WO2010083778A1 - Lung targeting injectable pharmaceutical composition of liposome - Google Patents

Abstract

A lung targeting injectable pharmaceutical composition of liposome is disclosed. It consists of particles or powders of medicine-carrying proliposomes for solid phase and the effervescent. The proliposomes and the effervescent are packaged separately before administration. The medicine-carrying proliposome consists of active medicine, phospholipids, cholesterols, surfactant and acidic carrier. The effervescent is selected from sodium bicarbonate solution or sodium carbonate solution. The proliposomes and the effervescent are mixed in manner of effervescent-dispersion before injection.

Description

 Lung targeting liposome pharmaceutical composition for injection

Technical field

 The invention relates to the technical field of pharmaceutical carrier administration, in particular to an injection-targeted lung-targeted liposome pharmaceutical composition for treating lung diseases with high lung targeted administration characteristics; the invention also relates to the drug combination The preparation method of the substance. Background technique

 Liposomes refer to a bilayered mites with a similar biofilm structure. It is a multi-layered foam formed by the dispersion of phospholipids in water. Each layer is a bilayer of lipids; the center of the bubble is separated from the layers by water, and the thickness of the bilayer is about 4. Currently, lipid It has been the most promising targeted drug delivery vehicle formulation for pharmaceutics and is a new formulation for tissue-targeted drug delivery systems, also known as biological missiles. It can embed a drug powder or solution in a nanometer-scale or micron-sized particle. The microparticle has a cell-like structure, and enters the living body to change the in vivo distribution behavior of the encapsulated drug, so that the drug is mainly sent to the lesion. Organs and organs, reduce the distribution of non-focal tissues and organs, so as to improve the efficacy of drugs and reduce the side effects of drugs.

 As a drug carrier, liposomes have the advantages of sustained release, targeting, low toxicity, improved drug stability and improved pharmacokinetic properties. However, ordinary liposomes enter the organism and are mainly phagocytosed by the reticuloendothelial system to activate the autoimmune function of the body and change the in vivo distribution behavior of the encapsulated drugs, so that the drugs are mainly in the reticuloendothelial system such as liver, spleen and bone marrow. In organs, other tissues and organs are poorly targeted. In recent years, there have been many targeted liposome studies on tissues and organs. However, the market for liposome preparations at home and abroad is still few and far between; more is staying in the laboratory stage, the main reasons are: 1 The preparation process of liposome preparation is not easy to be industrialized; 2 The liposome suspension is prone to aggregation, fusion and drug leakage during storage, especially the leakage of water-soluble drugs is more significant; at the same time, natural phospholipids are easily oxidized, Hydrolysis, it is difficult to meet the requirements of the stability of pharmaceutical preparations. 3 Organic residual problems are difficult to solve.

In China, the incidence of lung cancer, tuberculosis, lung infection and other diseases is high, and it is developing rapidly. In the treatment of lung diseases, lung-targeted drug delivery is very important because targeted therapy can deliver drugs directly to the lung tissue, so that the lungs form a high concentration to improve the efficacy, reduce the vice The role of reducing the effects of drug resistance.

 At present, the research on lung targeted drug delivery system at home and abroad mainly focuses on three aspects:

(1) Based on the pulmonary capillaries, the alveolar surface area is large, and the administration of pulmonary capillary mechanical filtration is used. For example, Huo et al. used a solvent evaporation method to prepare a cisplatin lung targeting microsphere with a polylactic acid-polyglycolic acid copolymer as an auxiliary material, and an average particle diameter of 12.8 μ πι, wherein 98% of the microspheres have a particle diameter of Between 5 and 30 μm, the lung cisplatin concentration was 212 μg/g after 15 minutes of rabbit ear vein administration, while the control group was only 1.37 g/ _g . The same method, Pazhou and other preparation of paclitaxel lung targeting microspheres, the average particle size of 9. 65 μ πι, 87. 18% of the microspheres between 5-15 μ πι, after the tail vein administration of the drug, the drug There is a significant increase in the distribution in the lungs. Zhang Na et al. prepared the Yanhuning gelatin microspheres by emulsion cross-linking method with an average particle size of 17.14 μ ηι. The experimental results show that the gelatin microspheres have certain lung targeting properties.

 (2) Administration studies based on particle size. For example, Ke l laway and Farr believe that liposomes larger than 2 μm have a lung-like nature, greater than 6 μm, and are usually trapped by mechanical filtration in the smallest capillary bed of the lung, taken up by mononuclear leukocytes. Lung tissue or lung air bubbles. Wang Jiansong et al. used a rotating membrane-freeze-thaw method to prepare a lung-targeted azithromycin liposome with an average particle size of 6.58 μ ιη, a surface charge of +19. 5 mV, and a retention time in the lung after administration of the tail vein. 4倍。 A significant increase in AUC value of about 8.4 times the azithromycin solution.

 (3) Administration studies based on solid lipid nanoparticle modification. For example, Wol fgang and

Ka rst en believes that polymer-modified solid lipid nanoparticles can reduce the uptake of drugs by the endothelial reticulocyte system, thus prolonging the time of drug circulation. Muller et al found that solid lipid nanoparticles modified with F68 do have The above effects; Zara, Serrano and other solid lipid nanoparticles modified with soy lecithin (80 ± 5 μ m) can not only increase the plasma AUC area, but also increase the concentration of the drug in the lungs, compared with the control group. , can increase by about 30%. It is believed that it is a kind of alveolar surfactant which is easily absorbed by the alveolar wall. Xiang et al. used F68-modified lung-targeted dexamethasone-type granules with a particle size of 552 ± 6.5 nm. After administration of the tail vein in mice, the concentration of the drug in the lungs was compared with the control group. 17. 8 times.

From the above literature, we can see that there are some problems in the research of lung-targeted drug delivery system at home and abroad: 1 Because the particle size is too large, the safety of intravenous drug administration may not be guaranteed; 2 The lung-specific targeting is not high enough, Increasing the concentration of lung drug also increases the drug concentration of liver and spleen, which may have toxic side effects on liver and spleen; 3 other than the classical pulmonary capillary bed is mechanically filtered as a target, the remaining lung targeting mechanism Not yet clear. Summary of the invention

 It is an object of the present invention to provide a lung-targeted liposome drug composition for injection which has a very small lung targeting effect and which has a small particle size and uniformity, and has a negatively charged physical property, safety and stability. The invention also relates to a process for the preparation of the pharmaceutical composition.

 The lung-targeting liposome pharmaceutical composition for injection according to the present invention comprises: a drug-loaded precursor liposome solid phase granule or a powder and an effervescent agent which are dispensed before administration; wherein the drug-loaded precursor liposome The solid phase granule or powder is Composition I or Composition II by weight:

 (1) Composition I

 Active drug 0. 001 10 Phospholipid lipid 0. 5 ~ 30 Cholesterol lipid 0. 25 - 15 Acid carrier 25 - 90 Surfactant 0. 1 ~ 30

 (2) Composition II

 In the composition I, the addition agent is added in parts by weight 0. 1 ~ 10;

 The granules having a particle size of 0.7, the granules having a particle size of 0.7. ~ 2. 0 μ πι, the zeta potential of the particles is -10 - 30mV.

