JP2008245747A - Epidermal affinity coating agent and medical instrument - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an epidermal affinity coating agent containing hyaluronic acid or its derivative which has such temperature responsiveness that it is hydrophilic at temperature lower than prescribed temperature T which is lower than living body temperature and becomes hydrophobic at temperature higher than the prescribed temperature. <P>SOLUTION: The epidermal affinity coating agent comprising a polymer material carrying hyaluronic acid or its derivative is characterized in that the polymer material is hydrophilic at temperature lower than the prescribed temperature T which is lower than the living body temperature and is hydrophobic at temperature higher than the prescribed temperature T. The polymer material is preferably obtained by block-polymerizing a compound, as an iniferter, having three or more N,N-dialkyl-dithiocarbamyl methyl molecule group in the same molecule with 3-N,N-dimethyl amino propyl acrylamide and N-isopropyl acrylamido. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention is capable of maintaining excellent epidermal affinity over a medium to long term, and is suitable for living tissue, in particular, an epidermal affinity coating agent for various medical devices as a member (surface contact device) that directly contacts the epidermis, The present invention relates to a medical device coated with this epidermal affinity coating agent.

  Medical devices are roughly classified into implantation equipment and surface contact equipment. Examples of implantable devices include cardiac pacemakers, artificial blood vessels, and stents. Examples of successful chemical inert materials that are not easily recognized as foreign substances from subcutaneous tissues, such as NiTi alloys and e-PTFE. Many.

  On the other hand, the epidermis is always in contact with the outside world, and not only is it always in contact with germs, but also various cleanings such as cleaning operations such as bathing and showering, irritation such as scouring clothes, pH changes due to stratum corneum metabolism and sweating, UV exposure It is considered that the tissue has higher foreign substance recognition and foreign substance removal functions than the subcutaneous tissue. This can be explained by the downgrowth phenomenon that occurs in pacemaker leads.

  Examples of the surface contact device include a dressing material and a urinary catheter. A surface contact device that is in direct contact with a living body's epidermis over the medium to long term is required to have low skin irritation and the like, but it is necessary to design a material that gives superiority in terms of foreign object recognition.

  Hyaluronic acid has been used for a long time as a skin protecting material and cosmetics for beautifying skin (for example, Document 1 below). Hyaluronic acid is a mucopolysaccharide composed of β (1-3) glucuronic acid and β (1-4) glocosamine having a molecular weight of about 50,000 to 8 million, and is freely soluble in water. Therefore, it is often used as a moisturizing ingredient to prevent skin dryness and is used in the form of an ointment.

  When coating the surface of a medical device as a surface contact device, it is necessary to fix hyaluronic acid to the surface of the material. Elution occurs due to contact with water during cleaning operations. If contact is made with a mucosal tissue having a large amount of water such as a urinary catheter, elution is performed faster.

  In order to solve this problem, there is a technique for fixing hyaluronic acid to the surface of a material through a chemical bond using a chemical cross-linking agent (for example, the following document 2), but there is a problem such as residual chemical cross-linking agent.

JP 2004-41586 A JP 7-313585 A

  The present invention solves the above-mentioned conventional problems, is water-soluble (hydrophilic) at a temperature lower than a predetermined temperature (T) lower than the living body temperature, and water-insoluble (at a temperature higher than the predetermined temperature ( It is an object of the present invention to provide hyaluronic acid or a derivative-containing epidermal affinity coating agent having a temperature responsiveness that is hydrophobic) and a medical device coated with the epidermal affinity coating agent.

  The skin-affinity coating agent of the present invention is a skin-affinity coating agent comprising a polymer material supporting hyaluronic acid or a derivative thereof, and the polymer material is at a temperature lower than a predetermined temperature (T) lower than the living body temperature. It is hydrophilic and is hydrophobic at a temperature higher than the predetermined temperature (T).

  The predetermined temperature (T) is preferably a temperature between 25 and 35 ° C.

  The polymer material preferably has a block copolymer chain of a cationic monomer and N-isopropylacrylamide or a derivative thereof.

  The polymer material uses a compound having three or more N, N-dialkyl-dithiocarbamylmethyl molecular groups in the same molecule as an iniferter, and a light-irradiation living polymerization of a vinyl monomer and N-isopropylacrylamide or a derivative thereof. It is preferable to be a branched polymer.

  The compound having three or more N, N-dialkyl-dithiocarbamylmethyl groups in the same molecule has a benzene ring as a nucleus and three or more N, N-dialkyl-dithio as a branched chain in this nucleus. Those having a carbamylmethyl molecular group bonded thereto are preferred. For this iniferter, either a cationic monomer and N-isopropylacrylamide or a derivative thereof may be polymerized first.

