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    • 专利摘要:
    Procedure for obtaining a sol-gel coating. Coating composition and use thereof. Process for obtaining a sol-gel coating on a substrate from 3-methacryloxypropyltrimethoxysilane (MAPTMS) and tetramethoxysilane (TMOS) and a phosphorus-based compound selected from tris (trimethylsilyl) phosphite and dimethyltrimethylsilylphosphite. Upon dissolution of the above components in an alcohol C1-C3water or a solution of an antimicrobial in water is added dropwise and it is left to react for 4- 48 hours at a temperature between 15-35ºC and 25-55% relative humidity to obtain a coating composition. The obtained composition is deposited on a substrate and dried. The invention also relates to the composition obtained and its application to substrates such as implants or implantable devices for biomedical use, as well as to the substrates thus coated. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2686890A1
    申请号:ES201730628
    申请日:2017-04-19
    公开日:2018-10-22
    发明作者:Antonia JIMÉNEZ MORALES；Amaya GARCÍA CASAS；Jaime Esteban Moreno；John Jairo AGUILERA CORREA
    申请人:Universidad Carlos III de Madrid；Instituto de Investigacion Sanitaria Fundacion Jimenez Diaz；
    IPC主号:
    专利说明:

    The present invention relates to a process for obtaining acoating from sol-gel technology. The present invention also relates tothe composition obtained by said procedure and its application in the fieldof biomedicine to coat substrates, such as implants, due to theirbiodegradable, biocompatible and adherent properties, as well as its capacity
    10 for controlled release of antimicrobials locally.
    STATE OF THE TECHNIQUE
    The use of metal and polymer biomaterials represents one of the most important advances
    15 important modern medicine. Within it, the use of biomaterials is of remarkable importance when we talk about implants such as joint prostheses and intravenous catheterization.
    Metal biomaterials are widely used in the manufacture of prostheses.
    20 joints in orthopedic and traumatological surgery, although they may also have polymeric components such as polymethylmethacrylate. Although the infection is a rare event in this type of implants (1-2% of the operated patients), it is one of the most devastating consequences due to the serious health problems it poses for the patient and the economic cost
    25 associate for Public Health. Since every year in Spain some
    70,000 hip interventions alone, it is estimated that each year this type of infection represents between four and eight million euros to public health.
    Although more than 50% of joint prosthesis infections (IPA) are caused by
    30 gram-positive microorganisms, mainly Staphylococcus aureus and S. epidermidis, recent publications indicate an increase in those produced by gram-negative bacteria, mainly enterobacteria, such as: Escherichia coli, and Pseudomonas aeruginosa.
    35 IPA prevention measures are of two types: environmental and prophylactic. The environmental measures during the surgical intervention focus on the operating room where high efficiency air particle filtration equipment is used, people traffic is limited, tight gowns are used by the surgical staff and the skin is disinfected . As prophylactic measures antibiotics are used, such as cefazolin or gentaminic between 60 and 120 minutes before the intervention.
    Despite these preventive measures, it is not possible to avoid 100% of the infections associated with these materials. After surgery, the tissue surrounding the prosthesis is avascular and / or necrotic and the concentration of antibiotics administered orally or parenterally that reaches the metal-tissue implant interface is lower than the
    10 detected in blood. This limitation cannot be overcome with an increase in the systemic dose of antibiotic as it would run the risk of causing organic toxicity. Thus, local antibiotic therapy is presented as a promising system of local prophylaxis or even treatment for such infections.
    15 According to the national data of the study program of prevalence of nosocomial infections in Spain, it is considered that around 70% of patients admitted to hospitals are carriers of an intravenous device at some time during their stay. These types of devices are usually made of polymer base, such as polyurethane, polyvinyl, polyethylene or Teflon. About 7% of
    20 patients with an intravenous device have a central venous catheter, placed temporarily or permanently. Also, in 4% of hospitalized patients the intravenous device is used for the administration of parenteral nutrition solutions.
    25 The use of vascular catheters sometimes causes local or systemic infections, such as uncomplicated or complicated bacteraemia. This type of complications has an important morbidity and a non-negligible mortality, being the most frequent cause that forces its withdrawal in any type of device. Bacteremia related to vascular catheters are found
    30 among the most frequent infections acquired in the hospital. At present it is estimated that between 15 and 30% of all nosocomial bacteraemias are related to the use of percutaneous intravenous devices. In certain hospitalization units, such as intensive care units (ICU), this type of infection has been associated with high morbidity, mortality
    35 attributable and added health cost very relevant. The main etiological agents of more than 95% of this type of infections are usually staphylococci (90% S.
    epidermidis and 5% S. aureus), although they can also be caused by enterobacteria, enterococci or yeasts «5% among all). Similarly to what happens in osteoarticular prostheses, local antibiotic therapy would be a promising local prophylaxis system directly associated with this type of
    5 medical devices that would prevent the appearance of infections associated with these types of devices and their serious medical consequences.
    Infections associated with fungal biomaterials, especially yeasts of the genus Gandida, are uncommon «1% of IPA and <2% in 10 catheter infections), but are usually associated with recurrent or even chronic infections, and candidemia. These infections require prolonged pharmacological treatments over time (more so than infections caused by bacteria) and expensive at the health and personal level, since the surgical approaches they require are usually aggressive and / or disabling, such as: amputation 15 in the case of IPAs. On the other hand, candidemias are a type of systemic infection caused by yeasts of the genus Gandida, whose mortality rate is between 40 and 60% of cases and which are very often the result of infections associated with biomaterials. Therefore, avoid and reduce as far as possible the adhesion and proliferation of yeasts on biomaterials
    20 would decrease the incidence of these infections and their devastating clinical consequences.
