CN1375288A

CN1375288A - Composite medicine for treating cerebrovascular diseases

Info

Publication number: CN1375288A
Application number: CN 02117704
Authority: CN
Inventors: 周桂荣
Original assignee: Individual
Current assignee: Individual
Priority date: 2002-05-13
Filing date: 2002-05-13
Publication date: 2002-10-23

Abstract

The present invention relating to a medicine combination used for curing cerebrovascular disease is a liposome of butylbenzene phthalein composed of butylbenzene phthalein and phosphatide emulsification in validity quantity to cure cerebrovascular disease with weight ratio of butylbenzene phthalein to phosphatide as 1 to 0.3-0.2. The medicine combination can be produced as the formulations of injection, transfusion and peroral medicine or put directly into milk or food to be eaten by the patients. The invented liposome of butylbenzene phthalein has modified the physical performance of butylbenzene phthalein so that the dissolvability of butylbenzene phthalein is raised for easy to be used as not only peroral medicine but also injection and transfusion in order to be absorbed fully by human body and the curative effect is enhanced and increased due to the phosphatide having been added in the medicine combination.

Description

A kind of pharmaceutical composition for the treatment of cerebrovascular disease

Technical field

The present invention relates to a kind of pharmaceutical composition for the treatment of cerebrovascular disease.

Background technology

Butyphthalide is the effective constituent that mainly contains in Herba Apii graveolentis and the seed thereof.The chemical name of butyphthalide is a dL-3-normal-butyl Phthalide, i.e. dL-3-n-Butylphthalidle (being called for short NBP) molecular weight 190.24.The pharmacotoxicological effect of butyphthalide has reported in literature, sees " novel pharmaceutical formulation and new technique " book, (People's Press) version in 1998.Butyphthalide (NBP) has protective effect to cerebral arteries and brain aorta, and brain injury and cerebral ischemia are had repairing, restitution, and anticonvulsant action is arranged, and brain lacks O ₂, during ischemia, adenosine triphosphate (ATP) and phosphagen (PCr) exhaust that sharply too much brain lactic acid makes neuronal function impaired, and butyphthalide (NBP) can obviously reduce the rising of lactic acid behind the broken end ischemia and the reduction of ATP and PCr.Use NBP 10-20mg/kg, can improve the behavior disorder that occurs behind the ischemia, dwindle infarct size, reduce water content.Butyphthalide (NBP) can improve the brain energy metabolism of complete cerebral ischemia, has and obviously dwindles the local cerebral ischemia cerebral infarct size, improves the neurological deficit effect.Can significantly improve dysmnesia and cerebral edema that the part causes, ischemic region local cerebral blood flow and pia mater encephali microcirculation are significantly increased effect.Has tangible anti-apoplexy effect.But because butyphthalide is a kind of water-fast oil-based liquid material, its formulation development limitation is bigger, should not directly be developed to multiple dosage forms such as injection, thereby limit butyphthalide use clinically, can not give full play to its therapeutical effect.

Summary of the invention

The physical property of butyphthalide for a change improves the dissolubility of butyphthalide, makes it easy to oral and is used for the human injection and venoclysis.Can be absorbed by human body fully, give full play to curative effect cerebrovascular disease.The present invention adopts several different methods such as injection method, reverse transfer method, the even method of high pressure breast that it is prepared into a kind of pharmaceutical composition for the treatment of cerebrovascular disease, promptly by the butyphthalide of treatment cerebrovascular disease effective dose and the butyphthalide liposome of phospholipid (natural phospholipid or synthetic phospholipid) emulsifying formation, wherein; the weight ratio of butyphthalide and phospholipid is 1: 0.3-20, preferred 1: 0.3-10.Butyphthalide is levo butyl phthalide preferably.Pharmaceutical composition butyphthalide liposome of the present invention can be prepared into parenterai administration dosage forms such as injection, transfusion, and peroral dosage form such as tablet, capsule dried frozen aquatic products, spray powder, also can directly add bread, milk is made the food with health care, and is edible for suffering from the cerebrovascular disease person.Because butyphthalide has the protection restitution to cerebral arteries, brain injury, cerebral ischemia; therapeutic effect to disease of brain is obvious; and phospholipid (natural phospholipid; synthetic phospholipid) has higher biological activity and nutritive value; can promote cholesterol and protein molecule in conjunction with and be present in the blood; alleviate blood vessel wall lipoid, suppress atherosclerotic generation, the effect that also has protection and recover cell.Since have in the molecule of phospholipid phosphate radical and the hydrophilic and hydrocarbon key hydrophobic group of amino alcohol because of, can make water oily two mix form stable colloid mutually.Phospholipid forms a boundary layer between water and oil are biphase, reduce the interfacial tension of profit.And phospholipid this as one of ingredient of cell membrane, with cell surface stronger affinity is arranged, can impel the butyphthalide medicine to combine and show and promote absorb with cell, improve the effect of bioavailability and enhancing drug effect, thereby change the physical action of butyphthalide, improve the dissolubility of butyphthalide, it is oral that it both had been convenient to, can be used for injection and venoclysis again, can be absorbed by the body fully, give full play to curative effect.And phospholipid plays emulsification in human plasma, can influence the transportation and the precipitation of cholesterol and fat, and atheromatous plaque is disappeared.So the adding of phospholipid more increases, has strengthened curative effect.Butyphthalide gel of the present invention is encapsulated in butyphthalide in the thin film of lipoid molecular layer formation, constitute the superminiature spheroid, have the pharmacological action of enhancing and curative effect, reduce the main ingredient consumption, alleviate toxicity and zest, increase the characteristics that liposome had such as cell permeability.

