CN118384134A - Tetrandrine aerosol inhalation solution, preparation method and application thereof - Google Patents
Tetrandrine aerosol inhalation solution, preparation method and application thereof Download PDFInfo
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- CN118384134A CN118384134A CN202410427745.XA CN202410427745A CN118384134A CN 118384134 A CN118384134 A CN 118384134A CN 202410427745 A CN202410427745 A CN 202410427745A CN 118384134 A CN118384134 A CN 118384134A
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- tetrandrine
- inhalation solution
- solution
- aerosol inhalation
- injection
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses a tetrandrine aerosol inhalation solution, which belongs to the technical field of aerosol inhalation, and comprises tetrandrine, a cosolvent, an osmotic pressure regulator and water for injection, wherein the concentration range of the tetrandrine solution is 1-100mg/ml, and the mass ratio of the tetrandrine to the cosolvent is 1-5:1, a step of; the invention also discloses a preparation method of the tetrandrine aerosol inhalation solution, which comprises the following steps: s1, weighing a cosolvent according to the prescription amount, and completely dissolving the cosolvent into water for injection; s2, weighing tetrandrine according to the prescription amount, adding the tetrandrine into the prepared S1 solution, and stirring to completely dissolve the tetrandrine; s3, weighing an osmotic pressure regulator according to the prescription amount, adding the osmotic pressure regulator into the prepared S2 solution, and filtering and sterilizing to obtain tetrandrine atomized inhalation solution; the tetrandrine aerosol inhalation solution has good aerosol performance and can effectively treat pulmonary fibrosis.
Description
Technical Field
The invention belongs to the technical field of aerosol inhalation, and particularly relates to tetrandrine aerosol inhalation solution, a preparation method and application thereof.
Background
Idiopathic pulmonary fibrosis (Idiopathic pulmonary fibrosis, IPF) is a progressive fibrotic interstitial pneumonia of unknown cause, and is frequently found in the elderly, with hidden onset, short patient life cycle, high exacerbation rate, median survival after diagnosis of 2-5 years, 5-year survival rate of 20% -25%, and mortality rate of patients even higher than that of various neoplastic diseases, also called "neoplastic diseases".
In recent years, the occurrence of diseases is obviously increased due to environmental factors, population aging factors and other factors, and the diseases become one of the diseases seriously threatening the health of people in the modern society. The current IPF treatment means are very limited, western medicines are mainly anti-fibrosis medicines represented by pirfenidone and nidazole, so that the risk of acute exacerbation can be reduced, the decline of lung function can be slowed down, but the diseases can not be cured, and adverse reactions can be generated to a certain extent. The only treatment at this stage that can extend the life expectancy of IPF patients is single or double sided lung transplantation, but with poor clinical accessibility. Therefore, the search for safe and effective drugs and therapeutic means for treating idiopathic pulmonary fibrosis remains a major challenge.
Tetrandrine (Tet) is a dibenzyl isoquinoline alkaloid extracted from radix Stephaniae Tetrandrae of Menispermaceae. As a Chinese medicinal monomer, tetrandrine has various biological activities, can effectively relieve the symptoms of experimental silicosis rats and clinical silicosis patients, and is proved to be used for preventing and treating various fibrosis diseases such as renal fibrosis, liver fibrosis, silicosis and the like clinically by oral administration or injection, but both of the tetrandrine can cause adverse reactions, such as slight sleepiness, hypodynamia, nausea, epigastric discomfort, facial pigmentation and the like after long-term oral administration. Due to the problems of adverse reaction and the like, the method has a certain limit in clinical application of treating fibrosis, so that a method capable of ensuring the curative effect of tetrandrine and reducing the incidence rate of adverse reaction is urgently needed.
The inhalation therapy has the advantages of small dosage, quick response and the like, has obvious advantages for treating respiratory diseases, and is the first choice therapy for treating respiratory diseases. Compared with the process of inhaling powder aerosol and aerosol, the preparation process of the atomized inhalation solution is relatively simple, and the medicine liquid can enter the respiratory tract along with normal breathing after being atomized by the atomizer without the need of the intentional cooperation of patients, so the preparation process has a wide application range and is favored by enterprises. The solubility of tetrandrine is poor, the national drug standard of the tetrandrine injection commonly used at present prescribes that hydrochloric acid is used as a cosolvent, sodium metabisulfite and sodium edetate are used as stabilizers, and the tetrandrine is easy to separate out due to the influences of the stabilizers, the cosolvent, the preparation method and the like, the pH value is greatly reduced in the storage process, and the irritation reaction such as pain and the like in the clinical use process is larger. In another patent, organic acids such as succinic acid, gallic acid, citric acid, etc. (CN 116270499A, CN101352439 a) are introduced as a cosolvent to increase the solubility of tetrandrine, however, whether it meets the formulation requirements Shang Weike for pulmonary administration is known. Therefore, how to prepare tetrandrine inhalation solution which meets the requirements of an aerosol inhalation preparation and can effectively treat pulmonary fibrosis at the same time, namely, the selection of cosolvent, stabilizer, osmotic pressure regulator, pH regulator and the like in the solution, and the determination of the drug concentration, the aerosol performance, the lung safety and the effectiveness of the inhalation solution are key problems to be solved by the invention.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a tetrandrine aerosol inhalation solution, a preparation method and application thereof.
A first object of the present invention is to provide a tetrandrine aerosol inhalation solution comprising the following components: tetrandrine, a cosolvent, an osmotic pressure regulator and water for injection;
the mass ratio of the tetrandrine to the cosolvent is 1-5:1, and the mass ratio of the tetrandrine to the water for injection is 1-100mg:1ml.
