CN101474155B - Lung-targeted medicine carrying precursor liposome for injection and method of use thereof - Google Patents

Abstract

The invention relates to the technical field of pharmaceutical carrier administration, in particular to the lung-targeted drug-loaded proliposome for injection and its application method. The present invention adopts solid dispersion technology to dissolve active drug, phospholipid lipid, cholesterol lipid, surfactant and acid type carrier in absolute ethanol or a mixed solvent of absolute ethanol and anhydrous ether to obtain solution A, to Add 0.1-1% of its volume of activated carbon for injection into solution A, stir and let it stand, and filter through a microporous membrane to obtain sterile and pyrogen-free solution B, and add sterile additives to the solution under sterile conditions In B, the organic solvent is then removed to obtain a solid granular or powder drug-loaded proliposome, which has a simple preparation process, low cost, controllable quality, good stability, and is suitable for industrial production. The invention provides drug-loaded liposomes prepared by effervescent dispersion technology with small and uniform particle size and a charge of -10 to -30mv. The liposome carrier can deliver more than 90% of the drug to the lungs, and has a significant effect on the lungs. Targeting effect, it is the best carrier drug delivery preparation for the treatment of lung diseases.

Description

Lung-targeted drug-loaded proliposome for injection and method of use thereof

technical field

The invention relates to the technical field of pharmaceutical carrier administration, in particular to the lung-targeted drug-loaded proliposome for injection and its application method.

Background technique

Liposome refers to a bimolecular vesicle with a structure similar to a biological membrane. It is a multilayered vesicle naturally formed by phospholipids dispersed in water. Each layer is a lipid bilayer. Separated by a water phase, the thickness of the bilayer is about 4 nm. It was first discovered by British Bangham and Standish in the 1960s when phospholipids were dispersed in water and observed with an electron microscope. In 1971, British Liman et al. began to use liposomes as drug carriers. Liposome is the most promising targeted drug delivery carrier in pharmacy. It can embed drug powder or solution in particles with a diameter of nanometer or micrometer. This particle has a cell-like structure and can enter the body to change The distribution of the encapsulated drug in the body makes the drug mainly sent to the tissues and organs of the lesion, and reduces the distribution of non-lesional tissues and organs, so as to achieve the purpose of improving the curative effect of the drug and reducing the side effects of the drug.

In the past 20 years, liposome has been one of the hot spots in the research field of new drug delivery systems at home and abroad. It has the advantages of sustained release, targeting, low toxicity, improved drug stability and improved pharmacokinetic properties. Ordinary liposomes enter the body and are mainly swallowed by the reticuloendothelial system to activate the body's autoimmune function, and change the distribution of the encapsulated drug in the body, so that the drug is mainly swallowed in the reticuloendothelial system such as liver, spleen and bone marrow. Poor targeting of other tissues and organs. In recent years, there have also been many studies on targeted liposomes for tissues and organs. However, there are still only a handful of listed products of liposome preparations at home and abroad so far, and most of them stay in the laboratory stage. The main reasons are: (1) The preparation process of liposome preparations is not easy for industrialized production; (2) liposome suspensions are prone to aggregation, fusion and drug leakage during storage, especially the leakage of water-soluble drugs is more significant, while natural phospholipids It is easy to oxidize and hydrolyze, and it is difficult to meet the requirements of the stability of pharmaceutical preparations; (3) the problem of organic residues is difficult to solve.

In order to solve the instability problem of common liposome preparations, the British scholar Payne proposed the concept of proliposomes (proliposomes) in 1986, and the mixed solution of liposome membrane material and medicine was stirred under reduced pressure. Gradually distributed on the surface of a soluble solid carrier to form a free-flowing solid powder formulation. Since the lipid bilayer structure has not yet formed, it is called proliposome, and the liposome suspension can be formed by adding water or buffer before use. Subsequently, self-assembling proliposomes appeared.

Currently, three types of drug-loaded proliposomes can be prepared using different preparation methods:

(1) Mixed micellar proliposomes

Add liposome membrane material and drug to the solution containing surfactant to make mixed micelles. Commonly used surfactants are less toxic glycocholate and deoxycholate. The method has the advantages that it is suitable for the preparation of fat-soluble protein drug proliposome, the drug can be integrated into the liposome membrane, and the encapsulation rate is nearly 100%. Its disadvantages are: the concentration of surfactant in the preparation is relatively high, and the encapsulation efficiency of water-soluble drugs is relatively low. For example, Potluri et al. used this method to prepare drug-loaded proliposomes with a ratio of drug:lipid:Tween-80 of 1:20:3.3, which greatly increased the solubility of progesterone, promoted oral absorption of drugs, and could also be used to prepare Immunoliposomes, etc.

(2) Automatic assembly of proliposomes

Dissolve the drug and liposome membrane material in an appropriate amount of organic solvent in a certain proportion to obtain a clear solution, which can spontaneously form a liposome suspension after being diluted with water or buffer to a certain extent. Alcohol-insoluble water-soluble drugs are added in a two-step dilution method to increase the encapsulation efficiency. The type of lipid, the ratio of lipid, alcohol, and water mixed solution, and the dilution method can all affect the particle size and encapsulation efficiency of the liposome obtained. The method has the advantages of simple operation, easy control of pyrogens and sterility, and the prepared drug-loaded proliposome also has a high encapsulation efficiency for water-soluble drugs. Its disadvantage is that the high concentration of organic solvent limits the clinical application of the preparation. For example, Wang et al. prepared aseptic Transparent blank proliposome solution, injecting this solution into normal saline or water for injection containing doxorubicin hydrochloride can spontaneously form drug-loaded proliposomes, with average particle sizes of (129.0±1.9) am and (112.9±8.6)am, encapsulation efficiency (98.1±0.6) and (96.5±0.2).

(3) Solid particle proliposome

Phospholipids, drugs, excipients and other materials are made into solid preparations by appropriate methods, and water or drug aqueous solution is added before use, and the liposome suspension is obtained by hydration at a phase transition temperature higher than that of phospholipids. The advantage of this method is that this type of proliposome is in a dry state, which can avoid the hydrolysis of phospholipids and drugs to a large extent, and improve storage stability. It is currently the most studied type of proliposome. Its shortcoming is: except freeze-drying method, its method for preparing solid particle proliposome all is difficult to meet the requirement of aseptic and non-pyrogenic; Generally speaking, the particle size of liposome suspension obtained by hydration is difficult to control.

