CN119302919A - A sodium pyruvate aerosol inhalation preparation and preparation method thereof - Google Patents
A sodium pyruvate aerosol inhalation preparation and preparation method thereof Download PDFInfo
- Publication number
- CN119302919A CN119302919A CN202411845839.5A CN202411845839A CN119302919A CN 119302919 A CN119302919 A CN 119302919A CN 202411845839 A CN202411845839 A CN 202411845839A CN 119302919 A CN119302919 A CN 119302919A
- Authority
- CN
- China
- Prior art keywords
- sodium pyruvate
- baicalin
- preparation
- berberine
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the field of biological medicine, and in particular relates to a sodium pyruvate atomization inhalation preparation and a preparation method thereof. The preparation method of the atomization inhalation preparation comprises the following raw materials, by weight, 0.04-0.09 part of baicalin-berberine/sodium pyruvate inclusion compound freeze-dried powder and 100 parts of physiological saline, wherein the preparation process of the baicalin-berberine comprises the steps of reacting berberine with 4-chlorophenyl glycidyl ether to obtain an intermediate A, mixing the intermediate A with baicalin solution, reacting under the condition of a catalyst, and purifying after the reaction is finished to obtain the baicalin-berberine. The sodium pyruvate aerosol inhalation preparation can effectively relieve asthma symptoms, and has excellent antibacterial property, stability and biological activity.
Description
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to a sodium pyruvate atomization inhalation preparation and a preparation method thereof.
Background
Bronchial asthma, abbreviated as asthma, is a common chronic inflammatory respiratory disease, and the pathogenesis includes airway chronic inflammation, airway hyperreactivity, airway neuromodulation disorder, genetic mechanism, respiratory tract virus infection and the like, and is mainly characterized in that the airway has symptoms of recurrent asthma, breathlessness, chest distress or cough and the like, and dyspnea and hypoxia can occur when serious. Often attacks or exacerbations at night and in the early morning. Asthma is related to genetic and environmental factors, wherein the genetic factors mainly determine the predisposition of patients, and the environmental factors such as various allergens, air quality, smoking, exercise, etc. are specific triggers. Common asthma types are exercise, pharmaceutical, occupational, allergic, etc. Symptoms of asthma are mainly wheezing, shortness of breath, chest distress or cough.
Sodium pyruvate is the sodium salt of pyruvic acid (pyruvicacid). Pyruvic acid is a keto acid containing three carbons, is colorless liquid, has smell similar to acetic acid, is an important intermediate metabolite in the process of sugar metabolism, and is a precursor of various useful compounds, so that the pyruvic acid has wide application in industry and scientific research of chemical industry, pharmacy, agrochemicals and the like. Along with the intensive research, the scholars find that sodium pyruvate can also be used as a medicament for treating asthma. The existing sodium pyruvate preparation has the problem of unsatisfactory effect on improving asthma symptoms, so that the asthma symptoms cannot be effectively and rapidly relieved.
Traditional Chinese medicines are favored by people because of the advantages of high safety, low toxic and side effects and the like. Baicalin (baicalin) is a flavonoid compound extracted and separated from dry roots of baical skullcap root (Scutellaria baicalensis Georgi) of dicotyledonous Labiatae, has remarkable biological activity, has antibacterial, anti-inflammatory, fire-purging and detoxifying, hemostasis, miscarriage prevention, antiallergic and spasmolytic effects, is also a specific inhibitor of mammal liver salivary enzyme, has the effect of regulating certain diseases, and has stronger physiological efficacy of anticancer reaction.
Berbamine is a dibenzyl isoquinoline alkaloid extracted from Coptidis rhizoma, radix Berberidis Amurensis, and Berberis Amurensis, and has antiarrhythmic, antitumor, and leukocyte proliferation promoting effects. At present, the two components derived from the traditional Chinese medicines are not subjected to chemical grafting modification and are used for relieving asthma symptoms.
Disclosure of Invention
The first aim of the invention is to provide an atomized inhalation preparation of sodium pyruvate, which has high stability and strong antibacterial performance.
The second aim of the invention is to provide a preparation method of sodium pyruvate atomization inhalation preparation, which is simple and easy to practice.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a sodium pyruvate atomization inhalation preparation comprises the following raw materials, by weight, 0.04-0.09 parts of baicalin-berbamine/sodium pyruvate inclusion compound freeze-dried powder and 100 parts of physiological saline;
the preparation process of the baicalin-berbamine comprises the following steps:
And (3) reacting the berberine with 4-chlorophenyl glycidyl ether to obtain an intermediate A, mixing the intermediate A with baicalin solution, reacting under the condition of a catalyst, and purifying after the reaction is finished to obtain the baicalin-berberine.
Further, the molar ratio of the intermediate A to the baicalin to the catalyst is 1:0.25-0.5:15-20, and the catalyst is triethylamine.
Further, the condition of the reaction of the intermediate A and the baicalin solution is that the reaction is carried out for 30-60 min at 75-90 ℃.