Preferably, the tetrandrine aerosol inhalation solution provided by the invention comprises the following components: tetrandrine, a cosolvent, an osmotic pressure regulator and water for injection;
the mass ratio of the tetrandrine to the cosolvent is 4:1, and the ratio of the tetrandrine to the water for injection is 30mg:1ml.
Preferably, the cosolvent is one or more of citric acid, tartaric acid, malic acid, succinic acid, gallic acid, lactic acid, acetic acid, gluconic acid, ferulic acid and glycyrrhizic acid.
Preferably, the osmotic pressure regulator is any one of glucose and sodium chloride.
Preferably, the osmotic pressure regulator is glucose, and the ratio of glucose to water for injection is 50 mg/1 ml.
Preferably, the osmotic pressure regulator is sodium chloride, and the ratio of the sodium chloride to the water for injection is 9 mg/1 ml.
The second object of the present invention is to provide a preparation method of the tetrandrine aerosol inhalation solution, comprising the following steps:
s1, respectively measuring tetrandrine, a cosolvent, an osmotic pressure regulator and water for injection according to the prescription amount for later use;
s2, adding the cosolvent measured in the step S1 into the water for injection measured in the step S1, and stirring to completely dissolve the cosolvent to obtain a solution 1;
s3, adding the tetrandrine measured in the step S1 into the solution 1 obtained in the step S2, and stirring to completely dissolve the tetrandrine to obtain a solution 2;
S4, adding the osmotic pressure regulator measured in the step S1 into the solution 2 obtained in the step S2, stirring to completely dissolve the osmotic pressure regulator, filtering, sterilizing, and obtaining the tetrandrine atomized inhalation solution.
Preferably, in step S3, the stirring temperature is 25-60 ℃, the stirring rotating speed is 100-400r/min, and the stirring time is 5-30min.
Preferably, in step S3, the pH of the solution 2 is 3-6.
Preferably, in step S4, the osmotic pressure of the tetrandrine atomized inhalation solution is 270-310mOsmol/kg.
A third object of the present invention is to provide an application of the tetrandrine aerosol inhalation solution in preparing a medicine for treating pulmonary fibrosis.
Compared with the prior art, the invention has the beneficial effects that:
(1) The tetrandrine aerosol inhalation solution provided by the invention meets the requirements of lung administration preparations;
(2) The tetrandrine aerosol inhalation solution has an aerosol particle size of 1-5 mu m, can be deposited in the lung, and has good aerosol performance;
(3) The tetrandrine aerosol inhalation solution has low anaphylaxis and no obvious irritation, can directly deliver target drugs to trachea and lung tissues through tracheal administration, increases the drug concentration and action time of the target tissues (trachea and lung), avoids the first pass effect of livers, lightens the burden of livers to a certain extent, and has better safety;
(4) The tetrandrine aerosol inhalation solution has obvious drug effect on a bleomycin-induced pulmonary fibrosis model rat, the airway resistance of the rat is obviously reduced when the tetrandrine aerosol inhalation solution is administrated for 28 days, the dynamic lung compliance is increased, the lung coefficient is reduced, the interstitial thickening and inflammatory reaction of the rat are reduced, the expression levels of alpha-SMA and Col-I in lung tissues are down-regulated, and the expression levels of Vimentin and TGF-beta protein in the lung tissues are obviously down-regulated, so that the tetrandrine aerosol inhalation solution disclosed by the invention can effectively treat pulmonary fibrosis.
Drawings
FIG. 1 is a graph showing the histopathological changes of oral cavity, nose, pharynx, trachea, lung, etc. of rats in a blank group, a solvent group and an aerosol inhalation administration group after 7 days of corresponding treatment;
FIG. 2 is a graph showing spraytec test results and typical particle size distribution of a tetrandrine aerosol inhalation solution provided by the embodiment of the present invention after being atomized by a PARI SPRINT atomizer;
FIG. 3 is a graph showing spraytec test results and typical particle size distribution of a tetrandrine aerosol inhalation solution provided by the embodiment of the present invention after being atomized by a pari sprintjunior atomizer;
FIG. 4 is a graph showing spraytec test results and typical particle size distribution of a tetrandrine aerosol inhalation solution provided by the embodiments of the present invention after being atomized by a PARI SPRINT STAR atomizer;
FIG. 5 is a diagram showing the result of spraytec test and typical particle size distribution of a tetrandrine aerosol inhalation solution provided by the example of the present invention after being atomized by a Wo and blue core atomizer;
FIG. 6 is a graph of tetrandrine amount in rat plasma after instillation, lavage, intravenous administration versus time;
FIG. 7 is a graph of the concentration of tetrandrine in the lungs of rats at various time points following instillation, lavage, and intravenous administration;
FIG. 8 is a graph showing the results of a lung imaging examination of rats under each test group;
FIG. 9 is a graph showing the effect of each test group on rat lung function;
Wherein, fig. 9A is RI airway resistance results and fig. 9B is Cdyn lung compliance results;
FIG. 10 is a graph showing the effect of each test group on rat lung factor;
FIG. 11 is a graph showing the effect of each test group on rat histopathology;
FIG. 12 is a graph showing the effect of each test group on the expression levels of alpha-SMA and Col-I in rat lung tissue;
Wherein A. Sham surgery group (Sham group); B. model group (BLM group); C. positive control group (PFD group); D. tetrandrine oral group (IG group); E. tetrandrine was inhaled into solution for 10min group; F. tetrandrine inhaled solution for 30min group;
FIG. 13 is a graph showing the effect of each test group on expression levels of Vimentin and TGF-beta proteins in rat lung tissue;
Wherein, FIG. 13A shows the expression level of Vimentin protein, and FIG. 13B shows the expression level of TGF-beta protein.
