KR20020060249A - Use of a buffer to prevent candida albicans infections on the skin - Google Patents

Abstract

The present invention relates to the use of components that can buffer within the pH range 2.0-5.5 for the preparation of skin-blocking or mucosal-blocking articles for preventing skin irritation and damage by Candida albicans. Examples of such articles are diapers, panty liners, absorbent articles such as sanitary napkins, bandages, wound dressings such as surgical tapes and casts, and finally gloves, artificial organs and indwelling catheters.

Description

USE OF A BUFFER TO PREVENT CANDIDA ALBICANS INFECTIONS ON THE SKIN}

Infection with Candida albicans can be a major problem with using skin barriers, muco-blocking and absorbent articles such as diapers, panty liners, sanitary napkins and wound dressings. Candida albicans has been found to correlate with the severity of diaper dermatitis (Benjamin L, Pediatrician 1987, suppl. 1, p. 21-26). There are researchers who consider Candida albicans as the main cause of some manifestations of diaper dermatitis (Leyden J and Kligman AM, Arch. Dermatol. 1978, vol 114, p. 56-59).

pH appears to be a major source of confusion and contradictions in relation to Candida ecology. In vivo Candida delivery can easily occur over a wide range of pH. pH may be an important factor in the pathological state of Candida albicans in vivo but is not exerted by acting on the rate of fungal growth, ie its biomass increase (Odds FC, Candida and Candidosis. review and bibliography.2nd ed. 1988, Bailliere Tindall). It is reported that the heterogeneity (homogeneity), the ability of Candida albicans to exist in the form of spores and filaments, is affected by pH (Buffo et al., Mycopathologia, vol. 85 (1984), p. 21-30 Odds (1988), supra. At mildly acidic pH, it is likely to be in the form of spores, and at neutral or higher pH, it is in the form of filaments. In addition, it has been shown that microfilaments play an important role during pH-regulated morphological transitions (Yokoyama et al., Microbiology, vol. 140 (1994), p. 281-287). Clinical observations of diabetic patients have been reported in which higher skin surface pH is possibly correlated to Candida interrogation (Yosipovitch et al., Diabetes Care, vol. 16 (1993), p. 560-563). As already mentioned, there is often a risk of infection, skin irritation and damage when covering the skin or mucous membranes with absorbent articles, wound dressings, casts, gloves, artificial organs and similar articles. WO 98/57677 and EP 0 202 126 both disclose that with respect to the use of absorbent articles, neutral or weakly alkaline pH can cause skin irritation and problems with odorous substances. According to the literature, these problems are caused by lipases and proteinases present in the skin and can be overcome by reducing the pH of the absorbent article. The literature does not give any particular information about the problems caused by Candida or how to reduce the toxicity of Candida albicans.

Summary of the Invention

It has now been found that the toxicity of Candida albicans can be sufficiently subtracted by reducing the pH of a skin barrier or mucosal-blocking article to a value in the range of 2.0 to 5.5. Thus absorbent articles (wound dressings such as diapers, sanitary napkins, panty liners or bandages) containing pharmaceutically acceptable non-toxic and non-irritating substances which can buffer within the pH range 2.0-5.5, Skin-blocking or mucosal-blocking articles such as casts, surgical tapes are used to prevent skin irritation and damage caused by Candida albicans.

The present invention relates to the use of a material that can buffer within a pH range 2.0-5.5 for the manufacture of skin-blocking or mucosal-blocking articles for preventing skin irritation and damage by Candida albicans. . Examples of such articles are absorbent articles such as diapers and sanitary napkins, wound dressings such as bandages, surgical tapes and casts, gloves, protheses and indwelling catheters.

1 shows an example of a diaper in which an acid buffer material may be added in accordance with the present invention.

2 discloses the natural distribution of skin surface pH in the forearm (forearm) of the 15 women. The result is the mean of the left and right arms.

