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WO2011142504A1 - Nanosphères polymères contenant de l'alcool hydroxybenzylique - Google Patents

Nanosphères polymères contenant de l'alcool hydroxybenzylique Download PDF

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Publication number
WO2011142504A1
WO2011142504A1 PCT/KR2010/005522 KR2010005522W WO2011142504A1 WO 2011142504 A1 WO2011142504 A1 WO 2011142504A1 KR 2010005522 W KR2010005522 W KR 2010005522W WO 2011142504 A1 WO2011142504 A1 WO 2011142504A1
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WIPO (PCT)
Prior art keywords
nanoparticles
hba
copolyoxalate
drug
hp0x
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Ceased
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PCT/KR2010/005522
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English (en)
Korean (ko)
Inventor
이동원
박현진
김세호
성경렬
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Industry Academic Cooperation Foundation of Chonbuk National University
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Industry Academic Cooperation Foundation of Chonbuk National University
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/12—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from polycarboxylic acids and polyhydroxy compounds
    • C08G63/16—Dicarboxylic acids and dihydroxy compounds
    • C08G63/18—Dicarboxylic acids and dihydroxy compounds the acids or hydroxy compounds containing carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/12—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from polycarboxylic acids and polyhydroxy compounds
    • C08G63/16—Dicarboxylic acids and dihydroxy compounds
    • C08G63/18—Dicarboxylic acids and dihydroxy compounds the acids or hydroxy compounds containing carbocyclic rings
    • C08G63/19—Hydroxy compounds containing aromatic rings
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82B—NANOSTRUCTURES FORMED BY MANIPULATION OF INDIVIDUAL ATOMS, MOLECULES, OR LIMITED COLLECTIONS OF ATOMS OR MOLECULES AS DISCRETE UNITS; MANUFACTURE OR TREATMENT THEREOF
    • B82B3/00—Manufacture or treatment of nanostructures by manipulation of individual atoms or molecules, or limited collections of atoms or molecules as discrete units
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention relates to oxalyl chloride, 1,4-cyclonucleic acid dimethanol
  • polymeric drug delivery systems can be classified as micro and nanoparticulate drug delivery systems or as complex polymeric drugs.
  • Particulate drug delivery systems physically mix drugs and protect them from the environment, including micelles and solid particles.
  • the composite polymer drug has a drug covalently attached to the branch of the polymer main chain through a linker.
  • linker examples are proteins, polysaccharides or synthetic polymers such as dendrimers and polyhydroxypropyl methacryl amides. This approach has led to significant improvements in drug stability and pharmacokinetic properties.
  • polymeric drug carriers containing such small amounts of drug may be a weak point in some applications.
  • One of the new approaches for the delivery of low molecular weight drugs is to combine the low molecular weight drug itself with the polymer main chain to deliver the drug.
  • the best function of these drug carriers is that the polymer itself is a controlled drug delivery system. This is because the degradation product itself is a therapeutic agent, and the polymer is completely degraded due to hydrolytically labile anhydrides and ester bonds in the backbone.
  • Inhalation-type drug delivery technology has recently been in the spotlight, delivering a therapeutic agent through the lungs with a large surface area and excellent permeability.
  • the market expanded from $ 7.5 billion in 1997 to $ 9 billion in 2000.
  • Avonex a treatment for multiple sclerosis (MS)
  • MS was introduced to Europe in 1996 and has posted annual sales of $ 600 million, growing more than 60% annually.
  • Inhaled insulin also starting in Europe, is expected to be $ 618.1 million in 2012 from $ 49.3 million in 2006 alone.
  • the demand for inhalable drug delivery technology which occupies most of the respiratory market, has continued to grow stably for the next five years and the technical demand expands.
  • inhaled insulin such as inhaled insulin
  • inhalation is a major driving force for the future evolution of the field of treatment.
  • inhalation with conventional injectable treatments such as inhaled insulin
  • the present inventors devised biodegradable and biocompatible peroxalate polymers in which hydroxybenzyl alcohol (HBA) was incorporated into the polymer main chain, and prepared them as nanoparticles.
  • HBA hydroxybenzyl alcohol
  • the nanoparticles have also been developed in inhaled drug delivery through the lungs.
