CN103040738B - Drug composition containing hydroxyfasudil compound - Google Patents
Drug composition containing hydroxyfasudil compound Download PDFInfo
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- CN103040738B CN103040738B CN201310008620.5A CN201310008620A CN103040738B CN 103040738 B CN103040738 B CN 103040738B CN 201310008620 A CN201310008620 A CN 201310008620A CN 103040738 B CN103040738 B CN 103040738B
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- hydroxyfasudil
- methionine
- pharmaceutical composition
- dihydrogen phosphate
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Abstract
The invention provides a drug composition containing a hydroxyfasudil compound, which comprises hydroxyfasudil, sodium dihydrogen phosphate, dextran 40, methionine and water for injection. A preparation method of the drug composition comprises the following steps of stirring and dissolving sodium dihydrogen phosphate, methionine, hydroxyfasudil and dextran with the water for the injection, adding active carbon for decoloration, filtering removing carbon, and then conducting filter sterilization and autoclaved sterilization. The drug composition containing hydroxyfasudil is simple in prescription and reduces the possibility of hypotension, the stability is improved by reasonable configuration, and application and popularization of a hydroxyfasudil injection is facilitated.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a kind ofly can alleviate angiospastic pharmaceutical composition that contains fasudil hydrochloride compound and preparation method thereof.
Background technology
Subarachnoid hemorrhage (Subarachnoid hemorrhage, SAH) be the acute hemorrhagic cerebrovascular diseases that brain bottom or brain and spinal cord vascular surface break due to Different types of etiopathogenises, blood flows directly into subarachnoid space, is called again primary subarachnoid hemorrhage.The common cause of disease is cerebral arteries deformity, aneurysm, hematologic disease etc.Subarachnoid hemorrhage accounts for 10% of acute apoplexy, accounts for 20% of hemorrhagic apoplexy.The tardy cerebrovascular the most serious complication after the twin SAH of being of fullying recover from an illness, often causes patient death or deformity.
At present conventional calcium-channel antagonists alleviates vasospasm.Slowly quiet of conventional nimotop 10mg～20mg/d, 1mg/h, continuous 5～14 days, or oral Nimoldipine, 20～40mg/ time, 3 times/day.But it is to illumination sensitivity, poor stability, and need to be containing in the solvent of ethanol, its use has been subject to certain restriction.
Fasudic hydrochloride (six hydrogen-1-(5-sulfur base isoquinolin)-(H)-Isosorbide-5-Nitrae-diazepine hydrochlorate)
Be a kind of novel calcium ion antagonist, can suppress cranial nerve cell damage, promote the recovery of brain function, improve memory and intelligence.Fasudic hydrochloride is Rho inhibitors of kinases, can effectively suppress kinase whose activation, suppresses myosin hydrogen chain phosphorylation, and blood vessel dilating improves cerebral blood flow, suppresses cranial nerve cell damage, thereby improves prognosis.Heze City the 3rd the People's Hospital applies Fasudic hydrochloride iatrotechnics cerebral vasospasm in recent years, has obtained good curative effect, has improved healing improvement rate, has reduced mortality rate.
Fasudil hydrochloride injection is current conventional dosage form, has the low advantage easy to use etc. of cost.But there are some researches show, there is certain side effect in Fasudic hydrochloride, be in particular in and occur sometimes the situations such as intracranial hemorrhage (1.63%) and digestive tract hemorrhage, pneumorrhagia, epistaxis, subcutaneous hemorrhage (0.29%) etc. be hemorrhage, in addition, also there is the symptom such as hypotension, anemia.Thereby, how to reduce side effect, improving drug safety is that fasudil hydrochloride injection has a difficult problem to be solved.
Summary of the invention
The object of the invention is to a kind of good stability, the pharmaceutical composition that contains fasudil hydrochloride compound that hypotension incidence rate is low.
For achieving the above object, the pharmaceutical composition that contains fasudil hydrochloride compound provided by the invention it comprise Fasudic hydrochloride, sodium dihydrogen phosphate, Dextran 40, methionine and water for injection.Particularly, pharmaceutical composition provided by the invention it comprise the component of following weight portion:
Preferably, pharmaceutical composition of the present invention it comprise the component of following weight portion:
More preferably, pharmaceutical composition of the present invention it comprise the component of following weight portion:
Pharmaceutical composition of the present invention, except aqueous injection, can also be made lyophilized powder, but is preferably aqueous injection (injection).
Sodium dihydrogen phosphate is pH value regulator, can guarantee that the pH value of configuration and storing process is stable, guarantees the stability of Fasudic hydrochloride.
Methionine is essential amino acid, participates in protein synthesis.Because it can not self generate in vivo, so must be obtained by outside.Will cause body internal protein biosynthesis block if methionine lacks, cause body damage.The membrane lipid over oxidation that in body, oxygen-derived free radicals causes is the reason that causes the multiple infringement of body.Lipid peroxide can be damaged primary and secondary lysosome membrane, and the acid phosphatase of the conduct hydrolysis that lysosome contains is discharged, and the organelle important to cell and mitochondrial membrane etc. causes damage, and methionine is resisted these infringements by number of ways.Methionine, at medicament Chang Zuowei antioxidant, has increased the stability of medicine.
