CN111904954A - Salbutamol liposome inhalant for respiratory system diseases - Google Patents
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Abstract
The invention discloses a salbutamol lipidosome inhalant for respiratory diseases, which comprises the following components: the salbutamol sulfate liposome is prepared from the following raw materials in parts by weight: 5-6 parts of salbutamol sulfate, 10-20 parts of lecithin and 30-40 parts of cholesterol; the carrier comprises mannitol, lactose and leucine, wherein the weight part ratio of the mannitol to the lactose is 1:0.3-3, and the weight of the leucine accounts for 1% -5% of the total weight of the carrier. The preparation method comprises the following steps: (1) preparing salbutamol sulfate micro powder; (2) preparing salbutamol sulfate liposome; (3) preparing a carrier; (4) and (5) filling into capsules. Compared with the prior art, the invention has the following advantages: the deposition effect is better; the absorption rate of the drug salbutamol sulfate is high; the toxic and side effects are small; the compliance of patients is good, especially for patients needing long-term treatment; the safety is good.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a salbutamol liposome inhalant for treating respiratory diseases.
Background
Asthma, also known as bronchial asthma, is a chronic airway inflammation involving various cells and cell components, which is often accompanied by increased airway responsiveness, resulting in recurrent symptoms of wheezing, shortness of breath, chest tightness and/or cough, which often occur during the night and/or early morning hours, and which is often accompanied by a wide and variable airflow obstruction that can be reversed either by itself or by therapy. Cough Variant Asthma (CVA), also known as Cough-type asthma, is a special type of early bronchial asthma and one of the common causes of chronic Cough in children.
Research shows that 70% of bronchial asthma belongs to allergic asthma, CVA is considered to be a special type of bronchial asthma at present, the pathogenesis of the CVA is the same as that of the asthma, the CVA is characterized by airway chronic nonspecific inflammation and airway hyperresponsiveness, and the CVA is mainly changed into bronchial smooth muscle spasm, airway mucosal edema, inflammatory cell infiltration, eosinophilic granulocyte aggregation and bronchial mucosal epithelial injury, which cause epithelial cell shedding, airway surface damaged vagus nerve peripheral receptors are exposed, the sensitivity to various stimuli is increased, local small airway contraction is caused, cough reflex is directly caused, and therefore symptoms and signs of asthma are avoided, and intractable cough is usually caused clinically. Typical asthma symptoms can appear months or years later if not actively treated. Because CVA patients often have no wheezing symptom, dry cough is the main clinical manifestation, and is easily confused with acute and chronic bronchitis, pharyngeal-borne cough, mycoplasma pneumonia and cough caused by ACEI drugs clinically, so that misdiagnosis often occurs. If not carefully analyzed, the antibiotic dose is increased or other antibiotics are used for treatment, which delays the disease condition, increases economic burden, reduces life quality and may cause irreversible damage to lung function.
The drugs currently used for treating cough variant asthma are mainly beta 2 receptor agonists, such as salbutamol, chlorpropaline, clenbuterol and the like. Salbutamol (Sal) is a selective beta 2 receptor agonist, can selectively activate beta 2 receptor of bronchial smooth muscle, activate adenylate cyclase, increase intracellular cyclic adenosine monophosphate (cAMP) content, reduce free calcium ions, inhibit release of isolated tracheal allergic medium and asthma attack caused by histamine and acetylcholine, and inhibit eosinophilic granulocyte exudation in allergic asthma delayed reaction, thereby relaxing bronchial smooth muscle and relieving bronchospasm. The traditional Chinese medicine composition has the advantages of quick response, capability of quickly improving symptoms of patients, spasmolysis, asthma relief and phlegm elimination, and has the defect of lasting effect and only plays a role in relieving asthma symptoms of the patients; prolonged application can lead to down-regulation of the beta receptor, desensitization of the patient to beta agonists, and even drug resistance that is ineffective in asthma treatment, as well as other side effects, most commonly seen in a few cases as muscle tremor, peripheral vasodilation and accelerated compensatory heart rate, headache, restlessness, and allergic response. The existing preparation forms comprise tablets, controlled release tablets, inhalants and the like, the inhalants can more effectively prevent pathological damage of airways, and meanwhile, the administration mode leads the action of the medicine to be better than intravenous injection administration in the aspect of maintenance time and better than oral administration in the aspect of onset time. Salbutamol sulfate inhalant is a common medicine for controlling acute attack of asthma (wheeze) because of convenient carrying and quick response.