  The medical device of the present invention is coated with the skin affinity coating agent of the present invention.

  The skin affinity coating agent of the present invention is hydrophilic and water-soluble at a temperature lower than the predetermined temperature due to the action of the polymer chain of N-isopropylacrylamide. Therefore, this skin-affinity coating agent is made hydrophobic (water-insoluble) by dissolving it in water and applying it to a living body or medical device, and then setting it to a temperature higher than a predetermined temperature. Adhere to. The adhering epidermal coating agent has an affinity for the epidermis of a living body by the supported hyaluronic acid or its derivative.

  This epidermal affinity coating agent can be stably stored for a long time as an aqueous solution, and can also be applied to a hybrid material or a living body.

  When the polymer material constituting the skin affinity coating agent has a cationic polymer block, hyaluronic acid or a derivative thereof has a negative charge because it has a carboxyl group having a high pKa. It is supported so as to form an ionic complex.

  When this polymer material has a plurality of branched chains made of a block copolymer of a cationic monomer and N-isopropylacrylamide or a derivative thereof, the adhesiveness of the skin-affinity coating agent to a medical device or the like is high. That is, in the case of a skin-affinity coating agent having a plurality of branched chains, if all of the plurality of branched chains in one molecule that are hydrophobically bonded to the surface of a medical device or the like do not peel at the same time, the molecule (polymer) Can not be peeled off from the material surface, and even if one piece is peeled off, if the remaining branched chain is bonded, the once peeled branched chain can be rebonded to the material surface. On the other hand, in the case of a linear block polymer having only one polymer chain in one molecule, if this one polymer chain is peeled off, the molecule is peeled off as it is, so that the adhesion is weak. Conceivable.

  The skin-affinity coating agent of the present invention comprises a polymer material carrying hyaluronic acid or a derivative thereof, and the polymer material is preferably a block having a cationic polymer block and a block of N-isopropylacrylamide or a derivative thereof. Has copolymer chains.

  As the polymer material, a compound having three or more N, N-dialkyl-dithiocarbamylmethyl groups in the same molecule is used as an iniferter, and this is irradiated with a cationic monomer and N-isopropylacrylamide or a derivative thereof. A branched polymer polymerized by living polymerization is preferred.

  In this specification, the iniferter is a polymerization initiator that generates radicals upon irradiation with light, a function as a chain transfer agent, a function that bonds with the growth terminal to stop the growth, and a polymerization when light irradiation stops. It is a molecule that functions as a polymerization initiator / termination agent for stopping.

  As a compound having three or more N, N-dialkyl-dithiocarbamylmethyl molecular groups in the same molecule, three or more N, N-dialkyl-dithiocarbamylmethyl molecular groups are bonded as a branched chain to the benzene ring. These are preferred, and specific examples are as follows. That is, as a 3-branched chain, 1,3,5-tri (bromomethyl) benzene and sodium N, N-dithiocarbamate (sodium N, N-dithiocarbamate) can be obtained by addition reaction in ethanol. , 3,5-tri (N, N-dithiocarbamylmethyl) benzene, and four branched chains include 1,2,4,5-tetrakis (bromomethyl) benzene and sodium N, N-dithiocarbamylate ( 1,2,4,5-tetrakis (N, N-dithiocarbamylmethyl) benzene obtained by addition reaction with sodium N, N-dithiocarbamate) in ethanol. Hexakis (N, N-dithio) obtained by addition reaction of bromomethyl) benzene and sodium N, N-dithiocarbamate in ethanol Rubamirumechiru) is a benzene.

  The above iniferter is almost insoluble in polar solvents such as alcohol, but is easily soluble in nonpolar solvents. The nonpolar solvent is preferably a hydrocarbon, an alkyl halide or an alkylene halide, and particularly preferably benzene, toluene, chloroform or methylene chloride, particularly toluene and chloroform.

  Monomers to be polymerized to this iniferter are a cationic monomer and N-isopropylacrylamide, and any of them may be polymerized first. In addition, (meth) acrylate represents an acrylate and / or a methacrylate.

  As the cationic monomer, vinyl monomers, particularly 3-N, N-dimethylaminopropylacrylamide, are suitable.

  To react the iniferter with the above monomer, prepare a raw material solution containing the iniferter and one monomer, and irradiate it with light, whereby the first step reaction product in which the one monomer is bonded to the iniferter Then, the other monomer is block copolymerized with each branched chain of the first step reaction product. As the solvent in this case, the solvent of the above iniferter may be used.

