SE448821B - MULTI-LAYABLE DEGRADABLE MATERIAL PROVIDED AS REPLACEMENT FOR BODY SLEEVEN AND WHICH DROPPING SPEED VARIES WITH THE DISTANCE FROM THE EXPOSED SURFACE PROCEDURE FOR ITS PREPARATION - Google Patents

Description

ZS 30 35 40 448 821 The term "exposed surface" used in the present invention refers to one or two surfaces of the product, in order to clarify that the rate of degradation of the polymer varies through the thickness of the material seen in the transverse direction. Thus, when the product is in the form of a wound dressing, the exposed surface of the product is the surface facing the wound. With regard to a vascular prosthesis, there are two exposed surfaces, one which consists of the lumen side of the product and another which faces the surrounding tissue.

According to one aspect of the invention, the rate of degradation may be reduced or increased in the direction from one side to the other side of the product. This is the case with, for example, a wound compress, in which it is desirable to have a higher degradation rate and larger pore size on the side of the compress facing the wound, while it is desirable to use a polymer with a lower degradation rate or a non-degradable one. polymer and lower pore size on the outside of the compress to protect against, for example, bacterial penetration.

In some cases, however, it is desirable to provide a wound dressing which has a higher degradation rate and lower pore size, such as 5-10 .mu.m, on the exposed surface of the compress, higher degradation rate and higher pore size, such as 50-100 .mu.m, in the intermediate part of the compress and a non-degradable protective outer layer with a porosity of the order of 1 .mu.m.

Thus, in the invention, the product is in the form of a multilayer but cohesive material, in which each layer independently of the others contains polymer with the same rate of degradation. By utilizing such multilayer technology, it is possible, as further explained below, to build up a product by stepwise application and precipitation of layers, in which the desired gradient of degradation rate over the product is obtained. Thus, in a vascular prosthesis, it is thus possible to arrange layers on the lumen side of the prosthesis wall containing polymers with high degradation rate to achieve rapid endothelial formation, some inner layers of the material containing polymer with lower degradation rate, so that the structural integrity of the product maintained for a sufficient period of time. In this embodiment, the degradation rate of the various layers may decrease outwardly from the center of the product or the product may contain at intervals layers of lower degradation rate alternating with layers of higher degradation rate. The multilayer variants of the product of the present invention can be prepared from a solution of a copolymer in a suitable solvent and coating a support with a uniform thickness of such a solution. The original layer resulting from coating of the carrier is then precipitated by treating the coating to displace solvents present in the coating with a precipitating solution, which comprises a fluid which is miscible with said solvent but acts as a precipitating non-solvent with respect to polymers. This procedure is then repeated the desired number of times to form a multilayer material.

It has been found that if any solvent is left in the precipitated polymer layer, repetition of the procedure to form an additional layer or an additional coating results in the formation of a mechanically strong bond between the first layer and the subsequent layers, which prevents successive delamination of the prosthesis wall when it is implanted in a living body. Such delamination is a disadvantage associated with the conventional technique and it generally results in the formation of distant aneurysm after implantation.

In the products of the present invention, the polymer used to prepare them may be any polymer useful in the context, i.e. a polymer which exhibits biocompatibility and in some cases blood compatibility and which is degradable in the desired manner upon implantation. However, it is preferable to use a copolyurethane, especially a block copolyurethane. When coating the carrier, it is preferred to use a solution containing less than 5 and especially less than about 3% by weight of polymer. The lower limit is not critical but is preferably not less than 0.1% by weight.

As the solvent, any solvent capable of dissolving the polymer used can be used, but preferred solvents are those selected from the group consisting of tetrahydrofuran, amide solvents and sulfoxide solvents. In addition to tetrahydrofuran, such solvents include dimethyl acetamide, dimethylformamide and dimethyl sulfoxide.

As a non-solvent, any fluid capable of precipitating the polymer can be used. A preferred solvent is water but also lower alkanols, such as ethanol, can be used, optionally in combination with water.