Further, the molar ratio of the berberine to the 4-chlorophenyl glycidyl ether is 1:1.2-1.5, and the reaction condition is that the berberine reacts for 2-4 hours at 55-70 ℃.
The preparation method of the baicalin-berberine/sodium pyruvate inclusion compound freeze-dried powder comprises the steps of taking a polymer as a carrier, loading sodium pyruvate and baicalin-berberine on the polymer by adopting an emulsion solvent volatilization method to prepare nano-particles, carrying out surface hydrophilic modification on the nano-particles, adding the modified nano-particles into a freeze-drying protective agent solution, and carrying out freeze-drying.
Further, the mass ratio of the sodium pyruvate to the baicalin-berbamine to the polymer is 1:1-10:1-10, and the polymer is selected from one of polylactic acid, polylactic acid-glycolic acid copolymer and polycaprolactone.
Further, the concentration of the hydrophilic compound adopted in the hydrophilic modification is 0.3-0.6 mol/L, the hydrophilic compound is selected from polyethylene glycol or polyvinylpyrrolidone, and the freeze-drying protective agent consists of mannitol and trehalose with the mass ratio of 1:1-2.
The freeze drying method comprises the steps of pre-freezing for 2-4 hours at a temperature of minus 30 ℃ to minus 40 ℃ under normal pressure, vacuumizing, preserving heat for 25-30 hours at a temperature of minus 5-30 Pa to minus 1-10 ℃, preserving heat for 1-2 hours at a temperature of 0-5 ℃, and preserving heat for 12-16 hours at a temperature of 25-30 ℃.
The method comprises the specific operation of adding an oil phase into a water phase under stirring, emulsifying and solidifying, centrifuging and washing, wherein the water phase is a polyvinyl alcohol solution, and the oil phase is one of a polylactic acid solution, a polylactic acid-glycolic acid copolymer solution and a polycaprolactone solution;
Wherein the mass concentration of the polyvinyl alcohol in the water phase is 0.8-1.5%.
A method for preparing sodium pyruvate atomized inhalation preparation comprises mixing baicalin-berbamine/sodium pyruvate clathrate lyophilized powder with physiological saline according to the above ratio.
The beneficial technical effects of the invention are as follows:
1. The invention provides a sodium pyruvate atomization inhalation preparation, which mainly comprises baicalin-berbamine/sodium pyruvate inclusion compound freeze-dried powder. Experiments show that baicalin, berbamine and sodium pyruvate are directly matched for use, and the effect is superior to that of single use of sodium pyruvate, so that the two components play a positive role in relieving asthma symptoms. The inventor further carries out structural modification on the berberine by reacting with 4-chlorophenyl glycidyl ether, then grafts the berberine with baicalin, and the effect of the compound is better than that of the compound obtained by matching baicalin, berberine and sodium pyruvate.
2. The invention adopts an emulsion solvent volatilization method to load baicalin-berbamine and sodium pyruvate onto a polymer carrier so as to enhance the absorption performance and stability of the medicine in the lung.
3. In addition, the sodium pyruvate aerosol inhalation preparation can effectively relieve asthma symptoms, and has excellent antibacterial property, stability and biological activity.
Drawings
FIG. 1 is a 1 HNMR of baicalin-berbamine in example 1 of the present invention.
Detailed Description
The following is a further detailed description of the invention in connection with certain preferred embodiments, and it is not to be construed that the invention is limited to such embodiments. It will be apparent to those skilled in the art that several simple deductions or substitutions may be made without departing from the spirit of the invention, and these should be considered to be within the scope of the invention. The specific conditions not specified in the examples were carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used, unless otherwise specified, are all conventional products obtained from commercial sources.
Examples
Example 1
The embodiment provides a sodium pyruvate atomization inhalation preparation, which consists of 0.06 parts of baicalin-berbamine/sodium pyruvate inclusion compound freeze-dried powder and 100 parts of physiological saline.
The preparation process of baicalin-berbamine comprises the following steps:
Reacting the berberine and the 4-chlorophenyl glycidyl ether for 3 hours at 60 ℃ according to the mol ratio of the berberine to the 4-chlorophenyl glycidyl ether of 1:1.3, cooling the reaction liquid to room temperature after the reaction is finished, and removing unreacted 4-chlorophenyl glycidyl ether by reduced pressure distillation to obtain an intermediate A;
Mixing the intermediate A with baicalin solution (DMF solvent) according to the mol ratio of 1:0.4:17 of the intermediate A, baicalin and triethylamine, reacting for 45min at 80 ℃ in the presence of triethylamine, immediately filtering the reaction solution after the reaction is finished, cooling to room temperature, adjusting the pH to 2 by using hydrochloric acid, crystallizing and filtering to obtain the compound.
