CN101138635B - Fibrin glue vasodilation agent sustained-release long-acting composition - Google Patents
Fibrin glue vasodilation agent sustained-release long-acting composition Download PDFInfo
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- CN101138635B CN101138635B CN2006101271400A CN200610127140A CN101138635B CN 101138635 B CN101138635 B CN 101138635B CN 2006101271400 A CN2006101271400 A CN 2006101271400A CN 200610127140 A CN200610127140 A CN 200610127140A CN 101138635 B CN101138635 B CN 101138635B
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Abstract
The present invention relates to a long acting composition of the fibrin glue vasodilating agent with sustained release property, which comprises a vasodilating agent and a spasmolysant of effective amount, fibrin glue that can delay the releasing of the vasodilating agent. The present invention is characterized in that the composition is a mixture of the fibrin glue and the vasodilating agent; the mixing concentration changes in the range from 0.1mg per ml to 10mg per ml according to various kinds of vasodilating agents. In the present invention, the long acting composition of the fibrin glue vasodilating agent with sustained release property has the following properties of good tissue compatibility, slow releasing of the drugs, long maintenance in the application area and reduction of the side effects to the human body. The present invention is applied in the control during surgery as well as the prevention and treatment after the surgery, which can cause the vasospasm attack. The present invention is particularly applied in the prevention and reduction of the convulsive seizure, which occurs in the coronary artery bypass grafting operation or after the operation. Therefore the pain of the patient is dramatically decreased and the cure rate is improved, and the recurrence is reduced.
Description
Technical field
The present invention relates to a kind of fibrin glue vasodilation agent sustained-release long-acting composition.Relating to a kind of blood vessel dilating that is used for that contains Fibrin Glue and vasodilation medicine that contains effective dose or spasmolytic medicine specifically avoids spasm and can keep the compositions of longer effective acting time.
Technical background
Coronary atherosclerotic heart disease (coronary heart disease) is the problem of a globalization.Along with the trend of aged tendency of population and people's lives mode, the change of quality of life, coronary heart disease becomes the principal disease that threatens the whole world healthy gradually.At present, for most patients with coronary heart disease, (coronary artery bypass graft, CABG) operation is best Therapeutic Method, can obviously improve patient's survival rate and quality of life to carry out coronary bypass grafting in early days.The tremulous pulse bypass has many advantages on long-term effect; but its disadvantage is in the art and the early stage easily generation of postoperative vasospasm; cause the bypass blood flow sharply to descend, cause the myocardial ischemia in this bypass domination district even postoperative myocardial infarction, arrhythmia or cardiac arrest take place.The endotheliocyte of vascular bypass can sustain damage during spasm, and vascular relaxing factor discharges and suppressed, and the atherosis incidence rate of tremulous pulse bypass at a specified future date also increases.Therefore tremulous pulse bypass spasm is very dangerous to the patient.Can play the effect of removing tremulous pulse bypass spasm with the herbal sprinkling of alleviating spasm in blood vessel surface or carry out injecting in blood vessel intracavitary administration, the arterial wall in the art.The spasm of postoperative then is difficult to control.With present evidence of coronary heart diseases, accepting CABG operation and postoperative, to face the number of patients of tremulous pulse bypass spasm threat very huge.If can solve the problem of early stage spasm behind the arterial bypass, will greatly improve the safety of tremulous pulse bypass.Therefore, how to prevent and treat the early stage spasm of tremulous pulse bypass spasm, particularly postoperative, become the most critical issue that improves patient's CABG survival rate.
In order to prevent the postoperative spasm, the method for vasodilation medicine effective dose in vivo is badly in need of effectively prolonging in this area, makes the patient spend the vasospasm critical days of postoperative.