    Regarding metallic materials there are numerous strategies focused on modifying the metal surface to provide it with bioactive properties. The 25 most studied techniques are: electrochemical techniques (K.-H. Kim et al., "Electrochemical surface modification of titanium in dentistry," Dent. Mater.J., Vol. 28, no. 1, pp. 20- 36, 200; MR Kaluet al., "Titanium dental implant surfaces obtained by anodic spark deposition -From the past to the future," Mater. ScL Eng. E, vol. 69, pp. 1429-1441, 2016; M. Kulkarni et al., "Titanium nanostructures for biomedical 30 applications," Nanotechnology, vol. 26, p. 62002 (1-18), 2015.), ionic implantation
    (S. Agarwal et al., "An experimental study of helium diffusion and helium induced microstructural evolution in ion implanted polycrystalline titanium nitride," Acta Mater., Vol. 121, pp. 1-14, 2016; A. Shypylenko et al. , "Effect of ion implantation on the physical and mechanical properties of Ti-Si-N multifunctional coatings for biomedical
    35 applications, "Mater. Des., Vol. 110, pp. 821-829, 2016.), thermal spraying (M. Gardon et al.," Enhancing the bioactivity of polymeric implants by means of cold gas
    spray coatings, "J. Biomed. Mater. Res. -Part B Appl. Biomater., vol. 102, no. 7, pp. 1537-1543,2014; JA Gan el al., Thermal spray lorming 01 lilanium and ils alloys . Elsevier Inc., 2015), and sol-gel technology (D. Arcos et al., "801-silica gel-based biomaterials and bone tissue regeneration," Acta Biomater., Vol. 6, no. 8, pp. 2874-88, Aug 5, 2010; R. 1. M. Asri et al., "A review of hydroxyapatite-based coating techniques: Sol-gel and electrochemical depositions on biocompatible metals," J. Mech. Behav. Biomed. Mater ., vol. 57, pp. 95--108, 2016) The present invention is proposed based on the latter The organ-inorganic hybrid sol-gel coatings emerged in the 1980s due to the expansion of procedures on 10 soft inorganic chemistry Sol-gel technology has attractive processing conditions (low temperatures, colloidal state versatility) that allows mixing organic and inorganic compounds at a nanoscopic scale ica In addition, it allows to design materials with ua measured properties "according to the final application. The sol-gel technology has been applied to obtain different functional materials such as 15 selective ion membranes (A. Jiménez-Morales et al., "A new silver-ion selective sensor based on a polythiacrown-ether entrapped by sol-gel," Electrochim. Acta, vol. 47, no. 13-14, pp. 2281-2287, 2002), electrochemical sensors (J. Wang, "Electrochemical biosensing based on noble metal nanoparticles," Microchim. Acta, vol. 177, no. 3-4, pp. 245-270, 2012), and corrosion protection of materials
    20 metal (J. Carbonell et al., "8canning electrochemical microscopy characterization of sol-gel coatings applied on M2024-T3 substrate fer corrosion protection," Corros. Sci., Vol. 111, pp. 625--636, 2016. Currently , several works focus on implementing said technique for biomaterial coating (T. Phan et al., "8tructural and anticorrosion performance characterization of phosphosilicate sol-gel
    25 coatings prepared from 3- (trimethoxysilyl) propyl methacrylate and bis [2 (methacryloyloxy) ethyl] phosphate, "Prog. Org. Coatings, vol. 89, pp. 123-131, Dec. 2015; MJ Juan-Díaz et al. , "Development of hybrid sol-gel coatings for the improvement of metallic biomaterials performance," Prog.Org. Coatings, vol. 96, pp. 42-51, 2015). The most prominent studies are based on particle incorporation
    30 of Ti02 (AGB Castro et al., "8ynthesis and electrochemical study of a hybrid structure based on PDMS-TEOS and titania nanotubes for biomedical applications.," Nanolechnology, vol. 25, no. 36, p. 365701, 2014;) , ZrO, (M. Catauro el al., "Corrosion behavior and mechanical properties of bioactive sol-gel coatings on titanium implants," Maler. Sci. Eng. C, vol. 43, pp. 375-382, 2014;) or SiO, (X. Wu el al., "Mechanically
    35 robust superhydrophobic and superoleophobic coatings derived by sol-gel method, "Mater. Des., Vol. 89, pp. 1302-1309, 2016), hydroxyapatite precursors (A. Durán et al.," Sol-gel coatings for protection and bioactivation of metals used in orthopedic devices, "J. Mater. ehem., vol. 14, no. 14, p. 2282, 2004; SCP Cachinho et al.," Titanium scaffolds for osteointegration: mechanical, in vitro and corrosion behavior ., "
    J. Mater. Yeah Mater. Med., Vol. 19, no. 1, pp. 451-7, 2008), or addition of compounds
    5 organic like chitosan (G. Toskas et al., "Chitosan (PEO) / silica hybrid nanofibers as a potential biomaterial for bone regeneration.," Carbohydr. Polym., Vol. 94, no. 2, pp. 713-22 , May 2013).
