CN104945381B - A kind of fasudil hydrochloride compound, preparation method and its pharmaceutical composition - Google Patents
A kind of fasudil hydrochloride compound, preparation method and its pharmaceutical composition Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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Abstract
The invention belongs to pharmaceutical technology fields, specifically, being related to a kind of fasudil hydrochloride compound, preparation method and its pharmaceutical composition.The fasudil hydrochloride compound is Fasudic hydrochloride dihydrate, shown in structural formula such as formula (I): pharmaceutical composition of the present invention is injection, preferably liquid drugs injection.Fasudil hydrochloride compound provided by the invention have compared with prior art it is lower draw it is moist, to improve the interior qualities such as product stability, validity, safety；And compared with the Fasudic hydrochloride crystal form of the prior art, Fasudic hydrochloride crystal form of the invention has preferable absorption characteristic and bioavilability.
Description
Technical field
The invention belongs to pharmaceutical technology fields, specifically, being related to a kind of fasudil hydrochloride compound, preparation method
And its pharmaceutical composition.
Background technique
Fasudic hydrochloride (fasudil hydrochloride, 1), chemical name are that (5- sulfonyl is different by hexahydro -1-
Quinoline) -1 (H)-Isosorbide-5-Nitrae-diazepine hydrochloride is the one of Japanese Asahi Kasei Corporation and Nagoya University cooperative development
Kind novel isoquinoline sulphonamide derivatives.As Ca in a kind of RHO kinase inhibitor and novel cell2+Antagonist, the medicine can lead to
The activity expansion blood vessel for increasing Myosin light chain phosphatase is crossed, the tension of endothelial cell is reduced, improves brain tissue microcirculation, protect
Protect ischemic tissue of brain, at the same can antagonism inflammatory factor, protect neural anti-apoptotic, promote nerve regneration.June nineteen ninety-five is by the Japanese rising sun
Chemical conversion lists a company, and in Discussion on Chinese Listed, is mainly used for ischemic caused by cerebral vasospasm after subarachnoid hemorrhage etc. within 2004
Property cranial vascular disease symptom improvement, clinical application range will also constantly extend, and market prospects are good.
CN102060845A discloses a kind of III crystal form and its preparation method and application of Fasudil, the hydrochloric acid method
Relax your V crystal form of ground, is radiated using Cu-Ka, the X-ray powder diffraction indicated with 2 θ angles 6.480,13.620,14.780,
16.700, peak has characteristic peak, preparation provided by the invention at 20.500,20.800,21.540,24.580,25.540 degree of 2 θ
Method, Fasudic hydrochloride crystal form of the invention have bioavilability high, and drug effect is significant, and stability is good, high income, purity is high
The features such as, it is suitable for industrial production, the present invention, which further discloses Fasudic hydrochloride, to be improved and preventing to be drawn by many reasons
The application of the ischemic cerebrovascular disease risen.
CN101985444A is related to a kind of V crystal form and its preparation method and application of Fasudic hydrochloride, the hydrochloric acid
Fasudil V crystal form, is radiated using Cu-Ka, the X-ray powder diffraction indicated with 2 θ angles 6.260,8.300,14.020,
20.960,23.860,25.580,27.020 have characteristic peak, and preparation method provided by the invention has purity is high, and impurity is small, more suitable
In industrial production, the present invention further discloses Fasudic hydrochlorides to improve and prevent the ischemic brain as caused by many reasons
The application of vascular diseases.
CN102060844A is related to a kind of IV crystal form and its preparation method and application of Fasudil, and the hydrochloric acid method is relaxed
Your IV crystal form of ground, is radiated using Cu-Ka, the X-ray powder diffraction indicated with 2 θ angles about 6.320,14.240,14.460,
17.040,22.640,22.940,25.400,25.700,28.100 degree of 2 θ have a characteristic peak, preparation method provided by the invention, and
The crystal form has the features such as high physical stability, purity is high under the normal temperature stored and used, and is more suitable for industrial production, sends out
The bright Fasudic hydrochloride that further discloses is in the application for improving and preventing the ischemic cerebrovascular disease as caused by many reasons.