FIG. 3 shows a chart showing the pH evolution of patch sites before, during and after application of patches buffered with acid buffer material and normal control patches.

Table I shows the results from a visual assessment of skin response to Candida albicans infection. ; And

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

The diaper 100 disclosed in FIG. 1 comprises, for example, a liquid permeable outer layer 1 made of a fibrous fabric or a porous plastic thin film, for example a liquid impermeable outer layer 2 made of a plastic thin film or a hydrophobic fibrous fabric and finally an outer layer ( 1) and (2), the absorbent body 3 is enclosed.

Diapers are intended to surround the lower part of the wearer's torso, like a pair of absorbent panties. It is therefore designed with two ends 4, 5 as well as narrower crutches between the ends, when the diaper is used, it is made to be placed on the wearer's crutches between the legs. In order to obtain the desired panty design, an adhesive flap 7 is placed close to the rear waist edge 8. In use, in order to hold the diaper together around the waist of the wearer, the adhesive flap is secured to the front part 5 of the diaper and close to the front waist edge 9.

In addition, the diaper according to FIG. 1 comprises pre-tensioned stretchable means 10, which may be composed of elastic straps, elastic yarns, elastic foams or another suitable material. The stretchable means 10 are shown in an expanded state for the sake of simplicity. However, as soon as they stop pulling (extension) they contract and form an elastic band in the diaper.

In the example shown in FIG. 1, the absorbent body 3 is formed by two layers 11, 12, an upper liquid-collection layer 11 and a lower layer 12 which spreads and distributes the liquid. The upper liquid-collecting layer must be able to receive a large amount of liquid quickly in a short time, that is, have a higher instantaneous liquid absorption, but the lower storage and distribution layer 12 must have a high liquid distribution capacity It must be possible to escape the liquid from (11) and to distribute it in the storage and distribution layer 12. The difference between layers 11 and 12 can be achieved by the density difference. More compacted fibrous tissue distributes the liquid better than fibrous tissue having a correspondingly lower density. Such low density tissues have higher instantaneous liquid absorption and lower distribution because of their larger pore size. It is also possible to use different fibrous tissues with different properties to achieve different absorbency. Chemically produced cellulose fluff pulp thus exhibits better distribution properties than mechanically or thermo-mechanically prepared pulp such as, for example, chemical-thermomechanical pulp (CTMP). Fibrous tissues containing chemically strengthened cellulose fibers exhibit higher instantaneous liquid absorption than conventional chemical pulp, but lower dispersibility. Other materials suitable as the collecting layer 11 may be a filler of natural fibers or a fluff nonwoven material.

The partially neutralized superabsorbent is mixed in the upper liquid collection layer 11 of the absorbent body 3. This superabsorbent acts as an acid buffer material according to the invention.

Conventional superabsorbents are mixed in the lower liquid storage and distribution layer 12 of the absorbent body. Since conventional superabsorbents are partially neutralized and have a higher total absorbency than pH-controlled superabsorbents, it is advantageous to put the conventional superabsorbents in the lower liquid storage layer 12.

Naturally, the present invention also includes other embodiments of the absorbent body. The absorbent body may contain both partially neutralized superabsorbents and conventional superabsorbents, and both superabsorbents may be equally distributed in both the upper and lower absorbent layers. In addition, it is possible to include only one type of superabsorbent material except cellulose fluff pulp. In such a case, the superabsorbent also acts as a pH-regulating material according to the invention.

Accordingly, the present invention relates to the use of ingredients capable of buffering within the pH range 2.0-5.5 to produce skin-blocking articles for preventing skin irritation and damage by Candida albicans. Any pharmaceutically acceptable non-toxic and non-irritating ingredient that can buffer within the stated range can be used. Examples of suitable buffering ingredients are pharmaceutically acceptable non-toxic and non-irritating buffer solutions, such as acetate buffers or sheets, such as superabsorbents that exhibit levels of neutralization in the range of 20-50%, and organic salt buffer solutions. Rate buffer. The buffer solution can be added directly to the skin-blocking or mucosal-blocking article. As an alternative, pharmaceutically acceptable gels containing buffer solutions can be added. Examples of suitable gels include gels commonly used for pharmaceutical purposes, such as agarose.