 The above active drug is a drug for treating lung cancer. It may be selected from the group consisting of docetaxel, paclitaxel, zoledronic acid, cisplatin, doxorubicin, topotecan, etoposide or cyclophosphamide.

 The above active drug is an anti-tuberculosis drug. From rifampicin, rifapentine or isoniazid. The above active drug is a drug for treating pneumonia. It is selected from the group consisting of ofloxacin, ribavirin, penicillin or cephalosporin.

 The above lipid lipid is selected from the group consisting of lecithin, soybean phospholipid, hydrogenated soybean lecithin, phosphatidylethanolamine, synthetic phosphatidylserine, phosphatidylinositol, sphingomyelin, egg phosphatidylcholine, two whale scorpion, two flesh Myristoyl lecithin, distearoylphosphatidylethanolamine, pegylated distearoylphosphatidylethanolamine in PEGylated phospholipid analog, methoxy pegylated distearoylphosphatidylethanolamine, and A pegylated phospholipid analog modified with a ligand such as folic acid.

The above cholesterol lipid is selected from the group consisting of cholesterol, cholesterol acetyl ester, cholesteryl hemisuccinate, β-sitosterol, cholesterol stearate, cholesterol palmitate, monomethyl polyethylene glycol-cholesterol, and folic acid. Ligand-modified polyethylene glycol-cholesterol. The above surfactant is selected from the group consisting of a Tween series, a sucrose fatty acid ester, a polyoxyethylene monooleate in a polyoxyethylene type nonionic surfactant, a polyoxyethylene hydrogenated castor oil, and a polyoxyethylene alkyl ether.

 The acid carrier described above is selected from an organic acid or an inorganic acid such as citric acid or/and tartaric acid.

 The above additive is an antioxidant or/and a solid dispersion carrier; wherein the antioxidant is a water-soluble or/and fat-soluble antioxidant selected from vitamin E or/and vitamin C; and the solid dispersion carrier is selected from the group consisting of mannitol. Glucose, sorbitol and polyvinylpyrrolidone.

 The above effervescent agent is an aqueous solution of sodium hydrogencarbonate or a sodium carbonate aqueous solution having a concentration of 2-10 by weight.

 The method for preparing a pulmonary targeting liposome pharmaceutical composition for injection according to the present invention comprises the following steps:

 (1) The composition I or the other substance of the composition II other than the additive is dissolved in a suitable amount of absolute ethanol or a mixed solvent of absolute ethanol and anhydrous diethyl ether to obtain a solution A in which a solvent is dissolved in a solvent. The volume ratio to anhydrous ether is 7-9: 3-1;

 (2) Adding a volume of 0.1 to 1. 0% of the activated carbon to the solution A, stirring and standing, using a microporous membrane having a pore diameter of less than or equal to 0.22 μm to be sterile and free of heat. Original solution

 (3) heating the solution to remove the organic solvent to obtain a solid phase-loaded precursor liposome granule or powder; when the composition has an additional agent, adding the sterile additive to the solution mash under aseptic conditions, and then Heating the organic solvent to obtain a solid phase-loaded precursor liposome granule or powder;

 (4) determining the content of the main drug in the composition of step (3), determining the amount of the preparation, and dispensing under aseptic conditions;

 (5) Formulating an effervescent agent: preparing a sodium hydrogencarbonate or sodium carbonate aqueous solution having a concentration of 2-10 by weight; adding a volume of the solution of 0.1 to 1. 0% of the activated carbon for injection, stirring and standing, using a pore diameter of less than or A microporous filter equal to 0.22 μm was over-treated to obtain a sterile and pyrogen-free effervescent.

 The method for using the above-mentioned lung-targeting liposome pharmaceutical composition for injection is as follows: according to the mass concentration (g/L) of 0.1 to 2, the effervescent agent is quickly injected into the pre-drug body fat by using a syringe. In the solid powder or granules, shake them vigorously to mix the two thoroughly. The mixed solution is administered to the patient in a slow instillation and used within 8 hours.

Physicochemical properties and biological properties of the drug-loaded precursor liposome and the recombinant drug-loaded liposome suspension thereof (according to the specific embodiments, the drug-loaded precursor liposomes of Examples 1 and 6 and their recombination Post-drug liposomal suspension): I. In vitro evaluation

 [finished product]

 This product is white or off-white solid particles or powder.

 [Hydration Dispersibility]

 When this product is reconstituted with sodium bicarbonate or sodium carbonate solution, a large amount of carbon dioxide gas is generated. After a few minutes of shaking, the bubbles disappear, forming a milky white suspension with good uniformity.

 [stability]

 1. Solid phase drug delivery precursor liposome solid particles or powder stability:

 (1) Influencing factors test, the sample is exposed to high temperature 60 ° C, light 4500 ± 500 LX 10 days stable quality, and high humidity (RH = 75 % 5%) 10 days, increased by more than 5%, liposome formation The ball is not good, the drug has crystallization, so the moisture content of the product must be strictly controlled.

 (2) Accelerated test, simulation of the listed packaging, under the condition of high temperature 25 ° C, RH = 75 % ± 5% for 6 months, the quality is unstable.

 (3) Long-term test, simulation of the listed packaging, tested under vacuum conditions of 4-8 °C for 24 months, the quality is stable.

 2. The liposome suspension was left at room temperature for 8 hours without precipitation and the quality was stable.

 [Particle size distribution and charge measurement]

 According to the clinical requirements, after immersing 100 times with 5% (by weight) glucose solution, the particle size and charge of the liposome were determined by laser particle size analyzer, and the average particle size was 1.12 ± 0.050 μm; the zeta potential of the particle was - 10~- 30mV.

 [morphological investigation]

 According to the clinical requirements, after leaching with 5% (by weight) glucose solution, the transmission of the liposome was good and the particle size distribution was hooked (see Figure 1).

 [Measurement of encapsulation rate]

 The 1000-fold oil microscope was used to observe the presence or absence of insoluble drug crystallization, and the high-speed centrifugation or dialysis method was used respectively, and the encapsulation efficiency was more than 90%.

 [Hemolysis test]

10 ~ 20 ml of blood was collected from the rabbit ear vein, and the fibrin was removed by stirring with a glass rod. 10 ml of fibrin blood was removed, 10 ml of physiological saline was added, centrifuged, and the supernatant was discarded. If it was washed by centrifugation for 2 to 3 times, The serum is not red. Then, according to the volume of blood cells, a 2% suspension was prepared with physiological saline. Take test tube 6 pieces, according to the arrangement of Table 1, successively added various solutions. The sixth tube is a control tube. Shake each tube and place in a 37 °C incubator. The results of 1, 2, 3, and 24 hours were recorded. If the solution became clear and stained with red, a red blood cell rupture was observed under the history of the microscope, indicating hemolysis.