CN102199123A is related to novel crystal forms and its medicinal application of a kind of Fasudil, wherein the crystalline substance of Fasudic hydrochloride
Type, which is characterized in that there is following spectrum characteristic, using Rigaku Rigaku Dmax-2500 type X powder diffraction (XRD)
Instrument analyzes the crystal phase of sample, Cu K α target, tube voltage 40kV, tube current 100mA, and X powder diffraction has following feature
Peak: there is peak at about 6.780,14.700,16.620,17.480,20.440,20.740,24.52 degree of 2 θ.
But since Fasudic hydrochloride is moist with drawing, agglomeration can be caused after moisture absorption, mobility decline, is deliquesced, crystal form
The variation of the physicochemical properties such as change, to influence the interior qualities such as product stability, validity, safety.However the prior art
Corresponding solution is not suggested that, crystal form involved in above-mentioned patent is also improved not to this.
Substance due to affected by various factors, makes intramolecular or molecular linkage mode change in crystallization, causes point
Son or atom are different in lattice vacancy arrangement, form different crystal structures.Polymorph in pharmaceuticals phenomenon be influence drug quality with
One of an important factor for clinical efficacy, therefore in Control of drug quality, crystal form is one of those important quality control index.Drug
Polymorphism have important influence to the quality of product.The different compound of crystal structure, since its molecules align has
The difference of sequence is respectively at different energy state, and usual unformed drug has biggish position energy, interparticle combination
Intensity is small compared with crystal form, and total per surface free energy is larger, the easy aquation in surface between particle, to cause to dissolve with crystalline azithromycin
The difference of degree.Molecule is different from arrangement in steric configuration, conformation in the structure cell of different crystal forms, and there are significance differences for making it dissolve property
Different, leading to preparation in vivo has different dissolution rates, directly affects absorption, distribution, excretion and the metabolism of preparation in vivo, most
Lead to the difference of clinical drug effect because of its bioavilability difference eventually.As " three kinds of crystal forms of Omeprazole are in rat intracorporal medicine generation
Dynamics compares " [three kinds of crystal forms of Omeprazole compare in the intracorporal pharmacokinetics of rat, and Gao Mei, Chen Qianqian wait traditional Chinese medicines in
Of science and toxicology, 2011, (25): 107-108] Omeprazole crystalline substance C, crystalline substance D, crystalline substance E200mg are given by disposable stomach-filling
kg-1, and the HPLC measuring method of Omeprazole in rat plasma sample is established, to three kinds of crystal forms of Omeprazole (crystal form C, D, E)
It is compared in the intracorporal pharmacokinetics process of rat, the results showed that, crystal form C has preferable absorption characteristic.
To overcome drawbacks described above, the present inventor starts with from Fasudic hydrochloride bulk pharmaceutical chemicals, has carried out a large amount of test, pleasantly surprised
Ground has obtained a kind of fasudil hydrochloride compound different from the prior art, the compound compared with prior art, have compared with
Low drawing is moist.
Summary of the invention
The first object of the present invention is to provide a kind of fasudil hydrochloride compound, the Fasudic hydrochloride chemical combination
Object have it is lower draw it is moist.
The second object of the present invention is to provide the preparation method of the fasudil hydrochloride compound.
The third object of the present invention is to provide a kind of pharmaceutical composition containing above-mentioned fasudil hydrochloride compound.
The first purpose to realize the present invention, the present invention adopts the following technical scheme:
A kind of fasudil hydrochloride compound, wherein the fasudil hydrochloride compound is Fasudic hydrochloride two
Hydrate, shown in structural formula such as formula (I):
X-ray powder diffraction pattern such as Fig. 1 that the fasudil hydrochloride compound is obtained using Cu-K alpha ray measurement
It is shown.
In Fig. 1 with 2 angles θ indicate 7.0 °, 10.2 °, 12.6 °, 20.9 °, 22.4 °, 23.3 °, 24.8 °, 27.2 °,
There is characteristic peak at 33.3 °, 36.7 °, 37.2 °, 40.7 °, 42.8 °, 44.0 ° and 45.0 °, error is ± 0.2 °.
