CN104324003A - Cytarabine liposome combination drug and its large-scale industrial production process and application - Google Patents

Abstract

The invention relates to a cytarabine lipidosome combined drug and a large-scale production process and application thereof, which are characterized in that the molar ratio of each component raw material of the cytarabine lipidosome combined drug is disclosed; the invention is characterized in that the invention also provides a large-scale industrial preparation method of the liposome combined medicament; the preparation method is characterized in that the preparation method is used for preparing a freeze-dried injection, an oral preparation, a spray or a suppository of the cytarabine lipidosome combined drug according to the pharmaceutically allowable dose; the cytarabine lipidosome combined drug is characterized in that the cytarabine lipidosome combined drug is used for resisting tumors.

Description

Cytarabine liposome combination drug and its large-scale industrial production process and application

This application is an application enjoying domestic priority. The country of the earlier application is China, and the patent application number of the earlier application is 201010240184.0, the application date is July 29, 2010, and the name is "Dissolution Ultrafiltration - Spray Drying - Molecular Dispersion Coating - Hydration Granulation - Freeze Drying Production Liposome Combination Drugs”; this application is a divisional application, the country of the previous application is China, the patent application number of the previous application is 201110212139.9, the application date is July 28, 2011, and the name is “Alprostadil and other lipids Plastid Combination Drugs and Its Large-scale Industrialized Production Process and Application”, the patent application number of which enjoys domestic priority is 201010240184.0, the application date is July 29, 2010, and the name is “Dissolution Ultrafiltration-Spray Drying -Molecular dispersion coating-hydration granulation-freeze-drying to produce liposome combination drug", July 12, 2013, in the "Notice of First Examination Opinion" with the serial number 2013070900958420, the examiner filed a divisional application .

technical field

The present invention relates to a kind of preparation method of large-scale industrial production liposome combination medicine, it is characterized in that, the subject of the invention is to use dissolving ultrafiltration-spray drying-molecular dispersion coating-hydration granulation-freeze-drying method, with unified formula, The process and equipment can not only produce liposome drug injections in a large industrial scale, but also can produce liposome drug oral preparations in a large industrial scale.

Background technique

The gap between my country's pharmaceutical technology and raw material drug preparation technology and the international advanced level is only within 5 years, and some have reached or exceeded the international advanced level, and the preparation technology is 20 years behind the international advanced level. At present, a large number of second-generation common preparations are produced, while third-generation sustained-release and controlled-release preparations, especially targeted preparations such as fourth-generation liposomes, are currently only in the laboratory research stage. The reasons are:

1. The existing production and research preparation of liposome drug technology injections and oral preparations have inconsistent formulations, processes, and equipment, which not only wastes resources and energy, but also requires a large investment, and the quality is not high, polluting the environment.

2. In the prior art, the methods for industrialized production of liposome drugs include: high-pressure homogenization, ultrasonication, organic solvent drying, spray drying, fluidized bed coating, and single-phase solution freeze-drying. High-pressure homogenization method and ultrasonic method can control the particle size, but high-energy crushing will damage the raw material medicine; the latter four methods cannot control the particle size and the particle size distribution is not concentrated, organic solvent residues, leakage, precipitation, coagulation, phospholipids Corruption and other quality issues;

3. The existing liposome preparation method makes the encapsulation rate of liposome drug carrier not reach 100%, and each batch fluctuates and changes greatly; the leakage rate is large, and the meaning of liposome drug is lost;

4. The production process is troublesome, energy-consuming and time-consuming, equipment investment is large, the prescription and process are not reliable and immature, resulting in uncontrollable, unstable and poor reproducibility of the preparation quality;

5. Improper methods of sterilization and depyrogenation, it is difficult to guarantee the aseptic and pyrogen-free operation throughout the whole process, and the lack of a high degree of sterility concept for liposome drugs leads to corruption of liposome drugs under bacterial erosion, decreased encapsulation efficiency, and leakage rate increases, the validity period is extremely short, and almost loses its medicinal value;

6. The number and size of insoluble particles in the injection exceed the standard;

7. Most raw materials, phospholipids, excipients, and solvents are selected without national drug quality standards, and new drug certificates and production approval documents cannot be approved even if they have patents. Registration is very difficult and takes a long time;

8. Breaking away from the real situation in China, it took nearly 10 years and more than 20 million yuan from the development to the production approval of liposome new drugs. Even the best drug invention patents, most companies dare not invest in development. It can be seen that during the period when the country is carrying out medical reform and the national essential drug system, from the second-generation preparations of national essential medicines, the product with the largest sales volume has been selected to upgrade to the fourth-generation liposome preparation, and the preparation technology innovation has been carried out to eliminate its side effects and adverse reactions. In this way, the sales volume of medicines is large, and the investment recovery time is short. To achieve the basic principles of safety, effectiveness, quality and economy.

Contents of the invention

The purpose of the present invention is to overcome the above-mentioned drawbacks of the prior art. The subject of the present invention is: with dissolution ultrafiltration-spray drying-molecular dispersion coating-hydration granulation-freeze-drying method, both large-scale industrial production of liposome drug injection and large-scale Industrial production of liposomal drug oral formulations. Provide the standard formula and standard preparation method of dissolving ultrafiltration-spray drying-molecular dispersion coating-hydration granulation-freeze drying for the industrial production of liposome combination drugs. The formation of the second-generation drug preparation innovation has been upgraded to the fourth-generation targeted preparation.

The present invention is achieved through the following technical solutions:

The standard molar ratio of each component raw material of the industrialized production liposome combination medicine of the present invention is as follows:

The raw material drug is highly fat-soluble or water-soluble, and the formula dosage is one-third to one-fifth of the minimum dosage of the existing second-generation corresponding oral or injection preparations. Preferably: a composition with a molar ratio of alprostadil to indapamide of 1:30, or a composition with a molar ratio of cefuroxime axetil to alprostadil of 2500:1, or fluconazole, or voriconazole, Either isosorbide dinitrate, or a combination of ribavirin and cefadroxil with a molar ratio of 1:1, or a combination of paclitaxel and alprostadil with a molar ratio of 333:1, or clindamycin phosphate or ganciclovir, or baicalin, or tanshinone IIA, or prostaglandin A ₁ , or meropenem, or pioglitazone, or rosiglitazone, or simvastatin, or Is cytarabine, or hydroxycamptothecin, or sodium nitroprusside, or valacyclovir, or doxorubicin, or etoposide, or adefovir dipivoxil, or The composition of Bavirin and Alprostadil at a weight ratio of 1000:1, or ligustrazine phosphate, or pazufloxacin mesylate, or cefpiramide sodium, or mitoxantrone, or argon hydrochloride Dansetron.

The average molecular weight of the phospholipid raw material is defined as 800D. The phospholipid raw material is a composition of hydrogenated soybean lecithin and polyene phosphatidylcholine, and the molar ratio is 1-5:0.5.

The antioxidant of the phospholipids is reduced glutathione.

The phospholipid film molecular diluent, or phospholipid dispersant, or phospholipid film dispersant, is also an antioxidant, which is dimercaprol.

The liposome drug-carrying dispersant, which is also an excipient, is xylitol.

The surfactant is sodium dehydrocholate.

The raw materials of each component of the liposome combination drug should have national standards, and all of them are national standards of pharmaceutical injection grade. It not only conforms to the national GMP standard, but also conforms to the provisions of the national "Measures for the Administration of Drug Registration", so as to facilitate industrial development.

