CN111714567A - Levo-salbutamol hydrochloride solution for inhalation and preparation method thereof - Google Patents
Levo-salbutamol hydrochloride solution for inhalation and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a levalbuterol hydrochloride solution for inhalation and a preparation method thereof. The invention provides a levalbuterol hydrochloride solution for inhalation, which comprises the following components in parts by weight per 100mL of water for injection: 10-60 mg of levalbuterol hydrochloride, 0.5-20 mg of safflower extract, 4.0-60 mg of active auxiliary agent and 10-25 mg of surfactant. The levalbuterol hydrochloride solution for inhalation provided by the invention can be absorbed by lung, has strong targeting effect, higher concentration locally and small dosage, can be better used for preventing and treating bronchial asthma, asthmatic bronchitis and bronchospasm of emphysema patients, and has the advantages of high safety, no preservative, stable quality and no side effect.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a levalbuterol hydrochloride solution for inhalation and a preparation method thereof.
Background
Bronchial asthma is the most common chronic disease of the respiratory tract in the world today. Nearly 3 million people worldwide are reported to suffer from bronchial asthma, and the number is increasing. At present, asthma becomes a killer which can harm human health seriously, causes wide attention of various countries in the world, and is listed as a chronic disease seriously harming human health by the ministry of health of China.
In recent years, with the deepening understanding of pathogenesis of bronchial asthma, the medicine treatment and research of asthma have made important progress. The medicines for treating asthma at present mainly comprise four types of beta 2-adrenoreceptor agonists, glucocorticoids, choline receptor antagonists and leukotriene antagonists, wherein the beta 2-adrenoreceptor agonists are the anti-asthma medicines which are most widely applied clinically and account for about 60 percent of the market share of the anti-asthma medicines.
The novel chiral drug levosalbutamol (Albuterol) is an adrenergic beta receptor agonist, has the chemical name of (R) -4- [2- (tert-butylamino) -1-hydroxyethyl ] -2- (hydroxymethyl) phenol, is a long-acting beta 2-adrenoreceptor agonist, has long lasting action time, can generate bronchodilatory action for at least 6 hours, has quick response, can take effect after 1-5 minutes of aerosol inhalation, and is used for preventing and treating bronchial asthma, asthmatic bronchitis and bronchospasm of emphysema patients. Can bind with beta receptor on human respiratory smooth muscle, increase intracellular cyclic adenosine monophosphate (cAMP) concentration, and cAMP further activates protein kinase A to phosphorylate myosin, reduce intracellular calcium ion concentration, and relax bronchial smooth muscle. Increased cAMP concentrations also inhibit the release of mast cell inflammatory mediators. Salbutamol is racemic body, wherein only levorotatory body has the function of relaxing bronchial smooth muscle, and dextrorotatory body has no function, but can combine with beta receptor to generate side effects of headache, dizziness, palpitation, finger trembling and the like. The levo-salbutamol is the (R) isomer which has specific action on treating asthma and is obtained after unnecessary (S) isomer is removed from the salbutamol racemate, the drug effect of the levo-salbutamol is 80 times of that of dextro-salbutamol, the absorption rate in vivo is higher than that of dextro-salbutamol, so the side effect is reduced, and the curative effect is further improved. The levosalbutamol can produce the same curative effect only by the dosage of the racemate 1/4, and the effect is better than that of the racemate when the dosage is 1/2. In Chronic Obstructive Pulmonary Disease (COPD), levalbuterol has a weaker pro-inflammatory response than salbutamol.
