WO2006032464A2

WO2006032464A2 - Method of treatment of acute exudative skin lesions and composition useful therefor

Info

Publication number: WO2006032464A2
Application number: PCT/EP2005/010151
Authority: WO
Inventors: Frederico Graf; Phillip Grob; Suzanne Gonser; Wolfgang THÜRLIMANN
Original assignee: Medinova Ag
Priority date: 2004-09-24
Filing date: 2005-09-20
Publication date: 2006-03-30
Also published as: WO2006032464A3

Abstract

The invention refers to the use of zinc oxide as unique pharmacologically active ingredient, in combination with a pharmaceutically acceptable hydrophilic vehicle, for the preparation of a pharmaceutical composition dedicated to the topical treatment of edges of chronic wounds and/or acute exudative skin lesions caused by intertrigo, decubitus, ulcus cruris, wet eczema, skin maceration, skin fissuring or skin photo damaging. The invention also provides a pharmaceutical composition comprising zinc oxide as unique pharmacologically active ingredient, in combination with a pharmaceutically acceptable hydrophilic vehicle.

Description

Method of treatment of acute exudative skin lesions and composition useful therefor

Field of the Invention

The present invention relates to the treatment of specific skin disorders, more particularly edges of chronic wounds and acute exudative skin lesions the healing of which requires simultaneous moisture uptake and antiseptic action.

Background of the Invention

The treatment of exudative skin disorders or lesions necessitates specific conditions among which moisture absorption and maintenance of an aseptic environment is crucial. This is particularly true when considering skin damages or lesions such as those resulting e.g. from wet eczema, ulcers, skin fissuring or severe burns. Within that frame one of the most appropriate treatments consists to avoid extensive skin maceration or occlusion and secondary contamination by pathogens as well, i.e. conditions which might prevent rapid, efficient and complete skin repair.

Zinc oxide is known since many years as a pharmaceutically active ingredient able to perform simultaneously as water absorbent and as antiseptic agent when provided together with compatible topical formulations. Numerous pharmaceutical compositions containing zinc oxide are commercially available today and even a few of them contain zinc oxide as the unique active agent: these compositions are today recommended for an application onto fragile and sensitive skins like that of infants or babies when the latter are affected by diaper rash, and furthermore where avoiding concomitant application of strong disinfectants, bactericides or antibiotics is an issue.

Most of the currently available zinc oxide based formulations used for a topical application are lipophilic creams, pastes or ointments which are supposed to further provide a waterproof protective barrier which would allow zinc oxide exercise its genuine water absorption capacity. This proved fairly efficient in the treatment of diaper rash affecting babies or infants, i.e. within an aggressive environment wherein factors like heat, humidity, pH increase and contamination by the stools are combined, although lipophilic formulations as such still exhibit some disadvantages - G. Ferrazini et al. "Microbiological Aspects of diaper dermatitis" in

Dermatology 206 (2003), p. 136-141 -.

It has been recently proposed to explore alternative ways to overcome these drawbacks like, e.g. shifting from lipophilic to hydrophilic carriers or excipients. Within such a frame US 4,512,978 discloses dermatological compositions used to treat certain diseases of the nail and skin, and containing urea, zinc oxide, castor oil and starch in a hydrophilic ointment; if desired these compositions can also contain additional ingredients like crude coal tar and hydrocortisone. It has now been surprisingly discovered that specifically fine tuned hydrophilic formulations could be used as vehicle for zinc oxide, i.e. a water insoluble active ingredient, when the latter is, however, the unique pharmacologically active ingredient of the composition.

The present invention has the merit to provide an efficient and inexpensive alternative to the man skilled in the art and then provide quite efficient means to treat a wide range of acute exudative skin lesions where a combined liquid absorption and antiseptic action is looked for.

Summary of the Invention

The present invention refers firstly to the use of zinc oxide as unique pharmacologically active ingredient in combination with a pharmaceutically acceptable hydrophilic vehicle, for the preparation of a pharmaceutical composition useful in the topical treatment of edges of chronic wounds and/or acute exudative skin lesions caused by intertrigo, decubitus, ulcus cruris, wet eczema, skin maceration, skin fissuring or skin photo damaging.

The invention further refers to a method of treatment of edges of chronic wounds and/or acute exudative skin lesions caused by intertrigo, decubitus, ulcus cruris, wet eczema, skin maceration, skin fissuring or skin photo damaging which comprises the topical administration of a pharmaceutical composition comprising zinc oxide as unique pharmacologically active ingredient in combination with a pharmaceutically acceptable hydrophilic vehicle.