The preparation methods of solid particle drug-loaded proliposomes include: ① fluidized bed coating method;: crush and sieve the carrier (sorbitol, lactose, etc.) spare. Dissolve phospholipids and polyvinylpyrrolidone in an appropriate amount of absolute ethanol, spray on the above-mentioned mixed powder by means of fluidized bed rotation and spraying, dry for a period of time after spraying, take out and sieve to obtain the product. ②Decompression drying method: often use an improved rotary evaporator to make the mixed solution of membrane material and drug gradually form a layer of phospholipid film on the surface of the solid phase carrier under reduced pressure and rotation, and obtain a precursor lipid with good fluidity after drying body particles. Most of the carriers used are porous water-soluble substances, such as sorbitol, mannitol, etc., and can also be inorganic salt substances. By using this method to prepare fat-soluble drug proliposomes, the hydration encapsulation efficiency can reach 100. Its disadvantages are: the use of highly toxic organic solvents such as chloroform and methanol, the uneven distribution of phospholipids on the surface of the carrier, and the complicated operation. ③ Spray drying method: This method is to dissolve or disperse liposome membrane materials, additives and drugs in a suitable solvent, and spray the lipid solution on the surface of lactose and other carriers to form powdery proliposomes. Liposomes can also be prepared first and then spray-dried. Its disadvantage is that it is often necessary to use highly toxic organic solvents such as chloroform and methanol. ④ Freeze-drying method: dissolve or disperse components such as phospholipids, drugs and additives in a suitable solvent, and use the freeze-drying method to obtain powdery or cake-like freeze-dried proliposomes. Similarly, liposomes can also be prepared first and then prepared by lyophilization. The advantage is that the phospholipid and the drug are relatively stable during the preparation process, and it is suitable for the preparation of heat-sensitive drug proliposome; the disadvantage is that the process is complicated and the cost is high.

In summary, the preparation method of proliposome is relatively simple, and the storage stability is greatly improved compared with the corresponding liposome suspension, but no proliposome product has been listed so far. Its possible main reason has: (1) the quality of proliposome is not easy to control, as the liposome particle size distribution that only relies on dilution or hydration operation to prepare is not uniform enough; (2) the encapsulation efficiency of water-soluble drug often (3) As a liposome preparation for intravenous administration, pyrogen, sterility is difficult to control, and only freeze-drying and automatic assembly of liposomes are present in the proliposome technology prepared at home and abroad Can meet the requirements, but the former cost is high, particle size is difficult to control, and the latter will use more organic solvents such as ethanol, benzyl alcohol, isopropanol; (4) organic solvent residues such as chloroform or methyl alcohol are difficult to control; (4) to The depth and breadth of proliposome research are not enough, and a technical platform for preparing proliposome has not yet been formed.

In my country, the incidence of lung diseases such as lung cancer, tuberculosis, and pulmonary infection is relatively high, and the incidence is increasing rapidly. In the treatment of lung diseases, lung-targeted drug delivery is very important. It can directly deliver the drug to the lung tissue, so that the lung can form a high concentration, so as to improve the curative effect, reduce side effects, and reduce the occurrence of drug resistance.

Lung-Targeted Delivery System (LTDS) refers to a new type of drug delivery system that can localize the drug concentration in the diseased tissue, cells or cells of the lung, with high efficacy and low side effects. According to different drug carriers, the lung-targeting carriers can be divided into liposomes, nanoparticles, and nanospheres.

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

(1) Based on the abundance of pulmonary capillaries and large alveolar surface area, drug administration research using pulmonary capillary mechanical filtration. For example, Huo et al. used the solvent evaporation method to prepare cisplatin lung-targeting microspheres with polylactic acid-polyglycolic acid copolymer as auxiliary materials. The average particle size was 12.8 μm, and 98% of the microspheres had a particle size of 5-30 μm. Among them, the concentration of cisplatin in the lungs of rabbits was 212 μg/g after 15 minutes of administration through the ear vein, while that of the control group was only 1.37 μg/g. In the same way, Yan Zhou et al. prepared paclitaxel lung-targeting microspheres with an average particle size of 9.65 μm, and 87.18% of the microspheres were between 5 and 15 μm. After administration of the mouse tail vein, the distribution of the drug in the lung increased significantly. Zhang Na et al. prepared Yanhuning gelatin microspheres by emulsification and cross-linking method, with an average particle size of 17.14 μm. The experimental results showed that the gelatin microspheres had certain lung-targeting properties.

(2) Drug administration research based on particle size. For example, Kellaway and Farr believed that liposomes larger than 2 μm are pulmonary, and liposomes larger than 6 μm are usually trapped by mechanical filtration in the smallest capillary bed of the lungs and taken up by mononuclear leukocytes into lung tissue or alveoli. Wang Jiansong et al. prepared lung-targeting azithromycin liposomes by rotating thin film-freeze-thaw method. The average particle size was 6.58 μm and the surface charge was +19.5 mV. The value is about 8.4 times that of azithromycin solution.

(3) Drug administration research based on the modification method of solid lipid nanoparticles. For example, Wolfgang and Karsten believe that polymer-modified solid lipid nanoparticles can reduce the uptake of drugs by the endothelial reticulum phagocytic system, thereby prolonging the time of drugs in the systemic circulation. Muller et al. found that solid lipid nanoparticles modified by F68 are indeed There are above-mentioned effects; Zara, Serrano etc. adopt soybean lecithin modified solid lipid nanoparticles (80 ± 5 μ m) not only to increase the area of drug in plasma AUC, but also to improve the concentration of drug in the lungs, compared with the control group, About 30% increase. , considered to be phospholipids as a alveolar surfactant that is readily absorbed by the alveolar walls. Xiang et al. used F68-modified lung-targeting dexamethasone lipid nanoparticles with a particle size of 552±6.5nm. After administration of the mouse tail vein, compared with the control group, the concentration of the drug in the lungs was 17.8 times that of the control group. .

From the above literature, it can be seen that there are some problems in the study of lung-targeted drug delivery system at home and abroad: (1) Because the particle size is too large, the safety of intravenous drug delivery may not be guaranteed; (2) Lung-specific targeting If it is not high enough, it will increase the drug concentration in the liver and spleen while increasing the drug concentration in the lung, which may cause toxic side effects on the liver and spleen; (3) In addition to the classic capillary bed of the lung that is intercepted by mechanical filtration as the target , the rest of the lung targeting mechanism is not yet clear.

Contents of the invention

The object of the present invention is to provide a lung-targeting drug-loaded proliposome for injection with remarkable lung-targeting effect, small and uniform particle size, good stability, controllable quality, and easy industrial scale production.

