JPH01124464A - Adhesion preventing film - Google Patents

Abstract

PURPOSE:To obtain an adhesion preventing film for preventing the adhesion of peripheral tissue such as a tendon to a bone at the time of the surgical operation of an arm, a leg, a hand or a finger, by forming a composition prepared by compounding a drug with a copolymer of polyamino acid and polyurethane into a film. CONSTITUTION:An adhesion preventing film is prepared by forming a composition prepared by compounding a drug with a copolymer of polyamino acid and polyurethane into a film. Polyamino acid is a polymer of N-carboxylic anhydride of alpha-amino acid and polyurethane is a polymer obtained by using aromatic diisocyanate, aliphatic diisocyanate, or alicyclic diisocyanate alone or in combination as a raw material. The copolymer consisting of 95-20wt.% of polyamino acid and 5-80wt.% of polyurethane is dissolved in a solvent and a drug is added to and mixed with the resulting solution to prepare composition which is, in turn, cast on a glass plate to be dried by hot air. It is necessary to select the thickness of the obtained film according to the necessary remaining number of days of the film in the body but said thickness is usually 5-100mum. As the drug to be used, ones showing a powdery form in a usual state, for example, an anti-inflammatory drug, an antibacterial agent, an analgesic or the like are designated.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to an anti-adhesion membrane. More specifically, the present invention relates to an anti-adhesion membrane used to prevent the crotch and the like from adhering to surrounding tissues, bones, etc. during surgical operations on the arms, legs, hands, fingers, etc.

(Conventional technology and its problems) When a finger, etc. is severed due to an accident, etc., bones, blood vessels, crotch, etc.
Surgical measures are taken to connect the muscles and other parts, and the patient waits for the parts to regenerate and heal.

At this time, for example, it is desirable that bones be repaired only with bones, hips with keys, muscles with muscles, that is, only things of the same type are repaired.
Usually, adhesions occur between bones, hips, muscles, etc. The calf originally moves by sliding through the tissue and plays a role in moving fingers, etc., so it is surrounded by a membrane called the fibular sheath, which allows the calf to fuse with the surrounding tissues, bones, etc. is prevented. However, this membrane is weak and will peel off during surgery, rendering it useless.

Therefore, after this type of surgery, the groin often fuses with surrounding tissues and bones, and the fingers are connected but unable to bend. For this reason, it is necessary to perform a second surgery to remove the area between the bone and the hip, resulting in increased physical and mental pain for the patient.

(Purpose of the Invention) The present inventors believe that if it is possible to prevent the adhesions of haze associated with the above-mentioned surgical operations, it will be very effective for functional recovery after surgery, and the present inventors will easily apply the method at the time of surgery. We conducted various studies with the aim of developing a means to prevent keys from collapsing.

[Structure of the invention]

For example, the present inventors used a cylindrical film made of a thin body-absorbable (biodegradable) film to cover the crotch during surgery to prevent adhesions. We thought of preventing adhesions by forming a crotch sheath, and developed a material and structure that is very suitable for this purpose, and completed the present invention.

That is, the gist of the present invention resides in an anti-adhesion film formed by forming a composition in the form of a film, which is a copolymer of polyamino acids and polyurethane mixed with a pharmaceutical agent.

The anti-adhesion membrane of the present invention has a film structure and is used by covering the crotch etc. during full-scale surgery.

That is, since it is used by being implanted in the human body, it requires various special physical properties as shown below.

■Biocompatibility: Since it is used by being implanted in living organisms, it should not cause foreign body reactions.

■Absorbable in the body: After a certain period of time (after the wound has healed), it will be broken down and absorbed into the body, and there is no need for re-surgery to remove it.

0 Body fluid permeability: Does not obstruct the passage of body fluids and nutrients necessary for healing.

■Flexibility Two: Be able to deform to fit various shapes of internal tissues.

■Tear resistance: Should not tear even when sutured with thread.

(2) Non-toxic The anti-adhesion membrane of the present invention uses a copolymer of polyamino acid and polyurethane as the base polymer.

This copolymer of polyamino acids and polyurethane is biocompatible because it contains amino acids that make up proteins and enzymes in living tissues, and it is bioabsorbable because the amino acid portion is decomposed in vivo. It also has

The polyurethane component also provides flexibility and tear resistance.

An example of a method for obtaining a copolymer of polyamino acid and polyurethane (hereinafter referred to as polyamino acid urethane) will be explained.