Detailed Description
In order that those skilled in the art will better understand the technical solution of the present invention, the present invention will be further described with reference to specific examples, but the examples are not intended to limit the present invention.
Example 1
The embodiment of the invention provides tetrandrine aerosol inhalation solution, which specifically comprises the following components:
Tetrandrine 3g, citric acid 750mg, sodium chloride 900mg and water for injection 100ml.
The embodiment of the invention also provides a preparation method of the tetrandrine aerosol inhalation solution, which comprises the following steps:
s1, respectively measuring 3g of tetrandrine, 750mg of citric acid, 900mg of sodium chloride and 100ml of water for injection according to the prescription amount for later use;
S2, adding the citric acid measured in the step S1 into the water for injection measured in the step S1, and stirring to completely dissolve the citric acid to obtain a solution 1;
s3, adding the tetrandrine measured in the step S1 into the solution 1 obtained in the step S2, magnetically stirring for 20min at 40 ℃ and the rotating speed of 200r/min, so that the tetrandrine is completely dissolved, and obtaining a solution 2, wherein the pH value of the solution 2 is 5.56;
S4, adding sodium chloride measured in the step S1 into the solution 2 obtained in the step S2, stirring to completely dissolve the sodium chloride, and then filtering the solution by using a G6 vertical melting funnel or a 0.22 mu m filter membrane to sterilize to obtain a clear and transparent tetrandrine atomized inhalation solution, wherein the osmotic pressure of the tetrandrine atomized inhalation solution is 285mOsmol/kg.
The tetrandrine aerosol inhalation solution prepared in this example was tested by HPLC-UV to obtain a final concentration of 30mg/ml of tetrandrine aerosol inhalation solution. After 60 days at room temperature, HPLC-UV detection did not decompose and the concentration was unchanged.
Example 2
The embodiment of the invention provides tetrandrine aerosol inhalation solution, which specifically comprises the following components:
2g of tetrandrine, 400mg of glacial acetic acid, 1g of glucose and 20ml of water for injection.
The embodiment of the invention also provides a preparation method of the tetrandrine aerosol inhalation solution, which comprises the following steps:
S1, respectively measuring 2g of tetrandrine, 400mg of glacial acetic acid, 1g of glucose and 20ml of water for injection according to the prescription amount for later use;
s2, adding the glacial acetic acid measured in the step S1 into the water for injection measured in the step S1, and stirring to completely dissolve the glacial acetic acid to obtain a solution 1;
s3, adding the tetrandrine measured in the step S1 into the solution 1 obtained in the step S1, magnetically stirring for 5min at 60 ℃ at the rotating speed of 400r/min to completely dissolve the tetrandrine to obtain a solution 2, wherein the pH value of the solution 2 is 5.28;
S4, adding the glucose measured in the step S1 into the solution 2 obtained in the step S2, stirring to completely dissolve the glucose, and then filtering the solution by using a G6 vertical melting funnel or a 0.22 mu m filter membrane to sterilize to obtain a clear and transparent tetrandrine atomized inhalation solution, wherein the osmotic pressure of the tetrandrine atomized inhalation solution is 310mOsmol/kg.
The tetrandrine aerosol inhalation solution prepared in this example was tested by HPLC-UV to obtain a final concentration of 100mg/ml tetrandrine aerosol inhalation solution.
Example 3
The embodiment of the invention provides tetrandrine aerosol inhalation solution, which specifically comprises the following components:
Tetrandrine 100mg, tartaric acid 100mg, sodium chloride 900mg and water for injection 100ml.
The embodiment of the invention also provides a preparation method of the tetrandrine aerosol inhalation solution, which comprises the following steps:
S1, respectively measuring 100mg of tetrandrine, 100mg of tartaric acid, 900mg of sodium chloride and 100ml of water for injection according to the prescription amount for later use;
S2, adding the tartaric acid measured in the step S1 into the water for injection measured in the step S1, and stirring to completely dissolve the tartaric acid to obtain a solution 1;
S3, adding the tetrandrine measured in the step S1 into the solution 1 obtained in the step S1, magnetically stirring for 30min at 25 ℃ and the rotating speed of 100r/min, so that the tetrandrine is completely dissolved, and obtaining a solution 2, wherein the pH value of the solution 2 is 3.02;
S4, adding sodium chloride measured in the step S1 into the solution 2 obtained in the step S2, stirring to completely dissolve the sodium chloride, and then filtering the solution by using a G6 vertical melting funnel or a 0.22 mu m filter membrane to sterilize to obtain a clear and transparent tetrandrine atomized inhalation solution, wherein the osmotic pressure of the tetrandrine atomized inhalation solution is 271mOsmol/kg.
The tetrandrine aerosol inhalation solution prepared in this example was tested by HPLC-UV to obtain a final concentration of 1mg/ml tetrandrine aerosol inhalation solution.
Comparative example 1
Several alcohol-water co-solvents (5% ethanol, 5% propylene glycol, 5% glycerol, 5% peg 400) and surfactant solutions (1% tween 80, 1% ec-35, 1% hs-15) were separately prepared. Then, respectively adding 20ml of different solvents into a 50ml centrifuge tube, adding a proper amount of tetrandrine powder, stirring at normal temperature to dissolve the powder, continuously adding the powder until the solution reaches a supersaturated state, and standing overnight; then, the mixture was centrifuged at 12000rpm for 10min, and the mixture was filtered through a 0.22. Mu.mL filter, and the filtrate was diluted with methanol at an appropriate ratio for liquid phase detection, so as to calculate the solubility of tetrandrine in different co-solvents. The test results are shown in table 1 below:
TABLE 1 solubility of tetrandrine in different co-solvents
The test results in table 1 above demonstrate that compared with the organic acid solution dissolution promoter selected in the examples of the present invention, the tested alcohol-water dissolution promoter system and surfactant solution have no significant dissolution promoter effect on tetrandrine, indicating that the organic acid solution is reasonable as the dissolution promoter in the examples of the present invention.