Another object of the present invention is to provide a method for using the lung-targeting drug-loaded proliposome for injection.

The lung-targeted drug-loaded proliposome for injection of the present invention is prepared by the following steps:

a. Take the following materials in the following proportions by weight:

Active drug 0.001～10 Phospholipid lipid 0.5～30 Cholesterol lipid 0.25～15

Surfactant 0～30 Acid carrier 25～90

And above-mentioned each material is dissolved in the mixed solvent of dehydrated alcohol and dehydrated ether, the solution A that obtains weight/volume percentage concentration is 5～30%, the volume ratio of dehydrated alcohol and dehydrated ether in the mixed solvent is 10～ 7: 0~3;

b. Add activated carbon for needles with a volume of 0.1-1% to solution A, stir and let it stand, and filter with a microporous membrane with a pore size less than or equal to 0.22 μm to obtain sterile and pyrogen-free solution B;

c. Add 0-10 parts by weight of sterile additives into solution B under sterile conditions, and then remove the organic solvent to obtain solid granular or powder drug-loaded proliposomes.

Wherein, the active drug can be a drug for treating lung cancer, such as docetaxel, paclitaxel, zoledronic acid, cisplatin, doxorubicin, topotecan, etoposide, cyclophosphamide, etc.; Anti-tuberculosis drugs, such as rifampicin, rifapentine, isoniazid, etc.; can also be used to treat pneumonia drugs, such as ofloxacin, ribavirin, penicillin, and cephalosporins.

The phospholipid lipids can be lecithin, soybean lecithin, hydrogenated soybean lecithin, phosphatidylethanolamine, synthetic phosphatidylserine, phosphatidylinositol, sphingomyelin, egg phosphatidylcholine, dicetyl phospholipid, Myristoyl phosphatidylcholine, distearoylphosphatidylethanolamine, pegylated distearoylphosphatidylethanolamine, methoxypegylated distearoylphosphatidylethanolamine and other pegylated phospholipid analogues, and Ligand-modified pegylated phospholipid analogs such as folic acid, or a mixture of the above two or more.

The cholesterol lipid can be cholesterol, cholesterol acetyl ester, cholesterol hemisuccinate, β-sitosterol, cholesterol stearate, cholesterol palmitate, monomethyl polyethylene glycol-cholesterol, folic acid, etc. Ligand-modified polyethylene glycol-cholesterol, or a mixture of the above two or more.

The surfactant can be polyoxyethylene-type nonionic surfactants such as Tween series, sucrose fatty acid ester, polyoxyethylene monooleate, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, etc. Or a mixture of the above two or more.

The acid carrier can be citric acid, tartaric acid, or a mixture of the two.

The additives can be antioxidants such as vitamin E, vitamin C, and hydrophilic polymers such as polyvinylpyrrolidone, or a mixture of the above two or more.

The method for using the lung-targeted drug-loaded proliposome for injection of the present invention is as follows: preparing an aqueous solution of sodium bicarbonate or an aqueous solution of sodium carbonate with a concentration of 2 to 10% by weight, and adding 0.1 to 1 volume of the solution to the solution. % of activated carbon for injection, stirred and left still, and filtered through a microporous membrane with a pore size less than or equal to 0.22 μm to obtain a sterile and pyrogen-free solution C; inject the prepared solution C into the drug-loaded prolipid with a syringe In the plastid powder or granules, after shaking rapidly for 2-10 minutes, dilute the concentrated drug-loaded proliposome solution into a glucose solution with a concentration of 5% by weight to a concentration of 0.1-2% by weight/volume , Slowly instill the drug to the patient within 8 hours.

The physical and chemical properties and biological properties of the drug-loaded proliposome and its reorganized drug liposome suspension of the present invention (according to the drug-loaded proliposome and its reorganized drug lipid in embodiment 1) plastid suspension):

1. In vitro evaluation

[Finished product traits]

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

[Hydration Dispersion]

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

[stability]

1. Stability of solid particles or powders of drug proliposomes:

(1) Influencing factor test, the sample is exposed to high temperature 60 ℃, light 4500 ± 500LX 10 days, the quality is stable, and high humidity (RH = 75% ± 5%) 10 days, the increase is greater than 5%, liposomes become spherical The property is not good, and the medicine has crystallization, so the moisture content of the product must be strictly controlled.

(2) Accelerated test, simulating the market packaging, tested for 6 months under the conditions of high temperature 25°C, RH=75%±5%, the quality was not stable.

(3) Long-term test, simulating the market packaging, under the vacuum condition of 4-8 ℃ for 12 months, the quality is stable.

2. After the reorganized liposome suspension is diluted with 5% (weight percent) glucose, it is placed at room temperature for 8 hours without precipitation, and the quality is stable.

[Particle size distribution]

According to clinical application requirements, after diluting 100 times with 5% (weight percent) glucose solution, the liposome particle size is measured by a laser particle size analyzer, and the average particle size is 1120 ± 50nm.

[Morphological investigation]

According to clinical use requirements, after diluting with 5% (weight percentage) glucose solution, adopt transmission electron microscope to measure, it can be seen that the liposome has good dispersion and uniform particle size distribution (see accompanying drawing 1).

[Measurement of Encapsulation Efficiency]

First observe whether there are insoluble drug crystals under a 1000 times oil microscope, and use high-speed centrifugation or dialysis respectively, and the encapsulation efficiency is close to 90%.

[Hemolytic test]

Take 10-20ml of blood from the rabbit's ear vein, stir it with a glass rod to remove the fibrin, take 10ml of the defibrinated blood, add 10ml of normal saline, centrifuge, discard the supernatant, if it is centrifuged and washed 2-3 times, so that the supernatant until it turns red. Then, according to the hematocrit volume, a 2% suspension was prepared with physiological saline. Take 6 test tubes and add various solutions according to the arrangement in Table 1. The sixth tube is the control tube. Each tube was shaken well and placed in a 37°C incubator. Record the results of 1, 2, 3, and 24 hours. If the solution becomes clear and stained red, and red blood cells rupture under the microscope, it means hemolysis.

No. Reconstituted liposome(ml) Saline(ml) 2% Erythrocyte supplement (ml) 123456 0.20.40.60.81.0Control 2.32.11.91.71.51.5 2.52.52.52.52.52.5

Results: No hemolysis was observed after 24 hours.