    There are several studies that use sol-gel technology to encapsulate molecules
    10 bioactive and control their release. In this type of study, coatings are not used, but instead of applying the product on a substrate, it dries until a ceramic is obtained, called xerogel (D. Quintanar Guerrero Guerrero, al., Ukrainian xerogels as pharmaceutical drug carriers., "Experl Opin Drug Deliv., Vol. 6, no. 5, pp. 485-498, 2009). Some antibiotics have been encapsulated
    15 by this technique, for example genatimine (Y.-C. Ho et al., "Cytotoxicity of formaldehyde on human osteoblastic cells is related to intracellular glutathione levels.,"
    J. Biomed. Mater .. Res. B. Appl. Biomater , vol. 83, no. 2, pp. 340-344, 2007) And vancomycin (S. Radin et al., "Controlied release of vancomycin from thin sol-gel films on titanium alioy fracture plate material," Biomateria / s, vol. 28, no. 9, pp. 1721-1729, 20 2007). To date, the organo-inorganic sol-gel coatings loaded with antibacterials described are composed of poly-E-caprolactone and a metal oxide (M. Caruto et al., "Novel sol-gel organic-inorganic hybrid materials for drug delivery" , J Appl Biomater Biomech, vol. 8 no. 1, pp. 42-51, 2010; T. Russo et al., "PoIY (Ecaprolactone) reinforced with sol-gel synthesized organic-inorganic hybrid fillers as 25 composite substrates for tissue engineering ", J Appl Biomater Biomeeh, vol. 8 no. 3, pp. 146-152, 2010), while hydrogels are composed of polylactidohyaluronic acid (DAC®) (L. Drago et al.," Does Implant Coating With Antibacterial-Loaded Hydrogel Reduces Bacterial Colonization and Biofilm Formation in VitroT, Clin Orlhop Re / at Res vol. 472, pp. 331 1-3323, 2016) or complex polymers derived from 30 acrylamide (D. Overstreet et aL, "Local Gentamicin Delivery From Resorbable Viscous Hydrogels 15 Therapeutically Eftec! Ive ", G / in Or.thop Re / at Res vol. 473, pp. 337-347, 2015). However, the work carried out by Hernández-Escolano, M. et al. 2012 (M. Hernández-Escolano et al., "The design and characterization of sol-gel coatings for the controlled-release of active molecules," J. Sol-Gel Sei. TeehnoJ., Vol.
    35 64, no. 2, pp. 442-451, Sep. 2012) in which they add a drug, procaine, to a sol-gel coating. The coating developed in this case has a
    chemical nature different from that of the invention since the silanes used are others. In addition, a phosphorus-based compound is not incorporated to improve osseointegration of the material in the body. With regard to patent documents, EP 2328627 discloses a metal or ceramic substrate comprising a porous sol-gel coating formed from at least two of the following compounds: a silane, a silicate and a polysiloxane, which form a network of silicon-carbon and silicon-oxygen bonds. US2008 / 0063693 discloses antimicrobial coatings for coating surfaces of a substrate, particularly medical devices. The antimicrobial coatings are composed of a hydrogel and a bioactive agent that includes a substantially water insoluble antimicrobial metal material that is solubilized within the coating. The chemical nature of the coatings disclosed in both EP2328627 and US2008 / 0063693 is completely different from that of the present invention since the precursors of the sol-gel method are different.
    15 The versatility of the present invention in comparison with the documents in terms of application method and adhesion to different substrates should be noted.
    DESCRIPTION OF THE INVENTION
    In a first aspect, the present invention relates to a process for obtaining a sol-gel coating on a substrate characterized in that it comprises the following steps: a) preparation of a solution of the 3-methacryloxypropyltrimethoxysilane (MAPTMS) and tetramethoxysilane silanes (TMOS), in a molar relationship
    25 MAPTMS: TMOS between 1: 1 and 1: 2 in a Cl-C3 alcohol, where the ratio between the sum of moles of MAPTMS and TMOS silanes and moles of Cl-C3 alcohol is between 1: 3 and 1: 6 , preferably 1: 3, b) adding a phosphorus-based compound selected from tris (trimethylsilyl) phosphite and dimethyltrimethylsilyl phosphite to the solution prepared in the
    30 step a), where the ratio between the moles of the phosphorus-based compound and the sum of moles of the MAPTMS and TMOS silanes is between 1: 15 and 1:25, preferably 1:20,
    e) addition of water dropwise on the solution resulting from step b), where the ratio between the sum of moles of MAPTMS and TMOS silanes and 35 moles of water is between 1: 3 and 1: 6, preferably 1 : 3, obtaining one
    colloidal solution,
    d) the colloidal solution obtained in step c) is allowed to react between 4 and 48 hours, preferably 24 hours, at a temperature between 15-35 oC and 25-55% relative humidity to obtain a coating composition comprising a polysiloxane network , that is, a network with Si-Q-Si links.
    Preferably, steps a) to d) are performed in a cabin where temperature and humidity can be controlled
    In a preferred embodiment of the invention, at least one antimicrobial compound is dissolved or dispersed in the water which is subsequently added dropwise onto the solution formed in step b).
    Preferably, in the event that the water has dissolved or dispersed an antimicrobial, the maximum amount thereof added will depend on its maximum water solubility. The concentration range of added antimicrobial shall be established between the maximum amount limited by its solubility in water and the non-addition thereof.
    As an example, for an antimicrobial that has a water solubility of at least 1 ~ 1 ml, the ratio between the moles thereof and the sum of moles of MAPTMS and TMOS silanes is between 0.000047: 1 and 0.002 : 1, more preferably between 0.001: 1 and 0.002: 1, and even more preferably 0.002: 1
    In the present invention, the term "antimicrobial" includes bactericidal and bacteriostatic, antifungal, antiviral, antiparasitic, antiseptic and disinfectant antibiotics.
    In a preferred embodiment, the antimicrobials are bactericidal or antifungal antibiotics. In a more preferred embodiment, the antibiotics are antibiotics belonging to the quinolone family, specifically fluoroquinolones, such as, for example, moxifloxacin. In another preferred embodiment, the antimicrobials are antifungals belonging to the triazole family such as, for example, the
    Fluconazole
    In a preferred embodiment of the invention, the C1-C3 alcohol in which the
    3-methacryloxypropyltrimethoxysilane (MAPTMS) and tetramethoxysilane (TMOS) solution is ethanol. However, methanol, propanol and iso-propanol could also be used.
    In a preferred embodiment of the invention the phosphorus-based compound istris (trimethylsilyl) phosphite.
    In order to obtain a coated substrate, the coating composition obtained in step d) is deposited on a substrate. The deposition of said composition on the
    The substrate can be carried out by means of the immersion technique, for which the substrate is immersed in the composition obtained in step d), or by spraying the coating composition on the substrate.
    The substrate is preferably an implant for medical-surgical use such as prostheses.
