CN111700883B - Salbutamol sulfate sustained-release inhalation preparation and production process thereof - Google Patents
Salbutamol sulfate sustained-release inhalation preparation and production process thereof Download PDFInfo
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Abstract
The invention belongs to the field of medicines, and particularly relates to a salbutamol sulfate sustained-release inhalation preparation and a production process thereof. The invention provides a salbutamol sulfate sustained-release inhalation preparation which comprises the following components in parts by weight: 120-140 parts of salbutamol sulfate complex liquid, 88-105 parts of liposome, 1-2 parts of emulsifier and 0.5-1.2 parts of stabilizer. The salbutamol sulfate sustained-release inhalation preparation provided by the invention can relieve acute asthma attack and has a good sustained-release effect. In addition, the salbutamol sulfate sustained-release inhalation preparation provided by the invention also has good storage stability and spraying stability.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a salbutamol sulfate sustained-release inhalation preparation and a production process thereof.
Background
With the rapid development of economy, the development of industry is particularly remarkable, and various diseases brought by the following environmental pollution problem are more and more concerned. Wherein, the small particles of PM2.5, PM10 and the like enter respiratory tract through human respiration, and the incidence rate of respiratory diseases is also obviously increased. At present, rapid treatment of the respiratory system and even treatment of the respiratory system can be adopted for the treatmentThe study of respiratory and pulmonary diseases has also become of particular importance. The traditional treatment modes of the diseases are oral administration and injection and external application, but the medicine has the defects of long drug effect exerting time, poor patient compliance and the like, and the inhalation administration gradually enters the visual field of people. The lung inhalation drug delivery is that the granular drug is delivered to the lung by a special drug delivery device and enters a human body in a non-invasive way, and can effectively realize targeted lung drug delivery, systemic drug delivery and macromolecular drug delivery. 3-4 hundred million alveoli in the lung, and the respiratory tract area is up to 70-140m2The area of the active ingredient is small, the thickness of alveolar epithelial cell walls or capillary walls is only 0.5-1 mu m, the distance of the drug passing through exchange is short, the membrane permeability is high, the absorption speed is high, and the drug easily penetrates through alveoli, so that the active ingredient is quickly transferred; the pulmonary alveolar capillary network under the mucosa is rich, the drug concentration can form gradient distribution, and the drug can effectively enter the blood circulation in sections. The lung provides a good environment for drug absorption due to the large absorption area and the small transmembrane spacing. The use of inhalation has been the main development for the treatment of pulmonary diseases.
Asthma is a chronic inflammatory disease of an airway involving various cells and cell components, can cause symptoms such as wheezing, shortness of breath, chest distress, cough and the like, is easy to attack or aggravate in the early morning and at night, is related to airway hyperreactivity, is often subjected to wide and variable reversible airflow limitation, and can be relieved by self or through treatment by most patients. Currently, about 3 hundred million people suffer from asthma worldwide, with one tenth of those in china and up to 4% per year. The proportion of people suffering from asthma and the risk degree of asthma are enough to attract high attention of experts at home and abroad, and the therapeutic effect of the inhalation administration mode for treating asthma is extremely good. The effective drugs for treating asthma in the market mainly comprise three types, namely budesonide, fluticasone propionate, salbutamol sulfate and the like, wherein the salbutamol sulfate is a beta 2-adrenoreceptor agonist, and the adenosine cyclase is activated, the adenosine cyclophosphate is promoted to increase, so that the smooth muscle of the bronchus is relaxed, the spasm of the smooth muscle of the bronchus is relieved, and the salbutamol sulfate is the first-choice drug for quickly treating the bronchial asthma, asthmatic bronchitis and emphysema at present. Most of the products of the salbutamol sulfate sold in the market are tablets and injection, and the salbutamol sulfate sustained-release type inhalation preparation is less, so that the salbutamol sulfate inhalation preparation which can relieve the acute attack of asthma and has good sustained-release effect is developed at present.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a salbutamol sulfate sustained-release inhalation preparation and a production process thereof. The salbutamol sulfate sustained-release inhalation preparation provided by the invention can relieve acute asthma attack and has a good sustained-release effect. In addition, the salbutamol sulfate sustained-release inhalation preparation provided by the invention also has good storage stability and spraying stability.