 [Security Test]

 Weighing the precursor liposome powder containing the docetaxel drug, and reconstituting 10 ml of the liposome suspension (about 1.2 mg of docetaxel) reconstituted with 5% by weight of sodium bicarbonate solution, from the rabbit The ear vein was slowly injected, and the drug was administered continuously for 10 days. The rabbit had no pyrogen reaction and no abnormalities in the veins of the ear vein.

 [Results]

 The lung-targeted liposome for injection had no hemolysis at the clinical dose, and there was no obvious stimulating effect on the rabbit ear vein. There was no pyrogen reaction in the rabbit, which indicated that the lung-targeted liposome for injection was safe.

 Second, in vivo evaluation

 Biological behavior research

 The mechanism of high lung targeting of the compositions of the invention is explored using pharmacokinetic methods.

 (1) animals

 The animal used in this study is 55 healthy New Zealand white rabbits (female and half) with a body weight of 1.95 to 2. 05 kg. It is provided by the Experimental Animal Center of Chongqing Medical University. Animals are free to eat and drink. According to the regulations on the use of experimental animals in the People's Republic of China, the Animal Ethics Committee of Chongqing Medical University approved the animal experiments involved in this project. After the trial, the rabbits were injected with injections to death.

 (2) Test design

55 rabbits were randomly divided into 1 group, 5 in each group, and then divided into 3 drug-administered groups. In the administration group 1 (group 1-5), the docetaxel liposome suspension was administered from the rabbit ear vein at a dose of 2 mg docetaxel per kg body weight, and the administration group 2 (6-10 groups) was administered. An equal dose of docetaxel injection, wherein the administration group 1 (group 1-4) and the administration group 2 (group 6-9) were sacrificed at 0. 25, 1. 5, 4, 8 and 24 h after administration. And Drug administration group 1 (5 groups) and administration group 2 (10 groups), after administration, 0.083, 0.5, 0.5, 1, 2, 4, 6, 8, 12, 24 h blood was collected from the ear vein. At the same time, after the final blood collection, immediately executed. Dosing group 3 (group 11) was not administered as blank plasma and tissue. The blood sample was centrifuged at 5000 rpm for 5 minutes to separate the plasma. After the rabbit was sacrificed, the heart, liver, spleen, lung, kidney, stomach and brain tissues were taken out, and the surface water of the tissue was blotted dry and accurately weighed, and then added every 1 g. 2 ml of physiological saline was subjected to slurry treatment.

 (3) Treatment of biological samples

 Take blank plasma and heart, liver, spleen, lung, kidney, stomach, brain sputum samples, accurately add different amounts of multi-line paclitaxel stock solution, and prepare the final concentration in the range of 0.02525 μg/ml-101 μg/ml. Prepare a standard curve. Drug extraction from tissues and plasma is achieved by precipitating proteins with a mixture of sterol/2M ammonium acetate (1:2 v/v). 1 ml of plasma or tissue, add 50 μl (50 μg/ml) of the paclitaxel internal standard sterol solution, add 3 ml of the mixture, vortex for 5 minutes, and sonicate in a water bath at 40 °C for 10 minutes, then 12,000 rpm After centrifugation for 5 minutes, the solution was transferred to a test tube, diluted about 4 times with water, and then slowly added to a solid phase extraction cartridge (Agilent, 0DSC18 column) previously activated with 2 ml of methanol and 2 ml of 0.01 M ammonium acetate buffer. After the sample solution is finished, use 2ml 0.01M ammonium acetate buffer, 2ml methanol/0.01M ammonium acetate buffer (1:9v/v), 2ml methanol/0.01M ammonium acetate buffer (2: 8v/). v) Rinse and then dry under vacuum for about 1 minute. The drug was then eluted with a 2 ml acetonitrile/methanol (1 lv/v) mixture. The organic solvent was evaporated under nitrogen at 40 ° C, reconstituted with 0.2 ml of the mobile phase, centrifuged at 12,000 rpm for 5 minutes, and the supernatant was taken for 20 μl into HPLC. The concentration of the drug in the plasma or tissue was calculated under the Excel software by the corresponding standard curve.

 (4) Pharmacokinetic analysis

 Using the 3P97 software provided by the Chinese Pharmacological Association, the drug concentration-time data was used to perform a series of model fitting calculations for pharmacokinetic parameters. The optimal pharmacokinetic model was determined based on the correlation coefficient and the AIC standard value, and the pharmacokinetic parameters were calculated. Three primary targeting parameters (Re, Te and Ce) were calculated to evaluate docetaxel lung targeting characteristics. Statistical differences in the test data were judged by SPSS 11.0 one-way analysis of variance.

 ( 5 ) Results

 Biodistribution evaluation in the lung

2 and 3, there is a significant difference in the distribution of docetaxel liposomes and injections in rabbits. For docetaxel injection (Fig. 2), the drug concentration distribution in the body from 0.25 h after administration was kidney, lung, stomach, spleen, liver, heart and brain, and the lung drug concentration was 7. 63ug/g, however, after 4 hours, the spleen drug concentration increased to the maximum, with a slow decrease, while the remaining tissues, although prolonged, decreased in concentration, indicating that the spleen has an absorption process.

Figure 3 shows the concentration of docetaxel in the lungs after administration of docetaxel liposomes from rabbit ear veins. The drug concentration in the lungs (51 0. 20 g/g, 0. 25 h ) significantly higher than other organizations. In contrast to paclitaxel injection, the concentration of lung drug increased from 7.6 g/g to 51 0. 20 μ _§ / _§ after 0.25 hour intravenous administration of docetaxel liposomes. According to the weight of each tissue of rabbit and its drug concentration (μg/g), the liposome carrier can deliver 9 3.6% of paclitaxel to the lungs after 0.25 hours of administration through the rabbit ear vein. A small amount was transmitted to the liver (5.17%), kidney (1.10%), stomach (0.77%), heart (0.11%), brain (0.03%) and spleen (0. 02) %).

 The lung targeting parameters were calculated according to the peak concentration (Cp) and the area under the curve (AUC) of docetaxel (see Table 1). From the perspective of targeting parameters, it was found that the lungs of the docetaxel liposomes prepared in this study were relatively The uptake rate Re was 28.91, which was significantly higher than other tissues and blood. The Re value is much larger than 1, indicating that the docetaxel is significantly encapsulated by the liposome carrier, thereby significantly increasing the targeting of the lung. Thus, it can be inferred that the liposome is more specific than the docetaxel injection. Docetaxel is delivered to the lungs.

Table 1: The enthalpy parameters of rabbits given docetaxel liposome and its injection after intravenous injection ^;

Tissue AUC ( gh /ml or g) ¹ e

Re ^b Ratio of T _e ^d

Sample Liposomes Injection Liposome Injection

 Plasma 0.17 0.32 0.53 14286.18 262.50 54.42 1.04

Heart 198.00 188.60 1.05 12.27 0.45 27.27 0.86

Liver 490.32 53.55 9.10 4.96 1.57 3.16 2.93

Spleen 285.39 224.88 1.27 8.51 0.37 23.00 1.09

Lung 2428.65 84.00 28.91 1.00 1.00 1.00 74.28

Kidney 132.18 126.64 1.04 18.37 0.66 27.83 1.41

Stomach 278.00 112.00 2.48 8.74 0.75 11.65 0.69

Brain 16.40 4.80 3.42 148.09 17.50 8.46 0.29

These values are arithmetic means. n=

 Osames

c T _e = (AUC) _luilg targeted / (AUC)untargeted'

Ratio of T _e — Te(iip _OSOmes )/T _e (i _n j _ec tion).