    15 or metal materials (osteoarticular prostheses, metal meshes, dental implants, screws, rods and plates of osteosynthesis material, suture clips, among others), and plastic materials (central and peripheral intravenous catheters, urinary catheters, surgical drainage tubes , surgical meshes, polymeric components of osteoarticular prosthesis, suture thread, synthetic heart valves, pacemakers,
    20 stents, genital prostheses, breast implants, cosmetic surgery implants such as: chin, cheekbones, etc., among others).
    Once the coating composition is deposited on a substrate, drying thereof is carried out. In a preferred embodiment, drying of the
    The composition deposited on the substrate is carried out at a temperature between 40 ° C and 60 ° C, at a pressure between 1 bar and 2 bars and for a time between 1 h and 24 h.
    The process of the present invention from 3-methacryloxypropyltrimethoxysilane (MAPTMS) and tetramethoxysilane (TMOS) and the phosphorus-based compounds mentioned 30 allows obtaining a sol-gel coating composed of a nebulizable organ-inorganic network and degradable under physiological conditions (biodegradable) and whose degradation products are not toxic to the surrounding tissue (biocompatible), in addition to favoring osseointegration, which makes it especially useful for coating implants or biomedical use implants. The degradation of the coating in aqueous media, such as a physiological medium, is based on a hydrolytic degradation that generates as
    By-products a compound based on silicon and water. The sol-gel method allows the product to be adapted to the application method required for the final piece. By optimizing the viscosity (for example, by controlling the time of step d) cited above) it is possible to apply the coating on the substrate by immersion or
    5 nebulizing the surface of the substrate by means of an aerosol.
    In addition, the coating obtained can contain and release during its degradation an antimicrobial, so it has bactericidal properties. This feature allows to prevent or treat locally the infection associated with polymeric and metallic biomaterials 10 in biomedical applications. The versatility of the sol-gel method allows to control the degradation time of the coating by modifying process parameters such as reaction time, temperature and drying time or the application of several layers of coating on the substrate. Through an electrochemical study of the degradation kinetics of the coating it is possible
    15 design a coating with the degradation rate required for each application.
    Another aspect of the invention relates to the coating composition obtained according to the process defined above comprising steps a) to d), as well as its use to coat an implant.
    A very important characteristic of the coating composition obtained by the process of the present invention (steps a) -d)) is that it is nebulizable, which allows its application by spray on a substrate, either of metallic or polymeric material of medical-surgical use that require antiseptic, prophylactic and / or therapeutic behavior. Being able to be nebulized, the coating composition allows only those parts of the substrates or implantable devices that, according to the judgment of the clinical professional or of the commercial house of the substrate, to be more susceptible to infection to be coated. On the other hand, the spray allows to control the quantity
    30 deposited on the implant according to its therapeutic purpose: prevention would be achieved with a thin layer, while local treatment would require thicker solgel layers.
    The composition of the invention is compatible with metal alloys, such as stainless steel, titanium based alloys, CrCoMo alloy and with polymers, such as polyurethane, polyvinyl and polyethylene.
    Another aspect of the invention relates to the substrate provided with a sol-gel coating obtained according to the first aspect of the invention. The substrate can be made of metal or polymeric material, preferably for biomedical use such as an implant. Examples
    5 non-limiting substrates are an intravenous catheter, a joint prosthesis, aosteoarticular prosthesis, a suture, a heart valve, etc.
    By the term alcohol e1-eJ is meant a linear or branched chain of 1 to 3 carbon atoms with at least one hydroxyl functional group. For the term alcohol 10 el-eJ. Examples of alcohol el-eJson are methane, ethanol, propanol and iso-propanol.
    In the present invention, as an implant is meant any prosthesis, tissue, device or synthetic solid substance that is placed in the body epicutaneously, percutaneously, intradermally, subdermally, intramuscularly and / or transosseously 15 for a certain or indefinite period of time to administer a treatment, solve some physioanatomic problem, or simply for aesthetic purposes. Examples (not limiting) of implants are: osteoarticular prostheses, metal meshes, dental implants, screws, rods and plates of osteosynthesis material, central and peripheral intravenous catheters, urinary catheters of all types, surgical drainage tubes, polymeric prosthesis components osteoarticular, surgical meshes, synthetic heart valves, mark steps, stents, genital prostheses, submuscular, subfascial or subglandular breast implants, submuscular or subfascial muscle implants, cosmetic surgery implants such as: chin, cheekbones, etc .; among others. Any definition of the implant is also included
    25 medical devices for surgical use that are placed on the body, such as sutures, staples, etc.
    Throughout the description and claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or
    30 steps For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples and figures are provided by way of illustration, and are not intended to be limiting of the present invention.
    35 BRIEF DESCRIPTION OF THE FIGURES
    FIG. 1: Shows micrographs made by scanning electron microscope at a magnification of 12000 of the surface of a sol-gel coating applied on a titanium-based substrate. A) coating without adding phosphorus-based compound, B) coating with phosphorus-based compound addition, and C) coating with phosphorus-based compound addition in a molar ratio of
    1: 20 with respect to silanes and an addition of moxifloxacin in a molar ratio of 0.002: 1 with respect to silanes.
    FIG. 2: Shows the maps obtained by scanning electrochemical microscopy
    10 (in English, Scanning Electrochemical Microscopy) of the metallic substrate at A) 2 h and B) 12 hours of immersion in a physiological fluid; of the coating with an addition of moxifloxacin in a molar ratio of 0.001: 1 with respect to the silanes at C) 2 h YD) 12 hours of immersion, and of the coating with an addition of moxifloxacin in a molar ratio of 0.002: 1 with respect to to silanes at E) 2 h YF) 12 hours of
    15 immersion
    FIG. 3: Formation of a bacterial film ("biofilm") of the different species
    Bacterial tested (left column) and amount of planktonic bacteria (not
    adhered to the coating) (right column) on the coating matrix of
    20 invention deposited on the substrate and dried, not including antimicrobial (P2) and with different concentrations of moxifloxacin: 25 mg / 20 mL (P2 + A25), which corresponds to a moxifloxacin molar ratio: sum of silane moles of 0.001: 1 and 50 mg / 20 mL (P2 + A50), which corresponds to a moxifloxacin molar ratio: sum of moles of silane of 0.002: 1.