[Safety test]

Take by weighing the proliposome powder containing docetaxel drug, use the 10ml liposome suspension (about 1.2mg docetaxel) of the sodium bicarbonate solution reorganization of 5% (percentage by weight), from the edge of rabbit ear Intravenous slow injection, continuous medication for 10 days, the rabbit did not appear pyrogen reaction and no abnormal phenomenon of ear vein blood vessels.

Results: The intravenous liposome formulation was safe.

2. In vivo evaluation

1. Method

(1) animals

The animals used in this study were 55 healthy New Zealand white rabbits (half and half female), weighing 1.95 to 2.05 kg, provided by the Experimental Animal Center of Chongqing Medical University, and the animals had free access to food and water. According to the regulations of the People's Republic of China on the use of experimental animals, the Animal Ethics Experiment Committee of Chongqing Medical University approved the animal experiments involved in this project. After the experiment, the rabbits were injected to death.

(2) Experimental design

The 55 rabbits were randomly divided into 11 groups, 5 in each group, and then divided into 3 administration groups. Administration group 1 (group 1-5), administered docetaxel liposome suspension from rabbit ear vein with 2 mg docetaxel dosage per kilogram of body weight, administration group 2 (group 6-10), administered Equal doses of docetaxel injection, in which administration group 1 (group 1-4) and administration group 2 (group 6-9), were sacrificed at 0.25, 1.5, 4, and 8 hours after administration. However, in administration group 1 (5 groups) and administration group 2 (10 groups), blood was collected from the ear vein at 0.083, 0.5, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration. At the same time, after the last blood collection, they were executed immediately. Dosing group 3 (group 11) was not given medicine, and served 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 tissue were taken out, the surface of the tissue was blotted dry and weighed accurately, and then added 2ml per 1g Physiological saline for homogenization.

(3) Processing of biological samples

Take blank plasma and homogenate samples of heart, liver, spleen, lung, kidney, stomach, and brain respectively, add different amounts of polyline paclitaxel stock solution precisely, prepare the final concentration in the range of 0.02525ug/ml-101ug/ml, and prepare the standard curve . Drugs were extracted from tissues and plasma by adding methanol/2M ammonium acetate (1:2v/v) mixture to precipitate proteins. Add 50ul (50ug/ml) paclitaxel internal standard methanol solution to 1ml of plasma or tissue, add 3ml of the mixed solution, vortex for 5 minutes, and sonicate in a water bath at 40°C for 10 minutes, then centrifuge at 12,000 rpm for 5 minutes, and dissolve the solution Transfer to the test tube, dilute about 4 times with water, then slowly add to the solid-phase extraction small column (Agilent, ODS C18 column) activated with 2ml methanol and 2ml 0.01M ammonium acetate buffer solution in advance, after the sample solution is loaded, Rinse with 2ml of 0.01M ammonium acetate buffer, 2ml of methanol/0.01M ammonium acetate buffer (1:9v/v), 2ml of methanol/0.01M ammonium acetate buffer (2:8v/v), and dry under vacuum about 1 minute. The drug was then eluted with 2 ml of acetonitrile/methanol (1:1 v/v) mixture. The organic solvent was evaporated under nitrogen gas at 40° C., reconstituted with 0.2 ml of mobile phase, centrifuged at 12,000 rpm for 5 minutes, and 20 ul of the supernatant was taken for HPLC determination. The drug concentration in plasma or tissue was calculated under the Excel software through the corresponding standard curve.

(4) Pharmacokinetic analysis

Using the 3P97 software provided by the Chinese Pharmacological Association, a series of model fittings were performed on the drug concentration-time data to calculate the pharmacokinetic parameters. Determine the best pharmacokinetic model according to the correlation coefficient and AIC standard value, and calculate the pharmacokinetic parameters. Three main targeting parameters (Re, Te and Ce) were calculated to evaluate the lung targeting characteristics of docetaxel. The statistical difference of the test data was judged by SPSS 11.0 one-way analysis of variance.

2. Results

Biodistribution Evaluation in the Lung

It can be seen from Figure 2 and Figure 3 that there are significant differences in the distribution of docetaxel liposome and injection in rabbits. For docetaxel injection (Fig. 2), the drug concentration distribution in the body after administration 0.25h from high to low is kidney, lung, stomach, spleen, liver, heart and brain, wherein the drug concentration in lung is 7.63ug/ g. However, after 4 hours, the drug concentration in the spleen increased to the maximum, and then decreased slowly, while the concentration in the rest of the tissues decreased continuously despite the prolonged time, indicating that the spleen has an absorption process.

Figure 3 shows that after administration of docetaxel liposomes from the marginal ear vein of rabbits, the liposomes can mainly deliver docetaxel to the lungs, and the drug concentration in the lungs (510.20ug/g, 0.25h) was significantly higher than other organize. Compared with paclitaxel injection, 0.25 hours after intravenous administration of docetaxel liposome, the drug concentration in the lungs increased from 7.63ug/g to 510.20ug/g. Calculate according to each tissue weight and drug concentration (ug/g) of rabbits, after 0.25 hours of drug administration through rabbit ear veins, the liposome carrier can deliver 93.6% of docetaxel to the lungs, and a small amount of docetaxel to the liver (5.17 %), kidney (1.10%), stomach (0.87%), heart (0.21%), brain (0.03%) and spleen (0.02%).

According to the peak concentration (Cp) and area under the curve (AUC) of docetaxel, the lung targeting parameters were calculated (see Table 1). From the analysis of the 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, significantly higher than other tissues and blood. The Re value is much greater than 1, indicating that the targeting of the lung is significantly increased after docetaxel is encapsulated by the liposome carrier. Therefore, it can be inferred that the liposome is more specific than docetaxel injection. Sexually deliver docetaxel to the lungs.

Table 1 Targeting ^parameters after intravenous administration of docetaxel liposome and its injection in rabbitsa

^a These values are arithmetic means, n=5.

^b R _e = (AUC) _liposomes / (AUC) _injection .

^c T _e ＝(AUC) _{lung targeted} /(AUC) _untargeted .

^d Ratio of T _e ＝T _e(liposomes) /T _e(injection) .

^e C _e ＝C _{max(liposomes)} /C _{max(injection)} .

The drug-loaded proliposome has obvious slow drug release characteristics. After intravenous administration in rabbits, most of the given drug dose is delivered to the lungs by the liposome carrier, indicating that it has obvious lung targeting. effect.

