CN100441187C

CN100441187C - Liposome vitamin A acid aerosol for treating chronic obstructive pulmonary disease

Info

Publication number: CN100441187C
Application number: CNB2006100950781A
Authority: CN
Inventors: 熊玮; 杨和平; 戴晓天
Original assignee: First Affiliated Hospital of TMMU
Current assignee: Third Military Medical University TMMU; First Affiliated Hospital of TMMU
Priority date: 2006-08-30
Filing date: 2006-08-30
Publication date: 2008-12-10
Anticipated expiration: 2026-08-30
Also published as: CN1927207A

Abstract

The invention relates to a bangosome retinoic acid aerosol which can prevent chronic obstructive pulmonary. The ingredients of the aerosol include: retinoic acid bangosome, cefepime or ceftazidime, fluormone or cetacort and distilled water. The mentioned retinoic acid bangosome is made of the following materials: 1-2 share (by weight) retinoic acid, 10-15 shares (by weight) cholesterol, 10-15 shares (by weight) lecithin and 0.01-0.2 VE. The producing procedures go as follows: mix 2-3 shares (by weight) retinoic acid bangosome with 0.1-0.2 cefepime or ceftazidime, 0.0005-0.0025 fluormone or 0.01-0.05 cetacort; add distilled water to the ingredients at the ratio of 1:15-1:20; fill the material into clean jars to get the aerosol.

Description

A kind of liposome vitamin A acid aerosol that is used for the treatment of chronic obstructive pulmonary disease

Technical field

The invention belongs to the respiratory disorder medicine, the particularly application of retinoic acid in preparation chronic obstructive respiratory disorder medicine.

Background technology

Chronic obstructive pulmonary disease (chronic obstructive pulmonary diseases, COPD) be the disease that a class is a feature with the incomplete reversibility flow limitation of air flue, its sickness rate is high and be and increase trend year by year, and at present, COPD has been global the fifth-largest disease.The pathological changes of COPD mainly shows as: because the repetitious stimulation of various paathogenic factors, cause airway epithelia cell cilium to stick together, lodge and take off mistake, epithelial degeneration, necrosis and hypertrophy, change life take place then, finally cause the mucociliary motor system impaired.

Normal person's respiratory tract has perfect defense function, and air flue mucociliary motor system is in core status, and wherein ciliated columnar epithelial cells is main cell component.Ciliated columnar epithelial cells is as the terminal cell in the cell cycle, and self can not breed reparation after damage; And the myxocyte of airway epithelia and basal cell, can partly enter cell cycle and breed, are divided into new ciliated columnar epithelial cells in the reparation after damage as the precursor of ciliated columnar epithelial cells.The air flue precursor is regulated by multiple factor to the atomization of ciliated columnar epithelial cells, therefore, promote the air flue precursor to break up by artificial foeign element to ciliated columnar epithelial cells, thereby repair air flue mucociliary motor system, reach generation and the development of blocking-up COPD, might become a kind of effective measures of early treatment COPD.

At present, smoking is to cause COPD that one of major reason of development takes place, so consider from etiology, smoking cessation is considered to slow down the effective measures of COPD progress, but for the COPD patient of having taken place, Drug therapy still is used for prevention and controlling symptoms, and purpose is to reduce the frequency and the order of severity of acute generation, and expectation can improve patient moving endurance and quality of life.Drug therapy mainly contains following several at present:

1, theophylline class medicine: as aminophylline, diprophylline, the not only expansible bronchus of this type of medicine, and can improve respiratory muscle intensity, and increase cardiac output, reduce pulmonary vascular resistance; Certain antiinflammatory, diuresis are arranged.But to old people and persistent fever, cardiac insufficiency, when the bad person of liver function uses theophylline class medicine, cause danger easily.

2, β ₂Receptor agonist such as salbutamol and terbutaline, β ₂Receptor mainly is distributed in stingy road and sucks or take β ₂Behind-the receptor agonist, little air flue can obviously be expanded, thereby alleviates or relief of symptoms, but β ₂The side effect of receptor agonist distends the blood vessels when being expansion bronchus, causes that pulmonary ventilation/blood flow is out of proportion; Excessive application can cause hand tremor, cardiopalmus etc.