In summary, the salbutamol sulfate in the prior art exists in a non-inhalant form, and has a great limitation on the efficacy. And the few inhalant-form medicines have the problems of poor uniformity of delivered dose, insufficient atomization performance, low fine particle dose and poor suspension effect, are easy to have the problems of layering, nonuniform content, increased particle size and the like, and cannot meet the clinical application requirements.
Disclosure of Invention
In order to partially solve the technical problems, the invention provides a salbutamol liposome inhalant for respiratory diseases and a preparation method thereof, and the specific technical scheme is as follows: a liposomal salbutamol inhalation for respiratory diseases, said inhalation comprising the following components: the salbutamol sulfate liposome and a carrier, wherein the salbutamol sulfate liposome accounts for 10-30% of the total weight of the inhalant; the salbutamol sulfate liposome is prepared from the following raw materials in parts by weight: 0.5-0.6 part of salbutamol sulfate, 1-2 parts of lecithin and 3-4 parts of cholesterol; the carrier comprises mannitol, lactose and leucine, wherein the weight part ratio of the mannitol to the lactose is 1:0.3-3, and the weight of the leucine accounts for 1% -5% of the total weight of the carrier.
The lactose is 95 wt% D90 coarse powder with particle size of 60-90 μm and 5 wt% D90 fine powder with particle size of 5-15 μm.
A method for preparing salbutamol liposome inhalant for respiratory system diseases comprises the following steps: (1) preparing salbutamol sulfate micro powder: weighing salbutamol sulfate, drying the salbutamol sulfate in vacuum, carrying out jet milling on the dried salbutamol sulfate, and controlling the granularity to be below 10 mu m to obtain salbutamol sulfate micro powder; (2) preparing salbutamol sulfate liposome: weighing lecithin, cholesterol and the salbutamol sulfate micro powder obtained in the step (1), adding acetone, stirring to dissolve all the components, and uniformly mixing to obtain a clear and transparent solution; putting the obtained solution into a round-bottom flask, volatilizing the solvent by a rotary evaporator to form a layer of uniform film on the inner wall of the round-bottom flask, and adding a phosphate buffer solution with the pH value of 7.4 to hydrate to obtain a suspension; subjecting the obtained suspension to ultrasonic treatment for 30min under ice bath condition, filtering with 0.8 μm microporous membrane, spray drying, and pulverizing to particle size of 1 μm-5 μm to obtain salbutamol sulfate liposome; (3) preparation of the carrier: dissolving lactose in deionized water, heating to 70 deg.C, adding mannitol and leucine while stirring to obtain mixture, spray drying, and pulverizing to obtain carrier with particle size of 63-90 μm; (4) and (3) uniformly mixing the salbutamol sulfate liposome obtained in the step (2) and the carrier obtained in the step (3), and filling the mixture into capsules to obtain the salbutamol sulfate liposome.
The drying temperature in the step (1) is 70-80 ℃, and the drying time is not less than 12 hours.
The method for uniformly mixing in the step (4) is mechanical stirring mixing, and the stirring speed of the mechanical stirring mixing is 400-500 rpm.
The salbutamol liposome inhalant is packaged by a capsule for an inhaler.
The unit packaging amount of the salbutamol liposome inhalant is 10-50 mg.