The invention refers, eventually, to a pharmaceutical composition useful in the topical treatment of acute exudative skin lesions, wounds or disorders mentioned here above.

Detailed Description of the Invention According to the present invention the pharmaceutically acceptable vehicle is generally made of any hydrophilic carrier, vehicle or excipient which is compatible with zinc oxide and which allows the latter to perform as desired, i.e. as an antiseptic agent and as water absorbent as well. Preferred hydrophilic vehicles consist in oil-in-water emulsions as those usually met in the pharmaceutical or cosmetic industry: as zinc oxide is neither soluble in water nor in oil its combination with the above oil-in-water emulsion is defined as a "3-phase semi-solid formulation". Such formulations exhibit, among many advantages, an increased water absorption capacity when compared e.g. with the classical 2-phase emulsions or creams.

One of the most preferred embodiments of this invention is represented by a semi-solid, hydrophilic cream-paste which can comprise zinc oxide in proportions which vary within a relatively wide range. Such a hydrophilic cream-paste is easily spreadable either onto or around the most sensitive parts of the wound or lesion subject to treatment, namely without causing an additional pain to the patient. Zinc oxide, as used according to this invention, can have the same grade and quality as those currently met in the pharmaceutical industry bearing in mind that the finest the zinc oxide particles are, the more water they will be able to absorb. Zinc oxide is usually present in proportions ranging from about 15 to about 35 weight %, preferably from about 20 to about 25 % of the total weight of the composition.

Quite interestingly it has been observed that for a given zinc oxide grade a composition according to this invention, i.e. a hydrophilic 3-phase formulation, could absorb up to 4 times more water than a corresponding lipophilic 3-phase formulation. For instance a hydrophilic cream-paste comprising about 20 weight % of zinc oxide has the capability to absorb water up to 16 % of its own weight.

As usually met in the art the hydrophilic vehicle can still comprise pharmaceutically acceptable preservatives, antioxidants, emulsifiers, stabilizers and the like. Eventually, although creams and cream-pastes represent the most preferred embodiments of this invention the hydrophilic vehicle can be in the form of a suspension, a gel or a lotion wherein zinc oxide particles are conveniently dispersed and stabilized.

The pharmaceutical composition, in its final form, can exist as a cream, a cream-paste, a gel or as a suspension and also in the form of e.g. a patch, a bandage or a non-occlusive dressing as illustrated in the examples here after.

Due to the specific nature of the emulsion used the oil phase of the composition can still play an important role while providing some waterproof barrier or at least some convenient protection to the damaged, consequently irritated and quite sensitive skin like e.g. protection against excessive dryness or secondary contamination by exogenous microorganisms. Its overall hydrophilic character, however, allows a smooth, progressive and efficient exudate uptake (water, serum, blood, urine, faeces, sudor...) from the lesion so that the zinc oxide particles can act as water absorbent in the most efficient way.

The removal of the excess of the composition, e.g. the above cream-paste, which has been initially spread onto or around the lesion and the subsequent cleaning or washing of the treated skin surface is definitely easier when compared to usual lipophilic compositions currently used today, precisely due to its overall hydrophilic character. According to the present invention there is further provided a method for the topical treatment of edges of chronic wounds and/or of acute exudative skin lesions making use of the pharmaceutical composition defined here above.

In most instances the composition, e.g. a cream-paste, is cautiously spread around the periphery of the lesion or wound subject to treatment, as close as possible to or onto the edges of the exudative area when a significant portion of skin or derma is directly exposed to the air like in the case of ulcers (ulcus cruris). Then a suitable wound dressing can be applied onto a somewhat wider portion of the damaged surface. Such a wound dressing can be made of a hydrocolloid material and can have the form of a patch, an elastic bandage or a non-occlusive dressing depending on the specific nature of the lesion or wound under consideration. It shall remain up to the man skilled in the art to select the most appropriate means and method of application.

Obviously, depending on the severity of the lesion subject to treatment like e.g. burns or radiation skin damaging, it also possible to spread the composition according to this invention onto the exudative lesion itself, totally or partially and in combination with the most suitable dressing.

