阅读说明：本技术 一种共载异烟肼和利福平的微球缓释制剂及其制备方法 (Microsphere sustained-release preparation loaded with isoniazid and rifampicin and preparation method thereof ) 是由 韩翠艳 党欣 周建文 周兆海 王丹 于 2021-09-30 设计创作，主要内容包括：本发明公开了一种共载异烟肼和利福平的微球缓释制剂及其制备方法,运用静电流体喷涂技术将异烟肼和利福平两种抗结核药物共同包载于PLGA微球中,微球平均粒径满足肺部给药有效粒径,包封率高。15天的体外药物释放实验表明微球中药物的累积释药率在40%～60%之间,达到了缓释的技术要求。本发明可有效提高结核药物在肺部的局部药物浓度,减少给药次数、降低毒副反应和提高药物的经济效益比。(The invention discloses a microsphere sustained-release preparation loaded with isoniazid and rifampicin and a preparation method thereof. In-vitro drug release experiments for 15 days show that the cumulative drug release rate of the drugs in the microspheres is between 40 and 60 percent, and the technical requirements of slow release are met. The invention can effectively improve the local drug concentration of the tuberculosis drug in the lung, reduce the drug administration times, reduce the toxic and side effects and improve the economic benefit ratio of the drug.)

1. A method for preparing microsphere sustained release preparation loaded with isoniazid and rifampicin together is characterized in that: the method comprises the following steps:

(1) the preparation process of the microsphere needs to be carried out in the dark, phospholipid and cholesterol are used as emulsifying agents, polyvinyl alcohol (PVA) is used as an emulsion aid, poly (lactic-co-glycolic acid) (PLGA) is used as a carrier material, the ratio of lactic acid to glycolic acid is 50:50 or 75:25, and the weight-average molecular weight is 2.3-5.2 ten thousand;

(2) adding 10-30 mg of precisely weighed isoniazid into a 0.5 ml of aqueous solution of the VA in the water phase, and carrying out water bath at 40 ℃ for 10 min;

(3) the oil phase is prepared by dissolving 15-40 mg of precisely weighed rifampicin, 250-750 mg of PLGA, 120-240 mg of phospholipid and 20-40 mg of cholesterol in 5 mL of mixed solution of dichloromethane and absolute ethyl alcohol, and performing water bath ultrasound for 5 min to promote the dissolution;

(4) adding the water phase into the oil phase, mixing, homogenizing and emulsifying for 2 min by a handheld homogenizer, and pumping into a 5 mL injector, wherein the volume ratio of the oil phase to the water phase is 1: 8-1: 12;

(5) the syringe is placed on a pushing injection pump of the electrostatic spinning machine, and the needle head is selected to be 21^#Establishing a high-voltage electric field between the needle head and the receiving device; after appropriate voltage, injection speed and receiving distance are set, the electrostatic spraying technology is applied to prepare the PLGA microsphere preparation carrying double medicines together, the receiving device is aluminum foil paper, and vacuum drying is carried out for 12 hours at room temperature.

2. The preparation method of microsphere sustained release preparation loaded with isoniazid and rifampicin together as claimed in claim 1, characterized in that: wherein the PVA concentration in the step (2) is between 0.5 and 2 percent, and the preferred concentration is 1.4 percent.

3. The preparation method of microsphere sustained release preparation loaded with isoniazid and rifampicin together as claimed in claim 1, characterized in that: wherein the preferable adding amount of PLGA in the step (3) is 350mg, and the preferable ratio of lactic acid to glycolic acid is 75: 25; the ratio of the phospholipid to the cholesterol is 6: 1-9: 1, and the preferable ratio is 6: 1.

4. The preparation method of microsphere sustained release preparation loaded with isoniazid and rifampicin together as claimed in claim 1, characterized in that: wherein the volume ratio of the oil to the water in the step (4) is 1: 10.

5. The preparation method of microsphere sustained release preparation loaded with isoniazid and rifampicin together as claimed in claim 1, characterized in that: wherein the rotating speed of the homogenizer is 8000-12000 rpm, and the preferred rotating speed is 10000 rpm.

6. The preparation method of microsphere sustained release preparation loaded with isoniazid and rifampicin together as claimed in claim 1, characterized in that: wherein the voltage on the electrostatic spinning machine in the step (5) is 8-12 kV, and the preferred voltage is 8 kV; the receiving distance is 10-20 cm, and the preferable distance is 10-15 cm; the injection speed is 0.1-0.3 mm/min, and the preferred speed is 0.2 mm/min.

