ES2466065A1 - Modification of polyurethane with polymers sensitive to biocompatible stimuli for loading and transfer of drugs (Machine-translation by Google Translate, not legally binding) - Google Patents

Abstract

Modification of polyurethane with polymers sensitive to biocompatible stimuli for loading and transfer of drugs. The invention relates to polyurethanes in the form of films, sheets or modified catheters, by means of gamma radiation (γ), with interpenetrating polymer network grafts (ipns) and semi-interprenetrates (s-ipns) sensitive to temperature and ph, which present a high biocompatibility, for its application as implantable systems of local release of drugs useful in the prevention and treatment of pathological or physiological conditions associated with the use of medical devices, in the development of topical, transdermal or transmucosal delivery systems of medicines or active substances and in the preparation of cosmetics. (Machine-translation by Google Translate, not legally binding)

Description

Modification of polyurethane with polymers sensitive to biocompatible stimuli for drug loading and transfer

Technical sector

The present invention relates to materials functionalized with polymers capable of incorporating drugs and releasing them. More specifically, it refers to polymer modified polyurethanes, manufactured products incorporating these polyurethanes and their uses.

State of the art

Polymeric materials are common components of implantable medical devices (probes, catheters, stents, prostheses, etc.) and of solid devices used in the application of drugs by various routes, mainly through skin and mucous membranes. At present there is a growing interest in optimizing the functionality of implantable medical devices, adding to its primary physical function the ability to act as drug release systems that prevent its recognition as a foreign object to the organism, improve its biocompatibility and minimize the risk of infections caused by microorganisms that adhere and proliferate on the surface resulting in the formation of biofilms. The incorporation of antimicrobial, anti-inflammatory and immunosuppressive agents on the surface of medical devices represents an effective procedure for the prophylaxis of infections and the prevention of inflammatory and immune responses. In addition, the drug-sanitary product combination products allow to reach higher local concentrations of drug than those achieved with systemic administration, making possible the localized treatment of pathologies with minimal risk of side effects in other areas of the organism.

Among the numerous procedures currently available to functionalize the surface of polymeric substrates, high-energy radiations such as gamma radiation (γ) and accelerated electrons have the ability to activate polymer chains without the participation of chemical initiators, such so that specific monomers can be grafted onto them. The degrees of modification (expressed as graft percentages) can be regulated through a careful selection of the exposure time (dose) of the material to the radiation and by the reaction conditions associated with the process. In addition to the high degree of purity of the graft product thus obtained, graft reactions produced by γ radiation have the advantage of being applicable to almost all polymer-monomer combinations, and allow regulating the depth of the material in which the graft can be produced. graft (Clough 2001; Gupta et al. 2004). However, there are no optimal general graft conditions, but for each polyromonomer combination the graft degree is a function of the interrelation between the intensity of radiation, the exposure time, the nature of the solvent and the concentration of monomers. In the particular case of polypropylene (rigid and non-biodegradable aliphatic polymer) it has been observed that the sequential graft of poly (N-isopropyl acrylamide) (PNIPAAm) and poly (acrylic acid) (PAAc) using the source pre-irradiation method of 60Co, it allows to obtain grafts constituted by interpenetrated networks of PNIPAAm and PAAc with capacity to house an antimicrobial drug, such as vancomycin, yield it in a sustained way for approximately 8 hours and effectively prevent the development of methicillin-resistant Staphylococcus aureus biofilms ( Muñoz-Muñoz, F. Ruiz, JC Alvarez-Lorenzo, C. et al. 2009. Novel interpenetrating smart polymer networks grafted onto polypropylene by gamma radiation for loading and delivery of vancomycin. Eur Polym J. 45: 1859-1867).

On the other hand, polyurethanes are especially suitable polymers as components of implantation systems and topical and mucosal administration of drugs due to their excellent heme-and bio-compatibility, elasticity and fatigue resistance (Moon Suk Kim, Jae Ho Kim, Byoung Hyun Min, Heung Jae Chun, Dong Keun Han, Hai Bang Lee. Polymeric Scaffolds for Regenerative Medicine, Polymer Reviews, 51: 23-52, 2011). However, they have a low capacity to act as medication transfer systems, a problem that is still unsatisfactory in a satisfactory way.

Description of the invention

The present invention provides modified polyurethanes so that it is possible to incorporate active substances therein and release them for a prolonged period of time, and thus solve the low capacity of the polyurethanes to act as drug delivery systems. Thus, the invention provides a polyurethane modified by surface or deep grafting, of interpenetrating polymer networks (IPNs) and semi-entrepreneurs (s-IPNs), which have a high biocompatibility and allow the incorporation and controlled transfer of drugs. The modification of the polyurethane is based on grafts of a polymer, which may be optionally crosslinked, and that is interpenetrated or semi-interpenetrated with another crosslinked polymer, and between both polymers there is no chemical bond, thus being both polymers independent of each other.

In one aspect, the invention is directed to a modified polyurethane characterized in that the polyurethane is grafted with a polymer A and a) said polymer A is forming part of a semi-interpenetrating network with a crosslinked polymer B; or b) said polymer A is crosslinked and is part of an interpenetrating network with a crosslinked polymer B; where polymer B is selected from poly (acrylic acid) and poly (methacrylic acid), and polymers A and B are independent of each other. In another aspect, the invention relates to medical material comprising a modified polyurethane as previously described.

