CN116327743A - Application of baicalein inhalation preparation in preparation of acute lung injury treatment drugs - Google Patents

Application of baicalein inhalation preparation in preparation of acute lung injury treatment drugs Download PDF

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CN116327743A
CN116327743A CN202310393097.6A CN202310393097A CN116327743A CN 116327743 A CN116327743 A CN 116327743A CN 202310393097 A CN202310393097 A CN 202310393097A CN 116327743 A CN116327743 A CN 116327743A
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baicalein
inhalation
preparation
acute lung
lung injury
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CN116327743B (en
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孙中英
叶思
李新路
丁白帆
葛展虹
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Nanjing Qinling Pharmaceutical Technology Co ltd
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Nanjing Qinling Pharmaceutical Technology Co ltd
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Abstract

The invention discloses application of baicalein inhalation preparation in preparing a medicine for treating acute lung injury, wherein the inhalation preparation is a liquid preparation or a powder aerosol. In an LPS-induced acute lung injury mouse model, the inhalation baicalein can obviously inhibit the weight loss, the inflammatory cytokine expression, the lung edema condition, the leukocyte infiltration condition and the pathological injury of the lung of the mouse, and the treatment effect of the medicament is dose-dependent. These effects indicate that: the development of baicalein for inhalation has great pharmaceutical prospect for treating acute lung injury.

Description

Application of baicalein inhalation preparation in preparation of acute lung injury treatment drugs
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of a baicalein inhalation preparation in preparation of a medicine for treating acute lung injury.
Background
Acute lung injury (Acute Lung Injury, ALI) is a clinically common critical condition with high morbidity and mortality, and if the optimal treatment time is missed, it is highly likely to develop respiratory distress syndrome (Acute Respiratory Distress Syndrome, ARDS), clinically manifested as severe hypoxia and dyspnea. At present, the treatment of ALI/ARDS is mainly through mechanical ventilation in clinic, but no clearly effective medicine exists in the aspect of medicine treatment, and the known hormone treatment has limited curative effect. Therefore, active search for drugs for treating acute lung injury diseases can effectively improve survival rate of patients suffering from ALI/ARDS.
In the aspect of respiratory disease treatment, the inhalant is an ideal drug administration agent which is rapidly developed clinically in recent years, and can form aerosol from the drug through an atomization system and directly reach the focus of the respiratory system for treatment through inhalation. Because the medicine can directly act on the focus of the respiratory system without being absorbed by the gastrointestinal tract after inhalation administration, compared with oral administration or other common dosage forms, the dosage form has obvious bioavailability and drug effect advantages, and the inhalation administration gradually becomes the first dosage form for treating lung diseases clinically.
Baicalein (Baicalein) is a monomer compound extracted and separated from Scutellariae radix, and has chemical name of 5,6,7-trihydroxyflavone (5, 6, 7-trihydroxyflavone) and molecular formula of C 15 H 10 O 5 (MW.270.24), the chemical formula is shown below:
Figure BDA0004176554190000011
baicalein has various pharmacological effects of resisting bacteria, resisting virus, protecting liver, promoting gallbladder function, and promoting urination, and is the content of Scutellariae radixOne of the highest flavonoids.
In the prior art, no research on treating acute lung injury by inhalation of baicalein exists, so that research and development of a new strategy for treating acute lung injury have important significance.
Disclosure of Invention
The invention aims to provide an application of baicalein inhalation preparation in preparing a medicament for treating acute lung injury.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the application of baicalein inhalation preparation in preparing medicament for treating acute lung injury is provided.
Further, the baicalein inhalation preparation is a liquid preparation or a powder spray.
Further, the liquid preparation comprises baicalein, sodium chloride, citric acid, sodium citrate, polysorbate 80 and water for injection, wherein the particle size of the baicalein is 0.5-10 mu m.
Still further, the content of baicalein is 2mg/mL-20mg/mL.