The technical scheme of the invention is as follows:
a salbutamol sulfate sustained-release inhalation preparation comprises the following components in parts by weight:
120-140 parts of salbutamol sulfate complex liquid, 88-105 parts of liposome, 1-2 parts of emulsifier and 0.5-1.2 parts of stabilizer.
Further, the salbutamol sulfate sustained-release inhalation preparation comprises the following components in parts by mass:
130 parts of salbutamol sulfate complex liquid, 95 parts of liposome, 1.6 parts of emulsifier and 0.9 part of stabilizer.
Further, the salbutamol sulfate composite liquid comprises the following components in parts by weight:
20-25 parts of salbutamol sulfate, 1-2 parts of polyethylene glycol, 0.2-0.5 part of polyvinylpyrrolidone, 1-3 parts of chitosan oligosaccharide and 680 parts of water 620-.
Further, the salbutamol sulfate composite liquid comprises the following components in parts by weight:
22 parts of salbutamol sulfate, 1.4 parts of polyethylene glycol, 0.3 part of polyvinylpyrrolidone, 2 parts of chitosan oligosaccharide and 660 parts of water.
Further, the preparation method of the salbutamol sulfate composite liquid comprises the following steps:
(1) mixing salbutamol sulfate, polyethylene glycol and polyvinylpyrrolidone, adding water which is 12-16 times of the total mass of the salbutamol sulfate, the polyethylene glycol and the polyvinylpyrrolidone, and stirring until the mixture is completely dissolved to obtain a material A;
(2) taking chitosan oligosaccharide, adding the residual amount of water into the chitosan oligosaccharide, stirring at the speed of 400-;
(3) adding the material B obtained in the step (2) into the material A obtained in the step (1), stirring at the speed of 400-600r/min for 20-30min, and standing to remove bubbles to obtain the material.
Further, the liposome consists of lecithin, glyceryl behenate and cholesterol in a mass ratio of 10-13:4-7: 1-2.
Further, the liposome consists of lecithin, glyceryl behenate and cholesterol in a mass ratio of 12:5: 1.
Further, the emulsifier is two or more of sucrose fatty acid ester, sodium stearyl lactate, alkyl polyglycoside and sorbitan oleate.
Further, the stabilizing agent consists of oleic acid and galactomannan according to the mass ratio of 8-12: 1-3.
Further, the stabilizer consists of oleic acid and galactomannan in a mass ratio of 10: 3.
Further, the production process of the salbutamol sulfate sustained-release inhalation preparation comprises the following steps:
s1 adding water into the emulsifier to obtain 0.3-0.8% emulsifier water solution;
s2 adding water into the stabilizer to prepare a stabilizer aqueous solution with the concentration of 3-5%;
s3, adding trichloromethane into the liposome, wherein the addition amount of the trichloromethane is 130 times of the liposome by mass, and stirring to dissolve the liposome to obtain a liposome solution;
s4, mixing the liposome solution obtained in the step S3 with salbutamol sulfate complex liquid, performing ultrasonic treatment for 1-3min, performing reduced pressure rotary evaporation at 40 ℃ to remove trichloromethane, adding the emulsifier aqueous solution obtained in the step S1, and soaking for 4-8h to obtain a mixed solution;
s5, homogenizing the mixed solution obtained in the step S4, wherein the homogenizing pressure is 80-150MPa, the homogenizing time is 20-30S, and homogenizing twice to obtain a homogenized solution; and (5) adding the stabilizer aqueous solution obtained in the step (S2) into the homogenized solution, homogenizing at the homogenizing pressure of 80-150MPa for 20-30S, and homogenizing twice to obtain the stabilizer.
The invention prepares the salbutamol sulfate compound liquid from salbutamol sulfate, polyethylene glycol, polyvinylpyrrolidone, chitosan oligosaccharide and the like, can ensure the slow release of the salbutamol sulfate, ensures the long time effect, and can ensure that the medicine is deposited in the lung to the maximum extent and prolongs the release of the medicine in the lung.
The stabilizing agent consisting of oleic acid and galactomannan according to a certain mass ratio is added in the invention, so that the dispersibility, uniformity and stability of the prepared salbutamol sulfate sustained-release inhalation preparation can be obviously improved, and the occurrence of agglomeration phenomenon is reduced, thereby ensuring that the particle size of the obtained product is maintained at a lower level, and in addition, the heat-resistant stability of the product can be improved, and the storage stability and the spraying stability of the product can be improved.