  • HBA-containing copolyoxalate oxayl chloride
  • 1,4-cyclohexamethanol 1,4-cyclohexamethanol
  • HBA-containing copolyoxalate HBA- incorporated copolyoxalate, HP0X. More specifically, HBA-containing copolyoxalate can be accelerated by hydrogen peroxide and hydroxy benzyl alcohol (HBA) is released to provide nanoparticles with anti-inflammatory and antioxidant effects.
  • X is an integer.
  • the compound is a copolyoxalate chain containing 1,4-cyclohexanedimethanol, which can be easily removed from the body due to unstable peroxalate esters in the copolyoxalate main chain.
  • Polyoxalate structures undergo ester hydrolysis to break down to oxal ic acid and diol under aqueous conditions.
  • Polyoxalates which contain aromatic peroxalate esters in the backbone, react with hydrogen peroxide for instantaneous decomposition into di and carbon dioxide.
  • Hydrogen peroxide is overproduced by neutrophiles that are stratified at macrophages and inflamed sites and rapidly breaks down aromatic peroxalate esters bonds.
  • the HBA-incorporated copolyoxalate (HPOX) compound of the present invention is a new stimulus responsive biodegradation which promotes degradation by reacting with hydrogen peroxide produced at high concentration in inflammatory cells. It is a polymer.
  • X is an integer.
  • 1,4-cyclohexanedimethanol of step a) was used as the main component of this copolymer because of its excellent biocompatibility.
  • 1,4-cyclonucleic acid dimethanol is an indirect food additive that has been approved for human consumption and has an excellent toxicity profile (LD50: 3200 mg / kg oral intake). In addition, it does not undergo significant enzyme conversion in vivo and is quickly removed from the body.
  • the HBA in step a) is one of the well-known phenolic compounds in various plants including carrot and palm orchid (Gymnadenia conopsea) and is the main active component of the traditional herbal medicine, Gastrodia elata. HBA has been reported to have anti-inflammatory, antioxidant and anti-angiogenic activity. In addition, HBAs have the ability to prevent brain damage through increased expression of antioxidant proteins encoding after transient focal cerebral ischemia.
  • HBAs are aromatic diol compounds in which phenol and methylene units are substituted with alcohols and are therefore suitable for the synthesis of polyoxalates using oxalyl chloride.
  • Therapeutic compounds HBAs are chemically bound into the polymer backbone without attachment as side groups, making them available for polymer degradation.
  • step a) The polymerization of step a) is tetrahydrofuran dried under nitrogen charge.
  • THF Tetrahydrofuran
  • 1,4-cyclohexanedimethanol and 4-hydroxybenzyl alcohol in dried THF and add triethylamine.
  • the triethylamine may act as a catalyst and a base for promoting the reaction by removing HCL generated in the polymer synthesis step as a reagent for making oxalate. This may include adding oxalyl chloride dissolved in dried THF to the mixture.
  • ⁇ 3i> in order to be able to prepare in the form of solid nanoparticles under drying, it is preferable that the molar ratio of 1,4-cyclohexane dimethyl methane and 4-hydroxybenzyl alcohol is 4: 1.
  • the nonpolar solvent of step b) is not limited thereto, but is cold nucleic acid.
  • copolyoxalate (hexane) is preferred, and the copolyoxalate can be obtained after purification through repeated precipitation in cold nucleic acids and drying under high vacuum.
  • the present invention also provides nanoparticles prepared using the copolyoxalate compound represented by the formula (1).
  • X is an integer.
  • the copolyoxalate compound represented by Chemical Formula 1 dissolved in DCM may be added to an emulsifier solution.
  • the emulsifier polyvinyl alcohol
  • Nanoparticles can be prepared by the oil-in-water emulsion method. More specifically, the copolyoxalate mixture added to the emulsifier solution to form an oil / water emulsion is sonicated and homogenized. The emulsion dog is added to a polyvinyl alcohol solution and homogenized. The remaining solvent is removed using a rotary evaporator and nanoparticles can be obtained by centrifuge.
  • the average size of the nanoparticles is preferably 300nm to lum, more preferably 500nm.