3, anticholinergic agents such as atropine, 654-2, this type of medicine works by the parasympathetic nervous in the antagonism bronchus.Though the bronchus spasmolysis effect is arranged, side effect such as xerostomia, thick sputum are difficult for bringing up, cardiopalmus is arranged because of it so clinical use is limited.

4, hormone such as prednisone still do not have the COPD patient who improves or tend to worsen for the capacity bronchodilator treatment state of an illness, and adding may be effectively with hormone therapy.But hormone causes water sodium storage and stays harmful effects such as bad, osteoporosis, and Most scholars thinks, the life-time service hormone only has 20% ~ 30% COPD conditions of patients to improve, and takes a large amount of hormones with mitigate the disease so the old people is only limited to short-term.

5, the antibiotic kind is many, should select for use according to patient's drug sensitive test result.But because of how outbreak repeatedly of COPD patient, the superinfection that causes because of the prevention abuse of antibiotics and some antibiotic liver, kidney, ototoxicity make its application limited.

6, protease inhibitor and antioxidant such as α ₁Antitrypsin, N-acetyl cysteine, protease can decompose the connective tissue composition in the matter, destroys lung tissue structure and causes emphysema.COPD patient exists oxidation antioxidation unbalance.But can cause that the high secretion of sputum increases the weight of dyspnea.

(retinoic acid RA) has different physiological roles to retinoic acid, and it is encouraging that RA has the effect that promotes cell differentiation most.By biochip technology, from people's airway epithelia cell of former generation, clone the inductive specific gene-spurt of RA, the formation and the function thereof of prompting RA and airway tissue have dependency.Have research to think, RA can suppress the airway epithelia cell injury of elastoser mediation; Also there is research to think that RA can suppress the squamous cell differentiation simultaneously by its specific receptor RAR stimulated mucus ciliated cell differentiation.

Along with going deep into of research, people realize the generation that retinoic acid participates in inflammatory cell gradually, and airway inflammation and various skin disease are all had therapeutical effect as psoriasis, glue sample baby, intractable verruca plana, acne, oral lichen planus, cutaneous T cell lymphoma, associating metronidazole treatment trichocryptosis, fulminant rosacea, lymphomatoid papulosis, general continuous acrodermatitis of property of treatment, keratosis palmaris etc.

Summary of the invention

The purpose of this invention is to provide a kind of liposome vitamin A acid aerosol formulations that is used for the treatment of the chronic obstructive respiratory disorder.

This liposome vitamin A acid aerosol formulations is made up of retinoic acid liposome, cefepime or ceftazidime, dexamethasone or hydrocortisone and distilled water.Described retinoic acid liposome adopts the raw material of following ratio of weight and number: retinoic acid 1～2, cholesterol 10～15, lecithin 10～15, vitamin E 0.01～0.2, be dissolved in the ethanol earlier, slowly inject the PBS buffer under the constant temperature stirring, by filtering with microporous membrane, obtain the retinoic acid liposome after the last lyophilization again.By ratio of weight and the number of copies 2～3 retinoic acid liposome is mixed with cefepime or ceftazidime 0.1～0.2, dexamethasone 0.0005～0.0025 or hydrocortisone 0.01～0.05, with mixture 1: 5 by ratio of weight and the number of copies～1: 20 ratio adding distilled water mixing again, divide in the clean aerosol jar of packing into to obtain aerosol formulations.

Wherein, the aperture of microporous filter membrane is 0.1 μ m, and the PH of PBS buffer is 7.2 ~ 7.4.

One, clinical result of use:

Select through having Patients with Chronic Obstructive Pulmonary Disease 23 examples that Therapeutic Method is failed to respond to any medical treatment repeatedly now, carry out clinical scale according to severity extent, comprise slight, moderate and severe patient, adopt the liposome vitamin A acid nebulization therapy respectively, using for 2 weeks is 1 course of treatment, the result shows, treat back 18 patients and reach normally, other 2 routine patients obtain taking a turn for the better, and cure rate is 18/23, effective percentage is 20/23, the treatment back stable curative effect length of holding time.

Influence to blood plasma inflammatory factor Endothelin (ET), tumor necrosis factor (TNF-a) detects.It plays an important role in the disease with tissue ischemia, anoxia and vascular endothelial injury for ET and TNF-a, and cardio-pulmonary function is had inhibitory action.This result of study shows that COPD patient's plasma ET obviously raises than the normal person, and is consistent with bibliographical information.Two groups of patient's blood plasma ET, TNF-a all descend after treatment, and the treatment group significantly is lower than matched group, the results are shown in following table, illustrates that this aerosol can effectively reduce COPD patient's blood plasma ET, TNF-a level.