Drug crystallization when, if using different solvent and technique, the number of permutations of the drug molecule in each crystal form structure cell
Mesh and position and latticed form are different, form different crystal structures, the crystal tool of this same drug there are two types of or two kinds
The phenomenon that above space structure and cell parameter, the i.e. polymorphism of drug.Different objects can be presented in the polymorphic of drug
Reason and engineering properties, including hygroscopicity, grain shape, density, mobility and compressibility etc., and then bulk pharmaceutical chemicals and preparation can be influenced
Preparation.
Prior art discloses a variety of crystal forms of Fasudic hydrochloride, such as III, IV, V crystal form.It should be noted that in X
In ray powder diffraction, the diffraction spectrogram obtained by crystalline compounds is often characteristic for specific crystal form,
The relative intensity of middle bands of a spectrum (especially in low angle) may because of crystallization condition, partial size and other determination conditions difference and
The advantage orientation effect of generation and change.Therefore, the relative intensity of diffraction maximum is not characteristic to targeted crystal form, is sentenced
It is disconnected whether it is identical as known crystal form when, it should be noted that the relative position at peak rather than their relative intensity.It is penetrated in X
Peak position usually is indicated away from d with 2 angles θ or crystal face in line powder diffraction spectrum.It is sent out after being compared through the crystal form with the prior art
Existing, the X-ray powder diffraction collection and the prior art of Fasudic hydrochloride dihydrate provided by the present invention have obviously not
The relative position at same peak, it is seen that it is a kind of novel crystal forms unlike the prior art.
The present invention further passes through draws moist test, surprisingly find Fasudic hydrochloride provided by the present invention with it is existing
Technology compare have it is lower draw it is moist.
Studies have shown that since the different crystal forms state of drug can seriously affect the clinical therapeutic efficacy of drug, drug poison
Side effect and drug quality etc..The present inventor gives the Fasudic hydrochloride of different crystal forms to rat oral gavage to evaluate different crystal forms
In the intracorporal pharmacokinetics of rat, test result shows: of the invention compared with the Fasudic hydrochloride crystal form of the prior art
Fasudic hydrochloride crystal form has preferable absorption characteristic and bioavilability.
The second purpose to realize the present invention, the present invention adopts the following technical scheme:
A kind of preparation method of the fasudil hydrochloride compound, wherein the preparation method includes following step
It is rapid:
1) dimethylformamide and water are configured to mixed solution A with the volume ratio of 1:3~5；
2) Fasudic hydrochloride bulk pharmaceutical chemicals are taken, the prepared mixed solution A of step 1) is added, stirring makes all to dissolve backward
Active carbon decoloring, filtering are added in acquired solution, obtains clear solution；
3) methylisobutylketone and isopropanol are configured to mixed solution B with the volume ratio of 1:3~4；
4) mixed solution B at room temperature, is added into the resulting clear solution of step 2) under ultrasonic field, finishes closing ultrasound
, it is cooled to 0~5 DEG C, 0.5~3 hour is stood, precipitates crystal, through being dried to obtain the fasudil hydrochloride compound.
The present inventor constantly changes by a large amount of test repeatedly using commercially available Fasudic hydrochloride bulk pharmaceutical chemicals as raw material
Becoming includes the experimental conditions such as solvent, anti-solvent, has finally obtained a kind of fasudil hydrochloride compound unlike the prior art,
Its XRD spectra shows the solid interior molecule arranging structure and the prior art of fasudil hydrochloride compound provided by the invention
In Fasudic hydrochloride it is different.
In the preparation method of fasudil hydrochloride compound of the present invention, it is skill commonly used in the art that active carbon decoloring, which is added,
Art means, may refer to any decolorization, and those skilled in the art, can basis without paying any creative work
Its own prior art grasped makes appropriate choice, and achieves the object of the present invention.
In above-mentioned preparation method, wherein the volume of mixed solution A described in step 2) and Fasudic hydrochloride bulk pharmaceutical chemicals
The ratio of quality is 5~8ml:1g.
The power of ultrasonic field described in step 4) is 0.4~0.8KW.
The additional amount of mixed solution B is 5~10 times of the volume of mixed solution A in step 4).
Third purpose to realize the present invention, the present invention adopts the following technical scheme:
A kind of pharmaceutical composition, wherein the pharmaceutical composition contains Fasudic hydrochloride chemical combination of the present invention
Object.
