WO2011100935A1

WO2011100935A1 - Dry material of hydrogel for wound dressing and its method of preparation

Info

Publication number: WO2011100935A1
Application number: PCT/CZ2011/000017
Authority: WO
Inventors: Nabanita Saha; Tomas Saha; Amarjargal Saarai
Original assignee: Univerzita Tomase Bati Ve Zline
Priority date: 2010-02-18
Filing date: 2011-02-15
Publication date: 2011-08-25
Also published as: CZ2010126A3; CZ302380B6

Abstract

The dry material of hydrogel substance for wound dressing made from synthetic and natural polymers contains gelatin and sodium alginate in the weight ratio 3:7 up to 7:3, whereby these two components create 100 wt. pts., and simultaneously contains 15-25 wt. pts of polyethylenglykol, 15-25 wt. pts of glycerine, 10-40 wt. pts of polyvinylalcohol nanofibres, 1 -3 wt. pts of natrium chloride, eventually further usual additives. A method of preparing the dry substance of hydrogel for wound dressing lies in t h a t initial aqueous polymeric solution of gelatin will be achieved during continuous stirring it in 180 - 220 wt. pts of water at the constant temperature 75 - 85°C, after dissolving whole volume of gelatin further components such as sodium alginate, polyethylene glycol, sodium chloride, glycerin and respectively sea buckthorn oil will be added to the initial aqueous polymeric solution of gelatin, whereupon stirring of this mixture will continue for 5 - 6 min at 250 - 350 rpm in order to a viscous hydrogel mass will be developed, then slowly a fraction of polyvinyl alcohol nanofibres will be added whereon the mixing speed of viscous mass will be reduced till 150 - 50 rpm, finally, the viscous mass will be poured into acrylic dishes of 25 mm diameter where it will be incubated at room temperature of 20 - 25°C until the whole volume of water is removed and the final dry material of hydrogel is achieved.

Description

Dry material of hydrogel for wound dressing and its method of preparation Field of Invention

The invention relates to dry substance of hydrogel for wound dressing used on bodies, in particular human bodies. The presented invention also relates to the method of preparation of such hydrogel for wound dressing.

Background Art

To date several hydrogels for wound dressing from synthetic and natural polymers as well as methods of their preparation are known. They are oriented to obtain a product with best mechanical, swelling and. other important physical properties, as well as with antibacterial and wound-healing properties.

There are several more requirements imposed on hydrogels for wound dressing. They should be soft and friendly to wounded body and at the same time they should resist the manipulations during application and thereafter. These requirements are rather contradictory and it is difficult to meet them sufficiently.

Orie of the known methods for manufacturing hydrogel for wound dressing is described in the WO 03/034900 document which discloses an intradermal patch with a permeable backing coated with a gel based on polyvinylpyrrolidone with certain average molecular weight (pref. 900.000 - 1.500.000 Dalton) in an amount of pref. 15 - 20 % of weight. The patches may comprise one or more additional components such as wound-healing agent, medicines, viscosity enhancing agents and humectants. The hydrogel material is placed on a base made from.^■ a material with sufficient mechanical properties and therefore no extra mechanical requirements are imposed on the hydrogel. , . . _.

Further process for adhering a polymeric hydrogel to a substrate is disclosed in US patent No. 5,480,717. This process is characterized by the adhering a polymeric hydrogel to a substrate in order to obtain a hydrogel laminate with greatly improved de-lamination resistance. According to this patent the preferred synthetic polymer for hydrogel is the cross-linked polyvinylpyrrolidone of particular molecular weight (pref. 200.000 - 300.000 Dalton) in an amount of pref. 40 - 50 % of weight in aqueous solution. The cross-linking of hydrogel is important with regard to the result adhesion value but it is not connected with the minimum of mechanical properties required, because they are assured by the substrate. It is said herein that if the molecular weight of the polyvinylpyrrolidone is too high it is not possible to obtain the solution with a high enough polyvinylpyrrolidone concentration and therefore the adhesion to the polymeric adhesive layers after irradiation is not acceptable. Moreover, the concentrations of the polyvinylpyrrolidone supposed in this patent are relatively high and it can lead to extending costs for such hydrogels.