  The concentration of the cationic monomer in the raw material solution is preferably 0.1 M or more, for example, 0.1 to 2.5 M. The concentration of N-isopropylacrylamide or a derivative thereof is preferably 0.1M or more, for example, about 0.1 to 2.5M.

  The concentration of the iniferter is preferably about 0.1 to 100 mM.

200-400 nm is suitable for the wavelength of the light to irradiate. The irradiation time of the light depends on the irradiation intensity, about 1 to 60 minutes are preferred, about 1 to 30 minutes at a low irradiation intensity of about 1μW ^/ cm ² ~10mW ^/ cm 2 is particularly preferred.

  The reaction product produced in the light irradiation step (first light irradiation step) using one monomer is preferably purified, and then preferably dissolved in alcohol and the second light irradiation using the other monomer. Perform the process. As the alcohol, methanol or ethanol, particularly methanol is preferable. The concentration of the first step reaction product in the alcohol solution is preferably about 0.01 mM to 100 mM.

  The polymerization degree of the cationic monomer is particularly preferably 10 to 6000, and the number average molecular weight of the polymer block of N-isopropylacrylamide or a derivative thereof is about 2,000 to 500,000, particularly about 3,000 to 150,000. Is preferred.

  Since the target branched polymer is produced in the reaction solution by this light irradiation, the skin-affinity coating agent comprising the branched polymer can be obtained by purification if necessary.

  The molecular weight of this branched polymer depends on the number of branched chains, but is preferably about 3,000 to 600,000, particularly 3,000 to 150,000, and more preferably about 3,000 to 100,000.

  The branched polymer thus produced has a polymer block of N-isopropylacrylamide or a derivative thereof. This polymer chain of N-isopropylacrylamide or a derivative thereof has a temperature dependency that becomes hydrophilic at a temperature lower than 30 ° C. and hydrophobic at a temperature higher than 30 ° C. It is water insoluble at temperatures above 30 ° C. and water soluble at temperatures below about 30 ° C.

  Therefore, an aqueous solution of an epidermal affinity coating agent having a temperature lower than about 30 ° C., for example, about 10 to 25 ° C. (concentration is preferably about 3 to 150 mg / mL) is attached to a living body or a medical device by application or the like. By raising the temperature to a higher temperature and drying as necessary, a water-insoluble, skin-friendly coating having a cationic polymer block is formed. In the case of a living body, the temperature increase at this time is performed by the body temperature of the living body. Since the formed skin-affinity coating has a plurality of branched chains containing a polymer block of N-isopropylacrylamide or a derivative thereof, it has high adhesion to a living body or a medical device and is difficult to peel off.

  Moreover, the branched polymer produced | generated in this way has a cationic polymer block. Hyaluronic acid or a derivative thereof is supported on the cationic polymer block so as to form an ionic complex. In order to support hyaluronic acid or a derivative thereof on this polymer material, it is preferable to add an aqueous solution of hyaluronic acid or a derivative thereof to a low temperature aqueous solution of the polymer material and mix them.

Examples of the medical device include a dressing material and a urinary catheter. When applied to a medical device, it is preferable to adhere about 0.1 to 30 mg of an epidermal affinity coating agent per 1 cm ² of the surface of the medical device.

Example 1
i) Synthesis of iniferter According to the following reaction formula, 1,2,4,5-tetrakis (NN-diethyldithiocarbamylmethyl) benzene was synthesized as follows.

  2.0 g of 1,2,4,5-tetrakis (bromomethylbenzene) and 12.0 g of sodium N, N-diethyldithiocarbamate were added to 10 mL of ethanol and stirred at room temperature for 4 days under light shielding. The precipitate was filtered, dried under reduced pressure, dissolved in 40 mL of chloroform, 50 mL of water was added, liquid-liquid extraction separation was performed, and sodium bromide was removed. After repeating this operation three times, the chloroform layer was dried with about 10 g of magnesium sulfate for 24 hours, filtered, added with n-hexane, purified by recrystallization, and a slightly light blue-white white Needle-like crystals of 1,2,4,5-tetrasakis (N, N-diethyldithiocarbamylmethyl) benzene were obtained (yield 90%). The starting material peak disappeared by high performance liquid chromatography, and it was confirmed that the purified product was a single substance.