Clinical trials have shown that the composition of this invention e.g. in the form of a cream-paste is quite well tolerated by the patients and that it does not cause any additional pain or irritation although generously spread around or even onto sensitive damaged skin areas like ulcers, open wounds or burns. It has also been observed that the composition is highly effective for assisting the damaged skin area to regenerate and to get eventually its initial, normal appearance.

Due to its specific, hydrophilic nature the composition according to this invention has still the advantage to be removable from the treated skin area using quite soft, smooth, non irritating means or conditions like detergent free washing solution or strips, bandages or pads impregnated with such a solution.

This method of treatment proved particularly efficient in the treatment of e.g. acute exudative skin lesions consecutive to troubles and/or diseases like diabetes, circulary disorders, cardiovascular disease, wet eczema, intertrigo or even surface surgery.

This method proved also quite efficient in the treatment of the edges of chronic wounds like ulcers (ulcus cruris), decubitus and skin fissuring or less severe lesions like those due to abrasions, cutting or photo skin damaging, hi those instances, where long term treatment is frequently necessary, the composition of the invention has the additional advantage to avoid the use of active ingredients like hydrocortisone or similar corticoids, especially when the subject is a young person or even a new-born.

One of the key features of the present invention resides in the use of a hydrophilic vehicle in combination with zinc oxide. Such a vehicle is preferably an oil-in-water emulsion or dispersion the oil phase of which comprises usual lipophilic ingredients like e.g. liquid or semi- liquid paraffin, white Vaseline®, oleic acid esters like oleic acid decyl- or dodecylester, isopropyl myristate, sorbitol esters like e.g. sorbitan monostearate. As hydrophilic ingredients the said composition can comprise, among others, high molecular weight alcohols or polyols like e.g. cetyl alcohol, polysorbates, ethylene or propyleneglycol and water.

The best performances have been achieved using an oil-in-water emulsion having an oil phase: water phase ratio comprised within a controlled range of values, usually comprised around 0.50: 1 and 1: 1, preferably between about 0.65: 1 and about 0.85: 1.

The above emulsion can further comprise stabilizers, antioxidants, preservatives or colorants currently met in the art.

The present invention is illustrated by means of the examples set here after; these examples are not meant, however, to restrict this invention in any way.

Example 1

Cream-paste formulation containing 20 % of ZnO a. Oil-in-waters emusion

Ingredients Parts by weight

Oil phase 35.00

Water phase 44.55

Preservatives 0.40

Antioxidants 0.05 b. Zinc oxide (micronized) 20.00

Total 100.00

Alternative cream-paste formulations can be prepared using e.g. 15, 18, 21 or 25 parts by weight of zinc oxide, the balance to a total of 100 parts by weight being achieved by means of the above emulsion wherein the oil phase : the water phase ratio has been kept unchanged.

Example 2

Treatment of intertrigo

Clinical trials have been performed under medical control following the GCP methods and regulations which apply currently in Europe. Intertrigo represents a subgroup of exudative skin disorders (dermatitis) which affects children, young adults and mature adults as well, and which presents the following symptoms. The latter have been subject to relevant watch and scored by medical experts during the trial as shown in Table 1.

Table 1

I Symptoms Scoring

Maceration scored form 0 (no maceration) to 3 (visible skin erosion)

Erythema scored form 0 (no erythema) to 3 (violet skin area)

Desquamation scored from 0 (no squama) to 3 (rough irregular squama) Pustules scored from 0 (no pustules) to 3 (converging pustules)

Edema scored from 0 (no edema) to 3 (strong and harden skin swelling)

24 adult patients (over 18 years old) with a total symptom score of at least 5 have been selected for the clinical trial. The treatment of the affected or damaged skin was performed twice a day during 2 weeks, while smoothly spreading the composition according to Example 1 (20 % ZnO) onto the relevant skin area. The relevant control was performed at the end of these 2 weeks of treatment.

The medical experts checked the selected patients and scored the relevant symptoms again, using the same scoring scale as that used for the selection. The experts defined the efficiency of the treatment from bad (inefficient) to quite good (complete healing) and their observations have been gathered in Table 2.

Table 2

Patients nb. quite good good moderate bad

24 9 (38%) 14 (58 %) 1 (4%) 0 (0%)

These results show that the treatment is effective in all of the selected cases.

The same experts checked simultaneously the innocuoushess (tolerance) of the composition used for the treatment scoring their observation from bad (pain or irritation) to quite good (no pain; no irritation); their conclusions have been gathered in Table 3.

