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WO2011088688A1 - Véhicule de médicament à base de micelles polymères comprenant un acide aminé en tant que stabilisateur - Google Patents

Véhicule de médicament à base de micelles polymères comprenant un acide aminé en tant que stabilisateur Download PDF

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Publication number
WO2011088688A1
WO2011088688A1 PCT/CN2010/077254 CN2010077254W WO2011088688A1 WO 2011088688 A1 WO2011088688 A1 WO 2011088688A1 CN 2010077254 W CN2010077254 W CN 2010077254W WO 2011088688 A1 WO2011088688 A1 WO 2011088688A1
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Prior art keywords
pharmaceutical composition
amino acid
polymer
block copolymer
amphiphilic block
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Ceased
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PCT/CN2010/077254
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English (en)
Chinese (zh)
Inventor
吴建梅
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NANJING FANTAI CHEMICAL MEDICAL RESEARCH INSTITUTE
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NANJING FANTAI CHEMICAL MEDICAL RESEARCH INSTITUTE
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a polymer micelle drug delivery system using amino acid as a stabilizer and its preparation.
  • 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.
  • 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, ⁇ -benzidine aspartate, ⁇ -benzyl glutamate, caprolactone, spermine.
  • CMC critical micelle concentration
  • 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.
  • anticancer drugs such as polysorbate 80 for docetaxel and polyoxyethylene castor oil for paclitaxel.
  • 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.
  • 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.
  • EPR permeabilization and retention
  • 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.
  • polyethylene glycol for example, the polymer PEG in our patent CN03105348, C brain 0610145383 is more than 10%
  • 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.
  • 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.
  • paclitaxel 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 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.
  • 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.
  • 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.
  • PEG polyethyl b.
  • mPEG monomethyl polyethylene glycol
  • povidone povidone
  • chitosan polymethacrylic acid
  • polymethacrylic acid and the like, and derivatives thereof.
  • Hydrophobic regions include, but are not limited to, polyoxypropylene, polystyrene, polyamino acids (eg, poly- ⁇ -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.
  • polystyrene polyamino acids (eg, poly- ⁇ -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.
  • amphiphilic block copolymers are: monomethyl polyethylene glycol-b-poly D
  • 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.
  • 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 ⁇ ), 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.
  • the polymer micelles When 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, ⁇ ⁇ ⁇ ⁇ , ⁇ , 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.
  • a suitable pharmaceutically acceptable carrier such as a binder as needed.
  • 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,
  • 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.
  • 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.
  • the stability of the polymer micelles to which arginine is added is better.
  • 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.
  • HPLC DIONEX with Ultimate3000 Pump, Ultimate3000 Autosampler, Ultimate3000 Column compartment, Ultimate3000 Variable Wavelength Detector, Chrome 1 eonTM workstation.
  • 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.
  • Encapsulation rate measured docetaxel in micelles / added amount X 100%
  • 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.
  • 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.
  • the product of R 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).
  • the filter was filtered through a 22 ⁇ m 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.

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Abstract

L'invention concerne un véhicule de médicament à base de micelles polymères comprenant un acide aminé en tant que stabilisateur et son procédé de préparation. Le véhicule de médicament à base de micelles polymères est composé d'un polymère séquencé amphiphile et d'un acide aminé. Le polymère séquencé amphiphile est un polymère diséquencé ou un polymère triséquencé et de préférence le mPEG-PDLLA. L'acide aminé est choisi parmi 20 acides aminés courants. Le rapport en poids entre le polymère amphiphile et l'acide aminé est de 100/0,01 à 1,00/99,99.
PCT/CN2010/077254 2010-01-19 2010-09-25 Véhicule de médicament à base de micelles polymères comprenant un acide aminé en tant que stabilisateur Ceased WO2011088688A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2010100010471A CN101773465B (zh) 2010-01-19 2010-01-19 以氨基酸为稳定剂的聚合物胶束载药系统
CN201010001047.1 2010-01-19

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WO2011088688A1 true WO2011088688A1 (fr) 2011-07-28

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ITBO20120368A1 (it) * 2012-07-06 2014-01-07 Alfa Wassermann Spa Composizioni comprendenti rifaximina e amminoacidi, cristalli di rifaximina derivanti da tali composizioni e loro uso.
US9498442B2 (en) 2010-03-05 2016-11-22 Alfa Wassermann S.P.A. Rifaximin powder, process for preparing the same an controlled release compositions containing said rifaximin useful for obtaining a long-lasting effect
EP3278799A4 (fr) * 2015-04-03 2018-12-05 Sichuan Kelun Pharmaceutical Research Institute Co. Ltd. Composition pharmaceutique de nanoparticules d'albumine et de docétaxel, procédé de préparation de ladite composition et son utilisation
US10258610B2 (en) 2011-07-29 2019-04-16 Alfasigma S.P.A. Pharmaceutical compositions comprising rifaximin, processes for their preparation and their use in the treatment of vaginal infections
US10285944B2 (en) 2005-03-07 2019-05-14 Alfasigma S.P.A. Gastroresistant pharmaceutical formulations containing rifaximin
US10428086B2 (en) 2014-05-12 2019-10-01 Alfasigma S.P.A. Solvated crystal form of rifaximin, production, compositions and uses thereof
US10703763B2 (en) 2005-03-03 2020-07-07 Alfasigma S.P.A. Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations

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CN102391517B (zh) * 2011-08-18 2013-06-26 中山大学 一种能智能释放药物的纳米胶束及其制备方法和应用
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CN105287402B (zh) * 2014-07-16 2018-01-16 西南药业股份有限公司 多西他赛聚合物胶束冻干制剂与专用溶剂的组合物
CN104523674B (zh) * 2014-12-11 2017-10-24 广州市上为医药科技有限公司 一种以奥沙利铂为主药成分的注射用组合物
CN107303273A (zh) * 2016-04-18 2017-10-31 北京大学 一种增强肿瘤细胞摄取的pH敏感聚合物胶束组合物
CN111035764B (zh) * 2018-10-14 2021-09-07 深圳市健元医药科技有限公司 一种治疗类风湿性关节炎的组合物及其制备方法
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