The nuclear magnetic characterization result of the obtained baicalin-berberine is shown in figure 1:
1H-NMR(400MHz,DMSO)δ=2.27（s,12H）,2.65（m,4H）,2.75-2.83（m,16H）,3.07（m,4H）,3.72-3.73（d,12H）,3.84（s,6H）,3.96（m,4H）,4.13（m,1H）,4.21-4.30（m,10H）,4.52（s,1H）,4.61（m,2H）,4.78（s,1H）,4.98（d,1H）,5.78-5.81（m,3H）,6.17（s,1H）,6.61（s,2H）,6.72（s,1H）,6.81-6.86（m,6H）,6.94-6.99（s,8H）,7.02-7.10（d,6H）,7.32-7.34（d,6H）,7.47-7.49（d,3H）,7.78（m,2H）,8.74（s,1H）,12.87（s,1H）, The above results confirm that the obtained product is the target product.
The preparation method of the baicalin-berbamine/sodium pyruvate inclusion compound freeze-dried powder comprises the following steps:
Dissolving polyvinyl alcohol in deionized water to obtain a water phase, wherein the mass concentration of the polyvinyl alcohol in the water phase is 1 percent for standby;
adding sodium pyruvate and baicalin-berbamine into polylactic acid solution (methylene dichloride is used as a solvent) according to the mass ratio of the sodium pyruvate to the baicalin-berbamine to the polylactic acid of 1:6:6, and starting stirring equipment to stir to obtain an oil phase, wherein the concentration of the polylactic acid in the oil phase is 0.1g/mL;
adding the oil phase into an aqueous phase under mechanical stirring, emulsifying and solidifying, centrifuging and washing a reaction solution after solidification is finished to obtain nano particles, dispersing the nano particles into a 0.4mol/L polyethylene glycol aqueous solution Z, adding the nano particles into a lyoprotectant solution, wherein the lyoprotectant solution consists of mannitol and an aqueous solution of trehalose with a mass ratio of 1:1, pre-freezing for 3 hours at normal pressure to 35 ℃, vacuumizing, preserving heat for 27 hours at 15Pa to 6 ℃, preserving heat for 1.5 hours at 2 ℃, and then heating to 27 ℃ and preserving heat for 14 hours to obtain the nano-particle.
The preparation method of the sodium pyruvate atomized inhalation preparation comprises the following steps:
The baicalin-berbamine/sodium pyruvate inclusion compound freeze-dried powder is compounded with physiological saline according to the proportion, so as to obtain the pharmaceutical composition.
Example 2
The embodiment provides a sodium pyruvate atomization inhalation preparation, which consists of 0.09 part of baicalin-berbamine/sodium pyruvate inclusion compound freeze-dried powder and 100 parts of physiological saline.
The preparation process of baicalin-berbamine comprises the following steps:
Reacting the berberine and the 4-chlorophenyl glycidyl ether for 2 hours at 55 ℃ according to the mol ratio of the berberine to the 4-chlorophenyl glycidyl ether of 1:1.5, cooling the reaction liquid to room temperature after the reaction is finished, and removing unreacted 4-chlorophenyl glycidyl ether by reduced pressure distillation to obtain an intermediate A;
Mixing the intermediate A with baicalin solution (DMF solvent) according to the mol ratio of 1:0.5:15 of the intermediate A, baicalin and triethylamine, reacting at 75 ℃ for 60min in the presence of triethylamine, immediately filtering the reaction solution after the reaction is finished, cooling to room temperature, adjusting the pH to 2 by using hydrochloric acid, crystallizing and filtering to obtain the compound.
The preparation method of the baicalin-berbamine/sodium pyruvate inclusion compound freeze-dried powder comprises the following steps:
Dissolving polyvinyl alcohol in deionized water to obtain a water phase, wherein the mass concentration of the polyvinyl alcohol in the water phase is 0.8 percent for standby;
adding sodium pyruvate and baicalin-berbamine into the poly lactic acid-glycolic acid copolymer solution (the solvent is methylene dichloride) according to the mass ratio of the sodium pyruvate to the baicalin-berbamine to the poly lactic acid-glycolic acid copolymer of 1:1:1, and starting stirring equipment to stir to obtain an oil phase, wherein the concentration of the poly lactic acid in the oil phase is 0.1g/mL;
adding the oil phase into an aqueous phase under mechanical stirring, emulsifying and solidifying, centrifuging and washing the reaction solution after solidification is finished to obtain nano particles, dispersing the nano particles into a 0.6mol/L polyethylene glycol aqueous solution, adding the nano particles into a freeze-drying protective agent solution, wherein the freeze-drying protective agent solution consists of mannitol and an aqueous solution of trehalose with a mass ratio of 1:1.5, pre-freezing for 4 hours at normal pressure to 30 ℃, vacuumizing, preserving heat for 25 hours at 5Pa to 10 ℃, preserving heat for 1 hour at 5 ℃, and then heating to 30 ℃ and preserving heat for 12 hours to obtain the nano-emulsion.
The preparation method of the sodium pyruvate atomized inhalation preparation comprises the following steps:
The baicalin-berbamine/sodium pyruvate inclusion compound freeze-dried powder is compounded with physiological saline according to the proportion, so as to obtain the pharmaceutical composition.
Example 3
The embodiment provides a sodium pyruvate atomization inhalation preparation, which consists of 0.04 part of baicalin-berbamine/sodium pyruvate inclusion compound freeze-dried powder and 100 parts of physiological saline.