The acid buffer material according to the invention is added to the skin-blocking article. As disclosed herein, the term "skin-blocking article" or "muco-blocking article" relates to an article for the purpose of covering human skin or mucous membranes. Skin-blocking articles or mucosal-blocking articles according to the invention may be absorbent articles such as diapers, physiological napkins, panty liners or wound dressings, surgical tapes, casts, gloves, artificial organs and indwelling catheters. How the acid buffer material is added is not important in the present invention, so it can be added to the skin-blocking article in a number of different ways. Examples of suitable methods for adding an acid buffer substance to a skin barrier article are administration of a solution containing an acid buffer substance, or administration of the substance in the form of a powder or gel. Administration can be performed in connection with the manufacture of the article or after the article is manufactured.

As disclosed herein, the term “pharmaceutically acceptable antimicrobial agent” relates to compounds commonly used to treat Candida infections, such as imidazole derivatives, nistatin and cyclopyroxolamine. These compounds are added to the skin barrier or mucosal-blocking article in amounts corresponding to conventional therapeutic amounts.

The invention will be described with reference to the accompanying drawings and tables. here:

Experimental work

A study was conducted to determine whether other ambient pHs affected Candida infections on the skin. Fifteen healthy female volunteers between the ages of 30 and 63 years (mean 44.5 years) participated. The following procedure and materials were used:

The experimental patch was made of conventional diaper material and punched into a circular disc with a diameter of 70 mm. The outside of the polyethylene and the inside of the nonwoven polypropylene (which faces the skin) were bonded together with a 10 mm edge around a 50 mm diameter inner circular center. The inner center consisted of approximately 0.85 g cellulose pulp and approximately 0.15 g superabsorbent polymer (IM 7100 and E127 / 97, Clairant GmbH, DE). The superabsorbent polymer is polyacrylic acid, which has been adjusted to either pH 4.5 or 6.0. It acts as a strong buffer system. 10 ⁴ cells per ml Candida albicans were suspended in physiological saline solution. Fifteen minutes before attaching to the forearm, 7 ml of this solution was added to each patch.

Skin surface pH was measured with Courage + Khazaka PH900, Mettler-Toledo flat electrode 304. The instrument was calibrated to pH 4.0 and 7.0 every morning and afternoon. Instrument accuracy is 0.1 units. Several drops of deionized water were added to the electrode before the measurement and the average of the three values was recorded.

The Candida albicans strain used was type H29, kindly presented by Lars Edebo, Department of Microbiology, Sahlgrenska University Hospital, Gteborg, Sweden professor. Cells were grown on Sabouraud's glucose-free medium at 37 ° C. for 24 hours prior to use.

A variation of the Williamson-Kligman scrub technique was used to evaluate the intrinsic dermal microflora and added Candida albicans. Stainless steel rings with an inner diameter of 2.6 cm and covering a skin area of 5.5 cm ² were used. 1 mm of sterile 0.075 M phosphate buffer (pH 7.9) containing 0.1% Triton X-100 was poured into the ring, gently rubbed the skin with a blunt sterile glass rod for 1 minute, and the fluid was removed with a Pasteur pipette (Faergemann J. Mapping the Fungi of the Skin.Handbook of non-invasive (non-invasive) methods and their skin, Chapter 10.2, CRC Press, 1995). Serial dilutions were performed in PBS and plates from dilutions were plated. Plates were incubated at 37 ° C. and read after 48 hours.

A pair of t tests were used to test statistical significance between the pH difference, the difference in the number of Candida organisms. The difference in observed skin damage was tested by the sign assay.