Technical Field

The invention provides a PLGA microsphere preparation capable of loading a water-soluble antituberculosis drug and a fat-soluble antituberculosis drug together on the same microsphere and a preparation method thereof, in particular to a microsphere sustained-release preparation loading isoniazid and rifampicin together and a preparation method thereof.

Background

Most of the tuberculosis is carried by spray, tubercle bacillus is phagocytized by alveolar macrophages, tissue cheese necrosis and liquefaction are caused, lung parenchyma lesion is caused, and if the cheese necrosis of lymph nodes breaks into bronchi, histopathological changes such as inflammatory exudation, cheese necrosis, granuloma and the like are caused at a focus part, so that the patients have lumen stenosis and lumen occlusion, and the treatment effect of atomization inhalation is poor. Poor local pulmonary blood transport also results in lower lung-targeted concentrations of antituberculotic drugs administered intravenously.

Isoniazid and rifampicin are first-line drugs for clinical treatment of pulmonary tuberculosis, and are also main drug administration varieties for bronchoscopic interventional therapy. When the compound is applied alone, the tubercle bacillus is easy to generate drug resistance, so that the drug resistance can be obviously reduced and the drug effect can be enhanced after the rifampicin and the isoniazid are applied in combination clinically. At present, the local administration technology under a bronchoscope is mature, the operation is safer, the injected medicament dosage is accurate and controllable, in addition, the drainage bronchus of the focus part of a patient can be directly observed through the bronchoscope, antitubercular medicaments are directly injected into the focus part through a catheter, the targeting property to the bronchogenic tuberculosis, multi-drug resistant tuberculosis and cavitary tuberculosis is stronger, the effective medicament concentration of the focus part can be achieved, meanwhile, the influence on the blood medicament concentration is smaller, and the occurrence probability of related complications is avoided. Most of the clinical applications at present are that antituberculosis drugs are firstly prepared into injection or suspension and then directly injected into the focus of pulmonary tuberculosis through interventional technology, but the preparation has poor pulmonary retention and needs frequent administration, and the compliance of patients is poor.

In pulmonary administration, the size of the drug particles affects the site of drug arrival. The deposition of the particles is influenced by three functions of gravity sedimentation, inertia embedding and Brownian motion, particles larger than 10 mu m are deposited in an upper respiratory tract and are quickly removed by cough, swallowing and ciliary motion, particles of 2-10 mu m can reach bronchus and bronchiole, particles of 3-5 mu m are mainly deposited in a lower respiratory tract, particles of 2-3 mu m can reach alveoli, and particles which are too small are easily discharged through expiration and cannot stay in the respiratory tract. Therefore, the particle size of 0.5 to 5 μm is most preferable. Regardless of the etiology mechanism of bronchial infection caused by mycobacterium tuberculosis or the generation principle of drug-resistant mycobacterium tuberculosis, the host of lung targeted delivery is macrophage, and particles with the diameter of 1-3 μm can be effectively absorbed by alveolar macrophage through phagocytosis. Therefore, the particle size of the slow release preparation carrying the antituberculosis drugs is controlled within the range of 1-3 mu m, and the method is an ideal method for maintaining the high drug level of alveolar macrophages.

The microspheres (microspheres) are micron-sized solid spherical particles, are usually prepared from natural or artificially synthesized polymers to form a sustained release preparation, have the particle size range of 1-250 microns, belong to the micron-sized, and can meet the particle size requirement of lung targeted intervention administration on drug particles. The preparation method of PLGA microspheres comprises emulsion solvent volatilization method, salting-out method, phase separation method, membrane emulsification method, spray drying method, electrostatic fluid spraying technology and supercritical fluid technology. For the microsphere preparation simultaneously loading two drugs, the most common method is an emulsion solvent volatilization method, but the problems of low yield, low encapsulation efficiency of water-soluble drugs, easy adhesion and aggregation of particles, organic solvent residue and the like exist. The electrostatic fluid spraying technology is a simple and easy method for preparing the polymer microsphere with the core-shell structure, and compared with the traditional method, the method has the following advantages in theory: (1) ultra-micron particle size; (2) the size distribution is narrow; (3) monodispersity; (4) the operation is simple, and the repeatability is good; (5) the package is facilitated; (6) high yield and wide application prospect in the field of medical application.

