JP2010017361A - Medical adhesive resin composition and medical tape - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an adhesive resin composition having low irritating properties to the skin as a medical adhesive. <P>SOLUTION: The medical adhesive resin composition contains polyhydroxyalkanoic acid, which is preferably produced by microbes. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a medical pressure-sensitive adhesive resin composition excellent in biocompatibility used in medical tapes and the like and a medical tape.

  Adhesives can be bonded to other surfaces with light pressure such as light finger pressure without the need for activation such as solvent and heat, and when peeling it again, it can be easily done without contaminating the adherend. It is an adhesive that can be peeled off. Further, medical adhesives represented by bandages and the like are required to have low adhesion to the skin and skin irritation. The pressure-sensitive adhesive is characterized by having viscoelastic behavior that tends to cause a flow with respect to an external force in order to realize adhesion with a weak pressure or the like. Therefore, a softener is mixed with the polymer as the base resin. Further, a tackifier may be added to impart tackiness, and a filler or the like may be added to improve cohesion.

  Conventionally, styrene butadiene rubber (SBR) type and acrylic resin type are known as base resins for medical adhesives from the viewpoint of viscoelasticity and cohesive strength. SBR can express adhesiveness by mixing various tackifiers, and has been the mainstream of adhesives for a long time. For example, this technique is disclosed in Patent Document 1.

On the other hand, in recent years, acrylic resins have been used as a base resin for medical adhesives. Acrylic resin not only has weather resistance and chemical resistance not found in SBR systems, but also has the advantage of being able to design adhesion to the adherend surface by copolymerizing any acrylic monomer. is doing. Therefore, the function of a tackifier can be expressed only with an acrylic resin. This technique is disclosed in Patent Document 2 and Patent Document 3.
JP-A-8-294528 Japanese Unexamined Patent Publication No. 63-309572 JP-A-8-103490

  Low irritation to the skin is essential as a required characteristic of adhesives for medical use. However, as long as the SBR resin or acrylic resin is used as a base, it is inevitable that a very small amount of unreacted monomer or oligomer or polymerization initiator residue is mixed. In particular, those who are sensitive to chemical substances have a problem that rash and inflammation occur even if the pressure-sensitive adhesive is made as low as possible.

  In order to obtain a hypoallergenic medical adhesive, a residual monomer or initiator residue-free base resin is required. The present invention has focused on polyhydroxyalkanoic acid (PHA), which is a polyester synthesized by microorganisms. By using polyhydroxyalkanoic acid whose copolymer composition is controlled to maintain viscoelasticity and cohesion as an adhesive base resin as a medical adhesive, it provides a low-irritant adhesive composition for the skin. is there.

  That is, this invention is a medical adhesive resin composition containing (1) polyhydroxyalkanoic acid. In this polyhydroxyalkanoic acid, the molar fraction of 3-hydroxybutanoic acid units in the polyhydroxyalkanoic acid is preferably 10 mol% or less, the weight average molecular weight is 10,000 or more, and the glass transition temperature is −20. It is preferable that it is below ℃. The polyhydroxyalkanoic acid preferably contains 0.1 mol% or more of a monomer unit having a double bond.

(2) Such polyhydroxyalkanoic acid can be obtained by any method, and is particularly preferably a polyhydroxyalkanoic acid produced by a microorganism. Is preferably a microorganism belonging to the genus Psuedomonas, and further, Pseudomonas putida or Pseudomonas sp. It is preferably at least one selected from SG4502 (Accession Number: NITE P-578).
(3) In addition, the polyhydroxyalkanoic acid of the present invention can be obtained from Pseudomonas sp. SG4502 (Accession Number: NITE P-578) may be produced by a genetically engineered product into which a polyhydroxyalkanoate synthase gene has been introduced, and Pseudomonas sp. It may be produced using a polyhydroxyalkanoate polymerizing enzyme derived from SG4502 (Accession Number: NITE P-578).

(4) Further, the present invention is a medical product in which a pressure-sensitive adhesive layer formed by using the medical pressure-sensitive adhesive resin composition containing polyhydroxyalkanoic acid obtained as described above is formed on a film substrate. Includes tapes for use.