Further, the powder spray comprises baicalein and one or more pharmaceutically acceptable carriers, wherein the particle size of the baicalein is 0.5-10 mu m.
Still further, the carrier is lactose or cyclodextrin. Preferably, the cyclodextrin is hydroxypropyl-beta-cyclodextrin.
Still further, the powder spray further comprises one or more pharmaceutically acceptable additives, wherein the additives are magnesium stearate.
At present, the related preparation of the baical skullcap root is an oral preparation, no inhalation preparation capable of rapidly reaching focus to exert drug effect is available, and the compound with anti-inflammatory effect at home and abroad is developed into the inhalation preparation, so that the compound has the advantages of rapid local effect, gastrointestinal degradation effect and liver first pass effect can be avoided, the drug is rapidly absorbed, the effect is rapid after administration, the drug is rapidly absorbed in the lung by means of respiratory mucosa and abundant capillaries of the lung, the drug rapidly enters the systemic circulation to achieve the treatment purpose, and the respiratory diseases can be effectively treated.
An inhaled formulation refers to a liquid or solid formulation of the drug substance dissolved or dispersed in a suitable medium for delivery to the lungs in aerosol or vapor form for local or systemic action. Depending on the type of formulation, the formulation may contain propellants, co-solvents, diluents, bacteriostats, co-solvents, stabilizers, etc., and the excipients should not affect the function of the respiratory mucosa or cilia. Inhalation formulations include inhalation aerosols, inhalation powder aerosols, inhalation sprays, inhalation liquid formulations and formulations which can be converted to vapor.
The technical scheme of the invention is that the development of the baicalein inhalation preparation is performed based on the remarkable drug effect of inhalation baicalein on LPS-induced acute lung injury of mice, and the baicalein inhalation preparation capable of rapidly reaching the lung to exert the treatment effect and the preparation method thereof are provided.
The animal experiment result in the invention shows that: in an LPS-induced acute lung injury mouse model, the inhalation baicalein can obviously inhibit the weight loss, the inflammatory cytokine expression, the lung edema condition, the leukocyte infiltration condition and the pathological injury of the lung of the mouse, and the treatment effect of the medicament is dose-dependent. These effects indicate that: the development of baicalein for inhalation has great pharmaceutical prospect for treating acute lung injury.
The research result of the invention shows that: the cyclodextrin hollow structure can realize the effect of carrying active ingredients, and meanwhile, the addition of magnesium stearate can effectively realize the effective separation of the active ingredients and cyclodextrin, and realize stable and controllable micro-particle dosage, thereby ensuring the stability of clinical dosage.
Drawings
FIG. 1 is a graph showing the particle size distribution of baicalein number 1 after jet milling.
FIG. 2 is a graph showing the particle size distribution of baicalein number 2 after jet milling.
FIG. 3 is a scanning electron microscope image of baicalein number 2 after jet milling.
FIG. 4 is a fine particle dose distribution diagram of baicalein inhalation suspension 1 in example 1.
FIG. 5 is a graph showing the dose distribution of fine particles of baicalein inhalation powder for use in example 2.
FIG. 6 is a scanning electron microscope image of hydroxypropyl-beta-cyclodextrin.
FIG. 7 is a scanning electron microscope image of the milled mixture of baicalein and hydroxypropyl-beta-cyclodextrin of example 3.
FIG. 8 is a graph showing the dose distribution of fine particles of baicalein inhalation powder for use in example 3.
FIG. 9 is a scanning electron microscope image of a sieved mixture of baicalein and hydroxypropyl-beta-cyclodextrin in example 4.
FIG. 10 is a graph showing the fine particle dose distribution of the baicalein inhalation powder for 0 day in example 4.
FIG. 11 is a graph showing the fine particle dose distribution of baicalein inhalation powder for 1 month after standing in example 4.
FIG. 12 is a scanning electron microscope image of the sieved mixture of baicalein and hydroxypropyl-beta-cyclodextrin and magnesium stearate in example 5.