At the beginning of the test, the skin microflora was determined by scrubbing. All subjects had coagulase-negative Staphylococci (range 170-25000 colony-forming units (cfu)). Two of the subjects had Diphteroid sp (range 50-2400 cfu). Four subjects had Bacillus sp (range 10-1200 cfu). One subject had S. aureus (10 cfu) on one arm.

The amount is given in colonization units per 5.5 cm ² skin. Prior to testing, no growth of Candida albicans was found in any subject.

At the start, the skin surface pH of 15 volunteers was measured and varied between 4.5 and 6.0. The average value was 5.2. The results are shown in FIG.

Patches preloaded with Candida suspension (10 ⁴ cells / ml) were taped to the forearms of volunteers. The patch had two different pH values and was randomly attached to the left or right arm. The patch was worn under strict obstruction for 24 hours. About 2 minutes after the patch was removed, the pH value of the skin was measured. When the patch was removed after 24 hours of occlusion, the pH was 5.1 +/- 0.18 and 5.7 +/- 0.29 (mean +/- SD) at each of two sites. At p <0.001 the difference is statistically significant (significant). The skin was visually inspected and sampled to determine the number of cfu of Candida in an area of 5.5 cm ² . Outline results are shown in Table II. No statistically significant difference (P = 0.64) was found between the “acidic” site and the control site. Growth was found in both arms of 13 subjects. Growth was found only in the "acidic" site in one subject and only in the control site in one subject.

After 48 hours, pH measurements were repeated as well as candida sampling. The pH measurement results are shown in FIG. 3. After 48 hours, ie, the patch was removed and the damage apparently apparent and after 24 hours, the results of Candida sampling showed that nine subjects had no growth of Candida albicans. Three subjects had low numbers (10-130 cfu) and one subject had increased growth since the previous day (1400 and 4300 cfu in the arms, respectively). Two subjects were missing in this case and therefore no microbiological data were obtained.

Skin damage was assessed visually. No reaction = 0; Weak response = 1; Obvious response = 2; Strong reaction = 3. The reading was invisible and the patch type was unknown to the evaluator. Skin reactions were also recorded on the photo. The visual evaluation of these skin reactions gave very clear results. In all 14 responders, the acidic site showed less severe reactions than the control site. Sign tests show a statistically significant difference at p <0.01 for differences in response at the two sites. Detailed results are shown in Table I.

As a result, it was found that the pH-induced difference was not due to the growth of inhibited Candida albicans. They are probably due to the pH effect on the virulence of the fungus and / or the improvement of the host's defense ability.

Claims (7)

Pharmaceutically acceptable, non-toxic and non-irritating ingredients which can be buffered within the pH range 2.0-5.5 for the preparation of skin-blocking or mucosal-blocking articles for preventing skin irritation and damage by Candida albicans The use of. PH, together with pharmaceutically acceptable antifungal agents such as imidazole derivatives, nystatin and cyclopyroxolamine, for the manufacture of skin-blocking or mucosal-blocking articles for preventing skin irritation and damage by Candida albicans Use of pharmaceutically acceptable, non-toxic and non-irritating ingredients that can buffer within the range 2.0-5.5. Use according to claim 1 or 2, characterized in that the pharmaceutically acceptable, non-toxic and non-irritating buffer component is a partially neutralized superabsorbent. Use according to claim 1 or 2, characterized in that the pharmaceutically acceptable, non-toxic and non-irritating buffer component is an organic acid buffer buffer solution. Use according to any of the preceding claims for the manufacture of skin-blocking or mucosal-blocking articles which are absorbent articles such as diapers, sanitary napkins, or pantyliners. 5. Use according to any one of claims 1 to 4, for producing skin-blocking or mucosal-blocking articles which are wound dressings, casts, surgical tapes, or similar articles. 5. Use according to any of the preceding claims for producing skin-blocking articles or muco-blocking articles which are gloves, artificial organs and indwelling catheter.