  ADVANTAGE OF THE INVENTION According to this invention, it becomes possible to provide the medical adhesive composition excellent in biocompatibility, ie, the low irritation with respect to skin, maintaining the adhesive force as a medical adhesive.

  The medical pressure-sensitive adhesive resin composition of the present invention is based on polyhydroxyalkanoic acid that can be synthesized by microorganisms and has excellent biocompatibility.

  Polyhydroxyalkanoic acid is a kind of polyester and is a microbial energy storage material. It is known that microorganisms accumulate as polyhydroxyalkanoic acid in the microbial cells when there are abundant nutrient sources outside the microbial cells. Microorganisms survive by depleting and metabolizing polyhydroxyalkanoic acid in the body when nutrients outside the cells are depleted. This polyhydroxyalkanoic acid is the only biopolymer having thermoplasticity, and is expected to be used industrially.

  However, the physical properties vary greatly depending on the structure of the monomer unit constituting this polyhydroxyalkanoic acid, that is, the individual hydroxyalkanoic acid. For example, polyhydroxyalkanoic acid having a 3-hydroxybutanoic acid unit as a main constituent monomer unit is crystalline. It has high properties and low flexibility, and its use as an adhesive is limited.

  The polyhydroxyalkanoic acid used in the present invention can be synthesized by a microorganism synthesis method, a biochemical synthesis method using an enzyme or the like, or a chemical synthesis method. Examples of the chemical synthesis method include a method in which a fatty acid lactone such as (R) -β-butyrolactone, ε-caprolactone, and δ-valerolactone is synthesized by a ring-opening polymerization method under a catalyst. From the viewpoint of excellent biocompatibility, it is preferable to use a synthesis method using a microorganism or a biochemical synthesis method. The synthesis method using a microorganism will be described below.

  In order to synthesize polyhydroxyalkanoic acid by a microorganism, it can be performed by culturing the microorganism under a condition in which a carbon source is excessively supplied and nitrogen, phosphorus and the like are limited to some extent. As the culture apparatus, a jar fermenter capable of controlling temperature, pH, dissolved oxygen amount and the like can be used. Prior to culturing, a medium containing a carbon source and other nutrients is preliminarily heat sterilized to prevent contamination by unintended microorganisms.

  Examples of microorganisms that synthesize polyhydroxyalkanoic acids include Pseudomonas putida, Pseudomonas oleovorans, Psuedomonas lauros genus, Pseudomonas citrus genus, and Pseudomonas renus Alkaligenes genus microorganisms such as Alcaligenes faecalis and Alcaligenes eutrophus are known. Among them, microorganisms belonging to the genus Pseudomonas are preferable. Domonas putida was further isolated from around the biodiesel fuel (BDF) production equipment as a new microbial strain by the applicant, and on June 2, 2008, it became an independent administrative agency, Product Evaluation Technology Foundation, Patent Microorganism Depositary Center. “Pseudomonas sp. SG4502” deposited under the deposit number NITE P-578 can be preferably used.

  There are no particular restrictions on the carbon source used during the cultivation, but acetic acid, propionic acid, butanoic acid, hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, acrylic acid, crotonic acid, 2-pentenoic acid, 2-hexenoic acid , Organic acids such as 2-heptenoic acid, 2-octenoic acid, 2-nonenoic acid, 2-decenoic acid, oils and fats, glycerin, alcohols, glucose, fructose, sucrose, sugars such as waste molasses, or biodiesel fuel by-products (BDFB) and this neutralized product are preferably used. Among these, a neutralized product of biodiesel fuel by-product (BDFB) is preferable in that a monomer unit having a double bond can be introduced into the resulting polyhydroxyalkanoic acid, as will be described later.