 Ce― Cmax{liposomes) / Cmax(injection).

2. Pharmacodynamic evaluation of a rat model

(1) Establishment of a tumor-bearing mouse model: A549 lung cancer cell line in good logarithmic growth phase was mixed with cells with 0.25% trypsin (1:250), and applied at 37 °C for 5 min; Repeat Blow the adherent cells, add an equal volume of medium containing 10% fetal bovine serum to prevent trypsin digestion; l Centrifuge at 5 rpm for 5 min; discard the supernatant and wash the pelleted cells 3 times with PBS; The cells were diluted to a cell concentration of 1 X 1 07 ce lls/mL; under sterile conditions, 3 1 06 A549 cells were subcutaneously inoculated into the back of each rat, and all inoculated nude mice were tumorigenic 10 days later.

 (2) Test group: 18 nude mice were randomly divided into 6 groups, 3 in each group: group 1 was tumor control group, sterile saline was injected; group 2 was blank liposome group (B lank LP Group 3 was docetaxel injection group (12 mg/kg); group 4-6 was docetaxel liposome group (3 mg/kg, 6 mg/kg and 12 mg/kg). All the above groups were administered once at the tumor site on 0, 3, 6 and 9 days, and the administration volume was 0.2 mL, and the neck was removed after 48 hours of withdrawal.

3. Pharmacodynamic evaluation of rabbit VX2 lung cancer model in situ

 (1) Construction model: The tumor tissue block was taken aseptically, placed in physiological saline, and cut into 1 leg tumor block on the ultra-clean table with ophthalmology. After anesthetizing the rabbit, cut the hair of the right chest, fix the supine position on the operating frame, disinfect the drape, (preferably under multi-slice spiral CT (MSCT) or medical thoracoscopy), along the right chest 4- 5 ribs In the case of a sterile syringe needle as a puncture needle, the flat needle core is longer than the needle about 0. 3cm, the prepared tumor tissue block is placed, then the needle is removed, and the wound is treated (be careful not to leak, to prevent pneumothorax after surgery) ), and let the rabbit return to normal, ending the surgery.

 (2) Program design: According to the experimental results of the mouse A549 lung cancer model, combined with the clinical situation, the experimental design of the project is specially formulated. Randomly divided into 5 groups, (A) blank control group; (B) docetaxel injection control group (administered once every three weeks); (C) docetaxel liposome group (administered once every three weeks); D) Docetaxel injection control group (once a week); (E) Docetaxel liposome group (administered once a week); Weekly chest thickness and layer thickness are 5匪 after administration CT scans were performed to observe tumor growth. The specific plan is as follows:

 One hundred and eight experimental rabbits were numbered and randomly divided into 10 groups, 10 in each group, and then randomly divided into 6 drug groups to observe the growth state of the tumors.

 The first group (10): The blank control group, that is, no administration, only saline.

 The second group (10): blank liposome group, ie no administration, only blank lipid suspension. The third group (30 rats): The drug was administered on the 2nd day after the operation, and the docetaxel liposome was administered weekly. The effective dose was 0.66 mg/kg for every 10 doses, and at least the low dose, medium dose, and high dose were set. Groups.

Group 4 (30): Dosage on the 2nd day after surgery, docetaxel liposomes every 2 weeks, each 10 effective doses of 0.66 mg/kg were used, and at least three groups of low dose, medium dose and high dose were set. Group 5 (10): On the second day after surgery, docetaxel injection was given every one week at a dose (3.3 mg/kg).

 Group 6 (10): On the second day after surgery, docetaxel injection was given every 2 weeks, and the effective dose was (6.6 rag/kg).

 Through the above modeling and experiments, the pulmonary targeting liposome pharmaceutical composition for injection of the present invention has obvious slow release characteristics, and after intravenous administration to rabbit, the majority of the drug dosage is administered by the liposome carrier. Delivery to the lungs indicates significant lung targeting. The liposome prepared by the present invention having a particle diameter of 0.7 to 2. 0 μm and having a charge of -1 0 to -3 OmV can improve the therapeutic effect of the corresponding drug by 7. 8 - 15. 5 times, thereby achieving a reduction The purpose of its side effects.

 The lung-targeting liposome pharmaceutical composition for injection according to the invention is prepared by a solid dispersion technique combined with an effervescent dispersion technique, and the drug and the lipid material are highly dispersed in a solid precursor composed of a hydrophilic material and an acid source auxiliary material. The liposome is then reconstituted with sodium bicarbonate or sodium carbonate solution during clinical use. Due to the rapid dissolution and collapse of the hydrophilic material and the acid source excipient, the simultaneous effervescent momentum of carbon dioxide promotes the formation of liposomes. The preparation process is simple, and only conventional pharmaceutical equipment is needed, which is easy to realize industrial scale production.

 The sterile pyrogen-free and organic residues of the liposome are easily controlled, and the highly toxic organic solvents such as chloroform and sterol used in the conventional liposome preparation method are avoided.

 Since the drug and the lipid material are highly dispersed in the carrier material, and when reconstituted with sodium bicarbonate or sodium carbonate solution, the particle size distribution of the obtained liposome is more uniform by the momentum generated by carbon dioxide, and the obtained lung for injection is targeted. The liposome drug composition has a liposome particle size of 0.7 to 2. Ο μ ηι, and the particle Ze ta potential is -1 0 ~ -30 mV, which can meet the requirements of clinical intravenous injection to ensure drug safety.

 Since the drug-loaded precursor liposome is present in a dry solid form, the liposome suspension prepared by the conventional method is prevented from prone to drug leakage, liposome aggregation, and oxidation of the lipid material. Liposomes are more stable, have a longer shelf life, and have a stability of up to 2 years. The cost is low, and the quality of the drug-loaded pro-liposomes produced is controllable.

Compared with the ordinary injection after intravenous administration, the drug-loaded liposome can deliver the majority of the administered drug to the lungs, while other tissues and organs are rarely distributed, so it has a very significant lung targeting effect. It is better used for the treatment of lung diseases, reducing systemic side effects, and is a well-targeted drug delivery platform for lung tissue for treating lung diseases. To lay the foundation for the construction of a lung-targeted liposome technology platform, It provides theoretical basis for the development of lung-targeted liposomes with independent intellectual property rights, which will have important scientific significance and practical value. DRAWINGS

 Figure 1 is a transmission electron micrograph (70,000 times) of a lung-targeted liposome pharmaceutical composition for injection; Figure 2 is a biodistribution map of docetaxel injection in rabbits;

 Figure 3 is a graph showing the biodistribution of lung-targeted docetaxel liposomes for injection in rabbits.