The present invention also provides the standard preparation method of the liposome combination medicine:

1. In the dissolving tank, dissolve the xylitol ingredients in the phosphate buffer for injection to form a solution of 10% by weight of xylitol, and steam sterilize the solution at 121°C for 20 minutes. When the solution temperature is At 20-25°C, use an ultrafiltration column with an ultrafiltration membrane with a molecular weight cut-off of 1000D to remove pyrogens and pyrogen molecular fragments in the solution, and take the solution obtained by ultrafiltration; The solution is divided into A and B solutions. The A and B solutions are respectively adjusted to pH 8.5 with 5%-8% analytical pure sodium hydroxide solution, and the A and B solutions are respectively filtered through membranes with a pore size below 0.05 μm. Remove insoluble particles, high-valent metal ions, and metal ion precipitates, and then use 8% analytically pure hydrochloric acid solution to adjust the pH value of A and B solutions to 5.0-8.0. If the raw material drug with strong water solubility is completely dissolved with an appropriate amount of water for injection, use a membrane with a molecular weight cut-off of 1000D to remove pyrogens, and the resulting ultrafiltered solution is combined into the B solution and stirred evenly, and then filtered through a membrane with a pore size below 0.05 μm to remove Bacteria and insoluble particles in the raw material drug solution. Raw drug liquid requires inspection of pyrogens and insoluble particles before it is allowed to be added to solution B. If the fat-soluble drug substance dissolves, follow the third step below.

2. Put the solution A in the spray dryer for the preparation of pharmaceutical injections. According to the normal spray drying method, the solution A is mixed and sprayed with the compressed air with a cleanliness of 100 grades (from the compressor, at room temperature) from the spray nozzle on the top of the equipment. It is mixed with the 100-grade clean air (introduced by the induced draft fan, high temperature) that enters the bottom of the equipment at a temperature of 150°C-190°C, and the gas-liquid is countercurrently mixed, and spray-dried into a porous particle dry powder of about 120-150 mesh. After drying, the dry material is stored at the bottom of the equipment for later use.

3. Add fat-soluble raw materials, phospholipids, and phospholipid dispersants to ethanol, stir and dissolve completely, and make a solution with a specific gravity of 1.0 to 1.2. After ultrafiltration through a membrane with a molecular weight cut-off of 1000D, then filter through a membrane with a pore size below 0.05 μm , Remove pyrogens, bacteria, and insoluble particles.

4. Put the dry granules of the composition of solution A prepared in step 2 into a boiling coating machine, and operate according to the normal method of boiling coating and boiling drying. First, divide the phospholipid ethanol solution prepared in step 3 into three equal volumes . At the bottom of the equipment, introduce a room temperature pure nitrogen flow that is anhydrous, sterile, oil-free, and free of particles with a particle size above 0.001 μm. Coating in a boiling fluidized state: First, the first part (one-third volume) of phospholipid ethanol solution is pumped to the coating nozzle in the middle of the equipment and compressed with 100-grade pure nitrogen. Mix and spray to the densest part of the material (xylitol) flow with a boiling height of 400mm-450mm in the machine, coat the surface of the boiling material particles, and the boiling material is highly uniformly mixed and dispersed at the same time, and is extremely fast The solvent is volatilized to form a porous solid coating thin layer, and the first one-third ethanol solution coating of phospholipids is completed, boiled and dried for 15 minutes, and then the B solution prepared in the first step is also divided into three parts, Coat one-third of the volume of the first B solution in an anhydrous, sterile, oil-free, and 100-grade pure nitrogen flow free of particles with a particle size above 0.001 μm, and coat it as described above. After coating, Boil and dry for 20 minutes, so that the first coating-drying operation is carried out; repeat the above-mentioned coating-drying operation, and perform the second and third times of the second and third volumes of the two solutions respectively. Alternate coating-drying operation of phospholipid solution and B solution according to the above operation. The outermost coating layer is a microporous dry substance layer of xylitol, or a microporous dry substance layer of a composition of a raw material drug and xylitol dissolved in water. After the third coating, the obtained coating is dried The residual moisture in the material is ≤1.0%, and the residual dimercaprol is ≤0.2%. Note that if it is a water-soluble bulk drug, the dry granules of solution A are coated three times with the bulk drug and xylitol in solution B, and the ethanol solution does not contain the bulk drug.

5. Add the same volume of water for injection as the phosphate solution for injection used in the first step into the batching tank, fill the tank with nitrogen to keep the pressure outside the tank equal, and heat to 60±5°C at a stirring speed of 100 rpm; Adjust the stirring speed to 500-700 rpm, and add the coated dry matter prepared in step 4 into the batching tank within 30 minutes to 60 minutes under nitrogen in the tank; after adding the coated dried matter, In the nitrogen-filled environment in the tank, keep the temperature at 60±5°C, and keep it for 60-120 minutes under stirring at 100 rpm; then cool the liquid medicine in the tank to 30-40°C under stirring at 100 rpm; Then, under stirring at 100 rpm, the antioxidant glutathione and sodium dehydrocholate were added to dissolve completely, and the pH value of the liquid was adjusted to 5.0-8.0.

6. Keep the temperature of the medicinal solution within the range of 30±5°C, under the nitrogen pressure of 0.1-0.2Mpa, filter the medicinal solution prepared in step 5 with a 0.15μm membrane, take the filtered medicinal solution, and obtain the particle size Liposome drug solution smaller than 150nm. The liposome medicinal solution is divided into vials according to the dosage of the medicine allowed by pharmacy, and half stoppered, and freeze-dried in the freeze-drying box of the freeze-drying unit. Until the residual moisture of the drug solid is less than 2%, the residual dimercaprol is less than 0.2%. Vacuum plugging, capping, after passing the inspection, enter the warehouse. A freeze-dried injection of nanometer particle size made into a liposome drug carrier. This freeze-dried injection can also be made into sterile spray.

7. Under the sterility level of 100, wash the lipid drug particles larger than 150nm intercepted on the filter membrane filtered in step 6 to 10% of the sterilized and depyrogenated 10% freshly prepared according to step 1 In the xylitol solution, measure the content of the total phospholipid raw material in the medicinal liquid, and adjust the volume of the medicinal liquid with the newly prepared 10% xylitol solution qualified for sterilization and depyrogenation, so as to control the total phospholipid content in the medicinal liquid at 40-80mg/ ml; Add this liquid medicine to another ingredient tank, under nitrogen gas, 100 rev/min stirring speed, heat to 50±5°C within 30-60 minutes, keep stirring in this temperature range for 60-120 minutes; then keep stirring Under nitrogen, at 100 rev/min, cool the liquid medicine to 20-25°C, divide the liquid medicine into 316L stainless steel trays, put them in the freeze drying box of another freeze-drying unit, and freeze-dry them in the usual way until The moisture content in the drug solid is less than 2%. The residue of dimercaprol is less than 0.2%. Obtain the liposome drug solid, pulverize the liposome drug solid to 80-100 mesh under 100-grade aseptic level, and make the aseptic enteric-coated oral preparation of the drug by the usual method according to the dosage allowed by pharmacy, aseptic Suppository.

8. All operations should be carried out in strict accordance with the sterile requirements of injections in the national GMP specification. Oral preparations must also follow the sterile requirements for injections.