The polyvinylpyrrolidone is the, appropriate synthetic polymer for the preparation of hydrogel for wound dressing, as can be seen from another, US patent No. 4,871 ,490. The method of this patent is based on pouring the aqueous solution of synthetic polymer, e.g. polyyinylpyrrolidone, natural; , polymer,, e.g. agar,_; and .so-called plasticizing_; agent, e.g. polyethylene glycol, into a mould imparting a shape to the hydrogel. After irradiatio the hydrogel for wound dressing is obtained according to this patent. Unlike the previous mentioned hydrogels this is a self-supporting material and as such it requires certain mechanical properties. The commercial formulas contain about 7 % of weight Polyyinylpyrrolidone and such amount can be seen still tqo high regarding the costs of the product. Moreover, these ibrmulations are said to be good at burn dressings, whilst their mechanical, swelling and drying properties fall behind current requirements in some respect. ^{! ;}

To eliminate some of the disadvantages of the before said methods and compositions, there are further methods or compositions being developed, such as the composition according to US patent No. 5,306,504. This solution is based on cross-linked polyvinylpyrrolidone, which is mixed with water-soluble multifunctional amines containing polymer. Polyvinyl-pyrrolidone has ring opened pyrrolidone acid groups which can react with the basics amine groups of the multifunctional amine-containing polymer to form a water-insoluble, water-swellable, cross-linked ampholyte salt. The preparation takes place in an aqueous medium with the water content 40 - 80 % of weight. A plasticizer - e.g. polyethylene glycol - can be used for tack development. The plasticizer may increase tack, however it decreases gel strength.

To achieve a more effective process cumulating two operations into one. a method described in US patent No. 5,540,033 regarding production of a sterile packaged adhesive hydrogel product was developed. The composition containing the polymer cross-linkable by irradiation and a cross-linking inhibitor is shaped into a desired shape by a common way, subsequently the shaped mixture is enclosed into a sealed package and subjected to dose of radiation sufficient to simultaneously cross-link and sterilize the mixture in order to obtain the final hydrogel product. Polymers used in this method are mainly polyethylene oxide, polyvinylpyrrolidone and/or mixture thereof (pref. 15 -25 % of weight of polvinylpyrrolidone). A cross-linking inhibitor is preferably an antioxidant as ascorbic acid. Regarding further additives a humectant such _:as polyethylene glycol can be used so as to improve the physical properties of the hydrogel. Also, cross-linking promoter as is ethylene glycol dimethacrylate can be present. This method can provide hydrogel with at least 80 % gel value and absorptive capacity (measured by the gel ratio) at least 5. This sophisticated composition reaches further improvement inthe properties of hydrogel and allows to cross-link and to sterilize the product in one step. However, the content of synthetic polymer and. the number of additives can lead to higher costs of obtained products.

The geWbrming system according to US patent No. 5,578,661 comprises an aqueous mixture of at least three polymeric components. The first of them is a water-soluble polymer, e.g. polyvinylpyrrolidone, in an amount of 3 - 5 % of weight. This component, can be mixed with polyethylene, oxide in a weight ratio from 10: 1 up to 25: 1. The second .polymeric component is an acid-containing polymer and the third polymeric component is an , ammo-containing polymer, e.g. heparin and . agar. The composition can also include additional components as bactericides and antibiotics for the curative actions, and humectant for increasing the solubility of the third or second component in the mixture. Such humectant is preferably polyethylene glycol. Regarding the content of polyvinylpyrrolidone in examples there is presented the content of 10 % of weight of the mixture. The gel ratio as a measure of the absorption capacity of hydrogels is able to exceed 5. This gel-forming system contains a great portion of polymeric components and manifold number of further components and so it can be rather expensive as well as the previous one.

