JPH0363061A - Medical adhesive - Google Patents

Abstract

PURPOSE:To obtain an adhesive for medical use having a good adhesion with a silicone product and with living body and a rapid curing speed when an operation is performed by using a specified alkoxysilane resin. CONSTITUTION:An adhesive is a one in which an alkoxysilyl group is introduced to each NCO group of all or a part of NCO groups in an NCO-terminated hydrophilic urethane prepolymer. As the NCO-terminated hydrophilic urethane prepolymer, a urethane prepolymer prepd. by reacting a polyisocyanate with a hydrophilic polyether polyol is cited. Introduction of the alkoxysilyl group is done by reacting an alkoxysilane of formula (I) with an NCO group. As the hydrophilic polyether polyol, an adduct of a compd. having at least two active hydrogens (polyols, polyvalent phenols etc.), with ethylene oxide, and if necessary, another alkylene oxide is cited.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a medical adhesive using an alkoxysilane resin.

[Prior Art] Conventionally, as medical silicone adhesives, one-component room-temperature curing type 5ILASTIC Medical Adheses have been used.
iveSllllcone Type A (manufactured by Dow Corning) was known.

[Problems to be solved by the invention] However, the 5ILs that have been used in the medical field
ASTIC Medical Adhesive 5ll
lcone Type A has excellent adhesion between silicone products when using silicone implant products, but is not satisfactory in terms of adhesion to a living body filled with body fluids. In addition, there were practical problems when used in surgical operations that require a long curing reaction time and prompt treatment. Therefore, this adhesive has been used only as an auxiliary means for bonding surgical silicone products.

[Means for Solving the Problems] When performing surgery using a silicone product, the present inventors
The present invention was achieved as a result of extensive research aimed at obtaining a medical adhesive that not only adheres well to silicone products but also adheres well to living organisms and has a quick curing time.

That is, the present invention is a medical adhesive in which alkoxysilyl groups are introduced into all or part of the NCO groups of an NCO-terminated hydrophilic urethane prepolymer.

Examples of the NCO-terminated hydrophilic urethane prepolymer in the present invention include the urethane prepolymers described in JP-A-82-148G6Ei and Japanese Patent Application No. 83-52918. That is, examples include urethane prepolymers made from polyisocyanates and hydrophilic polyether polyols (and other polyols as necessary).

Examples of polyisocyanates include fluorine-containing polyisocyanates (as exemplified in JP-A No. 57-108055), and the general formula OCN llCH2Rt C1h・NCO (where R `` is a carbon number of 1 to 20 perfluoroalkylene groups, including those containing one or more ether bonds), aromatic polyisocyanates [tolylene diisocyanate (TDI), diphenylmethane diisocyanate (
MDI), P-phenylene diisocyanate (PPDI)
), naphthylene diisocyanate, xylylene diisocyanate, etc., aliphatic polyinsyanate (hexamethylene diisocyanate, lysine diisocyanate, etc.),
Examples include alicyclic polyisocyanates (dicyclohexylmethane diisocyanate, isophorone diisocyanate, etc.), and mixtures thereof. These polyisocyanates are crude polyisocyanates such as crude TDI
, crude MDI [phosgene compound of crude diaminodiphenylmethane: polyaryl polyisocyanate] (PAP
I) It can also be used as

or modified polyisocyanates such as liquefied MDI.
It can also be used as, or in combination. Among these, preferred are fluorine-containing polyisocyanates.

Hydrophilic polyether polyols used in the production of NCO-terminated hydrophilic urethane prepolymers include compounds having at least two active hydrogens (polyols, polyhydric phenols, etc.) and ethylene oxide (hereinafter abbreviated as EO).
and, if necessary, adducts with other alkylene oxides (hereinafter the alkylene oxides will be abbreviated as AO).