In another aspect, the invention relates to a film comprising a modified polyurethane as previously described.

In another aspect, the invention relates to a process for the preparation of the modified polyurethane described above.

Detailed description of the invention

"Polyurethane" refers to a polymer that is synthesized by condensation of monomers and / or polymers containing two or more hydroxyl groups with monomers containing two

or more isocyanate groups. In a more particular aspect, the polyurethane is selected from aliphatic and aromatic polyurethanes. In a more particular aspect, the polyurethane is a cycloaliphatic poly (etherurethane) synthesized from methylene bis (p-cyclohexyl isocyanate), 1,4-butanediol, and poly (tetramethylene glycol); This polyurethane is commercially known as Tecoflex. Polyurethanes are materials that may be commercially available, and may even have such purity that they are applicable in medicine, by

example known by its commercial name as Tecophilic, Tecoplast, Tecothane,

Carbothane, Isoplast.

In a particular embodiment, the invention relates to a modified polyurethane as described above where the graft is superficial or deep.

A "graft" refers to a chemical anchor by a covalent bond, for example and as described above between polymer A and polyurethane. A "surface graft" refers to a graft in which the covalent bond is found on the surface of the polyurethane. A "deep graft" refers to a graft in which the covalent bond is inside the polyurethane.

In a particular embodiment, polymer A is a linear, branched or crosslinked homopolymer consisting of monomers selected from the group consisting of N-alkyl acrylamide, N, N-dialkylacrylamide, N- (aminoalkyl) acrylamide, N (hydroxyalkyl) acrylamide, N-arylacrylamide, N-arylalkyl acrylamide, N-alkyl methacrylamide, N, N-dialkylmethacrylamide, N- (aminoalkyl) methacrylamide, N- (hydroxyalkyl) methacrylamide, N- (alkyl phthalimide) acrylamide-N-arylmethacrylamide , where the amino group may be mono or di substituted by alkyl groups.

"Alkyl" refers to an acyclic linear or branched hydrocarbon chain, consisting of carbon and hydrogen atoms, without unsaturations, from 1 to 12, preferably from one to eight carbon atoms, more preferably from one to four carbon atoms, and which is attached to the rest of the molecule by a single bond, optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxy group, a carboxy group, an alkoxy group, a cyano group, a group nitro, a thioalkoxy group, a heteroalkyl group, a heterocyclic group or CF3, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, cyclopropyl, etc.

"Aryl" refers to an aromatic hydrocarbon of 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl radicals may be optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxy group, a carboxy group, an alkoxy group, a cyano group, a nitro group, a thioalkoxy group, an alkyl group or CF3.

In a more particular embodiment, polymer A is a linear, branched or crosslinked homopolymer consisting of monomers selected from the group consisting of N-isopropyl acrylamide, N- (2-aminoethyl) methacrylamide, N- (2-hydroxypropyl) methacrylamide, N- (3-Aminopropyl) methacrylamide, N- (isoButoxymethyl) methacrylamide, N- (n-Octadecyl) acrylamide, N- (Phthalimidomethyl) acrylamide, N- (tBOC-aminopropyl) methacrylamide, N, N-Diethylacrylamide, N, N -Dimethylacrylamide, N, N-Dimethylmethacrylamide, N- [2- (N, N-Dimethylamino) ethyl] methacrylamide, N- [3- (N, NDimethylamino) propyl] acrylamide, N- [3- (N, N-Dimethylamino ) propyl] methacrylamide, N-Benzylmethacrylamide, N-Diphenylmethylacrylamide, N-Dodecylmethacrylamide, N-Ethylmethacrylamide, N-Hydroxyethyl acrylamide, preferably N-isopropyl acrylamide.

In a more particular embodiment, polymer A is poly (N-isopropyl acrylamide).

A "semi-interpenetrating network" refers to a system consisting of a polymer that is not crosslinked and a polymer that is crosslinked, so for the purposes of the invention the semi-interpenetrated network described above refers to a polymer A which is not crosslinked and a crosslinked polymer B, where polymer A penetrates at molecular level the network that forms polymer B without forming any chemical bond between both polymers.

"Interpenetrating network" refers to a system consisting of two independent networks of crosslinked polymers in which the polymer chains of one network physically penetrate the other network without establishing any chemical bond between the polymers. Thus, for the purposes of the invention, polymer A constitutes the first network and polymer B constitutes the second network so that they form an interpenetrating network.

For the purposes of the invention, polymers A and B, although they are part of a network, are independent. "Independent polymers" means that a polymer or network consisting of a polymer physically penetrates the network consisting of the other polymer without establishing any chemical bond between the polymers. Said independent polymers respond independently to stimuli. Thus, for example, if polymer A is crosslinked poly (N-isopropyl acrylamide), the polymer A network is expanded at a temperature below 33 ° C and contracted at body temperature; while

if polymer B is crosslinked poly (acrylic acid), the polymer B network shrinks at pH

acid and is expanded to pH 7.4.

In a particular embodiment, the invention relates to a modified polyurethane wherein polymer A is poly (N-isopropyl acrylamide) and polymer B is poly (acrylic acid) (PAAc).