The lung-targeted drug-loaded proliposome for injection of the present invention is prepared by solid dispersion technology combined with effervescent dispersion technology, and the drug and lipid materials are highly dispersed in the solid proliposome composed of hydrophilic materials and acid source excipients. Body liposomes are then reconstituted with sodium bicarbonate or sodium carbonate solution during clinical use. Due to the rapid dissolution and collapse of hydrophilic materials and acid source excipients, the effervescent impulse of carbon dioxide produced at the same time promotes the formation of liposomes , its preparation process is simple, only conventional pharmaceutical equipment is needed, and it is easy to realize industrial scale production.

The liposome is sterile, pyrogen-free and organic residues are easy to control, avoiding strong toxic organic solvents such as chloroform and methanol used in conventional liposome preparation methods.

Since the drug and lipid material are highly dispersed in the carrier material, and when reconstituted with sodium bicarbonate or sodium carbonate solution, the resulting liposome particle size distribution is more uniform by means of the impulsive force generated by carbon dioxide, and the resulting liposome particle size 0.5 ~ 1.5um, with a charge of about -10 ~ -30mV, which can meet the requirements of clinical intravenous injection.

The prodrug liposome exists in the form of dry solid, avoiding the problems of drug leakage, liposome aggregation, lipid material oxidation and the like which are easy to occur in the liposome suspension prepared by conventional methods. Liposomes have better stability and a longer validity period, with a stability of up to 2 years. The cost is low, and the quality of the drug-loaded proliposome produced is controllable.

Compared with ordinary injection after intravenous administration, the drug-loaded proliposome can deliver most of the given dose of drug to the lungs, while the distribution of other tissues and organs is very small, so it has a very significant lung targeting effect , can be better used in the treatment of lung diseases, reduce systemic toxic and side effects, and is a good lung tissue-targeted drug delivery carrier for the treatment of lung diseases.

Description of drawings

Fig. 1 is the transmission electron micrograph (70,000 times) of proliposome recombination;

Fig. 2 is the biodistribution figure of docetaxel injection in rabbit;

Fig. 3 is a biodistribution diagram of lung-targeted docetaxel liposome for injection in rabbits.

Detailed ways

Example 1: The lung-targeted drug-loaded proliposome for injection is prepared by the following steps:

a. Take the following materials in the following proportions by weight:

Docetaxel 4mg

Dicetyl phospholipid 10mg

Hydrogenated Soy Lecithin 20mg

Cholesterol 15mg

Tween-80 20mg

Citric acid 90mg

And the above-mentioned substances were dissolved in absolute ethanol to obtain a 10% (mg/ml) solution A;

b. Add 0.5% of its volume of activated carbon for injection into solution A, stir and let it stand, and filter through a microporous membrane with a pore size of 0.22 μm to obtain sterile and pyrogen-free solution B;

c. Under sterile conditions, add 3 mg of polyvinylpyrrolidone solution B, and then remove the organic solvent under reduced pressure under general mechanical stirring to obtain solid granular drug-loaded proliposomes;

d. Determining the main drug content of the drug-loaded proliposome obtained in step c, determining the loading amount, and subpackaging under aseptic conditions.

The method for using the lung-targeted drug-loaded proliposome for injection is as follows: prepare an aqueous sodium bicarbonate solution with a concentration of 4% by weight, and add 0.5% of its volume of activated carbon for injection into the solution, stir and let it stand, and use the pore diameter Filter through a 0.22 μm microporous membrane to obtain a sterile and pyrogen-free solution C; use a syringe to inject the prepared solution C into the drug-loaded proliposome particles, and shake it rapidly for 6 minutes. The concentrated drug-loaded proliposome solution is diluted to a 0.5% (mg/ml) solution with a 5% glucose solution by weight, and is slowly infused to the patient within 8 hours.

The obtained docetaxel proliposome suspension has good uniformity, an average particle diameter of 1120±50nm, no crystallization of the main drug under a 1000 times oil lens, an encapsulation efficiency close to 90%, and a surface charge of -23.5mv.

Example 2: The lung-targeted docetaxel proliposome for injection is prepared by the steps in the following order:

a. Take the following materials in the following proportions by weight:

Docetaxel 0.001mg

Soy Lecithin 15mg

Phosphatidylserine 8mg

Cholesterol 10mg

Tween-80 20mg

Tartaric acid 60mg

Citric acid 10mg

And the above-mentioned substances were dissolved in absolute ethanol to obtain a 5% (mg/ml) solution A;

b. Add 0.1% of its volume of activated carbon for injection to solution A, stir and let it stand, and filter with a microporous membrane with a pore size of 0.15 μm to obtain sterile and pyrogen-free solution B;

c. Under sterile conditions, add 2 mg of vitamin E, 5 mg of mannitol and 3 mg of polyvinyl rolidone into solution B, and then remove the organic solvent under reduced pressure with general mechanical stirring to obtain solid granular polyvinyl rolidone. Paclitaxel proliposome;

d. Determining the content of the main drug in the docetaxel proliposome obtained in step c, determining the loading amount, and dispensing under aseptic conditions.

The using method of lung-targeted docetaxel proliposome for injection is: the sodium bicarbonate aqueous solution that preparation weight percent concentration is 2%, and its volume 0.1% activated carbon for injection is added in the solution, stirred and left standstill, adopts Filter through a microporous membrane with a pore size of 0.15 μm to obtain a sterile and pyrogen-free solution C; inject the prepared solution C into the docetaxel proliposome particles with a syringe, shake rapidly for 5 minutes, The concentrated docetaxel proliposome solution is diluted to a 0.1% (mg/ml) solution with 5% glucose solution by weight, and given to the patient by slow infusion within 8 hours.

The obtained docetaxel proliposome suspension has good uniformity, an average particle diameter of 1000±45nm, no crystallization of the main drug under a 1000 times oil lens, an encapsulation efficiency close to 93%, and a surface charge of -17.5mv.

Example 3: The lung-targeted docetaxel proliposome for injection is prepared by the steps in the following sequence:

a. Take the following materials in the following proportions by weight:

Docetaxel 8mg

Lecithin 30mg

β-Sitosterol 15mg

Tween-80 15mg

Tartaric acid 25mg

And the above-mentioned substances were dissolved in a mixed solvent of absolute ethanol and absolute ether, the volume ratio of absolute ethanol and absolute ether in the mixed solvent was 7:3, and a solution A of 30% (mg/ml) was obtained;

b. Add 0.3% of its volume of activated carbon for injection into solution A, stir and let it stand, and filter with a microporous membrane with a pore size of 0.18 μm to obtain sterile and pyrogen-free solution B;

c. Under sterile conditions, 5 mg of vitamin E was added to solution B, and then the organic solvent was removed by a closed-loop spray drying device to obtain powdered docetaxel proliposomes;

d. Determining the content of the main drug in the docetaxel proliposome obtained in step c, determining the loading amount, and dispensing under aseptic conditions.

