WO2011088688A1

WO2011088688A1 - Polymer micelle medicine carrier comprising amino acid as stabilizer

Info

Publication number: WO2011088688A1
Application number: PCT/CN2010/077254
Authority: WO
Inventors: 吴建梅
Original assignee: 南京泛太化工医药研究所
Priority date: 2010-01-19
Filing date: 2010-09-25
Publication date: 2011-07-28
Also published as: CN101773465A; CN101773465B

Abstract

A polymer micelle medicine carrier comprising amino acid as stabilizer and its preparation method are disclosed. The polymer micelle medicine carrier is composed of amphiphilic block polymer and amino acid. The amphiphilic block polymer is diblock polymer or triblock polymer and preferably is mPEG-PDLLA. The amino acid is chosen from 20 common amino acids. The weight ratio of amphiphilic polymer to amino acid is 100/0.01-1.00/99.99.

Description

Polymeric micelle drug loading system with amino acid as stabilizer

Technical field:

The present invention relates to a polymer micelle drug delivery system using amino acid as a stabilizer and its preparation.

Background technique:

Polymeric micelles are drug delivery systems developed in recent years for poorly soluble drugs. They are composed of amphiphilic block polymers with a low critical micelle concentration (CMC) (<100 g/ml) and a core. a shell-like structure in which the core is a hydrophobic portion and the shell is a hydrophilic portion. Polymer micelles can encapsulate poorly soluble drugs in the core portion to achieve solubilization of poorly soluble drugs. Drug-loaded polymer micelles often use biodegradable amphiphilic polymers as materials. Such amphiphilic polymers may be diblocks of AB type or triblock type ABA, BAB type. Document Torchi lin, VP, Structure and design of polymeric surfactant-based drug delivery systems. J Control Release, 2001. 73 (2-3): p. 137-72. Block copolymers have a critical micelle concentration (CMC) Low, high drug loading, in which the hydrophilic part (shell) is often polyethylene glycol, povidone, etc., the lipophilic part is often polyester, such as oxypropylene, lactic acid, L-lysine, days A polymer of butyrosine, β-benzidine aspartate, Υ-benzyl glutamate, caprolactone, spermine.

Many drugs are hydrophobic drugs, and their drug-forming properties need to be increased to improve their solubility. The method of solubilizing surfactant micelles to increase the solubility of the drug is a common method and is commonly used in the preparation of anticancer drugs, such as polysorbate 80 for docetaxel and polyoxyethylene castor oil for paclitaxel. However, there are many deficiencies in this type of solubilization method, including (1) the incidence of hypersensitivity, most surfactants have certain allergenicity, oleic acid in polysorbate 80 and castor oil in polyoxyethylene castor oil. With certain allergic properties, patients often need desensitization before using surfactant-containing preparations, such as the current commercial preparations of paclitaxel and docetaxel; (2) the specific distribution of drugs in the tumor is low, thus, Normal tissues are more toxic, and the maximum tolerated dose (MTD) is lower, which leads to the inability to distribute sufficient drugs at the tumor site during chemotherapy to make the tumor resistant; (3) The commercially available preparation is unstable, when the injection is compounded, The operation is complicated and it is easy to precipitate.

Compared with commonly used surfactant solubilizers, cosolvents (such as cyclodextrins) and latent solvents, the polymer micelle drug loading system selects biodegradable materials as materials, which are safer and have no obvious allergenicity. , hemolytic and irritating. More importantly, polymer micelles have greater permeabilization and retention (EPR), which enables passive targeting of tumor and inflammatory tissues, ie (1) polymers. Micelle The hydrophilic shell portion has a higher hydrophilicity, especially when the hydrophilic portion is a high proportion of polyethylene glycol (for example, the polymer PEG in our patent CN03105348, C brain 0610145383 is more than 10%, generally 40%), can avoid the resection of the reticuloendothelial system RES and the mononuclear giant cell system MPS, giving the polymer micelles a long cycle performance; (2) the polymer micelles have a small particle size, we apply The polymer micelles in the patents CN03105348, CN200610145383 have a particle size of about 20 nm, and the low particle size (generally less than 100 nm) can enhance the vascular permeability of the polymer micelles to supply the cancer to the vasculature and cause the substances to more easily retain the tumor, that is, the EPR effect is higher. Strong. The safety of polymer micelles and the passive targeting of tumors make it a new targeted drug delivery system, with anti-tumor drugs and therapeutic inflammation. Currently, paclitaxel polymer micelles for injection have entered clinical research and are already available in Korea. The preparation method of drug-loaded polymer micelles generally includes physical embedding method, chemical bonding method, electrostatic interaction method, gel-reconstitution method, emulsification-solvent evaporation method, and polymer micelles are dispersed in an aqueous solution and then freeze-dried to obtain a polymerization. The lyophilized product of the micelle can also be absorbed and solidified by a certain absorbent. Polymer micelles are usually used for injection and should be sterilized by filtration or autoclaved to ensure that the sterility of the preparation meets the requirements.