The solution for inhalation is a new administration form which is developed clinically in recent years, and is sprayed into the oral cavity of a patient through an air pump driving device such as a proper medical compression atomizer to form medicine mist, and medicine components in the mist are adhered to respiratory epithelium and further permeate into cells to play a medicine role. The aerosol inhalation administration can ensure that the medicine directly enters the air passage, has high inhalation rate, higher local concentration and small dosage, can be well tolerated by patients in the treatment process, can achieve the purposes of safe, targeted, quick-acting and efficient treatment, and is popular with clinicians and patients. In recent years, studies on the safety and effectiveness of levosalbutamol in clinical therapy have been reported. The levosalbutamol dosage forms which are on the market at home and abroad at present comprise oral solution, tablets, capsules, sustained-release capsules, injection, freeze-dried powder for injection and the like, and the administration methods of the dosage forms are oral administration or injection administration. The injection and oral dosage form has the advantages of systemic effect, great adverse reaction, low utilization rate, and even certain pain and inconvenience for patients.
Therefore, the levo-salbutamol inhalation solution with good stability is provided, the inhalant can be absorbed through the lung, has strong targeting effect and high safety, is safe and stable without adding preservatives, has no side effect, can effectively avoid the first pass effect caused by the liver when in oral administration, is more effective and direct than an oral preparation, takes effect more quickly and has high bioavailability.
Disclosure of Invention
In order to solve the problems in the prior art, the invention aims to provide a levalbuterol hydrochloride solution for inhalation and a preparation method thereof. The levalbuterol hydrochloride solution for inhalation provided by the invention can be absorbed by lung, has strong targeting effect, higher concentration locally and small dosage, can be better used for preventing and treating bronchial asthma, asthmatic bronchitis and bronchospasm of emphysema patients, and has the advantages of high safety, no preservative, stable quality and no side effect.
The technical scheme of the invention is as follows:
a levalbuterol hydrochloride solution for inhalation, per 100mL of water for injection, comprises the following components by weight: 10-60 mg of levalbuterol hydrochloride, 0.5-20 mg of safflower extract, 4.0-60 mg of active auxiliary agent and 10-25 mg of surfactant.
Further, the levosalbutamol hydrochloride solution for inhalation is prepared from the following components in parts by weight per 100mL of water for injection: levosalbutamol hydrochloride 40mg, safflower extract 10mg, active auxiliary agent 30mg and surface active agent 15 mg.
Furthermore, the levosalbutamol hydrochloride and the safflower extract are composed according to the weight ratio of 4: 1.
Further, the active auxiliary agent is chitosan oligosaccharide and tea polyphenol in a weight ratio of (3-8): 1.
Further, the active auxiliary agent is chitosan oligosaccharide and tea polyphenol in a weight ratio of 5: 1.
Still further, the chitosan oligosaccharide in the coagent has an average molecular weight of 1000Da or 3000 Da.
Further, the surfactant is one of lecithin, span 80 or polysorbate 60.
In addition, the invention also provides a preparation method of the levalbuterol hydrochloride solution for inhalation, which is characterized by comprising the following steps:
s1, weighing 20-60% of injection water, heating to 45-60 ℃, adding levalbuterol hydrochloride, a safflower extract, an active assistant and a surfactant, stirring for dissolving, and supplementing the injection water to 100mL to obtain a mixed solution;
s2, filtering the mixed solution obtained in the step S1 by a sterilization grade filter membrane, and filling and sealing the mixed solution and sterilizing the mixed solution in a 5mL or 10mL specification under the protection of nitrogen to obtain the product.
Furthermore, a sterilization process at 130 ℃ for 10min is adopted in the step S2.
Further, in step S2, the filter membrane is a polyvinylidene fluoride membrane, and the filter membrane has a pore size of 0.22 μm.