As previously stated, segmented aliphatic polyurethanes or segmented aromatic polyurethanes can be used in the practice of the technique of the present invention. For obtaining materials which are non-toxic, non-mutagenic and non-carcinogenic, it is preferable to use segmented aliphatic polyurethanes or to use another term aliphatic block polymers.

The polymeric material used in the invention can be conventionally prepared from aliphatic polyurethanes based on diisocyanates, for example in 1,2-diisocyanate, 1,5-diisocyanate pentane, hexamethylene diisocyanate, methane diisocyanate pentane, 1,9-diisocyanate nonane, 1,8- diisocyanatoctane, 1,4-diisocyanate butane, 4,4l-methylenebicyclohexyl diisocyanate, lysine diisocyanate, 1,4-transcyclohexane diisocyanate, dimethyl diisocyanate silane, diethyl diisocyanate silane.

In addition to such diisocyanates, polyols having an average molecular weight in the range of 100 to 10,000 can be used, for example poly- (ethylene derivative / p01Y (tetramethylene adipate), poly (1,4-cyclohexyldimethylene adipate), poly (hexamethylene oxalate), poly (hexamethyl), poly (ε-aprolactone), poly (tetramethylene oxide), poly (ethylene oxide), poly- (1,2-propylene oxide) As a chain extender, for example, 1,4-butanediol, 2,4,6-tris (dimethylaminomethyl) can be used. phenylglycerol, 3,6-dioxoooctane 1-8-diol, ethylenediol, diethylenediol, tetramethylenediamine, ethylenediamine, hexamethylenediamine, propylenediamine.

Copolvurethane nags are prepared in a conventional manner, for example by reacting a prepolymer, such as a polyether diol, with a diisocyanate, and the product obtained from this reaction can then be chain extended by reaction with a diol or diamine. By such a polymerization process, copolymers can be prepared which have preferred molecular weights and preferred viscosity in solution. By varying the molecular weight and viscosity of the polymer in solution, the degradation rate and porosity of the material produced can be controlled. However, different polymers with different degradation rates can be used in the different layers.

The selected polymeric material is dissolved in a suitable solvent of the type indicated above, and the proportions of polymer and solvent are selected in a suitable manner so as to obtain a percentage of solids in the formed solution. 448 821 one of less than 5% by weight and preferably less than 3% and preferably not less than 0.1% by weight. The coating solution was then used to coat a support to form an original coating of uniform thickness. As the carrier, any mechanical means of a suitable type can be used, such as a metal or glass plate or a metal or glass mandrel, preferably coated with a resistant plastic, such as polytetrafluoroethylene. The coating can be achieved by spraying, immersion or dipping or in some other conventional way.

The molecular weight of the polymer used in the manufacture of the products of the present invention can vary within fairly wide limits, but when using polyurethanes, the average molecular weight is preferably in the range of from about 5x103 to 106. A particularly preferred range is from approx. zx1o4 to sx1o5.

The product of the present invention which is a substitute for body tissue can be used in a variety of medical applications. It can thus be used as a vascular graft, as artificial skin or as a wound compress. In addition, it can be used as an elastic membrane for the replacement of eardrums, as an element for orthopedic surgery and as an anticoagulant line for blood transfusion.

The invention will now be further described by means of concrete examples, which, however, may not be construed as limiting the invention. In this connection reference is also made to the accompanying drawing, in which a casting device for producing a multilayer material in accordance with the present invention is shown.

The casting device shown in the drawing comprises a frame supporting a rotating cylinder A. The cylinder may be of sintered glass or may be coated on the surface with polytetrafluoroethylene, i.e. "FLUON" manufactured by ICI Limited, England. The cylinder A is arranged to be driven by an electric motor C via gears and a gear shaft B. The rotational speed of the cylinder A can be easily adjusted to regulate the coating formed on the cylinder.

The level of the polymer solution is indicated at D.

Example I General production procedure.