The measurement results of ¹ H NMR (in CDCl ₃ ) are σ7.48 (s, 2H, Ar—H), σ4.57 (s, 2H × 4, Ar—CH ₂ S—), σ4.03 (q, 2H). × 4, N—CH ₂ −, J = 10.7 Hz), σ 3.72 (q, 2H × 4, N—CH ₂ −, J = 10.7 Hz), σ 1.26 to 1.31 (t, 3H) × _8, became _{-CH 2 -CH 3, J = 6.6Hz} ).

ii) Synthesis of cationic homopolymer comprising 4-branched star polymer by photopolymerization According to the following reaction formula, 1,2,4,5-tetrakis [(N, N-diethyldithiocarbamyl) A cationic homopolymer composed of (poly (3-N, N-dimethylaminopropylacrylamide) -methyl] benzene (hereinafter sometimes referred to as pDMAPAAm) was synthesized.

That is, 0.043 g of 1,2,4,5-tetrasakis (N, N-diethyldithiocarbamylmethyl) benzene synthesized by i) above was dissolved in 10 mL of toluene, and 3-N, N-dimethylaminopropylacrylamide was dissolved. 5.2 g of (3-N, N-DMAPAAm) was added and mixed, and the total amount was adjusted to 20 mL with toluene. After purging with high-purity nitrogen gas for 5 minutes with vigorous stirring in a quartz cell, ultraviolet light was irradiated for 10 minutes with a 200 W high-pressure mercury lamp. The irradiation intensity was adjusted to 1 mW / cm ² (250 nm) using an illuminometer (UVR-1, TOPCON, Tokyo, Japan). The polymerization solution is concentrated by an evaporator, and the polymer is purified by reprecipitation with diethyl ether, dissolved in a small amount of water, filtered through a 0.2 μm filter, and lyophilized to obtain a 4-branched star homopolymer 1, A cationic polymer composed of 2,4,5-tetrakis [(N, N-diethyldithiocarbamyl (poly (3-N, N-dimethylaminopropylacrylamide) -methyl) benzene (pDMAPAAm) was obtained (polymerization rate 40 The molecular weight was determined to be 3700 by GPC.

The measurement results of ¹ H NMR (in CDCl ₃ ) are as follows: σ 3.10-3.39 (br, —NH—CH ₂ —), σ 2.25-2.42 (br, —CH ₂ —N (CH ₃ ) _{2), σ2.21 (br, -N} (CH 3) 2), σ1.48-1.76 (br, -CH 2 -CH -, - CH 2 -CH 2 -CH 2 -) became.

iii) Synthesis of polymer material (4-branched pDMAPAAm-b-pNIPAM) by block copolymerization of N-isopropylacrylamide to homopolymer According to the following reaction formula, tetrakis [(N, N-diethyldithiocarbamate) Mill (poly (3-N, N-dimethylaminopropylacrylamide) -block-poly- (N-isopropylacrylamide) -methyl] benzene (hereinafter sometimes referred to as pDMAPAAm-b-pNIPAM) was synthesized. .

  That is, 645 mg of the 4-branched pDMAPAAm homopolymer synthesized in the above ii) was dissolved in 10 mL of methanol, and 1.2 g of N-isopropylacrylamide (NIPAM) was mixed to adjust the total amount to 20 mL with methanol. Polymerization material pDMAPAAm-b-pNIPAM consisting of a block polymer of 4-branched pDMAPAAm and poly N-isopropylacrylamide (pNIPAM) after light irradiation polymerization under the same conditions as in ii) and purification in methanol / diethyl ether system (Polymerization rate 80%) was obtained. The molecular weight was measured to be 9,300 by GPC.

The measurement result of ¹ H NMR (in CDCl ₃ ) is as follows: σ 3.10-3.39 (br, —NH—CH ₂ —), σ 2.25-2.42 (br, —CH ₂ —N (CH ₃ ) ₂ ), σ 2.21 (br, —N (CH ₃ ) ₂ ), σ 1.48-1.76 (br, —CH ₂ —CH—, —CH ₂ —CH ₂ —CH ₂ —), σ 1.08 _{-1.23 (br, -CH- (CH 3} ) 2) became.

iv) Ion complexation with hyaluronic acid Ion complexation was possible by mixing the polymer material synthesized in (iii) above (4-branched pDMAPAAm-b-pNIPAM) and hyaluronic acid in an aqueous solution at about 20 ° C. .

