SK7882002A3 - Use of a buffer to prevent candida albicans infections on the skin - Google Patents

Abstract

The present application relates to using an ingredient capable of buffering within the pH range 2.0 - 5.5, for preparing a skin-occlusive or mucous membrane-occlusive article for preventing skin irritations and lesions caused by <i>Candida albicans</i>. Examples of such articles are absorbent articles, such as diapers, pantyliners and sanitary napkins, wound dressings, such as bandages, surgical tapes and plasters, and finally gloves, prostheses and indwelling catheters.

Description

Use of a buffer to prevent Candida albicans infections on the skin

Technical field

The present application relates to the use of a substance capable of buffering the pH in the range of 2.0-5.5 for the preparation of a product covering the skin or mucosa for the prevention of skin irritations and lesions caused by Candida albicans. Examples of such articles are absorbent articles such as diapers and sanitary napkins, wound dressings such as bandages, surgical belts and gypsum, gloves, prostheses, and established catheters.

BACKGROUND OF THE INVENTION

Infections caused by Candida albicans can pose a serious problem in connection with the use of skin-covering, mucous-covering and absorbent articles such as diapers, panty liners, pads and dressings. Candida albicans has been found to correlate with the severity of diaper dermatitis (Benjamín L, Pediatrician 1987, suppl. 1, pp. 21-26). There are authors who attribute a primary causative role to C. Albicans in some manifestations of diaper dermatitis (Leyden J. and Kligman A. M., Ar. Dermatol. 1978, vol. 114, pp. 56-59).

PH seems to be a major source of confusion and contradiction in the context of Candida's ecology. Carrying out the Candida microorganism in vivo can occur very easily over a wide pH range. pH may be an important factor in the pathological condition of C. albicans in vivo, but does not exert its effect by affecting the growth of the fungus, ie its biomass growth rate (Odds FC, Candida and Candidosis. A review and bibliography. 2 ^nd ed. 1988, Bailliere Tindall). Dimorphism, the ability of C. albicans to exist in blastospore and filamentary forms, is reported to be affected by pH (Buffo et al., Mycopathologia, Vol. 85 (1984), pp. 21-30; Odds (1988), supra). A slightly acidic pH is favorable for the blastospore form and a neutral pH or higher for the filamentous form.

In addition, microfilaments have been shown to play an important role during pH-regulated morphological passage (Yokoyama et al., Microbiology, vol. 140 (1994), pp. 281-287). Clinical observations of diabetic patients where higher skin surface pH may be correlated with yeast inflammation have been reported (Yosipovitch et al., Diabetes Čare, vol. 16 (1993), p. 560-563). As already mentioned, there is often a risk of infections, irritations and lesions of the skin when covering the skin or mucous membranes with absorbent articles, bandages, gypsum, gloves, prostheses and the like. WO 98/57677 and EP 0 202 126 disclose that neutral or mildly alkaline pH in conjunction with the use of absorbent articles can lead to skin irritation and odor problems. According to documents, these problems are caused by lipases and proteinases present on the skin and these problems can be overcome by lowering the pH of the absorbent article. The documents do not provide any specific information about the problems caused by Candida microorganisms or how to reduce the virulence of Candida albicans.

SUMMARY OF THE INVENTION

It has now been shown that the virulence ability of Candida albicans can be substantially impaired by lowering the pH of the skin or mucosa product to between 2.0 and 5.5. Thus, an article covering the skin or mucosa, such as an absorbent article (diaper, pad, panty or bandage, e.g., bandage), gypsum, surgical belt, said article comprising a pharmaceutically acceptable non-toxic and non-irritant capable of buffering pH in the range of 2; 5, used to prevent skin irritations and lesions caused by Candida albicans.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention relates to the use of a pH buffering agent in the pH range of 2.0-5.5 for the preparation of a skin-covering product for preventing irritations and lesions of the skin caused by Candida albicans. Any pharmaceutically acceptable, non-toxic and non-irritant capable of buffering the pH within the indicated range may be used. Examples of suitable buffers are superabsorbent particles having a neutralization level in the range of 20-50% and pharmaceutically acceptable, non-toxic and non-irritating buffers, for example organic salt buffers, for example acetate buffer or citrate buffer. The buffer can be directly added to the product covering the skin or mucosa. Alternatively, a pharmaceutically acceptable gel containing buffer may be added. Examples of suitable gels include those commonly used for pharmaceutical purposes, for example agarose.