In clinical position, handle vasospasm at arteriospastic local factor of bringing out and whole body possible factor, such as avoiding clamp and excessively involve the tremulous pulse bypass in the operation, in the art, postoperative corrects water, electrolyte and acid-base unbalance, uses vasodilation medicine expansion artery bypass and coronary artery etc.For example, use kavrin sprinkling or the bypass of the plain alkali salt water of small-mouthed jar gauze parcel tremulous pulse: (Papaverine PPV) is the stronger non-specific vasodilation of a kind of effect to papaverine, suppresses cyclic nucleotide phosphodiesterase, lax vascular smooth muscle.The action effect of PPV is relevant with route of administration, the local PPV that uses can make the spasm blood vessel obviously expand, be the most frequently used medicine of handling tremulous pulse bypass spasm in the present CABG art clinically, can effectively prevent and alleviate tremulous pulse bypass spasm with parcel tremulous pulse bypass of papaverine saline gauze or the plain alkali of sprinkling small-mouthed jar in the art.But the papaverine metabolism is very fast, and simple the sprinkling is difficult to keep the enough blood drug level of long-time arterial blood tube wall in the operation.And the effect that local application brings into play its prevention spasm is closed behind the breast once more in operation.Postoperative is taken calcium ion antagonist: calcium ion antagonist is the calcium channel blocade, by the voltage-dependent calcium channel on the selectivity retardance cell membrane, suppress the extracellular Ca2 ion and stride stream in the film, reduce intracellular calcium concentration, suppress vascular smooth muscle and shrink.Calcium ion antagonist has become the CABG routine administration and freedom of fatigue of present control tremulous pulse bypass spasm.Nifedipine and amlodipine are control tremulous pulse bypass spasm common drug.Postoperative is taken calcium ion antagonist (diltiazem etc.) prevention of arterial bypass spasm to a certain extent.But calcium ion antagonist Chang Buneng enables after surgery at once, causes the postoperative cardiac output to reduce because of meeting causes the decline of myocardial contraction, influences body tissue's organ perfusion, can cause hypotension, sinus bradycardia and heart failure etc. when consequence is serious.There is the patient of bibliographical information postoperative about 20% to tolerate to use the above-mentioned untoward reaction behind the calcium ion antagonist.If not influence stable circulation is that prerequisite lowers the calcium ion antagonist consumption, Chang Buneng reaches the blood drug level of effective antagonism bypass spasm.These all can limit the use of the early stage calcium ion antagonist of postoperative.
Fibrin Glue (fibrin glue) is a kind of operating hemostasis gel that is widely used in, it is made up of the sterilized water for injection (component I V) of diluent (component I I), freeze dried human zymoplasm and calcium 2+ (component III) and the dissolved constituent III of lyophilized human fibrinogen's (main gel, component I), composition I.Particularly, four kinds of components: component I and component I I, after component III and component I V mix in twos, mix the back by special syringe again and form colloid, simulation human body blood coagulation final stage.Behind each component uniform mixing, peptide chain A, the B between the Fibrinogen promptly formed fibrin monomer by the thrombin hydrolysis.The loose polymerization of fibrin monomer forms stable poly fibrin fibril after forming network structure under the VIII factor and calcium ion effect.Further more thus polymerization becomes powerful fibrin silk screen, forms the milky protein gel, and this glue is organized absorption about two weeks in human body.
Summary of the invention
The purpose of this invention is to provide a kind of vasodilator method of action time that prolongs.Further, the present invention is the slow-released carrier of medicine with the biological fibrin glue, a kind of fibrin glue vasodilation agent sustained-release long-acting composition is provided, said composition can be after using, keep the long effective function time in vitro and in vivo, thereby be used for to cause art control and the postoperative prevention and the treatment of vasospasm outbreak, particularly prevent and reduce in the coronary artery bypass graft surgery and postoperative convulsion that the misery that significantly alleviates the patient improves the postoperative cure rate and reduces and recurs.
The object of the present invention is achieved like this:
A kind of fibrin glue vasodilation agent sustained-release long-acting composition is characterized in that it contains the vasodilation of effective dose and spasmolytic and be enough to keep this vasodilation and biological fibrin glue that spasmolytic discharges.
Wherein, described vasodilation medicine or spasmolytic are selected from hydralazine, phentolamine, nitroglycerin, sorbitrate, calcium ion antagonist, nifedipine, sodium nitroprusside, papaverin hydrochloride, piperazines, beta receptor blocker, verapamil hydrochloride.
Wherein, the composite ratio of preferred Fibrin Glue and papaverin hydrochloride is 1 milliliter: 1 milligram～1 milliliter: 10 milligrams.The composite ratio of most preferred Fibrin Glue and papaverin hydrochloride is 1 milliliter: 3 milligrams.
The composite ratio of preferred Fibrin Glue and calcium ion antagonist nifedipine or amlodipine is 1 milliliter: 1 milligram～1 milliliter: 5 milligrams.
The composite ratio of preferred Fibrin Glue and nimodipine is 1 milliliter: 3 milligrams～1 milliliter: 8 milligrams.