 The columnar peaks in Fig. 2 or 3 respectively indicate that the active drugs in the animals are in the heart, liver, spleen, lung, respectively after administration of 0.25, 1.5, 4, 8, 24 h. The amount of kidney, stomach, and brain. As can be seen from Figure 3, at 0.25 hours, the drug was highest in the lungs. detailed description

 Example 1: The first embodiment of the composition II of the present invention

 a. Weigh the following materials in the following proportions:

 Docetaxel

 Two whale wax

 Hydrogenated soybean lecithin

 Cholesterol

 Tween 80

 Tannic acid

 And the above materials are dissolved in an appropriate amount of absolute ethanol to obtain a solution A;

 b, adding 0.5% of the activated carbon for injection to the solution A, stirring and standing, using a microporous membrane having a pore diameter of 0.22 μm to obtain a sterile and pyrogen-free solution;

 c, under sterile conditions, 3mg of polyvinylpyrrolidone solution B, and then under normal mechanical agitation under reduced pressure to remove the organic solvent to obtain a solid granular drug-loaded precursor liposome; d, The main drug content of the drug-loaded precursor liposome obtained in the step c was determined, and the amount was determined and dispensed under aseptic conditions.

e. Prepare a sodium bicarbonate aqueous solution having a concentration of 4 by weight; add 0.5% of the activated carbon for injection, stir and let stand, and use a drum filter with a pore size of 0.22 μm to pass through the sterile membrane to obtain a sterile and An pyrogen-free effervescent.

 The above-mentioned pulmonary targeting liposome pharmaceutical composition for injection is used as follows: by mass concentration

(g/L) is 0.5, quickly inject the effervescent into the drug-loaded precursor liposome particles with a syringe, shake vigorously for 6 minutes, then mix the two thoroughly, and configure the mixture to slowly instill into the patient. It is administered and used within 8 hours.

 The obtained docetaxel precursor liposome suspension has good hookability, and the particle size and charge of the liposome are measured by a laser particle size analyzer to obtain an average particle diameter of 1.12 ± 0. 050 μ πι; It is -23. 5mV. No crystallization of the main drug was observed under the 1000-fold oil mirror, and the encapsulation efficiency was close to 90%. Example 2: Second embodiment of the composition II of the present invention

 a. Weigh the following materials in the following proportions:

 Docetaxel 0. 1 mg

 Soy lecithin 1 5 mg

 Phosphatidylserine 8 mg

 Cholesterol 1 0 mg

 Tween - 80 20 mg

 Tartaric acid 60 mg

 Citrate 1 0 mg

 And the above materials are dissolved in an appropriate amount of absolute ethanol to obtain a solution A;

 b, adding a volume of 0.1% of the activated carbon for injection to the solution A, stirring and standing, using a microporous membrane having a pore diameter of 0.15 μ ηι, to obtain a sterile and pyrogen-free solution Β;

 c. Under sterile conditions, 2 mg of vitamin E, 5 rag of mannitol and 3 mg of polyvinyl cyanohydrin are added to solution B, and then the organic solvent is removed under reduced pressure under normal mechanical stirring to obtain a solid granular form. Docetaxel precursor liposome;

 d, determining the main drug content of the docetaxel precursor liposome obtained in step c, determining the dosage, and dispensing under aseptic conditions;

 l, a solution of a concentration of 2% aqueous solution of sodium bicarbonate; a volume of 0.1% of the activated carbon for injection, stirring and standing, using a pore size of 0. 15 μ πι pore filter, sterilized And pyrogen-free effervescent.

The above-mentioned pulmonary targeting liposome pharmaceutical composition for injection is used as follows: by mass concentration (g/L) is 0.1, quickly inject the effervescent into the drug-loaded precursor liposome particles with a syringe, shake vigorously for 5 minutes, then mix the two thoroughly, and slowly dispense the patient with the configured mixture. The drug is administered and used within 8 hours.

 The obtained docetaxel precursor liposome suspension has good hooking property, and the particle size and charge of the liposome are measured by a laser particle size analyzer to obtain an average particle diameter of 1. 0 ± 0. 045 μ πι; For - 17mV. No crystallization of the main drug was observed under the 1000-fold oil mirror, and the encapsulation efficiency was close to 93%. Example 3: The third embodiment of the composition II of the present invention

 a. Weigh the following materials in the following proportions:

 Docetaxel 8 mg

 Lecithin 30 mg

 --sitosterol 1 5 mg

 Tween - 80 15 mg

 Tartaric acid 25 mg

 And the above materials are dissolved in a suitable amount of anhydrous ethanol and anhydrous ether in a mixed solvent, the ratio of anhydrous ethanol to anhydrous ether in a mixed solvent of 7: 3, to obtain a solution A;

 b, adding a volume of 0.3% of the activated carbon for injection, stirring and standing, using a microporous membrane with a pore diameter of 0. 18 μ m to obtain a sterile and pyrogen-free solution B;

 c. Under sterile conditions, 5 mg of vitamin E is added to solution B, and then the organic solvent is removed by a closed circulation spray drying device to obtain a powdered docetaxel precursor liposome;

 d, determining the main drug content of the docetaxel precursor liposome obtained in step c, determining the dosage, and dispensing under aseptic conditions;

 l, 8% by weight of a concentration of 8% aqueous solution of sodium bicarbonate; plus a volume of solution of 0.3% of the activated carbon for injection, stirring and standing, using a microporous membrane with a pore size of 0. 18 μ πι too care, to obtain sterility And pyrogen-free effervescent.

The above-mentioned lung-targeting liposome pharmaceutical composition for injection is used as follows: According to the mass concentration (g/L) of 2.0, the effervescent agent is rapidly injected into the drug-loaded precursor liposome particles by a syringe. After vigorous shaking for 5 minutes, the two were thoroughly mixed, and the patient was slowly instilled with the formulated mixture and used within 8 hours. The obtained docetaxel precursor liposome suspension has good hooking property, and the particle size and charge of the liposome are determined by a laser particle size analyzer, and the average particle diameter is 0. 787 ± 0. 045 μ πι; -24. 5mV. No crystallization of the main drug was observed under the 1000-fold oil mirror, and the encapsulation efficiency was close to 100%. Example 4: Fourth Embodiment of Composition II of the Present Invention

 a. Weigh the following materials in the following proportions:

 Docetaxel 0. 1 mg

 Phosphatidylserine 5 mg

 Soy lecithin 20 mg

 Cholesterol Acetate 0. 25 mg

 Tween - 80 1 mg

 Citrate 25 mg

 And the above materials are dissolved in a mixed solvent of an appropriate amount of anhydrous ethanol and anhydrous ether, the volume ratio of anhydrous ethanol to anhydrous ether in a mixed solvent is 9:1, to obtain a solution A;

 b, adding a volume of 1% of the activated carbon for injection to the solution A, stirring and standing, using a microporous membrane with a pore size of 0. 10 μ m, to obtain a sterile and pyrogen-free solution B;

 c. Under sterile conditions, 1 mg of vitamin E and 1 mg of sorbitol are added to solution B, and then the organic solvent is removed by a closed-flow spray drying apparatus to obtain a powdery docetaxel precursor liposome;

 d, determining the main drug content of the docetaxel precursor liposome obtained in step c, determining the dosage, and dispensing under aseptic conditions;

 e, prepare a 5% by weight aqueous solution of sodium bicarbonate; add 1% of the volume of the injection of activated carbon, stir and stand, use a microporous membrane with a pore size of 0. θ θμηι over-consideration, to obtain sterile and no heat The original effervescent.