In the present invention, the pharmaceutical composition can be prepared into any suitable various dosage forms of the prior art, the present invention
Optimizing injection；It is furthermore preferred that pharmaceutical composition of the invention is liquid drugs injection.
In the present invention, the various dosage forms of described pharmaceutical composition can be prepared with reference to the prior art similar to dosage form, and
More creative works are paid without those skilled in the art, the purpose of the present invention can be realized.
In the present invention, the pharmaceutically acceptable carrier can be appointed according to corresponding dosage form by those skilled in the art
The selection of meaning, or be suitble to auxiliary material is obtained by simple experiment, and the selection of this supplementary product kind, dosage is without this
Field technical staff pays more creative works.
The preparation method further includes further by resulting pharmaceutical composition according to pharmaceutically acceptable method system
At liquid drugs injection.
Compared with prior art, the present invention has the advantage that
Fasudil hydrochloride compound provided by the present invention have compared with prior art it is lower draw it is moist, to mention
The interior qualities such as high product stability, validity, safety；And compared with the Fasudic hydrochloride crystal form of the prior art, this
The Fasudic hydrochloride crystal form of invention has preferable absorption characteristic and bioavilability.
Detailed description of the invention
Fig. 1 is that fasudil hydrochloride compound made from the embodiment of the present invention 1 is penetrated using the X- that Cu-K alpha ray measurement obtains
Line powder diffraction spectrum；
Fig. 2 is the TG map of fasudil hydrochloride compound made from the embodiment of the present invention 1；
Fig. 3 is that rat oral gavage gives 4mgkg-1Method relaxes ground in different moments blood plasma after the Fasudic hydrochloride of different crystal forms
Your mean blood plasma concentration-time graph.
Specific embodiment
With embodiment, further description of the technical solution of the present invention below, it will help to technical side of the invention
The advantages of case, effect have further understanding, and the scope of protection of the present invention is not limited for embodiment, protection scope of the present invention by
Claim determines.
[embodiment 1] fasudil hydrochloride compound
1) dimethylformamide and water are configured to mixed solution A with the volume ratio of 1:4；
2) Fasudic hydrochloride bulk pharmaceutical chemicals are taken, the prepared mixed solution A of step 1) are added, wherein the mixed solution A
Volume and Fasudic hydrochloride bulk pharmaceutical chemicals quality ratio be 7ml:1g, stirring make all dissolve after be added into acquired solution
0.1%g/ml activity carbon decoloring, filtering, obtain clear solution；
3) methylisobutylketone and isopropanol are configured to mixed solution B with the volume ratio of 1:3.5；
4) at room temperature, power be 0.6KW ultrasonic field under into the resulting clear solution of step 2) be added mixing it is molten
Liquid B, wherein the additional amount of mixed solution B is 7 times of the volume of mixed solution A, finishes closing ultrasonic field, is cooled to 3 DEG C, is stood
It 2 hours, precipitates crystal, through being dried to obtain the fasudil hydrochloride compound.
Resulting fasudil hydrochloride compound uses 2,400 II elemental analyser of U.S. Perkin-Elmer company PE,
Elemental analysis (%) calculated value: C (46.22), H (6.05), N (11.55), S (8.80), O (17.61), Cl (9.77), element point
Analyse (%) measured value are as follows: C (46.23), H (6.04), N (11.57), S (8.77), O (17.63), Cl (9.76)；
Resulting fasudil hydrochloride compound is subjected to cassette determination of moisture, result 9.91%.
Resulting fasudil hydrochloride compound is measured using Cu-K alpha ray, is obtained x-ray powder as shown in Figure 1 and is spread out
Penetrate map, in X-ray powder diffraction pattern with 2 angles θ indicate 7.0 °, 10.2 °, 12.6 °, 20.9 °, 22.4 °, 23.3 °,
There is characteristic peak at 24.8 °, 27.2 °, 33.3 °, 36.7 °, 37.2 °, 40.7 °, 42.8 °, 44.0 ° and 45.0 °, error is ±
0.2°。
Resulting fasudil hydrochloride compound is using U.S. Perkin-Elmer company PE Pyris Diamond TG warm
The thermogravimetric analysis figure that analyzer obtains is as shown in Fig. 2, thermogravimetric analysis experiment shows: the Fasudic hydrochloride of embodiment preparation
Close object contain 9.891% moisture content, this with containing 2 crystallizations water (theoretical value 9.904%) result within the error range.