The prepared levo-salbutamol hydrochloride solution for inhalation is added with a safflower extract, wherein the safflower is also named as yellow orchid, red orchid, grass safflower, compositae safflower, contains carthamin and safflower yellow. The fat oil is called safflower oil, and is oil and fat such as palmitic acid, stearic acid, arachidic acid, linoleic acid, linolenic acid, oleic acid, etc. The traditional Chinese medicine uses the drug property of safflower to treat various diseases from a very early time. The inventor of the application unexpectedly discovers that the combination of the levalbuterol and the safflower extract according to a certain proportion not only can be better used for preventing and treating bronchial asthma, bronchial spasm of patients with asthmatic bronchitis and emphysema, but also has good regulating function on the immune function of a human body due to the synergistic effect of the two components, can inhibit the generation of allergic substances by an organism, regulate the activity of immune cells and improve the damage of allergic reaction to the lung, so that the composition can be used for improving the acute attack of the bronchial asthma.
The prepared levosalbutamol hydrochloride solution for inhalation is also added with an active auxiliary agent consisting of chitosan oligosaccharide and tea polyphenol. Wherein, the chitosan oligosaccharide can obviously eliminate oxygen anion free radicals of human bodies, activate body cells, delay senility, inhibit harmful bacteria breeding on the surface of skin, prevent wounds from being infected by bacteria, permeate air and moisture, promote wound healing, and has the characteristics of no toxicity and complete absorption by organisms. Tea polyphenols have strong antioxidant and free radical scavenging effects, and can inhibit lipoxygenase and lipid peroxidation in skin mitochondria, thereby having antiaging effect. The two ingredients have synergistic effect, can strongly inhibit histamine release, inhibit anaphylaxis reaction caused by active factors such as antibody, epinephrine, enzyme, etc., and has remarkable curative effect on allergic diseases such as asthma, etc. Meanwhile, the prepared levosalbutamol hydrochloride solution for inhalation is more stable and can be stored for a long time.
Compared with the prior art, the levalbuterol hydrochloride solution for inhalation provided by the invention has the following advantages:
(1) the levosalbutamol hydrochloride solution for inhalation provided by the invention creatively adopts the combined medication of the levosalbutamol hydrochloride and the safflower extract, has obvious synergistic effect on treating the bronchospasm of patients with bronchial asthma, asthmatic bronchitis and emphysema, can effectively improve the treatment effect when the levosalbutamol is singly used, has quicker effect and high bioavailability.
(2) The levalbuterol hydrochloride solution for inhalation provided by the invention is safe and stable without adding a preservative, has no side effect, can effectively avoid the first-pass effect caused by the liver during oral administration, is more effective and direct than an oral preparation, and has simple preparation process and easy operation.
Detailed Description
The present invention is further illustrated by the following description of specific embodiments, which are not intended to limit the invention, and various modifications and improvements can be made by those skilled in the art based on the basic idea of the invention, but the invention is within the protection scope of the invention.
L-salbutamol hydrochloride, CAS:50293-90-8, available from Beierka Biotech, Guangzhou; safflower extract, available from shanxi scanty biotechnology ltd; chitosan oligosaccharide, CAS:148411-57-8, available from Sendzi Biotech, Inc., Shenzhen; tea polyphenols, CAS:27073-41-2, available from Nanjing Ponno Biotech, Inc. The other reagents used in the invention are common reagents and can be purchased from conventional reagent production and sale companies.
EXAMPLE 1L-salbutamol hydrochloride solution for inhalation
The levo-salbutamol hydrochloride solution for inhalation is prepared from the following components in parts by weight per 100mL of water for injection: levosalbutamol hydrochloride 10mg, safflower extract 0.5mg, active auxiliary agent 4.0mg and lecithin 10 mg.
The active auxiliary agent is chitosan oligosaccharide and tea polyphenol according to a weight ratio of 3: 1.
The chitosan oligosaccharide in the active aid has an average molecular weight of 1000 Da.
The preparation method of the levalbuterol hydrochloride solution for inhalation comprises the following steps:
s1, weighing 20% of injection water, heating to 45 ℃, adding levalbuterol hydrochloride, a safflower extract, an active assistant and lecithin, stirring for dissolving, and supplementing the injection water to 100mL to obtain a mixed solution;
s2, filtering the mixed solution obtained in the step S1 by a sterilization grade filter membrane, and filling and sealing the mixed solution and sterilizing the mixed solution in a 5mL specification under the protection of nitrogen to obtain the product.