Polyols include dihydric alcohols (ethylene glycol, propylene glycol, 1, 3- or 1,4-
Butylene glycol, neopentyl glycol, hydrogenated bisphenol A1, hydrogenated bisphenol F1, polytetramethylene glycol, polyester diol, terminal silanol polysiloxane compound, etc.), trihydric alcohol (trimethylolpropane, 1,2,4-butanetriol, 1, 2.6-hexanetriol, glycerin, polyester triol, etc.), tetra-hetahydric alcohol (
diglycerin, pentaerythritol, sorbitol,
sucrose, etc.). Examples of polyhydric phenols include bisphenols (bisphenol A1, bisphenol F1, bisphenol S, etc.). Among these, dihydric alcohols are preferred.

As AO, alkylene oxides having 3 to 4 carbon atoms, such as propylene oxide (hereinafter abbreviated as PO), butylene oxide (1,2-, 1,3-, 2,3- and 1.4
-butylene oxide) and two or more thereof. Among these, preferred is PO. EO and AO
When used in combination, a random copolymer, a block copolymer, or a mixture of both may be used. Preferably it is a random copolymer. The equivalent weight (molecular weight per hydroxy group) of hydrophilic polyether polyol is usually 100
-5,000°, preferably 200-3,000°. The oxyethylene content in the hydrophilic polyether polyol is usually 30% by weight or more, preferably 50 to 90% by weight.

When the oxyethylene content is less than 30% by weight, the hydrophilic ability decreases, so the reactivity with body fluids decreases and the curing speed becomes slow.

Other polyols that may be used along with the hydrophilic polyether polyol include low molecular weight polyols and/or
or hydrophobic polyols. Specific examples thereof include the polyols mentioned above (mentioned as raw materials for the R aqueous polyether polyol) and their AO adducts.

When other polyols are used in combination with the hydrophilic polyether polyol, the oxyethylene content in the total polyol is usually 30% by weight or more, preferably 50 to 90% by weight. The equivalent weight of the entire polyol (average) is usually too ~ 5
,000. Preferably it is 200-3,000.

A conventional method may be used to react polyisocyanates and polyether polyols to obtain an NCO-terminated hydrophilic urethane prepolymer, and the reaction may be carried out in the presence of a catalyst.

In the present invention, the alkoxysilanes for introducing an alkoxysilyl group include -film type % formula %) R is a hydrogen atom, an aliphatic and/or alicyclic and/or aromatic hydrocarbon having 1 to 10 carbon atoms; residue, U is 1
or 2, R1 is an alkyl residue having 1 to 4 carbon atoms, R2 is -(C
H20hO), -R', -Go-R', alkyl residue having 1 to 4 carbon atoms, m is 1 to 301, n is 1 to 8, p is 1 to 3, q is O to 2, and p+q is 3 or less. ) is a compound represented by

The reaction rate between the NCO-terminated hydrophilic urethane prepolymer and the alkoxysilane is
Alkoxysilanes are added so that 3% or more of the O groups, preferably 10 to 60%, are reacted. The reaction between the urethane prepolymer and the alkoxysilanes can be carried out by a conventional method.
The reaction may be carried out in the presence of a catalyst.

The medical adhesive of the present invention may also contain a silicone resin, a filler, a physiologically active drug, and the like, if necessary. Examples of the silicone resin include dimethylpolysiloxane, methylphenylborinoxane, fluorosilicone, amine-modified silicone, alkylaryl-modified silicone, and silane coupling agent. Fillers include inorganic powders such as lime powder, alumina powder, glass powder, kaolin, talc, calcium carbonate, barium aluminosilicate glass, titanium oxide, and colloidal silica; acrylic resins such as polymethyl acrylate and polymethyl methacrylate. powder; and organic-inorganic composite filler. Physiologically active drugs may be oil-soluble drugs, water-soluble drugs, powders, etc., and are not particularly limited, but include bactericides, local narcotics, antihistamines, anti-inflammatory analgesics, antibiotics, astringents, vitamins, Examples include antifungal agents, peripheral nerve paralyzing agents, blood circulation promoters, hormones, herbal medicine extracts/tinctures, herbal medicine powders, antihypertensive agents, and antianginal agents. The blending amount of these silicone resins, fillers, physiologically active drugs, etc. is usually 0 to 30%, preferably 0 to 10%, based on the weight of the medical adhesive of the present invention.
It is.

