EP1109584A1

EP1109584A1 - A composition capable of absorbing fluid

Info

Publication number: EP1109584A1
Application number: EP99938200A
Authority: EP
Inventors: Brian Nielsen
Original assignee: Coloplast AS
Current assignee: Coloplast AS
Priority date: 1998-08-31
Filing date: 1999-08-25
Publication date: 2001-06-27
Also published as: WO2000012144A1; AU5279299A

Abstract

A composition capable of forming a coherent gel when contacted with an aqueous fluid, said composition comprising a water soluble polymer, said polymer, when dissolved in an aqueous fluid, forms a water insoluble gel, characterized in that said composition comprises a non-aqueous mixture of at least two water soluble polymers or a salt thereof, said polymers having opposite charges and forming, when dissolved in an aqueous fluid, a water-absorbing, water-insoluble, coherent gel.

Description

TITLE

A composition capable of absorbing fluid.

FIELD OF THE INVENTION

The present invention relates to a composition, which is capable of absorbing fluids and at the same time forming a coherent gel. The composition may be used as an absorber in wound care products, sanitary articles, continence care, ostomy care or as an absorber in general.

In the treatment of chronic wounds it is desirable to have a product being able to adapt to the conformation of the wound, and at the same time being easy to remove from the wound. Pressure sores may e.g. have deep cavities and are often very suppurative. For this purpose, it is desirable to have a dressing being able to fit as tailored into the wound cavity and at the same time absorbing the exsudate coming from the wound. When the dressing needs to be exchanged, it is desirable if the dressing can be removed in one piece, without leaving remains of the dressing in the wound.

Powders, pastes, or fibre dressings for wound care which are capable of forming gels or foams when contacted with aqueous fluid are disclosed in several publications. Most of the references disclose dried gels, e.g. calcium alginate fibres and powders/pastes comprising cross-linked swellable particles. Usually these compositions comprises particles or fibres of dried gels being capable of absorbing wound exudate, but during the absorption there is little or no interaction or cross-linking between the involved molecules, and thus the wetted material will have a poor cohesion. The gel forming process does not take place when the composition is absorbing wound exudate from a wound, but during the prepara- tion of the composition before application to the wound.

European patent No. EP 0 048 323 discloses a wound treatment composition which comprises e.g. acrylpolymers and gellable polysaccharides. The compounds are brought in solution and mixed, and hereby form a gel. The gel is then dried and pulverised. When this powder is applied to a wound, the particles will swell absorbing the wound exudate, but remain insoluble and with no cohesion.

International patent application No. WO 92/00108 discloses a method of prepar- ing a water insoluble powder which is capable of absorbing aqueous or serous fluids as well as blood. The composition comprises independent cross-linked particles with little or no cohesion to one another.

In European patent application No. EP 0 380 253 A2 is disclosed a method for preparing a gel formed-in-place in the wound. The gel is formed by adding two liquids to the wound, said liquids reacting to form a gel with high cohesion.

However, the compounds has to be present as liquid suspensions, which gives a very limited absorption. The composition comprises an alginate (polysaccharide) and a cross-linking agent selected from di- or trivalent metal ions.

International patent application No. WO 97/33632 as well as European patent application No. EP 0 380 253 discloses a gel formed in situ from alginate and metal ions such as calcium. The composition comprises finely divided alginate and a finely divided carrier material (powder). As the powder absorbs fluid and dissolves the calcium ions, a calcium alginate gel is formed. The references are silent with respect to the cohesion and absorption. The gels are intended to serve as a matrix/carrier for antimicrobial compounds.

The above mentioned references disclose wound care products, being capable of adapting to the conformation of the individual wounds but they are difficult to remove from the wound in one piece and/or they have limited absorbing capacity. Dressings, such as fibre dressings, foams and hydrocolloids are easily removed in one piece, but they usually have a predetermined shape and are thus not able to adapt to the specific conformation of the individual wounds. Thus, there is still a need for a wound care dressing being capable of fitting individually to wounds as well as being easy to remove from the wound without remains and, at the same time, having a high absorption.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a composition capable of forming a coherent gel when contacted with an aqueous fluid, said composition comprising a water soluble polymer, said polymer, when dissolved in an aqueous fluid forms a water insoluble gel, to a method of preparation of such a composition and the use of such a composition for forming, in situ in a wound, a water insoluble, coherent gel.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a composition capable of forming a coherent gel when contacted with an aqueous fluid, said composition comprising a water soluble polymer, said polymer, when dissolved in an aqueous fluid, forms a water insoluble gel, said composition being characterised in that comprises a non-aqueous mixture of at least two water soluble polymers or a salt thereof, said polymers having opposite charges and forming, when dissolved in an aqueous fluid, a water-absorbing, water-insoluble, coherent gel.