In the step S2, a sterilization process at 130 ℃ for 10min is adopted.
In the step S2, the filter membrane is a polyvinylidene fluoride membrane, and the filter membrane pore size is 0.22 μm. Example 2A levalbuterol hydrochloride solution for inhalation
The levo-salbutamol hydrochloride solution for inhalation is prepared from the following components in parts by weight per 100mL of water for injection: 40mg of levosalbutamol hydrochloride, 10mg of safflower extract, 30mg of active auxiliary agent and 6015 mg of polysorbate.
The active auxiliary agent is chitosan oligosaccharide and tea polyphenol according to a weight ratio of 5: 1.
The chitosan oligosaccharide in the active additive has an average molecular weight of 3000 Da.
The preparation method of the levalbuterol hydrochloride solution for inhalation comprises the following steps:
s1, weighing injection water with the preparation amount of 40%, heating to 55 ℃, adding levalbuterol hydrochloride, a safflower extract, an active assistant and polysorbate 60, stirring for dissolving, and supplementing the injection water to 100mL to obtain a mixed solution;
s2, filtering the mixed solution obtained in the step S1 by a sterilization grade filter membrane, and filling and sealing the mixed solution and sterilizing the mixed solution in a 5mL specification under the protection of nitrogen to obtain the product.
In the step S2, a sterilization process at 130 ℃ for 10min is adopted.
In the step S2, the filter membrane is a polyvinylidene fluoride membrane, and the filter membrane pore size is 0.22 μm. Example 3A levalbuterol hydrochloride solution for inhalation
The levo-salbutamol hydrochloride solution for inhalation is prepared from the following components in parts by weight per 100mL of water for injection: 60mg of levosalbutamol hydrochloride, 20mg of safflower extract, 60mg of active auxiliary agent and 8025 mg of span.
The active auxiliary agent is chitosan oligosaccharide and tea polyphenol according to a weight ratio of 8: 1.
The chitosan oligosaccharide in the active aid has an average molecular weight of 1000 Da.
The preparation method of the levalbuterol hydrochloride solution for inhalation comprises the following steps:
s1, weighing 60% of injection water, heating to 60 ℃, adding levalbuterol hydrochloride, a safflower extract, an active assistant and span 80, stirring and dissolving, and then supplementing the injection water to 100mL to obtain a mixed solution;
s2, filtering the mixed solution obtained in the step S1 by a sterilization grade filter membrane, and filling and sealing each mixed solution with the specification of 10mL under the protection of nitrogen to sterilize, thus obtaining the compound preparation.
In the step S2, a sterilization process at 130 ℃ for 10min is adopted.
In the step S2, the filter membrane is a polyvinylidene fluoride membrane, and the filter membrane pore size is 0.22 μm. Comparative example 1 levosalbutamol hydrochloride solution for inhalation
The levo-salbutamol hydrochloride solution for inhalation is prepared from the following components in parts by weight per 100mL of water for injection: 40mg of levosalbutamol hydrochloride, 30mg of active auxiliary agent and 6015 mg of polysorbate.
The active auxiliary agent is chitosan oligosaccharide and tea polyphenol according to a weight ratio of 5: 1.
The chitosan oligosaccharide in the active additive has an average molecular weight of 3000 Da.
The preparation method of the levosalbutamol hydrochloride solution for inhalation is similar to that of example 2.
The difference from the example 2 is that the L-salbutamol hydrochloride solution for inhalation is not added with safflower extract.
Comparative example 2 an inhaled levosalbutamol hydrochloride solution
The levo-salbutamol hydrochloride solution for inhalation is prepared from the following components in parts by weight per 100mL of water for injection: l-salbutamol hydrochloride 40mg, safflower extract 10mg, chitosan oligosaccharide 30mg and polysorbate 6015 mg.