In a particular embodiment, the modified polyurethane of the invention is characterized in that the polyurethane is grafted with poly (N-isopropyl acrylamide), and

a) the poly (N-isopropyl acrylamide) is part of a semi-interpenetrating network with crosslinked poly (acrylic acid); or b) the poly (N-isopropyl acrylamide) is crosslinked and is part of an interpenetrating network with crosslinked poly (acrylic acid); where polymer B is selected from poly (acrylic acid) and poly (methacrylic acid), and polymers A and B are independent of each other. The graft of polymer A and the semi-interpenetrating or interpenetrating network, give the surface and mass of the modified polyurethanes of the present invention the ability to change their degree of swelling and, therefore, to regulate the loading process and of cession of drugs adjusting it to the conditions of pH and temperature of the physiological environment.

In a particular aspect, the invention relates to a modified polyurethane as previously described which also incorporates an active substance.

"Active substance" refers to any substance that is used in the treatment or prevention of a disease or that is used to improve the physical well-being of humans or animals. In a particular embodiment, the active substance is selected from hormones, antifungals, antibacterials, antivirals, spermicides, local anesthetics, anti-inflammatories, muscle relaxants, labor inducers, agents for the treatment of sexually transmitted disease. In a more particular embodiment, the active substance is selected from progesterone, medrogestone, medroxy-progesterone, cyclopirox olamine, metronidazole, clotrimazole, ketoconazole, miconazole, fenticonazole, thioconazole, sertaconazole, oxiconazole, itraconazole butaconazole, terconazole, saperconazole, troconazole, fluconazole, troconazole, saconaconazole, troconazole , econazole, nystatin, amphotericin B, clindamycin, trimethoprim, sulfamethoxazole, penicillins, cephalosporins, tetracyclines, doxycycline, bacitracin, lincomycin, colistin, polimixinaB, vancomycin, gentamicin, kanamycin, neomycin, streptomycin, erythromycin, amikacin, tobramycin, nonoxynol-9, octoxynol-9, menfegol, cyclodextrins, tetracaine, mepivacaine, lidocaine, benzocaine, procaine, beta-metasona, hydrocortisone, triamcinolone, mometasone, diclofenac, etodolac, ibuprofen, indomethacin, meloxicam, pland-estradiol, pinaxicam, beta-17 terbutaline, ritodrine, isoxsuprine, fenoterol, salambutol, hexoprenaline, metaproterenol, bitolt Erol and pirbuterol, prostaglandin PGF2 (dinoprostone), PGF2 (dinoprost), carboprost, sulprostone, misoprostol, gemeprost.

The modified polyurethanes of the invention that incorporate active substances are capable of releasing them in a sustained manner over time. Thus, in another aspect, the invention relates to a modified polyurethane as previously described for use as an active substance release system. In a more particular embodiment, the system is topical, transdermal or transmucosal release.

In another particular embodiment, the invention relates to an implant comprising a modified polyurethane as previously described.

In another aspect, the invention relates to medical material comprising a modified polyurethane as previously described. In a particular embodiment, medical material refers to catheters, balloons, probes, stents, gloves, condoms, porous membranes.

In a preferred embodiment, the invention relates to a catheter comprising a polyurethane as previously described.

In addition, the modified polyurethane of the invention can be in the form of a film. Thus, in one aspect, the invention relates to a film comprising a modified polyurethane as previously described. The invention also relates, in a particular way, to the film previously described for use as surface coating. Alternatively it refers to the use of the previously described film as surface coating. In another particular embodiment, the invention relates to modified polyurethane as previously described for use as medical material packaging, medical material wrapping or coating, release system coating.

In a particular embodiment, the invention relates to a medical material or a film that

it comprises a modified polyurethane as previously described, which in addition

It incorporates an active substance.

In a particular embodiment, the invention relates to a catheter or a film comprising a modified polyurethane as previously described, which further incorporates vancomycin.

In another particular embodiment, the invention relates to modified polyurethane as previously described for use in the manufacture of porous membranes, preferably hemodialyzers, oxygenators, hemoconcentrators.

In another particular embodiment, the invention relates to modified polyurethane as previously described for use as a coating of nutritional supplements.

In another aspect, the invention relates to modified polyurethanes as previously described, for use as a cosmetic or cosmetic coating.

In another aspect the invention relates to a process for the preparation of a modified polyurethane as described above, characterized in that the polyurethane is grafted with a polymer A and said polymer A is forming part of a semi-interpenetrating network with a crosslinked polymer. B, which comprises a) subjecting a polyurethane grafted with a polymer A to gamma irradiation in the presence of a crosslinked polymer B, and b) heating the material resulting from step a). In a particular embodiment, polymer A is poly (N-isopropyl acrylamide) and polymer B is poly (acrylic acid). For a better understanding, this product when polymer A is poly (Nisopropyl acrylamide) and polymer B is poly (acrylic acid) is named with the following code: (TFX-g-PNIPAAm-inter-net-PAAC).

In a particular embodiment, the invention relates to the modified polyurethane obtainable by the process described above.

It is of interest for the present invention, the intermediate polyurethane in the synthetic process previously described. Thus in a particular embodiment, the invention relates to a polyurethane grafted with a polymer A, polymer A as described above, preferably poly (N-isopropyl acrylamide). For a better understanding, to this product when polymer A is poly (N-isopropyl acrylamide) and polymer B is poly (acrylic acid)

It is named with the following code: (TFX-g-PNIPAAm).