N- of α-amino acid in a solvent without active hydrogen
A polyamino acid urethane resin liquid is obtained by reacting a carboxylic acid anhydride, a urethane prepolymer having an incyanate group at a terminal, and water, hydrazine, or an organic amine having an active hydrogen.

The organic solvents mentioned here include non-halogenated hydrocarbons,
Ethers, esters, ketones, etc. are preferred.

Examples of these solvents include benzene, toluene, xylene, cyclohexane, tetrahydrofuran, dioxane, methyl ethyl ketone, cyclohexanone, ethyl acetate, and the like. Examples of the halogenated solvent include ethylene dichloride, chloroform, and carbon tetrachloride.

N-carboxylic anhydrides of α-amino acids (hereinafter referred to as NCA) include γ-alkyl-glutamate NCA, glycine NCA, and L-alanine NCA.
Examples include CA, leucine NCA, isoleucine NCA, methionine NCA, and aspartic acid NC.

The urethane prepolymer having an isocyanate group at the terminal has an equivalent ratio of polyisocyanate and polyol of NGO1.
It is obtained by reacting under the condition of 0H>1.

As the polyisocyanate component, aromatic diisocyanates, aliphatic diisocyanates, and cycloaliphatic diisocyanates are usually used alone or in mixtures thereof. For example, tolylene-2,4-diisocyanate, 4.
4″-diphenylmethane diisocyanate, metaphenylene diisocyanate, 1.6-hexane diisocyanate, 1, 1o-decamethylene diisocyanate, 1.
Examples include 4-cyclohexane diisocyanate, 3-isocyanatemethyl-3.5.5-trimethylcyclohexyl isocyanate (isophorone diisocyanate), and the like.

Examples of the polyol component include polyether polyols, polyester polyols, and polycarbonate polyols, singly or in mixtures thereof. Examples of polyether polyols include polyethylene glycol, polypropylene ether glycol, polyethylene polypropylene ether glycol, polytetramethylene ether glycol, polypentamethylene ether glycol, and glycols having an aromatic ring obtained by adding propylene oxide or ethylene oxide to bisphenol A. etc.

A typical example of a polyester polyol is polycaprolactone polyol, or ethylene taucol, 1.

Those obtained by reacting diols such as 4-butanediol with dibasic acids such as adipic acid and sebacic acid are used.

The number average molecular weight of these polyethers, polyesters, and polycarbonate polyols is preferably 200 to 300 or more.

The water used in the present invention refers to ordinary water, and may be tap water, non-desalinated water, or desalinated water.

Hydrazine may be either anhydrous hydrazine or hydrated hydrazine, and hydrated hydrazine is industrially more advantageous in terms of safety.

Organic amines having active hydrogen include aliphatic primary diamines such as ethylenediamine and propanediamine, cycloaliphatic secondary diamines such as piperazine, and phenylenediamines.
Aromatic diamines such as diphenylmethane diamine are suitable.

α-amino acid N when obtaining polyamino acid urethane resin liquid
The weight ratio of CA and urethane prepolymer is 95:5 ~
20:80, more preferably 70:30-30
The range is near 0.

The amount of hydrazine and amine having active hydrogen to be used is preferably 1/2 equivalent or more, more preferably 2 equivalents, based on the incyanate group of the urethane prepolymer as an amine group.
/3 equivalent or more.

Water reacts with isocyanate groups to produce amino groups, so it can be used as a substitute for amines.

The amount of the organic solvent used is such that the resin concentration in the polyamino acid urethane (PAU) solution of the final product is usually in the range of 3 to 50% by weight in terms of the resulting resin solution, but preferably 1O
The weight should preferably be ~30%.

If the concentration is too high, the viscosity becomes extremely high and becomes gel-like, making it difficult to handle. Furthermore, if the concentration is too low, it is difficult to obtain a high viscosity (10,000 cps or more), resulting in poor versatility.

Further, in the present invention, the reaction temperature for producing the polyamino acid urethane resin liquid is preferably a temperature in the range of 10 to 60°C at which a high molecular weight polyamino acid single polymer can be synthesized from α-amino acid NCA. If the temperature is higher than 60°C, it becomes difficult for the amino acid chain to form an α-helical structure during copolymerization, so the degree of polymerization of the amino acid chain may not increase, and a product with a high molecular weight may not be obtained.