Liposomal medicine of the present invention, when sterile lyophilized injection is in use, when using transfusion hydration and dissolving in the vial, the phospholipid dispersant disperses the liposome drug-carrying body rapidly, and in xylitol liquid surface tension and Under the action of the surfactant, a uniform dispersion system of liposome drug-loaded particles with a single-chamber nanoparticle size in the range of 50nm-150nm is formed; oral preparations form particles with a particle size of 150-1000nm in the intestine. Encapsulation efficiency is 100%. The liposome drug-carrying body is dispersed in the infusion solution and the leakage rate is less than 5% within 6 hours, without precipitation, aggregation, and layering, and the dispersion is uniform. After oral administration, the medicine of the present invention is dispersed in the gastrointestinal tract fluid to form single-chamber and multi-chamber mixed liposome medicine, so as to improve the therapeutic index of the medicine.

Advantage of the present invention has:

1. With a unified formula, process and equipment, both liposome drug injections and liposome drug oral preparations can be produced industrially.

2. Prepare the fourth-generation targeted preparation with the innovative combination of the equipment innovation of the second-generation preparation and the innovative combination of the second-generation preparation process, so that the mysterious liposome drug can be industrialized and stably produced from the laboratory. It has developed a standardized formula and standardized preparation method for liposome combination drugs, and has a unified core formula and preparation method for injections, oral preparations, and other drug administration routes. It is produced in cheap equipment, which greatly saves workshops, equipment, and manpower. , time, energy, and zero discharge of the three wastes can also be achieved.

3. The present invention focuses on concept innovation to bring innovative technological breakthroughs: based on the basic principles of safety, effectiveness, high quality, and economy, the invention drug is dispersed into the infusion solution from the material selection, to the preparation process, to the use of the final liposome drug The sterility, pyrogen, particle size, particle size distribution, encapsulation rate, leakage rate, spoilage rate, sedimentation rate, coagulation rate, expiration date, etc. of the drug are all strictly in line with this basic principle throughout the process. The risk of industrialized development and marketing of the medicine of the present invention is small.

4. The core technology of the medicine in the present invention includes: the molar amount of phospholipid raw material input breaks through the amount of the prior art, which is 5 times the amount of the prior art and 10 times that of the raw material drug, and the raw material drug is selected to be fat-soluble or water-soluble. For the medicine of dispersant xylitol, the encapsulation rate of phospholipid to drug is much greater than that of xylitol, and the encapsulation rate reaches 100%. Blank liposomes are phagocytized by macrophages, so that the drug-loaded liposomes are less phagocytized, and the curative effect is higher; the surfactant dissolves in the liposome phospholipid membrane layer, which "blocks" the liposome bilayer, Reinforcement effect, because the liposome surfactant is a sodium salt, when the pH value of dissolving physiological saline and glucose is less than 6 infusion, part of its sodium salt becomes water-insoluble acid molecules, and enters the phospholipid bilayer, Instead of cholesterol, it also plays the role of "blocking" and strengthening liposome particles, so that the leakage rate is very small. Surfactants also have the effect of anti-liposome precipitation and aggregation in infusion, and strengthen the dispersion of liposomes into a uniform The role of liposome infusion; due to the addition of dimercaprol, a phospholipid film dispersant, when the coating is dry, the phospholipid film is molecularly dispersed in a microporous solid state instead of high-pressure impact crushing, and ultrasonic waves crush phospholipid film particles, which is more effective than high-pressure impact crushing The phospholipid raw material particles are tens of millions of times smaller, and xylitol replaces the volatilized dimercaprol during coating to form a molecular microporous solid dispersion system of phospholipid and xylitol, making xylitol a dispersant for liposomes This study found that xylitol also has the protective effect of protecting the liposome drug-carrying body from being damaged by small ice slag when freeze-drying, but mannitol has a stimulating effect on blood vessels when intravenous infusion; Anti-oxidation effect of mercaptopropanol protects glutathione, phospholipids, and raw materials from oxidation during coating, so that glutathione can act as an anti-oxidation and anti-peroxidation group in the body, and protect the liver from drug damage; Phospholipid materials This study found that hydrogenated soybean lecithin, a saturated phospholipid and polyene phosphatidylcholine composition, made liposomes stable, low leakage rate, and phospholipids had no antigens on the human body and no damage to the liver; the liposomes of the present invention The lyophilized injection is made into a liposome uniform dispersion system and then freeze-dried. When rehydrating, the physical and chemical properties of the liposome remain unchanged.

5. Due to the above effects, the particle size and particle size distribution of the drug of the present invention in the infusion remain unchanged, the encapsulation rate is 100%, the leakage rate is ≤ 5%, the corruption rate is 0%, the sedimentation rate is 0%, and the aggregation rate is 0%. , Eliminate the four worldwide problems of liposome drug refrigerator storage and transportation, decreasing content and encapsulation rate, increasing leakage rate, and validity period shorter than that of raw materials. Satisfactorily become an excellent and practical fourth-generation preparation.

6. In the liposome medicine prepared by the present invention, the phospholipids in the phospholipid film are dispersed in the phospholipid film absorption and release agent and the surfactant in a solid solution in a molecular state, and are smaller than the ultrasonic method and high-pressure homogeneous broken phospholipid particles by tens of millions. times; during coating-drying, the volatilization of solvent and dimercaprol makes the phospholipid film layer form countless microporous layers, which is much larger than the specific surface area of the network structure formed by the freeze-drying method, because the water in the solid during the freeze-drying process The molecular sublimation volatilization path is tens of millions of times longer than that of the coating layer, so that the network structure dissolves and coagulates; and because the phospholipid film layer and the xylitol layer are phospholipid film dispersant layers, the phospholipids are quickly and highly dispersed during hydration. These three advantages are more stable and more reproducible than the particle size of liposome particles formed by the prior art, forming a nanometer particle size range, and the particle size is normally distributed.

7. Since the selected phospholipids of the present invention are natural phospholipids, which are the constituents of the human body and microbial cell membranes, they have better targeted drug release function to the damaged parts of germs, virus cells, tumor cells and blood vessel walls, and have a high therapeutic index. Therefore, the raw materials The dosage is only one-third to one-fifth of the second-generation drug, and with the encapsulation of phospholipids, the adverse reactions of raw materials are almost gone. The consumption of raw materials is reduced, and the dosage of phospholipids is increased to ensure that the encapsulation rate reaches 100%, and there is a surfactant that "blocks" and strengthens the liposome, so the leakage rate is zero.

8. The phospholipid membrane dispersant of the combination medicine of the present invention is also the proppant of the phospholipid membrane coating. It is also a substance that controls the size of the liposome particle when the liposome is hydrated together with the surfactant, and they are caused by the formation of a certain range of surface tension in the aqueous solution. Xylitol can supply energy to patients with diabetes and liver disease, and is an ideal phospholipid membrane dispersant and excipient.

9. The phospholipid film diluent of the combined medicine of the present invention is soluble in ethanol and water, and volatilizes when spray-drying to form a microporous phospholipid film layer of the molecular state solid dispersion system of the phospholipid film. When hydrating, the phospholipid The phospholipids in the film are dispersed in the water with the degree of molecular fragmentation and the surface dispersant to form a uniform nanoparticle liposome drug carrier, and dimercaprol is an excellent liposome antioxidant. Protect phospholipids and drugs during coating.

10. The surfactant function of the combination medicine of the present invention is first to disperse the phospholipids into water when the phospholipids are hydrated, and secondly, in the infusion solution with a pH value of 4.0-6.0, it is acidified by sodium hydrochloride into a molecular structure organic acid , and enter the liposome bilayer, play the role of liposome "blocking" reinforcement, and the third acts as a surfactant on the liposome surface.