The medical adhesive of the present invention causes a reaction in the presence of a small amount of moisture, such as moisture in the air, and forms a strong film, so it is necessary to use anhydrous not only the main ingredient but also other compounding ingredients. Therefore, it is preferable to keep air out during manufacturing. The obtained medical adhesive can be stored for a long period of time, for example, by filling it into a container such as an ampoule that is sealed from air.

When using the medical adhesive of the present invention, application methods include, for example, a method using a brush, tweezers, a special spatula, and a method using a spray using Freon or nitrogen gas. Direct adhesion method in which the adhesive is applied directly to the affected area; Dacron, oxidized cellulose, collagen, chitin, polyurethane, polyester, polyvinyl alcohol, etc., and thin cloth or cotton-like materials such as veins, fascia, and muscles. Examples include a covering adhesion method in which a piece of biological tissue such as 100% is applied to the affected area and the present medical adhesive is applied.

In addition, the medical adhesive of the present invention utilizes its flexibility and bondability with living tissue to be used as a coating material for aneurysms, protective treatment of burns, labral wounds, etc., or as a sealing material for cerebrospinal fluid leakage, etc. It can be used as a sealing material by applying it to the affected area or by injecting it using a catheter or the like.

[Examples] The present invention will be further explained below with reference to Examples and Comparative Examples, but the present invention is not limited thereto. In the following, PPG is polypropylene glycol. The NCO-terminated hydrophilic urethane prepolymer was obtained by mixing and stirring polyisocyanates and polyether polyol dehydrated under reduced pressure, and reacting the mixture at a temperature of 80° C. for 8 hours.

Parts and % in Examples and Comparative Examples indicate parts by weight and % by weight, respectively.

Example 1 00N-CIh(CF2)acH2・NCO and polyether polyol (EO/PO random copolymer, average molecular weight 3°000, oxyethylene content ff180%) were reacted to produce an NCO-terminated hydrophilic urethane prepolymer. I got it.

30% of the NCO groups in this prepolymer react with γ-
Add aminopropyltrimethoxysilane and add 4 more
A medical adhesive was obtained by a time reaction.

A medical silicone rubber sheet for implants (2 crn x 3 cm) was placed in the small intestine of the rat, and fixed using the present medical adhesive to prevent displacement. The curing reaction was completed 5 minutes after application. The adhesive showed sufficient adhesion to the silicone rubber sheet and the living body.

Example 2 0CN-CH2(CF2)acH2・NCO was reacted with polyether polyol (E O/P O random copolymer, average molecular weight 4°000, oxyethylene content M60%) to produce an NCO-terminated hydrophilic urethane pret. A polymer was obtained.

50% of the NCO groups in this prepolymer react with γ-
Add aminopropyltrimethoxysilane and add 4 more
A medical adhesive was obtained by a time reaction.

According to the evaluation method of Example 1, the adhesion of the silicone rubber sheet to rats was investigated. The curing reaction was completed 5 minutes after application. The adhesive showed sufficient adhesion to the silicone rubber sheet and the living body.

Example 3 TDI and polyether polyol (EO/PO random copolymer, average molecular weight 3,000, oxyethylene content 80%) were reacted to obtain an NCO-terminated hydrophilic urethane prepolymer. γ-Mercaptopropyltrimethoxysilane with which 20% of the NCO groups in this prepolymer reacted was added, and the reaction was further carried out for 8 hours to obtain a medical adhesive.