Furthermore, if the reaction is carried out at high temperatures, the isocyanate group may undergo a biuret reaction with the urea bond produced by the reaction between the isocyanate group and the amino group, resulting in gelation.

A preferred method for producing a polyamino acid urethane resin stock solution includes (a) reacting a urethane prepolymer with water, hydrazine, or an organic amine containing active hydrogen in an organic solvent, and then adding α-amino acid NCA. How to make it react.

(b) A method in which α-amino acid NCA and urethane prepolymer are mixed in an organic solvent, and then water, hydrazine, or an organic amine having active hydrogen is added and reacted.

(c) Urethane prepolymer and water in an organic solvent,
A method of reacting hydrazine or an organic amine having active hydrogen, adding and mixing α-amino acid NCA, and then adding and reacting water, hydrazine, or an organic amine having active hydrogen.

etc.

An example of a mixture of polyurethane and polyamino acid is to add α-amino acid NCA and organic amine as an initiator to a polyurethane solution obtained by reacting diisocyanate, polyol, and optionally low molecular weight diol in an organic solvent. It is obtained by mixing a polyamino acid solution obtained by reaction in an organic solvent.

The anti-adhesion film of the present invention is prepared by blending the above-mentioned polyamino acid urethane with a drug that is soluble in the body and forming it into a film.

For film formation, for example, polyamino acid urethane is dissolved in a solvent such as benzene, toluene, xylene, dimethylformamide, tetrahydrofuran, dioxane, cyclohexanone, methyl ethyl ketone, ethyl acetate, butyl acetate, diethylene chloride, chloroform, carbon tetrachloride, etc. A medicine may be added and mixed to this, and the mixture may be cast onto a glass plate or the like and dried with hot air.

The thickness of the film needs to be selected depending on the number of days the film needs to remain in the body, etc., but is usually about 5 to 100 μm.

The medicine used is normally in powder form.

Examples include anti-inflammatory agents, antibacterial agents, analgesics, and the like.

The particle size of the drug is preferably about 0.1 to 10 μm from the viewpoint of dispersibility and the like. The amount of medicine added varies depending on the use, type of medicine, required duration of effect, etc., but it is usually 1 to 80% by weight or 3 to 50f! I%, more preferably 5
It is about 20% by weight.

The effects of using these powdered medicines are not limited to the pharmacological effects of these medicines.

In other words, when the anti-adhesion film of the present invention is applied, the compounded drug gradually dissolves from the film and exerts its pharmacological effect over a long period of time, that is, it has sustained release properties, and it can be used for sustained release implantation in the body. It also serves as a sex medicine. Furthermore, after the drug is dissolved, cavities are formed in the part of the film where the drug was present, making the film porous and body fluids flowing through the pores, making it a very favorable structure for healing effects. Become.

In addition, by processing the obtained film into a cylindrical shape, or by forming it into a cylindrical film from the beginning, providing a thread for pulling out inside the film, and tying Tsukiken to one end of the thread and pulling the thread. The oboro may be coated with an anti-adhesion film.

〔Example〕

The present invention will be explained in more detail with reference to examples below, but the present invention is not limited to the following examples unless it exceeds the gist thereof.

Example 1 Polytetramethylene ether glycol (OH value 56.
7) 989.5 g and 250 g of 4,4'-diphenylmethane diisocyanate were reacted at 70''C for 5 hours to obtain a urethane prepolymer having isocyanate groups at the ends.

123.1 g of 8 urethane prepolymer and γ-methy/L
23.1 g of /-L-glutamate NGAI was dissolved in 821 g of dimethylformamide and 2.71 g of hydrazine hydrogen hydride was added dropwise to react while stirring, and then 7.4 g of the urethane prepolymer was dissolved in 37 g of dimethylformamide and added thereto. After 2 hours reaction, viscosity 43000CP
An emulsion with good fluidity at 25°C was obtained.

Prednisolone, an anti-inflammatory agent, was added to this emulsion at 5% by weight, 10% by weight, and 20% by weight in the finished film state.
They were added and mixed so that the weight % was the same.

Each of these liquids was cast onto a glass plate and dried with hot air at 60'C for 60 minutes to obtain a film.

The resulting polyamino acid urethane film (sample A) with a thickness of 30 μm was highly flexible and had excellent tensile strength.

The following experiment was conducted to confirm the properties of this film as an anti-adhesion film.

The abdomens of 12 rats were opened, and the intestines of each rat were injured with a scalpel.