    25 FIG. 4: Results of the cytotoxicity tests of the coating of the invention deposited on the substrate and dried, not including antimicrobial (P2) and with different concentrations of moxifloxacin: 25 mg / 20mL (P2 + A25), which corresponds to a moxifloxacin molar ratio: sum of moles of silane 0.001: 1 and 50 mg / 20 mL
    30 (P2 + A50), which corresponds to a moxifloxacin molar ratio: sum of silane moles of 0.002: 1.
    FIG. 5: Formation of a fungal film ("biofilm") of Candida albicans ATCC 10231 (left) and amount of planktonic yeasts (not adhered to the coating) (right) on the matrix of the invention coating deposited on the substrate and dried, without include antimicrobial (P2) and with a concentration of
    13 mg / 20 mL fluconazole (P2 + F1 3), which corresponds to a moxifloxacin molar ratio: sum of silane moles of 0.0009: 1.
    FIG. 6: Spectra obtained by Nuclear Magnetic Resonance with silicon core
    5 f 9Si-NMR) of the coating composition (xerogel) obtained in step d) of theprocedure: P2 ', a xerogel with a molar ratio of MAPTMS and TMOS silanesof 1: 2 with an addition of tris (trimethylsilyl) phosphite in a molar ratio of 1:20 withwith respect to one mole of silos; P2 '+ A25', the xerogel with the same molar relationshipsthat P2 'and to which a quantity of moxifloxacin has been added in a relationship
    10 molar of 0.001: 1 with respect to silanes; and P2 '+ A50', the xerogel with the same molar ratios as P2 'and an amount of moxifloxacin in a molar ratio of 0.002: 1 with respect to silanes.
    EXAMPLES
    The invention will now be illustrated by tests carried out by the inventors, which demonstrates the effectiveness of the process and coating of the invention.
    Example 1: Preparation of the sol-gel coating with an addition of moxifloxacin in a molar ratio of O001: 1 v O002: 1 with respect to the MAPTMS and TMOS years / years
    The solubility of moxifloxacin (Sigma Aldrich) in water is 19.6 mg / ml.
    The following steps are carried out for the preparation of the coating: a solution of 3-methacryloxypropyltrimethoxysilane (MAPTMS, 98% Acros Organics) and tetramethoxysilane (TMOS, 98% Acros Organics) is prepared in a first glass vial of suitable size ) in a MAPTMS: TMOS 1: 2 molar ratio under vigorous agitation of 400-600 rpm,
    30 ethanol is added to the vial to a molar ratio 3 methacryloxypropyltrimethoxysilane (MAPTMS) and tetramethoxysilane (TMOS): 1: 3 ethanol under vigorous stirring of 400-600 rpm,
    a phosphorus-based compound, tris (trimethylsilyl) phosphite (~ 95% Sigma Aldrich) is added, where the ratio between the moles of the phosphorus-based compound and the sum of 35 moles of the MAPTMS and TMOS silanes is 1: 20; the mixture is allowed to disperse
    for at least 5 minutes,
    Moxifloxacin is dissolved in a second vial at a molar ratio of 0.001: 1,
    or 0.002: 1, with respect to the sum of moles of MAPTMS and TMOS silanes in an amount of distilled water, where the ratio between the sum of moles of silanes and water is 1: 3,
    5 the second vial is added dropwise to the first one under vigorous stirring of 400600 rpm,the synthesis is left for 24 hours controlling the temperature between 15-35 oCand 25-55% relative humidity, thus obtaining the coating composition.
    10 Substrate coating:
    The coating composition obtained after 24 hours of reaction is used to coat a titanium substrate. To do this, using a dip-coater (dip-coater), the substrate to be coated is introduced into a vial containing the
    15 coating composition at a speed of 200 mm / minute. Then the substrate is immediately removed from the sun at the same speed of 200 mm / minutes, thus minimizing the residence time of the substrate within the sun.
    Alternatively, the titanium substrate can be spray coated, for which,
    20 by means of a piston compressor (aerosol), the coating composition obtained after 24 h of reaction is applied on the substrate at a pressure of 3.5 bar for 10 seconds.
    Drying the coating:
    25 Once the substrate is coated, it is dried. For this, the coated substrate or substrates are placed on a horizontal surface and placed in an oven at 60 oC and 2 bars for one hour. After one hour, the temperature is switched off and the substrates are kept inside the stove with the
    30 pressure of 2 bars applied for at least 12 hours.
    Figure 1 shows micrographs made by scanning electron microscope of the surface of a sol-gel coating applied on a titanium-based substrate. A) coating without adding the phosphorus-based compound, B) coating 35 with the addition of the phosphorus-based compound, and C) coating with the addition of
    compound based on phosphorus in a molar ratio of 1: 20 with respect to silanes and an addition of moxifloxacin in a molar ratio of 0.002: 1 with respect to silanes.
    5 The sol-gel matrix has a grayish color while the areas with the highest phosphorus content have a clear color and with a rounded and localized morphology. It has been proven by the addition of the phosphorus-based compound the creation of specific localized areas with higher phosphorus content that will allow a better recognition of the surface by the cells due to the
    10 oxidation of phosphite to phosphate. This will contribute to improve the osseointegration of the substrate and therefore to increase the chances of success of the implant or implantable substrate for clinical use.