FIG. 13 is a graph showing the fine particle dose distribution of the baicalein inhalation powder for 0 day in example 5.
FIG. 14 is a graph showing the dose distribution of fine particles of baicalein inhalation powder for 1 month after standing in example 5.
FIG. 15 shows the results of measurement of the number of leukocytes, lymphocytes and neutrophils in the circulatory system of the mice of test example 1.
FIG. 16 shows the results of measurement of the expression levels of inflammatory factors IL-1. Beta., IL-6 and TNF-. Alpha.in serum of the mice of test example 1.
FIG. 17 shows the results of measurement of the expression levels of inflammatory factors IL-1. Beta., IL-6 and TNF-. Alpha.in alveolar lavage fluid of a mouse of test example 1.
FIG. 18 shows the results of the wet weight/dry weight ratio test of the lung of the mice of test example 1.
FIG. 19 shows the results of the measurement of the total protein concentration in the alveolar lavage fluid of the mouse of test example 1.
FIG. 20 shows the results of measurement of the number of leukocytes in the alveolar lavage fluid of test example 1.
FIG. 21 shows the results of pathological lesions of the lungs of the mice of test example 1.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The invention adopts the jet milling mode to control the particle size of the baicalein so as to ensure that the baicalein for inhalation prepared by the raw material medicine with the particle size can realize effective deposition of the lung.
Figure BDA0004176554190000031
The particle size distribution curve results in fig. 1 and 2 show that the particle size distribution curve after jet milling is a single peak with narrower distribution, and is close to normal distribution, which shows that the particle size distribution of baicalein is uniform. Therefore, the particle size of the baicalein can be effectively controlled by adopting an air flow crushing mode.
Example 1
Preparation method of baicalein inhalation suspension
In the process of preparing the atomized inhalation suspension, firstly, a proper amount of surfactant is added into water-soluble auxiliary materials to increase the wettability of baicalein, and the baicalein is fully infiltrated into the auxiliary material solution by adopting a high-speed shearing mode. Meanwhile, in order to ensure that the baicalein suspension can be effectively absorbed by the lung after being inhaled through the oral cavity, the embodiment ensures that the particle size of the baicalein can realize the following range by carrying out micronization treatment: x is X 10 ：0.5～1.5μm；X 50 ：1～5μm；X 90 ：2～10μm。
Baicalein inhalation suspension was prepared as follows.
Figure BDA0004176554190000041
In the above table, the formulation of the adjuvant solution is as follows:
prescription composition Single dose prescription
Polysorbate
80 2mg
Citric acid 0.56mg
Sodium citrate 1.0mg
Sodium chloride 17mg
Water for injection 2mL
The aerodynamic particle size of the aerosol inhalation formulation suspension 1 was analyzed using a cascade impactor and the results are shown in figure 4. Fig. 4 shows that the fine particle fraction (FPF%) in suspension 1 is higher, 41%, indicating that the aerosol inhalation suspension formulation can achieve higher pulmonary deposition rates.
Example 2
Preparation method of baicalein inhalation powder aerosol containing lactose
In order to improve the storage stability of the inhalation preparation, the embodiment provides a preparation method of baicalein inhalation powder fog agent, wherein the particle size of baicalein is in the following range by adopting a micronization mode: x is X 10 ：0.5～1.5μm；X 50 ：1～5μm；X 90 ：2～10μm。
The preparation method of the powder fog agent comprises the following steps:
1. weighing baicalein, a proper amount of magnesium stearate and lactose (ML 001), wherein the baicalein accounts for 4% -20% of the prescription; the prescription composition is as follows:
prescription composition Dosage of single dose Action
Baicalein (baicalein) 1mg Active ingredient
Magnesium stearate 0.02mg Lubricant
Lactose and lactose 10mg Carrier body
2. Sieving lactose 10mg and magnesium stearate (0.01 mg) to obtain carrier I;
3. sieving baicalein and residual magnesium stearate (0.01 mg), and mixing to obtain mixture II;
4. sieving and mixing the carrier I and the mixture II to obtain an intermediate;
5. the intermediate is filled in a capsule shell for inhalation, wherein the capsule shell is a gelatin capsule shell or a hydroxypropyl methylcellulose capsule shell for inhalation, and the filling amount is 10 mg-20 mg.