Compared with the prior art, the invention has the following advantages:
1. leucine is a surfactant and has hydrophobic and hydrophilic groups, and can enrich the particle surface in the spray drying process and possibly generate a hydrophobic surface; the change in hydrophilicity of the carrier plays an important role in the hygroscopic process and reduces the hygroscopicity of DPI formulations; this results in particles with less cohesion and may result in a reduction in particle size due to the surfactant action of leucine, thereby reducing the droplet size produced during atomization and hence providing better deposition.
2. The liposome is a drug carrier consisting of lipid bilayers, has greater similarity and histocompatibility with biological tissues, and can improve the absorption rate of the drug salbutamol sulfate by forming the liposome;
3. compared with tablets, the salbutamol liposome inhalant prepared by the invention has the advantages of quick response, small single administration dosage and reduced toxic and side effects; the patient inhales the medicine powder, and the difficulty of medicine administration cooperation does not exist; the propellant Freon is not used, so that the pollution to the atmosphere and the stimulation to the respiratory tract can be avoided; the medicine can be administrated in a capsule or vesicle form, the dosage is accurate, and the risk of overdose administration is avoided; the compliance of patients is good, especially for patients needing long-term treatment; the medicine has the local effect, the administration dosage is obviously reduced, the toxic and side effects are small, and the safety is good.
Drawings
Figure 1 is a graph of the pulmonary deposition profile of the drug of the salbutamol sulphate liposomal inhaler of examples 1-8;
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The fine salbutamol sulfate powder used in the following examples was obtained by the following method: weighing 100g of salbutamol sulfate, drying under vacuum at 80 ℃ for 24 hours, carrying out jet milling on the dried salbutamol sulfate, and controlling the particle size to be below 10 mu m to obtain salbutamol sulfate micro powder.
Example 1:
a method for preparing salbutamol liposome inhalant for respiratory system diseases comprises the following steps:
(1) preparing salbutamol sulfate liposome: weighing 20g of lecithin, 30g of cholesterol and 5g of salbutamol sulfate micro powder obtained in the step (1), adding acetone, stirring to dissolve all the components, and uniformly mixing to obtain a clear and transparent solution; putting the obtained solution into a round-bottom flask, volatilizing the solvent by a rotary evaporator to form a layer of uniform film on the inner wall of the round-bottom flask, and adding a phosphate buffer solution with the pH value of 7.4 to hydrate to obtain a suspension; subjecting the obtained suspension to ultrasonic treatment for 30min under ice bath condition, filtering with 0.8 μm microporous membrane, spray drying, and pulverizing to particle size of 1 μm-5 μm to obtain salbutamol sulfate liposome;
(2) preparation of the carrier: dissolving 104.7g of lactose in deionized water, heating to 70 ℃, adding 349g of mannitol and 4.8g of leucine in the process of continuously stirring to obtain a mixture, spray-drying the mixture, and crushing to obtain a carrier with the particle size of 63-90 mu m;
(3) and (3) mechanically stirring and uniformly mixing the salbutamol sulfate liposome obtained in the step (2) and the carrier obtained in the step (3) at the stirring speed of 450rpm, and filling into capsules, wherein the unit administration dosage of each capsule is 10 mg.