    Example 2: Degradation of the sol-ael coating in a physiological medium at 37 oC 15
    The degradation of the coating in a simulated physiological medium at 37 oC has been studied by means of a localized electrochemical technique: Scanning electrochemical microscopy, known as SECM by its acronym in English (Scanning Electrochemical Microscopy). The technique allows monitoring in situ the degradation of the coating by performing mappings that comprise an area of 1000x1000 iJm2 over time. The electrochemical activity of the medium is recorded by the addition of a mediator, ferrocenomethanol. The study of coatings with a moxifloxacin molar ratio with respect to silanes of 0.001: 1 and 0.002: 1 was performed. The study was also carried out on the uncoated metal substrate, in this case, a titanium-based substrate. Figure 2 shows the maps obtained at 2 h and 12 hours of immersion in the physiological fluid of the metal substrate (Figure AS) and of the coatings with an addition of moxifloxacin in a molar ratio of 0.001: 1 (Figure CD) and 0.002: 1 (Figure EF) with respect to silanes. It is observed how the coating with a smaller amount of antibiotic maintains its insulating properties 30 after 12 hours of immersion in the fluid. The insulating properties of the coating translate into obtaining currents less than 1 mA. The coating with higher amounts of antibiotic, however, has been located after 12 hours of immersion, localized areas of greater electrochemical activity. The appearance of these localized areas is due to the progressive loss of the coating which causes that in
    In certain areas the fluid is in contact with the metal substrate. The degradation kinetics of the coating is closely related to the amount of antibiotic added due to a different degree of crosslinking. Accordingly, the antibiotic addition can be formulated based on the degradation kinetics required for the coating.
    5 On the other hand, the release of moxifloxacin in physiological fluid at 37 oC can bestudy by two methods: absorbance and fluorescence. Moxifloxacin is acompound that forms a colored complex in the presence of Fe (lIl) whose absorbancecan be measured at wavelengths of 450 nm (W.F. EI-Hawary et al., "MutualSpectrophotometric Determination of Moxifloxacin Drug and lron (III) lons By
    10 Formation of a Complex Compound ", European Chemical Bulletin, Vol 2, n01 (2013». By means of a previous calibration curve, the concentration of antibiotic released can be known. The same procedure can be performed by fluorescence since the compound is excited and emitted signals at 296 and 471 nm, respectively (M. Bajgrowicz et al., "Release of Ciprofloxacin and Moxifloxacin From Daily Disposable
    15 Contact Lenses From an In Vitro Eye Model, "vol. 5, no. 6, 2016).
    Example 3: Study of the formation of a bacterial film (biofilm) in the substrate
    coated by the method of the invention by adding an antibiotic
    20 In the trials for the biofilm development study, 3 collection strains of three different species have been used: S. aureus 15981, S. epidermidis ATCC 35984 and Escherichia coli ATCC 25922. The three species of bacteria used were chosen to be responsible between 75 and 85% of infections associated with osteoarticular prostheses and more than 95% of infections associated with
    25 plastic materials for clinical use.
    Each species was cultivated in a biofilm formation inducing medium in the presence of a substrate consisting of a 15 mm diameter titanium disc made by powder metallurgy covered with one side by the coating of invention 30 loaded with different molar ratios of antibiotic with respect to at silanes: 0: 1 (P2), 0.001: 1 (P2 + A25) and 0.002: 1 (P2 + A50). After 24 hours of incubation with 5% CO2 at 3rC, the disks were washed three times in sterile physiological serum and the coating of each disc was completely scraped off and the concentration of bacteria grown and adhered to each of the coatings was estimated. by
    35 unit area. The concentration of bacteria not adhered (planktonic) but grown in the presence of each coating was estimated by absorbance at 600 nm.
    All trials were performed in triplicate. The statistical study was performed.
    using the STATA 11 .0 SpecialEdition software. The results are shown in the
    Figure 3.
    The results of these tests have shown a complete inhibition of
    bacterial biofilm formation and a drastic reduction in planktonic growth
    on and in the presence of the formulation P2 + A50.
    Example 4: Cytotoxicity studies of the coating prepared by the process of the present invention.
    The non-cytotoxicity of the products resulting from the coating of the invention was discarded using the commercial kit CytoTox 96® NonRadioactiveCytotoxicity. During this test the cytotoxicity that the coating of the invention could exert against a given concentration of MC3T3-E1 cells during their differentiation over 48 h was evaluated. Eight replicas were performed in each trial and it was performed in duplicate. The statistical study was performed using the STATA software
    11 .0 SpecialEdition.
    The results show that the products resulting from the degradation of the coating of the invention loaded or not loaded with moxifloxacin do not exert toxicity on the cells during their differentiation (Figure 4). These results undermine the biocompatibility of the coating obtained by the process herein.
    Invention
    Example 5: Preparation of the so / -oel coating with an addition of fluconazole in a molar ratio of O0009: 1 with respect to the silanes.
    30 The solubility of fluconazole (Sigma Aldrich) in water is 8-10 mg / ml
    The following steps are carried out to prepare the coating:
    a solution of 3-methacryloxypropyltrimethoxysilane (MAPTMS, 98% Acros Organics) and tetramethoxysilane (TMOS, 98% Acros Organics) in a molar ratio is prepared in a first glass vial of suitable size
    MAPTMS: 1: 2 TMOS under vigorous stirring of 400-600 rpm,
    Ethanol is added to the vial to a 3-methacryloxypropyltrimethoxysilane (MAPTMS) and tetramethoxysilane (TMOS): ethanol ratio of 1: 3 under vigorous stirring of 400-600 rpm,
    a compound based on phosphorus, tris {trimethylsilyl) phosphite (~ 95% Sigma
    5 Aldrich), where the ratio between the moles of the phosphorus-based compound and the sum of moles of the silanes is 1: 20; the mixture is allowed to disperse for at least 5 minutes,
    Fluconazole is dissolved in a second vial at a molar ratio of 0.0009: 1 with respect to the sum of moles of silanes in an amount of distilled water, 10 where the ratio between the sum of moles of silanes and water is of 1: 3, the second vial is added dropwise to the first one under vigorous stirring of 400600 rpm, the synthesis is left for 24 hours controlling the temperature between 15-35 oC and 25-55% relative humidity, thus obtaining the composition of coating. fifteen
    The coating of the substrate and drying thereof is carried out in the same manner indicated in example 1.