The following are embodiment 2-7, and the preparation method is the same as that of Example 1, and specific technological parameter is shown in Table 1:
Table 1
Perkin-Elmer company in the U.S. is used to fasudil hydrochloride compound obtained by embodiment 2 to embodiment 7
II elemental analyser of PE2400 carries out elemental analysis, cassette determination of moisture and is measured and used the U.S. using Cu-K alpha ray
Perkin-Elmer company PE Pyris Diamond TG thermal analyzer, as a result similar to Example 1, obtained x-ray powder
Diffracting spectrum (XRD) and thermogravimetric analysis (TG) figure are similar to Example 1.
[example of formulations 1] fasudil hydrochloride injection
Prescription:
Preparation method:
The water for injection of total configuration amount about 85% is taken, Fasudic hydrochloride made from embodiment 1 is added under nitrogen protection
Dihydrate 30g (in terms of Fasudic hydrochloride), 16g sodium chloride and 10mL benzyl alcohol stirring and dissolving, with 0.1mol/L hydroxide
Sodium solution adjusts pH value to 6.0, the active carbon of total volume 0.08% (g/mL), stirring and adsorbing 10min is added, filtering decarbonization adds
Water for injection stirs evenly, through 0.22 μm of filter membrane refined filtration, nitrogen charging encapsulating, 121 DEG C of moist heat sterilization 20min are to get institute to 2000mL
The fasudil hydrochloride injection stated.
[example of formulations 2] Fasudic hydrochloride liquid drugs injection
Fasudic hydrochloride dihydrate 2g (in terms of Fasudic hydrochloride), is added the note of 800ml made from Example 2
It penetrates and uses water, stirring makes to be completely dissolved, and adjusts pH to 6.0 with the sodium hydroxide and hydrochloric acid solution of 0.1mol/l, adds injection
Water is to 1000ml.0.5g active carbon, stirring 15min decarburization filtering, the 0.22 μm of miillpore filter refined filtration degerming of gained filtrate is added.
In the common ampoule bottle of 2ml, 121 DEG C of sterilizing 15min obtain Fasudic hydrochloride liquid drugs injection to intermediate for encapsulating after the assay was approved.
[example of formulations 3] Fasudic hydrochloride liquid drugs injection
Fasudic hydrochloride dihydrate 5g (in terms of Fasudic hydrochloride), is added the note of 800ml made from Example 3
It penetrates and uses water, stirring makes to be completely dissolved, and adjusts pH to 6.0 with the sodium hydroxide and hydrochloric acid solution of 0.1mol/l, adds injection
Water is to 1000ml.0.5g active carbon, stirring 15min decarburization filtering, the 0.22 μm of miillpore filter refined filtration degerming of gained filtrate is added.
In the common ampoule bottle of 2ml, 121 DEG C of sterilizing 15min obtain Fasudic hydrochloride liquid drugs injection to intermediate for encapsulating after the assay was approved.
[example of formulations 4] Fasudic hydrochloride liquid drugs injection
Fasudic hydrochloride dihydrate 10g (in terms of Fasudic hydrochloride), is added 800ml's made from Example 4
Water for injection, stirring make to be completely dissolved, and adjust pH to 6.0 with the sodium hydroxide and hydrochloric acid solution of 0.1mol/l, add injection
With water to 1000ml.0.5g active carbon, stirring 15min decarburization filtering is added, gained filtrate is removed with 0.22 μm of miillpore filter refined filtration
Bacterium.In the common ampoule bottle of 2ml, 121 DEG C of sterilizing 15min obtain Fasudic hydrochloride water needle to intermediate for encapsulating after the assay was approved
Agent.
[example of formulations 5] Fasudic hydrochloride liquid drugs injection
Fasudic hydrochloride dihydrate 20g (in terms of Fasudic hydrochloride), 10.5g sodium chloride made from Example 5,
Water for injection is added, is stirred to dissolve, with the pH to 3.60 of 0.1mol/L hydrochloric acid solution 80ml regulating liquid medicine, water for injection is added
To 1500ml；0.3g needle-use activated carbon is added in acquired solution, stirs 15 minutes, acquired solution is 1 μm using filter core aperture
Be filtered to remove active carbon, reuse aperture of filter material be 0.22 μm of refined filtration, encapsulating, 121 DEG C pressure sterilizing 15 minutes, lamp inspection to get
Fasudic hydrochloride liquid drugs injection.