Using the casting device shown in the drawing, the cylinder A is coated by dipping at room temperature with a polymer solution, the polymer coating being applied then precipitated with a non-solvent, optionally containing a minor amount of solvent. After the first layer of polymer has been deposited, this procedure is repeated for a desired number of cycles to produce superimposed layers of polymer coatings on the cylinder to form a multilayer prosthetic material of the desired mechanical strength and thickness. After depositing the desired number of layers on the cylinder A, the formed material is immersed in deionized water to remove all remaining solvents and non-solvents, and the material can then be washed with ethanol and dried on the cylinder at, for example, SOOC in a vacuum oven.

The average thickness of the individual polymer layer is in the range of approx. 0.01 to 0.2 mm, and the average pore size of the material produced is in the range of approx. 0.5 to 500 .mu.m. When using, for example, a concentration of polyurethane of about 2% by weight, an average pore size is obtained which is in the range of about 30 to 50 .mu.m.

When using the technique of the present invention, it is preferred that a certain amount of solvent be always left in the precipitated polymer coating at the moment when the subsequent polymer coating is deposited on the underlying one.

The initial coating resulting from the application of the polymer solution to the support is precipitated by treating the coating to displace solvents present in the coating with a precipitating solution which comprises as a main constituent a fluid which is miscible with said solvent but acts as a precipitating non-solvent. solvent with respect to the polymer, and further comprising as a minor component a solvent for the polyurethane. This procedure is then repeated the desired number of times to form a multilayer material.

It has been found that if any solvent is left in the precipitated polymer layer, repetition of the procedure to form an additional layer or coating results in the formation of new fibers, which form a mechanically strong bond between the first layer and the subsequent layer. This prevents gradual delamination of the graft wall during implantation in a living body. Such delamination is a disadvantage associated with the conventional technique and generally results in the formation of extensive aneurysms upon implantation.

This strong bonding between the layers can be achieved either by using a mixed solvent-non-solvent as indicated or by interrupting the precipitation solution treatment to leave a certain amount of solvent in the coating when applying the subsequent layer.

Although the invention is not limited to any particular theory or mechanism, there are various factors that can explain how the very strong bond is achieved. Thus, it has been observed that there are many fibers in the boundary region between two successive layers, which fibers appear to be interconnected probably due to the fact that many small fibers in the outer surface of the first layer are partially dissolved in the very dilute solvent contained. in the liquid non-solvent / solvent precipitation system. As soon as the new fibers are precipitated in the subsequent precipitation step, the partially dissolved fibers formed in the previous step are also reshaped, thus giving a mutual reading effect between the two subsequent layers.

There are also fibers precipitated in the second subsequent layer, which are enclosed in the pores in the first layer. Finally, there may also be a type of bonding effect between the fibers in the outer surface of the first layer and the inner surface of the second layer.

This results from the presence of small amounts of solvent left in the precipitated polymer.

The practical use of the product or material of the present invention may, of course, include reinforcing material, such as material in fibrous, woven or braided form.

Such reinforcement materials may be degradable or non-degradable.

It should be noted that the invention is not limited to the casting technique described above, but other methods for applying the polymer solution to a support can also be used. Application by spraying is thus useful and brushing technology is also conceivable.

Example II Preparation of degradable wound dressings.

A series of casting solutions were prepared from polyester urethane based on hexamethylene diisocyanate, poly (hexamethylene glutanate) diol and 1,4-butanediol. The solution was prepared from polyurethanes having molecular weight of A104, 4x104, s> <1o4, 6> <1o4 and moss. These individual casting solutions contained 4, s, 2, zman wine percent of said polyurethanes.

An anneal cast solution was prepared by dissolving E-sthane polyether urethane (trademark, Goodrich) in tetrahydrofuran at room temperature. The polymer solution is stirred. for half an hour and then filtered and stored in the dark in closed bottles for its use.