Methyl PEG-polylactic acid block copolymer (mPEG-PDLLA) micelles were first reported by X. Zhang of Canada (see references Zhang, X., etal., Anti-tumor efficacy and biodistribution of intravenous polymeric micel lar Paclitaxel. Anticancer Drugs, 1997. 8 (7): p. 696-701.), attracting widespread attention due to its desirable solubilization properties and EPR behavior, and patents US 5,877,205 and US 5,922,754. See references Yamamoto, Y., et al., Long-circulating poly (ethylene glycol ) -poly (D, L-lactide) block copolymer micelles with modulated surface charge. J Control Release, 2001. 77 (1-2): . 27-38. Samyang's Genexol PM is a paclitaxel polymer based on mPEG-PDLLA. It has good biocompatibility in vitro and in vivo, and no obvious toxicity. The paclitaxel isotope distribution shows that the micelles enter the body. Dissociates quickly, releases the drug, and the polymer degrades within 15 hours in the body. See references Kim, S. C., D. W. Kim, et al. (2001) . In vivo evaluation of polymeric micellar pacl itaxel formulation : toxicity and efficacy. J Control Release 72 (1-3): 191-202. However, the stability of the existing drug-loaded polymer micelles is not high, which affects its further promotion. Carstens, MG, PH de Jong, et al. (2008). The effect of core composition in biodegradable ol igomeric micel les as taxane formulations. Eur J Pharm Biopharm 68 (3): 596-606.

Taking paclitaxel as an example, when preparing paclitaxel polymer micelles using mPEG-PDLLA 55/45 (X/Y, X is the mass of PEG, Y is the mass of polylactide), the stability of the aqueous dispersion is only 24 hours. More than 30% of the drug leaked to 72 hours, see patent US20030143184. The current method for solving the stability of drug-loaded polymer micelles is mainly from polymer selection (Du, Chen et al. 2006). We applied a new polymer micelle in Chinese patent CN03105348. 3 to prepare polymer micelles using block copolymers of mPEG and PDLLA with a mass ratio of less than 50/50. This polymer micelle has increased the core. The lipophilicity can increase the drug loading and stability of the micelles. However, we have found that the research on the stability of polymer micelles by designing and synthesizing new polymers is costly, the safety challenge is large, and the solution is not satisfactory. US2007003625 claims a polymer drug delivery system with polylactic acid as a hydrophobic block. However, the solubilization ability of such a patent is not significantly improved for the stability of polymer micelles.

We examined the effect of different additives on the stability of polymer micelles. We have found that lipids have some improvement in the stability of polymeric micelles, see CN200610145383. However, the stability of this technique is still difficult for certain drugs to meet clinical needs, such as docetaxel, and the physical stability of polymer micelles is only a few minutes or hours. In the experiment, we unexpectedly found that adding some small molecular amino acids can improve the physical stability of the drug-loaded micelles. For example, the stability of the docetaxel polymer micelles is greatly improved after the addition of arginine, and can be stabilized for 5 days. the above. Amino acid is a generic term for a class of organic compounds containing amino and carboxyl groups. There are about 20 amino acids required by the human body. Amino acid is the basic building block of biologically functional macromolecular proteins, and is the basic substance that constitutes the protein required for animal nutrition. It is easy to obtain and has high safety.

The experiment found that amino acids can improve the physical stability of drug-loaded micelles, and no related research has been reported so far.