Example 2:
a method for preparing salbutamol liposome inhalant for respiratory system diseases comprises the following steps:
(1) preparing salbutamol sulfate liposome: weighing 15g of lecithin, 35g of cholesterol and 5g of salbutamol sulfate micro powder obtained in the step (1), adding acetone, stirring to dissolve all the components, and uniformly mixing to obtain a clear and transparent solution; putting the obtained solution into a round-bottom flask, volatilizing the solvent by a rotary evaporator to form a layer of uniform film on the inner wall of the round-bottom flask, and adding a phosphate buffer solution with the pH value of 7.4 to hydrate to obtain a suspension; subjecting the obtained suspension to ultrasonic treatment for 30min under ice bath condition, filtering with 0.8 μm microporous membrane, spray drying, and pulverizing to particle size of 1 μm-5 μm to obtain salbutamol sulfate liposome;
(2) preparation of the carrier: dissolving 29.4g of lactose in deionized water, heating to 70 ℃, adding 98g of mannitol and 1.4g of leucine in the process of continuously stirring to obtain a mixture, spray-drying the mixture, and crushing to obtain a carrier with the particle size of 63-90 mu m;
(3) and (3) mechanically stirring and uniformly mixing the salbutamol sulfate liposome obtained in the step (2) and the carrier obtained in the step (3) at the stirring speed of 450rpm, and filling into capsules, wherein the unit administration dosage of each capsule is 10 mg.
Example 3:
a method for preparing salbutamol liposome inhalant for respiratory system diseases comprises the following steps:
(1) preparing salbutamol sulfate liposome: weighing 15g of lecithin, 35g of cholesterol and 5g of salbutamol sulfate micro powder obtained in the step (1), adding acetone, stirring to dissolve all the components, and uniformly mixing to obtain a clear and transparent solution; putting the obtained solution into a round-bottom flask, volatilizing the solvent by a rotary evaporator to form a layer of uniform film on the inner wall of the round-bottom flask, and adding a phosphate buffer solution with the pH value of 7.4 to hydrate to obtain a suspension; subjecting the obtained suspension to ultrasonic treatment for 30min under ice bath condition, filtering with 0.8 μm microporous membrane, spray drying, and pulverizing to particle size of 1 μm-5 μm to obtain salbutamol sulfate liposome;
(2) preparation of the carrier: dissolving 28.14g of lactose in deionized water, heating to 70 ℃, adding 93.8g of mannitol and 6.4g of leucine in the process of continuously stirring to obtain a mixture, spray-drying the mixture, and crushing to obtain a carrier with the particle size of 63-90 mu m;
(3) and (3) mechanically stirring and uniformly mixing the salbutamol sulfate liposome obtained in the step (2) and the carrier obtained in the step (3) at the stirring speed of 450rpm, and filling into capsules, wherein the unit administration dosage of each capsule is 10 mg.
Example 4:
a method for preparing salbutamol liposome inhalant for respiratory system diseases comprises the following steps:
(1) preparing salbutamol sulfate liposome: weighing 10g of lecithin, 39g of cholesterol and 6g of salbutamol sulfate micro powder obtained in the step (1), adding acetone, stirring to dissolve all the components, and uniformly mixing to obtain a clear and transparent solution; putting the obtained solution into a round-bottom flask, volatilizing the solvent by a rotary evaporator to form a layer of uniform film on the inner wall of the round-bottom flask, and adding a phosphate buffer solution with the pH value of 7.4 to hydrate to obtain a suspension; subjecting the obtained suspension to ultrasonic treatment for 30min under ice bath condition, filtering with 0.8 μm microporous membrane, spray drying, and pulverizing to particle size of 1 μm-5 μm to obtain salbutamol sulfate liposome;
(2) preparation of the carrier: dissolving 28.14g of lactose in deionized water, heating to 70 ℃, adding 93.8g of mannitol and 6.4g of leucine in the process of continuously stirring to obtain a mixture, spray-drying the mixture, and crushing to obtain a carrier with the particle size of 63-90 mu m;
(3) and (3) mechanically stirring and uniformly mixing the salbutamol sulfate liposome obtained in the step (2) and the carrier obtained in the step (3) at the stirring speed of 450rpm, and filling into capsules, wherein the unit administration dosage of each capsule is 10 mg.