  In order to make the skin affinity treatment agent insoluble or sparingly soluble, the mixing ratio with hyaluronic acid was determined as follows. The relationship between the absorbance and temperature of a solution obtained by dissolving 20 mg of 4-branched pDMAPAAm-b-pNIPAM and hyaluronic acid in 2 mL of water in the range of 0 mg to 200 mg was plotted, and the cloud point was measured. It was confirmed that the cloud point shifted to a low temperature region when the amount of hyaluronic acid introduced was large. In order to be insoluble in water near the human body temperature, the amount of hyaluronic acid had to be about 50 mg or less.

v) Coating treatment 20 mg of the above polymer material (4-branched pDMAPAAm-b-pNIPAM block copolymer) and 15 mg of hyaluronic acid were dissolved in water to adjust the total amount to 2 mL. 10 μL of this solution was homogeneously cast onto a 2 cm × 3 cm square PET film and dried by a dryer to carry out coating treatment. The film was placed on a plate temperature-controlled at 37 ° C., and the contact angle was measured. The contact angle in this state was 15 °, and the hydrophilization phenomenon of the film surface presumed to be caused by hyaluronic acid was confirmed. When this film was continuously washed with warm water at 37 ° C., the contact angle of the surface gradually increased with the washing time and reached a plateau at about 44 °. Although the contact angle of the PET film approached 74 °, it was confirmed that hyaluronic acid was insolubilized and fixed.

Comparative Example 1
(N, N-diethyldithiocarbamylmethyl) benzene was prepared in the same manner as i) of Example 1 except that (bromomethyl) benzene was used instead of 1,2,4,5-tetrakis (bromomethylbenzene). Synthesized. The purified product was a colorless liquid, and the yield was about 93%.

The measurement results of ¹ H NMR (in CDCl ₃ ) are σ7.41 to 7.27 ppm (m, 5H, Ar—H), σ4.54 ppm (s, 2H, Ar—CH ₂ —S—), σ4.08 to 4.01 ppm (q, 2H, N—CH ₂ —), σ 3.72 ppm (q, 2H, N—CH ₂ —), σ 1.25-1.31 ppm (m, 6H, —CH ₂ —CH ₃ ) became.

  Next, a linear block polymer pDMAPAAm-b-pNIPAM having only one linear chain was synthesized according to the above methods ii) and iii), and the coating treatment and water washing on the PET film of (v) above The experiment was conducted. The contact angle increased from 15 ° to 74 ° just by washing lightly at 37 ° C., and it was confirmed that the coated polymer was quickly peeled off from the PET film.

  From the above, the superiority of the branched structure of Example 1 was confirmed. That is, in the skin-affinity coating agent of Example 1, if all of the pNIPAM blocks of a plurality of branched chains in one molecule that are hydrophobically bonded to the material surface do not exfoliate simultaneously from the material surface, the molecules are exfoliated from the material surface. If the remaining branched chain is bonded even if one peels, the branched chain once peeled can be recombined, so it is thought that it is firmly fixed to the material surface. . On the other hand, the linear block polymer synthesized in Comparative Example 1 has only one p-NIPAM polymer chain in one molecule. If this P-NIPAM polymer chain peels from the material surface, the molecule remains as it is. Since it peels from the surface of the material, it is considered weak against the cleaning treatment.

Claims (9)

In the skin affinity coating agent comprising a polymer material carrying hyaluronic acid or a derivative thereof,
The skin affinity coating, wherein the polymer material is hydrophilic at a temperature lower than a predetermined temperature (T) lower than a living body temperature, and is hydrophobic at a temperature higher than the predetermined temperature (T). Agent.   The skin affinity coating agent according to claim 1, wherein the polymer material has a block copolymer chain of a cationic monomer and N-isopropylacrylamide or a derivative thereof.   The skin affinity coating agent according to claim 2, wherein the cationic polymer block has a molecular weight of 2,000 to 500,000.   The epidermal affinity coating agent according to claim 3, wherein the block copolymer has a molecular weight of 3,000 to 600,000.   The skin affinity coating agent according to any one of claims 1 to 4, wherein the predetermined temperature (T) is a temperature of 25 to 35 ° C.   6. The cationic homopolymer according to claim 1, wherein the cationic homopolymer is an iniferter having a compound having three or more N, N-dialkyl-dithiocarbamylmethyl molecular groups in the same molecule. A skin-affinity coating agent characterized by being a branched polymer obtained by light-irradiating living polymerization.   7. The compound having three or more N, N-dialkyl-dithiocarbamylmethyl molecular groups in the same molecule as defined in claim 6, wherein the benzene ring is a nucleus and three or more N, N- A skin-affinity coating agent, wherein a dialkyl-dithiocarbamylmethyl molecular group is bonded.   The epidermal affinity coating agent according to claim 6 or 7, wherein the vinyl monomer is 3-N, N-dimethylaminopropylacrylamide.   A medical device coated with the epidermal affinity coating agent according to any one of claims 1 to 8.