CZ20003301A3 - A disposable absorbent composition comprising a dermatological component with an enzyme inhibitor - Google Patents

Abstract

The invention describes an absorbent article, at least one portion of which comprises a dermatological component with an enzyme inhibitor, which is at least partially transferred from the article to the skin of the wearer thereof upon normal contact, movement of the wearer and/or exposure to body heat. The enzyme inhibitor is transferred to the skin with the dermatological component and is available at the skin/urine and skin/feces interfaces, where it inhibits enzymatic activity on the skin and reduces or prevents the development of inflammation. Repeated application of similarly formulated articles to the wearer's skin provides an available source from which the enzyme inhibitor can continuously transfer to the skin and provide proactive protection against harmful enzymes in the treatment and/or prevention of diaper dermatitis.

Description

Disposable absorbent containing dermatological component with enzyme inhibitor

Technical field

The invention relates to absorbent articles such as diapers, training pants, incontinence pads, feminine hygiene articles, etc., which contain a dermatological component containing an enzyme inhibitor, primarily on a surface that comes into contact with the wearer. During normal wear of the article, the enzyme inhibitor is transferred with the dermatological component to at least a portion of the wearer's skin, where it can inactivate fecal enzymes and reduce redness and inflammation that can develop after prolonged exposure of the skin to body products.

State of the art

Diaper rash is a common form of irritation and inflammation of the areas of a child's body that are normally covered by a diaper. This condition is also called diaper dermatitis. Although it is certainly most common in children, it is not unique to them. Anyone who is incontinent to the extent that they require the use of absorbent materials can develop this condition. Susceptible individuals include newborns, the elderly, the seriously ill, or those who are bedridden. 21 C.F.R. 333 503 defines diaper rash as “an inflammatory skin condition in the diaper area (perineum, buttocks, lower abdomen, and inner thighs) caused by one or more of the following factors: moisture, occlusion, friction, prolonged contact with urine or feces or both, or mechanical or chemical •· ·

9 9 9 9 9 9 9 9

9 999 9999 99 99 irritation.” Doctors generally consider diaper rash or dermatitis to be a condition that, at its mildest, is a contact irritant dermatitis resulting from extensive skin contact with urine or feces, or both. Among the factors most commonly cited in connection with diaper rash are ammonia, enzymes in feces, bacteria, bacterial products, urine pH, and Candida albicans.

There are many types of disposable absorbent articles available, such as diapers, training pants, incontinence products, medical diapers, etc., which have a high absorbent capacity for urine and other body exudates. Disposable articles of this type typically comprise some type of liquid pervious topsheet, an absorbent core, and a liquid impervious backsheet. While these types of absorbent structures may be highly effective at absorbing liquids, they cannot absorb feces. Typically, feces become trapped between the outer surface of the liquid pervious topsheet and the wearer's skin, causing most of it to adhere to the wearer's skin. Thus, the skin is exposed to feces, often for long periods of time, and is susceptible to irritants present in the feces that cause or contribute to diaper rash.

Because enzymes are present in plants, soil, bacteria, milk, dairy products, and almost all animal tissues, as well as in the digestive juices of the gastrointestinal tract, they are almost always present in the diaper area that has been soiled with human excreta. Enzymes present in feces include proteolytic enzymes, lipases and other esterases and diesterases, ureases, and other enzymes including amylases, elastases, nucleases, etc. Although the relative contribution of the various types of enzymes involved in the development of skin irritation is not known, there is evidence that at least proteolytic and lipolytic enzymes in feces, which are of intestinal and/or pancreatic origin, have a direct influence on the development of skin inflammation in diaper dermatitis.

Studies with inhibitors designed to inhibit the enzymatic activity of various classes of proteases have shown that serine proteases, cysteine proteases, and metalloproteases are most likely responsible for the overall proteolytic activity of feces. Serine proteases, primarily trypsin and chymotrypsin, are known to be present in large quantities in the feces of healthy young children, and smaller but detectable quantities are present in the feces of healthy adults. Lipases, including esterases that hydrolyze dietary triglycerides, are also present in normal feces and are capable of hydrolyzing triglycerides and other glycerides found on human skin, producing irritating fatty acids and glycerol byproducts. When the skin is exposed to enzymes such as lipases and proteases present in body secretions, the protein-containing components of the skin can be damaged, resulting in irritation and inflammation. In addition, a breach of the skin barrier allows other components of urine and feces, ammonia, bacteria, etc., which would otherwise not be irritating, to penetrate through the broken skin barrier, causing further irritation and possible infection.