Example 5:
a method for preparing salbutamol liposome inhalant for respiratory system diseases comprises the following steps:
(1) preparing salbutamol sulfate liposome: weighing 15g of lecithin, 35g of cholesterol and 5g of salbutamol sulfate micro powder obtained in the step (1), adding acetone, stirring to dissolve all the components, and uniformly mixing to obtain a clear and transparent solution; putting the obtained solution into a round-bottom flask, volatilizing the solvent by a rotary evaporator to form a layer of uniform film on the inner wall of the round-bottom flask, and adding a phosphate buffer solution with the pH value of 7.4 to hydrate to obtain a suspension; subjecting the obtained suspension to ultrasonic treatment for 30min under ice bath condition, filtering with 0.8 μm microporous membrane, spray drying, and pulverizing to particle size of 1 μm-5 μm to obtain salbutamol sulfate liposome;
(2) preparation of the carrier: dissolving 60.97g of lactose in deionized water, heating to 70 ℃, adding 60.97g of mannitol and 6.4g of leucine while stirring continuously to obtain a mixture, spray-drying the mixture, and crushing to obtain a carrier with the particle size of 63-90 μm;
(3) and (3) mechanically stirring and uniformly mixing the salbutamol sulfate liposome obtained in the step (2) and the carrier obtained in the step (3) at the stirring speed of 450rpm, and filling into capsules, wherein the unit administration dosage of each capsule is 10 mg.
Example 6:
a method for preparing salbutamol liposome inhalant for respiratory system diseases comprises the following steps:
(1) preparing salbutamol sulfate liposome: weighing 15g of lecithin, 35g of cholesterol and 5g of salbutamol sulfate micro powder obtained in the step (1), adding acetone, stirring to dissolve all the components, and uniformly mixing to obtain a clear and transparent solution; putting the obtained solution into a round-bottom flask, volatilizing the solvent by a rotary evaporator to form a layer of uniform film on the inner wall of the round-bottom flask, and adding a phosphate buffer solution with the pH value of 7.4 to hydrate to obtain a suspension; subjecting the obtained suspension to ultrasonic treatment for 30min under ice bath condition, filtering with 0.8 μm microporous membrane, spray drying, and pulverizing to particle size of 1 μm-5 μm to obtain salbutamol sulfate liposome;
(2) preparation of the carrier: dissolving 91.45g of lactose in deionized water, heating to 70 ℃, adding 30.49g of mannitol and 6.4g of leucine in the process of continuously stirring to obtain a mixture, spray-drying the mixture, and crushing to obtain a carrier with the particle size of 63-90 mu m;
(3) and (3) mechanically stirring and uniformly mixing the salbutamol sulfate liposome obtained in the step (2) and the carrier obtained in the step (3) at the stirring speed of 450rpm, and filling into capsules, wherein the unit administration dosage of each capsule is 10 mg.
Example 7:
a method for preparing salbutamol liposome inhalant for respiratory system diseases comprises the following steps:
(1) preparing salbutamol sulfate liposome: weighing 15g of lecithin, 35g of cholesterol and 5g of salbutamol sulfate micro powder obtained in the step (1), adding acetone, stirring to dissolve all the components, and uniformly mixing to obtain a clear and transparent solution; putting the obtained solution into a round-bottom flask, volatilizing the solvent by a rotary evaporator to form a layer of uniform film on the inner wall of the round-bottom flask, and adding a phosphate buffer solution with the pH value of 7.4 to hydrate to obtain a suspension; subjecting the obtained suspension to ultrasonic treatment for 30min under ice bath condition, filtering with 0.8 μm microporous membrane, spray drying, and pulverizing to particle size of 1 μm-5 μm to obtain salbutamol sulfate liposome;
(2) preparation of the carrier: dissolving 96.25g of lactose in deionized water, heating to 70 ℃, adding 32.09g of mannitol while continuously stirring to obtain a mixture, spray-drying the mixture, and crushing to obtain a carrier with the particle size of 63-90 mu m;
(3) and (3) mechanically stirring and uniformly mixing the salbutamol sulfate liposome obtained in the step (2) and the carrier obtained in the step (3) at the stirring speed of 450rpm, and filling into capsules, wherein the unit administration dosage of each capsule is 10 mg.