The composite ratio of preferred Fibrin Glue and nitroglycerin is 1 milliliter: 0.1 milliliter～1 milliliter: 5 milliliters.
The composite ratio of preferred Fibrin Glue and phentolamine is 1 milliliter: 0.5 milligram～1 milliliter: 5 milligrams.
Described a kind of fibrin glue vasodilation agent sustained-release long-acting composition, it is characterized in that Fibrin Glue as the slow-released carrier of vasodilator with in the Rhizoma Atractylodis Macrocephalae or angiospastic treatment of postoperative and preventive use.
Fibrin Glue in described a kind of fibrin glue vasodilation agent sustained-release long-acting composition can postpone the release of contained vasodilator as the slow-released carrier of vasodilation medicine, makes this vasodilation keep long effective local concentration after using.More preferably, a kind of fibrin glue vasodilation agent sustained-release long-acting composition can postpone the release of contained vasodilator, makes this vasodilator can keep the effect of 14 days vasospasm after using.
According to the difference of contained vasodilator, fibrin glue vasodilation agent sustained-release long-acting composition of the present invention can reach the effect of multiple beneficial.For example the allergy rate is low, and the favorable tissue compatibility is arranged, and does not have toxic and side effects, does not influence wound healing, can progressively absorb, vasodilator stability is high, wound repairing, cavity filling stops blooding and need not second operation and takes out advantages such as vasodilator slow-released carrier, reduces patient's suffering of flesh.Can be applied to treat artery bypass grafting postoperative convulsion or other postoperatives prevention convulsion etc., provide the whole society a kind of effectively, safety, economy is treated new technique easily, and great economy and society benefit is arranged.
Description of drawings
Fig. 1 dedicated fiber albumin glue mixing injection;
The cumulative in vitro release profiles of the fibrin glue composition of Fig. 2 papaverin hydrochloride that the present invention contains;
Concentration in the dog blood vessel wall of the fibrin glue composition of Fig. 3 papaverin hydrochloride that the present invention contains;
The concentration of dog peripheral blood papaverine after the fibrin glue composition administration of Fig. 4 papaverin hydrochloride that the present invention contains;
Drug level in the blank blood vessel wall of dog periphery after two kinds of different modes administrations of the fibrin glue composition of Fig. 5 papaverin hydrochloride that the present invention contains and papaverin hydrochloride;
The dog peripheral arterial is all pressed after two kinds of different modes administrations of the Fibrin Glue of Fig. 6 papaverin hydrochloride that the present invention contains and papaverin hydrochloride.
The specific embodiment
Specify the present invention below in conjunction with embodiment and test example, embodiments of the invention and test example only are used to technical scheme of the present invention is described, and non-limiting essence of the present invention.
[embodiment one]
A kind of fibrin glue vasodilation agent sustained-release long-acting composition that can prevent and suppress spasm after the coronary artery bypass grafting, by Fibrin Glue with the vasodilator papaverin hydrochloride is composite forms, its composite ratio is 1 milliliter: 1 milligram.
Wherein:
Fibrin Glue is by the mammalian hair fiber proteinogen through viral inactivation treatment, human thrombin, the hemorrhage that fibrinolytic inhibitor and calcium chloride are formed.Final stage reaction with the simulation blood clotting forms fibrin with the thrombin activation Fibrinogen, is bonded in wound, hemostasis is arranged and promote the healing effect.
But situ configuration is used.First-selection is by component I I during use, it is main gel diluent dissolving papaverin hydrochloride, the main gel diluent that will contain papaverin hydrochloride again dilutes main gel (component I) by working specification, strict during use by the not Fibrin Glue operation instruction operation of hydrochloric papaverine, the Fibrin Glue that postoperative will contain kavrin is smeared or is sprayed on the tremulous pulse, by surgical protocols requirement sew up wound.
Also can be about to kavrin when the producd fibers albumin glue mixes with component I.The on-the-spot Fibrin Glue operation instruction of press is operated, and the Fibrin Glue that postoperative will contain kavrin is smeared or is sprayed on the tremulous pulse, by surgical protocols requirement sew up wound.
[embodiment two]
A kind of fibrin glue vasodilation agent sustained-release long-acting composition that can prevent and suppress spasm after the coronary artery bypass grafting, by Fibrin Glue with the vasodilator papaverin hydrochloride is composite forms, its composite ratio is 1 milliliter: 3 milligrams.