The preparation process of baicalin-berbamine comprises the following steps:
Reacting the berberine and the 4-chlorophenyl glycidyl ether for 4 hours at 70 ℃ according to the mol ratio of the berberine to the 4-chlorophenyl glycidyl ether of 1:1.2, cooling the reaction liquid to room temperature after the reaction is finished, and removing unreacted 4-chlorophenyl glycidyl ether by reduced pressure distillation to obtain an intermediate A;
Mixing the intermediate A with baicalin solution (DMF solvent) according to the mol ratio of 1:0.25:20 of the intermediate A, baicalin and triethylamine, reacting for 30min at 90 ℃ in the presence of triethylamine, immediately filtering the reaction solution after the reaction is finished, cooling to room temperature, adjusting the pH to 2 by using hydrochloric acid, crystallizing and filtering to obtain the compound.
The preparation method of the baicalin-berbamine-sodium pyruvate inclusion compound freeze-dried powder comprises the following steps:
dissolving polyvinyl alcohol in deionized water to obtain a water phase, wherein the mass concentration of the polyvinyl alcohol in the water phase is 1.5 percent for standby;
Adding sodium pyruvate and baicalin-berbamine into a polycaprolactone solution (the solvent is methylene dichloride) according to the mass ratio of the sodium pyruvate to the baicalin-berbamine to the polycaprolactone of 1:10:10, and starting stirring equipment to stir to obtain an oil phase, wherein the concentration of polylactic acid in the oil phase is 0.1g/mL;
Adding the oil phase into an aqueous phase under mechanical stirring, emulsifying and solidifying, centrifuging and washing the reaction solution after solidification is finished to obtain nano particles, dispersing the nano particles into 0.3mol/L polyvinylpyrrolidone aqueous solution, adding the nano particles into a freeze-drying protective agent solution, wherein the freeze-drying protective agent solution consists of mannitol and trehalose aqueous solution with the mass ratio of 1:2, pre-freezing for 2 hours at normal pressure to 40 ℃, vacuumizing, preserving heat for 30 hours at 30Pa and minus 1 ℃, preserving heat for 2 hours at 0 ℃, and then heating to 25 ℃ and preserving heat for 16 hours to obtain the nano-crystalline material.
The preparation method of the sodium pyruvate atomized inhalation preparation comprises the following steps:
The baicalin-berbamine/sodium pyruvate inclusion compound freeze-dried powder is compounded with physiological saline according to the proportion, so as to obtain the pharmaceutical composition.
Comparative example
Comparative example 1
Comparative example 1 provides a sodium pyruvate nebulization inhalation formulation consisting of 0.06 parts baicalin/sodium pyruvate clathrate lyophilized powder, 100 parts normal saline.
The preparation method of the baicalin/sodium pyruvate inclusion compound freeze-dried powder comprises the following steps:
Dissolving polyvinyl alcohol in deionized water to obtain a water phase, wherein the mass concentration of the polyvinyl alcohol in the water phase is 1 percent for standby;
Adding sodium pyruvate and baicalin into polylactic acid solution (solvent is dichloromethane) according to the mass ratio of sodium pyruvate to baicalin to polylactic acid of 1:6:6, and stirring by starting stirring equipment to obtain an oil phase, wherein the concentration of polylactic acid in the oil phase is 0.1g/mL for later use;
Adding the oil phase into an aqueous phase under mechanical stirring, emulsifying and solidifying, centrifuging and washing a reaction solution after solidification is finished to obtain nano particles, dispersing the nano particles into a 0.4mol/L polyethylene glycol aqueous solution, adding the nano particles into a freeze-drying protective agent solution, wherein the freeze-drying protective agent solution consists of mannitol and an aqueous solution of trehalose with a mass ratio of 1:1, pre-freezing for 3 hours at normal pressure to 35 ℃, vacuumizing, preserving heat for 27 hours at 15Pa to 6 ℃, preserving heat for 1.5 hours at 2 ℃, and then heating to 27 ℃ and preserving heat for 14 hours to obtain the nano-emulsion. The procedure is as in example 1.
Comparative example 2
Comparative example 2 provides a sodium pyruvate nebulization inhalation formulation consisting of 0.06 parts berbamine/sodium pyruvate clathrate lyophilized powder, 100 parts normal saline.