    Example 6: Study of the formation of a fbiofilmJ fungal film on the substrate 20 coated by the method of the invention by adding antifungal
    In a manner analogous to that specified in Example 3, the coating's antifungal capacity was tested by loading it with fluconazole with a collection strain of C. albicans, the fungal agent involved in more than 85% of fungal infections.
    25 associated with biomaterials. The main modifications with respect to the methodology used with the bacteria were two: (1) the inducing medium for the formation of specific biofilm of yeasts, and (2) the concentration of planktonic yeasts but grown in the presence of each coating was estimated by absorbance at 540 nm The results are shown in Figure 5.
    30 The results of these tests have been shown to reduce the formation of fungal biofilm 6 times and an approximately 50% reduction in planktonic growth on and in the presence of the P2 + F13 formulation. These results could be enhanced depending on the concentration of fluconazole contained in the sol-gel.
    Example 7: Characterization of the fxerogelJ polysiloxane network of the coating composition obtained in step dJ of the process of the present invention with moxifloxacin additions in a molar ratio of O001 v O 002 with respect to a
    mole of silanes using Silicon Core Nuclear Magnetic Resonance ¡Z9Si5 NMR).
    The chemical nature and the degree of cross-linking of the polysiloxane network is studied by NMR and a silicon core has been chosen since the precursors of the network are silicon based. The polysiloxane network is characterized by the formation of 10 siloxane, Si-O-Si bonds, and for such bonds to be formed, the silane must have at least one hydrolyzable group. A hydrolysable group is defined as that group which, together with a silicon atom, can be substituted by a hydroxyl group (-OH) provided by the water molecules involved in the hydrolysis reaction. Subsequently, and simultaneously once the hydrolysis reaction has begun, the condensation reaction occurs by releasing a water molecule that results in the formation of the siloxane bond. MAPTMS (R'-Si- (ORh) silane has 3 hydrolysable groups and the received signal is identified with the letter Tn, where n is the number of hydrolyzed groups that varies between O and 3 and which are identified at different chemical shifts ( 15) Thus, the Si-O-Si bonds generated by 20 MAPTMS are identified at: T 'at -42.8 ppm; T' 49.1 ppm; T 'at -57.7 ppm; and T3 at -67 , 3 ppm The TMOS (Si- (OR) 4) silane has 4 hydrolysable groups which are designated as Qn, where n is the number of hydrolysable groups that varies from O to 4 and which are identified as: QO a -78.5 ppm; Q1 to -85.0 ppm; Q2 to -91.2 ppm; Q3 to -101.0 ppm; and Q4 to -110.4 ppm. Additionally, at 12 ppm the received signal can be identified by 25 the formation of Si-P bonds generated by the reaction between the silanes and the phosphorus-based compound which contributes to increasing the cross-linking of the polysiloxane network Figure 6 shows the spectra obtained for: P2 ', a xerogel with a molar relationship of silan 1: 2 MAPTMS and TMOS with an addition of tris (trimethylsilyl) phosphite in a molar ratio of 1: 20 with respect to one mole of silanes; 30 P2 '+ A25', the xerogel with the same molar ratios as P2 'and to which a quantity of moxifloxacin has been added in a molar ratio of 0.001: 1 with respect to silanes; and P2 '+ A50', the xerogel with the same molar ratios as P2 'and an amount of moxifloxacin in a molar ratio of 0.002: 1 with respect to silanes.
    35 Table 1 shows the contributions of each silane to the formation of the polysiloxane network. The results show that the chemical nature of the polysiloxane bond of the P2 'network is constituted by a contribution of 41.9% by MAPTMS silane and 42.9% from TMOS. In addition, the reaction between the silanes and the phosphorus-based compound that generates the formation of an Si-P bond contributes a 15.2% contribution to the cross-linking of the network. It is noted that the addition of
    The antibiotic does not modify the degree of cross-linking of the polysiloxane network of the coating composition, since the contributions to cross-linking by MAPTMS and TMOS silanes, ie the Si-O-Si bonds. they only vary between 41,042.7% and 42.6-42.7%, respectively. The contribution to the remaining crosslinking is due to Si-P links.
    10 TABLE 1: Summary of the contributions of each year to the formation of the polysiloxane network of the 29Si_RMN spectra obtained from FIG. 6
    Synthesis Proportions related to (%) T 'T3 Q3 Q'Ratiob (%) T "Q"Yep
    P2 ' 10.731, 226.116.841, 942.915.2
    P2 '+ A25' 12.330.426.416.642.743.014.3
    P2 '+ A50' 10.630.425.217.441.042.616.4
    3 ,
    'relative proportions (%): 1 "= (1" I ¿7} 100; QJ = (QJ I¿ Q) · IOO
    ; = 1 j = 2
    3 3,
    15 b ratio (%) 1 '"= {¿1'I (¿T + ¿Q + Si -P)} IOO;
    ; =] ¡=] J = 2
    4 3 4 3 4
    Q "= {¿Q / (¿T + ¿Q + Si -P)} IOO; Si -P = {Si-PI ¿T + ¿Q + Si -P)} IOO
    j = 2 ¡=] j = 2;: 1 j = 2
    权利要求:
    Claims (22)
    [1]
    1. Procedure for obtaining a sol-gel coating on a substrate characterized in that it comprises the following steps:
    5 a) preparation of a solution of the 3-methacryloxypropyltrimethoxysilane silanes(MAPTMS) and tetramethoxysilane (TMOS), in a MAPTMS: TMOS molar ratio between
    1: 1 and 1: 2 in an e1-C3 alcohol, where the ratio between the sum of moles of MAPTMS and TMOS silanes and moles of alcohol e 1-e3 is between 1: 3 and 1: 6, b) addition of a phosphorus based compound selected from
    10 tris (trimethylsilyl) phosphite and dimethyltrimethylsilyl phosphite to the solution prepared in the previous step a) where the ratio between the moles of the phosphorus-based compound and the sum of moles of the MAPTMS and TMOS silanes is between 1: 15 and 1: 25. e) addition of water dropwise on the solution resulting from step b), where the ratio between the sum of moles of MAPTMS and TMOS silanes and moles of water
    15 is between 1: 3 and 1: 6, obtaining a colloidal solution, d) the colloidal solution obtained in step c) is allowed to react between 4 and 48 hours at a temperature between 15-35 ° e and 25-55% humidity relative to obtain a coating composition.