The result of the fine particle dose detection using a cascade impactor is shown in fig. 5. Figure 5 shows that the fine particle fraction (FPF%) of the inhaled powder aerosol is higher, 37%, indicating that under the prescription process, baicalein is easily separated from carrier lactose, and a higher lung deposition rate is obtained.
Example 3
Preparation method of cyclodextrin-containing baicalein inhalation powder aerosol by grinding process
In order to improve the storage stability of the inhalation preparation, the embodiment provides a baicalein inhalation powder fog and a preparation method thereof, wherein the particle size of baicalein is in the following range by adopting a micronization mode: x is X 10 ：0.5～1.5μm；X 50 ：1～5μm；X 90 ：2～10μm。
The preparation method of the powder fog agent comprises the following steps:
1. weighing baicalein and hydroxypropyl-beta-cyclodextrin, wherein the baicalein accounts for 4% -20% of the prescription; the prescription composition is as follows:
prescription composition Dosage of single dose Action
Baicalein (baicalein) 1mg Active ingredient
Hydroxypropyl-beta-cyclodextrin 20mg Carrier body
2. Grinding and mixing 20mg of beta-cyclodextrin and baicalein to obtain a mixture I to obtain an intermediate;
3. the intermediate is filled in a capsule shell for inhalation, wherein the capsule shell is a gelatin capsule shell or a hydroxypropyl methylcellulose capsule shell for inhalation, and the filling amount is 20 mg-30 mg.
And (3) observing the mixed state of the hydroxypropyl-beta-cyclodextrin and the intermediate by adopting a scanning electron microscope, wherein the hydroxypropyl-beta-cyclodextrin is a complete sphere or a broken sphere as shown in fig. 6 and 7, and the sphere of the hydroxypropyl-beta-cyclodextrin is destroyed after grinding, so that the raw material medicine is uniformly adsorbed on fragments.
The cascade impactor is adopted to detect the dosage of the micro-particles, and the detection result is shown in figure 8. Fig. 8 shows that the fine particle fraction (FPF%) of the powder aerosol prepared by the grinding process is 26%, and it is presumed that baicalein is not easy to fall off from the carrier, and the lung deposition rate is low, so that the powder aerosol is not easy to reach the lung.
Example 4
Preparation method of cyclodextrin-containing baicalein inhalation powder aerosol through sieving process
In order to increase the effective deposition amount of the inhalation preparation lung, the embodiment provides baicalein inhalation powder fog and a preparation method thereof, wherein the particle size of baicalein is in the following range by adopting a micronization mode: x is X 10 ：0.5～1.5μm；X 50 ：1～5μm；X 90 ：2～10μm。
The preparation method of the powder fog agent comprises the following steps:
1. weighing baicalein and hydroxypropyl-beta-cyclodextrin, wherein the baicalein accounts for 4% -20% of the prescription; the prescription composition is as follows:
prescription composition Dosage of single dose Action
Baicalein (baicalein) 1mg Active ingredient
Hydroxypropyl-beta-cyclodextrin 20mg Carrier body
2. Sieving and mixing 20mg of beta-cyclodextrin and baicalein to obtain a mixture I to obtain an intermediate;
3. the intermediate is filled in a capsule shell for inhalation, wherein the capsule shell is a gelatin capsule shell or a hydroxypropyl methylcellulose capsule shell for inhalation, and the filling amount is 20 mg-30 mg.
As shown in figure 9, the intermediate material mixed state is observed by a scanning electron microscope, and the spherical structure of the hydroxypropyl-beta-cyclodextrin can be maximally reserved by adopting a sieving process, and the baicalein is uniformly adsorbed on the spherical body of the hydroxypropyl-beta-cyclodextrin.
