WO2001045762A2

WO2001045762A2 - Wound healing medical pharmaceutical product

Info

Publication number: WO2001045762A2
Application number: PCT/BE2000/000150
Authority: WO
Inventors: Philippe Sollie
Original assignee: Flen Pharma, Naamloze Vennootschap
Priority date: 1999-12-20
Filing date: 2000-12-19
Publication date: 2001-06-28
Also published as: WO2001045762A3; AU5441001A; BE1013184A3

Abstract

The invention is related to a medical pharmaceutical product for topical use with a medically acceptable hydrophobic polymer that - once applied on a wound - cooperates with the wound and reacts with the produced wound exudate in such a way that the hydrophobic polymer is partially transformed into a hydrophilic polymer that creates a dispersion that is able to absorb wound exudate and that can dose the latter.

Description

Wound healing medical pharmaceutical product

The invention is relating to a medical pharmaceutical product with the which is principally intended for regulation of the moisture content of an open w ound, dependant on the state and the healing progression of the wound

In order to accelerate the healing of a wound, it is tried to keep the wound moist According to the state of the art, products applied on wounds are to be chosen according to the nature of the wound As it happens, a dry wound is treated with a dressing that has the capacity to hydrate the wound, while an exuding wound is treated with a moisture absorbing dressing, that removes the superfluous moisture from the wound surface The dressing applied on a moist wound will ensure that existing exudate is kept on the wound bed.

Hydrophi c polymers like cellulose polymers, pyrro don polymers, gelatine like polymers etc. are generally used in these dressings to bind wound moistuie

According to state of the art, for example, the natural Calcium algmate polymer, with neutral pH, is applied on a wound, under a dressing. Hereby, Calcium ions of the algmate polymer are exchanged with Sodium ions of the wound exudate as a result of which Sodium algmate is formed having other properties than Calcium algmate This Sodium algmate is a better gel-formmg agent thereby keeping the wound moist, which promotes healing of the wound.

During this ion exchange, the net concentration of ions in the polymer and m the wound exudate remains constant. The pH of the Algmate is also kept unchanged and neutral This state of the art has as a disadvantage that for each type of wound another dressing will have to be selected in order to approximate the ideal moist content for the healing of the wound. A dressing that has been applied will, as the wound is healing, become less appropriate. Furthermore, according to the state of the art, it is not possible to treat a mixed wound, having certain parts exuding while other parts are dry, in an ideal way This invention will remedy these disadvantages by presenting a medical pharmaceutical product that does not have these disadvantages, that furthermore ensures a better wound healing and has a controlling effect on micro-organisms such as bacteria

The main purpose of this invention is to present a medical pharmaceutical product, of which the composition and effect evolves along with the changing condition of the wound If, for example, in an initial phase, the wound exudes a lot, the product will absorb more moisture, according to the invention, while, when the wound is more dry, the product will promote a flow of moisture to the wound Moreover, the product acts very locally, so that, when applied on a mixed wound, each part of the wound is moistened m the most appropriate manner

To this purpose, the product contains, according to the invention, a medical acceptable hydrophobic polymer that, once applied on the wound, cooperates with the wound and reacts with the generated exudate, so that this hydrophobic polymer is transformed partially into a hydrophilic polymer, which forms a dispersion that is able to absorb exudate, and to dose the latter.

Functionally, said hydrophobic polymer is provided with free binding acidic functions which react with cationic or alkaline components of the wound exudate, whereby said hydrophobic polymer is transformed into a hydrophihc polymer in a, preferably colloidal, dispersion According to a preferred embodiment of the product, according to the invention, it contains hydrophihc colloids of a medical acceptable polymer with free binding acidic functions, that are partially neutralised, whereby these colloids reveal good hydration properties due to the neutralization of said free binding acidic functions

According to a particular embodiment of the product, according to the invention, said free binding acidic functions are neutralised when they get m contact with cationic or alkaline components of the wound exudate, whereby this neutralisation ensures the further hydration of said colloids.

According to a specific embodiment of the product, according to the invention, said hydrophobic polymer consists of acrylic acid which is transformed into a hydrated polyacrylate that is hydrophihc. Other details and advantages of the invention will appear from the following description of some specific embodiments of the medical pharmaceutical product, according to the invention; this description is only held up as an example and does not limit the scope of the claimed protection. The medical pharmaceutical product, according to the invention, contains a hydrophobic polymer which is applied on a wound, preferentially under a dressing. This polymer is required to be medically acceptable, this means that its toxicity is acceptable and it is not harmful for the body. a polymer with these properties is, according to the invention, selected in such a way that, when it is applied on a wound, it reacts with substances present in the wound exudate in order to regulate the moisture content of the wound.