The salbutamol sulfate sustained-release inhalation preparation prepared by the invention can release salbutamol sulfate from the salbutamol sulfate composite liquid to the liposome and then from the liposome to the lung tissue, and the dual sustained-release effect better prolongs the drug release time, thereby enhancing the effect of the drug on the lung.
Compared with the prior art, the invention has the following advantages:
(1) the salbutamol sulfate sustained-release inhalation preparation provided by the invention can relieve acute asthma attack and has a good sustained-release effect.
(2) The salbutamol sulfate sustained-release inhalation preparation provided by the invention also has good storage stability and spraying stability.
(3) The salbutamol sulfate sustained-release inhalation preparation provided by the invention has the advantages of high encapsulation efficiency, small particle size, small polydispersity index, large absolute value of Zeta potential and the like, which shows that the prepared salbutamol sulfate sustained-release inhalation preparation has uniform particle size distribution.
Detailed Description
The present invention is further described in the following description of the specific embodiments, which is not intended to limit the invention, but various modifications and improvements can be made by those skilled in the art according to the basic idea of the invention, within the scope of the invention, as long as they do not depart from the basic idea of the invention.
Lecithin in the present invention is available from tekang biotechnology limited, henna, cat #: 12547, respectively; sucrose fatty acid ester is available from Jiangsu Ribine bioengineering, Inc., cat #: 0984; galactomannans are available from shanxi tang biotechnology limited, cat #: 1235, and; alkyl polyglycosides are available from macro speciality chemical (guangzhou) ltd, model number: APG2000, cat # stock: 126.
example 1A Salbutamol sulfate sustained Release inhalation preparation
The salbutamol sulfate sustained-release inhalation preparation comprises the following components in parts by weight: 120 parts of salbutamol sulfate complex liquid, 88 parts of liposome, 1 part of emulsifier and 0.5 part of stabilizer; the liposome consists of lecithin, glyceryl behenate and cholesterol in a mass ratio of 10:7: 2; the emulsifier is composed of sucrose fatty acid ester and sodium stearoyl lactate according to the mass ratio of 4: 1; the stabilizer consists of oleic acid and galactomannan according to a mass ratio of 8: 3.
The salbutamol sulfate composite liquid comprises the following components in parts by weight: 20 parts of salbutamol sulfate, 1 part of polyethylene glycol with the molecular weight of 400, 0.2 part of polyvinylpyrrolidone with the molecular weight of 58000, 1 part of chitosan oligosaccharide with the molecular weight of 1000 and 620 parts of water.
The preparation method of the salbutamol sulfate composite liquid comprises the following steps:
(1) mixing salbutamol sulfate, polyethylene glycol and polyvinylpyrrolidone, adding water with the total mass of 12 times of the salbutamol sulfate, the polyethylene glycol and the polyvinylpyrrolidone, and stirring until the mixture is completely dissolved to obtain a material A;
(2) taking chitosan oligosaccharide, adding the residual amount of water into the chitosan oligosaccharide, stirring at the speed of 400r/min for 20min, standing for 3h, and defoaming to obtain a material B;
(3) adding the material B obtained in the step (2) into the material A obtained in the step (1), stirring at the speed of 400r/min for 20min, and standing to remove bubbles to obtain the material.
The production process of the salbutamol sulfate sustained-release inhalation preparation comprises the following steps:
s1 adding water into the emulsifier to prepare emulsifier water solution with the concentration of 0.3%;
s2 adding water into the stabilizer to prepare a stabilizer aqueous solution with the concentration of 3%;
s3 adding trichloromethane into the liposome, wherein the addition amount of the trichloromethane is 110 times of the mass of the liposome, and stirring to dissolve the liposome to obtain a liposome solution;
s4, mixing the liposome solution obtained in the step S3 with salbutamol sulfate complex solution, performing ultrasonic treatment for 1min, performing rotary evaporation at 40 ℃ under reduced pressure to remove trichloromethane, adding the emulsifier aqueous solution obtained in the step S1, and soaking for 4h to obtain a mixed solution;
s5, homogenizing the mixed solution obtained in the step S4 twice under the homogenizing pressure of 80MPa for 20S to obtain a homogenized solution; and (5) adding the stabilizer aqueous solution obtained in the step (S2) into the homogenized solution, homogenizing at the homogenizing pressure of 80MPa for 20S, and homogenizing twice to obtain the stabilizer.