[example of formulations 6] Fasudic hydrochloride liquid drugs injection
Fasudic hydrochloride dihydrate 40g (in terms of Fasudic hydrochloride), 12.6g sodium chloride made from Example 6,
Water for injection is added, is stirred to dissolve, with the pH to 3.90 of 0.1mol/L hydrochloric acid solution 30ml regulating liquid medicine, water for injection is added
To 1800ml；2.5g needle-use activated carbon is added in acquired solution, stirs 15 minutes, acquired solution is 1 μm using filter core aperture
Be filtered to remove active carbon, reuse aperture of filter material be 0.22 μm of refined filtration, encapsulating, 121 DEG C pressure sterilizing 15 minutes, lamp inspection to get
Fasudic hydrochloride liquid drugs injection.
[test example 1] draws moist comparative test
Drug draws the moist characteristic for referring to the material absorbing moisture is how many under certain temperature and damp condition.
Test specimen: Fasudic hydrochloride chemical combination made from the method according to the embodiment of the present invention 1 to embodiment 7 respectively
Object；
Control sample 1: Fasudic hydrochloride crystal form V made from the method according to CN101985444A embodiment 1；
Control sample 2: the hydration of Fasudic hydrochloride three and half made from the method according to CN102225929A embodiment 1
Object；
Control sample 3: Fasudic hydrochloride crystal form made from the method according to CN103864760A embodiment 1.
Take above-mentioned sample appropriate respectively, according to " Chinese Pharmacopoeia " (version in 2005) two annex XIX J drug draws moist tests
Guideline is tested.
Specific assay method is as follows:
1, a certain amount of test sample is taken to set a precise weighing (m1) stuffed glass weighing bottle (outer diameter 50mm, it is a height of
In 15mm), accurately weighed (m2)。
2, weighing bottleneck is placed in ± 1 DEG C of thermostatic drier of suitable 25 DEG C and (places ammonium chloride or ammonium sulfate saturation in lower part
Solution) or growth cabinet (set temperature is 25 DEG C ± 1 DEG C), relative humidity is in (80% ± 2%).
3, it places 24 hours.
4, weighing bottle lid, precise weighing (m are covered3)。
Percentage weight increase=(m3-m2)/(m2-m1) × 100%
5, draw moist feature description and draw defining for wet weight gain
It is great draw it is moist: draw wet weight gain not less than 15%.
Have draw it is moist: draw wet weight gain less than 15% and not less than 2%.
Slightly draw moist: drawing wet weight gain less than 2% and not less than 0.2%.
It deliquesces: absorbing enough moisture and form liquid.
Test result is shown in Table 2:
Table 2, Fasudic hydrochloride draw moist inspection result
| Sample | Draw moist (%) |
| Embodiment 1 | 3.32 |
| Embodiment 2 | 3.38 |
| Embodiment 3 | 3.34 |
| Embodiment 4 | 3.36 |
| Embodiment 5 | 3.40 |
| Embodiment 6 | 3.42 |
| Embodiment 7 | 3.39 |
| Control sample 1 | 13.13 |
| Control sample 2 | 13.19 |
| Control sample 3 | 13.26 |
Above-mentioned test result, which shows fasudil hydrochloride compound of the invention compared with prior art, has lower draw
It is moist.
Fasudil hydrochloride compound prepared by other embodiments of the present invention has also been carried out it is above-mentioned draw it is moist relatively try
It tests, the result obtained is similar.
[test example 2] Fasudic hydrochloride different crystal forms compare in the intracorporal pharmacokinetics of rat
1, drug
Investigational agent: Fasudic hydrochloride dihydrate made from the embodiment of the present invention 1；
Comparison medicine 1: Fasudic hydrochloride crystal form V made from the method according to CN101985444A embodiment 1；
Comparison medicine 2: three semihydrates of Fasudic hydrochloride made from the method according to CN102225929A embodiment 1.