The preparation method of the berbamine/sodium pyruvate inclusion compound freeze-dried powder comprises the following steps:
Dissolving polyvinyl alcohol in deionized water to obtain a water phase, wherein the mass concentration of the polyvinyl alcohol in the water phase is 1 percent for standby;
adding sodium pyruvate and berbamine into a polylactic acid solution (a solvent is methylene dichloride) according to the mass ratio of the sodium pyruvate to the berbamine to the polylactic acid of 1:6:6, and starting stirring equipment to stir to obtain an oil phase, wherein the concentration of the polylactic acid in the oil phase is 0.1g/mL for later use;
Adding the oil phase into an aqueous phase under mechanical stirring, emulsifying and solidifying, centrifuging and washing a reaction solution after solidification is finished to obtain nano particles, dispersing the nano particles into a 0.4mol/L polyethylene glycol aqueous solution, adding the nano particles into a freeze-drying protective agent solution, wherein the freeze-drying protective agent solution consists of mannitol and an aqueous solution of trehalose with a mass ratio of 1:1, pre-freezing for 3 hours at normal pressure to 35 ℃, vacuumizing, preserving heat for 27 hours at 15Pa to 6 ℃, preserving heat for 1.5 hours at 2 ℃, and then heating to 27 ℃ and preserving heat for 14 hours to obtain the nano-emulsion. The procedure is as in example 1.
Comparative example 3
Comparative example 3 provides a sodium pyruvate nebulization inhalation formulation consisting of 0.06 parts baicalin/berbamine/sodium pyruvate clathrate lyophilized powder, 100 parts physiological saline.
The preparation method of the baicalin/berbamine/sodium pyruvate inclusion compound freeze-dried powder comprises the following steps:
Dissolving polyvinyl alcohol in deionized water to obtain a water phase, wherein the mass concentration of the polyvinyl alcohol in the water phase is 1 percent for standby;
Adding the mixture of sodium pyruvate, baicalin and berbamine into a polylactic acid solution (the solvent is methylene dichloride) according to the mass ratio of the mixture of the sodium pyruvate, the baicalin and the berbamine to the polylactic acid of 1:6:6, and starting stirring equipment to stir to obtain an oil phase, wherein the concentration of the polylactic acid in the oil phase is 0.1g/mL for later use;
Adding the oil phase into an aqueous phase under mechanical stirring, emulsifying and solidifying, centrifuging and washing the reaction solution after solidification is finished to obtain nano particles, dispersing the nano particles into a 0.4mol/L polyethylene glycol aqueous solution, adding the nano particles into a lyoprotectant solution, wherein the lyoprotectant solution consists of mannitol and an aqueous solution of trehalose with a mass ratio of 1:1, pre-freezing for 3 hours at normal pressure to 35 ℃, vacuumizing, preserving heat for 27 hours at 15Pa to 6 ℃, preserving heat for 1.5 hours at 2 ℃, and then heating to 27 ℃ and preserving heat for 14 hours to obtain the nano-particle. The procedure is as in example 1.
Comparative example 4
Comparative example 4 provides a sodium pyruvate nebulization inhalation formulation consisting of 0.06 parts sodium pyruvate clathrate lyophilized powder, 100 parts physiological saline.
The preparation method of the sodium pyruvate clathrate freeze-dried powder comprises the following steps:
Dissolving polyvinyl alcohol in deionized water to obtain a water phase, wherein the mass concentration of the polyvinyl alcohol in the water phase is 1 percent for standby;
adding sodium pyruvate into a polylactic acid solution (the solvent is methylene dichloride) according to the mass ratio of sodium pyruvate to polylactic acid of 1:6, wherein the concentration of polylactic acid in the oil phase is 0.1g/mL for later use;
Adding the oil phase into an aqueous phase under mechanical stirring, emulsifying and solidifying, centrifuging and washing the reaction solution after solidification is finished to obtain nano particles, dispersing the nano particles into a 0.4mol/L polyethylene glycol aqueous solution, adding the nano particles into a lyoprotectant solution, wherein the lyoprotectant solution consists of mannitol and an aqueous solution of trehalose with a mass ratio of 1:1, pre-freezing for 3 hours at normal pressure to 35 ℃, vacuumizing, preserving heat for 27 hours at 15Pa to 6 ℃, preserving heat for 1.5 hours at 2 ℃, and then heating to 27 ℃ and preserving heat for 14 hours to obtain the nano-particle. The procedure is as in example 1.
Experimental example 1
The safety of the sodium pyruvate aerosol inhalation formulation of example 1 was tested as follows:
Experimental objects
20 Guinea pigs, and the weight is 290-320g;
experimental grouping
A negative control group, namely sodium chloride injection with the mass and volume percentage of 0.9 percent;
The experimental process comprises the steps of carrying out atomization inhalation administration (the dosage of sodium pyruvate is 8 mg/kg) by using an atomization device, continuously administering each group for 14d, and carrying out 1 time a day, wherein the administration volume is 1mL/kg. The administration period and recovery period were observed. All animals were sacrificed 24h after the last administration, and after deconstruction, the animal's lip, palate, tongue, nose, throat, trachea, lung were visually observed for stimulating reactions, whether congestion, red swelling, etc., were observed, and the final evaluation was performed according to visual observation, and the results are shown in table 1.
TABLE 1
As can be seen from table 1, under the experimental conditions, after the sodium pyruvate aerosol inhalation formulation was administered by the guinea pig aerosol inhalation, the respiratory system of the guinea pig was not significantly irritated, and the safety of the sodium pyruvate aerosol inhalation formulation of the present invention was verified.