Dextran 40 belongs to LMD, is typically used as lyophilized powder filler, but the present invention studies unexpected discovery, and suitably add dextran and can effectively reduce hypotension incidence rate, thus the drug safety of raising fasudil hydrochloride injection.Ironically, add separately dextran and easily precipitate, and in the environment existing at sodium dihydrogen phosphate and methionine time, deposited phenomenon significantly reduces.Infer that this environment has effectively played hydrotropy effect.
The present invention also provides a kind of method of preparing aforementioned pharmaceutical compositions, it comprises the steps: with water for injection successively by sodium dihydrogen phosphate, methionine, Fasudic hydrochloride and dextran stirring and dissolving, add activated carbon decolorizing, then filter carbon removal, then autoclaving after degerming after filtration.
The method of above-mentioned activated carbon decolorizing is, adds the active carbon of solution weight 0.1～0.5%, and 50 ℃ of following stirrings 15～30 minutes, then filter carbon removal.Above-mentioned filtration sterilization is the microporous filter membrane fine straining that adopts 0.22 μ m.Above-mentioned autoclaving is sterilizing 15～30 minutes at 105～125 ℃.
This pharmaceutical composition prescription of the present invention is simple, and has reduced hypostension, has increased stability by reasonable disposition, contributes to application and the popularization of Fasudic hydrochloride.
The specific embodiment
Following examples are used for further illustrating the present invention, but should not be construed as limitation of the present invention.Do not deviating under the prerequisite of the present invention's spirit and essence, modification made for the present invention or replacement, all belong to category of the present invention.As nothing particularly points out, embodiment of the present invention raw material used is commercial.
Embodiment 1 Fasudic hydrochloride pharmaceutical composition (injection)
Formula 1: Fasudic hydrochloride 30g, sodium dihydrogen phosphate 15g, Dextran 40 5g, methionine 3g, water for injection 2000ml.
Formula 2: Fasudic hydrochloride 10g, sodium dihydrogen phosphate 10g, Dextran 40 3g, methionine 2g, water for injection 500ml.
Formula 3: Fasudic hydrochloride 50g, sodium dihydrogen phosphate 20g, Dextran 40 10g, methionine 5g, water for injection 50000ml.
Formula 4: Fasudic hydrochloride 20g, sodium dihydrogen phosphate 13g, Dextran 40 3g, methionine 1g, water for injection 1000ml.
Formula 5: Fasudic hydrochloride 40g, sodium dihydrogen phosphate 17g, Dextran 40 7g, methionine 4g, water for injection 10000ml.
Preparation method is as follows:
Successively by sodium dihydrogen phosphate, methionine, Fasudic hydrochloride and dextran stirring and dissolving, add the active carbon of solution weight 0.3% with water for injection, 50 ℃ of following stirrings 20 minutes, then filter carbon removal, adopt the microporous filter membrane fine straining degerming of 0.22 μ m.After the inspection of semifinished product is qualified, sterile filling, and sterilizing 20 minutes at 120 ℃.
Embodiment 2
One, vascular stimulation test
30 of new zealand white rabbits getting body weight and be 2.0-2.5kg, are divided into 6 groups at random, 5 every group, comprise blank group, experimental group 1～5 (embodiment 1 configures 1～5).Adopt rabbit auricular vein slowly to inject, injection volume is 10ml/kg body weight/time (being diluted to Fasudic hydrochloride 0.5mg/ml by the configuration of embodiment 1～5 sodium chloride injection).Wherein blank group adopts sodium chloride injection, and experimental group 1-5 group adopts respectively the configuration 1～5 of embodiment 1, is dissolved in water for injection respectively rear injection.
Once a day, successive administration 7 days, after 24 hours, cut short the rabbit ear in last administration, be placed in 10% formalin fixed preparation, then send pathology to carry out histological examination (5 places at the different parts of rabbit auricular vein draw materials, and start centripetal end and do a section every 1cm from injecting initial position).
Through rabbit ear edge vein pathological examination, the auricular vein tube wall of blank group and experimental group 1～5 is complete, and endotheliocyte structure is clear, without obvious pathological changes, without cell infiltration.
Two, allergic experiment
Healthy guinea pig, body weight 300 ± 50g.Cavia porcellus is divided into 6 groups at random, and 10 every group, male and female half and half.Observe the anaphylaxis of Cavia porcellus intravenous injection sodium chloride blank group, experimental group 1-5 group, wherein blank group adopts sodium chloride injection, and experimental group 1-5 group adopts respectively embodiment 1 to configure 1-5, is dissolved in water for injection respectively rear injection.
Concrete grammar is: according to 1～5 group of blank group, experimental group, every other day gives only (configure by embodiment 1 1～5 configuration sodium chloride injection be diluted to 1.5mg/ml) of abdominal cavity Fasudic hydrochloride 0.5ml/ respectively, continuous three times, then within the 14th day and 21 days, attack respectively administration (2ml/ only), observe immediately 1 hour.
Result demonstration, all there is not obvious abnormal phenomena in blank group and experimental group 1-4 group.