For inhalation powder aerosol, increasing the effective deposition amount of the lung is a key index for improving the drug effect, so that the index is subjected to important research in the development process of prescription technology. As can be seen from the results of fig. 8 and 10, sieving maximizes the avoidance of structural damage to the cyclodextrin, and thus increases the effective deposition in the lungs, compared to the milling process; the prepared samples were left at room temperature for 1 month, and as can be seen from the results of fig. 10 and 11, the fine particle fraction (FPF%) was 35% and 31%, respectively, without significant drop, indicating that the key quality index was stable and controllable during the leaving process.
Example 5
Preparation method of baicalein inhalation powder spray containing cyclodextrin and magnesium stearate
1. Weighing baicalein, magnesium stearate and hydroxypropyl-beta-cyclodextrin, wherein the baicalein accounts for 4% -20% of the prescription; the prescription composition is as follows:
prescription composition Dosage of single dose Action
Baicalein (baicalein) 1mg Active ingredient
Magnesium stearate 0.02mg Lubricant
Hydroxypropyl-beta-cyclodextrin 20mg Carrier body
2. Sieving and mixing 20mg of beta-cyclodextrin and a proper amount of magnesium stearate (0.01 mg) to obtain a carrier I;
3. sieving baicalein and residual magnesium stearate (0.01 mg), and mixing to obtain mixture II;
4. sieving and mixing the carrier I and the mixture II to obtain an intermediate;
5. the intermediate is filled in a capsule shell for inhalation, wherein the capsule shell is a gelatin capsule shell or a hydroxypropyl methylcellulose capsule shell for inhalation, and the filling amount is 20 mg-30 mg.
And observing the mixed state of the intermediate materials by a scanning electron microscope, as shown in figure 12, the small-particle baicalein and magnesium stearate are uniformly adsorbed on the sphere structure of the hydroxypropyl-beta-cyclodextrin.
For the inhalation powder spray, the stability of the prepared preparation is a key index for influencing the clinical effectiveness of the product, and the prepared sample is placed for 1 month at room temperature, and the results of fig. 13 and 14 show that the proportion of the fine particles (FPF%) is 39% and 37%, respectively, and no obvious drop exists, so that the dosage of the fine particles is stable and controllable.
Test example 1
Research on treatment effect of inhalation baicalein on lipopolysaccharide-induced acute lung injury of mice
1. Experimental materials
(1) Medicament
Baicalein suspension for inhalation prepared in example 1 (2 mg/mL, 10mg/mL, 20 mg/mL).
(2) Experimental animal
C57BL/6J mice, male, 8 week old, purchased from Henan Skibe Biotech Co., ltd (laboratory animal production license: SCXK 2020-0005). Feeding in SPF environment at 20-25 deg.C and relative humidity of 30-70%, 12: lighting for 12h in a dark state; can drink water and eat.
(3) Reagent(s)
1) Lipopolysaccharide (LPS): sigma Co., ltd., cargo number: l2880.
2) PBS solution: naCl 8.0g, KH 2 PO 4 2.0g、Na 2 HPO 4 ·H 2 O1.56 g and KCl 0.20g were dissolved in 1000mL of ultrapure water, sterilized by autoclaving, and stored at 4 ℃.
3) IL-1 beta ELISA kit: ablronal company, cat: RK00006.
4) TNF-alpha ELISA kit: ablronal company, cat: RK00027.
5) IL-6ELISA kit: ablronal company, cat: RK00008.