The average molecular weight of the chitosan oligosaccharide is 3000 Da.
The preparation method of the levosalbutamol hydrochloride solution for inhalation is similar to that of example 2.
The difference from example 2 is that no tea polyphenols were added to the coagent.
Comparative example 3 an inhaled levosalbutamol hydrochloride solution
The levo-salbutamol hydrochloride solution for inhalation is prepared from the following components in parts by weight per 100mL of water for injection: 40mg of levosalbutamol hydrochloride, 10mg of safflower extract, 30mg of active auxiliary agent and 6015 mg of polysorbate.
The active auxiliary agent is chitosan oligosaccharide and tea polyphenol according to the weight ratio of 1: 1.
The chitosan oligosaccharide in the active additive has an average molecular weight of 3000 Da.
The preparation method of the levosalbutamol hydrochloride solution for inhalation is similar to that of example 2.
The difference from the example 2 is that the active auxiliary agent is chitosan oligosaccharide and tea polyphenol according to the weight ratio of 1: 1.
Test example I and curative effect verification test
1. Test materials: levosalbutamol hydrochloride solutions for inhalation prepared in examples 1-3, comparative examples 1-3.
2. The test method comprises the following steps: 70 guinea pigs that were eligible for the primary screening were randomly divided into 7 groups, which were saline control group, example 1 group, example 2 group, example 3 group, comparative example 1 group, comparative example 2 group, comparative example 3 group, and 10 animals per group. Each group of guinea pigs was placed in a 4L closed glass bottle, and subjected to central oxygen supply, spray inhalation therapy at 5L/rain flow for 180s for 4 consecutive days, after administration of 0.5h (day 1), 1h (day 2), 2h (day 3), and 3h (day 4), the guinea pigs were placed in a 4L solvent closed glass bottle, and spray inhalation of 0.8% histamine phosphate solution at 5L/rain flow for 10s for asthma induction, and the incubation period of the guinea pigs suffering from III-degree asthma (tic tumble) was recorded.
3. Test results
The test results are shown in table 1.
TABLE 1 asthma inducing latency test
As can be seen from table 1, the asthma-inducing latency of guinea pigs using the levosalbutamol hydrochloride solutions for inhalation prepared in examples 1 to 3 reached 135s or more at 30min after administration and 168s or more at 3h after administration, and among them, the effect of example 2 was the best and is the best example of the present invention. The inhalation levalbuterol hydrochloride solution prepared in the comparative example 1 is not added with the safflower extract, the time of the asthma-inducing latency of the guinea pig is obviously reduced compared with the time of the group of the example 2, and the asthma-inducing latency is only 128.5 +/-6.1 s after 3h, which shows that the synergistic effect of the safflower extract and the levalbuterol hydrochloride added in the inhalation levalbuterol hydrochloride solution prepared in the invention is obvious, the asthma-inducing latency of the guinea pig can be effectively prolonged, and the effect is obvious, continuous and stable.
Test example two, quality test of an aerosolized inhalation solution of levalbuterol solution
1. Test materials: levosalbutamol hydrochloride solutions for inhalation prepared in examples 1-3, comparative examples 1-3.
2. The test method comprises the following steps: the levosalbutamol hydrochloride solution for inhalation prepared in examples 1 to 3 and comparative examples 1 to 3 is placed in a constant temperature and humidity box with the temperature of 40 +/-2 ℃ and the humidity of RH 75% +/-5%, and samples are respectively taken at the end of 0 month, 3 months and 6 months, and the characters, pH, content and related substances are detected.
3. Test results
The test results are shown in table 2.