The above-mentioned pulmonary targeting liposome pharmaceutical composition for injection is used as follows: 1. The mass concentration (g/L) is 0.1, and the effervescent agent is rapidly injected into the drug-loaded precursor liposome particles by a syringe. After vigorous shaking for 10 minutes, the two were thoroughly mixed, and the patient was slowly instilled with the formulated mixture and used within 8 hours. The obtained docetaxel precursor liposome suspension was well-bonded, and the particle size and charge of the liposome were measured by a laser particle size analyzer to obtain an average particle diameter of 0.968 ± 0.075 μπι; and the zeta potential of the particle was -21.5 mV. No crystallization of the main drug was observed under the 1000-fold oil mirror, and the encapsulation efficiency was close to 94%. Example 5: The fifth embodiment of the composition II of the present invention:

 a. Weigh the following materials in the following proportions:

 Docetaxel 1.2 rag

 Hydrogenated Soy Lecithin 10 mg

 Cholesterol 10 mg

 Tween - 80 10 mg

 Tartaric acid 5 mg

 Citrate 20 mg

 And the above materials are dissolved in a mixed solvent of anhydrous ethanol and anhydrous ether, the volume ratio of water-free ethanol to anhydrous ether in the mixed solvent is 8:2, to obtain 8% (mg / ml) of the solution A;

 b, adding 0.8% of the activated carbon for injection to the solution A, stirring and standing, using a microporous membrane with a pore size of 0.22 μηη, to obtain a sterile and pyrogen-free solution Β;

 c. Under sterile conditions, 7 mg of vitamin E is added to the solution B, and then the organic solvent is removed under reduced pressure under normal mechanical stirring to obtain a granular docetaxel precursor liposome;

 d, determining the main drug content of the docetaxel precursor liposome obtained in step c, determining the dosage, and dispensing under aseptic conditions;

 e. Prepare a sodium bicarbonate solution with a concentration of 5% by weight; add 0.8% of the activated carbon for injection, stir to stand, and use a microporous membrane with a pore size of 0.22 μηι to obtain sterile and pyrogen-free Effervescent agent.

 The above-mentioned pulmonary targeting liposome pharmaceutical composition for injection is used as follows: According to the mass concentration (g/L) of 1.2, the effervescent agent is rapidly injected into the drug-loaded precursor liposome particles by a syringe, and vigorously vibrated. After shaking for 4 minutes, the two were thoroughly mixed, and the patient was slowly instilled with the formulated mixture and used within 8 hours.

The obtained docetaxel precursor liposome suspension was well-bonded, and the particle size and charge of the liposome were measured by a laser particle size analyzer to obtain an average particle diameter of 0.78 ± 0.075 μπι; and the zeta potential of the particle was -16.3 mV. No crystallization of the main drug was observed under the 1000-fold oil mirror, and the encapsulation efficiency was close to 97%. Example 6: Sixth embodiment of Composition II of the present invention:

 a. Weigh the following materials in the following proportions:

 Paclitaxel 0. 001 mg

 Soy lecithin 15 mg

 Cholesterol 10 mg

 Tween - 80 30 mg

 Tartaric acid 60 mg

 Citrate 10 mg

 And the above materials are dissolved in an appropriate amount of absolute ethanol to obtain a solution A;

 b, adding a volume of 0.1% of the activated carbon for injection, stirring and standing, using a microporous membrane with a pore size of 0. 15 μ m to obtain a sterile and pyrogen-free solution B;

c, under sterile conditions, 10m _g of vitamin E is added to solution B, and then the organic solvent is removed under reduced pressure with general mechanical stirring to obtain a solid granular drug-loaded precursor liposome;

 d, determining the main drug content of the drug-loaded precursor liposome obtained in step c, determining the dosage, and dispensing under sterile conditions;

 l, Preparation of a 2% by weight aqueous solution of sodium bicarbonate; solution volume of 0.1% of the activated carbon for injection, stirring and standing, using a pore size of 0. 15 μ πι microporous filter over-diagnosed, sterile And pyrogen-free effervescent.

 The above-mentioned pulmonary targeting liposome pharmaceutical composition for injection is used as follows: 1. The mass concentration (g/L) is 0.1, and the effervescent agent is rapidly injected into the drug-loaded precursor liposome particles by a syringe. After vigorous shaking for 5 minutes, the two were thoroughly mixed, and the patient was slowly instilled with the formulated mixture and used within 8 hours.

 The obtained docetaxel precursor liposome suspension has good hooking property, and the particle size and electric charge of the liposome are determined by a laser particle size analyzer to obtain an average particle diameter of 0.98 ± 0. 045 μ πι; -17. 3mV. No crystallization of the main drug was observed under the 1000-fold oil mirror, and the encapsulation efficiency was close to 100%. Example 7: Seventh embodiment of the composition II of the present invention

 a. Weigh the following materials in the following proportions:

Deazep Hydrogenated soybean egg phosphorus

 Cholesterol

 Tween 80

 Tartaric acid

 And the above materials are dissolved in a mixed solvent of an appropriate amount of anhydrous ethanol and anhydrous ether, the volume ratio of anhydrous ethanol to anhydrous ether in a mixed solvent is 7:3, to obtain a solution A;

 b, adding a volume of 0.3% of the activated carbon for injection, stirring and standing, using a microporous membrane with a pore diameter of 0. 18 μ m to obtain a sterile and pyrogen-free solution B;

 c. Under sterile conditions, 5 mg of vitamin E is added to solution B, and then the organic solvent is removed by a closed circulation spray drying device to obtain a powdered drug-loaded precursor liposome;

 d, determining the main drug content of the drug-loaded precursor liposome obtained in step c, determining the dosage, and dispensing under sterile conditions;

 l, a 8% by weight aqueous solution of sodium bicarbonate is prepared; a volume of solution of 0.3% of the activated carbon for injection, stirring and standing, using a microporous membrane with a pore size of 0. 18 μ η to be sterile And pyrogen-free effervescent.

 The above-mentioned pulmonary targeting liposome pharmaceutical composition for injection is used in such a manner that the effervescent agent is rapidly injected into the drug-loaded precursor liposome particles by a syringe at a mass concentration (g/L) of 1.5. After vigorous shaking for 3 minutes, the two were thoroughly mixed, and the patient was slowly instilled with the formulated mixture and used within 8 hours.