Experimental example 2
Experimental example 2 the encapsulation efficiency of the sodium pyruvate products of example 1, comparative examples 1-4 was tested as follows:
255nm is selected as the detection wavelength of sodium pyruvate, the content of which is measured by a UV method, and a standard curve of sodium pyruvate is established;
In the process of preparing the nano particles, 1mL of the reaction liquid obtained after the solid-liquid treatment of the example 1 and the comparative examples 1-4 is taken, the volume of the supernatant is measured by an ultraviolet spectrophotometer after centrifugation, the content of free sodium pyruvate in the supernatant is obtained by substituting absorbance into a standard curve, the encapsulation efficiency of sodium pyruvate is calculated, and a calculation formula is shown in table 2, wherein the encapsulation efficiency= (initial addition amount of sodium pyruvate-mass of free sodium pyruvate in the supernatant)/initial addition amount of sodium pyruvate is multiplied by 100%.
TABLE 2
As shown in Table 2, the sodium pyruvate clathrate compound prepared by the invention has higher encapsulation efficiency.
Experimental example 3
The antibacterial effect of the aerosol inhalation formulation of example 1 and comparative examples 1 to 4 was examined as follows:
Staphylococcus aureus liquid (10 8 CFU/mL, 100. Mu.L) and 900. Mu.L of the aerosol inhalation formulations of example 1 and comparative examples 1-4 were added to different shaking tubes and placed in a constant temperature shaking at 37 ℃. After 12 hours, the bacterial solution was diluted to 10 5 CFU/mL with PBS (pH 7.4), 80. Mu.L was added dropwise to an agar plate and spread evenly for 24 hours, then the colony count was observed and recorded, a blank control group (PBS) was set, and the bacterial inhibition ratio was calculated according to the following formula (blank colony count-experimental colony count)/blank colony count X100%, and the results are shown in Table 3.
The hemolytic streptococcus solution B (10 8 CFU/mL, 100. Mu.L) and 900. Mu.L of the aerosol inhalation preparation of the example 1 and the aerosol inhalation preparation of the comparative examples 1-4 are respectively added into different shaking tubes, and placed in constant temperature shaking at 37 ℃. After 12 hours, the bacterial solution was diluted to 10 5 CFU/mL with PBS (pH 7.4), 80. Mu.L was added dropwise to an agar plate and spread evenly for 24 hours, then the colony count was observed and recorded, a blank control group (PBS) was set, and the bacterial inhibition ratio was calculated according to the following formula (blank colony count-experimental colony count)/blank colony count X100%, and the results are shown in Table 3.
TABLE 3 Table 3
As can be seen from Table 3, the bacteriostasis effect of the atomized formulation of example 1 is significantly higher than that of comparative examples 1-4. The analysis shows that the freeze-dried powder in the atomized preparation in the embodiment 1 is prepared from sodium pyruvate and baicalin-berberine, the freeze-dried powder in the atomized preparation in the comparative embodiment 1 is prepared from sodium pyruvate and baicalin, the freeze-dried powder in the atomized inhalation preparation in the comparative embodiment 2 is prepared from berberine and sodium pyruvate, and the freeze-dried powder in the atomized preparation in the comparative embodiment 3 is prepared from a mixture of baicalin and berberine and sodium pyruvate. In conclusion, the baicalin-berbamine has strong effect of resisting staphylococcus aureus and beta-streptococcus hemolyticus. Namely, the sodium pyruvate atomization inhalation preparation has excellent antibacterial effect.
Experimental example 4
The pharmacodynamic properties of the atomized formulations of example 1 and comparative examples 1-3 were investigated as follows:
25 guinea pigs, weighing 290-320g, normally raising the guinea pigs under the conditions of 25 ℃ and humidity of 60 percent and 12 hours of alternate illumination, sequentially placing the guinea pigs into a closed bell jar of a cough and asthma inducing instrument, atomizing 0.6 percent histamine solution (physiological saline is used as a solvent) into the closed bell jar at an atomization speed of 0.15mL/min by using an ultrasonic atomizer for 15 seconds, stopping atomization, observing the asthma inducing latency of the guinea pigs (the period from the start of atomization to the occurrence of asthma symptoms dyspnea of the guinea pigs, and the occurrence of convulsions and falling of the guinea pigs), discarding the guinea pigs with the latency exceeding 2 minutes, screening 18 guinea pigs, and randomly dividing the guinea pigs into 6 groups, wherein one group is set as a blank control group.
The preparation method comprises the steps of 1.25g/kg of uratam solution was used for anesthesia of 18 guinea pigs by intraperitoneal injection, fixing the limbs and the head of the guinea pigs after 30min, starting jugular vein intubation and tracheal intubation, and measuring respiratory flow rate, intrathoracic pressure, respiratory flow rate change and tidal volume of each group of guinea pigs.