11. The present invention can make the liposome drug valid for one year, and adopts four effective measures: one is to add an antioxidant to protect the phospholipid film and the raw material from oxidation; the other is to coat the phospholipid dispersant on the phospholipid film The outside of the coating layer protects the phospholipid film layer; the third is that the oral preparation is also selected according to the injection material, sterilization and aseptic operation to eliminate the corruption and decomposition of the phospholipid by bacteria. This is a major mistake in all existing liposome oral preparations and even injection technologies Fourth, when the liposomes are dispersed in the infusion, 0.2% dimercaprol complexes the metal ions in the infusion, so that the metal ions brought in the infusion will not destroy the phospholipids and liposome drug-carrying bodies. Vitamin C-glutathione-dimercaptopropanol combination antioxidant, under the joint action of liposome surfactant and dispersant, no leakage, no precipitation, no layering, no aggregation, no oxidation, no corruption, thus The liposome-carrying body has really passed the difficulty of having practical use value. The liposome drug-carrying body is dispersed in the infusion, and the liposome combination drug is qualitatively changed due to the defect of the liposome itself and the effect of the infusion, which is also the major mistake of the present invention to make up for the prior art.

12. During the preparation process of the liposome drug of the present invention, both the phospholipid liquid and the phospholipid dispersion liquid are filtered through a membrane with a pore size of less than 0.05 μm (usually the preparation of injections is filtered through a 0.22 μm membrane), so that the insoluble particles The particle size is reduced to 1/4 of the allowable value, so that after the liposome is hydrated, the particles with a particle size of 50nm to 150nm are all liposome particles. The particle size and particle size distribution of liposome drug-loaded bodies can be accurately determined. This is also the place where the present invention makes up for the major mistakes of the prior art.

Detailed ways:

Example 1

The raw material drug is a liposome combination drug with strong fat solubility. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and methods of this embodiment:

1. In the dissolving tank, dissolve the xylitol ingredients in the phosphate buffer for injection to form a solution of 10% by weight of xylitol, and steam sterilize the solution at 121°C for 20 minutes. When the solution temperature is At 20-25°C, use an ultrafiltration column with an ultrafiltration membrane with a molecular weight cut-off of 1000D to ultrafilter the pyrogen and pyrogen molecular fragments in the solution, and take the solution obtained by ultrafiltration; The solutions are A and B solutions. Use 5%-8% analytically pure sodium hydroxide solution to adjust the pH value of A and B solutions to 8.5, respectively, and filter A and B solutions through membranes with a pore size below 0.05 μm to remove insoluble particles. , high-valent metal ions, and precipitates of metal ions, and then adjust the pH value of A and B solutions to 5.0-8.0 with 8% analytically pure hydrochloric acid solution. The raw material solution requires inspection of pyrogens and insoluble particles to be qualified.

2. Put the A solution in the medicinal injection grade spray boiling dryer, according to the normal method of spray drying, the A solution is mixed and sprayed out from the spray nozzle on the top of the equipment with the compressed air with a cleanliness of 100 (from the compressor, at room temperature) , mixed with the 100-grade clean air (introduced by the induced draft fan, high temperature) entering the bottom of the equipment at a temperature of 150°C-190°C, the gas-liquid is countercurrently mixed, and spray-dried into a dry powder of porous particles of about 120-150 mesh. After drying, the dry material is stored at the bottom of the equipment for later use.

3. Add fat-soluble raw materials, phospholipids, and phospholipid dispersants to ethanol and stir to dissolve completely. If the dissolution of the raw materials is not ideal, a small amount of dichloromethane can be added to the ethanol until the solubility of the raw materials is ideal. Try not to add And add as little dichloromethane as possible to make a solution with a specific gravity of 1.0 to 1.2. After ultrafiltration with a polytetrafluoroethylene membrane with a molecular weight cut-off of 1000D, it is then filtered through a titanium membrane with a pore size below 0.05 μm to remove pyrogens, bacteria, and insoluble substances. particle.

4. Dry the granules of the composition of solution A prepared in step 2, put them in a spray boiling coating-boiling dryer, and operate according to the usual method of boiling coating and boiling drying. First, the phospholipid ethanol solution prepared in step 3, etc. Divide the volume into three portions. At the bottom of the equipment, introduce a room temperature pure nitrogen flow that is anhydrous, sterile, oil-free, and free of particles with a particle size above 0.001 μm. Coating in a boiling fluidized state: First, the first part (one-third of the volume) of phospholipid ethanol solution is pumped to the coating nozzle in the middle of the equipment and mixed with compressed pure nitrogen of 100 grades , sprayed to the densest part of the flow of the material (fructose and mannitol composition) with a boiling height of 400mm-450mm in the machine, coating the surface of the boiling material particles, and the boiling material is highly uniformly mixed and dispersed at the same time, and extremely Quickly evaporate the solvent to form a thin layer of porous solid coating. The coating of the first third of the ethanol solution of phospholipids is completed, boiled and dried for 15 minutes, and then the B solution prepared in the first step is also divided into three equal parts. 1/3 of the volume of the first B solution in a 100-grade pure nitrogen flow that is anhydrous, sterile, oil-free, and free of particles with a particle size above 0.001 μm, and coated according to the above operation, after coating , boiled and dried for 20 minutes, so that the first coating-drying operation was carried out; the above-mentioned coating-drying operation was repeated, and the second and third times of the second and third parts of the two solutions were carried out respectively. The solution of volume carries out the alternate coating-drying operation of phospholipid liquid and B solution according to above-mentioned operation. The outermost coating layer is a microporous dry substance layer of xylitol, or a microporous dry substance layer of a composition of a raw material drug and xylitol dissolved in water. After the third coating, the obtained coating is dried The residual moisture in the material is ≤1.0%, the residual dichloromethane and ethanol are 0%, and the residual dimercaprol is ≤0.2%.

5. Add the same volume of water for injection as the phosphate solution for injection used in the first step into the batching tank, fill the tank with nitrogen to keep the pressure outside the tank equal, and heat to 60±5°C at a stirring speed of 100 rpm. Adjust the stirring speed to 500-700 rpm, fill the tank with nitrogen, and add the dried coated product prepared in step 4 into the batching tank within 30 minutes to 60 minutes. After adding the dried coated product, Under the environment of filling nitrogen in the tank, keep the temperature at 60±5° C., and keep it for 60-120 minutes under stirring at 100 rpm. Then, under stirring at 100 rpm, cool the liquid medicine in the tank to 30-40°C. Then, under stirring at 100 rpm, the antioxidant glutathione and sodium dehydrocholate were added to dissolve completely, and the pH value of the liquid was adjusted to 5.0-8.0.

6. Keep the temperature of the medicinal solution within the range of 30±5°C, under the nitrogen pressure of 0.1-0.2Mpa, filter the medicinal solution prepared in step 5 with a 0.15μm membrane, take the filtered medicinal solution, and obtain the particle size Liposome drug solution smaller than 150nm. The liposome medicinal solution is divided into vials according to the dosage of the medicine allowed by pharmacy, and half stoppered, and freeze-dried in the freeze-drying box of the freeze-drying unit. Until the solid residual moisture of the medicine is less than 2%, the residual dimercaprol is less than 0.2%, and the residual ethanol and dichloromethane are both 0%. Vacuum plugging, capping, after passing the inspection, enter the warehouse. Made into freeze-dried injection. This lyophilized injection can be made into sterile spray.