2, method
Take the Fasudic hydrochloride drug of different crystal forms appropriate, with appropriate normal saline at concentration 1.0gL-1Medicine
Liquid (in terms of base).
2.1, dosage regimen and sample acquire
Healthy male Wistar rat 18, is randomly divided into 3 groups.Fasting 12h, free water before being administered.Respectively with 4mg
kg-1Different crystal forms Fasudic hydrochloride stomach-filling, before administration (0h) and administration after 0.033,0.083,0.250,0.500,
0.750,1.000,2.000,3.000,4.000,6.000,8.000 and 12.000h through rat orbital vein take a blood sample about 0.4mL,
It is placed in the EP pipe for being coated with heparin, is centrifuged 10min (3500rmin-1), separated plasma saves to be measured in -70 DEG C of refrigerators.
The concentration mensuration of Fasudil in 2.2 blood plasma
Using the concentration of Fasudil in LC-MS/MS method measurement rat plasma and tissue.Using Di Ma company
Diamonsil C18Chromatographic column (150mm × 4.6mm, 5 μm) is separated, mobile phase: methanol-water-formic acid (volume ratio 80:
20:0.1), flow velocity: 0.6mLmin-1.Sample is after ethyl acetate extracts, just using the source atmospheric pressure chemical ionization (APCI)
Ionization mode, collision induced dissociation (collision-induced disso-ciation, CID) voltage is respectively 35ev (method
Relax ground you) and 25ev (diphenhydramine), with Selective reaction monitoring (select reaction monitoring, SRM) mode into
Row scanning quantitation, the ionic reaction for quantitative analysis are respectively m/z292 → m/z99 (Fasudil) and m/z256 → m/
Z167 (diphenhydramine).Sweep time: 0.3s.
Referring to " Fasudic hydrochloride is in the intracorporal absorption of rat and distribution ", [Zhang Chunhong, Liu Youping wait hydrochloric acid method for other
Ground that relax in the intracorporal absorption of rat and distribution [J] Shenyang Pharmaceutical University journal, 2011,28 (11): 906-911].
3, result
Rat oral gavage gives 4mgkg-1Fasudil in different moments blood plasma after the Fasudic hydrochloride of different crystal forms
Mean blood plasma concentration-time graph is shown in Fig. 3.
From figure 3, it can be seen that the cmax value of Fasudic hydrochloride crystal form of the invention is better than comparison medicine 1 and comparison medicine 2
Fasudic hydrochloride crystal form calculates AUC using trapezoidal method, the results showed that the AUC value of Fasudic hydrochloride crystal form of the invention
It is significantly better than the Fasudic hydrochloride crystal form of comparison medicine 1 and comparison medicine 2.Show Fasudic hydrochloride crystal form of the invention have compared with
Good absorption characteristic and bioavilability.
Claims (8)
1. a kind of fasudil hydrochloride compound, which is characterized in that the fasudil hydrochloride compound is that hydrochloric acid method relaxes ground
That dihydrate, shown in structural formula such as formula (I):
X-ray powder diffraction pattern such as Fig. 1 institute that the fasudil hydrochloride compound is obtained using Cu-K alpha ray measurement
Show.
2. a kind of preparation method of fasudil hydrochloride compound described in claim 1, which is characterized in that the preparation side
Method includes the following steps:
1) dimethylformamide and water are configured to mixed solution A with the volume ratio of 1:3~5；
2) Fasudic hydrochloride bulk pharmaceutical chemicals are taken, the prepared mixed solution A of step 1) is added, stirring makes after all dissolving to gained
Active carbon decoloring, filtering are added in solution, obtains clear solution；
3) methylisobutylketone and isopropanol are configured to mixed solution B with the volume ratio of 1:3~4；
4) mixed solution B at room temperature, is added into the resulting clear solution of step 2) under ultrasonic field, finishes closing ultrasonic field,
It is cooled to 0~5 DEG C, 0.5~3 hour is stood, precipitates crystal, through being dried to obtain the fasudil hydrochloride compound.
3. preparation method according to claim 2, which is characterized in that the volume and salt of mixed solution A described in step 2)
The ratio of the quality of sour Fasudil bulk pharmaceutical chemicals is 5~8ml:1g.