In another particular embodiment, the invention relates to a process for the preparation of a polyurethane grafted with a polymer A as previously described, comprising

a1) subjecting a polyurethane in the presence of a polymer A to gamma irradiation, and a2) heating the material resulting from step a1); or

b1) subjecting a polyurethane to gamma irradiation, and b2) heating the material resulting from step b1) in the presence of a polymer A.

In a particular embodiment, the invention relates to a process for the preparation of a modified polyurethane as described above, characterized in that the polyurethane is grafted with a polymer A and said polymer A is crosslinked and is part of an interpenetrating network with a crosslinked polymer B, comprising subjecting a grafted polyurethane with a crosslinked polymer A to gamma irradiation, in the presence of polymer B. In a particular embodiment, the invention relates to the modified polyurethane obtainable by the process described above.

It is of interest for the present invention, the intermediate polyurethane in the synthetic process previously described. Thus, in a particular embodiment, the invention relates to a polyurethane grafted with a crosslinked polymer A, polymer A as described above, preferably poly (N-isopropyl acrylamide). In another particular embodiment, the invention relates to a process for the preparation of a grafted polyurethane with a crosslinked polymer A as previously described, comprising: a) subjecting a grafted polyurethane with a polymer A as previously described, to gamma irradiation; or b1) subjecting a polyurethane to gamma irradiation, and b2) heating the material resulting from step b1) in the presence of a polymer A and a crosslinking agent. In a particular embodiment, the crosslinking agent is methylene bis (acrylamide). In a particular embodiment, polymer A is poly (N-isopropyl acrylamide) and polymer B is poly (acrylic acid). For a better understanding, the product resulting from step a) when polymer A is poly (N-isopropyl acrylamide) and polymer B is poly (acrylic acid) it is named with the following code: (net-TFX-g- PNIPAAm) and the product resulting from step b2) is named with the code (TFX-g-net-PNIPAAm).

The use of gamma radiation as a trigger for anchoring and crosslinking processes is advantageous since it does not require prior modification of polyurethane or prior obtaining of reactive polyurethane derivatives, unlike what happens when chemical anchoring procedures are applied (Hu et al. 2006; Cho and Kim, 2010; Hu et al. 2010).

In a particular embodiment, the gamma irradiation steps in the processes described above take place using 60Co sources. In a particular embodiment, the gamma irradiation steps in the processes of the invention take place at intensities between 2 to 20 kGy / h and applying irradiation doses between 2 and 60 kGy, more preferably at intensities between 2.5 to 10 kGy / h and applying irradiation doses between

2.5 and 50 kGy.

In another particular aspect, when the polyurethane is a cycloaliphatic poly (etherurethane) synthesized from methylene bis (p-cyclohexyl isocyanate), 1,4-butanediol, and poly (tetramethylene glycol), the percentage of poly (N-) grafting isopropyl acrylamide) in TFX-g-PNIPAAm, net-TFX-g-PNIPAAm and TFX-g-net-PNIPAAm is between 10% and 100% by weight of TFX. In a particular aspect, the content of poly (acrylic acid) is preferably between 10% and 200% by weight.

In a particular embodiment, the methods of the invention for obtaining modified polyurethanes, as described above, further comprise the incorporation of an active substance. This step can be carried out by immersing the modified polyurethane in a solution of the active substance.

Description of the figures

Figure 1. Inhibition haloes observed on plates seeded with Staphylococcus aureus (ATCC 25923) after incubation at 37 ° C for 24 hours in the presence of TFX catheters and

net-TFX-g-PNIPAAm-inter-net-PAAc with PNIPAAm grafted by P method or by method

D (codes as in Table 1), without loading with vancomycin and after loading vancomycin.

Codes: A1: TFX catheter (without vancomycin); A2: TFX catheter (loaded with vancomycin); B1: IPN40P-c (without vancomycin); B2: IPN40P-c (loaded with vancomycin); C1: IPN40D-c (without vancomycin); C2: IPN40D-c (loaded with vancomycin).

Figure 2. Vancomycin assignment profiles from IPN40 (), s-IPN40 (), IPN60 (), s-IPN60 (), IPN80 () and s-IPN80 (), in half buffer pH 7.4 phosphate at 37 ° C for net-TFX-g-PNIPAAm-inter-net-PAAc with PNIPAAm grafted by method P (a, b) or by method D (c, d) and tested in the wet state ( a, c) and dry (b, d).

Figure 3. Thrombus formed after 30 min incubation of blood on s-IPN40P-f (A), IPN60P-f (B), s-IPN60D-f (C), IPN60D-f (D), s-IPN60P -f (E), s-IPN40D-f (F), IPN40Df (G), IPN40P-f (H), unmodified TFXf (I), and positive control (J). The weight of the thrombi was normalized with respect to the weight of the thrombus obtained for the positive control.

Figure 4. Polymerization stages for the synthesis of grafts and networks of PNIPAAm, and IPNs and s-IPNs of NIPAAm / AAc in TFX catheters and films.

Examples of the invention

The following examples are illustrative of the invention and should not be construed as limiting thereof. Examples are included to illustrate the preparation of polyurethanes with PNIPAAm grafts interpenetrated with PAAc frameworks. Examples of hemocompatibility, and the ability of the compositions to incorporate drugs and transfer them in a controlled manner are also included.