The use method of lung-targeted docetaxel proliposome for injection is: the sodium bicarbonate aqueous solution that preparation weight percent concentration is 8%, and its volume 0.3% activated carbon for injection is added in the solution, stirred and left standstill, adopts Filter through a microporous membrane with a pore size of 0.18 μm to obtain a sterile and pyrogen-free solution C; inject the prepared solution C into the docetaxel proliposome particles with a syringe, and shake it rapidly for 3 minutes. The concentrated docetaxel proliposome solution is diluted to a 1.5% (mg/ml) solution with a 5% glucose solution by weight, and is slowly infused to the patient within 8 hours.

The obtained docetaxel proliposome suspension has good uniformity, an average particle diameter of 787±65nm, no crystallization of the main drug under a 1000 times oil lens, an encapsulation efficiency close to 100%, and a surface charge of -24.5mv.

Example 4: The lung-targeted docetaxel proliposome for injection is prepared by the steps in the following sequence:

a. Take the following materials in the following proportions by weight:

Docetaxel 0.1mg

Phosphatidylserine 5mg

Soy Lecithin 20mg

Cholesterol Acetyl Ester 0.25mg

Tween-80 1mg

Citric acid 25mg

And the above-mentioned substances were dissolved in a mixed solvent of absolute ethanol and absolute ether, the volume ratio of absolute ethanol and absolute ether in the mixed solvent was 9:1, and a solution A of 20% (mg/ml) was obtained;

b. Add 1% of its volume of activated carbon for injection to solution A, stir and let it stand, and filter through a microporous membrane with a pore size of 0.10 μm to obtain sterile and pyrogen-free solution B;

c. Under sterile conditions, add 1 mg of vitamin E and 1 mg of sorbitol to solution B, and then use a closed-loop spray drying device to remove the organic solvent to obtain powdered docetaxel proliposomes;

d. Determining the content of the main drug in the docetaxel proliposome obtained in step c, determining the loading amount, and dispensing under aseptic conditions.

The method for using the lung-targeted docetaxel proliposome for injection is as follows: prepare an aqueous solution of sodium carbonate with a concentration of 5% by weight, and add 1% of its volume of activated carbon for injection into the solution, stir and let it stand, and use the pore diameter Filter through a 0.10 μm microporous membrane to obtain a sterile and pyrogen-free solution C; inject the prepared solution C into the docetaxel proliposome powder with a syringe, and shake it rapidly for 10 minutes. The concentrated docetaxel proliposome solution is diluted to a 2.0% (mg/ml) solution with a 5% glucose solution by weight, and is slowly infused to the patient within 8 hours.

The obtained docetaxel proliposome suspension has good uniformity, an average particle size of 968±75nm, no crystallization of the main drug under a 1000 times oil lens, an encapsulation efficiency close to 94%, and a surface charge of -21.5mv.

Example 5: The lung-targeted docetaxel proliposome for injection is prepared by the steps in the following order:

a. Take the following materials in the following proportions by weight:

Docetaxel 2mg

Hydrogenated Soy Lecithin 10mg

Cholesterol 10mg

Tween-80 10mg

Tartaric acid 5mg

Citric acid 20mg

And the above-mentioned substances were dissolved in a mixed solvent of absolute ethanol and absolute ether, the volume ratio of absolute ethanol and absolute ether in the mixed solvent was 8:2, and a solution A of 8% (mg/ml) was obtained;

b. Add 0.8% of its volume of activated carbon for injection into solution A, stir and let it stand, and filter with a microporous membrane with a pore size of 0.22 μm to obtain sterile and pyrogen-free solution B;

c. Under sterile conditions, 7 mg of vitamin E was added to the solution B, and then the organic solvent was removed under reduced pressure under general mechanical stirring to obtain granular docetaxel proliposomes;

d. Determining the content of the main drug in the docetaxel proliposome obtained in step c, determining the loading amount, and dispensing under aseptic conditions.

The method for using the lung-targeted docetaxel proliposome for injection is as follows: prepare an aqueous solution of sodium carbonate with a concentration of 5% by weight, and add 0.8% of its volume of activated carbon for injection in the solution, stir and let it stand, and use the pore size Filter through a 0.22 μm microporous membrane to obtain a sterile and pyrogen-free solution C; inject the prepared solution C into the docetaxel proliposomal particles with a syringe, and shake it rapidly for 4 minutes. The concentrated docetaxel proliposome solution is diluted to a 1.2% (mg/ml) solution with a 5% glucose solution by weight, and is slowly infused to the patient within 8 hours.

The obtained docetaxel proliposome suspension has good uniformity, an average particle diameter of 750±75nm, no crystallization of the main drug under a 1000 times oil lens, an encapsulation efficiency close to 97%, and a surface charge of -16.3mv.

Example 6: The lung-targeted drug-loaded proliposome for injection is prepared by the following steps:

a. Take the following materials in the following proportions by weight:

Paclitaxel 0.001mg

Soy Lecithin 15mg

Cholesterol 10mg

Tween-80 30mg

Tartaric acid 60mg

Citric acid 10mg

And the above-mentioned substances were dissolved in absolute ethanol to obtain a 5% (mg/ml) solution A;

b. Add 0.1% of its volume of activated carbon for injection to solution A, stir and let it stand, and filter with a microporous membrane with a pore size of 0.15 μm to obtain sterile and pyrogen-free solution B;

c. Under sterile conditions, add 10 mg of vitamin E to the solution B, and then remove the organic solvent under reduced pressure with general mechanical stirring to obtain solid granular drug-loaded proliposomes;

d. Determining the main drug content of the drug-loaded proliposome obtained in step c, determining the loading amount, and subpackaging under aseptic conditions.

The method for using the lung-targeted drug-loaded proliposome for injection is as follows: prepare an aqueous sodium bicarbonate solution with a concentration of 2% by weight, and add 0.1% of its volume of activated carbon for injection into the solution, stir and let it stand, and use the pore size Filter through a 0.15 μm microporous membrane to obtain a sterile and pyrogen-free solution C; use a syringe to inject the prepared solution C into the drug-loaded proliposome particles, and shake it rapidly for 5 minutes. The concentrated drug-loaded proliposome solution is diluted with 5% glucose solution by weight to a 0.1% (mg/ml) solution, and is slowly infused to the patient within 8 hours.