Bile salts are also known to be present in body secretions. Bile salts normally act to form lipid emulsions in the body, thereby providing lipase activity at the lipid/water interface. Bile salts are also active when excreted in the feces and • · · ···· · · · · · · · · · · · · · · ·

9 999999 · · · · · · ·

9 9 9 9 9 9 9 9

9 9 9999999 99 99 other secretions and can act as coenzymes and enhance the activity of lipases that attack lipids in the stratum corneum of skin that is exposed to body secretions.

The irritant effects of faecal enzymatic activity on the skin are usually enhanced when urine is present and/or the skin is covered. The formation of ammonium hydroxide by the action of the bacterial enzyme urease on the urine results in an increase in pH, e.g. to values of 7.0 and above, at which the activity of proteases and other enzymes such as lipases present in the stool increases. For example, the optimal pH range for urease is 6.4-6.9, for trypsin 7.8-8.2 and for lipases 7.5-9.5. If the pH exceeds 7.0, free ammonia begins to be released from the urine, which is another irritating toxic compound acting on the skin. Urine itself can also contribute to the development of diaper rash by moistening the environment. Water, especially water in the form of urine, is particularly effective in reducing the skin barrier, thereby increasing the susceptibility of the skin to irritation by faecal enzymes. Since urine and feces are commonly present in the absorbent material at the same time and skin exposure for several hours is not uncommon, there are suitable conditions and sufficient time for these interactions to occur and subsequent skin damage. Another factor that contributes to the enhancement of enzymatic activity of the stool is its alkaline pH. For example, it is well known that although the stool of naturally breastfed infants is usually acidic, the stool of formula-fed infants is usually alkaline with a pH ranging from slightly alkaline (pH 7.2-7.5) to strongly alkaline (pH 8.7 and higher). Thus, formula-fed infants in particular are prone to developing diaper dermatitis due to increased enzyme activity in the stool due to the higher pH.

• · · · • · ·

In view of the effect of alkaline pH on increased enzyme activity in feces, several attempts have been made to maintain skin pH by using pH-adjusting agents, such as buffers or weak acids, in absorbent compositions or as additives in topical dermatological compositions. It is believed that effectively maintaining skin pH at its natural low pH (i.e., 3.0 to 5.5) may counteract the irritant effect of ammonia and reduce the activity of fecal enzymes. However, reducing skin enzyme activity in this way is quite difficult when feces are directly on the skin.

Certain antienzyme components have been added to topically applied compositions for the treatment and prevention of diaper rash caused by prolonged contact of human skin with body exudates. For example, U.S. 4,556,560 describes compositions containing water-soluble lipase inhibitors, preferably metal salts such as zinc chloride, in a barrier carrier such as polyethylene glycol. If the lipase inhibitor is incorporated into a diaper topsheet or absorbent core, it is preferably in an aqueous or volatile medium such as ethanol, which will facilitate transfer to the skin upon wetting of the diaper with urine. U.S. 5,091,193 describes compositions for application to the skin at diaper changes which contain a chelating agent such as folic acid, ethylenediaminetetraacetic acid (EDTA), etc., which limit the availability of metals that urease and proteases require as cofactors for activity. The preparation may further comprise a lipase substrate, such as a fatty alcohol ester or an added antienzyme, saturated or unsaturated, linear or branched, a zinc salt of a fatty acid with 2 to 22 carbon atoms ··· · · · · · · · • · · · « · · • · · · · · · *···· ·

While preparations for the treatment of diaper dermatitis have been described which contain certain inhibitors of enzyme activity, there has not yet been described a possibility of treating or preventing diaper dermatitis in which dermatological preparations containing enzyme inhibitors are contained in absorbent articles with automatic transfer to the skin of the wearer during normal wear of the adapted article or whose use, preferably repeated, automatically maintains sufficient levels of enzyme inhibitors in a selected area of the wearer's skin, thereby providing protection against fecal penetration and enzyme activity. In addition, absorbent articles with a dermatological component containing immobilized enzyme inhibitors (at room temperature) on the surface contacting the wearer have not previously been described, particularly in the top layer from which the dermatological component and enzyme inhibitor are transferred to the skin of the wearer after heating the dermatological component to body temperature.