Disclosure of Invention

The invention provides a microsphere sustained-release preparation loaded with isoniazid and rifampicin and a preparation method thereof, wherein an electrostatic fluid spraying technology is used for encapsulating two anti-tuberculosis drugs including isoniazid and rifampicin in PLGA microspheres, and the average particle size of the microspheres meets the effective particle size of pulmonary administration, so that the local drug concentration of the tuberculosis drugs in the lung can be effectively improved, the administration times are reduced, the toxic and side reactions are reduced, and the economic benefit ratio of the drugs is improved.

The technical scheme adopted by the invention for solving the technical problems is as follows: a method for preparing microsphere sustained release preparation loaded with isoniazid and rifampicin comprises the following steps:

(1) the preparation process of the microsphere needs to be carried out in the dark, phospholipid and cholesterol are used as emulsifying agents, polyvinyl alcohol (PVA) is used as an emulsion aid, poly (lactic-co-glycolic acid) (PLGA) is used as a carrier material, the ratio of lactic acid to glycolic acid is 50:50 or 75:25, and the weight-average molecular weight is 3.7-5.2 ten thousand;

(2) adding 10-30 mg of precisely weighed isoniazid into a 0.5 ml of aqueous solution of the VA in the water phase, and carrying out water bath at 40 ℃ for 10 min;

(3) the oil phase is prepared by dissolving 15-40 mg of precisely weighed rifampicin, 250-750 mg of PLGA, 120-240 mg of phospholipid and 20-40 mg of cholesterol in 5 mL of mixed solution of dichloromethane and absolute ethyl alcohol, and performing water bath ultrasound for 5 min to promote the dissolution;

(4) adding the water phase into the oil phase, mixing, homogenizing and emulsifying for 2 min by a handheld homogenizer, and pumping into a 5 mL injector, wherein the volume ratio of the oil phase to the water phase is 1: 8-1: 12;

(5) the syringe is placed on a pushing injection pump of the electrostatic spinning machine, and the needle head is selected to be 21^#Establishing a high-voltage electric field between the needle head and the receiving device; after appropriate voltage, injection speed and receiving distance are set, the electrostatic spraying technology is applied to prepare the PLGA microsphere preparation carrying double medicines together, the receiving device is aluminum foil paper, and vacuum drying is carried out for 12 hours at room temperature.

Wherein, the PVA concentration in the step (2) is between 0.5 percent and 2 percent; the preferred concentration is 1.4%.

The adding amount of PLGA in the step (3) is 250-750 mg, the preferable adding amount is 350mg, and the preferable ratio of lactic acid to glycolic acid is 75: 25; the ratio of the phospholipid to the cholesterol is 6: 1-9: 1, and the preferable ratio is 6: 1.

The volume ratio of oil to water in the step (4) is 1: 8-1: 12, and the optimal ratio is 1: 10; the rotating speed of the homogenizer is 8000-12000 rpm, and the preferred rotating speed is 10000 rpm.

Step (5), enabling the voltage on the electrostatic spinning machine to be 8-12 kV, and preferably enabling the voltage to be 8 kV; the receiving distance is 10-20 cm, and the preferable distance is 10-15 cm; the injection speed is 0.1-0.3 mm/min, and the preferred speed is 0.2 mm/min.

The invention has the beneficial effects that: the invention provides a PLGA microsphere preparation capable of loading water-soluble drug isoniazid and fat-soluble drug rifampicin, which solves the problem of low encapsulation efficiency of water-soluble drug; the prepared microsphere preparation can meet the requirement of a lung targeting narrow particle size range of 1-3 mu m, and the average particle size of the microsphere preparation is 1.85-2.36 mu m.

Drawings

FIG. 1 shows the surface morphology of microspheres observed with a glass slide under an optical microscope during the preparation of the microspheres.

FIG. 2 is a schematic diagram of the surface morphology of microspheres observed under a transmission electron microscope.

FIG. 3 is the in vitro drug release profile of isoniazid of the present invention.

Figure 4 is a graph of the in vitro drug release profile of rifampicin according to the present invention.

Detailed Description

The invention is further illustrated by the following experimental examples and examples. It should be properly understood that: the experimental examples and examples of the present invention are given only for illustrating the present invention, and do not limit the scope of the present invention. Any simple modification made on the premise of the method of the present invention falls within the scope of the claimed invention.