7. Under the sterility level of 100, wash the lipid drug particles greater than 150nm intercepted on the filter membrane filtered in step 6 to 10% xylitol solution that is sterilized and depyrogenated according to step 1 During the process, the content of the total phospholipid raw material in the liquid medicine was measured, and the volume of the liquid medicine was adjusted with a sterilized 10% xylitol solution qualified for depyrogenation, so as to control the total phospholipid content in the liquid medicine at 40-80 mg/ml. Add the liquid medicine to another ingredient tank, under nitrogen, stir at 100 rpm, heat to 50±℃ within 30-60 minutes, keep stirring in this temperature range for 60-120 minutes, and then keep under nitrogen, 100 Rotate per minute, cool the liquid medicine to 20-25°C, pack the medicine into 316L stainless steel trays, put it in the freeze-drying box of another freeze-drying unit, freeze-dry in the usual way, until the moisture in the solid medicine The residual amount is less than 2%, the residual amount of dimercaprol is less than 0.2%, and the residual amount of ethanol and dichloromethane is 0%. Obtain the liposomal drug solid, crush the liposome drug solid to 80-100 mesh under 100-grade aseptic level, and make the aseptic enteric-coated oral preparation of the drug by the usual method according to the dosage allowed by pharmacy, aseptic Suppository.

8. All operations should be carried out in strict accordance with the sterile requirements of injections in the national GMP specification. Oral preparations must also follow the sterile requirements for injections.

Example 2

The raw material drug is a liposome combination drug with strong fat solubility. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and method of this embodiment are the same as in Example 1.

Example 3

The raw material drug is a liposome combination drug with strong fat solubility. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and method of this embodiment are the same as in Example 1.

Example 4

The raw material drug is a liposome combination drug with strong fat solubility. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and method of this embodiment are the same as in Example 1.

Example 5

The raw material drug is a liposome combination drug with strong fat solubility. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and method of this embodiment are the same as in Example 1.

Example 6

The raw material drug is a liposome combination drug with strong fat solubility. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and method of this embodiment are the same as in Example 1.

Example 7

The raw material drug is a liposome combination drug with strong fat solubility. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and method of this embodiment are the same as in Example 1.

Example 8

The raw material drug is a liposome combination drug with strong fat solubility. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and method of this embodiment are the same as in Example 1.

Example 9

The raw material drug is a liposome combination drug with strong fat solubility. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and method of this embodiment are the same as in Example 1.

Example 10

The raw material drug is a liposome combination drug with strong fat solubility. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and method of this embodiment are the same as in Example 1.

The fat-soluble bulk drug described in the above examples, or the composition of cefuroxime axetil and alprostadil with a molar ratio of 2500:1, or fluconazole, or voriconazole, or isosorbide dinitrate, or A combination of ribavirin and cefadroxil with a molar ratio of 1:1, or a combination of paclitaxel and alprostadil with a molar ratio of 333:1, or clindamycin phosphate, or hydrogen artesunate or baicalin, or alprostadil, or tanshinone ⅡA, or prostaglandin A ₁ , or dihomo-γ-linolenic acid, or hydroxycamptothecin, or simvastatin, or It is pioglitazone, or rosiglitazone, or adefovir dipivoxil, or a combination of ribavirin and alprostadil at a weight ratio of 1000:1, or mitoxantrone.

Example 11

The raw material drug is a highly water-soluble liposome combination drug. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and methods of this embodiment:

1. In the dissolving tank, dissolve the xylitol ingredients in the phosphate buffer for injection to form a solution of 10% by weight of xylitol, and steam sterilize the solution at 121°C for 20 minutes. When the solution temperature is At 20-25°C, use an ultrafiltration column with an ultrafiltration membrane with a molecular weight cut-off of 1000D to ultrafilter the pyrogen and pyrogen molecular fragments in the solution, and take the solution obtained by ultrafiltration; The solutions are A and B solutions. Use 5%-8% analytically pure sodium hydroxide solution to adjust the pH value of A and B solutions to 8.5, respectively, and filter A and B solutions through membranes with a pore size below 0.05 μm to remove insoluble particles. , high-valent metal ions, and precipitates of metal ions, and then adjust the pH value of A and B solutions to 5.0-8.0 with 8% analytically pure hydrochloric acid solution. Dissolve the highly water-soluble raw material with an appropriate amount of water for injection, ultrafilter it with a membrane with a molecular weight cut-off of 1000D to remove pyrogens, combine it into solution B and stir evenly, and then filter through a membrane with a pore size below 0.05 μm to remove bacteria in the raw drug , In addition to insoluble particles. Raw drug liquid requires inspection of pyrogens and insoluble particles before it is allowed to be added to solution B.

2. Put the solution A in the spray dryer for the preparation of pharmaceutical injections, according to the normal spray drying method, the solution A is mixed and sprayed out from the spray nozzle on the top of the equipment with the compressed air with a cleanliness of 100 (from the compressor, at room temperature) , mixed with the 100-grade clean air (introduced by the induced draft fan, high temperature) entering the bottom of the equipment at a temperature of 150°C-190°C, the gas-liquid is countercurrently mixed, and spray-dried into a dry powder of porous particles of about 120-150 mesh. After drying, the dry material is stored at the bottom of the equipment for later use.

3. Add phospholipids and phospholipid dispersants to ethanol, stir and dissolve completely, and make a solution with a specific gravity of 1.0 to 1.2. After ultrafiltration through a membrane with a molecular weight cut-off of 1000D, then filter through a membrane with a pore size below 0.05 μm to remove pyrogens and bacteria. , Insoluble particles.

4. Dry the granules of the composition of solution A prepared in step 2, put them in a spray boiling coating-boiling dryer, and operate according to the usual method of boiling coating and boiling drying. First, the phospholipid ethanol solution prepared in step 3, etc. Divide the volume into three portions. At the bottom of the equipment, change to introduce a room temperature pure nitrogen flow that is anhydrous, sterile, oil-free, and free of particles with a particle size above 0.001 μm. Particles are coated in a boiling fluidized state: First, the first part (one-third of the volume) of phospholipid ethanol solution is pumped to the coating nozzle in the middle of the equipment and the compressed clean level is 100 pure Nitrogen is mixed and sprayed to the densest part of the flow of the material (fructose and mannitol composition) with a boiling height of 400mm-450mm in the machine, coating the surface of the boiling material particles, and the boiling material is highly uniformly mixed and dispersed at the same time. And the solvent is volatilized very quickly to form a thin layer of porous solid coating. The first third of the phospholipid ethanol solution coating is completed, boiled and dried for 15 minutes, and then the B solution prepared in the first step is also equally divided In three parts, one-third of the volume of the first part of solution B is coated in a 100-grade pure nitrogen stream that is anhydrous, sterile, oil-free, and free of particles with a particle size above 0.001 μm, and coated according to the above operation. After coating, boil and dry for 20 minutes, thus carried out the coating-drying operation for the first time; One volume of the solution is carried out in the alternate coating-drying operation of the phospholipid solution and the B solution according to the above operation. The outermost coating layer is a microporous dry material layer of a water-soluble raw material and xylitol composition. After the third coating, the residual moisture in the obtained coated dry material is ≤1.0%, and the remaining Dimercaprol≤0.2%, residual ethanol is 0%.

5. Add the same volume of water for injection as the phosphate solution for injection used in the first step into the batching tank, fill the tank with nitrogen to keep the pressure outside the tank equal, and heat to 60±5°C at a stirring speed of 100 rpm. Adjust the stirring speed to 500-700 rpm, fill the tank with nitrogen, and add the dried coated product prepared in step 4 into the batching tank within 30 minutes to 60 minutes. After adding the dried coated product, Under the environment of filling nitrogen in the tank, keep the temperature at 60±5° C., and keep it for 60-120 minutes under stirring at 100 rpm. Then, under stirring at 100 rpm, cool the liquid medicine in the tank to 30-40°C. Then, under stirring at 100 rpm, the antioxidants reduced glutathione and sodium dehydrocholate were added to dissolve completely, and the pH value of the liquid was adjusted to 5.0-8.0.