Using prepared casting solutions, a wound dressing is prepared according to the procedure set forth in Example I using a casting device equipped with a cylinder made of sintered glass. During the casting procedure, the cylinder is flushed continuously with deionized water. Water penetrates the pores of the sintered cylinder and causes uniform precipitation of the polymer on the surface of the cylinder. Using the five casting solutions of varying molecular weight of the polymer, five consecutive layers were deposited on the cylinder to form an average porosity ranging from about 70 to about 150 dan with ethanol, which is then evaporated. / um. Using the remaining casting solution, three more layers of polymer are deposited on the glass cylinder, and drying of these outer polymer layers gives a semipermeable membrane with a porosity in the range of 0.5 to 1 .mu.m. This membrane protects against bacterial penetration and allows the necessary fluid transport through the membrane.

The entire composite polymer material deposited on the cylinder is finally washed with ethanol, deionized water and again with ethanol. The material is removed from the cylinder, dried at 30 ° C under a vacuum of 20 mbar and placed in a plastic bag for sterilization. When used as a wound compress, the material shows excellent adhesion and flexibility. Due to the degradability of the polymer on the side exposed to the wound, epithelial formation and growth of new skin tissue is improved.

This artificial wound compress composed of two different joined membranes is placed with the degradable surface against the wound. ~ This degradable layer ensures good epithelial formation and successive tissue growth in the compress and is finally replaced with a new river; 10 15 20 25 30 35 448 821 synthesized stable binding tissue.

The upper layer made of non-degradable polyurethane ensures good transport speed for fluid, 1 to 4 mg / hr / cm2, and protects the wound from bacterial penetration.

This layer is finally torn from the healed wound.

This artificial skin protects the wound for at least 20 to 60 days without rejection and without requiring immune reduction.

It shows excellent adhesion to the wound and high flexibility.

Example III Preparation of degradable vascular prosthesis.

Two of the casting compositions described in Example 11 were used, namely the polyurethane containing having a molecular weight of 2x104 and the one having a molecular weight of 3x10. The procedure described in Example I was used for production using a mandrel instead of a cylinder. The prosthesis wall is composed of 30 layers of polyurethane with a molecular weight of 2x10 on the lumen side of the prosthesis and 3x10 on the opposite side of the prosthesis wall. In the preparation of the sixth, eleventh, sixteenth, twenty-first, twenty-sixth and outermost layers, polyxethane having a molecular weight of 3x105 was used in all of them. The outer layers are made of polyurethane with a molecular weight of Zx104.

When using the polymer with a lower molecular weight, a higher degradation rate is obtained. High degradation rate is desirable to ensure rapid endothelial formation and tissue growth. On the other hand, high molecular weight of the polymer results in lower degradation rate. The degradation procedure of the prosthesis is thus reduced in speed, so that its mechanical integrity is maintained for a sufficient period of time for the prosthesis to fulfill its function until new growth tissue achieves sufficient mechanical stability where the implantation was performed.

Example IV Preparation of partially degradable vascular prosthesis.

A polyether urethane having an average molecular weight of 4x105 based on 4,4'-methylenebicyclohexyl diisocyanate, poly (tetramethylene oxide) and 1,4-butanediol is dissolved in tetrahydrofuran at room temperature and precipitated with water / ethanol (9: 1 v / v ). The precipitated polymer is washed with distilled water and dried under vacuum. The dried polymer is then dissolved in dichloromethane to give a solution having a polymer concentration of Z% by weight. The polyurethane is precipitated with n-hexane and dried to constant weight.

The polyurethane thus prepared is used to prepare a casting solution by dissolving the purified polymer in tetrahydrofuran at room temperature, the concentration thereof being 1.8% by weight.

Using the procedure outlined in Example I, partially degradable vascular prostheses are prepared from the solution described above. However, before applying layers of polymer from such a casting solution, three layers from a casting solution containing degradable polyurethane of the type described in Example II but having an average molecular weight of about 3x10 4 are applied to the cylinder from the beginning. This results in the formation of a membrane with small pores in the range 5-10 .mu.m, to which are then applied to SO layers using the casting solution originally described in the present example. The average pore size of these additional layers is larger than that of the original membrane and is in the range of 30-60 .mu.m.

Because the lumen side of the prosthesis is based on material with a relatively small pore size and with the degradation rock, the speed of endothelial formation is increased while the subsequent layers of the prosthesis maintain its mechanical integrity for the required time.

