, crystallize out, namely 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

Volume Fasudic hydrochloride being dissolved in 35 DEG C is in the methanol of 10 times of Fasudic hydrochloride weight and the mixed solvent of acetonitrile, the volume ratio of methanol and acetonitrile is 3:1, after having dissolved, adds the ether solvent that volume is 6 times of Fasudic hydrochloride weight, room temperature is reduced the temperature in 1-2 hour, keep 3 hours in room temperature, then, then be cooled to 0-5 DEG C further, then, place 2-3 hour at 0-5 DEG C, crystallize out, namely 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 compositions

Consist of: Fasudic hydrochloride crystal 1 weight portion prepared by the present invention, arginine 0.001 weight portion.

Preparation method is:

(1) take Fasudic hydrochloride crystal and arginine in proportion, fully mix;

(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.

embodiment 3:the preparation of Fasudic hydrochloride compositions

Consist of: Fasudic hydrochloride crystal 1 weight portion prepared by the present invention, arginine 0.002 weight portion.

Preparation method is:

(1) take Fasudic hydrochloride crystal and arginine in proportion, fully mix;

(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.

embodiment 4:the preparation of Fasudic hydrochloride compositions

Consist of: Fasudic hydrochloride crystal 1 weight portion prepared by the present invention, arginine 0.003 weight portion.

Preparation method is:

(1) take Fasudic hydrochloride crystal and arginine in proportion, fully mix;

(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.

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 (4)

1. treat a medicine Fasudic hydrochloride compositions for ischemic cerebrovascular, it is characterized in that: described compositions consist of Fasudic hydrochloride 1 weight portion, arginine 0.001-0.003 weight portion; 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 for the treatment of ischemic cerebrovascular according to claim 1, is characterized in that: described compositions consist of Fasudic hydrochloride 1 weight portion, arginine 0.002 weight portion.

3. the medicine Fasudic hydrochloride compositions for the treatment of ischemic cerebrovascular according to claim 1 and 2, is characterized in that, the dosage form of described compositions is injection, and the preparation method of described injection comprises the following steps:

(1) take Fasudic hydrochloride crystal and arginine in proportion, fully mix;

(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.

4. the medicine Fasudic hydrochloride compositions for the treatment of ischemic cerebrovascular according to claim 1, is characterized in that, the crystal preparation method of described Fasudic hydrochloride is:

Volume Fasudic hydrochloride being dissolved in 35 DEG C is in the methanol of 10 times of Fasudic hydrochloride weight and the mixed solvent of acetonitrile, the volume ratio of methanol and acetonitrile is 3:1, after having dissolved, adds the ether solvent that volume is 6 times of Fasudic hydrochloride weight, room temperature is reduced the temperature in 1-2 hour, keep 3 hours in room temperature, then, then be cooled to 0-5 DEG C further, then, place 2-3 hour at 0-5 DEG C, crystallize out, namely obtains Fasudic hydrochloride crystal.