Embodiment

To carry out the grafting of PNIPAAm chains on Tecoflex (TFX) using the oxidative pre-irradiation method (method P), the TFX is irradiated to the air at room temperature using 60Co sources (Gammabeam 651 PT, Irradiation Unit and Radiological Safety of the Institute of Nuclear Sciences of the National Autonomous University of Mexico) at a dose of 5 to 10 kGy / h and applying irradiation doses between 2.5 and 50 kGy. The preradiated TFX is placed in glass ampoules containing aqueous solutions of NIPAAm with a concentration between 0.25 and 1.0 M. The ampoules are saturated with argon for 20 min, sealed and heated at 60 or 70 ° C for 45 to 420 min. The grafted polymers are washed with water and dried (under reduced pressure) at 40 ° C for 48 h. The percentage of grafted PNIPAAm is quantified by applying the equation:

in which Wf and Wi represent the weights of TFX after and before grafting, respectively.

To carry out the grafting of PNIPAAm chains on TFX using the direct method (method D), the TFX is placed in glass ampoules containing NIPAAm solutions with a concentration between 0.25 and 1.0 M in toluene. The ampoules are saturated with argon for 20 min, sealed and irradiated at room temperature using 60Co sources (Gammabeam 651 PT, Radiation Safety and Radiation Unit of the Institute of Nuclear Sciences of the National Autonomous University of Mexico) at irradiation intensities from 2.5 to 10 kGy / h and applying different doses between 2.5 and 50 kGy. The grafted polymers are washed with toluene and water and dried at 40 ° C for 48 h. The percentage of grafted PNIPAAm is quantified by applying equation 1.

To carry out the crosslinking of the PNIPAAm chains grafted onto TFX using the oxidative pre-irradiation method (method P) or the direct method (method D), the TFX-g-PNIPAAm is placed in glass ampoules containing distilled water and after saturation with argon for 20 min, the ampoules are sealed and irradiated at room temperature using 60Co sources (Gammabeam 651 PT, Radiation Safety and Radiation Unit of the Institute of Nuclear Sciences of the National Autonomous University of Mexico) at speeds of irradiation of 2.5 to 10 kGy / h and applying different doses of irradiation, between 2.5 and 50 kGy. The net-TFX-g-PNIPAAm obtained are washed with water and dried under vacuum.

To carry out the anchoring and crosslinking of PNIPAAm chains in a single step (TFX-g-net-PNIPAAm), the oxidative pre-irradiation method (method P) described above is applied and the pre-irradiated TFX is placed in ampoules of glass containing aqueous solutions of NIPAAm of concentration between 0.25 and 1.0 M and of methylene bis (acrylamide) (MBAAm) in proportion 0.05 to 2% by weight with respect to NIPAAm. The ampoules are saturated with argon for 20 min, sealed and heated at 60 or 70 ° C for 45 to 420 min.

To carry out the synthesis of the interpenetrated PAAc network, pieces of TFX-g-PNIPAAm, net-TFX-g-PNIPAAm or TFX-g-net-PNIPAAm are immersed in glass ampoules containing an aqueous solution of acrylic acid and MBAAm. After 1 to 10 hours, the pieces of TFX-g-PNIPAAm, net-TFX-g-PNIPAAm or TFX-g-net-PNIPAAm are removed from the solution, deposited in glass ampoules, frozen, degassed at vacuum, they are sealed, and then direct irradiation is used using 60Co sources (Gammabeam 651 PT, Radiation Safety and Radiation Unit of the Institute of Nuclear Sciences of the National Autonomous University of Mexico) at irradiation rates of 2.5 to 10 kGy / h and applying different doses between 0.5 and 3 kGy. The TFX-g-PNIPAAm-inter-net-PAAc and the net-TFX-g-PNIPAAm-inter-net-PAAc obtained are washed with water and dried under vacuum.

Example 1. Preparation of TFX-g-PNIPAAm-inter-net-PAAc and net-TFX-g-PNIPAAminter-net-PAAc

It was split from 2.5 cm long portions of Tecoflex polyurethane catheter (UmbilicathTM, Utah Medical Products, USA) and 1x4 cm portions of Tecoflex polyurethane films (TFX EG-93A, Lubrizol Advanced Materials, USA) of 0.5 mm thickness. First, they underwent the NIPAAm grafting processes using the P method or the D method at 7.4 kGy / h obtaining TFX-g-PNIPAAm.

To obtain semi-interpenetrated systems with a PAAc network, the TFX-g-PNIPAAm obtained were placed in glass ampoules with an aqueous solution of acrylic acid 25% weight / vol and MBAAm 1% weight / weight. After 6 hours, the TFX-g-PNIPAAm pieces were removed from the solution. . They were then introduced into empty glass ampoules, frozen by immersion in liquid nitrogen, degassed under vacuum, sealed and irradiated using 60Co sources (Gammabeam 651 PT, Radiation Safety and Radiation Safety Unit of the Institute of Nuclear Sciences of the National Autonomous University of Mexico) at 5 kGy / h applying an irradiation dose of 1.5 kGy. The TFX-gPNIPAAm-inter-net-PAAc obtained were washed with water and dried under vacuum. These materials are designated as s-IPN followed by a number that indicates the percentage of grafting in PNIPAAm and a capital letter P or D that refer to the P or D method used to graft PNIPAAm.