  The monomer unit of the polyhydroxyalkanoic acid produced can be adjusted depending on the carbon source used, for example, glycolic acid, lactic acid, 3-hydroxybutanoic acid, 4-hydroxybutanoic acid, malic acid, 3-hydroxyvaleric acid , Citric acid, 3-hydroxyhexanoic acid, 6-hydroxyhexanoic acid, 3-hydroxyheptanoic acid, 3-hydroxyoctanoic acid, 3-hydroxynonanoic acid, 3-hydroxydecanoic acid, 3-hydroxyundecanoic acid, 3-hydroxydodecane Examples of such monomer units include acids, and some of these monomer units may be selected from 3-hydroxyhexenoic acid, 3-hydroxyheptenoic acid, 3-hydroxyoctenoic acid, 3-hydroxynonenoic acid, 3-hydroxydecenoic acid, Such as 3-hydroxydodecenoic acid and 3-hydroxyundecenoic acid Carbon Una side chains - may be a monomer unit to be a form having a carbon double bond. The resulting polyhydroxyalkanoic acid is a copolymer of one or more such monomer units.

  As the medium for culturing, a complete medium or a synthetic medium such as LB medium, M9 medium, etc. is used, and the polyhydroxyalkane is cultured aerobically at pH 7-9, 30-50 ° C. for about 4 to 48 hours. Accumulate acid in cells. The polyhydroxyalkanoic acid is then recovered.

  In the recovery, first, the culture solution after completion of the culture is subjected to solid-liquid separation using a centrifuge or the like to recover the bacterial cell components. The polyhydroxyalkanoic acid can be recovered from the microorganisms by separating the polyhydroxyalkanoic acid component by lysozyme treatment or hypochlorous acid treatment to dissolve the bacterial cell component, or by using a Soxhlet extractor such as chloroform or methylene chloride. Solvent extraction can be used. The polyhydroxyalkanoic acid thus obtained can be purified by reprecipitation treatment or the like.

  The polyhydroxyalkanoic acid used in the present invention is not limited to the above-described method of producing by a microorganism, but, for example, a PHA synthase isolated from a novel strain “Pseudomonas sp. SG4502” (this PHA synthase is C3 Those classified as PHA synthase I showing substrate specificity for hydroxyacyl-CoA having a short chain length of about -6 and PHA synthase II showing substrate specificity for hydroxyacyl-CoA having a medium chain length of about C6-12 Can be produced by a recombinant gene introduced into another microorganism, or can be biochemically synthesized using an isolated enzyme. Biochemical synthesis can be obtained, for example, by reacting a carbon source serving as a substrate with CoA, acyl CoA synthetase, hydratase and the like in the presence of the above-described isolated PHA polymerase. A series of operations such as isolating a gene encoding PHA synthase and introducing it into other microorganisms can be achieved according to known means.

  Since the polyhydroxyalkanoic acid used in the present invention is used as a pressure-sensitive adhesive, it preferably has viscoelasticity. Therefore, when the 3-hydroxybutanoic acid unit which expresses high crystallinity is included, the molar fraction in the polyhydroxyalkanoic acid is preferably 10 mol% or less. This is because if the amount of 3-hydroxybutanoic acid monomer unit is too large, the crystallinity increases and it becomes difficult to obtain fluidity as an adhesive.

  Further, the weight average molecular weight of the polyhydroxyalkanoic acid used in the present invention is preferably 10,000 or more, more preferably 50,000 or more, and particularly preferably 100,000 or more. The upper limit is not particularly limited, but is usually 1 million or less. If the molecular weight is too low, the pressure-sensitive adhesive has insufficient cohesive force, causing a cohesive failure of the pressure-sensitive adhesive layer, and there is a problem that the pressure-sensitive adhesive layer remains on the adherend surface (skin etc.) during peeling. The weight average molecular weight can be measured by gel permeation chromatography and calculated using a standard polystyrene calibration curve.

  Further, the glass transition temperature of the polyhydroxyalkanoic acid of the present invention is preferably −20 ° C. or lower, more preferably −30 ° C. or lower, and particularly preferably −35 ° C. or lower. Although there is no particular lower limit, it is usually set to −100 ° C. or higher. When the glass transition temperature is too high, there is a problem that the pressure-sensitive adhesive becomes in a glass state, fluidity and adhesive strength are insufficient, and it does not function as a pressure-sensitive adhesive. The glass transition temperature can be measured with a differential scanning calorimeter (DSC).