The acidic buffer of the present invention is added to the skin-covering article. As used herein, the term &quot; skin-covering product &quot; or &quot; mucosal product &quot; refers to a product intended to cover the skin or mucosa of a human. The skin-covering or mucosal-covering article of the present invention may be an absorbent article, for example, a diaper, sanitary napkin, wound dressing or wound dressing, surgical belt, gypsum, gloves, prostheses, or an inserted catheter. It is not important for the invention how the acid buffer is added and, accordingly, can be added to the skin-covering product in a number of different ways. Examples of suitable methods for adding an acidic buffering agent to the skin covering product are administering a solution containing the acidic buffering agent or administering it in the form of a powder or gel. This administration may be carried out in conjunction with or after the manufacture of said product.

As used herein, the term "pharmaceutically acceptable fungicidal agent" refers to compounds commonly used to treat Candida infections, for example, imidazole derivatives, nystatin and ciclopirox olamine. These compounds are added to the product covering the skin or mucosa in amounts corresponding to conventional therapeutic doses.

and

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will now be described with reference to the accompanying drawings and tables, wherein:

Figure 1 shows an example of a diaper to which an acid buffer according to the invention can be added;

Figure 2 shows the natural distribution of the surface of the skin on the forearm from the palm side in 15 women. Observations are the mean values of the left and right hands;

Figure 3 is a diagram of the evolution of the pH of the patch site before, during and after the use of an acid-buffered patch and a conventional reference patch;

Table I presents the results of a visual evaluation of the skin response to Candida albicans' infection, and

Table II shows the growth of Candida albicans 24 hours after inoculation.

DETAILED DESCRIPTION OF THE INVENTION

The diaper 100 shown in Figure 1 consists of a liquid-permeable outer layer 1, for example made of fibrous fabric or perforated plastic film, an outer liquid-impermeable layer 2, for example made of plastic film or hydrophobic fibrous fabric, and finally an absorbent body 3 closed between the outer layers 1, 2.

The diaper should wrap the lower part of the wearer's torso as absorbent panties. It is therefore designed with two end portions 4, 5 as well as a narrower crotch portion 6 between the end portions to be positioned between the legs of the wearer in the crotch of the wearer. In order to achieve the desired shape of the panties, adhesive wings 7 are located at the rear waist edge 8. In use, the adhesive wings are attached to the front portion 5 of the diaper, close to the front waist edge 9 to hold the diaper around the wearer's waist.

The diaper of Figure 1 additionally comprises a biased elastic means 10, which may consist of elastic cords, elastic fibers, elastic foam or other suitable material. For simplicity, the elastic means 10 is shown in a stretched state. However, as soon as the stretching is complete, the elastic strips will contract and form in the diaper.

The absorbent body 3 in the example shown in Figure 1 is formed by two layers 11, 12, an upper, liquid-receiving layer 11 and a lower layer 12, which disperses and distributes the liquid. The upper fluid-receiving layer must be able to rapidly absorb a large amount of fluid within a short time, i. have a higher immediate fluid acquisition capability, but the lower storage and distribution layer 12 must have a high liquid distribution capability and be able to suck the fluid out of the receiving layer 11 and distribute the fluid in the storage and distribution layer 12. The differences between the layers 11, 12 can be achieved by density differences. A more compressed fibrous structure distributes fluid better than the corresponding lower density fibrous structure. Such a low density structure has a higher liquid absorption capacity and a lower distribution capacity due to the larger pore size. Different absorbent properties can also be achieved by using different fiber structures with different characteristics. The chemically produced cellulose pulp thus exhibits better distribution characteristics compared to, for example, mechanically or chemically-mechanically produced cellulose, for example chemo-thermomechanical cellulose (CTMP). The fibrous structure comprising chemically stiffened cellulosic fibers exhibits a greater ability to immediately absorb liquids but a lower distribution ability compared to conventional chemical cellulose. Other materials suitable as acquisition layers 11 may be natural fiber cotton or fluffy nonwoven.