Wherein:
Fibrin Glue is by the mammalian hair fiber proteinogen through viral inactivation treatment, human thrombin, the hemorrhage that fibrinolytic inhibitor and calcium chloride are formed.Final stage reaction with the simulation blood clotting forms fibrin with the thrombin activation Fibrinogen, is bonded in wound, hemostasis is arranged and promote the healing effect.
But situ configuration is used.First-selection is by component I I during use, it is main gel diluent dissolving papaverin hydrochloride, the main gel diluent that will contain papaverin hydrochloride again dilutes main gel (component I) by working specification, strict during use by the not Fibrin Glue operation instruction operation of hydrochloric papaverine, the Fibrin Glue that postoperative will contain kavrin is smeared or is sprayed on the tremulous pulse, by surgical protocols requirement sew up wound.
Also can be about to kavrin when the producd fibers albumin glue mixes with component I.The on-the-spot Fibrin Glue operation instruction of press is operated, and the Fibrin Glue that postoperative will contain kavrin is smeared or is sprayed on the tremulous pulse, by surgical protocols requirement sew up wound.
[embodiment three]
A kind of fibrin glue vasodilation agent sustained-release long-acting composition that can prevent and suppress spasm after the coronary artery bypass grafting, by Fibrin Glue with the vasodilator papaverin hydrochloride is composite forms, its composite ratio is 1 milliliter: 10 milligrams.
Wherein:
Fibrin Glue is by the mammalian hair fiber proteinogen through viral inactivation treatment, human thrombin, the hemorrhage that fibrinolytic inhibitor and calcium chloride are formed.Final stage reaction with the simulation blood clotting forms fibrin with the thrombin activation Fibrinogen, is bonded in wound, hemostasis is arranged and promote the healing effect.
But situ configuration is used.First-selection is by component I I during use, it is main gel diluent dissolving papaverin hydrochloride, the main gel diluent that will contain papaverin hydrochloride again dilutes main gel (component I) by working specification, strict during use by the not Fibrin Glue operation instruction operation of hydrochloric papaverine, the Fibrin Glue that postoperative will contain kavrin is smeared or is sprayed on the tremulous pulse, by surgical protocols requirement sew up wound.
Also can be about to kavrin when the producd fibers albumin glue mixes with component I.The on-the-spot Fibrin Glue operation instruction of press is operated, and the Fibrin Glue that postoperative will contain kavrin is smeared or is sprayed on the tremulous pulse, by surgical protocols requirement sew up wound.
[embodiment four]
A kind of fibrin glue vasodilation agent sustained-release long-acting composition that can prevent and suppress spasm after the coronary artery bypass grafting, by Fibrin Glue with the vasodilator nifedipine is composite forms, its composite ratio is 1 milliliter: 2 milligrams.
Other is substantially with [embodiment one].
[embodiment five]
A kind of fibrin glue vasodilation agent sustained-release long-acting composition that can prevent and suppress spasm after the coronary artery bypass grafting, by Fibrin Glue with the vasodilator nitroglycerin is composite forms, its composite ratio is 1 milliliter: 0.1～5 milliliter.
Other is substantially with [embodiment one].
[embodiment six]
A kind of fibrin glue vasodilation agent sustained-release long-acting composition that can prevent and suppress spasm after the coronary artery bypass grafting, by Fibrin Glue with the vasodilator sodium nitroprusside is composite forms, its composite ratio is 1 milliliter: 5 milligrams.
Other is substantially with [embodiment one].
[embodiment seven]
A kind of fibrin glue vasodilation agent sustained-release long-acting composition that can prevent and suppress spasm after the coronary artery bypass grafting, by Fibrin Glue with the vasodilator nimodipine is composite forms, its composite ratio is 1 milliliter: 3 milligrams.
[embodiment eight]
A kind of fibrin glue vasodilation agent sustained-release long-acting composition that can prevent and suppress spasm after the coronary artery bypass grafting, by Fibrin Glue with the vasodilator phentolamine is composite forms, its composite ratio is 1 milliliter: 0.5 milligram.
Other is substantially with [embodiment one].
[embodiment nine]
A kind of fibrin glue vasodilation agent sustained-release long-acting composition that can prevent and suppress spasm after the coronary artery bypass grafting, by Fibrin Glue and composite the forming of beta receptor blocker Propranolol, its composite ratio is 1 milliliter: 10 milligrams.
Other is substantially with [embodiment one].
