CN1235596C - Spray for treating asthma and its preparing method - Google Patents
Spray for treating asthma and its preparing method Download PDFInfo
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- CN1235596C CN1235596C CN 03112438 CN03112438A CN1235596C CN 1235596 C CN1235596 C CN 1235596C CN 03112438 CN03112438 CN 03112438 CN 03112438 A CN03112438 A CN 03112438A CN 1235596 C CN1235596 C CN 1235596C
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Abstract
The present invention belongs to the technical field medicine, which relates to a spraying agent containing low molecular heparin, phosphatide and hyaluronic acid and preparing technology thereof. The preparation can be sucked from nasal cavity or oral cavity through air pipe lung administration after atomized. The present invention has preferable therapeutic effect to pulmonary diseases, such as bronchial asthma, etc.
Description
Technical field:
The invention belongs to field of pharmaceutical technology, be a kind of be mainly used in pulmonary disease such as bronchial asthma contain Low molecular heparin, phospholipid, hyaluronic spray and preparation technology thereof.
Background technology:
Bronchial asthma (abbreviation asthma) is a kind of chronic inflammatory reaction that is brought out by anaphylactogen, virus, antibacterial, physical factor etc., shows as airway pressure obstacle and airway hyperreactivity.Airway inflammation is the topmost pathological change of asthma.The pathogenesis of asthma rate is up to 4%～10%, and sickness rate is on the rise in recent years.Treatment of asthma is mainly antiinflammatory and diastole trachea two aspects at present, the medicine that uses is glucocorticoid, beta 2 receptor agonist and theophylline class medicine, these medicines all have than significant side effects, and curative effect is not obvious sometimes, and the on-steroidal anti-asthmatic medicament that therefore developing the generation that can effectively control airway inflammation and Airway Remodeling does not have obvious systemic side effects again becomes the main direction of studying of present asthma control medicine.Preparation of the present invention is used for prevention and treatment asthma has better effects, and does not almost have side reaction to take place, and is a kind of comparatively ideal asthma preparation.
Low molecular heparin is a mucopolysaccharide class biochemical drug, has multiple biological activity and pharmacological action, except anticoagulant, thromboembolism preventing effect, also has antiinflammatory, antiallergic and immunosuppressive action.Asthma is actually a kind of allergic inflammation, Low molecular heparin can be by the effect of suppressor T cell, suppress neutrophilic granulocyte and the eosinophilic granulocyte infiltration to pulmonary, the number of ways such as early stage and late-onset asthma reaction that suppress allergen-induced act on asthma.Low molecular heparin is compared with unfraction heparin, and immunosuppressive action is strong, long half time, and safety is big, and hemorrhage side effect is little.Enter air flue after the Low molecular heparin atomizing sucks, directly act on trachea and pulmonary, instant effect, bioavailability height.Experiment shows that the Low molecular heparin atomizing sucks the effective percentage that can effectively improve the asthma conventional therapy, has better therapeutical effect to asthma.
Phospholipid is that (PS extensively is present in alveolar and airway surface to pulmonary surfactant, and the normal physiological function of keeping lung is played an important role for Pulmonary Surfactact, major function composition PS).Recent study shows that PS is its phospholipid composition particularly, has for inflammatory reaction normal and the damage lung and emphasizes to save function, and certain antiinflammatory action is arranged; Discover that for the asthmatic guinea pigs lung-douching fluid wherein protein content is higher by 350% than normal group, content of phospholipid does not have significant difference, and surface activity obviously descends, and shows surface activity and albumen/phospholipid ratio significant correlation.When pulmonary disease shows effect, suitably replenish phospholipid composition, can play a role to the recovery of pulmonary function.In addition, phospholipid is a kind of well behaved surfactant, enter trachea and lung after, help the mucous removing of respiratory tract, thereby help the treatment of pulmonary disease such as asthma.