The paclitaxel proliposome suspension obtained has good uniformity, an average particle diameter of 980nm±45nm, no crystallization of the main drug under a 1000 times oil lens, and an encapsulation efficiency close to 100%.

Example 7: The lung-targeted drug-loaded proliposome for injection is prepared by the following steps:

a. Take the following materials in the following proportions by weight:

Dezapig 3mg

Hydrogenated soybean lecithin 0.5mg

Cholesterol 8mg

Tween-80 15mg

Tartaric acid 25mg

And the above-mentioned substances were dissolved in a mixed solvent of absolute ethanol and absolute ether, the volume ratio of absolute ethanol and absolute ether in the mixed solvent was 7:3, and a solution A of 30% (mg/ml) was obtained;

b. Add 0.3% of its volume of activated carbon for injection into solution A, stir and let it stand, and filter with a microporous membrane with a pore size of 0.18 μm to obtain sterile and pyrogen-free solution B;

c. Under sterile conditions, add 5 mg of vitamin E to solution B, and then use a closed-loop spray drying device to remove the organic solvent to obtain powdered drug-loaded proliposomes;

d. Determining the main drug content of the drug-loaded proliposome obtained in step c, determining the loading amount, and subpackaging under aseptic conditions.

The method for using the lung-targeted drug-loaded proliposome for injection is as follows: prepare an aqueous sodium bicarbonate solution with a concentration of 8% by weight, and add 0.3% of its volume of activated carbon for injection into the solution, stir and let it stand, and use the pore diameter Filter through a 0.18 μm microporous membrane to obtain a sterile and pyrogen-free solution C; use a syringe to inject the prepared solution C into the drug-loaded proliposome particles, and shake it rapidly for 3 minutes. The concentrated drug-loaded proliposome solution is diluted to a 1.5% (mg/ml) solution with a 5% glucose solution by weight, and is given to the patient by slow infusion within 8 hours.

The obtained dezazopyrrole proliposome suspension has good uniformity, an average particle diameter of 1200nm±62nm, no crystallization of the main drug under a 1000 times oil lens, and an encapsulation efficiency close to 100%.

Example 8: The lung-targeted drug-loaded proliposome for injection is prepared by the following steps:

a. Take the following materials in the following proportions by weight:

Azithromycin 0.1mg

Lecithin 25mg

Cholesteryl hemisuccinate 2mg

Tween-80 1mg

Citric acid 45mg

And the above-mentioned substances were dissolved in a mixed solvent of absolute ethanol and absolute ether, the volume ratio of absolute ethanol and absolute ether in the mixed solvent was 9:1, and a solution A of 20% (mg/ml) was obtained;

b. Add 1% of its volume of activated carbon for injection to solution A, stir and let it stand, and filter through a microporous membrane with a pore size of 0.10 μm to obtain sterile and pyrogen-free solution B;

c. Under sterile conditions, add 8 mg of vitamin C to solution B., and then use a closed-loop spray drying device to remove the organic solvent to obtain powdered drug-loaded proliposomes;

d. Determining the main drug content of the drug-loaded proliposome obtained in step c, determining the loading amount, and subpackaging under aseptic conditions.

The use method of the lung-targeted drug-loaded proliposome for injection is: the preparation weight percentage concentration is the sodium carbonate aqueous solution of 5%, and adds the activated carbon for injection of its volume 1% in the solution, stirs and stands still, adopts the pore diameter of Filter through a 0.1 μm microporous membrane to obtain a sterile and pyrogen-free solution C; use a syringe to inject the prepared solution C into the drug-loaded proliposome powder, and shake it rapidly for 10 minutes. The drug-loaded proliposome solution is diluted with 5% glucose solution by weight to a 2.0% (mg/ml) solution, and is slowly infused to the patient within 8 hours.

The obtained azithromycin proliposome suspension has good uniformity, an average particle diameter of 800nm±45nm, no crystallization of the main drug under a 1000 times oil lens, and an encapsulation efficiency close to 95%.

Example 9: The lung-targeted drug-loaded proliposome for injection is prepared by the following steps:

a. Take the following materials in the following proportions by weight:

Ribavirin 8mg

Phosphatidylethanolamine 10mg

Cholesterol 10mg

Tween-80 10mg

Tartaric acid 5mg

Citric acid 20mg

And the above-mentioned substances were dissolved in a mixed solvent of absolute ethanol and absolute ether, the volume ratio of absolute ethanol and absolute ether in the mixed solvent was 8:2, and a solution A of 8% (mg/ml) was obtained;

b. Add 0.8% of its volume of activated carbon for injection into solution A, stir and let it stand, and filter with a microporous membrane with a pore size of 0.20 μm to obtain sterile and pyrogen-free solution B;

c. Under sterile conditions, add 10 mg of vitamin E to the solution B, and then remove the organic solvent under reduced pressure with general mechanical stirring to obtain granular drug-loaded proliposomes;

d. Determining the main drug content of the drug-loaded proliposome obtained in step c, determining the loading amount, and subpackaging under aseptic conditions.

The using method of the lung-targeting drug-loaded proliposome for injection is: the preparation weight percentage concentration is the sodium carbonate aqueous solution of 5%, and adds the active carbon for injection of its volume 0.8% in the solution, stirs and leaves standstill, adopts the pore diameter of Filter through a 0.20 μm microporous membrane to obtain a sterile and pyrogen-free solution C; use a syringe to inject the prepared solution C into the drug-loaded proliposome particles, and shake it rapidly for 4 minutes. The drug-loaded proliposome solution is diluted to a 1.2% (mg/ml) solution with a 5% glucose solution by weight, and is slowly infused to the patient within 8 hours.

The obtained ribavirin proliposome suspension has good uniformity, an average particle diameter of 750nm±35nm, no crystallization of the main drug can be seen under a 1000 times oil lens, and the encapsulation efficiency is close to 100%. the

Example 10: The lung-targeted drug-loaded proliposome for injection is prepared by the following steps:

a. Take the following materials in the following proportions by weight:

Isoniazid 0.1mg

Hydrogenated Soy Lecithin 2mg

β-Sitosterol 9mg

Tween-80 18mg

Citric acid 40mg

Tartaric acid 35mg

And the above-mentioned substances were dissolved in absolute ethanol to obtain a 20% (mg/ml) solution A;

b. Add 0.2% of its volume of activated carbon for injection to solution A, stir and let it stand, and filter with a microporous membrane with a pore size of 0.22 μm to obtain sterile and pyrogen-free solution B;

c. Under sterile conditions, 9 mg of polyvinylpyrrolidone was added to solution B, and then the organic solvent was removed under reduced pressure under general mechanical stirring to obtain granular drug-loaded proliposomes;

d. Determining the main drug content of the drug-loaded proliposome obtained in step c, determining the loading amount, and subpackaging under aseptic conditions.