Following the above mentioned hydrogel systems in order to further improve the physical properties of the obtained hydrogel materials in wound dressing, in particular the mechanical, swelling and drying properties, the material according to US patent application No. 2008/0033064 has been developed. This method of preparing hydrogel for wound dressing comprises the step of providing initial aqueous solution containing at least 15 % of synthetic polymer cross-linkable by irradiation (based on the weight of the mixture) at least one humectant,. a natural polymer and water, pouring the initial aqueous solution into a mould for shaping, allowing the aqueous solution to mature in the mould during a period of time sufficient to obtain a semi-product having a content of at least 35 % of synthetic polymer, removing the semi-product thus shaped from the mould and subjecting the semi-product to irradiation in order to cross-link an sterilize the semiproduct. The aqueous solution comprises at least 15 % of synthetic polymer, which is cross-linkable by irradiation. This hydrogel system as described allows to achieve even better properties of the final product - hydrogel for w und dressing and, moreover, the method couples advantageously two steps - cross-linking and sterilization. However, the efficiency of this system - as well as of the previous ones - depends on the content of the irradiation cross-linkable polymer - polyvinylpyrrolidone. In order to fulfil this requirement on the content of polyvinylpyrrolidone there are lowered the other characteristics of the hydrogel, which have to be thereafter improved by adding of further components to this system. Thus the result price of hydrogel increases. This is the main disadvantage of the methods of preparing the hydrogel for wound dressing known so far which however cannot be overrun without essential change in formation of these hydrogels and in the technological process.

So as to restrain the above mentioned disadvantages and insufficiencies of the hydrogel for wound dressing known so far in preparation technologies , the hydrogel for wound dressing according to CZ utility model 18770 has been developed. The principle of the related technical solution consists in that the hydrogel contains polyvinylpyrrolidone having molecular weight of 30 -50,000 Dalton, carboxymethyl cellulose or collagen, agar, polyethylene glycol having molecular weight of 200 - 20,000 Dalton, glycerin, and respectively contains at least one antibacterial and/or antiseptic agent, advantageously boric acid, whereas all the mentioned components together gain 0 - 10 w/v % of hydrogel and the remaining part onto 100 w/v % amount of water.

Hydrogel for wound dressing according to the mentioned utility model has got advantageously a round or square shape, thickness of 2 - 3 mm and the area of 500 - 6000 mm².

The resultant product has about 94-90 % moisture content. The weight decrease in final product (hydrogel) from the initial weight of solution is about 10 - 30 %. Regarding the main polymers, it is possible to complement polyvinylpyrrolidone by using either carboxymethyl cellulose or collagen to achieve more or less similar performance.

Regarding the other components, agar acts as a gelling agent, polyethylene glycol performs as a healing component and glycerin represents humectant. Boric acid - if used - acts as antiseptic cum antibacterial agent. Presence of boric acid within hydrogel for wound dressing resists microbial infection on minor burns and cuts of skin besides providing cool feelings.

The considerable advantage of the hydrogel for wound dressing according to this utility model is its cost effectiveness. This hydrogel is eco-friendly and easy to store and use. Regarding its end-user qualities, this hydrogel for wound dressing due to its semi transparent character allo ws instant monitoring of healing process w hich is a very important advantage. Moreover, it improves the conditions of healing process thanks to its praiseworthy absorption capability. Besides, this hydrogel is not sticky on the skin.

The last mentioned hydrogel represents a very good and successful alternative in the field of healing hydrogels. However, this one as well as all the previously known hydrogels for medical use are delivered on the market in the wet form, with the great content of water. This fact is caused by the effort to reach the highest user comfort enabling the promptness of using; however, on the other hand, it has more considerable disadvantages. The main common disadvantage of all so called "wet hydrogels" is the fact that they cannot be stored for a long time (loss of water, germs proliferation). Simultaneously the wet hydrogels are very sensitive and demanding so as to maintain the sterilized, germ free conditions during the handling and storage. Moreover, the wet hydrogels contain usually up to 95% water, which is almost state equilibrium, thus they are not able to absorb much exudates during the healing process, which is their considerable disadvantage. The high weight content of water by wet hydrogels leads to multiple increasing of their delivery costs and thus the increase of final price of product.