The essence of the invention

The invention describes an absorbent article, a portion of which comprises a dermatological component comprising an enzyme inhibitor, from which the dermatological component including the enzyme inhibitor is at least partially transferred from the article to the skin of a wearer of the article during normal contact, movement of the wearer and/or body heat. An enzyme inhibitor is any substance that reduces the activity of one or more enzymes, preferably at an IC ₅₀ , as defined below, of not more than 500 micromolar (μΜ). Suitable enzyme inhibitors for use in this article are protease inhibitors, lipase inhibitors, elastase inhibitors, urease inhibitors, amylase inhibitors, etc., as well as bile salt inactivators that would otherwise act as cofactors for lipases. The dermatological composition typically contains about 0.001% to about 50% of the enzyme inhibitor, more preferably from 0.01% to 25%, more preferably from 0.1% to 10%, and most preferably from 0.1% to 5%.

The nature of the dermatological component containing the enzyme inhibitor can vary considerably, but in one preferred embodiment it is solid or semi-solid at room temperature (20°C). In a preferred embodiment, the dermatological component further comprises about 5% to 95% of a plasticizer which is plastic or liquid at 20°C. The dermatological component should further comprise about 5% to 95% of a substance which is capable of immobilizing the plasticizer in the composition and which has a melting point of at least about 35°C. The part of the absorbent composition containing the dermatological component with the enzyme inhibitor should preferably be the surface which is in contact with the user, preferably the liquid-permeable topsheet.

Since the enzyme inhibitor is transferred to the skin with the dermatological component, it is therefore available at the skin/urine and skin/feces interfaces, where it inhibits enzymatic activity on the skin and reduces or prevents the development of inflammation. Repeated use of similarly formulated compositions offers an available source from which the enzyme inhibitors are continuously transferred to the skin, where they accumulate and provide proactive protection against harmful enzymes in the treatment and/or prevention of diaper dermatitis.

Overview of images in drawings φ φ φ φ φ φ • φ

Φ Φ 1 • ··<

Figure 1 is a schematic representation of an absorbent article in the form of a diaper according to the present invention.

Figure 2 is a side view showing the placement of a skin analog used in a dermatological ingredient transfer test and/or a protease inhibitor transfer test.

Figure 3 is a plan view showing the placement of a skin analog used in a dermatological ingredient transfer test and/or a protease inhibitor transfer test.

Detailed description of the invention

I. Definition

The term "comprising" as used herein means that various components, ingredients, or steps may be used together in the practice of the present invention. Accordingly, the term "comprising" also includes the narrower terms "consisting primarily of" and "consisting of".

The term "modified device", as used herein, means that the absorbent device contains a dermatological component on its surface or at least is capable of moving towards the surface contacting the user.

The term "wearer-contacting surface" of an absorbent article is one or more surfaces of any part of the article that comes into contact with the wearer during wear. Wearer-contacting surfaces include, but are not limited to, portions of the topsheet, the limb • · · • · · · · ·

cuffs, waist area, side stripes, fastening loops, etc., which touch the user during wear.

The term "dermatological ingredient", as used herein, means any ingredient containing an enzyme inhibitor that is transferred to the skin of a user of the treated article by normal contact, movement of the user, and/or body heat during normal wear.

The term “IC ₅₀ ” means the inhibitory concentration (e.g., micromolar concentration, μΜ) of a substance (inhibitor) that will reduce the level of substrate cleavage by an enzyme by 50% when measured by standard in vitro enzyme activity assays, see below. IC ₅₀ is calculated according to the equation IC ₅ o = (I)/((v/v i)-1), where (I) is the inhibitory concentration tested, v is the level of substrate cleavage in the absence of the inhibitor, and V i is the level of substrate cleavage in the presence of the inhibitor. As will be described below, the IC50 of an enzyme inhibitor can be measured using the Purified Enzyme Method or the Fecal Enzyme Method.

Other terms are defined here on their first use.

All percentages, coefficients and ratios used herein are weighted unless otherwise stated.

II. Enzyme inhibitors

Inhibitors of enzyme activity are well known and are classified as competitive inhibitors (which compete with the substrate for binding to the active site of the enzyme) and non-competitive inhibitors (which inactivate the enzyme by binding to a site other than the active site). Many enzymes, such as metalloproteases, are inactivated by substances that bind to the metal group of the enzyme. Chelating agents are effective inhibitors of other enzymes that require the presence of metal ions for activation, such as calcium, cobalt, copper, magnesium, manganese, sodium, potassium, or zinc ions. Since enzymes are proteins, antibodies are also effective as enzyme inhibitors against specific enzymes.