To prepare grafts with the two crosslinked networks, the TFX-g-PNIPAAm obtained by methods P and D, which were placed in glass ampoules containing distilled water, were started and, after saturation with argon for 20 min, were irradiated at temperature ambient using 60Co sources (Gammabeam 651 PT, Radiation Safety and Radiation Unit of the Institute of Nuclear Sciences of the National Autonomous University of Mexico) at 7.4 kGy / h applying an irradiation dose of 10 kGy. The net-TFX-g-PNIPAAm obtained were washed with water, dried under vacuum and placed in glass ampoules with an aqueous solution of acrylic acid 25% weight / vol and MBAAm 1% weight / weight. After 6 hours, the net-TFX-g-PNIPAAm pieces were removed from the solution, frozen by immersion in liquid nitrogen and degassed under vacuum. They were then introduced into empty glass ampoules that were sealed and irradiated using 60Co sources (Gammabeam 651 PT, Radiation Safety and Radiation Unit of the Institute of Nuclear Sciences of the National Autonomous University of Mexico) at 5 kGy / h applying an irradiation dose of 1.5 kGy. The net-TFX-g-PNIPAAm-inter-net-PAAc obtained were washed with water and dried under vacuum.

Another procedure for preparing grafts with the two crosslinked networks, consisted of preradiating TFX at 8 kGy / h at 30 kGy and then placing it in glass ampoules containing aqueous solutions of 0.5 M NIPAAm and methylene bis (acrylamide) (MBAAm) in proportion 0.7% by weight with respect to NIPAAm, to anchor and cross-link PNIPAAm chains in a single step (TFX-g-net-PNIPAAm). The ampoules were saturated with argon for 20 min, sealed and heated at 70 ° C for 60 min. The TFX-g-net-PNIPAAm obtained were washed with water, dried under vacuum and placed in glass ampoules with an aqueous solution of acrylic acid 25% weight / vol and MBAAm 1% weight / weight. After 6 hours, the net-TFX-g-PNIPAAm pieces were removed from the solution, frozen by immersion in liquid nitrogen and degassed under vacuum. They were then introduced into empty glass ampoules that were sealed and irradiated using 60Co sources (Gammabeam 651 PT, Irradiation and Safety Unit

5 Radiological of the Institute of Nuclear Sciences of the National Autonomous University of Mexico) at 5 kGy / h, applying an irradiation dose of 1.5 kGy. The TFX-g-netPNIPAAm-inter-net-PAAc obtained were washed with water and dried under vacuum.

Codes used: The net-TFX-g-PNIPAAm-inter-net-PAAc and the TFX-g-net-PNIPAAminter-net-PAAc are designated as IPN and IPN-2 steps, respectively, followed by a

10 number indicating the percentage of grafting in PNIPAAm and a capital letter P or D that refer to the P or D method used to graft PNIPAAm. The letters c and p indicate polyurethane in the form of a catheter or film, respectively.

Tables 1a and 1b summarize the graft percentages achieved.

Table 1a (catheters) and 1b (film). Percentages of grafting of PNIPAAm and PAAc in polyurethanes 15 with inter-penetrated PNIPAAm grafts with PAAc frameworks.

Catheter Code

Grafted PNIPAAm (%) interpenetrated net-PAAc

PNIPAAm / PAAc (% mol / mol)

Percentage of graft on TFXc-g-IPN (%)

IPNc-2steps

20 (0.8) 17/83 (0.5) 66.7 (0.5)

IPN40P-c

43 (1.0) 32/68 (1.1) 96 (3.2)

s-IPN40P-c

40 (1.4) 28/72 (1.3) 106 (3.4)

IPN60P-c

63 (1.3) 35/65 (1.0) 131 (4.7)

s-IPN60P-c

59 (3.8) 30/70 (1.3) 139 (6.1)

IPN80P-c

82 (5.5) 34/66 (4.4) 183 (6.1)

s-IPN80P-c

77 (6.0) 37/63 (4.0) 162 (2.2)

IPN40D-c

40 (0.9) 24/76 (0.6) 111 (3.7)

s-IPN40D-c

40 (2.2) 24/76 (0.2) 115 (4.3)

IPN60D-c

62 (2.7) 30/70 (0.5) 148 (2.3)

s-IPN60D-c

59 (1.0) 29/71 (0.2) 149 (2.8)

IPN80D-c

81 (2.1) 33/67 (0.6) 170 (4.1)

Movie Code

Grafted PNIPAAm (%) interpenetrated net-PAAc

PNIPAAm / PAAc (% mol / mol)

Percentage of graft on TFXp-g-IPN (%)

IPN40P-p

43 (3.6) 26/74 (1.5) 119 (1.1)

s-IPN40P-p

42 (4.0) 25/75 (1.1) 123 (6.4)

IPN60P-p

62 (2.2) 33/67 (3.0) 147 (3.8)

s-IPN60P-p

61 (3. 2) 30/70 (1.2) 158 (9.1)

IPN80P-p

82 (2.0) 34/66 (3.7) 175 (8.4)

s-IPN80P-p

79 (1.2) 36/64 (2.9) 162 (6.5)