It has surprisingly been found that when combining at least two water soluble polymers or a salt thereof, said polymers having opposite charges it is possible to form a gel in situ in a wound by applying the composition of the invention in the form of a powder which will then absorb moisture from the wound and form a water-absorbing, water-insoluble, coherent gel filling the wound cavity. The coherence of the gel enables a removal thereof as an integral unit without leaving remains in the wound.

The invention also relates to a method for the preparation of a composition capable of forming a coherent gel when contacted with an aqueous fluid, said composition comprising a water soluble polymer, said polymer, when dissolved in an aqueous fluid, forms a water insoluble gel, said composition being characterised in that comprises a non-aqueous mixture of at least two water soluble polymers or a salt thereof, said polymers having opposite charges and forming, when dissolved in an aqueous fluid, a water-absorbing, water-insoluble, coherent gel in which the water soluble polymers in the form of powders are mixed intimately, optionally together with a pharmaceutical ingredient.

The present invention furthermore relates to the use of a composition capable of forming a gel when contacted with an aqueous fluid, said composition comprising at least two water soluble polymers which, when dissolved in an aqueous fluid, forms a water-absorbing, water-insoluble, coherent gel, said composition comprising a non-aqueous mixture of at least two water soluble polymers or salt thereof, said polymers having opposite charges for forming, in situ in a wound, a water-insoluble, coherent gel.

In one embodiment of the invention the composition comprises at least two differ- ent polymers, said polymers having functional groups of opposite charges.

The polymer used according to the present invention may be polyionic/polyfunc- tional polymers such as polysaccharides, synthetic or semi-synthetic polymers or cellular or extracellular materials. It is preferred to use polysaccharides.

In a preferred embodiment of the composition according to the invention it comprises at least two hydrophilic, water soluble polymers with opposite charged functional groups. When these polymers are brought in contact with an aqueous fluid, they begin to dissolve. As the polymers dissolves the opposite charged functional groups will form ionic links between the polymers, hereby forming a coherent gel, said gel being water insoluble, but water absorbing and water- swellable. The gel may have an extremely high cohesion due to the number of cross-linking points and the conformation of the polymers. Thus, when a composition according to the invention is applied to a wound, it will start absorbing exudate and forms a gel filling a wound cavity. It is preferred that the polysaccharides used according to the invention include ionically charged derivatives of cellulose such as CMC, ionically charged derivatives of hemicellulose, ionically charged derivatives of chitin, chitosan or derivatives thereof, ionically charged derivatives of starches, alginates, pectin/pectat or derivatives thereof, carboxy methyl glucan, hyaluronic acid, carragenans, ionically charged derivatives of glycomannan, xanthan, ionically charged derivatives of guar gum, ionically charged derivatives of locust bean gum, glucosamines, gluco- saminoglycans such as heparan sulphate, chondroitin sulphate or keratan sulphate, and proteins and polypeptides such as heparin or collagen.

It is especially preferred to use polysaccharides such as CMC or other ionically charged cellulose derivatives, ionic charged chitin derivatives, chitosan or derivatives thereof, alginates, pectin/pectat, hyaluronic acid, carragenans, ionically charged derivatives of guar, glucosaminoglycans such as chondroitin sulphate, keratan sulphate or carboxy methyl glucan.

The polymers are preferably present in a water soluble form, which some polysaccharides only are, when they are present as a salt. This applies for CMC, chitin derivatives chitosan or derivatives thereof, alginates, pectin/pectat, hyaluronic acid, carragenans, xanthan, derivatives of guar, derivatives of locust bean gum, glucosamines, glucosaminoglycans such as heparan sulphate, chondroitin sulphate or keratan sulphate.