To this end, the present invention provides a pharmaceutical carrier comprising an amino acid as a stabilizer, which is composed of an amphiphilic block copolymer and an amino acid. The pharmaceutical carrier has the characteristics of high stability.

Disclosure of the Invention - An object of the present invention is to provide a pharmaceutical composition comprising a drug, an amphiphilic block copolymer and an amino acid.

The pharmaceutical composition of the present invention may further contain other pharmaceutically acceptable carriers as needed.

The pharmaceutical composition of the present invention, wherein the amphiphilic block copolymer and the amino acid may be compounded in any weight ratio. Preferably, the weight ratio of the two is 1-100: 0.1-100, and a particularly preferred weight ratio is 100: 0.5 to 30. The most preferred weight ratio is 100: 1-15.

The pharmaceutical composition of the present invention, wherein the amphiphilic block copolymer belongs to the prior art, may include a diblock and a triblock, and constitutes an amphiphilic block copolymer hydrophilic region including but not limited to polyethyl b. Glycol (PEG), monomethyl polyethylene glycol (mPEG), povidone, chitosan, polymethacrylic acid, and the like, and derivatives thereof. Hydrophobic regions include, but are not limited to, polyoxypropylene, polystyrene, polyamino acids (eg, poly-β-benzoyl-L-aspartic acid, polyfluorene-benzyl-L-glutamate, polyaspartic acid, etc.) ), polyester (polycaprolactone), biodegradable polymer materials (such as polylactic acid, polyglycolic acid and its Derivatives, etc.) act as hydrophobic blocks of the copolymer. Among the preferred amphiphilic block copolymers are: monomethyl polyethylene glycol-b-poly D, L-propylene glycol copolymer (mPEG-PDLLA). The pharmaceutical composition of the present invention, wherein the amino acid includes any one or more amino acids, and the common 20 amino acids, such as glycine, alanine, valine, leucine, isoleucine, serine, threonine Acid, aspartic acid, asparagine, glutamic acid, glutamine, arginine, lysine, histidine, cysteine, methionine, phenylalanine, tyrosine, Tryptophan, valine.

The pharmaceutical composition of the present invention can be produced by the following method: Drug, amino acid, amphiphilic block copolymer is dissolved in an organic solvent. After removing the organic solvent, a gel-like mixed polymer micelle is obtained. The organic solvent refers to a nonaqueous solvent selected from the group consisting of, but not limited to, acetonitrile, short-chain fatty alcohol, acetone, diethyl ether and the like.

The pharmaceutical composition of the present invention can be prepared by physical embedding, chemical bonding, electrostatic interaction, gel-resolution, emulsification-solvent evaporation, etc., gel-resolution method, wherein gel is preferred. - Reconstitution method.

The polymer micelles are dispersed in an aqueous solution and then freeze-dried to obtain a polymer micelle lyophilized product, which can also be absorbed and solidified by a certain absorbent.

Recombination of polymer micelles can obtain mixed polymer micelles below 100 nm (if the particle size is too large, it can be homogenized by high-speed homogenization or high-pressure milk homogenization to a state lower than ΙΟΟηιιι), and the polymer micelle can pass certain The preparation process, such as freeze drying, spray drying, rotary evaporation, vacuum evaporation, film evaporation, etc., is further prepared into a suitable preparation such as an injection, an eye drop, an external preparation, an oral preparation, an aerosol, a powder, and the like.

When the polymer micelles are used for injection administration, they can be subjected to filter sterilization or autoclaving to ensure the sterility of the preparation meets the requirements. The pharmaceutical composition of the present invention, wherein the drug comprises various hydrophobic drugs and hydrophilic drugs, preferably a hydrophobic drug, more preferably the following drugs:

Paclitaxel, docetaxel, cisplatin, carboplatin, oxaliplatin, 5-fluorouridine, etoposide, phenylalanine mustard, chlorambucil, hexamethyl melamine, methotrexate, Methyl nitrosourea, norvinine, teniposide, homoharringtonine, hydroxycamptothecin, and anti-VEGF drugs;