  As the polyhydroxyalkanoic acid of the present invention, those having a double bond introduced into the side chain of the monomer unit can be preferably used. Polyhydroxyalkanoic acid in which a double bond is introduced into the side chain of such a monomer unit may be used as it is, but for example, when there is a problem in the cohesive strength of the adhesive due to insufficient molecular weight, Crosslinking or chain extension may be performed using heat or light in the presence of heat or a photopolymerization initiator, and adhesiveness and the like can be improved.

  Although there is no restriction | limiting in the crosslinking agent and initiator to be used, As a crosslinking agent, the monomer, bismaleimide, etc. which have several acryloyl groups and methacryloyl groups can be used. Further, the content of the monomer unit having a double bond in the polyhydroxyalkanoic acid is preferably 0.1 mol% or more, and preferably 30 mol% or less. This is because if the content is too small, crosslinking or chain extension is difficult, and if the content is too large, it is difficult to obtain a uniform crosslinking reaction product. There is no problem even if the unit content exceeds 30 mol%.

  As the medical adhesive resin composition, the polyhydroxyalkanoic acid may be used as it is, but if necessary, a tackifier (tackifier), a plasticizer, and a filler may be blended and used. . As the tackifier, rosin, rosin derivative, coumarone / indene resin, polyterpene resin, phenol resin, petroleum hydrocarbon resin and the like can be used. As the plasticizer, mineral oil, liquid polybutene, liquid polyacrylate, phthalate such as lanolin, dibutyl phthalate, and the like can be used. As the filler, zinc oxide, aluminum hydroxide, titanium oxide, calcium carbonate, clay and the like can be used.

  Although there is no restriction | limiting in particular in the ratio of each component, When other components are included, it is preferable to make polyhydroxyalkanoic acid in all compositions into 10 mass% or more, and it is more preferable to set it as 10-80 mass%.

  The medical pressure-sensitive adhesive composition according to the present invention has sufficient adhesiveness, and it is possible to eliminate irritation to the skin by using polyhydroxyalkanoic acid which is a biological material.

  The medical tape of this invention can be obtained by forming the adhesive layer formed using the said medical adhesive resin composition on a film base material. The production method is not particularly limited, and various known methods can be used.

  The substrate is not particularly limited, and various materials such as a polyvinyl chloride film, a polyethylene film, a polyester film, a polypropylene film, an ethylene-propylene copolymer film, and an ethylene-vinyl acetate copolymer film can be used. .

  The thicknesses of the pressure-sensitive adhesive layer and the base material layer are not particularly limited, but are generally about 10 μm to 5000 μm, respectively.

(1) Preparation of polyhydroxyalkanoic acid First, polyhydroxyalkanoic acid was prepared by the culture method as follows.

The NR medium and MS medium used for the culture are as follows.

(Table 1)
Composition of NR medium (in 1L of medium)
Bacto East Extract 3g
Bacto peptone 10g
Erlich Skipjack Extract 10g
(Table 2)
Composition of MS medium (in 1 L of medium)
Disodium hydrogen phosphate 3.6g
Potassium dihydrogen phosphate 1.5g
Ammonium chloride 0.5g
Magnesium sulfate heptahydrate 0.0104g
Trace element aqueous solution 0.05mL
Next, “Pseudomonas sp. SG4502” was inoculated into 2 mL of NR medium and cultured at 45 ° C. for 8 hours, and then the culture was inoculated into 100 mL of fresh NR medium and cultured overnight with shaking. 60 mL of this culture solution was added to an Erlenmeyer flask (manufactured by Iwaki) containing 1.2 L of MS medium, and cultured with shaking at 45 ° C. A carbon source was added at 1% (wt / vol) at the start of the culture and at 12, 24, and 36 hours. As the carbon source, sodium dodecanoate, sodium octoate, sodium acetate, and neutralized BDFB were used. After culturing each for 48 hours, the cells were collected by centrifugation at 4 ° C. and 8000 × g for 15 minutes, washed with 20% ethanol aqueous solution, 100% ethanol aqueous solution and distilled water in this order, and then freeze-dried. To obtain dry cells. The results are shown in Table 3.