Hyaluronic acid is high-molecular weight straight-chain polysaccharide, extensively is present in the various tissues of animal, and water and the property and the viscoelasticity of height arranged.Containing hyaluronic medicinal liquid has stronger tack, and medicine is played a role for a long time, possesses certain slow releasing function; To the airway surface Carboxymethyl Chitin, reduce patient pulmonary sense of discomfort; The hyaluronic acid pair cell has protective effect, and can resist cationic protein, and antiinflammatory action is arranged.Therefore, in this spray, add a certain amount of hyaluronic acid, can strengthen and prolong it the treatment of asthma effect.
Summary of the invention:
The objective of the invention is to develop curative effect better, easy to use contain Low molecular heparin, phospholipid, hyaluronic spray, suck pulmonary administration by nasal cavity or oral cavity through trachea by atomizings such as manual pump or ultrasound atomizer back, reach the purpose of preventing and treating pulmonary disease such as bronchial asthma.
Low molecular heparin refers to Low molecular heparin and its esters or other the pharmaceutically useful derivant of molecular weight between 3000～8000 among the present invention.Refer in particular to low molecular heparin calcium and low molecular sodium heparin.
Phospholipid refers to phosphatidylcholine (lecithin), PHOSPHATIDYL ETHANOLAMINE (cephalin) or its pharmaceutically useful derivant among the present invention.Refer in particular to phosphatidylcholine (lecithin).
Hyaluronic acid refers to that by the mean molecule quantity that glucuronic acid-N-n acetylglucosamine n is formed for disaccharidase unit be 10 among the present invention
5～10
7The straight chain polymer polysaccharide.
The main component of spray of the present invention is Low molecular heparin, phospholipid, hyaluronic acid, can also contain and anyly be used in the pulmonary administration preparation usually and in these preparations, be stable adjuvant, comprise antibiotic antiseptic, antioxidant, stabilizing agent, emulsifying agent, help absorbent, correctives, buffer agent and isotonic agent etc.
Can on the basis of this basic comprising, add other pharmacological components as required, as the effective ingredient of bronchodilators, anti-inflammatory drug, Claritin, immunoregulation medicament or other treatment pulmonary disease.Wherein bronchodilators comprises albuterol, terbutaline, and anti-inflammatory drug comprises how beclometasone, cloth ground get, and Claritin comprises sodium cromoglicate, ketotifen, and immunoregulation medicament comprises the Bacillus typhi lipopolysaccharide.
The prescription of spray involved in the present invention is: in 100 milliliters, contain Low molecular heparin 25000～1500000 anti-FXa units, phosphatidase 10 .1～10 grams, hyaluronic acid 0.01～0.5 gram, and contain antibiotic antiseptic ethyl hydroxybenzoate 0.03～0.15 gram or chlorobutanol 0.5 gram, antioxidant vitamin E 0.01～0.20 gram or sodium sulfite 0.1～0.5 gram, emulsifier tween-80 0.1～4.0 gram waits the phosphate buffer of pharmaceutic adjuvant and etoh solvent, propylene glycol and PH6～8.
The prescription of spray involved in the present invention is: in 100 milliliters, also contain antibiotic antiseptic ethyl hydroxybenzoate 0.03～0.10 gram or chlorobutanol 0.5 gram, antioxidant vitamin E 0.01～0.20 gram or sodium sulfite 0.1～0.5 gram, emulsifier tween-80 0.1～4.0 gram, the phosphate buffer of etoh solvent, propylene glycol and PH6～8.
Spray preparing process involved in the present invention is: in 100 milliliters, hyaluronic acid is dissolved in 30 ml waters; Get phospholipid and fat-soluble adjuvant is dissolved in the ethanol, add phosphate buffer and be diluted to about 50 milliliters, add hyaluronic acid solution, add Low molecular heparin and water soluble adjuvant, stirring and dissolving adds phosphate buffer to 100 milliliter promptly.
Spray preparing process involved in the present invention also can be: in 100 milliliters, hyaluronic acid is dissolved in 30 ml waters; Adopt reverse-phase evaporation and ultrasonic method that phospholipid is scattered in the phosphate buffer, add hyaluronic acid solution, add Low molecular heparin and adjuvant, stirring and dissolving adds phosphate buffer to 100 milliliter promptly.