To this purpose the polymer consists of free binding acidic functions to react with cationic or alkaline components of the wound moisture.

When the product, according to the invention, is applied on an exuding wound the polymer reacts with the wound moisture by extracting ions out of it and, subsequently, by forming complexes or salts. Because of this, the concentration of charged ions or amino acids in the polymer is raised while the concentration of ions or amino acids in the wound is lowered accordingly. Due to this formation of salts and complexes in the polymer, the polymer is partially neutralised and the pH increases, thereby changing the electrostatic properties of the polymer. In this way the polymer becomes, among others, hydrophilic so as to able to absorb wound exudate from the wound when the latter is too moist.

This structural change in the polymer due to complex and/or salt formation on the wound bed does not occur in the applied wound healing products according to the state of the art.

In this way the polymer is activated, whereby, due to the hydrophilic nature of the build up complexes and/or salts, a colloidal dispersion is formed. A gel like product is formed because hydrophilic parts of the colloidal polymer bind wound exudate.

According to these reactions that take place on the polymer, protons are released to benefit the wound healing process. In this way a polymer is used in the invention with such a structure and prepared m such way that the moisture retentive properties of the polymer are dependent upon the presence or absence of chemical substances in the wound exudate These substances are for example, dependent on the nature of the wound, the body's own substances such as inflammation mediators, growth factors, ions, ammo acids, etc

In a preferred embodiment of the product, according to the invention, the polymer is partially hydrated by mixing it with a suitable amount of moisture, for example water, in such way that the polymer is partially neutralised and is transformed into a hydrophilic polymer as a colloidal dispersion The activity of such a polymer is dependent on the presence or absence of wound moisture, also named exudate

In exuding wounds or wounds that are producing moist, certain substances present in the exudate will activate the polymer by forming complexes and/or salts Because of this the moisture binding capacity of the polymer raises and the polymer will absorb moisture out of the wound

In case of a dry wound, in absence of wound exudate, and therefore in absence of these bodies own substances, the polymer is not activated and thus no wound exudate is absorbed Since little or no exudate is present, the polymer will remain hydrophobic and therefore it will not absorb additional exudate from the wound The present moisture, originating from the dressing, is only slightly bound by the non or partially activated polymer and will be transferred preferentially to the dry wound When the product with the polymer is applied m this way on the wound, it will cover this wound through which the evaporation of the moisture is slowed down The acidic pH of the polymer, which exists from the beginning, will control proliferation of microorganisms In a mixed type of wound, the activity of the polymer is dependent, among others, on the presence or absence of the underlying wound exudate Due to local activity of the polymer it will be, dependent on the local situation of the wound, correspondingly locally activated and absorb moisture, or it will be not activated and liberate moisture

Prior to application on a wound, the polymer can be partially activated by electrical charged particles, what bnngs about a limited moisture absorbing capacity Foi this purpose the polymer will be moistened before application on the wound in such a way that a determined amount of moisture will be slightly bound to the polymer

When thereupon the polymer is applied on a dry wound m form of a dressing, this dressing will cede the bound moisture to the dry wound, whereby the wound will absorb this moisture and thus a moist environment is created

When this dressing comes m contact with a wound environment in which new electrical charged particles are present (an exuding wound), the latter will further activate the polymer and the moisture binding forces will increase in a way that the moist exudate is absorbed from the wound The liberated protons will control the proliferation of micro-organisms because of the fact that they will selectively be taken up by the proton pump in the micro-organisms' cell wall

When there is a lot of exudate, the binding force with the particles from the wound exudate will be more pronounced and the polymer will become more hydrophihc compared to a wound with little exudate Consequently, the moist absorbing capacity of the polymer changes proportionally to the amount of exudate m the wound

Different organic acidic polymers can be used for the product m accordance with the invention These polymers were not yet applied in wound care since it was expected that these polymers would have an irritating effect on the wound With the product, according to the invention, it is concluded that, contrary to the expectations, these polymers have a strong healing effect on a wound, which effect is even significantly better than in conventional therapeutic applications for wound healing