Instrument and reagent

1.1 Instrument: LC1000 type high performance liquid chromatograph (Shandong Lunan Rainbow chemical instruments Co., Ltd.), FA3004G type electronic analytical balance (Changzhou Wantai balance instruments Co., Ltd.), KS-2500 type ultrasonic cleaner (Ningbo Kesheng instruments Co., Ltd.), SHZ-D (III) circulating water type vacuum pump (Chengyi Hua instruments Co., Ltd.), DF101-S heat collection type constant temperature magnetic stirrer (Chengyi instruments Co., Ltd.), PHS-3C digital display acidity meter (Shanghai Puchun measuring instruments Co., Ltd.), Evolution 300 ultraviolet visible spectrophotometer (TG Moslem Feishire science and technology (China Co., Ltd.), high speed centrifuge (Henan Hongyo industries Co., Ltd.), SS-2535DC quiet point spinning equipment (Beijing Yongle industries development Co., Ltd.), MT-30K type homogenizer (Zhongzhou Mi Youyi instruments Co., Ltd.), NANO-ZS90 nanometer particle size analyzer (Malvern), RCZ-8B dissolution tester (Shanghai Lu Shuo industries, Ltd.)

1.2 reagent: methanol (chromatographically pure), acetonitrile (chromatographically pure), phosphoric acid, dichloromethane, absolute ethanol (Kemiou chemical reagent, Inc., Tianjin), disodium hydrogen phosphate (Kaiton chemical reagent, Inc., Tianjin), phosphate buffer (0.01M pH 7.2-7.4 Beijing Solebao scientific and technological Co., Ltd.), polyvinyl alcohol (PVA 124) (national drug group chemical reagent, Inc.)

1.3 materials: rifampin control (batch No. F0201A, Dalian biotechnology limited), isoniazid control (batch No. D1208A, Dalian biotechnology limited), PLGA (75: 25, MW =42000, batch No. 20200623017, 50:50, MW =23000, batch No. 20190428278, Jinan Dagang biotechnology limited), phospholipids (Lipoid S100 germany), cholesterol (BWJ 4217-2016 beijing century Okogaku biotechnology limited), BIOSHARP dialysis bag (MW 14000) (beijing lankan Koroke technology limited).

Secondly, drug loading rate and encapsulation rate

Precisely weighing 3 parts of 5 mg microspheres, dissolving with 10 mL of mobile phase for 4h under the condition of keeping out of the sun, centrifuging at 8000 rpm for 4 min at high speed, taking supernatant fluid, filtering with 0.22 μm microporous membrane, detecting the peak area of the drug by HPLC, and substituting the peak area into a standard curve formula to calculate the content of the drug in the microspheres. The Drug Loading (Drug Loading DL) and Encapsulation Efficiency (Encapsulation Efficiency EE) of the microspheres were calculated according to the following formulas.

Drug loading (DL,%) = weight of drug contained in microsphere/total weight of microsphere × 100%

Encapsulation efficiency (EE,%) = actual drug amount in microsphere/theoretical drug amount in microsphere × 100%.

Experimental example 1 in vitro analysis method of Isoniazid and rifampicin

Rifampicin and isoniazid ultraviolet spectrophotometry: rifampicin has maximum absorption at 238 nm, 254 nm and 334 nm and minimum absorption at 298 nm by full wavelength scanning. Isoniazid has an absorption maximum at a wavelength of 262 nm. Comprehensive analysis 262 nm was used as the detection wavelength for rifampicin and isoniazid analysis.

The HPLC detection methodology of rifampicin and isoniazid comprises the following steps: Besil-C18 (5 μm, 4.6X 250 mm), ultraviolet spectrophotometer detection wavelength: 262 nm, sample size: 20 muL, column temperature: 25 ℃, flow rate: 1.0 mL/min, mobile phase A: disodium hydrogen phosphate solution (0.02 mol/L) was adjusted to pH 4.0 with phosphoric acid, mobile phase B: methanol: acetonitrile (volume ratio 1: 2). The volume ratio of the mobile phase A to the mobile phase B is constant at 95:5 in the first 10 min; the mobile phase A is reduced from 95% to 35% in 10-20 min, and the mobile phase B is increased from 5% to 65%; the volume ratio of the mobile phase A to the mobile phase B is constant at 35:65 within 20-30 min; the volume ratio of the mobile phase A to the mobile phase B is constant at 95:5 within 30-35 min.