TABLE 2 accelerated test data for inhalation levalbuterol hydrochloride solutions
Table 2 the results show: in comparative examples 2 and 3, when the components and the ratio of the active auxiliary agent added in the invention are changed, the prepared levo-salbutamol hydrochloride solution for inhalation becomes turbid at the bottom, the content is obviously reduced, and related impurities are increased after the levo-salbutamol hydrochloride solution for inhalation is placed in a constant temperature and humidity cabinet with the temperature of 40 +/-2 ℃ and the humidity of RH 75% +/-5% for 6 months. The stability of the solution of the levosalbutamol hydrochloride for inhalation prepared by the embodiment of the invention in long-term storage is also obviously superior to that of the comparative example, the solution is not easy to be polluted or oxidized and deteriorated, and the solution can be stored for a long time.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (10)
1. The levosalbutamol hydrochloride solution for inhalation is characterized by comprising the following components in parts by weight per 100mL of water for injection: 10-60 mg of levalbuterol hydrochloride, 0.5-20 mg of safflower extract, 4.0-60 mg of active auxiliary agent and 10-25 mg of surfactant.
2. Levosalbutamol hydrochloride solution for inhalation according to claim 1, consisting of the following components in weight per 100mL of water for injection: levosalbutamol hydrochloride 40mg, safflower extract 10mg, active auxiliary agent 30mg and surface active agent 15 mg.
3. Levosalbutamol hydrochloride solution for inhalation according to claim 1 or 2, characterized in that the levosalbutamol hydrochloride and the safflower extract are composed in a weight ratio of 4: 1.
4. Levosalbutamol hydrochloride solution for inhalation according to claim 1 or 2, wherein the active auxiliary is chitosan oligosaccharide and tea polyphenol in a weight ratio of (3-8): 1.
5. Levosalbutamol hydrochloride solution for inhalation according to claim 1 or 2, characterized in that the co-agent is chitosan oligosaccharide and tea polyphenol in a weight ratio of 5: 1.
6. Levosalbutamol hydrochloride solution for inhalation according to claim 5, characterized in that the chitosan oligosaccharide in the co-agent has an average molecular weight of 1000Da or 3000 Da.
7. Levosalbutamol hydrochloride solution for inhalation according to claim 1 or 2, characterised in that the surfactant is one of lecithin, span 80 or polysorbate 60.
8. A process for the preparation of a solution of levalbuterol hydrochloride for inhalation according to any one of claims 1 to 7, comprising the steps of:
s1, weighing 20-60% of injection water, heating to 45-60 ℃, adding levalbuterol hydrochloride, a safflower extract, an active assistant and a surfactant, stirring for dissolving, and supplementing the injection water to 100mL to obtain a mixed solution;
s2, filtering the mixed solution obtained in the step S1 by a sterilization grade filter membrane, and filling and sealing the mixed solution and sterilizing the mixed solution in a 5mL or 10mL specification under the protection of nitrogen to obtain the product.
9. The method for preparing a levalbuterol hydrochloride solution for inhalation according to claim 8, wherein sterilization at 130 ℃ for 10min is employed in step S2.
10. The method for preparing a levalbuterol hydrochloride solution for inhalation according to claim 8, wherein in step S2, said filter membrane is a polyvinylidene fluoride membrane, and the pore size of said filter membrane is 0.22 μm.
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| CN110755413A (en) * | 2019-11-04 | 2020-02-07 | 扬子江药业集团上海海尼药业有限公司 | Ambroxol hydrochloride solution for inhalation and preparation method thereof |
| CN110898039A (en) * | 2018-09-18 | 2020-03-24 | 北京盈科瑞创新药物研究有限公司 | L-salbutamol hydrochloride solution preparation for inhalation and preparation method thereof |
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| CN110898039A (en) * | 2018-09-18 | 2020-03-24 | 北京盈科瑞创新药物研究有限公司 | L-salbutamol hydrochloride solution preparation for inhalation and preparation method thereof |
| CN110755413A (en) * | 2019-11-04 | 2020-02-07 | 扬子江药业集团上海海尼药业有限公司 | Ambroxol hydrochloride solution for inhalation and preparation method thereof |
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