    Method for obtaining a sol-gel coating, according to claim 1, characterized in that the water added in step c) comprises at least one dissolved or dispersed antimicrobial compound.
    [3]
    3. Procedure for obtaining a sol-gel coating according to claim
    25 2, characterized in that the antimicrobial compound has a solubility in water of at least 1 Jlg / ml and the ratio between the moles thereof and the sum of moles
    MAPTMS and TMOS silanes are between 0.000047: 1 and 0.002: 1.
    [4]
    4. Procedure for obtaining a sol-gel coating according to claim
    30 3, characterized in that the ratio between the moles of the antimicrobial compound and the sum of moles of the MAPTMS and TMOS silanes is between 0.001: 1 and 0.002: 1.
    [5]
    5. Procedure for obtaining a sol-gel coating according to claim
    4, characterized in that the ratio between the moles of the antimicrobial compound and the sum of moles of the MAPTMS and TMOS silanes is 0.002: 1.
    [6]
    6. Method for obtaining a sol-gel coating according to any of claims 2 to 5, characterized in that the antimicrobial compound is selected from at least one antibiotic belonging to the family of fluoroquinolones or at least one antifungal belonging to the family of triazoles
    [7]
    7. Method for obtaining a sol-gel coating according to claim 6, characterized in that the antimicrobial compound is the antibiotic moxifloxacin or the antifungal fluconazole.
    Method for obtaining a sol-gel coating, according to any of the preceding claims, wherein the C1-C3 alcohol is ethanol.
    [9]
    9. Procedure for obtaining a sol-gel coating, according to any of
    the preceding claims, wherein the ratio between the sum of moles of the 15 MAPTMS and TMOS silanes and the moles of C1-C3 alcohol is 1: 3.
    [10]
    10. Method for obtaining a sol-gel coating according to any of the preceding claims, characterized in that a phosphorus-based compound is tris (trimethylsilyl) phosphite.
    [11]
    11. Method for obtaining a sol-gel coating according to any of the preceding claims, wherein the ratio between the moles of the phosphorus-based compound and the sum of moles of the MAPTMS and TMOS silanes is 1: 20.
    Method for obtaining a sol-gel coating, according to any of the preceding claims, characterized in that the ratio between the sum of moles of MAPTMS and TMOS silanes and moles of water is 1: 3.
    [13]
    13. Procedure for obtaining a sol-gel coating, according to any of
    The preceding claims, characterized in that in step d) the colloidal solution is allowed to react for 24 hours.
    [14]
    14. Procedure for obtaining a sol-gel coating, according to any of
    The preceding claims, characterized in that the coating composition 35 obtained in step d) is deposited on a substrate.
    [15]
    fifteen. Method for obtaining a sol-gel coating according to claim 14, characterized in that the coating composition obtained in step d) is deposited on a substrate by immersing the substrate in said coating composition.
    [16]
    16. Method for obtaining a sol-gel coating, according to claim 14, characterized in that the coating composition obtained in step d) is deposited on a substrate by spraying said coating composition onto said substrate.
    [17]
    17. Method for obtaining a sol-gel coating according to any of claims 14 to 16, characterized in that the substrate is an implant.
    [18]
    18. Procedure for obtaining a sol-gel coating, according to any of
    15 claims 14 to 16 characterized in that drying of the coating composition is carried out once it has been deposited on the substrate.
    [19]
    19. Procedure for obtaining a sol-gel coating according to claim
    18, characterized in that the drying is carried out at a temperature between 40 ° C and 60 ° C, at a pressure between 1 bar and 2 bar and for a time between 1 h and 24 h.
    [20]
    20. Coating composition obtained in any of claims 1 to
    [13]
    13.
    21. Use of the composition described in claim 20 to coat an implant.
    [22]
    22. Use of the composition according to claim 21 wherein the implant is a medical-surgical implant selected from the following: osteoarticular prosthesis, metal mesh, dental implant, screw, rod, osteosynthesis material plate,
    30 suture clip, central and peripheral intravenous catheter, urinary catheter, surgical drainage tube, surgical mesh, polymeric component of osteoarticular prosthesis, suture thread, synthetic cardiac valve, pacemaker, s / enl, genital prosthesis, submuscular, subfascial breast implant or subglandular, submuscular or subfascial muscle implant, chin implant and cheekbone implant.
    [23]
    2. 3. Substrate comprising a sol-gel coating obtained by any of claims 14 to 19.
    [24]
    24. Substrate according to claim 23 wherein the substrate is an implant.
    [25]
    25. Substrate according to claim 24 selected from osteoarticular prosthesis, metal mesh, dental implant, screw, rod, osteosynthesis material plate, suture clip, central and peripheral intravenous catheter, urinary catheter, surgical drainage tube, surgical mesh, polymeric prosthesis component osteoarticular thread
    10 suture, synthetic heart valve, step mark, stent, genital prosthesis, breast implant submuscular ° subfascial muscle implant, chin implant and cheekbone implant.
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    同族专利:
    公开号 | 公开日
    WO2018193145A1|2018-10-25|
    ES2686890B2|2019-04-08|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US20080063693A1|2004-04-29|2008-03-13|Bacterin Inc.|Antimicrobial coating for inhibition of bacterial adhesion and biofilm formation|
    GB2462883A|2008-08-29|2010-03-03|Univ Sheffield Hallam|Antimicrobial sol-gel coating|
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