[embodiment ten]
A kind of fibrin glue vasodilation agent sustained-release long-acting composition that can prevent and suppress spasm after the coronary artery bypass grafting, by Fibrin Glue with the vasodilator verapamil hydrochloride is composite forms, its composite ratio is 1 milliliter: 10 milligrams.
Other is substantially with [embodiment one].
[embodiment 11]
A kind of fibrin glue vasodilation agent sustained-release long-acting composition that can prevent and suppress spasm after the coronary artery bypass grafting is by Fibrin Glue and beta receptor blocker Propranolol and Ca
2+Antagonist nifedipine three is composite to form, and its composite ratio is 1 milliliter: 10 milligrams: 2 milligrams, promptly Propranolol concentration is 10 mg/ml, and nifedipine concentration is 2 mg/ml.
Wherein:
Fibrin Glue is by the mammalian hair fiber proteinogen through viral inactivation treatment, human thrombin, the hemorrhage that fibrinolytic inhibitor and calcium chloride are formed.Final stage reaction with the simulation blood clotting forms fibrin with the thrombin activation Fibrinogen, is bonded in wound, hemostasis is arranged and promote the healing effect.
But situ configuration is used.During use by component I I, it is main gel diluent dissolving Propranolol, the main gel diluent that will contain Propranolol again dilutes main gel (component I) by working specification, component I V (water for injection) dissolves nifedipine, and the water for injection that will contain nifedipine again dilutes component III by working specification.Strictness is by the Fibrin Glue operation instruction operation that does not contain vasodilator during use, and the Fibrin Glue that postoperative will contain nifedipine and Propranolol is smeared or is sprayed on the tremulous pulse, by surgical protocols requirement sew up wound.
Also can when the producd fibers albumin glue, be about to Propranolol and mix, nifedipine is mixed with component III with component I.The on-the-spot Fibrin Glue operation instruction of press is operated, and the Fibrin Glue that postoperative will contain Propranolol and nifedipine is smeared or is sprayed on the tremulous pulse, by surgical protocols requirement sew up wound.
The present invention is further illustrated below by concrete experiment and use and drug mechanism thereof.
[test example one] fibrin glue gel vigor and stability are measured
Solidify the vitality test method: (according to " lyophilized human fibrinogen makes and vertification regulation " in the Chinese biological goods rules), in small test tube, add thrombin solution (3IU/ml) 0.5ml, put and observe its setting time in 37 ℃ of waters.Be no more than 60 seconds.
[test example two] Fibrin Glue physical behavior is observed
Fibrinogen contacts the back and produces soluble fibrin polymers with thrombin, the X III factor is by thrombin activation, the activatory X III factor impels the soluble protein polymer to be converted into insoluble fiber polymer, and forms network structure, and gel becomes finer and close behind 3～4min.Gel is creamy white, and is flexible, and increase pressure has liquid to disengage, and disengages liquid after the decompression and sucks again in the colloid, vibrates and be extruded with to be beneficial to disengaging of liquid.See under the mirror that gel surface is membranaceous, inside is the silk-like proteins structure, therebetween the full of liquid granule.Carry the fibrin glue composition of vasodilation medicine and matched group perusal and mirror observe down invariably with.
[test example three] the present invention contains the release in vitro of the fibrin glue composition of papaverin hydrochloride
For the examination material: the sample that the embodiment of the invention 2 is prepared
Analyze content and result:
The outward appearance of Fibrin Glue and form: the milky gel, flexible, increase pressure has liquid to disengage, and disengages liquid after the decompression and sucks again in the colloid, vibrates and be extruded with to be beneficial to disengaging of liquid.See under the mirror that gel surface is membranaceous, inside is the silk-like proteins structure, therebetween the full of liquid granule.