The partially neutralized superabsorbent is admixed to the topsheet 11 of the absorbing body liquid 3. This superabsorbent acts as the acid buffer of the present invention.

The conventional superabsorbent is admixed to the backsheet 12 for storing and distributing fluids to the absorbent body. It is preferable to place the conventional superabsorbent in the lower fluid storage layer 12 because the conventional superabsorbent has a higher overall absorption capacity compared to the partially neutralized and pH-regulating superabsorbent.

The invention naturally also covers other embodiments of the absorbent body. The absorbent body may contain both partially neutralized superabsorbents and conventional superabsorbents, and both superabsorbents may also be distributed in the upper and lower absorbent layers. Moreover, with the exception of cellulose pulp, only one type of superabsorbent material can be used. In this case, the superabsorbent material also acts as a pH regulator according to the present invention.

Experimental work

A study was conducted to determine if different environmental pHs affected Candida infections on the skin. Fifteen women, healthy volunteers between 30 and 63 years of age (mean 44.5) participated. The following routine procedures and materials were used:

Experimental patches were made of conventional diaper materials and embossed as circular discs with a diameter of 70 mm. The outer side of polyethylene and the inner side (which will be placed towards the skin) of the nonwoven polypropylene were glued together with a 10 mm edge along the inner circular core with a diameter of 50 mm. The inner core consisted of about 0.85 g cellulose and about 0.15 g superabsorbent polymer (IM 7100 and E 127/97, Clairant GmbH, DE). The superabsorbent polymer was polyacrylic acid, which was adjusted to either pH 4.5 or 6.0. It acts as a powerful damping system. 10 ⁴ cells per ml of C. albicans were suspended in saline. 7 ml of this solution was added to each patch 15 minutes before sticking to the forearms.

The skin surface pH was measured with a Courage + Khazaka PH900 instrument with a Mettler-Toledo 304 flat electrode. Each morning and afternoon, the instrument was calibrated to pH 4.0 and 7.0. The instrument accuracy is 0.1 units. On the electrode

Ί added a few drops of deionized water prior to measurement and recorded an average of three values.

The C. albicans strain used was type H29, kindly provided by Professor Lars Edebo, Department of Microbiology, University Hospital Sahlgrenska, Goteborg, SE. Cells were cultured on Sabouraud glucose agar at 37 ° C for 24 hours before use.

A modification of the Williamson-Kligman ster technique was used to evaluate resident skin microflora and added C. albicans. A stainless steel ring with an inner diameter of 2.6 cm and covering a skin area of 5.5 cm ^{2 was used} . One millimeter of sterile 0.075 M phosphate buffer (pH 7.9) containing 0.1% Triton X-100 was poured into a ring and the skin was gently rubbed with a blunt sterile glass rod for one minute and liquid was removed with a Pasteur pipette (Faergemann J. Mapping the Fungi of the Skin, Handbook of Non-invasive Methods and the Skin, Chapter 10.2, CRC Press, 1995). Serial dilutions were made in PBS and the dilution samples were plated. Plates were incubated at 37 ° C and read after 48 hours.

The paired t test was used to test for statistical significance between pH differences and Candida number differences. The differences in the observed skin lesions were tested by the sign test.