A full-thickness defective layer of the rat's back skin was surgically created under anesthesia, and the affected area was covered with a medical silicone rubber sheet around which a medical adhesive was applied. After 5 minutes of covering, sufficient adhesive strength was observed between the silicone rubber sheet and the living body.
I was able to protect the affected area.

Comparative Example 1 5ILASTIC Medica manufactured by Dow Corning
lAdheslve 5ilicone Type A
The adhesion between a silicone rubber sheet and a living body was investigated according to Example 3. It did not harden even after 30 minutes after application. Observation after 24 hours showed that although the adhesion to the silicone rubber sheet was good, sufficient adhesion was not observed to the living body.

Comparative Example 2 0CN・0112 (CF2)4'CH2・NCO and polyether polyol (EO/PO random copolymer,
Average molecular weight 3°000, oxyethylene content 80%)
A medical adhesive made of an NCO-terminated hydrophilic urethane prepolymer was obtained.

According to the evaluation method of Example 3, the adhesion of the silicone rubber sheet to rats was investigated. The curing reaction was completed 5 minutes after application. Although sufficient adhesion of the adhesive to living organisms was observed, almost no adhesion was observed to the silicone rubber sheet, and interfacial peeling occurred after curing.

[Effects of the Invention The medical adhesive of the present invention has the following effects. i.e. silicone medical devices (e.g. catheters,
Drain tubes, sheets, cannulae, artificial joints,
In surgical operations using artificial bones, artificial breasts), ■
It has the effect of providing certainty and reliability in surgical operations because of its reliable adhesion between living bodies and silicone products, (1) fast curing time, and (2) being a flexible curing composition that can follow the movements of living bodies.

Conventionally, medical adhesives have been used as a means of suturing during surgical operations.
Recently, it has attracted attention due to its many advantages such as reliable hemostasis at bleeding sites. On the other hand, although silicone medical devices (e.g. catheters, drain tubes, sheets, cannulae, artificial joints, artificial bones, artificial breasts) have been widely used in surgical procedures, conventional medical adhesives However, it was intended for either silicone medical devices or living organisms, and could not be used for either.

From the above points, the application of the adhesive of the present invention to surgeries using silicone medical tools makes it possible to use a suturing technique using an adhesive technique in addition to the conventional suture technique, thereby reducing surgical time. Significant medical benefits include shortening, prevention of bleeding, prevention of leakage of enzymes from the digestive tract, avoidance of stenosis accidents in the smallest blood vessels, reinforcement of nerve junctions, temporary fixation prior to suturing, and certainty by using sutures and adhesives together. Improvements in technology are seen to be effective. In addition, it is effective in providing high reliability and high performance not only in surgery but also in all medical fields, such as bonding wounds and incisions, and treatment by gradually releasing drugs in combination with physiologically active drugs. .

Claims (1)

[Claims] 1. A medical adhesive in which alkoxysilyl groups are introduced into all or part of the NCO groups of an NCO-terminated hydrophilic urethane prepolymer. 2. The medical adhesive according to claim 1, wherein the NCO-terminated hydrophilic urethane prepolymer is a prepolymer of polyisocyanates and hydrophilic polyether polyols. 3. The medical adhesive according to claim 2, wherein the polyisocyanate is a fluorine-containing polyisocyanate. 4. Introduction of alkoxysilyl group is done using the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X is -SH, -NHR, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, -(NHCH_2CB_2)_u-NHR , R is a hydrogen atom, an aliphatic and/or alicyclic and/or aromatic hydrocarbon residue having 1 to 10 carbon atoms, u is 1 or 2, and R^1 is an alkyl residue having 1 to 4 carbon atoms. The group, R^2 is -
(CH_2CH_2O)_m-R^1, -CO-R^1
, an alkyl residue having 1 to 4 carbon atoms, m is 1 to 30, n is 1 to 8, p is 1 to 3, q is 0 to 2, and p+q is 3 or less. The medical adhesive according to any one of claims 1 to 3, which is obtained by reacting an alkoxysilane represented by the following formula with an NCO group.