  Each dried microbial cell obtained above was subjected to extraction of polyhydroxyalkanoic acid using a Soxhlet extractor (manufactured by Shibata) using chloroform as a solvent, and then the solvent was removed by an evaporator and dried under reduced pressure to give a product ( Polyhydroxyalkanoic acid) was obtained. The amount of polyhydroxyalkanoic acid obtained is shown in Table 3.

Then the molecular structure of the polyhydroxyalkanoate obtained in the above was confirmed by ^{1 H-NMR} using a nuclear magnetic resonance method (NMR). NMR measurement, using MSL400 spectrometer (manufactured by ^Bruker), was carried out at 25 ° C. at a frequency of 400MHz to ¹ H. ¹ H-NMR spectra of sodium dodecanoate, sodium octoate, sodium acetate, and neutralized BDFB, respectively, as a carbon source and the resulting product are shown in FIGS. 1-4, all the products are polyhydroxyalkanoic acid, and polyhydroxyalkanoic acid containing no unsaturated bond when sodium dodecanoate, sodium octoate, or sodium acetate is used as a carbon source. In contrast, when neutralized BDFB was used as a carbon source, a monomer unit having an unsaturated bond was introduced, and the resulting polyhydroxyalkanoic acid had a monomer unit having no unsaturated bond. It was found to be a polymer composed of monomer units having unsaturated bonds.

  Further, the results of measuring the molecular weight of the obtained polyhydroxyalkanoic acid are shown in Table 3. The molecular weight was measured by gel permeation chromatography (GPC). The measurement was performed by connecting two TSKgel SuperHZM-H columns (6.0 nm ID × 150 mm; manufactured by Tosoh Corporation) in series and using chloroform as the mobile phase. , 40 ° C., and a flow rate of 0.3 mL / min. A calibration curve was prepared using pure polystyrene, and each number average molecular weight (Mn), each weight average molecular weight (Mw) and molecular weight distribution (Mn / Mw) were calculated.

  Furthermore, the composition of the monomer unit constituting the polyhydroxyalkanoic acid obtained above was analyzed by gas chromatography. The measurement method and conditions are as shown below. First, each polyhydroxyalkanoic acid was dissolved in a mixed solution of 2 mL of 15 wt% methanol sulfate solution and 2 mL of chloroform and treated at 100 ° C. for 140 minutes for alcoholysis. After cooling, 1 mL of ultrapure water was added and mixed well, allowed to stand and separated into two layers. This lower layer was recovered, and insolubles were removed by filtration through a filter. Of these, 0.5 mL and 0.5 mL of a chloroform solution containing 0.1 vol% methyl caprylate were mixed, and the temperature was analyzed with a capillary gas chromatograph GC-2010 (manufactured by Shimadzu Corporation) equipped with FID. The methyl esterified product of the unit was identified. As the column, a fused silica capillary column DB-5 (column inner diameter 0.25 mm, liquid layer film thickness 0.25 μm, column length 30 m; manufactured by Shimadzu Corporation) was used. The analysis was performed under the analysis conditions of an initial temperature of 90 ° C. for 5 minutes, a heating rate of 5 ° C./minute, and a final temperature of 250 ° C. for 2 minutes. The results are shown in Table 4. In Table 4, 3HB, 3HHx, 3HO, 3HD, and 3HDD represent 3-hydroxybutanoic acid (C4), 3-hydroxyhexanoic acid (C6), 3-hydroxyoctanoic acid (C8), and 3-hydroxy, respectively. Decanoic acid (C10) and 3-hydroxydodecanoic acid (C12) are shown.

Further, the glass transition temperature of polyhydroxyalkanoic acid prepared using sodium dodecanoate as a carbon source was measured with a differential scanning calorimeter, which was −45 ° C., and other polyhydroxyalkanoic acids had almost the same glass transition. Shown the temperature.