The composition according to the invention comprises a mixture of anionic and cationic polymer in the ratio of 10/90 - 90/10, more preferred 20/80 - 80/20 and most preferred 70/30 - 30/70.

Cationic functional group linked to a polymer according to the invention may e.g. be amines, phosphines or imines. The amine groups may be primary, secondary or tertiary amines. Anionic functional group linked to a polymer according to the invention may e.g. be groups such as phosphate, sulphate, thiosulphate, carboxyl or functional groups such as acid chlorides or anhydrides.

A preferred embodiment of the invention comprises sulphate, carboxyl or phosphate as anionic groups, and primary amine groups as cationic groups attached to a polymer, preferably a polysaccharide.

Normally the polymers are only soluble in water when the functional groups are charged. This means that the polymers usually are in the form of a salt, such as sodium alginate instead of alginic acid.

If the polymers not are charged, and hence water insoluble, the polymer can be given a charge by treatment with a solubiliser to provide a polymer salt, which is then dried and pulverised. Alternatively, the cationic and anionic polymer powders are blended with a solubiliser in a dry form. When the composition is wetted, the solubiliser will dissolve first, and then dissolve the polymers, whereafter the gel is formed by the cross-linking of the polymers.

If one of the polymers are not present in a water soluble form, the composition may also comprise a solubiliser. If the composition e.g. comprises alginic acid and chitosan glutamate, the right amount of sodium hydroxide may be incorporated in the composition. Hereby when the composition is contacted with an aqueous fluid, the sodium hydroxide solubilises the alginic acid by turning it into sodium alginate. Solubilised sodium alginate and chitosan glutamate will then form a gel.

In a preferred embodiment of the invention is used a chitosan salt, which is cationic in aqueous solution and carboxy methyl cellulose (CMC) salt and/or hyaluronic acid salt, which is anionic in aqueous solution. The composition according to the invention can be used in different physical forms, e.g. as powder, granulate, paste/cream or as fibres.

The composition of the invention may be prepared by a mixing procedure known per se from mixing of dry constituents. The composition may be packed in metered quantities for single or multiple applications.

In one embodiment of the invention, the composition is used in the form of a wound care product such as a wound dressing. The composition according to the invention comprises both a cationic and an anionic charged polymer. The polymers are present in a powder form, where the powders are homogeneous mixed into a powder mixture. When the powder mixture is spread on an exuding wound, the polymers will absorb the wound exudate and begin to dissolve. The dissolved polymers will cross-link and form a coherent gel, adapting the same shape as the wound. The thus formed gel is water-insoluble, but water absorbing, and will continue to absorb wound exudate after the formation of the gel. When the dressing needs to be changed, the cohesion of the gel will be so high, that the gel can be removed in one piece from the wound.

In order to provide a handle to the gel for facilitating the removal thereof, a strip of web, e.g. gauze or cotton, can be placed in the wound cavity before applying the composition. The strip does not necessarily cover all of the wound, but will extend across the limit of the wound at least at one side. When the coherent gel is formed due to the wetting of the polymers, the strip will be incorporated in the gel. When the dressing needs to be exchanged, the part of the strip extending from the wound area will provide a grip or handle, which can be used to lift off the gel without having to pick or peel in the wound to grip the gel.

In another embodiment of the composition of the invention the polymer powders are homogeneously dispersed in a substantially non-aqueous, liquid carrier, giving a composition in the form of a more or less viscous cream/paste. The paste or cream is brought in contact with an exuding wound, absorbs the wound exudate and turns into a coherent gel.

In a third embodiment of the composition of the invention the polymers are present in the form of a fibre bandage. When the fibres are wetted by the exudate, the polymers are dissolved and the fibre structure of the composition disappears and turns into a coherent gel. Despite the fact that such bandage consists of a gel made by dissolved fibres, there will be no fibres left in the wound when the dressing is removed from the wound.

The composition can be used as such or as a part of a wound dressing optionally covered with top a film and optionally a release liner.

In another embodiment of the invention the composition comprises one polymer having functional groups of opposite charges. The polymer present can be poly- functional/polyionical with both anionic and cationic groups attached to the polymer. Such a polymer may be a polymer having both amines and acid groups attached to the polymer.