6. Keep the temperature of the liquid medicine within the range of 30±5°C, under the nitrogen pressure of 0.1-0.2Mpa, filter the liquid medicine prepared in step 5 with a 0.15μm membrane, and take the filtered liquid medicine to obtain a particle size smaller than 150nm liposome drug solution. The liposome medicinal solution is divided into vials according to the dosage of the medicine allowed by pharmacy, and half stoppered, and freeze-dried in the freeze-drying box of the freeze-drying unit. Until the residual moisture of the drug solid is less than 2%, the residual dimercaprol is less than 0.2%, and the residual ethanol is 0%. Vacuum plugging, capping, after passing the inspection, enter the warehouse. Made into freeze-dried injection. This lyophilized injection can be made into a sterile spray.

7. Under the sterility level of 100, wash the lipid drug particles greater than 150nm intercepted on the filter membrane filtered in step 6 to 10% of the newly prepared wood that is qualified for sterilization and depyrogenation according to step 1. In the sugar alcohol solution, measure the content of the total phospholipid raw material in the medicinal liquid, and adjust the volume of the medicinal liquid with a sterilized and depyrogenated 10% xylitol solution, so as to control the total phospholipid content in the medicinal liquid at 40-80mg/ml. Add the liquid medicine to another ingredient tank, under nitrogen, stir at 100 rpm, heat to 50±℃ within 30-60 minutes, keep stirring in this temperature range for 60-120 minutes, and then keep under nitrogen, 100 Rotate per minute, cool the liquid medicine to 20-25°C, pack the medicine into 316L stainless steel trays, put it in the freeze-drying box of another freeze-drying unit, freeze-dry in the usual way, until the water in the solid medicine The content is less than 2%, the residual dimercaprol is 0.2%, and the residual ethanol is 0%. Obtain the liposome drug solid, pulverize the liposome drug solid to 80-100 mesh under 100-grade aseptic level, and make the aseptic enteric-coated oral preparation of the drug by the usual method according to the dosage allowed by pharmacy, aseptic Suppository.

8. All operations should be carried out in strict accordance with the sterile requirements of injections in the national GMP specification. Oral preparations must also follow the sterile requirements for injections.

Example 12

The raw material drug is a highly water-soluble liposome combination drug. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and method of this embodiment are the same as those in Embodiment 11.

Example 13

The raw material drug is a highly water-soluble liposome combination drug. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and method of this embodiment are the same as those in Embodiment 11.

Example 14

The raw material drug is a highly water-soluble liposome combination drug. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and method of this embodiment are the same as those in Embodiment 11.

Example 15

The raw material drug is a highly water-soluble liposome combination drug. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and method of this embodiment are the same as those in Embodiment 11.

Example 16

The raw material drug is a highly water-soluble liposome combination drug. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and method of this embodiment are the same as those in Embodiment 11.

Example 17

The raw material drug is a highly water-soluble liposome combination drug. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and method of this embodiment are the same as those in Embodiment 11.

Example 18

The raw material drug is a highly water-soluble liposome combination drug. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and method of this embodiment are the same as those in Embodiment 11.

Example 19

The raw material drug is a highly water-soluble liposome combination drug. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and method of this embodiment are the same as those in Embodiment 11.

Example 20

The raw material drug is a highly water-soluble liposome combination drug. The molar ratio of each raw material component of the standard is as follows:

The standard preparation steps and method of this embodiment are the same as those in Embodiment 11.

The water-soluble raw material drug described in embodiment 11 to embodiment 20: preferably ganciclovir, or cytarabine, or sodium nitroprusside, or valacyclovir, or doxorubicin, or Etoposide, or ligustrazine phosphate, or levofloxacin hydrochloride, or cefpiramide sodium, or ondansetron hydrochloride, or meropenem.

Comparison of technical economy and quality indicators

Conclusion: the technology of the present invention prepares liposome drug-carrying body and compares with existing homogeneous freeze-drying method, fluidized bed coating method technology system liposome drug-carrying body, the present invention's technical economy and main quality index are all superior to homogeneous Quality freeze-drying method, quality index is all better than fluidized bed coating method.

Pharmacodynamic verification test:

1. Pharmacodynamic verification test of anti-gastric ulcer drugs: Jiankang rats were selected as experimental animals, regardless of gender, weighing 200-250g, 8 in each group. See the test results table for the drugs and doses used. Before the experiment, the rats were fasted for 24 hours and allowed to drink water freely. The abdominal cavity was opened under ether anesthesia, a glass tube with an inner diameter of 5 mm and a length of 30 mm was placed vertically on the serosa surface of the gastric body, and 0.2 ml of glacial acetic acid was added into the lumen. After 1.5 minutes, dip a cotton swab in glacial acetic acid, and suture the surgical incision. Normal diet after operation, randomly set up a blank control group 1 and a positive control group 1 on the second day, the blank control group was administered with normal saline, 0.5ml/time, intraperitoneal injection, and the positive control group was administered with famotidine. Physiological saline is dissolved, and 0.5ml/time is taken, and the liposome drug administration group of the present invention is divided into injection administration group and oral administration group. Liposomal drug injection administration, liposome drug dissolved with physiological saline, get 0.5ml/time. Administration for 15 days, twice a day, once every 12 hours. Divided into injection and oral administration. Samples prepared in each embodiment were administered for 3 consecutive days. After 15 days of administration, the stomach was dissected and fixed with formaldehyde, the ulcer area was measured in mm ² , and the average ulcer area of each group was calculated.

Pharmacodynamic test results table:

Visible, above-mentioned medicine of the present invention curative effect is higher than contrast positive medicine.

2. Pharmacodynamics test of anti-infective drugs:

(1) Animal selection: Select mice infected with animal experimental models prepared by the Experimental Animal Center, weighing 18-22 g, half male and half male, and randomly divided into groups, with 50 animals in each group.

(2) Infection strains: two groups of model mice with pneumonia caused by Staphylococcus aureus and model mice with pneumonia caused by Streptococcus pneumoniae.

(3) Amount of infectious bacteria: The 100% minimum lethal dose (100% MLD) of the tested strains was measured by the Experimental Animal Center as the amount of infectious bacteria.

(4) Infection route: Dilute the bacterial stock solution with 5% peptin to the required concentration (determined by the Experimental Animal Center), and inject it through the tail vein.