The tetrandrine aerosol inhalation solutions prepared in examples 1 to 3 of the present invention have substantially the same atomization properties, so that only the tetrandrine aerosol inhalation solution prepared in example 1 of the present invention was subjected to the subsequent experimental evaluation.
1. Respiratory tract mucosa irritation test and allergy test
1. Oral-nasal exposure aerosol inhalation administration on rat respiratory tract mucous membrane irritation test
1.1 Test conditions
The rats are adaptively fed for 5 days, the rats are respectively grouped according to female and male animals, the weights of the animals are weighed on the day of grouping, and the number of the animals participating in grouping is as follows: female mice 9; the animals were randomly grouped according to body weight of the animals, and the rats were divided into a blank group, a solvent group and a drug group. Wherein, the blank group is given physiological saline; the solvent group was proportioned according to the citric acid content of example 1 of the present invention, and the pH was adjusted to 5.5 with sodium citrate, the osmotic pressure was adjusted to 290mOsmol/kg with sodium chloride, and tetrandrine was not added; the tetrandrine aerosol inhalation solution prepared in the example 1 of the present invention was administered in a pharmaceutical composition at an aerosol concentration of 30mg/ml. Fixing the rats in an oral-nasal exposure tower, and adopting a Bairui red core atomizer to carry out atomization administration, wherein each time of continuous atomization is carried out for 30min, once a day, and the administration is carried out for 7 days continuously. Before each administration, observing whether the nasal mucosa and the oral mucosa of the rat have the phenomena of redness, bleeding, ulcer and the like in the visible range; immediately after administration, the animals were observed for local irritation symptoms (e.g., asthma, cough, vomiting, asphyxia, etc.), general status, behavior, signs, etc. of the animals. The viscera such as nasal mucosa, oral mucosa, throat, trachea and lung of the animal are taken and fixed by 10% formalin solution. The nasal cavity was decalcified with 5% formic acid, all tissues were dehydrated, paraffin embedded, tabletted, and finally hematoxylin-eosin (HE) stained.
1.2 Test results
Fig. 1 is a graph showing histopathological changes of oral cavity, nose, pharynx, trachea, lung and the like of rats subjected to corresponding treatment for 7 days in a blank group, a solvent group and a drug group, and as can be seen from fig. 1, the tetrandrine atomized inhalation solution prepared in example 1 of the present invention has no obvious influence on the general condition of the rats after being subjected to oral-nasal exposure and atomization inhalation for 7 days. Histopathological changes of oral cavity, nose, pharynx, trachea, lung and the like of the administration group are similar to those of a blank control group, no obvious changes are seen, and the results show that the tetrandrine atomized inhalation solution does not cause irritation to rats after oral and nasal exposure and atomization inhalation.
2. Active systemic allergy test in mouth-nose exposed aerosol inhalation administered guinea pigs
2.2 Test conditions
At the end of the adaptation, animals were grouped before dosing, the weight of the group was weighed on the day of the grouping, and the male and female groups were individually grouped. Number of animals participating in the group: female mice: 12; male mice: 12.
Sensitization phase: oronasal exposure tower: ventilation 1L/L. Animals in the administration group are fixed on an oral-nasal exposure system, and the tetrandrine atomized inhalation solution prepared in the embodiment 1 of the invention is atomized and administrated for 30min by adopting a Bairui red core atomizer, and the administration is carried out once every other day for 3 times.
Animals were fixed in the oronasal exposure system during the challenge phase and were given an aerosol for 60min on day 14 and 21 after the last sensitization, respectively.
The negative control group was administered by inhalation through the mouth and nose after atomizing air. Sensitization: the atomized air was administered for 30min, once every other day, 3 times in total. Excitation: atomized air was administered for 60min on days 14 and 21 after the last sensitization. The positive control group was administered by inhalation through the mouth and nose after atomizing the ovalbumin solution. Sensitization: the ovalbumin is prepared into 2mg/mL sensitization solution by sodium chloride injection, and the sensitization solution is atomized for 15min and is administrated once every other day for 3 times. Excitation: the ovalbumin is prepared into 4mg/mL excitation solution by sodium chloride injection, and the excitation solution is atomized for 30min on 14 th day and 21 th day after the final sensitization.
The following index observations were made during the experiment: during sensitization, daily observations record the general symptoms of the animals. Systemic anaphylaxis: immediately after challenge, to 30 minutes, animals were observed for the presence of the indicated symptoms as shown in table 2 below. The rate of allergic reaction was recorded and calculated.
TABLE 2 symptoms of allergic reactions
2.2 Test results
(1) General conditions: during sensitization, animals in each group independently move, drink water and ingest, so that the urine and the feces are normal, and the mental state is good; the hair color is glossy, no abnormal secretion is seen in the mouth, nose and eyes, and no abnormal respiration is seen. None of the animals in each group had died during sensitization.
(2) Allergic reaction: in the excitation stage, the negative control group has no anaphylactic reaction symptom, and the anaphylactic reaction incidence rate is 0. After the positive control group guinea pigs are excited, allergic reactions such as urination, cyanosis, dyspnea, spasm and the like appear, and finally the positive control group guinea pigs die, and the incidence rate of the allergic reactions is 100%. After the animals of the administration group are stimulated, systemic anaphylactic reactions such as vertical hair, cough, dyspnea and the like are not generated, the anaphylactic reaction incidence rate is 0, and the experimental results are shown in the table 3 below.