 The obtained docetaxel precursor liposome suspension has good hookability, and the particle size and charge of the liposome are determined by a laser particle size analyzer to obtain an average particle diameter of 1. 2 ± 0. 062 μ ηι; -18. 6mV. No crystallization of the main drug was observed under the 1000-fold oil mirror, and the encapsulation efficiency was close to 100%. Example 8: The first embodiment of the composition I of the present invention

 a. Weigh the following materials in the following proportions:

 Azithromycin

 Lecithin

 Cholesteric succinate

 Tween 80

Tannic acid And the above materials are dissolved in a mixed solvent of an appropriate amount of anhydrous ethanol and anhydrous ether, the volume ratio of anhydrous ethanol to anhydrous ether in a mixed solvent is 9: 1, to obtain a solution A;

 b, adding 1% of the activated carbon for injection to the solution A, stirring and standing, using a microporous membrane having a pore size of 0. πμπι, to obtain a sterile and pyrogen-free solution Β;

 c. The solution B is removed by a closed-flow spray drying device to obtain a powdered drug-loaded precursor liposome;

 d, determining the main drug content of the drug-loaded precursor liposome obtained in step c, determining the dosage, and dispensing under sterile conditions;

 e. Prepare a sodium bicarbonate solution with a concentration of 5% by weight; add 1% of the activated carbon for injection, stir and let stand, and use a microporous membrane with a pore size of 0. Ι μιη to get sterile and no The effervescent agent of the pyrogen.

 The above-mentioned pulmonary targeting liposome pharmaceutical composition for injection is used as follows: According to the mass concentration (g/L) of 0.2, the effervescent agent is rapidly injected into the drug-loaded precursor liposome particles by a syringe, and vigorously vibrated. After shaking for 3 minutes, the two were thoroughly mixed, and the patient was slowly instilled with the formulated mixture and used within 8 hours.

 The obtained docetaxel precursor liposome suspension had good hookability, and the particle size and charge of the liposome were measured by a laser particle size analyzer to obtain an average particle diameter of 1.2 ± 0.062 μπι; and the Zeta potential of the particle was -19.9 mV. No crystallization of the main drug was observed under the 1000-fold oil mirror, and the encapsulation efficiency was close to 95%. Example 9: Second embodiment of the composition I of the present invention

 a. Weigh the following materials in the following proportions:

 Ribavirin

 Phosphatidylethanolamine

 Cholesterol

 Tween 80

 Tartaric acid

 Tannic acid

 And the above materials are dissolved in a suitable amount of anhydrous ethanol and anhydrous ether in a mixed solvent, the ratio of anhydrous ethanol to anhydrous ether in a mixed solvent of 8: 2, to obtain a solution A;

b. Add 0.8% of the activated carbon for injection to the solution A, stir and stand, and use the pore diameter. a microporous filter of 0. 20 μ m was over-treated to obtain a sterile and pyrogen-free solution B;

 c. The solution B is removed by a closed-flow spray drying device to obtain a powdered drug-loaded precursor liposome;

 d, determining the main drug content of the drug-loaded precursor liposome obtained in step c, determining the dosage, and dispensing under sterile conditions;

 l, 5% by weight of a solution of 5% by weight of sodium bicarbonate; a volume of solution of 0.8% of the activated carbon for injection, stirring and standing, using a microporous membrane with a pore size of 0. 20 μ πι, to obtain sterility And pyrogen-free effervescent.

 The above-mentioned pulmonary targeting liposome pharmaceutical composition for injection is used as follows: according to the mass concentration (g/L) of 1.0, the effervescent agent is rapidly injected into the drug-loaded precursor liposome particles by a syringe, After vigorous shaking for 4 minutes, the two were thoroughly mixed, and the patient was slowly instilled with the formulated mixture and used within 8 hours.

 The obtained docetaxel precursor liposome suspension has good hooking property, and the particle size and electric charge of the liposome are measured by a laser particle size analyzer to obtain an average particle diameter of 0.75 士0. 035 μ ιη; the particle Ze ta potential It is -18. 2mV. No crystallization of the main drug was observed under the 1000-fold oil mirror, and the encapsulation efficiency was close to 100%. Example 1 0: Eighth embodiment of the composition II of the present invention

 a. Weigh the following materials in the following proportions:

 Isoniazid 0. 1 mg

 Hydrogenated Soy Lecithin 2 mg

 --sitosterol 9 mg

 Tween - 80 18 mg

 Citrate 40 mg

 Tartaric acid 35 mg

 And the above materials are dissolved in an appropriate amount of absolute ethanol to obtain a solution A;

 b, adding a volume of 0.2% of the activated carbon for injection to the solution A, stirring and standing, using a microporous membrane having a pore size of 0.22 μπι, to obtain a sterile and pyrogen-free solution Β;

 c. Under sterile conditions, 9 mg of polyvinylpyrrolidone is added to the solution B, and then the organic solvent is removed under reduced pressure using a general mechanical stirring to obtain a granulated drug-loaded precursor liposome;

d, determining the main drug content of the drug-loaded precursor liposome obtained in step c, determining the loading, and in the sterile strip Sub-package;

 The sterilized microporous membrane with a pore size of 0.22 μm was used to prepare the sterilized solution. And pyrogen-free effervescent.

 The above-mentioned lung-targeting liposome pharmaceutical composition for injection is used as follows: according to the mass concentration (g/L) of 0.2, the effervescent agent is rapidly injected into the drug-loaded precursor liposome particles by a syringe, After vigorous shaking for 7 minutes, the two were thoroughly mixed, and the patient was slowly instilled with the formulated mixture and used within 8 hours.

 The obtained docetaxel precursor liposome suspension has good hookability, and the particle size and charge of the liposome are determined by a laser particle size analyzer to obtain an average particle diameter of 0.95 ± 0. 055 μ ιη; -22. 7mV. No crystallization of the main drug was observed under the 1000-fold oil mirror, and the encapsulation efficiency was close to 85 %. Example 11: Nineth embodiment of the composition II of the present invention

 a. Weigh the following materials in the following proportions:

 Rifampin 0. 5 mg

 Lecithin 1. 5 mg

 Cholesterol palmitate 0. 3 mg

 Tween - 80 0. 5 mg

 Tartaric acid 30 mg

 And the above materials are dissolved in an appropriate amount of absolute ethanol to obtain a solution A;

 b, adding a volume of 0.6% of the activated carbon for injection to the solution A, stirring and standing, using a microporous membrane with a pore size of 0.22 μηι, to obtain a sterile and pyrogen-free solution Β;

 c. Under sterile conditions, add 1 mg of vitamin C and 1 mg of vitamin C to solution B, respectively, and then remove the organic solvent by a closed-flow spray drying device to obtain a powdered drug-loaded precursor liposome;

 d, determining the main drug content of the drug-loaded precursor liposome obtained in step c, determining the dosage, and dispensing under sterile conditions;

e, a 2% by weight aqueous solution of sodium bicarbonate is prepared; a volume of 0.5% of the activated carbon is added to the solution, and the mixture is stirred and placed, and the microporous membrane having a pore diameter of 0.22 μm is used for the sterilizing. And pyrogen-free effervescent. The above-mentioned pulmonary targeting liposome pharmaceutical composition for injection is used as follows: by mass concentration

(g/L) is 0.8, quickly inject the effervescent into the drug-loaded precursor liposome particles with a syringe, shake vigorously for 7 minutes, then mix the two thoroughly, and slowly dispense the patient with the configured mixture. The drug is administered and used within 8 hours.