Example V Preparation of a partially degradable vascular prosthesis.

Two casting solutions were prepared from polyester urethane based on hexamethylene diisocyanate-1,4-butanediol and poly (ethylene adipate) diol having a molecular weight of 500 (solution A) and 1500 (solution B).

These individual casting solutions contained 1.5 resp. 2.1% by weight of said polyurethanes.

Vascular prostheses were prepared by casting on the mandrel 10 layers of solution B followed by deposition on these layers followed by 40 layers of solution A according to the procedure described in Example I on a mandrel instead of a cylinder.

Due to the faster degradation of the material in said 10 layers constituting the lumen side of the prosthesis, the endothelial formation procedure is accelerated, while the remaining part of the 44: 10 11 448 821 prosthesis made of other material with lower degradation rate maintains the required mechanical the integrity of the prosthesis during the healing procedure.

While the invention has been described with reference to certain specific examples using certain materials, solvents, etc., and specific techniques for applying the various layers, it should be noted that the invention is by no means limited to such particular features since related variations and modifications are made. obvious to those skilled in the art. The invention is therefore not limited other than as appears from the scope of the appended claims.

Claims (14)

448 821 12 PATBNTKRAV _ An integral product in the form of a multilayer material, which is a substitute for body tissue consisting of an at least partially degradable, flexible material comprising a polymer matrix with a porous structure, characterized in that the rate of degradation of the polymer in the matrix varies with the distance from the exposed surface or surfaces of the product, the variation in degradation rate being achieved by the polymer in the different layers having different molecular weights. A product according to claim 1, wherein certain inner layers of the material contain polymer with a lower degradation rate to extend the structural integrity of the product. Product according to claim 1 or 2 in the form of a vascular prosthesis. Product according to any one of claims 1 - 3 in the form of a wound compress or skin graft. A product according to claim 3, wherein the matrix adjacent to the lumen surface of the prosthesis is composed of a polymer with a higher degradation rate than that of the inner parts of the prosthesis. Product according to claim 5 based on a multilayer material, wherein the layer on the lumen side is composed of a polymer with a higher degradation rate than the layers in the central part of the prosthesis, the pore size being correspondingly lower on the lumen side than in the central part. The product of claim 1, wherein the variation in degradation rate is achieved by using different polymers of different molecular weights in the different layers. The product of claim 1, wherein the number of layers is at least 5, wherein some intermediate layers are composed of a higher molecular weight polymer to extend the structural integrity of the product upon implantation. A product according to claim 5 embodied as a multilayer material, wherein the part of the matrix facing the living tissue is composed of a polymer with a lower molecular weight than the adjacent outer surface, the degradation rate being correspondingly higher on the tissue side than on the outer side . A product according to any one of the preceding claims, wherein the synthetic polymer matrix comprises a copolyurethane. (i) \; \ 13 448 821 The product of claim 10, wherein the copolyurethane is a block copolymer. A process for the preparation of the product according to any one of claims 1 to 11, comprising the steps of: (a) preparing a copolymer solution using a solvent; (b) coating a substrate with a uniform thickness of said solution; (c) precipitating the original coating resulting from step (b) to form a physically stable structure with pores substantially evenly distributed therein by treating the coating with the precipitating solution which is miscible in said solvent but acts as a precipitator non-solvent with respect to the copolymer, and then repeating steps (a) - (c) as needed to form a multilayer material, characterized in that in step (a) a solution containing less than 5% by weight of polymer is prepared , leaving a certain amount of solvent in each previous layer when subsequent layers are applied. The method of claim 12, wherein the solution prepared in step (a) contains less than about 3% by weight and in particular less than about 2% polymer. A process according to claim 12 or 13, wherein the precipitating solution comprises as a main component a fluid which is miscible in said solvent but acts as a precipitating non-solvent with respect to the polymer, and further comprises as a minor component a solvent for the polymer, whereby in repetition of steps (a) - (c) due to the presence in the precipitation solution of a certain amount of solvent mechanical bonding is obtained between said initial coating and the subsequent coating.