Example 8:
a method of preparing an inhalant of salbutamol for respiratory diseases comprising the steps of:
(1) weighing 5g of salbutamol sulfate micro powder, and repeating the step of preparing salbutamol sulfate liposome in the embodiment 6 to obtain the treated salbutamol sulfate micro powder;
(2) preparation of the carrier: dissolving 8.75g of lactose in deionized water, heating to 70 ℃, adding 2.92g of mannitol while continuously stirring to obtain a mixture, spray-drying the mixture, and crushing to obtain a carrier with the particle size of 63-90 mu m;
(3) and (3) mechanically stirring and uniformly mixing the treated salbutamol sulfate micro powder obtained in the step (2) and the carrier obtained in the step (3) under the condition that the stirring speed is 450rpm, and filling the mixture into capsules, wherein the unit administration dosage of each capsule is 10 mg.
Test example 1: determination of encapsulation efficiency
The encapsulation efficiency of the salbutamol sulfate liposome prepared in example 1, example 2 and example 4 was measured, and the results are shown in the following table 1:
| examples | Encapsulation efficiency (%) |
| Example 1 | 92.1 |
| Example 2 | 93.4 |
| Example 4 | 91.9 |
TABLE 1
The encapsulation efficiency test results show that the encapsulation efficiency of the embodiments 1, 2 and 4 is more than 90%, which shows that the salbutamol sulfate liposome prepared by the method for preparing the salbutamol sulfate liposome and the proportion of the components in the invention are better in encapsulation efficiency and good in encapsulation effect.
Test example 2: determination of form, solubility and hygroscopicity of salbutamol sulfate liposome inhalant
And (3) morphology observation: the surface appearance of the powder particles was observed by a scanning electron microscope. And (3) uniformly dispersing the sample on double-sided adhesive, spraying gold, and observing under a scanning electron microscope. The accelerating voltage is 15kV, and the magnification is 1000-4000 times.
Determination of solubility: taking 2 dry powder inhalant capsules, opening the capsule shell, putting the content powder into a test tube with a plug and containing 2ml of water, shaking for 1min, and observing the dissolution condition. If the powder is soluble and the solution is clear, the solubility is acceptable, and if the solution is cloudy, the solubility is not acceptable.
Measurement of hygroscopicity: the determination is carried out according to the guiding principle of the drug hygroscopicity test (appendix XIX J of the second part of the 2005 edition of Chinese pharmacopoeia). The hygroscopicity of a drug refers to the property of a substance to absorb moisture under certain temperature and humidity conditions. The method is only used as an indication for expressing the hygroscopicity of the medicine, is suitable for being collected and carried by Chinese pharmacopoeia and meets the requirements of drying weight loss or moisture limit under the text item of the variety. And can also be used as a reference for selecting proper packaging and storage conditions of the medicine. The specific determination method is as follows: (1) placing a certain amount of the test sample in a glass weighing bottle (the outer diameter is 50mm, the height is 15mm) with a plug and precisely weighing (m2) according to a known precise weighing (m 1); (2) placing the open port of the weighing bottle in a proper constant temperature drier (the lower part is placed with ammonium chloride or ammonium sulfate saturated solution) at 25 +/-1 ℃ or a climatic chamber (the set temperature is 25 +/-1 ℃) and the relative humidity is (80% +/-2%); (3) standing for 24 hours; (4) the lid of the weighing bottle was closed, and precision weighing (m3) was performed; (5) hygroscopicity characterization and definition of hygroscopicity weight gain are extremely hygroscopic: the moisture-inducing weight is not less than 15%; moisture absorption: the moisture-drawing weight increment is less than 15% and not less than 2%; slightly hygroscopic: the moisture-inducing and weight-increasing amount is less than 2% and not less than 0.2%; deliquescence: sufficient water is absorbed to form a liquid. Percent weight gain (m3-m2)/(m2-m 1). times.100%
The results are shown in Table 2 below:
| examples | Form of the composition | Solubility in water | Moisture-wicking property |
| Example 1 | Spherical, quasi-spherical | Qualified | 3.0 |
| Example 2 | Spherical, quasi-spherical | Qualified | 2.9 |