 The obtained docetaxel precursor liposome suspension has good hooking property, and the particle size and electric charge of the liposome are measured by a laser particle size analyzer to obtain an average particle diameter of 1. 05 ± 0. 055 μ πι; For -20. lmV. No crystallization of the main drug was observed under the 1000-fold oil mirror, and the encapsulation efficiency was close to 95%. Example 12 Pharmacodynamic evaluation

 According to the two animal pharmacodynamic models given above, the anti-tumor effect of the composition of Example 1, ie, docetaxel liposome, on nude mice bearing A549 lung tumors was obtained through experiments and calculations. The ED50 is about 9.6 times. The ED50 of the docetaxel is about 1. 6 times.

 The anti-tumor effect of docetaxel liposome on rabbit VX2 lung cancer was obtained by experiments and calculations. The effect of docetaxel liposome was increased by about 15.5 times than that of docetaxel injection.

 The antitumor effect of the composition of Example 6, i.e., paclitaxel liposome on A549 lung tumor mice, was obtained by experiments and calculations, and the difference between paclitaxel injection and paclitaxel liposome was about 7.8 times.

 The paclitaxel effect of paclitaxel liposome on in situ rabbit VX2 lung cancer was obtained by experiment and calculation. The therapeutic effect of paclitaxel liposome was improved by about 10. 7 times compared with paclitaxel injection.

Claims

Claim A lung-targeted liposome pharmaceutical composition for injection, which comprises a drug-loaded precursor liposome solid phase granule or powder and an effervescent agent before administration; wherein the drug-loaded precursor liposome solid phase granule Or the powder is Composition I or Composition II by weight:  (1) Composition I  Active drug 0. 001 - 10 Phospholipid lipid 0. 5 ~ 30 Cholesterol lipid 0. 25 - 15 Acid carrier 25 - 90 Surfactant 0. 1 ~ 30  (2) Composition II  In the composition I, the addition agent is added in parts by weight 0. 1 ~ 10;  (3) The active drug and the effervescent agent in the composition I or the composition II are formulated into a lung-targeted liposome pharmaceutical composition for injection by a mass concentration (g/L) of 0.1 to 1-2, and the particle size thereof is 0. 7 ~ 2. 0 μ ιη, the zeta potential of the particles is - 10 ~ - 30mV.  The lung-targeting liposome pharmaceutical composition for injection according to claim 1, wherein the active drug is a drug for treating lung cancer.  The lung-targeting liposome pharmaceutical composition for injection according to claim 2, wherein the drug for treating lung cancer is selected from the group consisting of docetaxel, paclitaxel, zoledronic acid, cisplatin, and doxorubicin , Topotecan, Etoposide or Cyclophosphamide.  The lung-targeting liposome pharmaceutical composition for injection according to claim 1, wherein the active drug is an anti-tuberculosis drug.  The lung-targeting liposome pharmaceutical composition for injection according to claim 4, wherein the anti-tuberculosis drug is selected from the group consisting of rifampicin, rifapentine or isoniazid.  The lung-targeting liposome pharmaceutical composition for injection according to claim 1, wherein the active drug is a pneumonia drug.  The lung-targeting liposome pharmaceutical composition for injection according to claim 6, wherein the therapeutic pneumonia drug is selected from the group consisting of ofloxacin, ribavirin, penicillin or cephalosporin. The lung-targeting liposome pharmaceutical composition for injection according to claim 1, wherein the lipophobic lipid is selected from the group consisting of lecithin, soybean phospholipid, hydrogenated soybean lecithin, hydrogenated lecithin, and phospholipid Acylethanolamine, synthetic phosphatidylserine, phosphatidylinositol, sphingomyelin, egg choline choline, smectin bismuth, dimyristoyl lecithin, distearoyl acylethanolamine, pegylated phospholipid In the analogy, pegylated distearoyl decanoylethanolamine, decyloxy pegylated distearoylphosphatidylethanolamine, and pegylated phospholipid analogs modified with ligands such as folic acid.  The lung-targeting liposome pharmaceutical composition for injection according to claim 1, wherein the cholesterol-based lipid is selected from the group consisting of cholesterol, cholesterol acetyl ester, cholesterol succinate, and β-valley. Polyethylene glycol-cholesterol modified with a ligand such as sterol, cholesterol stearate, cholesterol palmitate, monodecyl polyethylene glycol-cholesterol, and folic acid.  The pulmonary targeting liposome pharmaceutical composition for injection according to claim 1, wherein the surfactant is selected from the group consisting of a Tween series, a sucrose fatty acid ester, and a polyoxyethylene type nonionic surface. Polyoxyethylene monooleate, polyoxyethylene hydrogenated castor oil and polyoxyethylene alkyl ether in the active agent.  The pulmonary targeting liposome pharmaceutical composition for injection according to claim 1, wherein the acid carrier is selected from the group consisting of citric acid or / and tartaric acid.  The pulmonary targeting liposome pharmaceutical composition for injection according to claim 1, wherein the additive is an antioxidant or/and a solid dispersion carrier; wherein the antioxidant is water soluble or And a fat-soluble antioxidant selected from the group consisting of vitamins or/and vitamin C; the solid dispersion carrier is selected from the group consisting of mannitol, glucose, sorbitol and polyvinylpyrrolidone.  The lung-targeting liposome pharmaceutical composition for injection according to claim 1, wherein the effervescent agent is an aqueous solution of sodium hydrogencarbonate or an aqueous solution of sodium carbonate having a concentration of 2-10 by weight.  14. A method of preparing the pulmonary targeting liposome pharmaceutical composition of claim 1 comprising the steps of:  (1) The composition I or the other substance of the composition II other than the additive is dissolved in a suitable amount of absolute ethanol or a mixed solvent of absolute ethanol and anhydrous diethyl ether to obtain a solution Α, wherein the solvent is anhydrous ethanol. The volume ratio to anhydrous ether is 7-9: 3-1;  (2) Adding a volume of 0. 1 ~ 1. 0% of the activated carbon for injection to the solution, stirring and standing, using a microporous membrane having a pore diameter of less than or equal to 0.22 μπι, to obtain a sterile and Pyrogen-free solution;  (3) heating the solution to remove the organic solvent to obtain a solid phase-loaded precursor liposome granule or powder; when the composition has an additional agent, adding the sterile additive to the solution mash under aseptic conditions, and then Heating the organic solvent to obtain a solid phase-loaded precursor liposome granule or powder; (4) determining the main drug content of the composition of step (3), determining the amount of the preparation, and subdividing under aseptic conditions Load  (5) Formulating an effervescent agent: preparing a sodium hydrogencarbonate or sodium carbonate aqueous solution having a concentration of 2-10 by weight; adding a volume of the solution of 0.1 to 1. 0% of the activated carbon for injection, stirring and standing, using a pore diameter of less than or A microporous membrane equal to 0.22 μm was over-treated to obtain a sterile and pyrogen-free effervescent; and dispensed under sterile conditions.