An example of such a composition could be sodium carboxy methyl chitosan acetate (a salt of carboxy methyl chitosan).

In a still further embodiment of the invention the composition comprises one or more active ingredients, e.g. a pharmaceutical medicament. This opens for a combined medical treatment of a wound, where the polymers absorb wound exudate and the pharmaceutical medicaments will be applied to the wound. The pharmaceutical medicaments will either be incorporated in the dressing or migrate to the wound surface and promote its function. .

Examples of such pharmaceutical medicaments includes a cytochine such as a growth hormone or a polypeptide growth factor such as TGF, FGF, PDGF, EGF, IGF-1, IGF-2, colony stimulating factor, transforming growth factor, nerve stimulating growth factor and the like giving rise to the incorporation of such active substances in a form being apt to local application in a wound in which the medicament may exercise its effect on the wound, other medicaments such as bactehostatic or bactericidal compounds, e.g. iodine, iodopovidone complexes, chloramine, chlorohexidine, silver salts such as sulphadiazine, silver nitrate, silver acetate, silver lactate, silver sulphate, silver sodium thiosulphate or silver chloride, zinc or salts thereof, metronidazol, sulpha drugs, and penicillin's, tissue- healing enhancing agents, e.g. RGD tripeptides and the like, proteins, amino acids such as taurine, vitamins such ascorbic acid, enzymes for cleansing of wounds, e.g. pepsin, trypsin and the like, proteinase inhibitors or metalloprote- inase inhibitors such as lllostat or ethylene diamine tetraacetic acid, cytotoxic agents and proliferation inhibitors for use in for example surgical insertion of the product in cancer tissue and/or other therapeutic agents which optionally may be used for topical application, pain relieving agents such as lidocaine or chincho- caine, emollients, retinoids or agents having a cooling effect which is also considered an aspect of the invention.

The invention is explained more in detail in the working examples below disclosing embodiments and properties of compositions of the invention. It is evident that many variations may be made without diverging from the invention the scope of which is set forth in the appended claims.

MATERIALS AND METHODS

DETERMINATION OF ABSORPTION AND COHESION Determination of the absorption and cohesion was carried out using an agar plate. Upon the agar plate a cotton web strip was placed, only covering a part of the agar. A metered amount of the powder mixture was evenly spread on top of the agar, and the container was then sealed occlusively for 16 hours. The powder, now having absorbed liquid from the agar and thereby turning into a gel, was then removed and weighed, and the absorption was calculated in g/g. The cohesion of the gel was determined when the gel was removed from the agar and was classified according to the rating indicator shown in the Table 1 below.

Following polymer materials were used:

Cao chitosans from Sonat YC - chitosans form Youngdeok Chitosan CO., LTD. CC - chitosan from Seafresh Chitosan CO., LTD. BEI - chitosan from Biopolymer Engineering Inc. SeaCure 343 from Pronova Biopolymers Sodium alginate from Danisco Ingredients Akucell 0701 from Akzo Nobel Sodium Hyluronate from Pronova Carrageenan from Hercules

Table 1

The absorption and cohesion of different gels were tested, as described in the following examples.

EXAMPLE 1

Preparation of powdery compositions according to the invention:

In the following examples, chitosan is used as cationic component. The chitosan was dispersed in water. Then, the chitosan was dissolved in the water by adding acetic acid to the dispersion turning the amino groups of chitosan from non-ionic R-NH₂ into cationic R-NH₃ ⁺ groups. The solution was freeze-dried and pulverised, providing a chitosan salt powder. The cationic powder is mixed until homogeneity with an anionic powder prepared in an analogous manner from CMC using NaOH. If not otherwise stated, the mixture was a ratio of 50 % of each polymer.

EXAMPLE 2 Preparation of the gels according to the invention and determination of the influence of the viscosity of the cationic component on the absorption and cohesion. The gels according to the invention were prepared as disclosed in Example 1. The results of the test are listed below in Table 2.

Table 2

Dynamic viscosity: 1% solution in 1 % acetic acid, capil ary viscosimeter.

As appears from the table, the higher molecular weight of the polymers, the higher absorption and cohesion is achieved.