Moreover, it has been established that the product, according to the invention, besides the regulation of moisture content of a wound, shows some additional effects such as a shorter healing time and an antimicrobial function Infections of the wound are rarely seen when the product, according to the invention, is applied

The product, according to the invention, can be applied in different ways for the healing of wounds Thus, the concerned polymer can for example, in a well-known manner, be integrated in a dressing or it can be applied on the wound in an ointment By means of illustration of the different possible compositions and manufacturing methods of the product, according to the invention, some examples are given below:

Example 1 :

As polymer a hydrated polyacrylate polymer is used (PP). This polymer forms complexes with electrically charged proteins or amino acids of the wound (possibly as a Zwitter ion). The structure and activity of the polymer is changed by this complexation reaction. Hydration of the polyacrylate polymer (PP) is effected by mixing the polyacrylate with an equal amount of glycerine and an amount of water of five times the amount of polyacrylate polymer and by mixing also with a short measure of electrically charged particles.

This hydrated polyacrylate polymer is applied on the exuding part of the wound so that it can react with Leucine from the wound as illustrated below:

polyacrylate polymer PP + i-Leucine — > [LeucinePP]** + H⁺.

The formed complex [LeucinePP]** has properties that are adapted to the kind of wound where a high concentration of Leucine is present. These new properties concern a better absorption capacity, an improved wound healing effect and an improved effect on microbial flora.

Example 2: Part of an amount of alginate polymer (AP) is hydrated by means of reaction with Lysine (an amino acid). Thus the alginate polymer is hydrated in an analogous way as the polyacrylate polymer in example 1 but with Lysine instead of i-Leucine. On a moist wound the moisture binding activity of this complex is further strengthened by the presence of electrically charged particles in the wound moist (for example Ca^"+ ions, amino acids, proteins).

Thus the reaction with Lysine is written as follows:

2 equivalents [AP] + 1 equivalent Lysine — > 1 equivalent [Lysine AP]*

When the formed product is applied on an exuding wound, the complex [LysineAP]* will react with Sodium ions of the wound exudate and form a new complex with release of protons:

[LysineAP]* + Na⁺ of the wound exudate — > Na [LysineAP]** + H⁺

This complex reveals new properties to be better suited for this kind of wound. This new properties are an improved moisture absorbing capacity, an improved effect on wound healing and on microbial decontamination.

Example 3 :

Drugs can also be used in the hydration reaction of a polymer instead of amino acids, ions or proteins: for example polysihcate polymer (PP). The silicic acid partially reacts with the drug, partially remains as free acid in the product. Lidocain, a local anaesthetic, is used in this example:

[PP] + Lidocain → [Lidocain PP]*

When applied on exuding wounds, this complex will react with Al³⁺ ions for example:

[LidocainPP]* + Al⁺⁺⁺ → Al [LidocainePP]** + H⁺. Alkaloids and corticosteroids can also be used as drugs in this type of products.

Example 4: Also organic ammonia compounds out of the wound moisture can react with the polymer. Pectic acid is used as polymer in the following example. Part of the polymer remains as free acid.

In a first phase the polymer is allowed to react with Lysine according to the reaction equation below: 2 equivalents [PP] + 1 equivalent Lysine — 1 equivalent [Lysine PP]*

Subsequently, this product is applied on an exuding wound, on which a reaction according to the reaction equation below takes place:

1 equivalent [Lysine PP]* + R-NH₄ ⁺ of the wound moisture -» R- NH₄ ⁺[Lysme PP]** + H⁺. This complex reveals new properties to be better suited for this kind of wound. These new properties are an improved moisture absorbing capacity, an improved effect on wound healing and on microbial flora.

Example 5: Other not yet mentioned polymers, that can be used as acid, if necessary after chemical modification, are eligible for the product, according to the invention, if pE < 12,8 and pH of a 1% solution is inferior to 6,5. Preferentially pE < 10 and pH < 5 for a 1% solution of the polymer.

In this case, pE is the equilibrium constant of the following reaction. P + W → PW where P is the abbreviation for the polymer and W is the abbreviation for the body's own particles from the wound. PW is the abbreviation for the complex of both polymer and body's own particles from the wound. The equilibrium constant E of this reaction can be presented in a simplified way by E = (P).(W)/(PW) and, in view of the nature of the reactions, this equilibrium constant E can be approximated by the ionisation constant K of the polymer in water of

25°C. Consequently, the invention is relating to polymers with a pKa or pKb smaller than 12,8.