Example 2A Salbutamol sulfate sustained Release inhalation formulation
The salbutamol sulfate sustained-release inhalation preparation comprises the following components in parts by weight: 140 parts of salbutamol sulfate composite liquid, 105 parts of liposome, 2 parts of emulsifier and 1.2 parts of stabilizer; the liposome consists of lecithin, glyceryl behenate and cholesterol in a mass ratio of 13:4: 1; the emulsifier consists of alkyl polyglycoside and sorbitan oleate according to the mass ratio of 3: 2; the stabilizer consists of oleic acid and galactomannan according to the mass ratio of 12: 1.
The salbutamol sulfate composite liquid comprises the following components in parts by weight: 25 parts of salbutamol sulfate, 2 parts of polyethylene glycol with the molecular weight of 400, 0.5 part of polyvinylpyrrolidone with the molecular weight of 58000, 3 parts of chitosan oligosaccharide with the molecular weight of 1000 and 680 parts of water.
The preparation method of the salbutamol sulfate composite liquid comprises the following steps:
(1) mixing salbutamol sulfate, polyethylene glycol and polyvinylpyrrolidone, adding water with the mass 16 times of the total mass of the salbutamol sulfate, the polyethylene glycol and the polyvinylpyrrolidone, and stirring until the mixture is completely dissolved to obtain a material A;
(2) taking chitosan oligosaccharide, adding the residual amount of water into the chitosan oligosaccharide, stirring at the speed of 600r/min for 30min, standing for 5h, and defoaming to obtain a material B;
(3) and (3) adding the material B obtained in the step (2) into the material A obtained in the step (1), stirring at the speed of 600r/min for 30min, and standing to remove bubbles to obtain the material.
The production process of the salbutamol sulfate sustained-release inhalation preparation comprises the following steps:
s1 adding water into the emulsifier to prepare emulsifier water solution with the concentration of 0.8%;
s2 adding water into the stabilizer to prepare a stabilizer aqueous solution with the concentration of 5%;
s3 adding trichloromethane into the liposome, wherein the addition amount of the trichloromethane is 130 times of the mass of the liposome, and stirring to dissolve the liposome to obtain a liposome solution;
s4, mixing the liposome solution obtained in the step S3 with salbutamol sulfate complex solution, performing ultrasonic treatment for 3min, performing rotary evaporation at 40 ℃ under reduced pressure to remove trichloromethane, adding the emulsifier aqueous solution obtained in the step S1, and soaking for 8h to obtain a mixed solution;
s5, homogenizing the mixed solution obtained in the step S4 twice under the homogenizing pressure of 150MPa and the homogenizing time of 30S to obtain a homogenized solution; and (4) adding the stabilizer aqueous solution obtained in the step (S2) into the homogenized solution, homogenizing at the homogenizing pressure of 150MPa for 30S, and homogenizing twice to obtain the stabilizer.
Example 3A Salbutamol sulfate sustained Release inhalation formulation
The salbutamol sulfate sustained-release inhalation preparation comprises the following components in parts by weight: 130 parts of salbutamol sulfate complex liquid, 95 parts of liposome, 1.6 parts of emulsifier and 0.9 part of stabilizer; the liposome consists of lecithin, glyceryl behenate and cholesterol in a mass ratio of 12:5: 1; the emulsifier is composed of sucrose fatty acid ester and alkyl polyglycoside according to the mass ratio of 2: 5; the stabilizer consists of oleic acid and galactomannan according to the mass ratio of 10: 3.
The salbutamol sulfate composite liquid comprises the following components in parts by weight: 22 parts of salbutamol sulfate, 1.4 parts of polyethylene glycol with the molecular weight of 400, 0.3 part of polyvinylpyrrolidone with the molecular weight of 58000, 2 parts of chitosan oligosaccharide with the molecular weight of 1000 and 660 parts of water.
The preparation method of the salbutamol sulfate composite liquid comprises the following steps:
(1) mixing salbutamol sulfate, polyethylene glycol and polyvinylpyrrolidone, adding water with the total mass of 14 times of the salbutamol sulfate, the polyethylene glycol and the polyvinylpyrrolidone, and stirring until the mixture is completely dissolved to obtain a material A;
(2) taking chitosan oligosaccharide, adding the residual amount of water into the chitosan oligosaccharide, stirring at the speed of 450r/min for 25min, standing for 4h, and defoaming to obtain a material B;
(3) and (3) adding the material B obtained in the step (2) into the material A obtained in the step (1), stirring at the speed of 450r/min for 25min, and standing to remove bubbles to obtain the material.