  • the present invention also provides a drug delivery agent comprising the nanoparticles. More specifically, HBA-incorporated copolyoxalate (HP0X) nanoparticles release HBA, which reduces production of TNF- ⁇ and inhibits NO production in LPS-activated RAW 264.7 macrophages.
  • HP0X is a very effective drug carrier due to its salient features such as biodegradability, biocompatibility, anti-inflammatory and antioxidant properties. In particular, HP0X may be used to treat inflammatory diseases such as acute liver failure and acute lung injury. Useful drug carriers can be provided.
  • the present invention provides a drug carrier, characterized in that the drug is supported on the nanoparticles.
  • the drug is preferably theophyline, naringenin.
  • the nanoparticles of the present invention can be in the form of inhaled drug delivery through the lungs, which can greatly contribute to the improvement of medical technology of human beings.
  • the drug carrier of the present invention provides a drug carrier, characterized in that the drug carrier for treating lung disease.
  • Nanoparticles of the present invention can act as a drug itself, but can see a synergistic effect through parallel with existing inflammatory therapeutic agents. These nanoparticles are manufactured in various drug delivery forms, such as inhalation and injection, for lung disease, acute / chronic hepatitis,
  • nanoparticles of the present invention will be developed in the form of inhaled drug delivery through the lungs, which will greatly contribute to the improvement of medical technology of human beings.
  • FIG. 2 is the —spectrum of HBA-incorporated copolyoxalate (HPOX) in which HBA in CDC1 3 is synthesized.
  • HPOX HBA-incorporated copolyoxalate
  • FIG. 6 is a ⁇ analysis of copolyoxalate nanoparticles using RAW 264.7 cells.
  • FIG. 7 shows copolyoxalate Na for NO production in LPS-treated RAW 264.7 cells. Inhibitor effect of no microspheres. Each value is the average of four experiments. ( ⁇
  • FIG. 8 shows the results of Western blotting to see if it reduces production of iNOS in LPS-treated RAW 264.7 cells.
  • Figure 9 shows inhibition of TNF-a production by HP0X nanoparticles in LPS treated RAW 264.7 cells. Each value is the average of four experiments. ( ⁇ S.D) ** P ⁇ 0. () 1 is
  • 1,4-Cyclohexanedimethanol (21.96 'ol) and 4-hydroxybenzyl alcohol (5.49' ol) ol well-dried 20 mL under nitrogen Dissolve in tetrahydrofuran (THF) and add triethylamine (60 ⁇ ol) dropwise at 4 ° C.
  • THF tetrahydrofuran
  • triethylamine 60 ⁇ ol
  • oxalyl chloride 27.45 ⁇ ol
  • the reaction product was maintained in the presence of nitrogen at room temperature for 6 hours, and extracted with dichloromethane to produce a polymer and precipitated in cold nucleic acid (hexane) to obtain a polymer.
  • the molecular weight of the polymer is polystyrene -25000 (polydispersity) using polystyrene standards and by gel permeation chromatography (Gel Permeation Chromatography, GPC, Futech, Korea)
  • the hydrolysis rate of copolyoxalate was studied by measuring the molecular weight by gel permeation chromatography (GPC), GPC, Futecs, Korea.
  • the polymer was ground to fine particles and placed in phosphate buffer at 37 ° C. Polymer samples were mixed with gentle stirring and hydro lyzed polymers were collected at specific times. The hydrolyzed molecular weight was measured by time period and measured by GPC to compare the reduced amount by percentage.
  • the structure and size of the polyoxalate nanoparticles were observed by Scanning Electron Microscopy (SEM, Hitachi).
  • HP0X polymer (5mg) contains ImL of PBS (pH 7.4) at 37 ° C. Was added. Test tubes were kept kept in 37 ° C incubation. Prepare test tubes containing the same amount of HP0X polymer, remove the test tubes from the incubation for each time period to be measured, freeze and freeze-dry. The dried samples were dissolved in THF (Tetrahydro furan) and examined by Gel Permeation Chromatography (GPC) to determine the reduced molecular weight over time as a percentage of the initial molecular weight before degradation.