Antibiotic drugs: such as chloramphenicol, erythromycin, erythromycin, erythromycin, medimycin, josamycin, clarithromycin, rotamycin, sulfadiazine, trimethoprim,吠妥因、, 利平平, rifaximin, Isobutyl rifamycin, dapsone, acesulfame, miconazole, itraconazole, quinolone antibiotics, etc.;

Cardiovascular drugs: such as nifedipine, nicardipine, nitrendipine, nilvadipine, cinnarizine, perhexiline, domortamine, digitalis, digoxin, scutellaria, and de-B Alfalfa, propafenone, amiodarone, nitroglycerin, pentaerythritol, cyclomandelic acid, tocopheryl nicotinate, etc.; Antidiabetic drugs: such as toluene yellow butyl urea, glibenclamide, gliclazide, etc.;

Non-steroidal anti-inflammatory drugs: such as clemastine, cyproheptadine, phenothiazine, ketotifen, tranis and the like.

The pharmaceutical composition of the present invention, when prepared into a different preparation such as an injection, an eye drop, a topical preparation, an oral preparation, an aerosol, a powder, or the like, may be added with a suitable pharmaceutically acceptable carrier such as a binder as needed. And fillers, diluents, lubricants, disintegrating agents, coloring agents, flavoring agents, wetting agents, and the like, which are all prepared in the prior art and can be prepared according to the methods of the prior art.

The pharmaceutically acceptable carrier is selected from the group consisting of: mannitol, sorbitol, sodium metabisulfite, sodium hydrogen sulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin C, disodium EDTA, calcium EDTA a monovalent alkali metal carbonate, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, D-glucoside, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and its derivatives, alginate, gelatin, polyvinylpyrrolidone, glycerol, soil temperature 80, agar, calcium carbonate, Calcium hydrogencarbonate, surfactant, polyethylene glycol, cyclodextrin, β-cyclodextrin, phospholipid materials, kaolin, talc, calcium stearate, magnesium stearate, and the like.

The composition of the present invention is used according to the condition of the patient at the time of use, and can be taken 1-3 times a day, week, and month, each time 1-20 doses, such as: 1-20 sticks or tablets or tablets.

The pharmaceutical composition of the present invention, wherein the hydrophilic region of the amphiphilic block copolymer includes, but is not limited to, polyethylene glycol (PEG), monomethyl polyethylene glycol (mPEG), povidone, chitosan , polymethacrylic acid and the like and derivatives thereof. The derivative of the hydrophilic region of the block copolymer refers to a derivative obtained by modifying the end of the hydrophilic region with a specific affinity for certain organs, tissues, cells, organelles, molecules, including tissue or cell specificity. Sexual proteins or peptides, growth factors, vitamins and their analogues (such as folic acid), polysaccharides, glycopeptides or glycoproteins, steroids and their analogues, hormones, cofactors, genetic molecules, certain drug molecules. For example, peptides and proteins containing CNSRLHLRC, CENWWGDVC, WRCVLREGPAGGCAWFNRHRL, and CLSSRLDAC fragments specific for the brain; peptides and proteins containing CLPVASC and CGAREMC fragments specific for the kidney; peptides specific for the lung containing CGFECVRQCPERC, CGFELETC, CTLRDR C and CIGEVEVC fragments , protein; peptides and proteins containing CVALCREACGEGC fragments specific for skin; polypeptides and proteins containing SWCEPGWCR fragments specific for the spleen; polypeptides and proteins containing YSGKWGW fragments specific for the small intestine, polypeptides and proteins specific for the uterus containing GLSGGRS fragments Polypeptides and proteins containing LMLPRAD fragments specific for the adrenal gland; polypeptides and proteins containing CRDVVSVIC and CSCFRDVCC fragments specific for retinal tissue; polypeptides, proteins, proteins or proteins inhibiting the binding of integrin-expressing cells to extracellular matrix proteins The polypeptide contains CRGDC, CRGDCL, NGR (AHA), DGR (AHA), CRGDCA, RCDVVV, SLIDIP, TIRSVD, KRGD, RRGP and B RGDL Fragments; antibodies with tumor specificity; polypeptides and proteins containing CDCRGDCFC and CNGRCVSGCAGRC fragments specific for the solid membrane of the solid tumor; and other molecules with specific affinity for tumor cells. The beneficial effects of the present invention are illustrated below by test data:

1. Comparison data of amino acids and no amino acids:

Pipette 2 ml of 50mg/ml polymer acetonitrile solution into the eggplant bottle, add 2 ml of 5mg/ml docetaxel acetonitrile solution, place the eggplant bottle on the rotary evaporator, decompression (-0. IMPa), The temperature of the water bath was 5 CTC, the rotation speed was 20 rpm, and the evaporation was carried out for 30 minutes. 10 ml of water for injection was added, the eggplant bottle was removed, and the mixture was vortexed for 1 minute. The solution was filtered through a 0.22 μm filter to obtain a filtrate. The mixture was packed in a 10 ml vial; the polymer micelles were prepared in the same manner, and the water for injection was replaced with 0.2 mg/ml aqueous solution of arginine to obtain arginine-polymer micelles. Observe the stability of the two micelles separately.

It was found that the physical appearance of arginine-polymer micelles was stable for more than 5 days, while the polymer gel without arginine was stable for only 30 minutes.

The above tests show that:

The stability of the polymer micelles to which arginine is added is better.

2. Comparison data of different copolymers and amino acid ratios:

Preparation and stability of docetaxel pharmaceutical composition ί粒3⁄4

2. 1 Preparation of the pharmaceutical composition: Take 10 ml of 50 mg/ml polymer acetonitrile solution to the eggplant bottle, add 10 ml of 5 mg/ml docetaxel acetonitrile solution, and place the eggplant bottle on the rotary evaporator. Above, decompression (-0. IMPa), water bath temperature 50 Ό, rotation speed 20 rpm, rotary evaporation for 30 minutes, add 50 ml 0. 2mg / ml arginine aqueous solution for vortex for 1 minute, remove the eggplant bottle, The mixture was vortexed for 1 minute, and the resulting solution was filtered through a 0.22 μm filter. The filtrate was placed in a 10 ml vial, 2 ml each, and immediately lyophilized to give a white solid. The solid was added with 0.9% sodium chloride injection or 5% glucose injection 5 ml to prepare a clear, translucent pale blue opalescent docetaxel polymer micelle solution.

The obtained micelle solution was static at 25 ° C for 24 h. The results of the visual inspection showed that the solution was clear and transparent, no turbidity and no precipitation, and no drug crystals were precipitated at the bottom of the vial.

Different ratios of docetaxel polymer micelles were prepared, see table below - Table 1

mPEG2000-PDLLA 40/60

Prescription number arginine ke docetaxel

Gram

1 5 0. 2 1 2 10 0. 2 1 18

3 5 1 1 22

4 10 1 1 20

5 7. 5 0. 6 1 23

2. 2 Determination of the content of docetaxel in the pharmaceutical composition:

Immediately sample 1 ml of the compounded docetaxel polymer solution, immediately add 1 ml of acetonitrile at 4 ° C, mix, inject into a liquid chromatograph, record the chromatogram, and calculate the docetaxel content by external standard method.

HPLC conditions:

HPLC : DIONEX with Ultimate3000 Pump, Ultimate3000 Autosampler, Ultimate3000 Column compartment, Ultimate3000 Variable Wavelength Detector, Chrome 1 eonTM workstation.

Column: Acclaim® 120, C18, 5 μ m, 120 A, 4. 6 X 250 mm , DIONEX

Column temperature: 35 °C

Wavelength: 230 nm

Mobile phase: acetonitrile: water 50 : 50

Flow rate: lml/min

Injection volume: 5 μ 1

2. 3 physical stability of the pharmaceutical composition:

The above docetaxel polymer micelles for injection were mixed with physiological saline (0.9% sodium chloride solution) to a docetaxel concentration of 4 mg/inL. Place and observe the appearance and properties of polymer micelles at different times, and determine the particle size and docetaxel encapsulation efficiency.