The production process of the salbutamol sulfate sustained-release inhalation preparation comprises the following steps:
s1 adding water into the emulsifier to prepare emulsifier water solution with the concentration of 0.5%;
s2 adding water into the stabilizer to prepare a stabilizer aqueous solution with the concentration of 4%;
s3 adding trichloromethane into the liposome, wherein the addition amount of the trichloromethane is 120 times of the mass of the liposome, and stirring to dissolve the liposome to obtain a liposome solution;
s4, mixing the liposome solution obtained in the step S3 with salbutamol sulfate complex solution, performing ultrasonic treatment for 2min, performing rotary evaporation at 40 ℃ under reduced pressure to remove trichloromethane, adding the emulsifier aqueous solution obtained in the step S1, and soaking for 6h to obtain a mixed solution;
s5, homogenizing the mixed solution obtained in the step S4 twice under the homogenizing pressure of 120MPa for 25S to obtain a homogenized solution; and (4) adding the stabilizer aqueous solution obtained in the step (S2) into the homogenized solution, homogenizing at the homogenizing pressure of 120MPa for 25S, and homogenizing twice to obtain the stabilizer.
Comparative example 1 Salbutamol sulfate sustained Release type inhalation preparation
The salbutamol sulfate sustained-release inhalation preparation comprises the following components in parts by weight: 130 parts of salbutamol sulfate complex liquid, 95 parts of liposome, 1.6 parts of emulsifier and 0.9 part of stabilizer; the liposome consists of lecithin, glyceryl behenate and cholesterol in a mass ratio of 12:5: 1; the emulsifier is composed of sucrose fatty acid ester and alkyl polyglycoside according to the mass ratio of 2: 5; the stabilizer consists of oleic acid and galactomannan according to the mass ratio of 1: 1.
The salbutamol sulfate composite liquid comprises the following components in parts by weight: 22 parts of salbutamol sulfate, 1.4 parts of polyethylene glycol with the molecular weight of 400, 0.3 part of polyvinylpyrrolidone with the molecular weight of 58000, 2 parts of chitosan oligosaccharide with the molecular weight of 1000 and 660 parts of water.
The production process of the salbutamol sulfate compound solution and the salbutamol sulfate sustained-release inhalation preparation is similar to that of the embodiment 3.
The difference from example 3 is that the stabilizer consists of oleic acid and galactomannan in a mass ratio of 1: 1.
Comparative example 2 a salbutamol sulfate sustained release inhalation formulation
The salbutamol sulfate sustained-release inhalation preparation comprises the following components in parts by weight: 130 parts of salbutamol sulfate complex liquid, 95 parts of liposome, 1.6 parts of emulsifier and 0.9 part of stabilizer; the liposome consists of lecithin, glyceryl behenate and cholesterol in a mass ratio of 12:5: 1; the emulsifier is composed of sucrose fatty acid ester and alkyl polyglycoside according to the mass ratio of 2: 5; the stabilizer is oleic acid.
The salbutamol sulfate composite liquid comprises the following components in parts by weight: 22 parts of salbutamol sulfate, 1.4 parts of polyethylene glycol with the molecular weight of 400, 0.3 part of polyvinylpyrrolidone with the molecular weight of 58000, 2 parts of chitosan oligosaccharide with the molecular weight of 1000 and 660 parts of water.
The production process of the salbutamol sulfate compound solution and the salbutamol sulfate sustained-release inhalation preparation is similar to that of the embodiment 3.
The difference from example 3 is that the stabilizer is oleic acid.
Comparative example 3 a salbutamol sulfate sustained release inhalation formulation
The salbutamol sulfate sustained-release inhalation preparation comprises the following components in parts by weight: 22 parts of salbutamol sulfate, 95 parts of liposome, 1.6 parts of emulsifier and 0.9 part of stabilizer; the liposome consists of lecithin, glyceryl behenate and cholesterol in a mass ratio of 12:5: 1; the emulsifier is composed of sucrose fatty acid ester and alkyl polyglycoside according to the mass ratio of 2: 5; the stabilizer consists of oleic acid and galactomannan according to the mass ratio of 10: 3.