Table 3

Patients nb. quite good good moderate bad

24 13 (54 %) 11 (46 %) 0 (0%) 0 (0%)

These results show that the treatment is well tolerated by all the selected patients.

Example 3

Treatment of edges around chronic wounds

Ulcus cruris and decubitus represent another subgroup of exudative skin disorders affecting patients suffering e.g. of diabetes, circulatory disorders, or cardiovascular disease. The main symptoms which have been retained for performing the corresponding clinical trial are listed in Table 4 and include the same scoring range as provided in Example 2.

Table 4

Symptoms Scoring

Erythema scored form 0 (no erythema) to 3 (violet skin area)

Maceration scored form 0 (no maceration) to 3 (visible skin erosion)

Edema scored from 0 (no edema) to 3 (strong and harden skin swelling)

8 adult patients (over 18 years old) with a total symptom score of at least 3 have been selected for the clinical trial. The treatment of the affected or damaged skin was performed on a periodical basis over a period extending up to day 4 weeks depending the severity of the wound to be treated, while smoothly spreading the composition according to Example 1 (20 % ZnO) around the relevant skin area (i.e. chronic wound), more specifically adjacent to the border of the affected area. The relevant control was performed after 4 weeks.

The medical experts checked the selected patients and scored the relevant symptoms again using the same scoring scale as that used for the selection. The experts defined the efficiency of the treatment from bad (inefficient) to quite good (complete healing) and their observations have been collected in Table 5.

Table 5

Patients nb. quite good good moderate bad

29 10 (34 %) 15 (52 %) 3 (10%) 1 (3%)

These results show that the treatment is effective in more than 80 % of the selected cases.

These experts checked simultaneously the innocuousness (tolerance) of the composition used for the treatment scoring their observation from bad (pain or irritation) to quite good (no pain; no irritation); their conclusions have been gathered in Table 6.

Table 6

Patients nb. quite good good moderate bad

These results show that the treatment is well tolerated by almost all the selected patients.

Claims

1. The use of zinc oxide as unique pharmacologically active ingredient in combination with a pharmaceutically acceptable hydrophilic vehicle, for the preparation of a pharmaceutical composition useful in the topical treatment of edges of chronic wounds and/or acute exudative skin lesions caused by intertrigo, decubitus, ulcus cruris, wet eczema, skin maceration, skin fissuring or skin photo damaging .

2. The use according to claim 1 wherein the pharmaceutically acceptable hydrophilic vehicle is oil-in-water emulsion based cream, cream-paste, suspension, dispersion or gel.

3. The use according to any of the preceding claims wherein the zinc oxide proportion is from about 15 to about 35 weight %, preferably from about 20 to about 25 weight % of the weight of the pharmaceutical composition

4. A method of treatment of edges of chronic wounds and/or acute exudative skin lesions caused by intertrigo, decubitus, ulcus cruris, wet eczema, skin maceration, skin fissuring or skin photo damaging which comprises the topical administration of a pharmaceutical composition comprising zinc oxide as unique pharmacologically active ingredient in combination with a pharmaceutically acceptable hydrophilic vehicle.

5. The method of claim 4 wherein the pharmaceutically acceptable hydrophilic vehicle is a oil-in-water emulsion based cream, cream-paste, suspension, dispersion or gel

6. The method according to any of the preceding claims wherein the zinc oxide proportion is from about 15 to about 35 weight %, preferably from about 20 to about 25 weight % of the weight of the pharmaceutical composition.

7. The method according to any of the preceding claims wherein the topical treatment comprises the application of the pharmaceutical composition in the wound environment, e.g. on the edges of the lesion.

8. A pharmaceutical composition useful in the topical treatment of edges of chronic wounds and/or of acute exudative skin lesions caused by intertrigo, decubitus, ulcus cruris, wet eczema, skin maceration, skin fissuring or skin photo damaging , which comprises zinc oxide as unique pharmacologically active ingredient in combination with a pharmaceutically acceptable hydrophilic vehicle.

9. The composition according to claim 8 wherein the pharmaceutically acceptable hydrophilic vehicle is oil-in-water emulsion based cream, cream-paste, suspension, dispersion or gel.

10. The composition according to any of the preceding claims wherein the zinc oxide proportion is from about 15 to about 40 weight %, preferably from about 20 to about 25 weight % of the weight of the pharmaceutical composition.