Determination of encapsulation efficiency: Immediately sample 1 ml of the prepared docetaxel polymer solution, immediately add 1 ml of 4 ° C acetonitrile, mix, inject into the liquid chromatograph, record the chromatogram, calculate the docetaxel by external standard method. The content, the encapsulation efficiency of docetaxel is calculated as follows:

Encapsulation rate = measured docetaxel in micelles / added amount X 100%

See the table below

Table 2

mPEG2000-PDLLA 40/60

Prescription number arginine ketocitazide encapsulation rate % particle size m g

2. 4 Chemical stability study of pharmaceutical compositions

The above docetaxel polymer micelles for injection were mixed with physiological saline (0.9% sodium chloride solution) to a docetaxel concentration of 4 mg/mL. Place, sample at different times, determine the content of docetaxel and related substances.

The prepared docetaxel polymer solution was allowed to stand at 25 ° C for 24 hours, sampled 1 ml, immediately added 1 ml of 4 ° C acetonitrile, and mixed, and the docetaxel content was calculated by external standard method. The results are shown in the following table.

table 3

mPEG2000-PDLLA 40/60

Prescription number arginine ketocitazide content%

Gram

1 5 0. 2

2 10 0. 2 95. 42

3 5 1 63. 09

4 10 1 81. 65

5 7. 5 0. 6 81. 34 The percentage of all impurity peaks in the total area (excluding solvent peaks) is shown in the table below.

Table 4

The above tests show that:

Amphiphilic block copolymer and amino acid weight ratio of 100: 1-15 is the best Compared with the prior art, the pharmaceutical carrier of the present invention has the advantages of large drug loading and high stability, and can be proved by the measurement of the particle diameter of the micelle and the determination of the drug content in the examples.

detailed description:

The following are examples of the patent, but the following examples do not limit the scope of the patent.

Example 1 Synthesis of Amphiphilic Block Copolymer mPEG-PDLLA

Weigh 16g of methyl polyethylene glycol and 24g of lactide, put it in a closed reactor, add 50mg of stannous octoate, heat up to 120-14CTC under nitrogen gas to melt the solid, and raise the temperature to 150-18CTC reaction. 6 hours. Cooled to give a crude white solid. The crude product was dissolved in 1 ml of dichloromethane, and then added to 100 ml of diethyl ether under stirring, filtered, and washed three times with diethyl ether. The product was dried under vacuum for 24 hours.

The product of R (D-chloroform as solvent) was used to determine the mass ratio and molecular weight of methyl polyethylene glycol and polylactic acid in the polymer at a peak area ratio of 5. 2 ppm (PLA) and 3. 6 ppm (PEG).

Example 2 Preparation of Docetaxel Polymer Micelle

Pipette 10 ml of 50mg/ml polymer acetonitrile solution into the eggplant bottle, add 10 ml of 5mg/ml docetaxel acetonitrile solution, place the eggplant bottle on the rotary evaporator, decompress (-0. IMPa), Water bath temperature 5 CTC, rotation speed 20 rpm, rotary evaporation for 30 minutes, add 50 ml 0. 2mg / ml arginine aqueous solution for vortex for 1 minute, remove the eggplant bottle, vortex to vortex for 1 minute, the resulting solution Filtration through a 0.22 μm filter, the filtrate was placed in a 10 ml vial, 2 ml each, and immediately lyophilized to give a white solid.

Example 3 Preparation and Stability of Paclitaxel Polymer Micelle

Pipette 6ml 50mg/ml polymer acetonitrile solution into the eggplant bottle, add 6IB1 lOmg/ml paclitaxel acetonitrile solution, place the eggplant bottle on the rotary evaporator, decompression (-0. IMPa), water bath temperature 50 °C , rotating at 20 rpm, rotary evaporation for 30 minutes, adding 25 ml of 0. 2 mg / ml aqueous solution of aspartic acid to hydrate for 1 minute, remove the eggplant bottle, vortex to vortex for 1 minute, the resulting solution was passed through 0. The filter was filtered through a 22 μm filter, placed in a 10 ml vial, 2.5 ml each, and immediately lyophilized to a white solid. Solidified plus 0.9% sodium chloride injection or 5% glucose injection 5 ml was prepared to prepare a clear and transparent pale blue opalescent paclitaxel polymer micelle solution. The obtained micelle solution was static at 25 ° C for 24 h. The results of the visual inspection showed that the solution was clear and transparent, no turbidity and no precipitation, and no drug crystals were precipitated at the bottom of the vial. The particle size was determined to be 15 nm.