The release in vitro of medicine: accurate respectively title is decided papaverin hydrochloride 7.5mg and is added in component I I and two bottles of component I V, and jolting is dissolved fully until medicine.The component I I and the component VI that will contain medicine then dissolve biological fibrin glue main body and catalyst respectively.Get disposable special syringe, one is exclusively used in extraction biological fibrin glue main body solution, another is exclusively used in the extraction catalyst solution, snaps in respectively to push away on the liquid support (to notice that the liquid in two syringes must wait capacity, does not leave bubble), two syringe coneheads are connected on the connection needle stand securely, again nozzle is installed to the conehead that connects needle stand, after the inspection non-loosening seepage, biogum is injected teat glass, add normal saline 10ml, put in the constant temperature 37 degree water-baths.The concussion back is respectively at 0.5,1,2,4, and 6h after precision is measured 1ml, replenishes the 1ml normal saline immediately.Add standard sodium hydrogen phosphate buffer 2ml again.The vibration back in vitro adds chloroform 2ml to each on solution suspendible device, and vibration with the centrifugal 30min of 4000r/min, is taken off a layer organic facies chloroform, and nitrogen dries up.Methanol constant volume is measured for chromatograph to 0.5ml.Chromatographic condition: chromatographic column is Yi Lite Hypersil ODS2 (5 a μ m) post, 4.6mm*250mm, and mobile phase is methanol: water: triethylamine 550: 500: 0.45, the detection wavelength is 238nm, column temperature: room temperature.Flow velocity: 1ml/min.
Fig. 1 is a dedicated fiber albumin glue mixing injection.
Fig. 2 is the cumulative in vitro release profiles that contains the fibrin glue composition of papaverin hydrochloride.Illustrate that the medicine in the fibrin glue vasodilation agent sustained-release long-acting composition can slowly release external.
[test example four] contains the free blood vessel experiment of dog of the fibrin glue composition of papaverin hydrochloride
For the examination material: the sample that the embodiment of the invention 2 is prepared
Test method and result:
Animal Anesthesia: with common dog (Department Of Medicine, Peking University's physiology is that Experimental Animal Center is bought, and meets country's " laboratory animal quality standard "), 1-2 year, body weight 20-25Kg, male and female are not limit, and are animal pattern.Fasting is 24 hours before the dog art, prohibits water 6 hours.Use speed to sleep new II injection according to the 0.15ml/Kg intramuscular anesthesia.
Operation technique: after the satisfaction of flesh pine is weighed, be fixed in operating board, give penicillin 3,200,000 units and go into 100ml normal saline and the lasting intravenous drip of 500ml 5% glucose sodium chloride.Bilateral axillary fossa and groin preserved skin and routine disinfection drape cut skin and subcutaneous connective tissue along the tremulous pulse traveling, free bilateral axillary artery and bilateral femoral arterial 6-8cm.Carefully peel off tremulous pulse peripheral nerve, vein and connective tissue, take out tremulous pulse, stand-by after the distilled water rinsing.
Two broken ends of fractured bone were used No. 0 silk thread ligation respectively after the tremulous pulse that will dissociate was cut into a plurality of 2-3cm segments, used above-mentioned concentration papaverine saline soak and the fibrin glue composition that contains kavrin to smear respectively.Situation use distilled water simply washes the tremulous pulse sample in the clinical operation 0.5 simulate after hour.
0.5h, 1h after the administration, 2h, 4h, 6h sampling, saline group sample are used and are put into quick freezing censorship behind the aseptic specimen bottle labelling after the simple rinsing of distilled water 3 times of flowing; Fibrin Glue kavrin sustained-release long-acting composition group sample is inspected by ready samples with 3 quick freezing of method rinsing after divesting fast and adhering to gel.
Weigh, shears shreds, and adds 1ml water, standard sodium hydrogen phosphate buffer 2ml, and mixing fully vibrates on solution suspendible device.Add chloroform 2ml again, the vibration back is with the centrifugal 30min of 4000r.Get organic facies lower floor, nitrogen dries up, and methanol constant volume is used for chromatography to 0.5ml.Chromatographic column is Yi Lite HypersilODS2 (5 a μ m) post, 4.6mm*250mm, and mobile phase is methanol: water: triethylamine 550: 500: 0.45, the detection wavelength is 238nm, column temperature: room temperature.Flow velocity: 1ml/min.
Fig. 3 is the interior concentration of dog blood vessel wall that contains the fibrin glue composition of papaverin hydrochloride.Illustrate after drug release in the fibrin glue vasodilation agent sustained-release long-acting composition comes out and to penetrate blood vessel wall.
[test example five] contains the zoopery of the fibrin glue composition of papaverin hydrochloride
For the examination material: the sample that the embodiment of the invention 2 is prepared
Test method and result:
Animal Anesthesia is with common dog (Department Of Medicine, Peking University's physiology is that Experimental Animal Center is bought, and meets country's " laboratory animal quality standard "), 1-2 year, and body weight 20-25Kg, male and female are not limit, and are animal pattern.Fasting is 24 hours before the dog art, prohibits water 6 hours.Use speed to sleep new II injection according to the 0.15ml/Kg intramuscular anesthesia.