| Example 3 | Spherical, quasi-spherical | Qualified | 2.3 |
| Example 4 | Spherical, quasi-spherical | Qualified | 2.1 |
| Example 5 | Spherical, quasi-spherical | Qualified | 2.2 |
| Example 6 | Spherical, quasi-spherical | Qualified | 2.1 |
| Example 7 | Spherical, quasi-spherical | Qualified | 4.1 |
| Example 8 | Irregularity, wrinkle | Qualified | 4.4 |
TABLE 2
The liposome inhalants of salbutamol sulfate prepared in examples 1-7 have a spherical or spheroidal shape, and the salbutamol sulfate prepared in example 8 is not prepared into liposome, so that the obtained inhalants have irregular shapes and appear wrinkles and cavities. The comparison result shows that the shape of the inhalant obtained by preparing the salbutamol sulfate into the liposome can be spherical or spheroidal, which is beneficial to improving the fluidity of fine powder; the difference between example 7 and other examples shows that the incorporation of leucine can prevent moisture and improve the stability of the present inhalant.
Test example 3: deposition assessment of salbutamol sulfate
The in vitro drug deposition rate of salbutamol sulfate liposome inhalant was determined using a new generation of pharmaceutical impactor (NGI). The determination method comprises the following steps: each of the capsules 1 prepared in examples 1 to 8 was taken and loaded into an inhalation device TurbopinTMInternally, the button at the bottom end of the device is pressed by fingers to puncture the bottom end of the capsule, the vacuum pump is started, and the air flow is set to be 60L/min (by the inhalation device Turbopin)TMIntrinsic internal resistance decision); the inhaler was connected to the adapter and inserted into the inhalation port, and the inhaler was removed after 4 seconds of aspiration and 1 capsule replaced. Thus 10 capsules were co-aspirated.
Dry powder preparations in adapter, throat, preseparator, s1, s2, s3, s4, s5, s6, s7, MOC (s1-s7, MOC correspond to grade 1-8 collection pans, respectively) were collected with absolute ethanol and the contents were determined. The Fraction of respirable Fine Particles (FPF), the effective deposition rate of the drug FPF, reflecting the ability of the drug to be delivered to the lungs, in particular FPF equal to the amount of drug received in the four collection pans s3 to s6 divided by the total amount of drug in the device, results as shown in figure 1, from the analysis of figure 1, that the aerosolization behaviour is different for each formulation, example 6 with a much higher ratio of the amount of salbutamol sulphate deposited in the stages s3 to s6 to the total amount of drug in the device than for the other DPI formulations (the above stages s3 to s6 are areas where particles are deposited in the lungs); examples 1-7 the ratio of the amount of salbutamol sulfate deposited at the s3 to s6 stages to the total amount of the drug in the device is much better than that of example 8, which shows that salbutamol sulfate is prepared into liposome which is not prepared, and is directly spray-dried into fine powder, and the obtained fine powder is wrinkled and has holes, so that the emptying rate and the deposition amount of effective parts of the finally prepared inhalant are not qualified; the results of examples 1-6 show that the proportion of each component in example 6 is beneficial to improving the lung deposition rate of salbutamol sulfate and is more beneficial to exerting the drug effect of the salbutamol sulfate; the comparison of example 6 with example 7 shows that the incorporation of leucine provides advantages for an inhaler formulation, which, due to the surfactant action of leucine, results in particles with less cohesion and possibly a reduction in particle size, thereby reducing the droplet size generated during atomisation and hence better deposition.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (7)
1. A liposomal salbutamol inhalation for respiratory diseases, wherein said inhalation comprises the following components: the salbutamol sulfate liposome and a carrier, wherein the salbutamol sulfate liposome accounts for 10-30% of the total weight of the inhalant; the salbutamol sulfate liposome is prepared from the following raw materials in parts by weight: 5-6 parts of salbutamol sulfate, 10-20 parts of lecithin and 30-40 parts of cholesterol; the carrier comprises mannitol, lactose and leucine, wherein the weight part ratio of the mannitol to the lactose is 1:0.3-3, and the weight of the leucine accounts for 1% -5% of the total weight of the carrier.