Experimental example 2 prescription optimization of PLGA microsphere preparation Process

1. Single factor investigation: according to the preparation method, the ratio of phospholipid to cholesterol, the addition amount of phospholipid cholesterol, the rotating speed, the concentration of water phase PVA, the concentration of oil phase PLGA, the volume ratio of oil to water, the voltage, the receiving distance, the injection speed, the dosage ratio and the ratio of dichloromethane to absolute ethyl alcohol in the oil phase are selected as influencing factors for controlling the quality of the microspheres, and single-factor experiments are carried out by taking the average particle size and the encapsulation rate as evaluation indexes. According to experimental results, the addition amount of phospholipid cholesterol is 1.4-5.6%, the oil-water volume ratio is 1: 8-1: 10, the receiving distance is 10-15 cm, and the influence of the dosing ratio on the encapsulation rate of the medicine and the particle size of the microsphere is small. And when the volume ratio of the dichloromethane to the absolute ethyl alcohol is 4:1 and 3:2, the preparation with the bead structure of the spinning microsphere is formed.

2. Box-Behnken design-response surface method optimization prescription: according to the result of the single-factor test, the drug loading and encapsulation rates of rifampicin and isoniazid are used as evaluation indexes, the phospholipid/cholesterol ratio, the PVA concentration, the PLGA concentration, the injection speed and the drug dosage are used as factors, each factor is set to be 3 levels, namely low, medium and high, and a five-factor three-level response surface analysis test is carried out. The final optimal process: phospholipid/cholesterol ratio (6: 1), PVA concentration (1.40%), PLGA concentration (7.00%), bolus injection speed (0.20 mm/min), drug delivery amount (52.64 mg), INH drug loading amount (5.98%), RFP drug loading amount (6.11%), INH encapsulation efficiency (71.78%) and RFP encapsulation efficiency (84.73%).

3. Process verification

5 batches of microsphere preparations are prepared according to the optimal conditions screened by the response surface test, the results are shown in the table below, the measured values and the predicted values RSD of the rifampicin, isoniazid drug-loading rate and encapsulation rate of the prepared microspheres are less than 5%, and the microspheres can be used as the optimal prescription of the isoniazid-rifampicin-PLGA microsphere preparation.

Thirdly, the particle size distribution and the microsphere surface morphology

1. Particle size distribution and average particle size: dissolving microspheres prepared by an optimal formula in normal hexane, carrying out ice bath ultrasonic treatment for 30 s, and placing the microspheres in a detection pool of a NANO-ZS90 nanometer particle size analyzer, wherein the detected particle size is 2.06 +/-0.86 microns, and the particle size is PDI: 0.38 +/-0.06, more uniform particle size distribution, Zeta potential: 17.80 +/-5.05 mV, and the solution is stable.

2. The surface appearance of the microsphere is as follows: the microspheres were prepared by observing the microspheres with a glass slide under an optical microscope, as shown in FIG. 1. The microsphere suspension prepared by the optimal formula is dripped into a copper mesh for 2.0 percent phosphotungstic acid negative staining, and the microspheres are observed to be spherical, have good sphericity and more uniform size distribution under a Hitachi7700 type transmission electron microscope after being naturally air-dried, as shown in figure 2.

Example 1

The preparation method of the lung targeting PLGA microsphere preparation carrying both isoniazid and rifampicin comprises the following steps:

(1) the water phase is prepared by precisely weighing 26mg of isoniazid, adding the isoniazid into 0.5 ml of 1.4% PVA water solution, and carrying out water bath at 40 ℃ for 10 min;

(2) the oil phase is prepared by dissolving precisely weighed rifampicin 26mg, 7% PLGA (lactic-glycolic acid 75: 25), phospholipid 60 mg and cholesterol 10 mg in 5 mL of mixed solution of dichloromethane and absolute ethyl alcohol, and performing water bath ultrasound for 5 min to promote dissolution;

(3) adding the water phase into the oil phase, mixing, homogenizing and emulsifying for 2 min at 1000 rpm of a handheld homogenizer, and pumping into a 5 mL syringe;

(4) injection syringePlacing on a push injection pump of an electrostatic spinning machine, selecting a needle 21^#A high voltage electric field is established between the needle and the receiving device. After setting the voltage of 8kV, the injection speed of 0.20 mm/min and the receiving distance of 10 cm, preparing the PLGA microsphere preparation carrying the double medicines together by using an electrostatic spraying technology, wherein the receiving device is aluminum foil paper, and carrying out vacuum drying for 12 h at room temperature.