After the satisfaction of operation technique flesh pine is weighed, be fixed in operating board, give penicillin 3,200,000 units and go into 100ml normal saline and the lasting intravenous drip of 500ml 5% glucose sodium chloride.Bilateral axillary fossa and groin preserved skin and routine disinfection drape cut skin and subcutaneous connective tissue along the tremulous pulse traveling, free bilateral axillary artery and bilateral femoral arterial 6-8cm.Carefully peel off tremulous pulse peripheral nerve, vein and connective tissue, expose tremulous pulse.
Anesthesia back peripheral arterial is put pipe and is connect pressure transducer, modular pressure and monitor.Organize in contrast with papaverin hydrochloride saline gauze parcel.Every artery administration 2.5ml of saline group (the plain alkali 7.5mg of hydrochloric small-mouthed jar), local uniform is sprayed; Every the tremulous pulse of fibrin glue composition group that contains papaverin hydrochloride contains the Fibrin Glue 2.5ml of 7.5mg kavrin, evenly is applied in artery surface.The sample dog is concentrated raising after giving sew up wound more than 12 hours, and postoperative vein every day uses the penicillin prevention infection.
1h, 2h, 4h, 8h, 12h, 24h, 48h, 72h, 7d, 14d sampling after the administration, take off before the blood vessel, except that far away, the nearly broken ends of fractured bone of ligation, the ligation of still needing is got blood vessel sections two ends and is polluted in the lumen of artery to prevent that medicine from entering, the same isolated experiment of method for subsequent processing.Get the peripheral blood sample censorship by 0.5h 1h, 2h, 4h after the administration simultaneously.And 5min, 10min, 20min, 30min, 1h, 2h, 3h, 4h peripheral arterial blood pressure after peripheral arterial blood pressure and the medication before the recording medicine.In addition, randomly draw the distant place peripheral blood vessel sample of part dog 1h, 4h after administration, the same method is handled the back censorship.
Weigh, shears shreds, and adds 1ml water, standard sodium hydrogen phosphate buffer 2ml, and mixing fully vibrates on solution suspendible device.Add chloroform 2ml again, the vibration back is with the centrifugal 30min of 4000r.Get organic facies lower floor, nitrogen dries up, and methanol constant volume is used for chromatography to 0.5ml.Chromatographic column is Yi Lite HypersilODS2 (5 a μ m) post, 4.6mm*250mm, and mobile phase is methanol: water: triethylamine 550: 500: 0.45, the detection wavelength is 238nm, column temperature: room temperature.Flow velocity: 1ml/min.
Fig. 4 is the concentration that contains the fibrin glue composition administration dog peripheral blood papaverine of papaverin hydrochloride; Fig. 5 contains the fibrin glue composition of papaverin hydrochloride and the interior drug level of the blank blood vessel wall of two kinds of different modes administration dog peripheries of papaverin hydrochloride.Illustrate with Fibrin Glue papaverine compositions group comparatively speaking, papaverine saline group has shown in the higher papaverine concentration of peripheral blood with in the higher papaverine concentration of administration place far-end, it is many that this shows that the whole body of the plain alkali salt water of small-mouthed jar administration group papaverine absorbs, and estimates that the systemic side effects of papaverine is big.And at the agents area blood vessel, the drug level of Fibrin Glue papaverine compositions group is higher than the plain alkali salt water of small-mouthed jar group, illustrates that the spasmolytic effect meeting of Fibrin Glue papaverine compositions group is better than the plain alkali salt water of small-mouthed jar group.
Fig. 6 contains the Fibrin Glue of papaverin hydrochloride and two kinds of different modes administration Canis familiaris L. peripheral arterials of papaverin hydrochloride are all pressed.The arteriotony that shows Fibrin Glue papaverine compositions group dog is kept stable, and fluctuating margin is less, each time point there was no significant difference.And papaverine saline soak group dog blood pressure stabilization is poor, administration occur about 1 hour with administration before greater than the fluctuation of blood pressure of 30mmHg.In certain sense, the papaverine saline soak is removed in the arteriospastic method safety and is remained to be discussed really.