At the beginning of the study, the skin microflora was determined using a sterile test. All subjects had coagulase negative Staphylococci (range 170-25000 colony forming units (KTJ)). Two of the subjects had Diphteroid sp. (range 50-2,400 cfu). Four subjects had Bacillus sp. (range 10-100 cfu). One subject had S. aureus on one hand (10 cfu).

Quantities are given in colony forming units per 5.5 cm skin. No subject was found to have any growth of C. albicans prior to the study.

Initially, the skin surface pH of 15 volunteers was measured and found to be between 4.5 and 6.0. The mean value was 5.2. The results are shown in Figure 2.

Patches saturated with Candida suspension (10 ⁴ cells / ml) were adhered to the forearms of the volunteers. The patches had two different pH values and were randomly placed on either the left or right hand. The patches were worn under tight cover for 24 hours. The patches were removed and skin pH was measured after approximately 2 minutes. When the patches were removed after 24 hours of coating, the pH was 5.1 +/- 0.18 and 5.7 +/- 0.29 (mean +/- SD) at two respective sites. The difference is statistically significant at p <0.0001. The skin was visually examined and samples were taken to determine the number of CFUs of Candida on an area of 5.5 cm ² . The summarized results are shown in Table II. There was no statistically significant difference between the acidic site and the reference site (P = 0.64). Growth was observed on both hands in 13 subjects. For one subject, growth was found only at the 'acid' site and for one subject only at the reference site.

After 48 hours, the pH measurement as well as the sampling of Candida were repeated. The results of the pH measurements are shown in Figure 3. The results of sampling the Candida microorganism after 48 hours, i. 24 hours after removal of the patches and when the lesions were visually evident, they showed that 9 subjects had no growth of C. albicans at all. Three subjects showed low numbers (10,130 cfu) and one subject had increased growth from the previous day (1,400 and 4,300 cfu per hand). Two subjects were missing on this occasion and therefore no microbial data could be obtained.

Skin lesions were evaluated visually. No reaction = 0; weak reaction = 1; evident response = 2; strong response = 3. The reading of the results was anonymous and the patch type was unknown to the evaluator. Skin reactions were also recorded in the photographs. This visual assessment of skin reactions gave a very clear result. The acid site had less severe reactions than the reference site in all 14 subjects that responded. The sign test shows a statistically significant difference at p <0.001 for the difference in response at two sites. A detailed result is presented in Table I.

Thus, it has been shown that the differences induced by pH are not due to the inhibited growth of Candida albicans. They are likely to be caused by the effect of pH on the virulence ability of the fungus and / or the improvement of host defense.

Claims (7)

PATENT CLAIMS Use of a pharmaceutically acceptable, non-toxic and non-irritating substance capable of buffering the pH in the range of 2.0-5.5 for the preparation of a product covering the skin or mucosa to prevent irritations and lesions of the skin caused by Candida albicans. 2. Use of a pharmaceutically acceptable, nontoxic and non-irritant pH-buffering agent in the range of 2.0-5.5 together with a pharmaceutically acceptable fungicidal agent such as an imidazole derivative, nystatin and ciclopirox olamine for the preparation of a skin or mucosal product for preventing irritation and skin lesions caused by Candida albicans. Use according to claim 1 or claim 2, characterized in that the pharmaceutically acceptable, non-toxic and non-irritating buffer is a partially neutralized superabsorbent. Use according to claim 1 or claim 2, characterized in that the pharmaceutically acceptable, non-toxic and non-irritating buffer is an organic acid salt buffer. Use according to any one of claims 1 to 4 for the preparation of an article covering the skin or mucous membrane, which is an absorbent article, such as a diaper, sanitary napkin or sanitary napkin. Use according to any one of claims 1 to 4 for the preparation of a product covering the skin or mucosa which is a wound dressing, a plaster, a surgical belt or the like. I I Use according to any one of claims 1 to 4 for the preparation of a product covering the skin or mucosa which is a glove, prosthesis or catheter.