Enzyme inhibitors suitable for the absorbent compositions described herein typically have IC ₅₀ values of up to about 500 μΜ, more preferably up to about 250 μΜ, and most preferably up to about 100 μΜ. It is understood that certain inhibitors (e.g., EDTA) will have higher IC 50 values, but will still be useful in the absorbent compositions described herein. Materials for which the molecular weight cannot be determined will reduce enzyme activity by at least 50% at a concentration not exceeding about 5% by weight in the dermatological composition. Representative methods for measuring enzyme inhibitory activity are mentioned below.

Any type of enzyme inhibitor may be utilized in the dermatological composition transferable to the skin of a user from the absorbent article of the present invention, including any naturally occurring inhibitor of plant, microbial and/or animal origin (including human) and synthetically prepared chemical inhibitors. Enzyme inhibitors may be hydrophilic or hydrophobic in nature and may therefore be soluble in water or a hydrophobic vehicle. Enzyme inhibitors are typically present in the dermatological composition at a concentration of from 0.001% to about 50% by weight, more preferably from 0.01% to about 25%, more preferably from 0.1% to about 10%, and most preferably from 0.1% to 5%. Because of the variety of inhibitors

enzymes used in the invention, the effective concentration of each inhibitor must be determined separately, which is common in the art.

Enzyme inhibitors can be used alone or as a mixture of enzyme inhibitors, such as a "cocktail" of inhibitors in a single absorbent device. Additionally, different enzyme inhibitors can be used in the dermatological component at different locations in a single absorbent device.

Due to the diversity of enzymes present in feces and other body secretions, it can be expected that substances that inhibit certain classes of enzymes (e.g., proteases) will also inhibit enzymes that cleave substrates other than those in question (e.g., proteins and peptides). Therefore, inhibitors that inhibit proteases may also inhibit lipases and other esterases, amylases, and/or ureases, and vice versa.

Preferably, inhibitors of enzymes and/or coenzymes most commonly found in feces or other body secretions are added to the dermatological component of the inventive absorbent composition. The most suitable enzyme inhibitors are inhibitors of proteolytic enzymes, such as trypsin, chymotrypsin, aminopeptidase and elastase; lipases; bile salts; amylases; and/or ureases.

Examples of suitable protease inhibitors for use in the present invention that are believed to inhibit the type of protease listed in parentheses include, but are not limited to, soybean trypsin inhibitor and other plant-based trypsin inhibitors such as lima bean (Phaseolus limensis) protease inhibitor,

• · • · · · · · « • · · • » · » • · · · · · * · • · · · · ♦ · c · protease inhibitor from corn and the like; Bowman-Birk inhibitor (serine and trypsin-like protease inhibitor); pancreatic trypsin inhibitor, such as bovine pancreatic alkaline trypsin inhibitor and other pancreatic trypsin inhibitors obtained from animals; egg white trypsin inhibitor (serine and trypsin-like protease inhibitor); ovomucoids containing ovoinhibitors, such as from chicken or turkey egg white (trypsin and chymotrypsin inhibitors); chymostatin (serine and chymotrypsin-like protease inhibitor); aprotinin (serine protease inhibitor); leupeptin and its analogues, such as propionyl-leupeptin, Ν-α-t-BOC-deacetylleupeptin (serine and cysteine protease inhibitor); bestatin and its analogues, such as epibestatin and nitrobestatin (aminopeptidase and metalloprotease inhibitors); amastatin and its analogues, such as epiamastatin (aminopeptidase inhibitor); antipain (trypsin inhibitor); antithrombin III (serine protease inhibitor); hirudin (thrombin-like serine protease inhibitor); cystatin (egg white cysteine protease inhibitor); E-64 (trans-epoxysuccinyl- _L- leucylamido-(4-guanidino)butane) and its analogues (cysteine protease inhibitor); and ₂ macroglobulin (universal endoprotease inhibitor); oci-antitrypsin (trypsin inhibitor); pepstatin and its analogues, such as acetylpepstatin, pepstatin A, Nle-Sta-Ala-Sta (aspartyl protease inhibitor); apstatin (aminopeptidase P inhibitor); (2R)-2mercaptomethyl-4-methylpentanoyl-b-(2-naphthyl)-Ala-Ala amide (matrix metalloprotease inhibitor); (2R)-2-mercaptomethyl-4-methylpentanoyl-Phe-Ala amide (matrix metalloprotease inhibitor); N-acetylLeu-Leu-methioninal (calpain inhibitor); N-acetyl-Leu-Leunorleucinal (calpain inhibitor); p-aminobenzoyl-Gly-Pro- _D -Leu-DAla hydroxamic acid (matrix metalloprotease inhibitor); 2(R)(N-(4-methoxyphenylsulfonyl)-N-(3-pyridylmethyl)amino)-3-methylbutano-hydroxamic acid (metalloprotease inhibitor); L-chloro3-(4-tosylamido)-7-amino-2-heptanone-HCl (TLCK), L-1-chloro-3-(4-tosylamido)-4-phenyl-2-butanone (TPCK), tranexamic acid, glycerhysic acid, 18-p-glycerretinoic acid and corresponding salts, stearylglycerretinate, colloidal oat extracts, elhibin, zinc salts, iodoacetate, phenylmethylsulfonyl fluoride, phosphoramidon, 4-(2aminoethyl)-benzenesulfonyl fluoride HCl, 3,4-dichloroisocoumarin, quercetin, etc. and mixtures thereof.