TABLE 3 record of allergic reaction symptoms in rats
As can be seen from the results shown in Table 3, the tetrandrine atomized liquid prepared in the example 1 of the present invention was negative in the active systemic allergy test of rats after the tetrandrine atomized liquid was inhaled by atomization, which indicates that the tetrandrine atomized liquid prepared in the example 1 of the present invention is not prone to allergy.
2. The following is a study on the pharmaceutical properties of the tetrandrine aerosol inhalation solution prepared in example 1 of the present invention
1. Evaluation of atomizing Property
The tetrandrine atomized inhalation solution prepared in the embodiment 1 of the invention is atomized by a plurality of atomizers which are already marketed, wherein the atomized particle size at the central position is 1-5 mu m, and the tetrandrine atomized inhalation solution can be deposited in the lung and has better atomization performance.
1.1 Test conditions
The particle size distribution, the atomization time and the atomization rate of the tetrandrine atomized inhalation solution prepared in the embodiment 1 of the invention after being atomized by a plurality of common atomizers are evaluated by a laser diffraction method, and the specific method is as follows:
1) The atomizers are respectively connected with the atomizing compressor, so that the atomizers are not separated from the atomizing compressor under the specific gas flow rate and pressure of the compressor, and 2ml of tetrandrine atomized inhalation solution prepared in the embodiment 1 of the invention is filled in the atomizers. The mass of the atomizer before and after dosing was recorded.
2) The inlet of the laser diffractometer is connected inductionport, the outlet of the laser diffractometer is connected with an external filter, the external filter is connected with a vacuum pump, the inlet of the laser diffractometer is connected with a flowmeter, the vacuum pump is turned on, the gas flow rate at the inlet is regulated to be stable to 15L/min (+ -5%), and the flowmeter is dismounted.
3) After the gas flow rate was adjusted, software (Spraytec software version.20, malvern) was opened on the computer and SOP was set (test mode: a continuous mode; refractive index of the particles: 1.33; dispersion medium: air; refractive index: 1.00 And then begins testing the optical path background.
4) And tightly connecting the atomizer with the inlet end of inductionport after the background test is qualified. And then starting the compressor to atomize and test the particle size of the drug particles, stopping the test when the aerosol concentration is rapidly reduced, and closing the atomizer. Taking down the atomizer at the inlet, weighing, and calculating the atomization rate.
5) During the analysis, the particle size distribution (D (10), D (50), D (90)) and the laser intensity transmission were continuously monitored. The time to start measuring the sudden drop in aerosol concentration is the total time of nebulization.
1.2 Test results
The test results are shown in the following table 4 and fig. 2-5, and it can be seen from the results in table 4 and fig. 2-5 that the droplet size D (50) generated by several atomizers is between 3.09 μm and 4.87 μm, and all reach the lung deposition particle size requirement, which indicates that the tetrandrine atomized inhalation solution prepared in the embodiment 1 of the present invention has good atomization performance. Meanwhile, different atomizers have certain difference in atomization particle size distribution, and can be selected according to requirements.
TABLE 4 results of spraytec test of tetrandrine nebulized inhalation solution nebulized by different nebulizers
2. Comparing the pharmacokinetic properties of tetrandrine in the tetrandrine aerosol inhalation solution prepared in example 1 of the present invention in parallel in three modes of administration, i.e. oral administration, intravenous injection and tracheal administration
2.1, Test methods
SPF SD rats, weighing 210-250g, male, were selected and jugular vein cannulated one day prior to the experiment. 15 rats successfully placed in vein were selected and randomly divided into 3 groups, including a tracheal administration group (tracheal instillation), a gastric lavage group and a intravenous infusion group, 5 each. Each group of animals was dosed at 27mg/kg in a single dose. Each group was collected by intravenous catheterization for about 150 μl of blood before, 5, 10, 20, 40, 60min, 2, 3, 5, 7, 9, 11, 24, 48, and 72h after dosing, respectively, and then an equal volume of physiological saline was replenished from the intravenous catheterization. The blood sample was placed in a 1.5mL heparin anticoagulation EP tube, centrifuged at 10000rpm for 2min at 4℃and the supernatant plasma was transferred to a new 1.5mL EP tube and stored at-80℃until analysis.
2.2 Test results
The test results are shown in Table 5 and FIG. 6 below, and it can be seen from the results of Table 5 and FIG. 6 that the total systemic exposure of tetrandrine to rats was highest following intravenous administration, followed by instillation and lowest following intragastric administration. The absolute bioavailability after instillation administration is 80.51-98.19%, which is higher than 61.85-78.26% of that after gastric lavage administration. Although the systemic exposure level of the instilled tetrandrine in the rat body is not as high as that of intravenous injection, the total exposure of the tetrandrine is less than 1/2 of that of the injection, and the reduction of the systemic exposure relative to the injection is favorable for the safety of administration, can improve the effectiveness relative to the oral administration, and has certain advantages in treating respiratory diseases relative to the injection and the oral administration of the tracheal instillation.
TABLE 5 systemic exposure levels and bioavailability of tetrandrine in rats following different modes of administration
Note that: f is the absolute bioavailability for this mode of administration, and the calculation formula is (AUC for the target mode of administration multiplied by the injected dose) divided by (AUC for intravenous administration multiplied by the dose for the target mode of administration).