[test example six] the present invention contains the animal spasmolytic effect experiment of the fibrin glue composition of papaverin hydrochloride
For the examination material: the sample that the embodiment of the invention 2 is prepared
Test method and result:
Animal Anesthesia is with common dog (Department Of Medicine, Peking University's physiology is that Experimental Animal Center is bought, and meets country's " laboratory animal quality standard "), 1-2 year, and body weight 20-25Kg, male and female are not limit, and are animal pattern.Fasting is 24 hours before the dog art, prohibits water 6 hours.Use speed to sleep new II injection according to the 0.15ml/Kg intramuscular anesthesia.
After the satisfaction of operation technique flesh pine is weighed, be fixed in operating board, give penicillin 3,200,000 units and go into 100ml normal saline and the lasting intravenous drip of 500ml 5% glucose sodium chloride.Breast is opened in conventional center, adopts the free IMA technology of pleura outward.Under the help of cardiac stabilizer, the localized immobilization anastomotic stoma keeps the wild depletion of blood of anastomosis and helps to appear anastomotic stoma in conjunction with the aerosol spraying system.Left anterior descending branch all coincide with IMA, adopts great saphenous vein and all the other target vessels to coincide then.Organize in contrast with papaverin hydrochloride saline gauze parcel, administration 2.5ml (the plain alkali 7.5mg of hydrochloric small-mouthed jar), local uniform is sprayed; The fibrin glue composition group that contains papaverin hydrochloride whenever contains the Fibrin Glue 2.5ml of 7.5mg kavrin, evenly is applied in artery surface.Dog is concentrated raising after giving sew up wound, and postoperative vein every day uses the penicillin prevention infection.Detect creatine kinase isozyme and cardiac muscle troponin I and monitoring electrocardiogram with postoperative in the art.Between organizing, two groups of results compare.The result shows in 2 hours that the heart rate of the plain alkali salt water of small-mouthed jar group and pulsatility index are faster than the Fibrin Glue sustained-release long-acting composition group that contains the plain alkali of small-mouthed jar, but index there was no significant difference between two groups; After 2 hours, the sample electrocardiogram of the plain alkali salt water of small-mouthed jar group 1/3 shows obvious myocardial ischemia and changes, give small-mouthed jar plain alkali injection back sx or disappearance, the Fibrin Glue sustained-release long-acting composition group that contains the plain alkali of small-mouthed jar does not see that complication such as ventricular arrhythmia, myocardial infarction and low cardiac output take place, two weeks back execution zootomy, as seen operation place arterial anastomosis mouth is unobstructed, big absorption of Fibrin Glue.Take out the blood vessel of medicine-feeding part, the method for pressing [test example five] detects the concentration of the plain alkali of small-mouthed jar, still has and can exist by detected medicine, and medicament contg is greater than 10ng/mg.
Claims (4)
1. fibrin glue vasodilation agent sustained-release long-acting composition, it is characterized in that it contains the vasodilation or the spasmolytic of effective dose, with the biological fibrin glue that is enough to keep this vasodilation or spasmolytic release, wherein said vasodilation or spasmolytic are selected from papaverin hydrochloride, describedly be enough to keep the biological fibrin glue that this vasodilation or spasmolytic discharge and be selected from Fibrin Glue, the composite ratio of Fibrin Glue and papaverin hydrochloride is 1 milliliter: 1 milligram～1 milliliter: 10 milligrams.
2. fibrin glue vasodilation agent sustained-release long-acting composition according to claim 1 is characterized in that the composite ratio of described Fibrin Glue and papaverin hydrochloride is 1 milliliter: 3 milligrams.
3. fibrin glue vasodilation agent sustained-release long-acting composition according to claim 1 is characterized in that Fibrin Glue is used for the treatment of art and postoperative spasm and the purposes of prevention as the vasodilation drug carrier.
4. fibrin glue vasodilation agent sustained-release long-acting composition according to claim 3, it is characterized in that described purposes is prevention and reduces in the coronary artery bypass graft surgery and postoperative convulsion, alleviate patient's misery, improve the postoperative cure rate and reduce recurrence.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6054122A (en) * | 1990-11-27 | 2000-04-25 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| CN1695740A (en) * | 2005-05-20 | 2005-11-16 | 云南省第二人民医院 | Composite body of fiber protein adhesive and antibiotics in use for treating infection in deep part, and application |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6054122A (en) * | 1990-11-27 | 2000-04-25 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| CN1695740A (en) * | 2005-05-20 | 2005-11-16 | 云南省第二人民医院 | Composite body of fiber protein adhesive and antibiotics in use for treating infection in deep part, and application |
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