Chelating agents have been found to be useful as inhibitors of both proteases and ureases at concentrations from 0.1% to about 2%. Examples of chelating agents are phytic acid, nitrile triacetic acid, EDTA, diethylenetriaminepentaacetic acid, hydroxyethylethylenediaminetriacetic acid and their respective salts, described in U.S. Patent 5,091,93, issued to Enjolras on February 25, 1992, which is incorporated herein by reference.

For use in the absorbent articles of the present invention, we prefer protease inhibitors that have inhibitory activity that is not limited to a single class of proteases. Such compounds include, but are not limited to, hexamidine and its salts, pentamidine and its salts, benzamidine and its salts and derivatives, p-aminobenzamidine and its salts and derivatives, and guanidinebenzoic acid and its salts and derivatives, such as those described in U.S. 5,376,655, issued to Imaki et al. on December 27, 1994, which is incorporated herein by reference. Other proposed protease inhibitors are the polymeric derivatives of guanidinebenzoic acid described in copending U.S. application Ser. No. 09/041,196 (T. L. Underiner et al.), which was filed concurrently with this application.

* ·» >· ·» ·· · · · · · · • · · · · · · • ····· • > » » * · ······ · · · · · · · · · · · • · · · · · · · · • · · · *· »

For use with the present invention, we prefer the following protease inhibitors: soy trypsin inhibitor, aprotinin, hexamidine (e.g., hexamidine diisothionate), p-aminobenzamidine, leupeptin, pepstatin A, chymostatin, and polymeric derivatives of guanidine benzoic acid (described in copending U.S. application Ser. No. 09/041,196, which is incorporated herein by reference). The most preferred protease inhibitors are soy trypsin inhibitor, hexamidine, p-aminobenzamidine, and the foregoing polymeric derivatives of guanidine benzoic acid.

It is known that ureases are inhibited in the presence of trace amounts of heavy metal ions such as silver, copper, etc. Thus, trace amounts (as little as 0.001% or less) of salts of these metals are good inhibitors of ureases. Other suitable urease inhibitors include, but are not limited to, acetylhydroxamic acid and its derivatives, such as cinnamoylhydroxyamic acid and other alkylhydroxamic acids, salts and derivatives thereof; phosphoramidate and its derivatives. Such compounds are competitive inhibitors of ureases at concentrations of about 2 micromolar (μΜ). Chelating agents have been found to be good inhibitors of both proteases and ureases at concentrations of from 0.1% to about 2%. Examples of chelating agents are phytic acid, nitrile triacetic acid, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid, hydroxyethylethylenediaminetriacetic acid and their respective salts, described in U.S. Patent 5,091,193, which is incorporated herein by reference. Other urease inhibiting compounds are described in U.S. Patent 3,952,862 (Kraskin), which is incorporated herein by reference, and include amino acid compounds such as hydroxyalkyl amino acids, sulfhydryl amino acids, aminosulfonic acids, compounds ·· ·

9 9

9 9 9 » ···· · • · ·

9 • 9 9 9 9

9 9 9 9

9 9 9 9 9 • · 9 9 9

9 99 99 aminophosphonic acids ether amino acids, such as methoxyethyliminodiacetic acid, ethylene-bis-(oxypropylaminodiacetic acid), ethylene-bis-(oxyethyliminodiacetic acid), aminomethylphosphonic acid (Ν,Ν-diacetic acid), etc. and aminopolycarboxylic acid compounds, including acids and salts of diethylenetriaminepentaacetic acid (DTPA), N-hydroxyethylenediaminetriacetic acid (HEDTA), etc.