  • THF Tetrahydro furan
  • RAW 264.7 cells were seeded at a concentration of 1 ⁇ 10 6 cells / well in a 24 well plate. The cells were incubated for 24 hours at various concentrations of nanoparticles (lOmg / mL ⁇ 100mg / mL), and then the culture medium was removed. Then, 1 mL of the culture solution was added and 20pL MTT reagent was added and cultured for 4 hours. When purple crystals were produced, 10 mL of dimethyl sulfoxide solution was added thereto, followed by 10 minutes of incubation, and the microphone was measured at 570 nm using a plate reader.
  • RAW 264.7 cells (1 ⁇ 10 6 cells / well in a 24 well plate) were treated at different concentrations of HP0X nanoparticles and then inflamed to determine whether HP0X nanoparticles themselves are involved in anti-inflammatory effects.
  • LPS lipopolysaccharide
  • TNF ⁇ a tumor necrosis factor alpha
  • HPOX was synthesized from a one-step condensation reaction between oxalyl chloride and two diols, cyclohexanedimethanol and HBA. 1 shows the synthesis and degradation of copolyoxalate.
  • the introduction of HBAs other than cyclonucleic acid dimethanol did not cause any synthetic complications and the procedure used for the synthesis of polyoxalates was suitable for the synthesis of copolymers.
  • the polymerization proceeded in dry THF to give the corresponding copolymer under nitrogen gas.
  • the resulting copolyoxalate was purified through repeated precipitation in cold nucleic acids and a yellow solid was obtained after drying under high vacuum.
  • the chemical structure of the polyoxalate was found to be- ⁇ . Methylene protons in the hydroxyl groups of 1,4-cyclonuclear dimethanol appear at 3.5 ppm. Large peaks below 4.2 ppm are due to the methylene of adjacent oxalate ester bond Matched both. Two polyline aromatic quantum peaks were found at 7.2 and 7.5 ppm, and both benzyl groups were found at 5.3 ppm. These results suggest that oxalyl chloride, two diols, and 1,4-cyclohexanedimethanol to generate peroxalate containing peroxalate esters bonds. successful polymerization from the condensation reaction between dimethanol) and HBA (FIG. 2).
  • the molar ratio of 1,4-cyclohexanedimethanol to HBA used for polymer synthesis was 4: 1. Comparing the integration ratio between 2d protons and 2c protons, it was also confirmed that copolymerization yielded a 4: 1 molar ratio of 1,4-cyclohexanedimethanol to HBA.
  • the HP0X obtained from this reaction has a molecular weight (MW) of -25000 which corresponds to the degree of polymerization of ⁇ 100 repeated units with a polydispersity index of 1.8 (FIG. 3).
  • the rate of hydrolysis of HP0X was measured under physiological conditions. Degradation of polyoxalate by hydrolysis of water was investigated by measuring the molecular weight of the polymer by crushing it into fine powder and incubating under aqueous conditions. 4 shows the hydrolysis characteristics of HP0X. It has a half-life of less than 12 hours at pH 7.4 and means that HP0X is hydrolytically degraded. To confirm hydrolytic degradation of HP0X, fine copolymer powder was added at 37 ° C for 24 hours.
  • HP0X was formulated into nanoparticulates using poly (vinyl alcohol) as an emulsifier by an oil-in-water emulsion method. Particle size and structure were examined using a scanning electron microscope (SEM). HP0X Nano Me The lip globules were spherical spheres with a smooth surface and an average diameter of 500 nm or less, which is a form for increasing the exposure area to cells (FIG. 5). The polymer had a half-life of 12 hours of hydrolysis but appeared to have sufficient hydrophobicity to formulate into nanoparticles under aqueous conditions. HP0X nanoparticles in this range may be suitable for the maturation of intracellular and extracellular drug carriers.
  • a drug carrier including phagocytosis by macrophages by the macrophages easily phagocytosis of foreign substances in the range of 0.5 ⁇ 3 / / m.
  • MTT assay was performed using RAW 264.7 cells. Cells were incubated in various amounts of HP0X nanoparticles for 24 hours and the viability of the cells was measured (FIG. 6). HP0X nanoparticles showed minimal cytotoxicity in a dose-dependant manner. No cytotoxicity was observed in the nanoparticles of. Cells treated with 50 and 100 / zg nanoparticles showed a slight decrease in cell viability. This may suggest that copolyoxalate nanoparticles may be acceptable for use as drug carriers.