The anti-adhesion membrane was sutured and fixed to the inside of the peritoneum of 10 rats (no tearing occurred in the film during suturing), and the open abdomen was also sutured.

The remaining two rats were sutured without applying an anti-adhesion membrane.

After 1 week, 2 weeks, 1 month, 2 months, and 3 months, the rats to which the anti-adhesion membrane had been applied were subjected to laparotomy again, and the development of adhesions, membrane decomposition, and foreign body reaction were observed. Shown in the table.

Table 1 Inflammatory reaction and foreign body reaction were determined by cutting out the tissue in contact with the anti-adhesion membrane each time, preparing tissue specimens using formalin fixation, and histologically determining the degree of cell infiltration using hematoxylin and eosin staining. .

In addition, when rats to which the anti-adhesion membrane was not applied were subjected to laparotomy after one month, the injured intestine part was found to have adhered to the intestinal wall and peritoneum that had been in contact with it.

Example 2 (1) Synthesis of polyurethane solution 80/201-lylene diisocyanate 2 mmol, polytetramethylene glycol (molecule ff 12000) 1
mol and 1.2 mol of hydrazine hittride were reacted in dimethylformamide to obtain a terminal amino group polyurethane solution (20% by weight once).

(2) Synthesis of polyamino acid urethane Add 3 g of L-o isine NcA to 250 ml of benzene? 35 g of the polyurethane solution obtained in (1) above was added to the solution and reacted at 40''C for one day to obtain polyamino acid urethane.

(3) Production of film Prednisolone, an anti-inflammatory agent, was added and mixed to this solution so that the amount of the finished film was 10% by weight.

This liquid was cast onto a glass plate and dried with hot air at 60°C for 60 minutes. After drying, peel the film from the glass plate to a thickness of 10
An anti-adhesion membrane of μ was obtained.

Prepare 10 chickens and connect the 1st and 21st needles of the third heel
An incision was made with a scalpel to expose the nodal part, and the superficial flexor muscle Oboro and the deep flexor muscle Key, which were divided into two 5-lips running within the fibular sheath, were exposed. These crotches were mechanically damaged with a scalpel and the crotch sheaths were removed.

The flexor calcanis profundus muscle groin was wrapped with the anti-adhesion film obtained above, and the flexor calcanis profundus muscle key and the flexor calcanis superficialis muscle were wrapped together with the anti-adhesion film. The ends of the film were sewn together with 6-0 nylon thread to form a cylindrical shape.

In this state, the incision was sutured and changes in the anti-adhesion membrane over time were observed.

After 1 week, 2 weeks, 1 month, 2 months, and 3 months, the chicken leg with the anti-adhesion membrane was incised again, and the state of adhesions, membrane decomposition, and foreign body reaction were observed. Shown in Table 2.

Table 2 Inflammatory reactions and foreign body reactions were determined by cutting out the tissue that was in contact with the anti-adhesion membrane each time, preparing tissue specimens by formalin fixation, and histologically determining the degree of cell infiltration using hematoxylin and eosin staining.

When the leg of a chicken to which the anti-adhesion film was not applied was cut open after one month, it was found that the crotch had adhered to the tissue and bone surrounding the crotch that had been in contact with the leg.

(Effects of the Invention) The anti-adhesion membrane of the present invention is highly flexible and has tear strength that can withstand suturing with thread, and since the drug is dispersed in crystalline form, it can be implanted in the body for sustained release. It works as a sex drug and has very useful effects in practice, such as not requiring removal due to its absorbability in the body.

Claims (5)

[Claims] (1) An anti-adhesion film formed by forming a composition in the form of a film, which is a copolymer of polyamino acids and polyurethane mixed with a pharmaceutical agent. (2) The anti-adhesion film according to claim 1, wherein the polyamino acid is a polymer of N-carboxylic anhydride of α-amino acid. (3) The anti-adhesion film according to claim 1, wherein the polyurethane is a polymer made from aromatic diisocyanate, aliphatic diisocyanate, or cycloaliphatic diisocyanate alone or a mixture thereof. . (4) The anti-adhesion film according to claim 1, wherein the copolymer of polyamino acids and polyurethane consists of 95 to 20% by weight of polyamino acids and 5 to 80% by weight of polyurethane. (5) The anti-adhesion film according to claim 1, wherein the film made of a copolymer of polyamino acid and polyurethane has a thickness of 5 to 100 μm.