The production process of the salbutamol sulfate sustained-release inhalation preparation comprises the following steps:
s1 adding water into the emulsifier to prepare emulsifier water solution with the concentration of 0.5%;
s2 adding water into the stabilizer to prepare a stabilizer aqueous solution with the concentration of 4%;
s3 adding trichloromethane into the liposome, wherein the addition amount of the trichloromethane is 120 times of the mass of the liposome, and stirring to dissolve the liposome to obtain a liposome solution;
s4, adding water into the salbutamol sulfate, wherein the adding amount of the water is 30 times of the mass of the salbutamol sulfate, and obtaining salbutamol sulfate water solution;
s5, mixing the liposome solution obtained in the step S3 with the salbutamol sulfate aqueous solution obtained in the step S4, performing ultrasonic treatment for 2min, performing reduced pressure rotary evaporation at 40 ℃ to remove chloroform, adding the emulsifier aqueous solution obtained in the step S1, and soaking for 6h to obtain a mixed solution;
s6, homogenizing the mixed solution obtained in the step S5 twice under the homogenizing pressure of 120MPa for 25S to obtain a homogenized solution; and (4) adding the stabilizer aqueous solution obtained in the step (S2) into the homogenized solution, homogenizing at the homogenizing pressure of 120MPa for 25S, and homogenizing twice to obtain the stabilizer.
Test example I, Performance test
1. Test materials: salbutamol sulfate sustained release formulations prepared in example 1, example 2, and example 3.
2. The test method comprises the following steps:
2.1 determination of encapsulation efficiency
(1) Preparing a salbutamol sulfate solution with the concentration of 900.0 mu g/mL, precisely measuring 2mL in a dialysis bag, putting the dialysis bag into 50mL of dialysate, oscillating at the constant temperature of 37 ℃ at the rotating speed of 50r/min for sampling at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h and 7h respectively, sucking 2mL of the solution each time, then supplementing 2mL of constant-temperature release medium, and fixing the volume to 10 mL. Filtering with 0.45 μm filter membrane, sampling the filtrate, measuring peak area A, and calculating the cumulative release curve of salbutamol sulfate from the standard curve. The amount of free drug was calculated as the time for the salbutamol sulphate to reach equilibrium inside and outside the dialysis bag.
(2) Determination of encapsulation efficiency: precisely measuring 2mL of salbutamol sulfate sustained-release inhalation preparation in a dialysis bag, putting the dialysis bag into 50mL of dialysate, oscillating at constant temperature of 37 ℃ at the rotating speed of 50r/min, taking the dialysate when the salbutamol sulfate inside and outside the dialysis bag obtained in the step (1) reaches the equilibrium time, carrying out sample injection measurement, recording a chromatogram, calculating the amount of free drugs, and calculating the encapsulation rate according to the following formula. The encapsulation efficiency (total drug amount in liposomes-free drug amount)/(total drug amount encapsulated and unencapsulated in liposomes) x 100%.
2.2, determination of particle size and polydispersity index: the particle size of the test material was measured using a Nano-ZS90 laser particle sizer, data was processed using dynamic light scattering software, and the average particle size and polydispersity index were recorded.
2.3, measurement of Zeta potential: the Zeta potential of the test material was measured using a Zeta potential analyzer.
3. And (3) test results: the test results are shown in table 1.
Table 1: performance test results of salbutamol sulfate sustained-release inhalation preparation
| Inspection item | Example 1 | Example 2 | Example 3 |
| Encapsulation efficiency/% | 72.34 | 78.69 | 86.12 |
| Particle size (nm) | 245.2 | 183.8 | 126.7 |
| Polydispersity index | 0.058 | 0.029 | 0.016 |
| Zeta potential (mV) | -12.1 | -16.1 | -18.2 |
As can be seen from table 1, the salbutamol sulfate sustained-release inhalation formulations prepared in examples 1, 2 and 3 of the present invention have the advantages of high encapsulation efficiency, small particle size, small polydispersity index, large absolute value of Zeta potential, etc., which indicates that the salbutamol sulfate sustained-release inhalation formulations prepared in the present invention have uniform particle size distribution, and the best overall performance in example 3, which is the best example of the present invention.
Test example two, stability test
1. Test materials: salbutamol sulfate sustained release formulations for inhalation prepared in example 3, comparative example 1, comparative example 2.