  • NO is known as a pro-inflammatory mediator in the onset of inflammation and its production is promoted by inducible nitric oxide synthases (iNOS).
  • iNOS inducible nitric oxide synthases
  • results of Western blotting to confirm that HP0X nanoparticles reduce the production of iNOS in LPS-treated RAW 264.7 macrophages are as follows. Stimulation of cells by treatment of LPS significantly increased the production of iNOS, and the addition of HBA completely inhibited the production of iNOS. When the concentration of HP0X was added to the cells, the production of iNOS protein gradually decreased as the concentration of HP0X increased. Referring to FIG. 8, the darker the band, the stronger the protein, the more iNOS is generated. As a result, it was confirmed that the NO inhibitory effect of HBA is due to the inhibition of iNOS production.
  • TNF-a is a cytokine involved in systemic inflammation and is produced by macrophages after stimulation by LPS or interlukin-1 (IL-1).
  • TNF- ⁇ is widely used in previous studies to measure inflammatory responses as a variety of drugs and drug carriers. Macrophages were previously stimulated with LPS and treated with HP0X nanoparticles and levels of TNF- ⁇ were measured at post treatment day 1 post. 9 demonstrates the effect of HP0X on TNF-a production.
  • LPS treatment resulted in a marked increase in TNF-a production by macrophages.
  • HPOX nanoparticulates reduced LPS-induced TNF- ⁇ production in a dose-dependent manner by cells.
  • HP0X nanoparticles less than 50 Ug were not noticeable, but were found to slightly reduce TNF-a production. However, P0X did not inhibit TNF-a production. These results support that HBA released from HP0X nanoparticles exert an anti-inflammatory effect.
  • the present invention provides oxalyl chloride, 1,4-cyclonucleodioxide

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Abstract

La présente invention concerne un procédé permettant l'obtention de HPOX, c'est-à-dire de copolyoxalate dans lequel est incorporé du HBA, en utilisant du chlorure d'oxalyle, du 1,4-cyclohexaméthanol, et du HBA. L'invention concerne plus particulièrement des nanosphères présentant une activité anti-inflammatoire et antioxydante dans la mesure où le copolyoxalate dans lequel est incorporé du HBA est susceptible de réagir sélectivement uniquement au peroxyde d'hydrogène et de se décomposer sous l'action de l'alcool p-hydroxybenzylique (HBA) ainsi libéré. Les nanosphères de la présente invention peuvent s'utiliser en tant que telles comme médicament. Toutefois, on pourra obtenir des effets de synergie en les combinant à des anti-inflammatoires conventionnels. Ces nanosphères, qui peuvent être préparées sous forme de divers vecteurs d'administration médicamenteuse telle que l'inhalation ou l'injection, pourront être décomposées par le peroxyde d'hydrogène produit en excès en raison notamment d'affections pulmonaires, de l'hépatite aiguë ou chronique, de la maladie d'Alzheimer, de la maladie de Parkinson, de l'arthrite, et d'affections cardiovasculaires telles que l'athérosclérose, de façon à libérer les médicaments, et ainsi être administrées sous forme d'un polymère biodégradable réagissant au stimulus et capable de traiter les affections.
PCT/KR2010/005522 2010-05-10 2010-08-19 Nanosphères polymères contenant de l'alcool hydroxybenzylique Ceased WO2011142504A1 (fr)

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KR102835111B1 (ko) * 2023-05-17 2025-07-16 전북대학교산학협력단 과산화수소 감응형 복합 고분자 화합물을 포함하는 나노입자 및 이의 약물전달체 용도

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9844564B2 (en) 2012-09-28 2017-12-19 Industrial Cooperation Foundation Chonbuk University PVAX copolymer and PVAX microparticles comprising the same
US10717810B2 (en) 2013-08-07 2020-07-21 Rutgers, The State University Of New Jersey Polymeric biomaterials derived from monomers comprising hydroxyacids and phenol compounds and their medical uses
EP3030265B1 (fr) * 2013-08-07 2021-11-17 Rutgers, The State University of New Jersey Biomatériaux polymères issus de monomères comprenant des hydroxyacides et des composés phénol, et leurs utilisations médicales

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