IPN40D-p

38 (1.7) 22/78 (1.8) 102 (1.8)

s-IPN40D-p

37 (1.2) 21/79 (0.1) 103 (3.0)

IPN60D-p

65 (0.2) 31/69 (1.1) 156 (5.7)

s-IPN60D-p

64 (1.6) 30/70 (2.9) 160 (1.4)

IPN80D-p

79 (3.1) 35/65 (1.3) 164 (6.8)

s-IPN80D-p

75 (2.2) 35/65 (2.2) 169 (6.5)

Example 2. Ability to respond to changes in temperature and pH of TFX-gPNIPAAm-inter-net-PAAc and net-TFX-g-PNIPAAm-inter-net-PAAc

5 The degree of swelling and the critical temperature (LCST) of the materials obtained according to example 1 were evaluated in aqueous buffered media of pH between 2 and 11 in the temperature range of 5 to 46 ° C. The temperature response, ST, was determined as the ratio between the maximum and minimum swellings that the materials undergo pH 7.0 as a function of temperature. The pH response, SpH, is

10 determined as the ratio between the maximum and minimum swelling that materials experience at 25 ° C as a function of pH. The results obtained are shown in Tables 2a and 2b.

Table 2a (catheters) and 2b (film). Maximum swelling (W∞), lower critical dissolution temperature (LCST), critical pH and temperature (ST) and pH (SpH) sensitivity of polyurethanes with interpenetrated PNIPAAm grafts with PAAc frameworks.

Catheter Code

W∞ (%) LCST (° C) ST Critical pH Sph

IPNc-2steps

fifty 32 1.1 5.8 7.3

IPN40P-c

146 31 1.3 5.5 9.0

s-IPN40P-c

232 25 1.2 5.2 6.6

IPN60P-c

150 29 1.3 5.1 16.6

s-IPN60P-c

262 28 1.2 5.3 13.2

IPN80P-c

324 29 1.3 5.1 18.2

s-IPN80P-c

115 31 1.4 5.2 9.7

IPN40D-c

241 32 1.3 6.3 3.7

s-IPN40D-c

282 28 1.1 6.5 5.8

IPN60D-c

243 28 1.2 6.3 5.2

s-IPN60D-c

299 26 1.1 6.3 6.1

IPN80D-c

287 26 1.1 6.2 7.3

s-IPN80D-c

315 25 1.1 6.2 6.6

Movie Code

W∞ (%) LCST (° C) ST Critical pH Sph

IPN40P-p

146 31 1.3 5.7 12.4

s-IPN40P-p

219 30 1.2 5.7 10.2

IPN60Pp

147 31 1.3 5.7 6.9

s-IPN60P-p

192 26 1.1 5.6 8.8

IPN80P-p

202 29 1.4 5.3 5.9

s-IPN80P-p

121 31 1.2 5.3 4.5

IPN40D-p

208 31 1.2 6.6 4.1

s-IPN40D-p

224 25 1.1 6.3 7.6

IPN60D-p

224 27 1.2 6.5 8.7

s-IPN60D-p

248 25 1.1 6.4 7.3

IPN80D-p

225 25 1.2 6.3 8.9

s-IPN80Dp

240 24 1.1 6.4 7.2

Example 3. Vancomycin incorporation capacity of TFX-g-PNIPAAm-inter-net-PAAc and net-TFX-g-PNIPAAm-inter-net-PAAc and antimicrobial effect

The materials obtained according to example 1 were immersed in phosphate buffer pH 8 to 5

5 ° C for 24 h to cause swelling of the two polymeric networks that constitute the graft. Then, they were transferred to 5 ml of vancomycin solution (0.4 mg / ml, filtered through 0.22 µm membranes) and incubated for 4 days at 5 ° C protected from light. The amount of vancomycin incorporated into the materials was determined by difference between the initial and final drug concentrations in the medium, quantified

10 by UV spectrophotometry at 280 nm. Unlike the unmodified TFX that presented a low capacity for incorporation of vancomycin (<12.7 mg / g), the grafted materials incorporate high amounts of drug (Table 3a and 3b).

The materials loaded with vancomycin were placed on Mueller-Hinton agar plates in which Staphylococcus aureus was previously seeded (ATCC 25923). The plates are

15 incubated at 37 ° C for 24 hours and then inhibition halos were measured (Figure 1). Untreated TFX used as a control did not result in inhibition of microbial growth. In contrast, grafted materials loaded with vancomycin resulted in significant inhibition halos.

Table 3a (catheters) and 3b (film). Quantities of incorporated vancomycin and halos of 20 inhibition observed in plaques seeded with Staphylococcus aureus (ATCC 25923).