(5) Test method: Divide the mice into two groups: A. the model mouse group of Staphylococcus aureus-induced pneumonia, and B. the model mouse group of Streptococcus pneumoniae-induced pneumonia. Carry out no administration control, clindamycin phosphate for injection control prepared by the prior art, and drug control of the present invention. There were 50 model animals in each group. Immediately after infection, it is administered intravenously or orally, and is given again every 6 hours. Animal reactions were observed, and the number of dead mice was recorded for 7 consecutive days. See the test results table for the drugs used, their doses, and their effects:

3.1 Pharmacodynamic verification test of anti-myocardial ischemic drugs:

Healthy mice, regardless of sex, weighing 18-20 g, were selected, 10 in each group. Myocardial ischemia was induced in mice with isoproterenol (a mouse model of myocardial ischemia was prepared by the Experimental Animal Center). A blank control group and a positive drug control group were set up. The positive control drug was nitroglycerin, administered once a day for 10 days. After 10 days, perform double staining of ischemic or infarcted myocardium, that is, N-BT or TTC staining; quantify myocardial ischemia and infarction area under a microscope, and calculate the ratio of the average value of each group to the average value of the positive control group and the average value of the blank control group percentage. The drug used, dose, and administration method are shown in the table of pharmacodynamic test results:

3.2 Pharmacodynamic tests of antihypertensive drugs:

Spontaneously hypertensive rats (SHR) were selected, 10 in each group, and 10 in each group with renal vascular stenosis. The blood pressure and heart rate were measured in the control period first, and the drug was administered after the blood pressure was stable. The blood pressure was measured 2 hours before and 3 hours after the administration, and the administration period was 2 weeks. It is effective when the blood pressure drops above 20mmHg after 3 hours of administration. See the table of pharmacodynamic test results for the drugs used, doses, and administration methods:

4. Pharmacodynamics test of antineoplastic drugs:

Rat tumor model was selected: Wacker carcinosarcoma (W256) type. The weight is 50-70g, and there are 10 animals in each group. A negative control group and a positive control group were set up. The negative control group was injected with normal saline, and the positive control group was treated with currently available paclitaxel. Administration once a day, treatment time 15 days. The animals were sacrificed 24 hours after drug withdrawal, the tumor mass was dissected and removed, and the tumor weight was weighed. The formula for calculating curative effect evaluation is:

Tumor inhibition rate%=(C-T)/CX100%

When the inhibition rate is greater than 30%, it is effective.

Test result table:

project Tumor inhibition rate% Remark Currently available paclitaxel injection 50mg/kg intraperitoneal injection 70 Example 11-16 Ifosfamide 500mg/kg intraperitoneal injection 75 Example 1-5 Intraperitoneal injection of paclitaxel and alprostadil 50mg/kg 88 Example 11-15 Cytarabine 2mg/kg intraperitoneal injection 83 Example 16-20 Hydroxycamptothecin 8m/kg intraperitoneal injection 78 Example 16-20 Doxorubicin 20mg/kg intraperitoneal injection 81 Example 16-20 Etoposide 100mg/kg intraperitoneal injection 82 Example 6-10 Mitoxantrone 20mg/kg intraperitoneal injection 78 Example 11-15 Ondansetron hydrochloride 8mg/kg intraperitoneal injection 95% antiemetic rate Antineoplastic drugs cause vomiting Example 15-20 Water-soluble vitamin 100mg/kg intraperitoneal injection 100% effective Nutritional supplements for cancer patients

5. Pharmacodynamics test of hypoglycemic drugs: the drug of the present invention can stimulate insulin secretion, so normal healthy mice were selected, 15 in each group. Experimental mice were fasted (with free access to drinking water) for 5 hours and administered once a day. Blood was taken 2 hours after the administration, and the serum glucose value was measured. Continuous administration for 7 days. Calculate the average decrease rate of blood sugar (compared with the blank control group). It is effective if the blood sugar reduction rate is greater than 20%. See the test results table for the drugs used, their doses and routes of administration:

6. Pharmacodynamics test of antiviral drugs:

Mouse encephalitis model: mice weighing 11-13g, male or female, 15 mice in each group. HSV-1 Sm44 strain, intraperitoneal injection of the virus can cause encephalitis death, calculated LD ₅₀ . Then the intraperitoneal injection of HSV-1 virus doses of virus LD ₀ 1/2, 1/4, 1/8 for 2 days each, once a day. Calculate the mortality rate, the average number of living days, and compare the protection rate of death and the prolongation of life rate with the drug treatment group. The treatment group was administered for 15 days, twice a day. See the test results table for the drugs, doses, and routes of administration:

7. Pharmacodynamics test of antifungal drugs: choose healthy mice with a body weight of 18-20 g, half male and half male. Randomly divided into 6 groups, immediately after infection and 6 hours after tail vein injection, 10 in each group, used as a systemic infection fungal disease model. Cryptococcal encephalitis fungal strains were used as infection strains. First measure the 100% minimum lethal dose (100% MLD) of the strain to mice as the amount of infectious bacteria. Immediately and 6 hours after infection, the tail vein injection was administered, and the face was administered for 7 days, and the mortality rate of the animals was recorded and compared with that of the blank control group.

The test results are as follows:

It can be seen from the above pharmacodynamic test results that the liposome combination drug of the present invention is comprehensively superior to the currently available corresponding drugs prepared by the prior art in terms of safety, stability and curative effect.

Claims (6)

1. a cytarabine liposome composition of medicine, is characterized in that, cytarabine liposome composition of medicine nanometer particle size lyophilized injection, or the aseptic enteric oral preparation of cytarabine liposome composition of medicine; The proportioning of the molal quantity of each component raw material of cytarabine liposome composition of medicine nanometer particle size lyophilized injection and cytarabine liposome composition of medicine aseptic enteric oral preparation is as follows:

The mean molecule quantity of lecithin materials all defines and calculates with 800D, and lecithin materials is the compositions of hydrogenated soy phosphatidyl choline and polyene phosphatidylcholine, and mole ratio is the compositions of 1-5:0.5;

The antioxidant of phospholipid is reduced glutathion;

Phospholipid dispersions, or claim immobilized artificial membrane dispersant, or claim immobilized artificial membrane molecular state diluent, being again antioxidant, is dimercaprol;

Liposome medicine carrying body dispersant is again excipient, is xylitol, xylitol is except the amount of above-mentioned molal quantity proportioning, as cytarabine liposome composition of medicine nanometer particle size lyophilized injection with outward, also to use as the aseptic enteric oral preparation of cytarabine liposome composition of medicine by following provisions recruitment: the xylitol solution of 10% is that phosphate buffer makes solvent, xylitol amount and phosphate solution amount all should be determined according to the liposome medicament amount being greater than 150nm particle diameter, newly increase, exceed 10% xylitol solution of the amount in above-mentioned formula, the Lipid pharmaceutical being greater than 150nm particle diameter is scattered in sterilizing, in the 10% freshly prepd xylitol solution that depyrogenation is qualified, measure the content being greater than the particle diameter liposome medicament total phospholipids raw material of 150nm in liposome medicament dispersion medicinal liquid, and adjust medicine liquid volume with qualified freshly prepd 10% xylitol solution of sterilizing depyrogenation, reach and to control in medicinal liquid total phospholipids content at 40-80mg/ml, refer to (7) step of preparation method,

Surfactant is sodium dehydrocholate;

The normalized process for preparing of cytarabine liposome composition of medicine:

(1) by cytarabine liposome composition of medicine nanometer particle size lyophilized injection xylitol dosage, the weight percent solution of 10% of xylitol is dissolved in injection phosphorus phthalate buffer, by this solution 121 DEG C of steam sterilizations 20 minutes, when solution temperature is 20-25 DEG C, with the ultrafiltration post ultrafiltration of the ultrafilter membrane of molecular cut off 1000D, except the pyrogen in solution and pyrogen molecule fragment, get the solution that ultrafiltration obtains; Again at room temperature, the solution that decile ultrafiltration obtains, be divided into A, B solution, A, B solution are used respectively the analytical pure sodium hydroxide solution adjust pH 8.5 of 5%-8%, by A, B solution respectively through the membrane filtration mistake in less than 0.05 μm aperture, remove the precipitate of insoluble particle, high volence metal ion, metal ion, then be 5.0-8.0 with the analytically pure hydrochloric acid solution adjust pH of 8% respectively by A, B solution;