The method for using the lung-targeting drug-loaded proliposome for injection is as follows: prepare an aqueous solution of sodium bicarbonate with a concentration of 7% by weight, and add 0.2% of its volume of activated carbon for injection into the solution, stir and let it stand, and use the pore size Filter through a 0.22 μm microporous membrane to obtain a sterile and pyrogen-free solution C; use a syringe to inject the prepared solution C into the drug-loaded proliposome particles, and shake it rapidly for 7 minutes. The concentrated drug-loaded proliposome solution is diluted to a 0.3% (mg/ml) solution with a 5% glucose solution by weight, and is given to the patient by slow infusion within 8 hours.

The obtained isoniazid proliposome suspension has good uniformity, an average particle diameter of 950nm±55nm, no crystallization of the main drug under a 1000 times oil lens, and an encapsulation efficiency close to 85%.

Example 11: The lung-targeted drug-loaded proliposome for injection is prepared by the following steps:

a. Take the following materials in the following proportions by weight:

Rifapentine 0.5mg

Lecithin 1.5mg

Cholesterol Palmitate 0.3mg

Tween-80 0.5mg

Tartaric acid 30mg

And the above-mentioned substances were dissolved in absolute ethanol to obtain a solution A of 23% (mg/ml);

b. Add 0.6% of its volume of activated carbon for injection into solution A, stir and let it stand, and filter through a microporous membrane with a pore size of 0.22 μm to obtain sterile and pyrogen-free solution B;

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

d. Determining the main drug content of the drug-loaded proliposome obtained in step c, determining the loading amount, and subpackaging under aseptic conditions.

The use method of the lung-targeted drug-loaded proliposome for injection is: the preparation weight percentage concentration is the sodium carbonate aqueous solution of 2%, and adds the active carbon for injection of its volume 0.6% in the solution, stirs and stands still, adopts the pore diameter of Filter through a 0.22 μm microporous membrane to obtain a sterile and pyrogen-free solution C; use a syringe to inject the prepared solution C into the drug-loaded proliposome powder, and shake it rapidly for 7 minutes. The drug-loaded proliposome solution is diluted with 5% glucose solution by weight to a 0.8% (mg/ml) solution, and is slowly infused to the patient within 8 hours.

The obtained rifapentine proliposome suspension has good uniformity, an average particle diameter of 1050nm±55nm, no crystallization of the main drug under a 1000 times oil lens, and an encapsulation efficiency close to 95%.

Claims (4)

1. The lung-targeted drug-loaded proliposome for injection is characterized in that it is prepared by the steps in the following order: a. Take the following materials in the following proportions by weight: Active drugs 0.001～10 Phospholipid lipids 0.5～30 Cholesterol lipids 0.25～15 Surfactant 0～30 Acid carrier 25～90 And above-mentioned each material is dissolved in absolute ethanol or the mixed solvent of absolute ethanol and absolute ether, obtain weight/volume percentage concentration and be solution A of 5～30%, absolute alcohol or absolute ethanol and absolute The volume ratio of water to ether is 10～7:0～3; b. Add activated carbon for injection with a volume of 0.1-1% to solution A, stir and let stand, and filter with a microporous membrane with a pore size less than or equal to 0.22 μm to obtain sterile and pyrogen-free solution B; c. Under sterile conditions, add 0-10 parts by weight of sterile additives to solution B, and then remove the organic solvent to obtain solid granular or powder drug-loaded proliposomes; The active drug is docetaxel, paclitaxel, dezapig, zoledronic acid, cisplatin, azithromycin, topotecan, etoposide, cyclophosphamide, rifampicin, rifapentine, isoniazid Hydrazine, ofloxacin, ribavirin, penicillin, and cephalosporins; The surfactant is Tween series, sucrose fatty acid ester, polyoxyethylene monooleate, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, or a mixture of two or more thereof; The acid carrier is citric acid, tartaric acid, or a mixture of the two; The aseptic additive is vitamin E, vitamin C, mannitol, glucose, sorbitol, polyvinyl rolidone, or a mixture of two or more thereof. 2. the using method of lung targeting drug-loaded proliposome for injection as claimed in claim 1, is characterized in that: the preparation weight percent concentration is 2～10% sodium bicarbonate aqueous solution or sodium carbonate aqueous solution, and in Add 0.1-1% of its volume of activated carbon for injection into the solution, stir and let it stand, and filter it with a microporous membrane with a pore size less than or equal to 0.22 μm to obtain a sterile and pyrogen-free solution C; then, use a syringe to prepare The solution C of the drug-loaded proliposome is injected into the drug-loaded proliposome powder or granule, and after being shaken rapidly for 2 to 10 minutes, the concentrated drug-loaded proliposome solution is diluted into a glucose solution with a concentration of 5% by weight to Weight/volume percentage The concentration is 0.1-2%, it is completely stable within 8 hours and can be used for injection. 3. The lung-targeted drug-loaded proliposome for injection according to claim 1, characterized in that: a, the phospholipid lipids are lecithin, soybean lecithin, hydrogenated soybean lecithin, phosphatidylethanolamine, synthetic phosphatidylserine, phosphatidylinositol, sphingomyelin, egg phosphatidylcholine, dicetyl phospholipid, Dimyristoyl phosphatidylcholine, distearoyl phosphatidylethanolamine, pegylated distearoyl phosphatidylethanolamine, methoxypegylated distearoyl phosphatidylethanolamine, or a mixture of two or more of the above ; b. The cholesterol lipids are cholesterol, cholesterol acetyl ester, cholesterol hemisuccinate, β-sitosterol, cholesterol stearate, cholesterol palmitate, monomethyl polyethylene glycol-cholesterol, folic acid Ligand-modified polyethylene glycol-cholesterol, or a mixture of the above two or more; The above-mentioned phospholipid lipid: cholesterol lipid = 2:1. 4. The lung-targeted drug-loaded proliposome for injection according to claim 1, characterized in that: the particle size of the liposome is 800-2000nm, and the charge is -10-30mv. the

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