2. The test method comprises the following steps:
2.1 storage stability test
Three batches of salbutamol sulfate sustained-release inhalation formulations prepared in example 3, comparative example 1, and comparative example 2 were prepared in parallel, and the particle size, zeta potential, polydispersity index, and encapsulation efficiency of the test material were examined at 0 day. Then stored at 25 ℃ for 10 days and 20 days, respectively. After the storage period, the particle size, zeta potential, polydispersity index and encapsulation efficiency of the test material were determined.
2.2 spray stability test
Three batches of salbutamol sulfate sustained-release inhalation formulations prepared in example 3, comparative example 1, and comparative example 2 were prepared in parallel, and the particle size, zeta potential, polydispersity index, and encapsulation efficiency of the test material were examined at 0 day.
Taking 4mL of salbutamol sulfate sustained-release inhalation preparation in three batches prepared in parallel, atomizing the test material by adopting a Bairui atomizer to obtain aerosol, collecting the atomized material by using a multistage medicinal impactor (NGI), and detecting the particle size, zeta potential, polydispersity index and encapsulation efficiency of the material.
3. And (3) test results: the test results are shown in tables 2 and 3.
Table 2: influence of different storage time at 25 ℃ on various indexes of salbutamol sulfate sustained-release inhalation preparation
As can be seen from table 2, the particle size, polydispersity index, zeta potential, and encapsulation efficiency of the salbutamol sulfate sustained release inhalation formulation prepared in example 3 of the present invention were varied to some extent after storage for 10d and 20d at 25 ℃, however, the salbutamol sulfate sustained release inhalation formulation prepared in example 3 of the present invention was more stable at 25 ℃ than those of comparative examples 1-2.
Table 3: indexes of salbutamol sulfate sustained-release inhalation preparation before and after atomization
As can be seen from table 3, the indexes of the salbutamol sulfate sustained release inhalation formulation prepared in example 3 of the present invention before and after atomization, such as particle size, zeta potential, polydispersity index and encapsulation ratio, were not changed much, which indicates that only a small amount of free drug was released in advance during atomization and no agglomeration occurred. The salbutamol sulfate sustained-release inhalation preparation prepared in the comparative examples 1-2 has larger change degree of each index before and after atomization, so that the salbutamol sulfate sustained-release inhalation preparation has more excellent spray stability.
Test example three, anti-asthma test
1. Test materials: the salbutamol sulfate sustained release type inhalation formulations prepared in example 3 and comparative example 3.
2. Test subjects: common-grade albino guinea pigs weighing 250 g.
3. The test method comprises the following steps:
the guinea pig is sequentially placed into a 4L closed bell of a multifunctional cough inducing asthma apparatus, 0.6% histamine solution (prepared by normal saline) is atomized into the closed bell for 15s at an atomization speed of 0.15mL/min by an ultrasonic atomizer, the asthma inducing latency of the guinea pig is observed after the atomization is stopped, namely, the time from the beginning of the atomization to the occurrence of asthma symptoms, such as dyspnea, convulsion and falling of the guinea pig is shortened, the screened guinea pig is discarded after the latency exceeds 2min, the guinea pig can be freely eaten and drunk with water, and the animal to be tested is fasted one day before the experiment. The screened guinea pigs were weighed and then were anesthetized by intraperitoneal injection of urethane solution at 1.25g/kg, after the guinea pigs were completely anesthetized, the guinea pigs were fixed with their limbs and heads on their abdomen, the neck skin was incised, jugular vein intubation (rinsing with 0.1% heparin sodium solution) and tracheal intubation were performed, and muscles of the fourth and fifth ribs of the right chest of the guinea pigs were isolated and divided into the thoracic septal membrane.
Guinea pigs were randomly divided into 2 groups of 6 animals each, half male and female. After the operation of each guinea pig is carried out according to the steps, each guinea pig is placed into a physiological box to start recording and detecting the state of the guinea pig, and after the state of the guinea pig is stabilized for 20min, the following pharmacodynamic test procedure is carried out.
(1) Histamine stimulation prior to dosing: injecting 0.5mL of 15ug/mL histamine intravenously at a speed of 1mL/min, observing the physiological state of the animal, wherein the animal can generate symptoms of dyspnea, recording the parameters such as the reduction of tidal volume, the increase of intrathoracic pressure, the reduction of respiratory flow rate, the increase of respiratory frequency and other indexes, continuing to record each parameter after the intravenous stimulation is finished, and starting administration and stimulation after the animal state is stable.