3. Comparing the distribution characteristics of the tetrandrine aerosol inhalation solution prepared in the embodiment 1 of the invention in the lung in parallel under three administration modes of oral administration, intravenous injection and tracheal administration
3.1, Test method
30 SPF-grade male SD rats were selected. Rats were randomly divided into 3 groups, including a tracheal instillation group, a gastric lavage group, and a static injection group, 9 rats per group, with a 3mg/kg dose. Animals in each group were anesthetized for 3 animals 5, 30, and 60min after dosing, the abdominal aorta was rapidly collected (heparin anticoagulated) and the blood was removed, the lungs were removed, physiological saline was used to rinse the surface and the surface moisture was blotted with filter paper, and the weight was as follows: volume ratio 1:4 (lung) in saline, ice bath homogenate, transfer homogenate 50 μl to fresh 1.5mL EP tube, store at-80 ℃ until analysis. 3 animals were also taken as blank groups, anesthetized before each group was dosed and lungs were harvested and homogenized in the same manner and stored at-80 ℃.
3.2 Test results
The test results are shown in fig. 7, and it can be seen from the results of fig. 7 that tetrandrine can be detected in lung tissue 5min after instillation, gastric lavage and intravenous injection; the instillation and intravenous injection can maintain high concentration, the instillation can maintain high concentration within 60min, and the concentration in lung tissue is Yu Jing injection after 60 min; after instillation and intravenous injection, the concentration of tetrandrine in lung tissue is 409.4-1777.1 times and 407.3-751.8 times of that in blood plasma respectively, which indicates that instillation administration has higher lung/blood coefficient than injection administration and can lead more medicine to be distributed to the lung; the concentration of tetrandrine in the lung tissue of the rat after the gastric lavage administration is lower, the lung/blood coefficient is 30.4-152.9, which is lower than that of instillation and intravenous injection administration.
According to the results, compared with the traditional oral preparation, the atomization inhalation preparation tetrandrine prepared by the embodiment of the invention has high tissue affinity, and the lung tissue shows higher drug concentration after the tracheal administration and intravenous injection administration, but the drug concentration of the lung tissue gradually decreases after 30min of injection administration, and the tracheal administration can maintain higher concentration within 60min, so that certain advantages are shown; due to the first pass effect of the liver, the drug concentration in lung tissues after the administration of the lavage is obviously lower than that of the administration of the tracheal and intravenous injection; the tracheal administration is taken as a local administration mode, can directly deliver target drugs to lung tissues, increases the drug concentration and the action time of the target tissues (pneumo-lung), avoids the first pass effect of the liver, lightens the burden of the liver to a certain extent, and has better safety. The above results suggest that topical administration via the trachea provides significant advantages over oral administration for the treatment of disease.
4. The rat model of the pulmonary fibrosis induced by bleomycin is adopted to observe the pharmacodynamic effect of the tetrandrine atomized inhalation solution prepared in the embodiment 1 of the invention by oral-nasal exposure atomized inhalation
4.1, Test methods
The method comprises the following steps: SPF-grade Sprague Dawley male rats weighing about 180-220 g. 10 rats after 5 days of adaptive feeding are randomly selected as a sham operation group (sham), 10% of chloral hydrate is respectively injected into the rest rats according to the amount of 3mL kg-1 for anesthesia, the anesthesia depth is based on the condition that the skin or the toes of the rats are pinched by toothed forceps for non-shrink reaction, and then animal molding is carried out on the anesthetized rats, wherein the specific operation is as follows: the anesthetized rat is in a supine position, is provided with a dental rubber band, and is fixed on an animal fixing table by a cotton thread rope for four limbs, so that the head and neck of the rat and the sight of an operator are kept on the same straight line; Aiming the light source of the flashlight at the lower jaw of the rat, slightly pulling the tongue of the rat out of the mouth towards one side of the corner of the mouth by using tissue forceps, adjusting the light angle of the flashlight to enable the pipeline of the throat of the rat to be visible, then wiping the secretion of the throat of the animal by using a sterile cotton swab, upwards bending the bending end of the cannula, stretching the mouth cavity from the middle of the upper incisor of the rat and slightly pushing the cannula, slightly picking up the cannula when the cannula touches the tongue root of the rat, and inserting the cannula into the trachea of the rat until about 2cm remains outside the upper incisor. The method comprises the steps of sucking a required amount of bleomycin solution by a 1ml disposable sterile syringe, connecting a self-made cannula, slowly pushing and injecting, and after instillation, extracting 0.5ml air by the syringe, connecting the cannula to rapidly push and inject, so that instillation liquid is diffused deep into lung tissues. Immediately after the air injection, the cannula is pulled out, so that the rat is kept upright for 5 seconds and then is put back into the rat cage to be awakened. The experimental operation of the false operation group is consistent with the molding of bleomycin, but the trachea is dripped with the physiological saline with the same volume. The following day bleomycin model surviving animals were randomly divided into 5 groups, the number of rats in each group being the same. These 5 groups of rats were designated as model group (BLM), positive control group (PFD, 50mg.kg -1), tetrandrine oral administration group (IG, 27mg.kg -1), tetrandrine inhalation solution 10min group (Ato 10 min) and tetrandrine inhalation solution 30min group (Ato 10 min), respectively. The sham operation group (sham) and the model group begin to administer corresponding doses of physiological saline daily in a mode of gastric lavage in the 2 nd die, the positive control group begins to administer corresponding doses of pirfenidone daily in the 2 nd die, the tetrandrine oral administration group begins to administer corresponding doses of the tetrandrine aerosol inhalation solution prepared in the embodiment 1 of the invention daily in the 2 nd die, the tetrandrine inhalation solution 10min group and the tetrandrine inhalation solution 30min group begin to administer corresponding doses of the tetrandrine aerosol inhalation solution prepared in the embodiment 1 of the invention respectively in a mode of oral and nasal aerosol daily in the 2 nd die for 10min and 30min, The specific atomization operation is as follows: placing the rats in an oral-nasal exposure tower for fixation, atomizing the liquid medicine by adopting a Bairui red core atomizer according to ventilation volume of 1L/mouse, atomizing and inhaling tetrandrine atomized inhalation solution for corresponding time, continuously dosing for 28d, killing the rats at 29d, and observing the following indexes:
(1) Rat lung imaging examination
After 1h of last dose, rats were anesthetized (dose as before) while Micro CT scan parameters were set as follows: tube voltage 90kV, tube current 88 μa, imaging field 72 x 36nm. The rat is in prone position after anesthesia, the limbs are unfolded, the head is advanced, then chest CT tomography is performed for about 10 minutes, and the image is reconstructed by SIMPLEVIEWER software after the scanning is completed.