Nature of the invention

The stated disadvantages and inefficiencies of so far known hydrogels for wound dressing and the ways of their preparation have been to a large extent removed at the dry material of hydrogel for wound dressings as per the invention and the way of production of the substance of the hydrogel. The nature of the invention lies in the fact, that the hydrogel substance contains gelatin and Sodium alginate in weight ration of 3:7 - 7:3, where both these components represent 100 of wt. pts. of the mixture; parallel to this the dry substance also contains polyethylenglykol in the amount of 15-25 wt. pts., 15-25 wt. pts. of glycerine, nanofibres of polyvinyl alcohol in the amount of 10-40 wt. pts., sodium chloride in the amount of 1-3 wt. pts., eventually other usual ingredients. The dry substance of the hydrogel may further contain sea buckthorn oil in the amount of up to 15 wt. pts. This dry substance has a flat shape, pref. round of square, is usually l-2mm thick and has area of 40-200 000 mm².

The preparation method of the dry hydrogel material according to the invention lies preparation of a base water polymer solution of gelatin by continuous stirring of gelatine in 180-220 wt. pts. of water at constant temperature between 75 and 85 Celsius degrees. After complete dissolving of the gelatine volume other components are being added (except for nanofibres) and the mixture is again continuously stirred for 5 to 6 minutes at the speed of 250-350 r.p.m., whereby a viscid substance is created. Afterwards fractions of nanofibres of polyvinyl alcohol are gradually added, and the speed of stirring is decreased to 150-50 r.p.m.; finally the viscid substance is poured to flat dishes and is left to mature at room temperature of 20-25 Celsius degrees until all water has been evaporated and the final dry hydrogel substance is achieved.

Gelatine helps regeneration of damaged tissues and absorbs blood of detached body fluids. Sodium alginate holds back water and acts as antimicrobial agent. Polyethylenglykol acts as a substitute of damaged skin membrane, glycerine as a humectant agent, natrium chloride as surfactant. Nano fibres of polyvinyl alcohol create a fibre matrix and improve mechanical strength of the achieved whole. Sea buckthorn oil acts as a healing agent and also helps to diminish subsequent scarves of healed wounds.

The main advantage of the dry material of hydrogel for wound dressing according to this invention is its' long term storage capacity/ability, in comparison to the known "wet" hydrogels. There are two main reasons for its prolonged longevity: there is no danger of loss of water and, moreover, in the dry substance the germ proliferation is extremely reduced.

Another important advantage of the dry material of hydrogel for wound dressing according to this invention is the fact that the weight of dry hydrogels is reduced under 50% (ca 40%) compared to wet hydrogels. The products of the invention are light and so their delivery costs are lowered, too.

One more important advantage of "dry" hydrogels as per the invention is the fact that they can be prepared before use with lower degree of saturation by water - under the equilibrium point - and so they can absorb subsequently absorb a lot of exudates during the healing process.

The described hydrogels according to this invention can contain some additional medicines - water soluble means for wound protection, healing acceleration and prevention of wound infection. The resulting wet matrix prepared before use is macroporous and has therefore good oxygen diffusion properties. Thanks to the presence of polyvinyl alcohol nanofibres, the hydrogel according to the invention can be used as gauze pad or sponge dressing for external use. Examples

The invention is closely explained through the examples of specific implementation as follows.

E x a m p l e 1

The initial polymer solution, containing 40 wt. pts of gelatin in 190 vvt. pts of water was achieved through continuous stirring at the constant temperature of 75°C. As soon as the entire volume of gelatin has been dissolved, further components were added: sodium alginate 60 wt. pts, polyethylene glycol 16 wt. pts, sodium chloride 1 ,5 wt. pts, glycerin 16 wt. pts; stirring of this mixture continued for 5 min at 250 rpm. To the resulting viscous hydrogel mass then slowly a fraction of polyvinyl alcohol nanofibres in an amount of 15 wt. pts was added, the mixing speed of the viscous mass was reduced till 60 rpm. Finally, the viscous mass was dosed in aseptic environment to set of acrylic dishes with diameter of 25 mm and thickness 2 mm. Afterwards the hydrogel was removed from the dishes and was left to dry at room temperature of 20°C. During the incubation process the whole volume of water was removed from the viscous mass and the final dry material of hydrogel has been achieved. The resulting product of pale yellow colour has got the thickness of 1.4 mm and area of 490 mm².