2. A liposomal salbutamol inhalation according to claim 1 for respiratory diseases characterized by: the lactose adopts 95 wt% D90 coarse lactose powder with particle size of 60-90 μm and 5 wt% D90 fine lactose powder with particle size of 5-15 μm.
3. A process for the preparation of a liposomal salbutamol inhalation according to any one of claims 1 to 2, comprising the steps of: (1) preparing salbutamol sulfate micro powder: weighing salbutamol sulfate, drying the salbutamol sulfate in vacuum, carrying out jet milling on the dried salbutamol sulfate, and controlling the granularity to be below 10 mu m to obtain salbutamol sulfate micro powder; (2) preparing salbutamol sulfate liposome: weighing lecithin, cholesterol and the salbutamol sulfate micro powder obtained in the step (1), adding acetone, stirring to dissolve all the components, and uniformly mixing to obtain a clear and transparent solution; putting the obtained solution into a round-bottom flask, volatilizing the solvent by a rotary evaporator to form a layer of uniform film on the inner wall of the round-bottom flask, and adding a phosphate buffer solution with the pH value of 7.4 to hydrate to obtain a suspension; subjecting the obtained suspension to ultrasonic treatment for 30min under ice bath condition, filtering with 0.8 μm microporous membrane, spray drying, and pulverizing to particle size of 1 μm-5 μm to obtain salbutamol sulfate liposome; (3) preparation of the carrier: dissolving lactose in deionized water, heating to 70 deg.C, adding mannitol and leucine while stirring to obtain mixture, spray drying, and pulverizing to obtain carrier with particle size of 63-90 μm; (4) and (3) uniformly mixing the salbutamol sulfate liposome obtained in the step (2) and the carrier obtained in the step (3), and filling the mixture into capsules to obtain the salbutamol sulfate liposome.
4. A method of preparing a liposomal salbutamol inhalation for respiratory diseases according to claim 3, wherein: in the step (1), the drying temperature is 70-80 ℃, and the drying time is not less than 12 hours.
5. A method of preparing a liposomal salbutamol inhalation for respiratory diseases according to claim 3, wherein: the method for uniformly mixing in the step (4) is mechanical stirring mixing, and the stirring speed of the mechanical stirring mixing is 400-500 rpm.
6. A liposomal salbutamol inhalation according to claim 1 for respiratory diseases characterized by: the salbutamol liposome inhalant is packaged by a capsule for an inhaler.
7. A liposomal salbutamol inhalation according to claim 1 for respiratory diseases characterized by: the unit package of the salbutamol liposome inhalant is 10-50 mg.
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| CN101889994A (en) * | 2010-06-01 | 2010-11-24 | 中国药科大学 | A kind of albuterol sulfate sustained-release inhalation powder mist and preparation method thereof |
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| CN101889994A (en) * | 2010-06-01 | 2010-11-24 | 中国药科大学 | A kind of albuterol sulfate sustained-release inhalation powder mist and preparation method thereof |
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| CN113456590A (en) * | 2021-07-22 | 2021-10-01 | 药大制药有限公司 | Salbutamol lipid aerosol |
| CN113456590B (en) * | 2021-07-22 | 2023-02-03 | 药大制药有限公司 | Salbutamol lipid aerosol |
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