EXAMPLE 3 Influence of different types of chitosans from different suppliers with respect to absorption and cohesion when used as cation in a composition according to the invention prepared as disclosed in Example 1. The results appear from Table 3. Table 3

As appears from the table, the different chitosan cations have different absorption and cohesion properties. It is thus possible to adjust the absorption and cohesion to a desired value.

EXAMPLE 4

Influence of different anionic polymers from different suppliers has been tested in the same manner. The influence on the absorption and cohesion properties of the gel is listed in the below Table 4.

Table 4

* not measurable

It appears from the table that the absorption and cohesion properties vary with the structure of the anions. This indicates that some anions are more preferred than others depending on the desired properties.

EXAMPLE 5

Influence of different organic acids used for dissolving chitosan. The influence on the absorption and the cohesion properties of the gel are shown in Table 5 below. Table 5:

As appears from the table, the choice of solubiliser has influence on the absorption and cohesion properties of the gel.

EXAMPLE 6

This example will indicate the maximum absorption capacity of the powders/gels. After a gel was formed using the procedure of example 1 , the gel was immersed in excess saline water for further 24 hours, allowing the gel to absorb liquid and become completely saturated. The absorption was calculated in g/g. The cohesion, when maximum absorption is reached, was also determined. The results appear from Table 6.

Table 6

As can be seen from Table 6, the composition of the invention still has a high absorption capacity after the gel is formed combined with a strong cohesion.

EXAMPLE 7

Use of more than two polymers. A gel was prepared as shown in Example 1 , with the exeption that the anion was substituted by two anions, so the ratio between cation/anions was 50/25/25. The cohesion and absorption was determined. The results appear in Table 7. Table 7

EXAMPLE 8

Different ratio of cation/anion. A gel was prepared as shown in Example 1 , with the exeption that the ratio between cation/anion was 65/35. The cohesion and absorption was determined. The results appear in Table 8.

Table 8

Claims

1. A composition capable of forming a coherent gel when contacted with an aqueous fluid, said composition comprising a water soluble polymer, said polymer, when dissolved in an aqueous fluid, forms a water insoluble gel, charac- terised in that said composition comprises a non-aqueous mixture of at least two water soluble polymers or a salt thereof, said polymers having opposite charges and forming, when dissolved in an aqueous fluid, a water-absorbing, water- insoluble, coherent gel.

2. A composition as claimed in claim 1 , characterised in that the polymers comprise functional groups of opposite charges.

3. A composition as claimed in claim 2 characterised in that the cationic functional groups are amines, such as primary, secondary or tertiary amines, phosphines or imines.

4. A composition as claimed in claim 2 or 3, characterised in that the anionic functional groups are phosphate, sulphate, thiosulphate or carboxyl groups.

5. A composition as claimed in any of claims 1 - 4, characterised in that the polymers are polyionic polymers such as a natural or synthetic or semi-synthetic polymer such as a polysaccharide, a protein or a cellular or extracellular material.

6. A composition as claimed in any of claims 1 - 5 characterised in that the cationic polymer is chitosan and the anionic polymer is a salt of carboxy methyl cellulose (CMC) or of hyaluronic acid.

7. A composition as claimed in any of claims 1 - 6 characterised in that the composition is in the form of a powder or a granulate or fibres or in the form of a non-aqueous paste.

8. A composition as claimed in any of claims 1 - 7 characterised in that it comprises one or more active ingredients such as a pharmaceutical medicament.

9. Use of a composition capable of forming a gel when contacted with an aqueous fluid, said composition comprising at least two water soluble polymers which, when dissolved in an aqueous fluid, forms a water-absorbing, water- insoluble, coherent gel, said composition comprising a non-aqueous mixture of at least two water soluble polymers or salt thereof, said polymers having opposite charges for forming, in situ in a wound, a water-insoluble, coherent gel.

10. A method for the preparation of a composition capable of forming a coherent gel when contacted with an aqueous fluid, said composition comprising a water soluble polymer, said polymer, when dissolved in an aqueous fluid, forms a water insoluble gel, said composition being characterised in that it comprises a substantially non-aqueous mixture of at least two water soluble polymers or a salt thereof, said polymers having opposite charges and forming, when dissolved in an aqueous fluid, a water-absorbing, water-insoluble, coherent gel in which the water soluble polymers in the form of powders are mixed intimately, optionally together with a pharmaceutical ingredient.