(2) Lung function detection: dynamic lung compliance and lung resistance were measured for each rat after tracheal intubation after anesthesia with 3% sodium pentobarbital.
(3) And (3) lung coefficient detection: lung tissue was isolated, called lung weight, and lung coefficients were calculated.
(4) Histopathological examination: the left lung was fixed with 10% formaldehyde for histological examination, paraffin-embedded, sectioned (5 μm thick), and subsequently HE stained for each tissue section, and observed for pathological changes of lung tissue under light microscopy. HE staining was used to judge the degree of inflammation.
(5) Immunofluorescence method for detecting relative expression level of alpha-smooth muscle actin (alpha-SMA) and type I collagen (Col-I) in rat lung tissue
Paraffin sections were deparaffinized for antigen retrieval, blocked for 30min at room temperature, and then sections were incubated with the corresponding primary antibodies (α -SMA,1:100; col-I, 1:100) overnight at 4 ℃. The sections were washed with PBS and incubated for 1h at room temperature after the secondary antibody was added dropwise. And (3) performing PBS (phosphate buffered saline) film-washing again, performing counterstain by DAPI, incubating at room temperature in a dark place, sealing the film, shooting by a fluorescence microscope, and performing image acquisition by SLIDEVIEWER software.
(6) Westernblot detection of Vimentin (Vimentin) and transforming growth factor beta 1 (TGF-beta) protein expression levels in rat lung tissue
Cutting right lung into 1cm3 pieces, placing into a freezing tube, and storing in a refrigerator at-80deg.C. When the determination is carried out, 50-100 mg of lung tissue is taken out from a refrigerator at the temperature of minus 80 ℃, washed by PBS, sheared and put into a refiner, and the total protein of the lung tissue is extracted by RIPA lysate. Protein is quantified by BCA method, then Loading buffer is added for denaturation (100 ℃ C., 5 min), 50 mug of protein is separated by 8% SDS-PAGE electrophoresis, membrane transfer is carried out, 1h (5% skimmed milk powder) is blocked at room temperature, vimentin (1:1000), TGF-beta (1:1000) and beta-actin (1:1000) are respectively incubated, TBST is washed for 3 times, secondary antibody (1:2000) is incubated, ECL luminescence is carried out, a gel imaging system collects a strip picture, finally image J software is adopted for calculating gray values, and the relative expression level of the protein to be detected is represented by the ratio of the gray value of target protein/beta-actin.
4.2, Test results:
(1) Influence of tetrandrine aerosol inhalation solution on rat lung imaging
As can be seen from FIG. 8, the lung CT of the rats in the sham operation group has no abnormality, clear lung texture, uniform transmittance, no too high or too low dense shadow, no abnormal lines and no flaky shadow. The lung texture of the model group rats is fuzzy after molding for 28 days, the transmittance is uneven, and dense shadows and honeycomb patterns are changed. The above performance was lighter in the pirfenidone dosed group and the tetrandrine inhaled solution 30min group compared to the model group.
(2) Influence of tetrandrine aerosol inhalation solution on rat lung function
As can be seen from fig. 9, after modeling 28d, airway resistance was significantly increased in rats in the model group compared to the sham group (P < 0.001). Lung compliance was significantly reduced (P < 0.001). The airway resistance of the tetrandrine inhaled solution 10min group and 30min group was significantly reduced compared to the model group (P < 0.001). Pirfenidone, tetrandrine, inhaled solution of tetrandrine in 10min group and 30min group had significantly elevated lung compliance (P < 0.001). The efficacy of the nebulized group on airway resistance and lung compliance in model animals was slightly better than that of the oral group.
(3) Influence of tetrandrine aerosol inhalation solution on rat lung coefficient
As can be seen from fig. 10, after molding 28d, the lung factor of rats in the model group was significantly increased (P < 0.001) compared to the sham surgery group, and the lung factor of rats in the group was significantly decreased (P < 0.001) compared to the model group by pirfenidone, orally and inhaled by aerosol for 10min, 30 min.
(4) Influence of tetrandrine nebulized inhalation solution on rat histopathology
As can be seen in FIG. 11, after molding 28d, the alveoli of the sham operated group had intact structure and no apparent inflammatory fine infiltration was seen. The lung tissue of the rat in the model group can be infiltrated by a large amount of inflammation, and the alveolar space is obviously thickened; a large number of foam cells aggregate in the alveolar space; the whole lung is seen as a diffuse solid change from the bronchus to the surrounding lung tissue, and the lung function is lost. The pathological changes of the tetrandrine inhalation solution 10min group and the tetrandrine inhalation solution 30min group are relieved compared with the model group, and the interstitial thickening and inflammatory reaction are relieved, wherein the tetrandrine inhalation solution 30min group has better effect.