(2) Preparation of pressure-sensitive adhesive Next, a pressure-sensitive adhesive was prepared using the obtained polyhydroxyalkanoic acid.

Example 1
60 g of each obtained polyhydroxyalkanoic acid was dissolved in 40 g of acetone to obtain a medical pressure-sensitive adhesive resin composition, which was applied to a 50 μm-thick PVC film so that the dry film thickness was 20 μm and dried. Thus, an adhesive film was obtained. Three pieces of the obtained adhesive film cut into 2 cm squares were attached to the inside of the upper arm, the abdomen, and the thigh, respectively. Each adhesive film showed good adhesion to the skin and was not peeled off by sweat or the like. In addition, when peeled after 24 hours, no adverse effects on the living body such as inflammation or adhesive residue on the skin were observed.

Example 2
Using 60 g of each obtained polyhydroxyalkanoic acid, 20 g of a polyterpene resin as a tackifier and 20 g of dibutyl phthalate as a plasticizer are dissolved in 60 g of methyl ethyl ketone, applied to a 50 μm thick PVC film and dried. When an adhesive film was obtained in the same manner as in Example 1 and evaluated in the same manner, all of the adhesive films showed good adhesion to the skin and were not peeled off by sweat or the like. In addition, when peeled after 24 hours, no adverse effects on the living body such as inflammation or adhesive residue on the skin were observed.

Using "Pseudomonas sp. SG4502", there FIG shows a ¹ H-NMR spectrum of polyhydroxyalkanoate prepared sodium dodecanoate as a carbon source. It is a figure which shows the < ¹ > H-NMR spectrum of the polyhydroxy alkanoic acid prepared using "Pseudomonas sp. SG4502" and using sodium octanoate as a carbon source. It is a figure which shows the < ¹ > H-NMR spectrum of the polyhydroxy alkanoic acid prepared using "Pseudomonas sp. SG4502" and using sodium acetate as a carbon source. It is a figure which shows the < ¹ > H-NMR spectrum of the polyhydroxyalkanoic acid prepared using "Pseudomonas sp. SG4502" and using neutralized BDFB as a carbon source.

Claims (11)

  A medical adhesive resin composition comprising polyhydroxyalkanoic acid.   The medical adhesive resin composition according to claim 1, wherein a molar fraction of 3-hydroxybutanoic acid units in the polyhydroxyalkanoic acid is 10 mol% or less.   The medical pressure-sensitive adhesive resin composition according to claim 1 or 2, wherein the polyhydroxyalkanoic acid has a weight average molecular weight of 10,000 or more.   The medical adhesive resin composition according to any one of claims 1 to 3, wherein the polyhydroxyalkanoic acid has a glass transition temperature of -20 ° C or lower.   The medical adhesive resin composition according to any one of claims 1 to 4, wherein the polyhydroxyalkanoic acid contains a monomer unit having a double bond in an amount of 0.1 mol% or more.   The medical pressure-sensitive adhesive resin composition according to any one of claims 1 to 5, wherein the polyhydroxyalkanoic acid is produced by a microorganism.   The medical pressure-sensitive adhesive resin composition according to claim 6, wherein the polyhydroxyalkanoic acid is produced by a microorganism belonging to the genus Psuedomonas.   The polyhydroxyalkanoic acid may be Pseudomonas putida or Pseudomonas sp. The medical adhesive resin composition according to claim 7, which is produced by at least one selected from SG4502 (Accession Number: NITE P-578).   The polyhydroxyalkanoic acid is Pseudomonas sp. The medical adhesive resin composition according to any one of claims 1 to 5, which is produced by a genetically modified product into which a polyhydroxyalkanoate polymerizing enzyme gene of SG4502 (accession number: NITE P-578) is introduced.   The polyhydroxyalkanoic acid is Pseudomonas sp. The medical adhesive resin composition according to any one of claims 1 to 5, which is produced using a polyhydroxyalkanoate polymerizing enzyme derived from SG4502 (Accession Number: NITE P-578).   The medical tape formed by forming the adhesive layer formed using the medical adhesive resin composition in any one of Claims 1-10 on a film base material.

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