Examples of such polymers are chemically modified cellulose polymers and starch polymers such as carboxymethylcellulose and carboxymethylstarch.

Hydroxyl groups on these polymers have been replaced by carboxylic acid groups. Consequently, these polymers can also react with cations out of the wound moisture, according to the mechanism described above, to form a consistent colloidal dispersion and create an acidic environment on the wound.

Obviously other acidic groups, like, for example, sulfonic acid groups, can be substituted for carbonic acid groups on the reactive sites of the polymer.

To further illustrate the product, according to the invention, some more concrete and detailed embodiments of the invention are presented below.

Example 6:

22 grams of carboxymethylcellulose is mixed with 7 grams of Sodium hydroxide 9 % in a solution of ethanol ad 100 grams. A diluted solution of NH₄OH is added slowly while stirring until the product has reached such a viscosity that it can be applied easily on the wound.

Example 7:

3 grams of carboxymethylcellulose is mixed with 2,7 grams Arginin in an aqueous solution ad 100 grams. The carboxymethylcellulose polymer is homogeneously dispersed in the water, while under stirring a diluted solution of Arginin is added and if applicable the remaining amount of water.

Example 8: 5 grams of an alginate polymer is homogeneously dispersed in half the amount of glycerine ad 100 g. During the next step a diluted dispersion of Sodium hydroxide is added during intense mixing. Further the remaining part of glycerine is mixed in the thus obtained product.

Example 9:

11 grams of Gastric Mucin polymer is homogeneously dispersed in half the amount of solvent ad 100 grams. The solvent consists of Macrogol, water and ethanol in the proportion 30/60/10. A diluted dispersion of Lidocain is slowly added while intense mixing. Further the remaining part of this solvent is added in the preparation.

Example 10:

65 grams of glycoprotein polymer is homogeneously dispersed in half the amount of solvent ad 100 grams. The solvent consists of glycerine, hexanol and water in a proportion of 60/20/20. During the next step diluted Sodium hydroxide is added slowly while intense mixing. Thereupon the remaining solvent is to be added to this mixture.

Example 11 :

In this example different hydrocolloids are mixed together with tackifying agents in order to get a dressing.

5 grams of Silic acid polymer is homogeneously dispersed in 50 grams of water. A diluted dispersion of Sodium hydroxide is added slowly while intense mixing.

Thereupon 1 gram of Aluminium hydroxide, 7 grams of methylcellulose and 3 grams of pectin are dispersed in this mixture according to a generally known method. Finally another 50 grams of water is added during mixing.

In the example products mentioned above, it is taken care off the fact that during manufacturing a suited product form and product consistency is reached in order to apply it easily on the wound.

Claims

1. Medical pharmaceutical product for topical use, characterised in that it contains a medically acceptable hydrophobic polymer which, when applied on a wound, cooperates with the wound and reacts with the produced wound exudate in such a way that this hydrophobic polymer is partially transformed to a hydrophilic polymer that creates a dispersion that is able to absorb wound exudate and that can dose the latter.

2. Product according to claim 1, characterised in that said hydrophobic polymer shows free acidic groups that react with cationic or alkaline compounds in the wound exudate, by which the hydrophobic polymer is transformed into a hydrophilic polymer in a colloidal dispersion.

3. Product according to any one of claims 1 to 2 characterised in that this contains hydrophilic colloids of a medically acceptable polymer with free acidic groups that are partially neutralised, whereby these colloids show good hydration due to the neutralization of said acidic groups.

4. Product according to claim 3, characterised in that said free acidic groups neutralise when they get in contact with cations or alkaline products of the wound exudate, whereby this neutralization ensures a further hydration of said colloids. 5. Product according to any one of claims 1 to 4, characterised in that the hydrophobic polymer has a pE < 12,8 and that a 1% solution of this polymer shows a pH < 6,

5.

6. Product according to any one of claims 1 to 4, characterised in that said hydrophobic polymer has a a pE < 10,0 and that a 1 % solution of this polymer has a pH < 5,0.

7. Product according to any one of claims 1 to 6, characterised in that said hydrophilic polymer consists of a hydrated polyacrylate.

8. Product according to any one of claims 1 to 7, characterised in that it contains organic acid polymers.

9. A dressing to apply on wounds, characterised in that it contains the product according to one of the claims 1 to 8.

10. A wound healing ointment, characterised in that it contains the product according to one of the claims 1 to 9.