(5) Effect of tetrandrine nebulized inhalation solution on expression levels of alpha-SMA and Col-I in rat lung tissue
As can be seen from FIG. 12, after the molding for 28d, the expression levels of alpha-SMA and Col-I in the lung tissue of the rats in the model group were significantly increased, and the expression levels of alpha-SMA and Col-I in the lung tissue of the rats were significantly decreased in the positive drug group and the tetrandrine group inhaled into the solution for 30min group.
(6) Effect of tetrandrine nebulized inhalation solution on expression levels of Vimentin and TGF-beta proteins in rat lung tissue
As can be seen from fig. 13, after 28d of administration, bleomycin was able to significantly up-regulate the expression levels of Vimentin and TGF- β protein in rat lung tissue after molding (P <0.001 and P < 0.001) compared to sham; the expression level of Vimentin and TGF-beta protein was significantly down-regulated in the 30min group of tetrandrine inhalation solutions (P <0.05 and P < 0.01).
The results show that the tetrandrine aerosol inhalation solution provided by the embodiment of the invention has certain effect advantages in the aspect of drug effect, and is specifically expressed in the following steps:
(1) The tetrandrine aerosol inhalation solution provided by the embodiment of the invention is slightly superior to oral administration in some drug effect indexes, such as lung function indexes, CT scanning, histopathology and coefficients, alpha-SMA and Col-I;
(2) The administration dose of the tetrandrine aerosol inhalation solution provided by the embodiment of the invention is about 1/171 of the oral dose, is obviously lower than the oral dose, and the exposure of the drug in the whole body is obviously reduced, specifically, the inhalation dose of animals is taken as the inhalation administration dose, and the administration dose is calculated by the calculation formula:
Drug equilibrium concentration time of administration average respiratory rate average tidal volume
The actual administration concentration of single atomization of the group with atomization of 30min is 0.155 mg.kg-1, and the oral dosage is 27 mg.kg -1, and the comparison of the oral dosage and the atomization administration dosage proves that the administration dosage of the tetrandrine atomization inhalation solution provided by the embodiment of the invention is obviously lower than the oral dosage, so that the safety risk possibly caused by high dosage administration of the tetrandrine atomization inhalation solution can be avoided.
In conclusion, the tetrandrine aerosol inhalation solution provided by the embodiment of the invention can improve lung function and lung morphological lesions of rats with lung fibrosis models, reduce the expression level of alpha-SMA and Col-I in lung tissues, and down regulate the expression level of Vimentin and TGF-beta proteins in the lung tissues, and the results show that the tetrandrine aerosol inhalation solution has an inhibitory effect on bleomycin-induced rat lung fibrosis.
It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.
Claims (10)
1. A tetrandrine aerosol inhalation solution, comprising the following components: tetrandrine, a cosolvent, an osmotic pressure regulator and water for injection;
the mass ratio of the tetrandrine to the cosolvent is 1-5:1, and the mass ratio of the tetrandrine to the water for injection is 1-100mg:1ml.
2. The tetrandrine aerosol inhalation solution according to claim 1, comprising the following components: tetrandrine, a cosolvent, an osmotic pressure regulator and water for injection;
the mass ratio of the tetrandrine to the cosolvent is 4:1, and the ratio of the tetrandrine to the water for injection is 30mg:1ml.
3. The tetrandrine aerosol inhalation solution according to claim 1 or 2, wherein the dissolution promoter is any one or more of citric acid, tartaric acid, malic acid, succinic acid, gallic acid, lactic acid, acetic acid, gluconic acid, ferulic acid, glycyrrhizic acid.
4. The tetrandrine aerosol inhalation solution according to claim 1 or 2, wherein the osmotic pressure regulator is any one of glucose and sodium chloride.
5. The tetrandrine aerosol inhalation solution of claim 4, wherein the osmolality regulator is glucose, the ratio of glucose to water for injection is 50 mg/1 ml.
6. The tetrandrine aerosol inhalation solution according to claim 4, wherein the osmotic pressure regulator is sodium chloride, the ratio of sodium chloride to water for injection is 9 mg/1 ml.
7. A method for preparing a tetrandrine aerosol inhalation solution according to any one of claims 1 to 6, comprising the steps of:
s1, respectively measuring tetrandrine, a cosolvent, an osmotic pressure regulator and water for injection according to the prescription amount for later use;
s2, adding the cosolvent measured in the step S1 into the water for injection measured in the step S1, and stirring to completely dissolve the cosolvent to obtain a solution 1;
s3, adding the tetrandrine measured in the step S1 into the solution 1 obtained in the step S2, and stirring to completely dissolve the tetrandrine to obtain a solution 2;
S4, adding the osmotic pressure regulator measured in the step S1 into the solution 2 obtained in the step S2, stirring to completely dissolve the osmotic pressure regulator, filtering, sterilizing, and obtaining the tetrandrine atomized inhalation solution.
8. The method for preparing an aerosol inhalation solution of tetrandrine according to claim 7, wherein in the step S3, the stirring temperature is 25-60 ℃, the stirring rotation speed is 100-400r/min, the stirring time is 5-30min, and the pH value of the solution 2 is 3-6.
9. The method for preparing a tetrandrine aerosol inhalation solution according to claim 7, wherein in the step S4, the osmotic pressure of the tetrandrine aerosol inhalation solution is 270-310mOsmol/kg.
10. Use of a tetrandrine aerosol inhalation solution according to claim 1 for the preparation of a medicament for the treatment of pulmonary fibrosis.
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