15 Mug/mL of histamine was intravenously injected at a rate of 1mL/min for 30min, and then 0.8mg/kg of sodium pyruvate was inhaled by aerosol inhalation for 2min, and after 5min, 15 mug/mL of histamine was intravenously injected for 0.5mL, and after 30min, each group of guinea pigs were kept stable, and each group of parameters was recorded. After 4h of dosing, 15. Mu.g/mL histamine 0.5mL was intravenously injected, and the guinea pigs were kept steady, and each set of parameters was recorded. Airway resistance = change in intrathoracic pressure/change in respiratory flow rate, dynamic lung compliance = tidal volume/change in intrathoracic pressure, wherein the value of the change in respiratory flow rate does not take the directly measured respiratory flow rate value as the source of the calculated data, but rather the differential value of the tidal volume over time (the magnitude of the change in the volume of the chest over time) is the change in respiratory flow rate, because only when gas actually enters the lungs, it will exert the gas exchange function and cause the thoracic relief motion, thereby causing the change in tidal volume.
The calculated airway resistance and dynamic lung compliance value at each animal steady state are taken as normal values before excitation, and after excitation, the value with the largest change amplitude of the airway resistance and the dynamic lung compliance is taken as the airway resistance and the dynamic lung compliance value after administration, and the calculation formula of the change rate is as follows:
Airway resistance change rate= (post-firing airway resistance maximum value-pre-firing airway resistance normal value)/pre-firing airway resistance normal value;
Dynamic lung compliance change rate = (minimum post-challenge dynamic lung compliance-normal pre-challenge dynamic lung compliance)/normal pre-challenge dynamic lung compliance. The results of each group were averaged and are shown in Table 4.
TABLE 4 Table 4
As can be seen from table 4, compared with the blank control group and comparative examples 1 to 3, the sodium pyruvate aerosol inhalation formulation of example 1 showed a significant decrease in the airway resistance increase rate after administration and a significant increase in the dynamic lung compliance decrease rate, which indicates that the asthma of guinea pigs was significantly alleviated after the aerosol administration and the maintenance effect was better after the time was prolonged. The above results indicate that the sodium pyruvate aerosol inhalation preparation of the present invention has excellent bioactivity.
Finally, the above embodiments are only for illustrating the technical solution of the present invention, and are not limited thereto. While the basic principles and main features of the present invention have been described above with specific embodiments, modifications or substitutions may be made thereto without departing from the spirit of the invention as claimed.
Claims (10)
1. The sodium pyruvate atomization inhalation preparation is characterized by comprising the following raw materials, by weight, 0.04-0.09 part of baicalin-berbamine/sodium pyruvate inclusion compound freeze-dried powder and 100 parts of physiological saline;
the preparation process of the baicalin-berbamine comprises the following steps:
And (3) reacting the berberine with 4-chlorophenyl glycidyl ether to obtain an intermediate A, mixing the intermediate A with baicalin solution, reacting under the condition of a catalyst, and purifying after the reaction is finished to obtain the baicalin-berberine.
2. The sodium pyruvate aerosol inhalation preparation according to claim 1, wherein the molar ratio of the intermediate A to baicalin to the catalyst is 1:0.25-0.5:15-20, and the catalyst is triethylamine.
3. The sodium pyruvate aerosol inhalation formulation according to claim 1, wherein the intermediate a is reacted with the baicalin solution under the condition of 30-60 min at 75-90 ℃.
4. The sodium pyruvate aerosol inhalation formulation according to claim 1, wherein the molar ratio of berberine to 4-chlorophenyl glycidyl ether is 1:1.2-1.5, and the reaction condition is that the reaction is carried out for 2-4 hours at 55-70 ℃.
5. The sodium pyruvate aerosol inhalation preparation according to claim 1 is characterized in that the preparation method of the baicalin-berberine/sodium pyruvate inclusion compound freeze-dried powder comprises the steps of taking a polymer as a carrier, loading sodium pyruvate and baicalin-berberine on the polymer by adopting an emulsion solvent volatilization method to prepare nano particles, carrying out surface hydrophilic modification on the nano particles, adding the modified nano particles into a freeze-drying protective agent solution, and carrying out freeze drying.
6. The aerosol inhalation formulation of claim 5, wherein the mass ratio of sodium pyruvate, baicalin-berbamine and polymer is 1:1-10:1-10, and the polymer is one of polylactic acid, polylactic acid-glycolic acid copolymer and polycaprolactone.
7. The sodium pyruvate aerosol inhalation preparation according to claim 5, wherein the hydrophilic compound adopted in the hydrophilic modification has a concentration of 0.3-0.6 mol/L, the hydrophilic compound is selected from polyethylene glycol or polyvinylpyrrolidone, and the lyoprotectant consists of mannitol and trehalose in a mass ratio of 1:1-2.
8. The sodium pyruvate aerosol inhalation formulation according to claim 5, wherein the freeze drying is specifically performed by pre-freezing for 2-4 hours at a temperature of-30 ℃ to-40 ℃ under normal pressure, vacuumizing, preserving heat for 25-30 hours at a temperature of 5-30 Pa, -1 to-10 ℃, preserving heat for 1-2 hours at a temperature of 0-5 ℃, and then raising the temperature to 25-30 ℃ and preserving heat for 12-16 hours.