The medication of spray involved in the present invention is: inhalation after the low concentration preparation can adopt instruments such as ultrasound atomizer with medical liquid atomizing; Inhalation after high concentrate formulation can adopt manual pump with medical liquid atomizing, as the Microhaler suction apparatus that adopts German Fei Fu company to produce.
The specific embodiment:
To further illustrate the present invention in following implementation column, these embodiment only are used to the present invention is described and to the present invention without limits.
Embodiment 1
To prepare 100 milliliters of sprays: hyaluronic acid 0.1 gram is dissolved in 30 ml waters standby; Phosphatidase 10 .2 gram, ethyl hydroxybenzoate 0.03 gram, vitamin E 0.05 gram is dissolved in 5 milliliters of ethanol, adds tween 80 0.3 gram, adds 50 milliliters of phosphate buffers, after merging with hyaluronic acid solution, stirs evenly, and adds low molecular heparin calcium 2.5 * 10
4Anti-FXa unit, stirring and dissolving adds phosphate buffer to 100 milliliter.
Embodiment 2
To prepare 100 milliliters of sprays: hyaluronic acid 0.05 gram is dissolved in 30 ml waters standby; Phosphatidase 10 .5 gram, ethyl hydroxybenzoate 0.03 gram, vitamin E 0.05 gram is dissolved in 10 milliliters of ethanol, adds tween 80 0.8 gram, adds 60 milliliters of phosphate buffers, after merging with hyaluronic acid solution, stirs evenly, and adds low molecular heparin calcium 5 * 10
5Anti-FXa unit, stirring and dissolving adds phosphate buffer to 100 milliliter.
Embodiment 3
To prepare 100 milliliters of sprays: hyaluronic acid 0.05 gram is dissolved in 30 ml waters standby; Phosphatidase 10 .5 gram is dissolved in 2 milliliters of ether, adds 5 milliliters of phosphate buffers, and rotary evaporation is removed ether, adds 60 milliliters of phosphate buffers, and solution is merged with hyaluronic acid solution after supersound process, stirs evenly, and adds low molecular heparin calcium 5 * 10
5Anti-FXa unit, ethyl hydroxybenzoate 0.03 gram, sodium sulfite 0.2 gram, stirring and dissolving adds phosphate buffer to 100 milliliter.
Embodiment 4
Test the preparation with preparation: hyaluronic acid 1.0 grams are dissolved in 300 ml waters standby; Phosphatidase 12 .0 gram, ethyl hydroxybenzoate 0.3 gram, vitamin E 0.5 gram is dissolved in 50 milliliters of ethanol, adds tween 80 3.0 grams, adds 500 milliliters of phosphate buffers, after merging with hyaluronic acid solution, stirs evenly, and adds low molecular heparin calcium 2.5 * 10
5Anti-FXa unit, stirring and dissolving adds phosphate buffer to 1000 milliliter, behind 0.45 μ m filtering with microporous membrane promptly.
Case is selected and grouping: through the asthma attack phase of clinical definite patient's 48 examples, and male 25 examples, women 23 examples at 16～69 years old age, are divided into treatment group (27) and matched group (21 example) at random.The treatment group gives 20 milliliters of ultrasonic atomizatios of liquid preparation of the present invention and sucks except that conventional therapy, and 1 time on the one, 7 is a course of treatment; The matched group conventional therapy.
Observation of curative effect: measuring lung function index before and after the treatment is 1s FEC (FEV
1) and 1s FEC/expiration vital capacity (FEV
1/ FVC); Curative effect judging standard is breathed the standard that sick association of system asthma group is formulated according to Chinese Medical Association.
Result of the test: two groups of patients all have clear improvement in treatment back pulmonary function, but the improvement of treatment group obviously is better than matched group; And the effective percentage of treatment group is apparently higher than matched group (P＜0.01), and wherein clinic control rate treatment group is 41%, and matched group is 10%.