The preparation method of pharmaceutical composition butyphthalide liposome of the present invention is that phospholipid is added stirring and dissolving in the entry, make the solution of concentration range about 0.5%, add butyphthalide according to butyphthalide and phospholipid weight ratio 1: 0.3-20, with the strong emulsifying of mulser, with the rotating speed is per minute 3000-10000 rotary speed agitating solution 10-20 minute, become white and milky white solution, no oil droplet exists, and gained liquid is the butyphthalide liposome.Butyphthalide liposome of the present invention is directly added milk or making bread etc. be cerebrovascular disease patient functional health-care food; Water for injection is added the butyphthalide liposome to be the butyphthalide injection or to annotate transfusion; Butyphthalide is added excipient such as lactose, mannitol, maltodextrin, the butyphthalide liposome can be made dried frozen aquatic products, clinical in glucose or physiological saline solution use; Or with a kind of or several adjuvants such as butyphthalide liposome adding maltodextrin, pregelatinized Starch, lactose, behind the miscible or suspendible, become butyphthalide micro encapsulation powder, tabletting after adding diluent, binding agent, granulation incapsulates or adding lubricant, sugar coating with spray dryer spray is dried.

The specific embodiment

Implement 1, with butyphthalide 250 grams, lecithin 100 grams add 230 milliliters of waters for injection and carry out homogenize with dispersion emulsifying machine, Revolution Per Minute 3000-10000 changes, time 5-10 minute liquid butyphthalide liposome, water to 1000 milliliter is penetrated in after-teeming, uses microporous filter membrane pressure filtration, embedding is in 2 milliliters of ampoules, logical nitrogen seals, 100 ℃ of sterilizations in 30 minutes.

Implement 2, get butyphthalide 1000 grams, soybean phospholipid 300 grams, add 3000 milliliters of ethanol, 40000 milliliters of ultrasonic emulsifications of water with water-bath 40-50 in the rotary evaporator ℃ of recovery ethanol, are warming up to 60-70 ℃ to milky, distill out part water and must contain the solution of butyphthalide liposome, directly add fresh milk for the cerebrovascular disease patients.

Implement 3, get 800 milliliters of waters for injection, add 9 gram injection sodium chloride, transfer pH=4-7, add 0.5 gram pin charcoal with the hydrochloric acid of 0.05N and the sodium hydroxide of 0.05N, be heated with stirring to 100 ℃, be incubated 15 minutes, filtering decarbonization filters the back and adds synthetic phospholipid (dipalmitoyl phosphatidyl choline) 10g, stirring and dissolving, after adding oily levo butyl phthalide 1 gram again, use the mulser homogenize, moisturizing to 1000 milliliter, use microporous filter membrane pressure filtration, fill is led to nitrogen, blooming in infusion bottle, roll lid, 100 ℃ of sterilizations in 30 minutes.

Implement 4, with butyphthalide 1000g and soybean phospholipid 20,000 g and the homogenize of water mulser, add mannitol, pregelatinized Starch miscible after, spray do butyphthalide micro encapsulation powder, add diluent, the binding agent granulation incapsulates.

Claims

1, a kind of pharmaceutical composition for the treatment of cerebrovascular disease, the butyphthalide of the treatment cerebrovascular disease effective dose of serving as reasons and phospholipid emulsifying and the butyphthalide liposome that constitutes.

2, the pharmaceutical composition of treatment cerebrovascular disease according to claim 1 is characterized in that in the said butyphthalide liposome, the weight ratio of butyphthalide and phospholipid is 1: 0.3～20.0.

3, the pharmaceutical composition of treatment cerebrovascular disease according to claim 1 and 2, the weight ratio that it is characterized in that butyphthalide and phospholipid is 1: 0.3～10.0.

4, the pharmaceutical composition of treatment cerebrovascular disease according to claim 1 and 2 is characterized in that said butyphthalide is a levo butyl phthalide.

5, a kind of pharmaceutical preparation wherein comprises the butyphthalide liposome as claimed in claim 1 of effective dose, and excipient is or/and adjuvant.

6, a kind of pharmaceutical preparation wherein comprises the butyphthalide liposome as claimed in claim 1 and the water for injection of effective dose.