Example 4 Preparation and Stability of Oxaliplatin Polymer Micelle

Pipette 25 ml of 50mg/ml polymer acetonitrile solution into the eggplant bottle, add 5ml 50mg/ml oxaliplatin acetonitrile solution, place the eggplant bottle on the rotary evaporator, decompression (-0. IMPa), water bath Temperature 5 (TC, rotation speed 20 rpm, rotary evaporation for 30 minutes, add 25 ml 0. 2mg/ml aqueous solution of aspartic acid to hydrate for 1 minute, remove the eggplant bottle, and vortex for 1 minute. The resulting solution was filtered through a 0.22 μm filter and placed in a 10 ml vial, 2. 5 ml each, immediately lyophilized. Color solid. Solidified with 9% sodium chloride injection or 5% glucose injection 5 ml compounded to prepare a clear and transparent light blue opalescent oxaliplatin polymer micelle solution. The obtained micelle solution was static at 25 ° C for 24 h. The results of the visual inspection were as follows: The solution was clear and transparent, no turbidity and no precipitation, and no drug crystals were precipitated at the bottom of the vial. The particle size was determined to be 30 nm.

Claims

Claim

A pharmaceutical composition of a polymer micelle, characterized in that the composition contains a drug, an amphiphilic block copolymer and an amino acid, and the composition spontaneously forms a polymer micelle in water.

The pharmaceutical composition according to claim 1, which further comprises a pharmaceutically acceptable carrier as needed.

3. A pharmaceutical composition according to claim 1, wherein the amphiphilic block copolymer and the amino acid are ratioable in any weight ratio.

The pharmaceutical composition of claim 1, wherein the amphiphilic block copolymer and the amino acid have a weight ratio of 1-100:0.11 to 100.

5重量。 The pharmaceutical composition of claim 1 wherein the amphiphilic block copolymer and amino acid weight ratio of 100: 0. 5-30.

The pharmaceutical composition according to claim 1, wherein the amphiphilic block copolymer and the amino acid have a weight ratio of 100:1 to 15.

7. The pharmaceutical composition according to claim 1, wherein the amphiphilic block copolymer comprises a diblock and a triblock, and the hydrophilic region of the amphiphilic block copolymer comprises polyethylene glycol. , monomethyl polyethylene glycol, povidone, chitosan, polymethacrylic acid and derivatives thereof, hydrophobic regions include polyoxypropylene, polystyrene, polyamino acid, polyester, etc., wherein biodegradation is preferred Molecular material.

The pharmaceutical composition according to claim 1, wherein the amino acid is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, and day. Asparagine, glutamic acid, glutamine, arginine, lysine, histidine, cysteine, methionine, phenylalanine, tyrosine, tryptophan or valine.

9. The pharmaceutical composition of claim 1 which spontaneously forms polymeric micelles in an aqueous solution.

10. The pharmaceutical composition according to claim 1, wherein the drug is selected from the group consisting of antitumor drugs: paclitaxel, docetaxel, cisplatin, carboplatin, oxaliplatin, 5-fluorourine, etoposide Glycosides, phenylalanine mustard, chlorambucil, hexamethyl melamine, methotrexate, nitrosourea, norvinine, teniposide, homoharringtonine, hydroxycamptothecin And anti-VEGF drugs;

Antibiotics: chloramphenicol, erythromycin, erythromycin, erythromycin, methicillin, josamycin, clarithromycin, rotamycin, sulfadiazine, trimethoprim, guanidine Oralin, Lidiping, rifaximin, Isobutyl rifamycin, dapsone, acesulfame, miconazole, itraconazole, quinolone antibiotics; Cardiovascular drugs: nifedipine, nicardipine, nitrendipine, nilvadipine, cinnarizine, perhexiline, domortamine, digitoxin, digoxin, scutellaria, and acetaminophen Purpura, propafenone, amiodarone, nitroglycerin, pentaerythritol, cyclomandelic acid, tocopheryl nicotinate;

Antidiabetic drugs: toluene yellow butyl urea, glibenclamide, glipizide;

Non-steroidal anti-inflammatory drugs: clemastine, cyproheptadine, phenothiazine, ketotifen, tranilast.