Catheter

Vancomycin load (mg / g) Inhibition zone (mm)

IPN40P-c

64.9 25

s-IPN40P-c

64.3 25

IPN60P-c

70.1 25

s-IPN60P-c

82.5 25

IPN40D-c

83.2 26

s-IPN40D-c

94.6 twenty

IPN60D-c

84.8 22

s-IPN60D-c

89.7 2. 3

Movie

Vancomycin load (mg / g) Inhibition zone (mm)

IPN40P-p

65.8 30

s-IPN40P-p

66.7 28

IPN60P-p

64.9 25

s-IPN60P-p

70.4 25

IPN40D-p

80.5 28

s-IPN40D-p

87.8 30

IPN60D-p

88.6 30

s-IPN60D-p

89.4 27

Example 4. Ability to control the transfer of vancomycin from TFX-gPNIPAAm-inter-net-PAAc and net-TFX-g-PNIPAAm-inter-net-PAAc

The materials loaded with vancomycin following the procedure of Example 3 were transferred to test tubes with 5 ml of phosphate buffer pH 7.4 at 37 ° C. At regular time intervals samples were taken from the transfer medium and the vancomycin concentration was quantified by UV spectrophotometry at 280 nm. All grafted materials resulted in sustained transfer profiles for at least 24 h, as reflected in Figure 2.

Example 5. Thrombogenicity of TFX-g-PNIPAAm-inter-net-PAAc and net-TFX-gPNIPAAm-inter-net-PAAc

Unmodified and modified TFX sheets with the PNIPAAm and PAAc graft were swollen in phosphate buffer pH 7.4 at 37 ° C for 2 hours and then 0.1 ml of Sprague-Dawley rat anticoagulated blood was deposited. Thrombus formation began with the addition of 0.01 ml of 0.1M CaCl2. After 30 min, the reaction was stopped by adding water (2.5 ml) and the thrombus formed was recovered from the surface of the materials with a spatula and fixed with 37% formaldehyde. The thrombi were dried under vacuum and weighed. As a positive control, a glass Petri dish was used. The results obtained are shown in Figure 3. The grafted materials showed a thrombogenic activity much lower than that of unmodified TFX.

Claims (17)

 Claims 1. Modified polyurethane characterized in that the polyurethane is grafted with a polymer A) said polymer A is part of a semi-interpenetrating network with a crosslinked polymer B; or b) said polymer A is crosslinked and is part of an interpenetrating network with a crosslinked polymer B; where polymer B is selected from poly (acrylic acid) and poly (methacrylic acid), and polymers A and B are independent of each other.

2.

Modified polyurethane according to claim 1, wherein polymer A is a linear, branched or crosslinked homopolymer consisting of monomers selected from the group consisting of N-alkyl acrylamide, N, Ndialkylacrylamide, N- (aminoalkyl) acrylamide, N- ( hydroxyalkyl) acrylamide, Narilacrylamide, N-arylalkyl acrylamide, N-alkyl methacrylamide, N, N-dialkylmethacrylamide, N- (aminoalkyl) methacrylamide, N- (hydroxyalkyl) methacrylamide, N- (alkyl phthalimide) acrylamide aryl acrylamide, N-aryl acrylamide, N-alkyl , where the amino group may be mono or di substituted by alkyl groups.

3.

Modified polyurethane according to claims 1 and 2, wherein the polyurethane is grafted with poly (N-isopropyl acrylamide), and

a) the poly (N-isopropyl acrylamide) is part of a semi-interpenetrating network with crosslinked poly (acrylic acid); or b) the poly (N-isopropyl acrylamide) is crosslinked and is part of an interpenetrating network with crosslinked poly (acrylic acid); where polymer B is selected from poly (acrylic acid) and poly (methacrylic acid), and polymers A and B are independent of each other.

Four.

Modified polyurethane according to any one of claims 1 to 3, which further incorporates an active substance.

5.

Modified polyurethane according to any of the preceding claims, wherein the active substance is selected from hormones, antifungals, antibacterials, antivirals, spermicides, local anesthetics, anti-inflammatories, muscle relaxants, labor inducers, agents for the treatment of sexually transmitted disease.

6.

Implant comprising a modified polyurethane according to any one of claims 1 to 5.

7.

Medical material comprising a modified polyurethane according to any one of claims 1 aS.

8.

Catheter comprising a modified polyurethane according to any one of claims 1 aS.

9.

Film comprising a modified polyurethane according to any one of claims 1 to 5.

10.

Catheter or film comprising a modified polyurethane according to any one of claims 1 to 5, which further incorporates vancomycin.

eleven.

Use of a modified polyurethane, as described in any one of claims 1 to 5, as an active substance release system.

12.

Use of the film according to claim 9, as surface coating.

13.

Use of a modified polyurethane, as described in any one of claims 1 to 5, as medical material packaging, medical material wrapping or coating, release system coating.

14.

Use of a modified polyurethane as described in any one of claims 1 to 5, as a coating of nutritional supplements.

fifteen.

Use of a modified polyurethane as described in any one of claims 1 to 5, as a cosmetic or cosmetic coating.

16.

Process for the preparation of a modified polyurethane as described in claim 1, characterized in that the polyurethane is grafted with a polymer A and said polymer A is forming part of a semi-interpenetrating network with a crosslinked polymer B, comprising

a) subjecting a grafted polyurethane with a polymer A to gamma irradiation in the presence of a crosslinked polymer B, and b) heating the material resulting from step a).

17.

Process for the preparation of a modified polyurethane as described in claim 1, characterized in that the polyurethane is grafted with a polymer A and said polymer A is crosslinked and is part of an interpenetrating network with a crosslinked polymer B, which comprises subjecting a polyurethane grafted with a crosslinked polymer A at gamma irradiation, in the presence of polymer B.

A1 A2 Figure 1 Figure 2 Figure 3  TFX grafted with s-IPN Figure 4