9. The atomized inhalation preparation of sodium pyruvate according to claim 5, wherein the specific operation of the emulsion solvent volatilization method comprises adding an oil phase into a water phase under stirring, emulsifying and solidifying, centrifuging and washing, wherein the water phase is a polyvinyl alcohol solution, and the oil phase is one of a polylactic acid solution, a polylactic acid-glycolic acid copolymer solution and a polycaprolactone solution;
Wherein the mass concentration of the polyvinyl alcohol in the water phase is 0.8-1.5%.
10. A method for preparing a sodium pyruvate atomization inhalation preparation, which is characterized in that baicalin-berbamine/sodium pyruvate inclusion compound freeze-dried powder is compounded with normal saline according to the proportion of claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202411845839.5A CN119302919A (en) | 2024-12-16 | 2024-12-16 | A sodium pyruvate aerosol inhalation preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202411845839.5A CN119302919A (en) | 2024-12-16 | 2024-12-16 | A sodium pyruvate aerosol inhalation preparation and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN119302919A true CN119302919A (en) | 2025-01-14 |
Family
ID=94192242
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202411845839.5A Pending CN119302919A (en) | 2024-12-16 | 2024-12-16 | A sodium pyruvate aerosol inhalation preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN119302919A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116322759A (en) * | 2020-10-16 | 2023-06-23 | 吉利德科学公司 | Phospholipid compounds and their uses |
-
2024
- 2024-12-16 CN CN202411845839.5A patent/CN119302919A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116322759A (en) * | 2020-10-16 | 2023-06-23 | 吉利德科学公司 | Phospholipid compounds and their uses |
Non-Patent Citations (2)
| Title |
|---|
| H H LEE等: ""Potential antitumor agents. 64. Synthesis and antitumor evaluation of dibenzo[1, 4]dioxin-1-carboxamides: a new class of weakly binding DNA-intercalating agents"", 《JOURNAL OF MEDICINAL CHEMISTRY》, vol. 35, no. 2, 24 January 1992 (1992-01-24), pages 258 - 266, XP002379888, DOI: 10.1021/jm00080a009 * |
| 王峥涛等: "《中药化学》", vol. 1, 30 September 2009, 上海科学技术出版社, pages: 82 - 89 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1304290A (en) | Pulmonary and nasal delivery of Raloxifene | |
| JP2002532430A (en) | Treatment of severe chronic bronchitis (bronchiectasis) using aerosolized antibiotics | |
| CN113332244B (en) | Antiviral oral spray and preparation method thereof | |
| US20200316003A1 (en) | Fudosteine Solution Preparation for Aerosol Inhalation, and Preparation Method Therefor | |
| JPH0211570B2 (en) | ||
| EP1407776B1 (en) | A pharmaceutical colloidal preparation comprising hyaluronic acid biopolymers useful in the treatment of respiratory diseases | |
| CN119302919A (en) | A sodium pyruvate aerosol inhalation preparation and preparation method thereof | |
| CN107174949A (en) | A kind of indoor air purification compound formulation and preparation method thereof | |
| CN100574757C (en) | The compositions of acetylcysteine or its salt and anti-infectives | |
| CN113546089A (en) | Application of 1-ethyl-3,7-dimethylxanthine in the preparation of medicine for treating pneumonia | |
| CN111000901A (en) | Novel method for treating bronchitis by gasifying and inhaling eucalyptus oil | |
| Mussa et al. | Effects of the Crude Aqueous Extract and Isolated Fractions of Morinnga Stenpetalla in Leaves in Normal and Diabetic Mice | |
| CN103860543B (en) | Isoforskolin is in the application preventing and treating in chronic obstructive pulmonary disease | |
| WO2020244493A1 (en) | Organic extract of thistle plant, use thereof and composition | |
| CN114073686B (en) | Application of m-cresol in medicine for treating coronavirus infectious diseases | |
| CN106474122B (en) | Pharmaceutical composition of amoxicillin and clavulanate potassium and application thereof | |
| CN119679785A (en) | A composite preparation containing pyruvate and its preparation method and application | |
| CN115154487B (en) | Polysaccharide salt fog mixture containing probiotics fermentation liquor and used for protecting respiratory tract and application thereof | |
| CN114869896B (en) | Application of cholesterol in modification of oseltamium Wei Fangmian, anti-influenza virus compound and preparation method thereof | |
| CN116019823B (en) | Pharmaceutical composition for treating children hand-foot-mouth disease and application of pharmaceutical composition | |
| CN103269585B (en) | The super sulfated disaccharide for the treatment of elastoser associated conditions | |
| CN114668834B (en) | Composition for treating pneumonia or lung injury and application thereof | |
| CN107550911A (en) | A kind of method of the genistein derivative treatment canker sore containing phenylpiperazine | |
| EP4382531A1 (en) | Crystal forms of kuding saponin a compound, pharmaceutical composition and use thereof | |
| Wang et al. | Ozone therapy ameliorates lipopolysaccharide-induced acute lung injury in mice by inhibiting the NLRP3/ASC/caspase-1 axis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |