CA2093262A1 - Anti-skin rash preparation - Google Patents

Anti-skin rash preparation

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Publication number
CA2093262A1
CA2093262A1 CA 2093262 CA2093262A CA2093262A1 CA 2093262 A1 CA2093262 A1 CA 2093262A1 CA 2093262 CA2093262 CA 2093262 CA 2093262 A CA2093262 A CA 2093262A CA 2093262 A1 CA2093262 A1 CA 2093262A1
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CA
Grant status
Application
Patent type
Prior art keywords
ph
skin
method according
body fluid
suppressor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA 2093262
Other languages
French (fr)
Inventor
Shalom Levi
Stephen Daren
Original Assignee
Shalom Levi
Stephen Daren
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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/20Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing organic materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/24Heavy metals; Compounds thereof
    • A61K33/26Iron; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/24Heavy metals; Compounds thereof
    • A61K33/30Zinc; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/42Phosphorus; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/18Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing inorganic materials

Abstract

ABSTRACT
Skin irritations due to contact with an excreted body fluid such as urine are avoided by buffering such fluid to a pH within the range of from 4.5 to 6.0 and notably 5.0 to 5.5. Suitable buffering substances or compositions are used for this purpose to which optionally an enzyme inhibitor or suppressor may be added.
There are disclosed diapers, sanitary napkins, pads as well as dry compositions and creams, bearing buffering compositions suitable for this purpose.

Description

3 ~ ~ ~

ANTI-SKIN RAS~I PREPAI~TION

5 FlELD OF THE INV~NTION
This invention relates to a method and means for preventing skin irritation due to the adverse conditions which prevail when body f luids are kept in contact with the skin over extended periods of time. Such conditions commonly occur during use, both with infants and adults of 10 sanitary napkins, pads and the like. Due to the combined effects of moisture, pH, fecal enzymes (especially urease) and bacteria (especially s. aureus and candida albicans), nappy rash, dermatitis or vaginitis may be caused.
The invention also relates to improved absorbent matrices such lS as diapers with which the above afflictions are significantly avoided.

BACK~ROUN~D OF THE IN'VENTION
With known disposable diapers a large part of let urine is absorbed by super-absorbent polymers. However, the problem of the 20 combined ef~ects of increased pH and enzymatic activities in diapers and sanitary napkins have only partly been resolved [see, e.g. Davis et al., Pediatric Dermatology, Vol. 6, No. 2, 102-108 (1989)].

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- 2 - 2~3'~2 It is well known that the optimal pH range ~or most enzymes and bacteria found in the body is pH 6.0 to 9Ø For ulease the maxirnum activity in aqueous media occurs at p~l 6.5 [Biochemistry: A.L. Lehninger, 2nd ed., Wolth Publishers, Inc., N.Y., p. 51]. On the other hand, the no~nal 5 pH for skin health is within the range of from about 4.5 to about 5.5.
Above pE~ 6.0, the skin is attacked, mainly by enzymes and bacteria, and where the pH rises above 7 - also by free arnmonia.
Urine contains only a few hundred ppm of ammonia existing predominantly as non-toxic ammonium ions due to the pH of the urine which is usually below pH 7.0 (95% ranges 5.1 to 6.8). However, when the pH of the urine rises above pE~ 7.0, arnmonium ions of the urine are converted into *ee amrnonia, which is toxic and an irritant to the skin.
Urine contains relatively large quantities of urea (about 20 g/l). Human feces bacteria as well as bacteria present on the skin and in excreted body 15 fluids such as sweat, menstrual blood and smegma contain i.a. the en~yme urease which decomposes urea and thereby liberates ammonia.
This phenomenon occurs particularly vehemently in cases in which skin portions of the body are diapered or padded. Under such conditions there occurs intimate contact between urine and feces whereupon 20 urea decomposes to ammonia and the pH of the urine starts to rise. As the pH rises toward pH 7.0 and above, the activities of fecal proteases and lipases and bacteria, which are pH sensitive, increase rapidly. The bacteria excrete more urease and the damaging cycle continues [Griffith, D.P. et al., The J. of IJrology, Vol. 119, 9-15 (1978)]. These enzymatic and bacterial 25 activities have been identified as the main cause of diaper dermatitis.
A similar problem arises with sanitary napkiYls upon contact between urine and menstrual blood.

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THE PRIOR AiRT
1l1 order to break the clamaging cycle at its onset; it is desirable to suppress the initial activity of the urease ancl bacteria, and thereby prevent the formation of ammonia and the consequent rise of the pH. The core of S disposable diapers contains as a rule an absorbing gel which retains the urine and thereby achieves some control of urine pH [Campbell, R.L. et al., J.
Amer. Acad. Dermatol., Vol. 17, No. 6, 978-997 (1987)], and also partial separation of the urine from the feces. However, the sodium salt of polyacrylic acid, from which most of the gellants are prepared has a pH of approximately 6.5, which is still very conducive to enzymatic and bacterial activities in general and urease activity in particular. Furthermore, since the gel is ;nsoluble, its buffering control is restricted to that part of the urine which diffuses into the gel and is retained therein, while any non-absorbed urine is not affected. Accordingly, statistical clinical evaluation of the performance of these so-called super-absorbent diapers showed only small, albeit signiElcant, decreases in the incidence of diaper rash [Campbell, R.L.
et al., J. Am. Acad. Dermatol., 17, 6 (1987), p. 984; Davis, J.A. et al., Pediat. Dermatol., Vol 6, 2~ 102-108 ~1989)].
Deactivation of urease by synthetic compounds has been proposed by several workers. U.S. 4,517,007 discloses the use of phosphor-amides for the inhibition of urease in urea organophosphate-based fertilizers.
The use of these substances in diapers is also suggested but no information regarding their performance or toxicity is given.
Coppi et al. [Arzneim-Forsch. (Drug. Res.) 20, Nr. 3 (1970), ~5 384-386] dernonstratecl in hyperaminonamic patients the in vivo deactivation of urease by acetohydroxamic acid and the in vitro deactivation of urease by ascorbic acid. Other urease inhibitors include heavy metals such as zinc, iron, molybdenum and nickel. For exarnple, U.S. 4,5S6,560 discloses the slow release of water-soluble zinc salts from an absorbent material.

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Ascorbic acid is well known for its beneficial effec~s as a skin-nourishing agent, and often appears in cosmetic forrnulations. Both ascorbic acid and phosphoric acid have been used in conjunction with iron iI compounds as deodorants in diapers.
JP S8/104276 and JP 57/11997 describe the use of hydroxamic acid and its salts in conjunction with cationic surfactants in disposable diapers, and claims to prevent skin rashes caused by ammonia.
U.S. 3,567,820 teaches incorporating organic cation exchange resins in an ointrnent for application to skin afflicted with ammonia dermatitis, or diaper rash. The purpose of such a resin is to remove ammonium ions present in urine or amrnonia produced in situ by bacterio-logical or enzymatic activity.

3 describes the use of natural or synthetic zeolites as ion exchange resins, to remove ammonia from urine. This reference suggests the addition of a buf~er in the pH range, "preferably", "approxi-mately" or "near" 7. Such buffers could include disodium hydrogen phosphate and boric acid buffers in the pH range 6 to 8. However, as will be detailed hereinafter, this is just the pH range to be avoided.
EP 202,126 and EP 202,127 teach the inclusion of low molecular weight organic and inorganic acids in localized reg;ons of the diaper with the purpose o~ maintaining the skin pH within the range uf from about 4.0 to about 5.5, and for this the pH of the urine must be reduced to even lower values. Operating according to EP 202,127 has thus the considerable disadvantage of causing the skin to be in contact with acidic urine at pH 3.0 to 4Ø Since the normal skin pH is within the narrow range of from about 4.5 to about 5.S, these lower pHs dramatically alter the physiological conditions of the skin and may lead to skin irritation.
EP 311,344 teaches to incorporate non-volatile antimicrobial agents in diapers. Such an incorporation may actually be deleterious to the - s - 2~32~2 skin, when large populations of micraorganisms are present. Many anti-microbial agents act on bacteria by breaking down the cell walls, thereby releasing the content of the cells, including urease. Thus, urease-containing bacteria, which are present in ~eces and on the skin, will actually increase S the concentration of urease in urine, when such antimicrobial agents are included.

SUMMARY OF THE INYENTION
It has been found, in accordance with the invention, that it is 10 possible to prevent, or at least substantially to inhibit, the ~evelopment ofunhealthy skin conditions resulting from contact with excreted body fluids, by inhibiting the activity of enzymes present in such fluids, e.g. urease in case of urine. It has further been found that a simple, effective and efficient way to obtain this result is to control the pH of the body fluid.
The present invention is based, i.a., on the surprising observa-tion that, as distinct from aqueous solutions in which the onset of significant activity of the en~yme urease is known to be within the pH range of from about 4.0 to about 5.0, in urine the onset of significant enzymatic activity is at a higher pH within the range of 5.5 to 6.0, while at the pH range of 4.5 to 5.5 the activity is significantly lower. It is a well known fact that the pH
of healthy skin is within the range of 4.5 to 5.5. Oue to the above surprising observation made in accordance with the present invention, the control of harmfi~l enzymes occu~s at a pH range which essentially coincides with that of healthy skin.
2S By one aspect the invention provides a method of preventing the development of skin rash and other unhealthy skin conditions resulting from contact of the skin with at least one body fluid~ comprising maintaining the pH of said at least one body fluid in contact with the skin within the . . . , . , .. . . ~ - , .. . . .

- 6- 2~32~2 range of from about 4.5 to about 6.0 by adding thereto a non-toxic, skin-tolerable body fluicl-soluble buf~er.
If desired a urease inhibitor or suppressor may be used in conjunction with said buffer.
By another aspect, the invention provides a formulation for preventing the development of skin rash and other unhealthy skin conditions resulting from contact of the skin with at least one body fluid, comprising a non-toxic, skin-tolerable, body fluid-soluble binary or single substance buffer capable of maintaining the pH of a body fluid within the range of from about 4.5 to about 6.0, together with a suitable non-toxic, skin-tolerable inert carrier.
If desired, the said formulation may also contain a urease inhibitor or suppressor.
In accordance with the invention the above formulation may be in form of a cream comprising said non-toxic, skin-tolerable, body lluid-soluble buffer together with a cream base. If desired, said cream also includes at least one urease inhibitor or suppressor.
By another embodiment the invention provides a solid or liquid soap comprising said non-toxic1 skin-tolerable, body fluid-soluble buffer, if desired together with at least one urease inhibitor or suppressor.
By still a further aspect, the invention provides an abosrbent matrix bearing a formulation of the kind specified, which absorbent matrix may, for example, be a diaper, a pad or a napkin.
One of the important applications of this invention is the pre~ention of skin irritation and rashes due to urine, in particular in diapers.In regard to this application the invention affords the great advantage that reduction in skin irritation due to urease activity and to liberated ammonia, is achieved without any risk of skin damage due to low skin pH values below the natural range of from about 4.5 to about 5.5. I~ is to be noted in ,: .
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this comlection that in accordance with the invention this is achieved by - adjusting only the pH of the body fluid which comes into contact with the skin, e.g. urine, while the pH of the skin itself remains in the homeostasis range. In this respect, the invention differs significantly from some prior art which seeks to control chemical and biological processes on the skin by reducing the skin pH to below 4.5. It should ~Irther be noted that by e~ectively controlling the pH of a body fluid that comes into contact with the skin and adjusting it to a level within the natural range of skin pH, optimal control of skin conditions is obtained while at the same time external alteration of the skin pH is avoided.
In the performance of the invention, typically a buffer is used for maintaining the pH of the body fluid within the range of from about 4.5 to about 6Ø In addition, according to an embodiment of the invention, a pH stabilizer selected from the group of metal carbonates and oxides that are sparingly soluble at a pH above about 5.0 and begin to dissolve at a pH of about 5.0 is added, whereby the stipulated lower limit of the desired pH
range is maintained. Thus, should the pH of the urine decrease to 5.0, the said pH stabilizer dissolves into the urine and prevents a drop of the pH
below about 5Ø
The preferred pH range for the purposes of the present invention is from about 5.0 to about 5.5.
Illustrative and non~limitative examples of buffers suitable for the purposes of the present invention are potassium dihydrogen phosphate, ascorbic acid/ascorbic acid salt, citric acid/citric acid salt or citric 2S acid/phosphate buffers.
II1 consequence of the activity of enzymes in an excreted body fluid, e.g. urease in the case of urine, the pH of the fluid tends to rise.
Accordingly, in order to ensure that the pH remains below pH 6 over .
'-' ~ ~ ' 8- ~9~2 ex~ended periocls of time, an enzyme inhibitor, e.g. urease inhibitor or suppressor in case of urine, is used in conjunction with a buffer.
Examples of urease suppressors or inhibitors are substances selected from the group of organic acids, heavy metal salts, heavy metal oxides, aliphatic hyclroxamic acids and their salts, specific examples being ascorbic acid, citric acid, zinc acetate, zinc carbonate, ~inc oxide, aceto-hydroxamic acid.
In accordance with one emboc~iment of the invention, the buffer components and, if desired, the pH stabilizer, and also if desired, the urease suppressor or inhibitor, all in dry form, are embedded in an absorbent matrix such as a diaper, napkin or pad. The active ingredients may conveniently be first mixed with an inert carrier and then dispersecl into the absorbent matrix. Illustrative examples of suitable carriers are talc, natura!
or synthetic zeolites and clay, e.g. attapulgite. The inert carIier is useful for the purpose of enabling uniform distribution of the active components in the matrix.
According to another embocliment of the inveIltion, the buffer components and, if desired, the pH stabilizer and further if desired, the urease suppressor or inhibitor are applied to the skin as a crearn.
BRIEF DESClRIPIlON OF THE DRAWINGS
~Fig. 1 shows the pH dependence of urease activity in urine;
Fig. 2 is a literature reproduction and shows the pH dependence of urease activity in an aqueous urea solution;
Fig. 3 shows the rate of ammonia production by urease in an aqueous urea solution and the increase in pH of the aqueous urea solution as a function of time; and Fig. 4 shows the rate of ammonia production by urease in urine and the increase in pH of the urine as a function of time.

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,-.- , 2~3~6'~-EXP~ERIMENTAL PlROCEDlJl~:S
Urine was sollected daily fiom four adult subjects and was used within sixteen hours of the collection. When not in use, the urine and 5 all other solutions were stored in a ref~igerator at 4C.
By the very nature of being a biological material, the urine mixture differed each day with respect to the pH, ammonia content and self-buffering. Accordingly, each experiment was performed against a blank from the same urine sample.
The presence of urease in feces is not a well de~ined quantity.
Therefore, for convenience, purchased urease (Sigma, I~I.Wt. = 4a2,700, 24,000 ,u molar unit per gram) was used. The amount of urease aclded to the urine (5 units/50 mls. urine) was chosen so that for every urine sample tested in the absence of a buffer or inhibitor, the pH rose to above pH 7 15 duling one hour. This simulates the conditions which are likely to occur in the case of diaper rash.
The incubation experiments were performed in a thermostated bath at 37.0-38.0C. The pH of the urine was determined using a combined glass electrode (Metrohm), and the total ammonia using an Orion 9512 20 electrode. This ammonia electrode is sensitive only to free ammonia.
Therefore, since below pH 7 only negligible amounts of free ammonia exist, the ammonium ions were converted to free ammonia by adding 0.25 ml of 10M sodium hydroxide to each urine sample. On sampling the urine, it was found necessary to dilute the samples by a factor of five in distilled water 25 in order to enter the linear range of the ammonia electrode.
In the following examples and tables the term "ammonia"
refers to the total content of ammonium ions (NH4+) and ammonia (NH3), it being understood that below pH 7, li~tle or no free ammonia actually exists in the uline.

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- lo- 2~3262 -Example 1 Reacti~vitY of Urease in lJrine at 'Vario s pH Va!~les Six stoppered Erlenmeyer flasks with Teflon-coated magnetic bar stirrers were each filled with 50 ml urine (ammonia content 340 ppm., 5pH = 6.1). Using either phosphate or citrate bu-ffers, the pH of the urine in each flask was adjusted to a dif~erent value in the pH range 4 to 11. The flasks were placed in a thermostated bath at 38C for 15 mimltes for equilibration, and then 1 ml. of -urease solution (containing 5 units) was added to each flask. After 60 minutes, the flasks were withdrawn from the 10bath and the final pH and ammonia contents were determined. The activity of the urease was calculated by dividing the increase in the ammonia concentration (Q[NH3~MH4~] ppm) by the residence time in the batll after the addition of the urease (~t).
In Fig. 1, ~[NH3~NH4']/~t is expressed as the percent of 15maximal activity of the urease enzyme in urine and is plotted as a f~nction of the pH for the various samples. As seen, the urease activity increases steeply between p~I 5-6.8 while the rate of ammonia formation in the range pH 5-5.5 is only about 5-37% of the peak rate at pH 6.8. In an aquçous urea solution, on the other hand, 50-75% of peak activity is observed at 20pH 5.0 to 5.5, as shown in Fig. 2 which is reproduced from A.L. L,ehninger, "Biochernistry", p 51.

Exam~le 2 ReactivitY of Urease in Urine and Aqueous Urea 25Urease, S UllitS (Sigma) were added to 50 mls. urea (British Drug House - BDH 20 g/l~ and urine (50 mls.) at 38C, as in Example 1.
Samples were withdrawn periodically and tested for pH and ammonia concentration. The results are presented in Figs. 3 and 4, respectively. In terms of ammonia production, the urease is about three times more reactive , !
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2~3~2 in urine than in aqueous urea. On the o~her hand, the increase in p~I of the urine is less than in aqueous urea showing the self-buffering capacity of urine.
The maximum rate of production of ammonia in urine as given by the slope of the graph [NH3+NH4~] ppm vs. time, is in the pH range 6.8 to 7.8.

Example 3 Lack of Inhibition by A~cids Alone To 50 ml. samples of urine (pH 6.52, [NH3+NH4~] 232 pprn) there were added ascorbic acid (46.5 mg), citric acid (20 mg), rnaleic acicl (23 mg) and lactic acid (80% solution) to give a constant pH 5.5. For comparison, urine alone, and urine containing hydrochloric acid, adjusted to pH 5.7, were also tested Urease (5 units) was added at 38C, and after three hours each sample was analyzed for pH and total ammonia. The increase in total ammonia was calculated by: ~ [NH3+NH4t] = [NH3+NEI4+]
after incuba~ion -[NH3+NH4~] in urine before incubation. The results are gi-ren in Table I below Table I
After three hours _ _ _ . _. , Added to urine ~nitial pH pH [NH3+NH~+] ~ [NH3+NH ,+~
, ~ _ _ .
___ 6.52 8.62 889 657 _ . . _ ~ _ Ascorbic Acid 5.5 8.45 998 766 ~_ _. _ _ .
Citric Acid _ _ 5.5 _ 8.45_960_ _ ?28 Maleic Acid 5.5 8.40 924 692 _ . __ _ 80% Lactic Acid 5 5 8 50 998 766 Acid _ 5 7 8.45 960 722 l~e acids were equal in behavior, and actually had all accelerating effect on the formation of ammonia.

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Exam~
C: h natioll of Pho.sphate B7lf~er With Acids To 50 ml. sarnples of urine (p~I 6.0, [NH3~NH4~] = 407 ppm) there was added monopotassium phosphate (MKP) (500 mg) as buffer. This S reduced the pH of the urine to 5.45. Various acids were added to further retluce the pH to 5Ø The experiment was conducted as in Example 2. The results after three hours are given in Table I:l.

Table II
I Aftler three hours __ _ _ _ - I
urine Initial p~I pH [NH3+NH4-~ ppm ~ tNH3~N~
___ 6.0 8.32 1298 _ ~9 ¦ MKP (500 mg) S.45 5.92 953 546 I . . . I
l MKP + Ascor- 5.0 5.2 475 68 I bic Acicl (60 .
l . . . . _ . _ _ . , ~ _ I MKP ~ Citric 5.0 5.1 440 33 20 l (30 mg) . ~ __ , . - --~1 I MKP ~ MaIelC 5 0 5.12 475 68 I
¦ ACid (30 mg) I . . . ~ _ ¦MKP + 80% 5.0 5.25 514 1()7 l l Lactic Acid ¦ (0-02 ml) ~ _ ~ _ ! MKP + ~y- 5.0 5.12 494 87 drochloric Acid ~ _ __ _ These results are attributable to the further reduction of the pH ~om 5.45 to 5.00 and to the increase of buffering capacity of the urine solution.
This explains the difference between Table I and Table II.

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- 13- ~0~32~2 -Exam~5 l[nhibitin~ E~fect of Acetohydroxamic Acid an(l a Buf~eE

To 50 ml. samples of urine (pH 6.14, [NH3+NH~] = 500 ppm) MKP
5 (500 mg~ was added as buf-fer. I'o one sample acetohydroxamic acid (Sigma, 30 mg) was added as well. The e~periment was performed ~s in Example ~. After three hours, the results were as ~ollows:

Table III
_ _ ~
Agter three hours ~ _ _ _ . _ _ ¦ Added to urine Initial pH pH ~3+NH~Ippm ~ [N~3~NH41 ___ 6.1D~ 8.01 1~56 956 ~_ __ ¦ MKP 5.45 5.86 718 218 MKP ~ aceto- 5.45 5.55 500 O
hydroxam~c ac~d J
. .

The combination of buffer and acetohydroxamic acid totally suppressed the ammonia ~ormation. Reported in vitro inhibition in aqueous urea by acetohydroxamic acid alone at similar temperatures and concentra-tions at pH 7.0 is ~nly 79.3% (Coppi and Bonardi, ibid).

Example fi Inhibiting Ef~ect oP Zinc Salts To 50 ml. samples of urine (pH 5.70, [NH3-~NH4~] = 356 ppm) there were added MKP, zinc acetate, zinc carbonate and ascorbic acid in the amounts given below. Urease (5 units) was added, as in Example 1. After three hours the results were as follows:

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1~- 2~3262 -Table I~

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After tllree hours l ~ ~ __ _ Added to urine ~nitial p~I P~ ~NH3 ~NH~t] ppm ~ [NH3~NH4+] l ~ _ _ _ __ I
___ 5.708.3~ 1281 925 _ _ . . _ _ MI~P (500 mg) 5.225.92 6~3 267 _ .... , _. I
Zinc Acetate 5.406.91 675 319 ~30 mg) ~ _ _ MKP (500 mg) 5.08s 40 452 96 -~ Zinc Acetate (30 mg) ~ _ _ _ _ _ (30 mg) 5.738.08 1136 780 _ _ MKP (500 mg) 5.305.88 623 267 -~ Zinc Carbonate (30 mg) _ _ _ 11 MKP (500 mg) 5.105.52 490 134 Zinc Carbonate (30 mg) + ascorbic acid (30 mg) _ =

As seen, zinc acetate is a strong inhibitor alone (65% inhibition), and 25 in combination with the buffer, MKP, 90% inhibition is achieved. Due to its poor solubility, zinc carbonate is much less e-ffective (16% inhibition).
The presence of zinc carbonate is, however, valuable in preventing too low pH values (pH ~5.0) from being attained. For example, in the presence of zinc carbonate, ascorbic acid (30 mg) only reduced the pH by 0.12 units 30 relative to MKP alone.

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E',xamE~le 7 - T.llc as_D~ing Agellt To 50 mls~ urille (pH 6.47, [NH3+NH4~l = 169 ppm) there were 5 added, as in the previous examples, zinc acetate (30 mg), talc (500 mg) and talc (500 mg) with ~inc acetate (30 mg).
Mer three hours, the results were as follows:

Table V
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After three hollrs _ _ _ _ Added to urine Initial pH P~ [~H3tNH.,~] ppm ~ ~JH3+N~3[4~
_ _ ~
___ 6.47 8.65 10g2 923 _ ~ _ . _ _ ....
Zinc Acetate5.80 8.45 861 692 ~_ . _ Talc 6.47 8.65 861 692 _ . _ _ _ _ _ Talc + Zinc5.82 8.S0 665 496 Acetate _ _ _= _ The talc surprisingly has an inhibiting effect on ammonia formation equal to that, in this par~icular case, of zinc acetate. No synergism, however, exists between the two, and their combined reduction in ammonia is additive.

~Examp1e 8 Ef~ects of phosphate, ascorbic citrate and acetate bu-f~ers OD urease activit~ in urine To 50 ml. samples of urine (pH 6.50, fNH3+NlH4~] = 323 ppm) 500 mg (3.85 x 10-3M~ of MKP and equimolar quantities of the organic acids: ascorbic, citric and acetic were added. The pE~ of the resulting 30 solutions were adjusted to 5.30 by a few drops of concentrated KOEI.

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, - 16- 2~932~2 Urease (5 units~ was added a~ 37.5C and a-fter three hours of incubation - each sarnple was analyzed for pE~ and total ammonia. The res~lts are ~given in Table VI below.

Table VI
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Afl:er three hours l _ ._ _ . _ .
Added to urine Illitial pH pH rNH3~NH4~] ppm ~ [NEI3~P~H~] ¦
._ . _ _ . . ~_ I
___ 6.50 8.1j 120~ 879 l ~ _ _ _ ~ I
MKP (500 rng? 5.30 5.50 _ 500 177 _ Ascorbic acid 5.30 5.40 458 _ 135 Citric acid S.30 5.35 438 115 ___. .......... . ._.
Acetic acicl 5.30 5.25 500 1~7 Example ~
E~fects of Zinc Carbonate and Zinc Oxide as pH Stabilizers in Urine Four stoppered Erlenmeyer flasks with Teflon coated magnetic bar stirrers were each filled with 50 ml urine (pH = 5.7). The pH of the urine in each flask was adjusted to a value of 4.50 by adding concentrated sulfllric 20 acid. To two flasks (Flask No. 1 and Flask No. 2) 73 mg of zinc earbonate.
(M.W. = 125) were added and an eguimolar amount, 47 mg, of zinc oxide (M.W. = 81) was added to the other two flasks (Flask No. 3 and Flask No. 4). The flasks were placed in a thermostated bath at 38C and the pH
in each flask was measured one hour and three hours after the beginning of 2S the incubation. In Table VII the pH readings of each flask at both times are presented.

.. . . .

, , , ' ' "

'`' ' ""'''., .

2~3~-2 Table VII
_ =_=
Initial ~r 1 hour plEI aîter 3 hours plEI Flaslc Flask Flask Flask No. 1 No. 2 No. 3 No. 4 --4 50 ~--5 l~
l~ 4.50_ 5.06 l 5.0~ 5.09 l ~-.10 Example 10 Activity of Various Formulations The following folmulations were tested as in Example 1.

_ ~
No. Formulation F~:Urine alone. pH 6.54 NH3+NH4+ - 160 ppm.
F'2: MKP - 500 mg F3: MKP - 500 mg Ascorbic Acid = 30 mg Zinc acetate = 20 mg ~inc Carbonate = 20 mg _ Talc = 500 mg lS l F4 MKP = 500 mg Ascorbic Acid = 30 mg Talc = 500 mg Zinc Carbonate = 40 mg Fs: MKP = 700 mg Table ~III
_ = - -- - = -- -, -¦_~ Affer three hours ~ ¦
~ Initial pH pH H3~NH~+] ppm ~ [NH3~NlEI~] ¦¦
I Fl 6.54 8.38 294~ 2782 I _ _. ~1 F2 5.74 6.27 1171 1011 F3 5.60 6.14 1077 917 _ _~ . Il F4 5.72 6.12_ -~1l?l ~
Fs _ 5 66 5 95 950 790 - ,. . ,.:. :, . . . . .

. ~ :,; . . .

, . ~- .

This urine sample was unusually reactive and~ 4 times more ammonia than the previous samples Despite this ~act, fhe buffer (F2) gave 64% inhibitis)n, as did ~onnulation F4 Formulation F3 gave 67%
inhibition Increased bu~fer alone ~F5) gave 72~/o inhibition.
Examp~ 11 Activit~ ol~ Var~ous Formulations The fo]lowing formulations were tested as in Example 1 . ~
No. Formulatiorl ~__ _ _ F6: Urine alone. pH 6.1 NH3~NH"~ ~ 340 ppm.
F7 MKP = 700 mg `
_ ~
F8 MKP = 500 mg Zinc acetate = 20 mg Talc = S00 mg Ascorbic Acid = 30 mg Zinc Carbonate - 20 mg ~ ., Table IX

. ~. =e _ . _ ~
~fter three hours - I
_ Iniiial p~[ p~I H3+N~ +] ppm _~I3+NH4+] ¦
F6 6.1 8.5 1367 1027 _ _ F75 3 5.67 548 208 l _ _ _ . ~_ F8 5 0 5 50 527 18'7 25 _ _ _ _ The increased amount of MKP (700 mg) gave 80% inhibition. The fonnulation F8 (570 mg. active compounds) gave 82% inhibition.

, . .. . -.

, , :,: ~ .,.
~, . . .

~ .. . .

~ 19 --2~93~'6~
Example 12 - Preparation of Diaper A typical diaper contains the formulation of the invention in powder form, dispersed immediately below the surface material. Typical S powder weight is 1-10 g per each diaper, depending on diaper size.
A powder consisting of a mixture of 500 g of acid-washed attapulgite, 500 g of MKP and 20 g of ascorbic acid was delivered through a hopper in 3 g batches. 300 Diapers were Iprepared and weighed ten at a time, to show an average weight increase of 30 g/10 diapers, as compared 10 with regular diapers.
The amount of powder used will be proportional to the size of the matrix. Typical weights employed in a sanitary pad are in the range 0.1-1.0 g.

Example 13 Preparation of Skin Cream Into 50 ml. water at 50C, 2 g of a viIIyl alcohol-vinylacetate copolymer (20% acetate) were added slowly with stirring. After dissolution of the polymer there were further added 300 mg ascorbic acid, S0 mg zinc 20 acetate and 550 mg rnonopotassium phosphate. The solution was allowed to cool to room temperature and then aqueous sodiurn hydroxide (10 M) was slowly added with stirring until a pH 5.0 was obtained.
To 17.5 g of the above solution were added 10 g lanolin, 8.7 g sesame oil and 6.0 g of hot paraffin wax mixed with 2.5 g hot paraffin oil.
25 The whole mixture was thoroughly mixed until a smooth cream was obtained.

, .., ,, . , . , . , ... ..~ ,. ,., ...~

, , .

Claims (39)

1. A method of preventing the development of skin rash and other unhealthy skin conditions resulting from contact of the skin with at least one body fluid, comprising maintaining the pH of said at least one body fluid in contact with the skin within the range of from about 4.5 to about 6.0 by adding thereto a non-toxic, skin-tolerable and body fluid-soluble buffer.
2. A method according to Claim 1, wherein the pH of said at least one body fluid in contact with the skin is maintained within the range of from about 5.0 to about 5.5.
3. A method according to Claim 1, further comprising adding a pH stabilizer selected from the group of metal salts and oxides which are sparingly soluble at a pH above about 5.0 and begin to dissolve at a pH of about 5Ø
4. A method according to Claim 1, wherein a binary buffer system is used.
5. A method according to Claim 4, wherein said binary buffer system is selected from the group of ascorbic acid and a salt thereof, citric acid and a salt thereof and citric acid/phosphate buffers.
6. A method according to Claim 4, wherein said binary buffer system comprises an inorganic buffer and an organic acid.
7. A method according to Claim 1, wherein said non-toxic, skin-tolerable and body fluid-soluble buffer is a single chemical substance.
8. A method according to Claim 7, wherein said buffer is potassium dihydrogen phosphate.
9. A method according to Claim 1, wherein said at least one body fluid is urine.
10. A method according to Claim 9, further comprising adding to the urine a urine-soluble urease inhibitor or suppressor.
11. A method according to Claim 10, wherein the urease inhibitor or suppressor is selected from the group of non-toxic heavy metal salts, non-toxic heavy metal oxides, aliphatic hydroxamic acids and their salts, and carbonate salts.
12. A method according to Claim 10, wherein the urease inhibitor or suppressor is selected from the group of ascorbic acid and citric acid.
13. A method according to Claim 11, wherein the urease inhibitor or suppressor is selected from the group of zinc acetate, zinc carbonate, zinc oxide, iron (II) carbonate and iron (III) carbonate.
14. A method according to Claim 11, wherein the urease inhibitor or suppressor is an acetohydroxamic acid.
15. A method according to Claim 1, wherein a skin portion is covered with an absorbent matrix bearing said non-toxic, skin-tolerable, body fluid-soluble buffer.
16. A method according to Claim 15, wherein said absorbent matrix also bears at least one urease inhibitor or suppressor.
17. A method according to Claim 15, wherein said absorbent matrix also bears a pH stabilizer selected from the group of metal salts and oxides which are sparingly soluble at a pH above about 5.0 and begin to dissolve at a pH of about 5Ø
18. A method according to Claim 15, wherein the absorbent matrix is selected from the group of disposable diapers, sanitary napkins and pads.
19. A method according to Claim 1, wherein said non-toxic, skin-tolerable, body fluid-soluble buffer is applied to the skin as a cream.
20. A method according to Claim 19, wherein said cream also includes at least one urease inhibitor or suppressor.
21. A method according to Claim 19, wherein said means also includes a pH stabilizer selected from the group of metal salts and oxides which are sparingly soluble at a pH above about 5.0 and begin to dissolve at a pH of about 5Ø
22. A method according to Claim 1, wherein said non-toxic, skin-tolerable, body fluid-soluble buffer is embedded in a soap.
23. A formulation for preventing the development of skin rash and other unhealthy skin conditions resulting from contact of the skin with at least one body fluid, comprising a non-toxic, skin-tolerable, body fluid-soluble binary or single substance buffer selected to maintain the pH of said at least one body fluid within the range of from about 4.5 to about 6.0, together with a suitable non-toxic, skin-tolerable inert carrier.
24. A formulation according to Claim 23, wherein the buffer is selected to maintain the pH of said at least one body fluid within the range of from about 5.0 to about 5.5
25. A formulation according to Claim 23, wherein the buffer is selected from the group of potassium dihydrogen phosphate, ascorbic acid and a salt thereof, citric acid and a salt thereof and citric acid/phosphate buffer.
26. A formulation according to Claim 23, further comprising a urine-soluble urease inhibitor or suppressor.
27. A formulation according to Claim 26, wherein the urease inhibitor or suppressor is selected from the group of organic acids, non-toxic heavy metal salts, non-toxic heavy metal oxides, aliphatic hydroxamic acids and their salts, and carbonate salts.
28, A formulation according to Claim 26, wherein the urease inhibitor or suppressor is selected from the group of ascorbic acid and citric acid.
29. A formulation according to Claim 27, wherein the urease inhibitor or suppressor is selected from the group of zinc acetate, zinc carbonate, zinc oxide, iron (II) carbonate and iron (III) carbonate.
30. A formulation according to Claim 27, wherein the urease inhibitor or suppressor is an acetohydroxamic acid.
31. A formulation according to Claim 28, further comprising a pH
stabilizer selected from the group of metal carbonates and oxides which are sparingly soluble at a pH above about 5.0 and begin to dissolve at a pH of about 5Ø
32. A formulation according to Claim 23, wherein the carrier is selected from the group of talc, natural zeolites, synthetic zeolites and clay.
33. A formulation according to Claim 32, wherein the carrier is attapulgite.
34. A formulation according to Claim 23, being in cream form.
35. A formulation according to Claim 23, being of liquid or solid soap form.
36. An absorbent matrix bearing a formulation according to Claim 23.
37. An absorbent matrix according to Claim 36, further bearing a non-toxic skin-tolerable, body fluid-soluble urease inhibitor or suppressor.
38. An absorbent matrix according to Claim 36 further bearing a pH stabilizer selected from the group of metal carbonates and oxides which is sparingly soluble at a pH above about 5.0 and begins to dissolve at a pH
of about 5Ø
39. An absorbent matrix according to Claim 36, further bearing a non-toxic, skin-tolerable, body fluid-soluble urease inhibitor or suppressor.
CA 2093262 1992-04-03 1993-04-02 Anti-skin rash preparation Abandoned CA2093262A1 (en)

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EP0564307A1 (en) 1993-10-06 application
FI931437A0 (en) 1993-03-30 application
FI931437D0 (en) grant
JPH0656664A (en) 1994-03-01 application

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