Table 1 liang group patients clinical curative effect
| Group | The example number | Clinic control | Produce effects | Take a turn for the better | Invalid | Effective percentage (%) |
| The treatment group | 27 | 11 | 16 | 0 | 0 | 100 |
| Matched group | 21 | 2 | 13 | 3 | 3 | 71 |
Lung function parameter variation before and after the table 2 liang group patient (x ± s)
| Group | Time | FEV 1(L) | FEV 1/FVC(％) |
| Treatment group (n=27) | After treating before the treatment | 1.39±0.53 2.50±0.58 | 53.05±11.16 79.32±9.15 |
| Matched group (n=21) | After treating before the treatment | 1.41±0.62 1.78±0.53 | 54.91±11.47 66.98±9.01 |
Claims (5)
1. the spray of the treatment asthma of a pulmonary administration, it is characterized in that basic comprising is in 100 milliliters, contain Low molecular heparin 25000～1500000 anti-FXa units, phosphatidase 10 .1～10 grams, hyaluronic acid 0.01～0.5 gram, described Low molecular heparin is meant heparin or its esters of molecular weight between 3000～8000, described phospholipid is meant phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, and described hyaluronic acid is meant that the mean molecule quantity of being made up of for disaccharidase unit glucuronic acid-N-n acetylglucosamine n is 10
5～10
7The straight chain polymer polysaccharide.
2. spray according to claim 1, described Low molecular heparin is meant low molecular heparin calcium or low molecular sodium heparin.
3. spray according to claim 1, described phospholipid is meant phosphatidylcholine.
4. spray according to claim 1 is characterized in that also containing one or more and is selected from following pharmacological component: bronchodilators, anti-inflammatory drug, Claritin, immunoregulation medicament.
5. spray according to claim 1, it is characterized in that in 100 milliliters, also contain antibiotic antiseptic ethyl hydroxybenzoate 0.03～0.10 gram or chlorobutanol 0.5 gram, antioxidant vitamin E 0.01～0.20 gram or sodium sulfite 0.1～0.5 gram, emulsifier tween-80 0.1～4.0 gram, the phosphate buffer of etoh solvent, propylene glycol and PH6～8.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03112438 CN1235596C (en) | 2003-06-24 | 2003-06-24 | Spray for treating asthma and its preparing method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03112438 CN1235596C (en) | 2003-06-24 | 2003-06-24 | Spray for treating asthma and its preparing method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1471923A CN1471923A (en) | 2004-02-04 |
| CN1235596C true CN1235596C (en) | 2006-01-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 03112438 Expired - Fee Related CN1235596C (en) | 2003-06-24 | 2003-06-24 | Spray for treating asthma and its preparing method |
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100400097C (en) * | 2005-08-22 | 2008-07-09 | 上海医药工业研究院 | Insulin liquid formulations for nose administration |
| CN101361980B (en) * | 2007-08-07 | 2011-07-20 | 山东省生物药物研究院 | Heparin phospholipid composite suitable for non-injection administration and preparation method thereof |
| CN101433521B (en) * | 2007-11-14 | 2012-08-08 | 中国医学科学院药用植物研究所 | Medicinal inhalable particles, pulmonary inhalation using the same and preparation method thereof |
| CN101897719B (en) * | 2010-08-04 | 2012-01-25 | 中国人民解放军第三军医大学 | Medical composite used for treating smoke inhalation lung injury |
| CN105456236A (en) * | 2015-10-29 | 2016-04-06 | 刘春丽 | Preparation method of improved cinnamyl aldehyde solution for cough provocation test |
| CN105920020B (en) * | 2016-06-23 | 2019-01-08 | 潘海英 | A kind of pharmaceutical composition and its preparation method and application for treating pulmonary disease |
| CN109260181A (en) * | 2017-07-17 | 2019-01-25 | 北京盈科瑞创新药物研究有限公司 | Heparin nebulization sucking pharmaceutical solutions and preparation method thereof |
| CN109464396A (en) * | 2018-12-27 | 2019-03-15 | 沈阳亿欣源生物科技有限公司 | A kind of spray containing heparan composition |
| CN113679085B (en) * | 2021-08-20 | 2023-06-02 | 山东沛学生物工程有限公司 | Electronic atomization tobacco juice and preparation method thereof |
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- 2003-06-24 CN CN 03112438 patent/CN1235596C/en not_active Expired - Fee Related
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