When using the product for wound dressing on human or animal body, it is necessary prior to its application to dip it in sterile distilled water at room temperature under aseptic environment.

E x m p l e 2

The initial polymeric solution, containing 60 vvt. pts of gelatin in 210 vvt. pts of water was achieved through continuous stirring at the constant temperature of 85°C. As soon as whole volume of gelatin has been dissolved further components were added: sodium alginate 40 wt. pts, polyethylene glycol 24 wt. pts, sodium chloride 2,5 wt. pts, glycerin 24 wt. pts; stirring of this mixture continued for 6 min at 350 rpm. To the resulting viscous hydrogel mass then slowly a fraction of polyvinyl alcohol nanofibres in an amount of 35 wt. pts was added, the mixing speed of the viscous mass was reduced to 140 rpm. Finally, the viscous mass was under aseptic environment dosed to a set of acrylic dishes with diameter 25 mm and thickness 2 mm where it incubated and dried at room temperature of 25°C. During the incubation process whole volume of water was removed from the viscous mass and the final dry substance of hydrogel has been achieved. The resulting product of pale yel low colour has got the thickness of 1 .6 mm and area of 490 mm².

When using the product for wound dressing on human or animal body, it is again necessary prior to its application to dip it in sterile distil led water at room temperature under aseptic environment.

Industrial Applicability

The hydrogel for wound dressing according to this invention will be used for medical purposes for treating burns and large wounds. It can be applied in the area of surgery in the postoperative care as it enables easy and painless monitoring of the healing process. Thanks to its absorption capability it will find use also in special purposes like covering of slowly healing or very damaged tissues. The hydrogel wound covering according to this invention can help also in crisis situations for prompt first-aid treatment of wounded persons. Applications in veterinary medicine are possible, too.

Claims

C L A I M S

1. Dry material of hydrogel for wound dressing made from natural and synthetic polymers, characterized by that it contains gelatin and sodium alginate in weight ratio 3:7 - 7:3, whereas this two parts together constitute 100 wt. pts and, simultaneously, the substance contains polyethylene glycol 15-25 wt. pts, glycerin 15-25 wt. pts, polyvinyl alcohol nanofibers 10 - 40 wt. pts, sodium chloride 1 - 3 wt. pts, eventually other usual additives.

2. Dry material of hydrogel for wound covering according to claim 1, characterized by that it contains sea-buckthorn oil up to 15 wt. pts.

3. Dry material of hydrogel for wound covering according to claim ^characterized by that it has got the flat shape, preferably round or oval shape, the thickness 1 -2 mm and the area 400 to 200000 mm²

4. A method of preparing the dry material of hydrogel for wound dressing according to claim 1, eventually claim 2 and/or 3, consisting in physical technique under control heating, characterized by that initial aqueous polymeric solution of gelatin will be achieved during continuous stirring it in 180 - 220 wt. pts of water at the constant temperature 75 - 85°C, after dissolving whole volume of gelatin further components such as sodium alginate, polyethylene glycol, sodium chloride, glycerin and respectively sea buckthorn oil will be added to the initial aqueous polymeric solution of gelatin, whereupon stirring of this mixture will continue for 5 - 6 min at 250 - 350 rpm in order to a viscous hydrogel mass will be developed, then slowly a fraction of polyvinyl alcohol nanofibers will be added whereon the mixing speed of viscous mass will be reduced till 150 - 50 rpm, finally, the viscous mass will be poured into acrylic dishes of 25 mm diameter where it will be incubated at room temperature of 20 - 25°C until the whole volume of water is removed and the final dry substance of hydrogel is achieved.