2. The experimental method comprises the following steps:
24 model mice are selected and randomly divided into 4 groups according to body weight, namely a model control group, a low, medium and high dose group of tested samples, and 6 mice in each group. The remaining 6 mice were normal controls. The following table is provided:
Figure BDA0004176554190000071
Figure BDA0004176554190000081
the model control group, the tested sample low dose (2 mg/mL), the medium dose (10 mg/mL) and the high dose (20 mg/mL) groups of mice were subjected to tracheal instillation of LPS (10 mg/kg), and a lung injury model of the mice was established. After the first administration is molding for 3 hours, the administration is carried out by adopting a lung liquid quantitative atomizer for intratracheal atomization, the administration is carried out for 1 time per day, the continuous administration is carried out for 3 days, and the administration volume is 0.1mL.
The mice were weighed daily for a total of 4 times during the experiment.
On day 4 of the experiment, 3 mice per group were bled for routine blood determination. The remaining 3 mice in each group were bled and serum isolated and the levels of inflammatory factors IL-1. Beta., IL-6 and TNF-alpha were measured in the mouse serum by ELISA experiments.
All mice were euthanized after blood collection, lungs were taken to weigh the wet weight, lung tissue was lyophilized at-80 ℃, lung dry weight was weighed, and lung wet weight to dry weight ratio was calculated.
The method comprises the steps of taking a mouse alveolar lavage fluid, detecting the levels of inflammatory factors IL-1 beta, IL-6 and TNF-alpha in the lavage fluid through an ELISA (enzyme-linked immunosorbent assay), detecting the total protein concentration in the lavage fluid through a BCA (broadcast-specific area) experiment, and counting white blood cells of the lavage fluid.
Mice lungs were fixed with 4% paraformaldehyde and then sectioned in paraffin for HE staining.
3. Statistical methods:
all metering data to
Figure BDA0004176554190000082
The comparison between groups is shown using one-way variance (ANOVA) analysis. P (P)<The difference was considered statistically significant at 0.05.
4. Experimental results:
inhalation of baicalein suspension can reduce the number of leukocytes, lymphocytes and neutrophils in the circulatory system of mice (see fig. 15); ELISA kit shows that the baicalein suspension for inhalation can reduce the expression level of inflammatory factors IL-1 beta, IL-6 and TNF-alpha in the serum of mice (see figure 16); ELISA kit shows that the baicalein suspension for inhalation can reduce the expression level of inflammatory factors IL-1 beta, IL-6 and TNF-alpha in the alveolar lavage fluid of the mice (see figure 17); inhalation of baicalein suspension can reduce the rise of wet weight and dry weight ratio of lung of mice (see figure 18); inhalation of baicalein suspension reduced total protein concentration in mouse alveolar lavage fluid (see figure 19); inhalation of baicalein suspension reduced the number of leukocytes in the alveolar lavage fluid of mice (see fig. 20); inhalation of baicalein suspension can alleviate pathological injury of mouse lung (see figure 21).
From the above results, it was found that the baicalein suspension for inhalation has a good therapeutic effect on lipopolysaccharide-induced acute lung injury mice.

Claims (7)

1. The application of baicalein inhalation preparation in preparing medicament for treating acute lung injury is provided.
2. The use according to claim 1, characterized in that: the baicalein inhalation preparation is liquid preparation or powder spray.
3. The use according to claim 2, characterized in that: the liquid preparation comprises baicalein, sodium chloride, citric acid, sodium citrate, polysorbate 80 and water for injection, wherein the particle size of the baicalein is 0.5-10 mu m.
4. A use according to claim 3, characterized in that: the content of baicalein is 2mg/mL-20mg/mL.
5. The use according to claim 2, characterized in that: the powder spray comprises baicalein and one or more pharmaceutically acceptable carriers, wherein the particle size of the baicalein is 0.5-10 mu m.
6. The use according to claim 5, characterized in that: the carrier is lactose or cyclodextrin.
7. The use according to claim 5, characterized in that: the powder spray also comprises one or more pharmaceutically acceptable additives, wherein the additives are magnesium stearate.
CN202310393097.6A 2023-04-13 Application of baicalein inhalation preparation in preparation of acute lung injury treatment drugs Active CN116327743B (en)

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