(2) by solution A in the spray dryer preparing pharmaceutical injection agent level, by spraying dry well-established law, solution A by the spraying nozzle at equipment top with cleanliness factor 100 grades of compressed airs, by compressor come, room temperature, mixing ejection, the temperature entered with device bottom 150 DEG C of-190 DEG C of 100 grades of pure airs, are attracted by air-introduced machine, high temperature, gas-liquid counter current mixes, and is spray dried to 120-150 order left and right porous granule dry powder; Dry complete, it is for subsequent use that dried material leaves this device bottom in;

(3) stirring and dissolving in fat-soluble crude drug cytosine arabinoside, phospholipid, phospholipid dispersions dimercaprol to ethanol is added respectively complete, make proportion 1.0 to 1.2 solution, through the membrane ultrafiltration of molecular cut off 1000D, again through less than 0.05 μm aperture membrane filtration mistake, except pyrogen removal, antibacterial, insoluble particle;

(4) the composition dries granule of the solution A (2) step prepared, is put in boiling seed-coating machine, by boiling coating and the operation of airpillow-dry well-established law, first divides three parts by phospholipid alcoholic solution equal-volume prepared by (3) step, introducing is changed into anhydrous in device bottom, aseptic, without oil, without the room temperature purity nitrogen air-flow of the particle of more than 0.001 μm particle diameter, at 40 DEG C of-65 DEG C of temperature, coating under boiling fluidized state is carried out to the dry thing particle of the xylose that (2) step is obtained: first by the phospholipid alcoholic solution of 1/3rd volumes of first part, by being that 100 grades of pure nitrogen gas mix with compressed clean rank in the coating nozzle in the middle part of transport pump to equipment, being sprayed onto boiling in machine in spray form is highly the thick of 400mm-450mm material xylitol stream, at boiling material particle surface coating, material simultaneous altitude under boiling is mixed and dispersion equably, and make solvent volatilize as quick as thought, form porosu solid coating thin layer, the alcoholic solution feed liquid coating of first three/monophosphatide completes, airpillow-dry 15 minutes, the B solution first step prepared again is decile three parts also, by 1/3rd solution of the volume of first part of B solution anhydrous, aseptic, without oil, in 100 grades of purity nitrogen air-flows without the particle of more than 0.001 μm particle diameter, by aforesaid operations coating, after coating, airpillow-dry 20 minutes, carry out first time coating-drying process like this, repeat above-mentioned coating-drying process, the solution carrying out 1/3rd volumes of second part of second, third time two kinds of solution, the 3rd part respectively, by aforesaid operations, carries out the alternately coating-drying process of phospholipid liquid and B solution, outermost layer coatings is the dry nitride layer of xylitol micropore, for the third time after coating, and residual moisture content≤1.0% in the coating dried material obtained, residual dimercaprol≤0.2%,

(5) in material-compound tank, add the isopyknic water for injection of injection phosphorus acid salt solution with the first step, in tank, inflated with nitrogen and tank external pressure maintain an equal level, and under 100 revs/min of mixing speeds, are heated to 60 ± 5 DEG C; Tune speed of agitator is 500-700 rev/min, in tank under inflated with nitrogen, in 30 minutes to 60 minutes, dry for coating obtained for the 4th step thing is joined in material-compound tank; After adding the dry thing of coating, in tank under inflated with nitrogen environment, keep temperature 60 ± 5 DEG C, and keep 60-120 minute under stirring at 100 revs/min; Under stirring at 100 revs/min again, tank inner liquid medicine is cooled to 30-40 DEG C; Under stirring at 100 revs/min again, add antioxidant glutathion and sodium dehydrocholate respectively and dissolve completely, and adjust medicinal liquid pH value 5.0-8.0;

(6) keeping fluid temperature within the scope of 30 ± 5 DEG C, under 0.1-0.2Mpa nitrogen pressure, crossing the obtained medicinal liquid of (5) step by 0.15 μm of membrane filtration, getting the medicinal liquid of filtration, obtain the liposome medicinal liquid that particle diameter is less than 150nm; Allow the dosage subpackage liposome medicinal liquid of this medicine in cillin bottle by pharmaceutics, and partly jump a queue, well-established law lyophilization in the freeze drying box of lyophilization unit; To medicine solid residue moisture for being less than 2%, dimercaprol residual quantity is for being less than 0.2%, and vacuum tamponade, rolls lid, and be up to the standards laggard storehouse; Make the lyophilized injection of the nanometer particle size of liposome medicine carrying body; This lyophilized injection also can be made into aseptic spray;

(7) under 100 grades of sterilization grade, the Lipid pharmaceutical granule being greater than 150nm that the filter membrane (6) step filtered retained is washed by the 1st step operation, sterilizing, freshly prepd 10% xylitol solution of depyrogenation; The standby definition of this brand-new: the xylitol solution of 10% is that phosphate buffer makes solvent, xylitol amount and phosphate liquid measure all should be determined according to the liposome medicament amount being greater than 150nm particle diameter, it is 10% xylitol solution that newly increase, the amount exceeded in formula, measure the content of total phospholipids raw material in medicinal liquid, and with the qualified freshly prepd 10% xylitol solution adjustment medicine liquid volume of sterilizing depyrogenation, reach and to control in medicinal liquid total phospholipids content at 40-80mg/ml; This medicinal liquid is joined in another batching filling, and under rushing nitrogen, 100 revs/min of mixing speeds, are heated to 50 ± 5 DEG C in 30-60 minute, keep this temperature range to stir 60-120 minute; Under keeping rushing nitrogen again, 100 revs/min of rotating speeds, cooling medicinal liquid is to 20-25 DEG C, and medicinal liquid is dispensed in the rustless steel pallet of 316L, and be put in the freeze drying box of another lyophilizing unit, well-established law lyophilization, to medical solid, moisture is less than 2%; Dimercaprol residual quantity is for being less than 0.2%; Obtain liposome medicament solid, liposome medicament solid under 100 grades of sterilization grade, be crushed to 80-100 orders, the dosage allowed by pharmaceutics, well-established law makes the aseptic enteric oral preparation of this medicine, asepticly fastens agent.

2., according to the normalized process for preparing of cytosine arabinoside plastid composition of medicine according to claim 1, it is characterized in that, in manufacturing step: (1) step is dissolving ultrafiltration; (2) step is spraying dry; (3) step portion is molecular dispersion and ultrafiltration; (4) step is molecule dispersion coating; (5) step is that aquation pelletize adds antioxidant; (6) step is lyophilization lyophilized injection; (7) step is lyophilization donsole formulation; Be summarized as: the method for the preparation of industrialization liposome medicament of dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-cryodesiccated molecular dispersion method.

3. according to cytarabine liposome composition of medicine according to claim 1, it is characterized in that, the dosage allowed by pharmaceutics, makes the lyophilized injection of cytarabine liposome composition of medicine, or is mixed with spray by well-established law again.

4. according to cytarabine liposome composition of medicine according to claim 1, it is characterized in that, cytarabine liposome composition of medicine is the aseptic enteric oral preparation of the cytarabine liposome composition of medicine that pharmaceutics allows, or the aseptic suppository of cytarabine liposome composition of medicine.

5., according to cytarabine liposome composition of medicine according to claim 1, it is characterized in that, its purposes is for antitumor.

6., according to a kind of cytarabine liposome composition of medicine according to claim 1, it is characterized in that, its industrialization manufactures the combination that equipment used is dissolving tank-ultrafiltration post-spray dryer-boiling seed-coating machine-freezer dryer.