23 patient's blood plasma ET, TNF-a change before and after the liposome vitamin A acid nebulae inhalation

Two, to the toxicity test of cultured cell:

The aerosol formulations sample is done 2 times of serial dilutions with cell culture fluid since 1: 10 concentration, and mtt assay calculates the cell proliferation index.The results are shown in following table, illustrate that this disinfectant solution on cell proliferation does not make significant difference.

The retinoic acid liposome is to the propagation influence of Hep-2 cell

Three, medicine stability test:

Liposome vitamin A acid aerosol room temperature high speed centrifugation (3000-20000rpm/10-30min) does not have precipitation and lamination and takes place, 45 ℃ incubate bathe 1h or 4 ℃ of cold preservation 1h after, with above-mentioned similarity condition high speed centrifugation, electricity there is no precipitation and layering appearance.

The retinoic acid liposome aerosols of the present invention's preparation is a kind of complex, has good absorption function, can effectively reach the trachea part, the liposome packing can make retinoic acid effectively see through the micropore barrier, effectively absorbed in the part, other organs are not caused damage, finally reach the result that drug effect increases, stability increases.Therefore liposome vitamin A acid aerosol can increase the concentration that medicine arrives local tracheal greatly, prolongs retinoic acid in the action time of trachea, helps the performance of drug effect, has reduced the generation of retinoic acid side effect.Generally speaking, have advantages such as good stability, drug effect is long, evident in efficacy, preparation is convenient, low or have no side effect.

Vitamin A acid aerosol of the present invention can also produce multiple therapeutic effect with multiple components compatibility, as antibiotic, hormone, vaccine etc., thereby uses different concentration to reach different therapeutic purposes.

The specific embodiment

Retinoic acid and cefepime, dexamethasone compatibility are made aerosol, have the active and glucocorticoid receptor (GR) specificity of high local anti-inflammatory is arranged, suck the back and remarkable antiinflammatory action is arranged in pulmonary, but sb.'s illness took a turn for the worse for mitigation symptoms and prevention, and most patients state of an illness in 1～2 week is alleviated to some extent among the embodiment 1-6.But also can add other compositions, reach the purpose of effective treatment.

The foregoing description, all be earlier with retinoic acid, cholesterol, lecithin, vitamin E is dissolved in the 200ml ethanol, PH was 7.2～7.4 PBS buffer under slowly injection constant temperature stirred, further by containing the microporous filter membrane that the aperture is 0.1 μ m, with the sealing of sample inflated with nitrogen, obtain the retinoic acid liposome after the lyophilization.Again the retinoic acid liposome is mixed with cefepime or ceftazidime, dexamethasone or hydrocortisone, mix with distilled water again, divide in the clean aerosol jar of packing into promptly to obtain its aerosol formulations.

Claims

1, a kind of liposome vitamin A acid aerosol that is used for the treatment of chronic obstructive pulmonary disease is characterized in that: be made up of retinoic acid liposome, cefepime or ceftazidime, dexamethasone or hydrocortisone and distilled water; Described retinoic acid liposome adopts the feedstock production of following ratio of weight and number: retinoic acid 1～2, cholesterol 10～15, lecithin 10～15, vitamin E 0.01～0.2, above-mentioned raw materials is dissolved in ethanol earlier, slowly inject the PBS buffer under the constant temperature stirring, by filtering with microporous membrane, last lyophilization obtains the retinoic acid liposome again; By ratio of weight and the number of copies 2～3 retinoic acid liposome is mixed with cefepime or ceftazidime 0.1～0.2, dexamethasone 0.0005～0.0025 or hydrocortisone 0.01～0.05, with mixture 1: 5 by ratio of weight and the number of copies～1: 20 ratio adding distilled water mixing again, divide in the clean aerosol jar of packing into to obtain aerosol formulations.

2, liposome vitamin A acid aerosol according to claim 1 is characterized in that: the aperture of microporous filter membrane is 0.1 μ m.

3, liposome vitamin A acid aerosol according to claim 1 is characterized in that: the PH of PBS buffer is 7.2-7.4.