(2) Histamine was given 4min after dosing: withdrawing the flow head connected to the wall of the tracing box, connecting the spray head of the compression atomizer with the tracheal cannula, atomizing and inhaling the salbutamol sulfate sustained-release inhalation preparation for 2min for the animal, withdrawing the administration device, reconnecting the flow head with the derived tracheal cannula, after the animal is stabilized for 4min, injecting 15ug/mL histamine by vein for 0.5mL, observing the change of parameters, waiting for the animal to be stabilized, and continuously recording the parameters.
(3) Histamine stimulation was given after 4 h: after 4h of administration, 0.5mL of histamine, 15ug/mL, was injected intravenously, the change in parameters was observed, and the parameters were recorded for 5min after the animal was in a stable state.
4. And (3) test results: the recorded data were used to calculate the rate of increase of airway resistance and the rate of decrease of dynamic lung compliance in guinea pigs under different conditions, and the test results are shown in table 4.
Table 4: indexes of salbutamol sulfate sustained-release inhalation preparation before and after administration
As can be seen from table 4, the increase rate of airway resistance still decreased significantly and the decrease rate of dynamic lung compliance still increased significantly after 4 hours of administration of the salbutamol sulfate sustained-release inhalation formulation prepared in example 3 of the present invention, compared to before administration, and thus it can be seen that the salbutamol sulfate sustained-release inhalation formulation of the present invention has an obvious asthma-relieving effect. Compared with the comparative example 3, the salbutamol sulfate sustained-release inhalation preparation has more remarkable asthma relieving effect.
Claims (1)
1. The salbutamol sulfate sustained-release inhalation preparation is characterized by comprising the following components in parts by mass: 130 parts of salbutamol sulfate complex liquid, 95 parts of liposome, 1.6 parts of emulsifier and 0.9 part of stabilizer; the liposome consists of lecithin, glyceryl behenate and cholesterol in a mass ratio of 12:5: 1; the emulsifier is composed of sucrose fatty acid ester and alkyl polyglycoside according to the mass ratio of 2: 5; the stabilizer consists of oleic acid and galactomannan according to the mass ratio of 10: 3;
the salbutamol sulfate composite liquid comprises the following components in parts by weight: 22 parts of salbutamol sulfate, 1.4 parts of polyethylene glycol with the molecular weight of 400, 0.3 part of polyvinylpyrrolidone with the molecular weight of 58000, 2 parts of chitosan oligosaccharide with the molecular weight of 1000 and 660 parts of water;
the preparation method of the salbutamol sulfate composite liquid comprises the following steps:
(1) mixing salbutamol sulfate, polyethylene glycol and polyvinylpyrrolidone, adding water with the total mass of 14 times of the salbutamol sulfate, the polyethylene glycol and the polyvinylpyrrolidone, and stirring until the mixture is completely dissolved to obtain a material A;
(2) taking chitosan oligosaccharide, adding the residual amount of water into the chitosan oligosaccharide, stirring at the speed of 450r/min for 25min, standing for 4h, and defoaming to obtain a material B;
(3) adding the material B obtained in the step (2) into the material A obtained in the step (1), stirring at the speed of 450r/min for 25min, standing to remove bubbles, and thus obtaining the material B;
the production process of the salbutamol sulfate sustained-release inhalation preparation comprises the following steps:
s1 adding water into the emulsifier to prepare emulsifier water solution with the concentration of 0.5%;
s2 adding water into the stabilizer to prepare a stabilizer aqueous solution with the concentration of 4%;
s3 adding trichloromethane into the liposome, wherein the addition amount of the trichloromethane is 120 times of the mass of the liposome, and stirring to dissolve the liposome to obtain a liposome solution;
s4, mixing the liposome solution obtained in the step S3 with salbutamol sulfate complex solution, performing ultrasonic treatment for 2min, performing rotary evaporation at 40 ℃ under reduced pressure to remove trichloromethane, adding the emulsifier aqueous solution obtained in the step S1, and soaking for 6h to obtain a mixed solution; s5, homogenizing the mixed solution obtained in the step S4 twice under the homogenizing pressure of 120MPa for 25S to obtain a homogenized solution; and (4) adding the stabilizer aqueous solution obtained in the step (S2) into the homogenized solution, homogenizing at the homogenizing pressure of 120MPa for 25S, and homogenizing twice to obtain the stabilizer.
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