4. preparation method according to claim 2, which is characterized in that the power of ultrasonic field described in step 4) is 0.4
~0.8KW.
5. preparation method according to claim 2, which is characterized in that the additional amount of mixed solution B is mixing in step 4)
5~10 times of the volume of solution A.
6. a kind of pharmaceutical composition, which is characterized in that the pharmaceutical composition contains hydrochloric acid method described in claim 1 and relaxes ground
That compound.
7. pharmaceutical composition according to claim 6, which is characterized in that the pharmaceutical composition is injection.
8. pharmaceutical composition according to claim 7, which is characterized in that the injection is liquid drugs injection.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1183782A (en) * | 1995-07-03 | 1998-06-03 | 旭化成工业株式会社 | 1 -(5 -isoquinolinesulfonyl) homopiperazine hydrochloride hydrates |
| 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 |
| CN102020635A (en) * | 2009-09-10 | 2011-04-20 | 河北凯盛医药科技有限公司 | Preparation method of hydrochloride Fasudil hemihydrate |
| 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 |
| 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 |
| 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 |
| CN102225929A (en) * | 2011-05-12 | 2011-10-26 | 天津市汉康医药生物技术有限公司 | Compound of stable Fasudil hydrochloride hydrate |
| CN103864760A (en) * | 2014-03-10 | 2014-06-18 | 洪军 | Hydroxyfasudil compound |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102120739A (en) * | 2010-01-07 | 2011-07-13 | 成都欣捷高新技术开发有限公司 | Preparation method of fasudil hydrochloride |
| CN102241669B (en) * | 2010-05-13 | 2013-07-31 | 吉林省博大伟业制药有限公司 | Preparation method of fasudil hydrochloride |
| CN101863880B (en) * | 2010-06-12 | 2012-08-01 | 陶灵刚 | Fasudil hydrochloride compound and novel method thereof |
| CN102020636A (en) * | 2010-11-25 | 2011-04-20 | 江苏万邦生化医药股份有限公司 | Method for synthesizing and purifying Fasudil hydrochloride |
| CN102775387B (en) * | 2011-05-13 | 2014-08-20 | 深圳海王药业有限公司 | Method for refining fasudil hydrochloride |
| CN103030629B (en) * | 2011-10-10 | 2015-02-25 | 南京亿华药业有限公司 | Method for preparing fasudil hydrochloride |
| CN102603715A (en) * | 2012-03-31 | 2012-07-25 | 苏州工业园区南华生物科技有限公司 | Synthesis and preparation method of fasudil hydrochloride |
| CN103509002B (en) * | 2012-06-20 | 2015-05-13 | 徐州万邦金桥制药有限公司 | Purification decolorization method of fasudil hydrochloride |
| CN102924436B (en) * | 2012-11-30 | 2014-03-19 | 南京正大天晴制药有限公司 | Refining method of fasudil hydrochloride |
| CN103044403A (en) * | 2013-01-05 | 2013-04-17 | 成都天翼医药科技有限公司 | Preparation method of fasudil hydrochloride |
| CN103450157B (en) * | 2013-08-28 | 2015-03-18 | 合肥久诺医药科技有限公司 | Preparation method for high-purity hydroxyfasudil semihydrate |
| CN104098547B (en) * | 2014-07-28 | 2016-08-24 | 天津红日药业股份有限公司 | A kind of process for purification of Fasudic hydrochloride |
-
2015
- 2015-06-24 CN CN201510350890.3A patent/CN104945381B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1183782A (en) * | 1995-07-03 | 1998-06-03 | 旭化成工业株式会社 | 1 -(5 -isoquinolinesulfonyl) homopiperazine hydrochloride hydrates |
| CN102020635A (en) * | 2009-09-10 | 2011-04-20 | 河北凯盛医药科技有限公司 | Preparation method of hydrochloride Fasudil hemihydrate |
| 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 |
| 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 |
| 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 |
| CN102225929A (en) * | 2011-05-12 | 2011-10-26 | 天津市汉康医药生物技术有限公司 | Compound of stable Fasudil hydrochloride hydrate |
| CN103864760A (en) * | 2014-03-10 | 2014-06-18 | 洪军 | Hydroxyfasudil compound |
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