Example 2

The preparation method of the lung targeting PLGA microsphere preparation carrying both isoniazid and rifampicin comprises the following steps:

(1) the water phase is prepared by precisely weighing 30mg of isoniazid, adding into 0.5 ml of 1.4% PVA water solution, and carrying out water bath at 40 ℃ for 10 min;

(2) the oil phase is prepared by dissolving precisely weighed rifampicin 22mg, 7% PLGA (75: 25), phospholipid 60 mg and cholesterol 10 mg in 5 mL of mixed solution of dichloromethane and absolute ethyl alcohol, and performing ultrasonic treatment in water bath for 5 min to promote dissolution;

(3) adding the water phase into the oil phase, mixing, homogenizing and emulsifying for 2 min at 1000 rpm of a handheld homogenizer, and pumping into a 5 mL syringe;

(4) the syringe is placed on a pushing injection pump of the electrostatic spinning machine, and the needle head is selected to be 21^#A high voltage electric field is established between the needle and the receiving device. After setting the voltage of 8kV, the injection speed of 0.20 mm/min and the receiving distance of 10 cm, preparing the PLGA microsphere preparation carrying the double medicines together by using an electrostatic spraying technology, wherein the receiving device is aluminum foil paper, and carrying out vacuum drying for 12 h at room temperature.

Example 3

The preparation method of the lung targeting PLGA microsphere preparation carrying both isoniazid and rifampicin comprises the following steps:

(1) the water phase is prepared by precisely weighing 30mg of isoniazid, adding into 0.5 ml of 1.4% PVA water solution, and carrying out water bath at 40 ℃ for 10 min;

(2) the oil phase is prepared by dissolving precisely weighed rifampicin 22mg, 7% PLGA (50: 50), phospholipid 60 mg and cholesterol 10 mg in 5 mL of mixed solution of dichloromethane and absolute ethyl alcohol, and performing ultrasonic treatment in water bath for 5 min to promote dissolution;

(3) adding the water phase into the oil phase, mixing, homogenizing and emulsifying for 2 min at 1000 rpm of a handheld homogenizer, and pumping into a 5 mL syringe;

(4) placing the syringe at restOn the injection pump of the electric spinning machine, the needle head is selected 21^#A high voltage electric field is established between the needle and the receiving device. After setting the voltage of 8kV, the injection speed of 0.20 mm/min and the receiving distance of 10 cm, preparing the PLGA microsphere preparation carrying the double medicines together by using an electrostatic spraying technology, wherein the receiving device is aluminum foil paper, and carrying out vacuum drying for 12 h at room temperature.

Experimental example 3 measurement of in vitro drug Release

In the above embodiment, 3 mL of PBS release medium solution with ph of 7.2 to 7.4 is added, and then the mixture is put into a dialysis bag which is processed in advance, after both ends are fastened, the mixture is put into a rotating basket of a full-automatic dissolution apparatus, 100 mL of PBS solution with ph of 7.2 to 7.4 is used as a release medium, the set temperature is (37 ± 0.5) ° c, the rotation speed is 100 r/min, the sampling time is set to 0.5 h, 1 h, 2 h, 4h, 8 h, 12 h, 24h, 2 d, 3 d, 5d, 7 d, 10 d, 15d, the HPLC method is used to measure the drug concentration of isoniazid and rifampicin in the release medium, the cumulative drug release percentage is calculated, and an in vitro release curve is drawn, and the results are shown in fig. 3 and fig. 4.

And (4) conclusion: the rifampicin and isoniazide are simultaneously encapsulated in the PLGA microspheres for the first time through an electrostatic fluid spraying technology, the average particle size of the rifampicin and isoniazide is 1-3 mu m which meets the particle size range of lung targeted drug delivery, the encapsulation rate of the water-soluble drug isoniazide is more than 71%, and the encapsulation rate of the fat-soluble drug rifampicin is more than 83%. The product is observed to be spherical under a scanning electron microscope, the surface is smooth, and the size distribution is uniform. In vitro drug release experiments show that the two drugs do not have burst release phenomenon in 24 hours, the cumulative drug release rate of 15d isoniazid is 61.47 +/-0.42 percent, and the cumulative drug release rate of rifampicin is 39.23 +/-0.74 percent.