Three, clinical experiment
The standard that cardiovascular and cerebrovascular disease academic conference in the Chinese Medical Association whole nation is formulated per year, through head and or waist wear and make a definite diagnosis, and opening that cranium is looked at descending deformity aneurysm clip occlusion straight or blood vessel inner spring circle embolotherapy at once after radiography.Within postoperative 3,7,10 days, carry out respectively cranium brain Doppler and check, wherein once blood flow of middle cerebral artery speed adds resistance toly, is generation cerebral vasospasm.The apoplexy neurological functional deficit standards of grading that state of an illness weight is formulated according to the 4th the cerebrovascular meeting in the whole nation are divided into 3 types, amount to 100 routine patients.
Postoperatively fall cranium pressure, hemostasis, antiinflammatory according to routine dehydration, in postoperative two weeks, give fasudil hydrochloride injection.100 routine patients are divided into two groups every group 50, wherein one group (A group) injection embodiment 1 configures 1 fasudil hydrochloride injection, and the configuration of the fasudil hydrochloride injection of another group (B group) injection is: Fasudic hydrochloride 30g, sodium dihydrogen phosphate 15g, water for injection 2000ml.Injected dose is 30mg, is diluted to 100ml with physiology hydrochloric acid, intravenous drip, and the time is 40min.Record the blood pressure of quiet front and back.Before and after quiet of result A group between ± 5mmHg, there is not hypotension situation in blood pressure; Quiet front and back of B group occur that 4 routine Blood pressure drops are more than 10mmHg, and wherein hypotension has appearred in 1 example.Blood pressure significant difference between A, B group, but in vasospasm, there is no significant difference alleviating.
Embodiment 3 stability tests
The sample that embodiment 1 configures 1～5 gained and contrast 1 sample of (embodiment 1 configure in 1 do not add sodium dihydrogen phosphate and methionine), carry out detection and the long-term stable experiment of the indexs such as outward appearance, clarity, related substance and content according to the requirement of " Chinese Pharmacopoeia " (2010 editions).
Content assaying method: measure according to high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2010).Chromatographic condition and system suitability: with octadecylsilane chemically bonded silica be filler; Take 0.08moL/L potassium dihydrogen phosphate-acetonitrile-10% TBAH-triethylamine (88: 12: 0.5: 2.5) (with phosphorus acid for adjusting pH value 7.0) is as mobile phase; Detection wavelength is 220nm.Number of theoretical plate calculates and should be not less than 3000 by fasudil peak.Algoscopy: it is appropriate that precision measures this product, dilutes the solution of making hydrochloric fasudil 20 μ g in every 1ml, as need testing solution by mobile phase.Precision measures 20 μ l injection liquid chromatographies, records chromatogram.Separately get Fasudic hydrochloride reference substance appropriate, accurately weighed, add mobile phase and dissolve and dilute the solution of making in every 1ml containing 20 μ g, be measured in the same method,, to obtain final product with calculated by peak area by external standard method.
Get experimental example 1 and configure 1～5 sample, in 2 ℃, 40 ℃ of soil of temperature, under native 5% condition of relative humidity 75%, place 6 months, carry out accelerated test, measure active constituent content wherein, the results are shown in Table 1.
Table 1 accelerated test result
Accelerate to observe by the constant temperature of six months, related substance and content that embodiment 1 configures 1～5 each fasudil hydrochloride injection are all qualified, and other every inspections all conform with the regulations.Show that fasudil hydrochloride injection of the present invention has good stability, in cool place, dry place preserves, and within 2 years effect phases, can keep steady quality.
Although above used general explanation, the specific embodiment and experiment, the present invention is described in detail, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (4)
1. contain a pharmaceutical composition for fasudil hydrochloride compound, its component by following weight portion forms:
2. pharmaceutical composition according to claim 1, it comprises the component of following weight portion:
3. pharmaceutical composition according to claim 1, it comprises the component of following weight portion:
4. prepare the method for pharmaceutical composition described in claim 1～3 any one for one kind, it comprises the steps: with water for injection successively by sodium dihydrogen phosphate, methionine, Fasudic hydrochloride and dextran stirring and dissolving, add activated carbon decolorizing, then filter carbon removal, then autoclaving after degerming after filtration.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310008620.5A CN103040738B (en) | 2013-01-10 | 2013-01-10 | Drug composition containing hydroxyfasudil compound |
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| CN201310008620.5A CN103040738B (en) | 2013-01-10 | 2013-01-10 | Drug composition containing hydroxyfasudil compound |
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| CN103040738A CN103040738A (en) | 2013-04-17 |
| CN103040738B true CN103040738B (en) | 2014-06-18 |
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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 |
| CN1989967A (en) * | 2005-12-29 | 2007-07-04 | 周长海 | Freeze drying injection of fasudil hydrochlorate and hydrate thereof |
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Application publication date: 20130417 Assignee: Hainan Herui Pharmaceutical Co., Ltd. Assignor: Luo Cheng Contract record no.: 2015990000015 Denomination of invention: Drug composition containing hydroxyfasudil compound Granted publication date: 20140618 License type: Common License Record date: 20150107 |
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