Other suitable urease inhibitors are described in U.S. Patent 5,409,903, issued to Polak et al. on April 25, 1995, which is incorporated herein by reference. This patent discloses urease inhibitors such as divalent magnesium phosphate, dialdehyde polysaccharides, and zeolite, used alone, in combination with each other, or with compounds of calcium, calcium acetate, calcium chloride, calcium gluconate, and calcium lactate, or similarly with compounds of magnesium, magnesium chloride, and magnesium citrate.

Suitable lipase inhibitors include, inter alia, water-soluble salts of metals such as cadmium, cobalt, copper, iron, molybdenum, silver, lanthanum, tin and zinc. Examples of lipase inhibiting compounds are described in U.S. Patent 4,556,560, incorporated herein by reference, and include zinc chloride, zinc acetate, zinc nitrate trihydrate, zinc nitrate hexahydrate, ferrous chloride, ferrous chloride tetrahydrate, ferric chloride, ferric chloride monohydrate, ferric chloride hexahydrate, ferrous lactate, ferric lactate, ferric malate, ferrous nitrate, ferric nitrate hexahydrate, ferric nitrate _9H20 , ferrous sulfate and its hydrates, ferric sulfate and its hydrates, cupric sulfate pentahydrate, stannous chloride, cobalt chloride and lanthanum chloride, zinc salts of saturated and unsaturated monocarboxylic acids of 6 to 12 carbons, block copolymers of propylene oxide and ethylene oxide (e.g., marketed under the name Pluronic® and Tetronic® from BASF Corp.), glycerol triesters of fatty acids of 2 to 20 carbons, such as triacetin, and the like. Other suitable lipase inhibitors are described in U.S. Pat. No. 5,091,193, incorporated herein by reference, and include fatty alcohol esters, such as saturated or unsaturated, linear or branched alkyl acetate, lactate or propionate of 10 to 20 carbons, saturated or unsaturated, linear or branched zinc salts of fatty acids of 2 to 22 carbons, such as those formed with propionic acid, isobutyric acid, caproic acid, undecylenic acid, and the like, zinc salts of aminoacylated acids, such as propionylcysteine, propionylhydroxyproline, or caproylcysteine, and the like. Suitable concentrations of these lipase inhibitors have been found to be from 0.01% to about 10%.

Other suitable lipase inhibitors, described in our patent application EP97/120 699 (G. Palumbo et al.), are specific esters that act as a surrogate substrate for faecal lipases and are therefore competitive lipase inhibitors. The formulas of these esters are:

where R1 and each _R2 are independently acyl groups of 2 to 22 carbons or alkyl, alkenyl, arylalkyl, hydroxyalkyl • · · 9 9 9 9 9 99

9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9 9 ♦ · ···· · · · ····· i / 9 9 · ·· · · · · · · · · · · · · · · · · · · · · · · · · · · groups of 1 to 24 carbon atoms or hydrogen, whereby at least one Ri or R ₂ is such an acyl group, R ₃ , R ₄ , R ₅ , R ₆ , R 7 , Rs and R ₉ are either alkyl, alkenyl, arylalkyl, hydroxyalkyl, alkoxy groups of 1 to 24 carbons, hydroxy groups or a hydrogen atom; R10 and Rn are either alkyl, alkenyl, arylalkyl, hydroxyalkyl, alkoxy groups of 2 to 24 carbons, hydroxy groups or hydrogen; A and B can be C1 - C6 linear or branched alkylene, alkenylene, alkoxylene, hydroxyalkylene groups; the values of x range from 0 to 15; the values of y are either 0 or 1, with the proviso that when x=2 and y=0, at least one R2 is an alkyl, alkenyl, aralkyl, hydroxyalkyl group of 1 to 24 carbons or a hydrogen atom.

Other examples of lipase inhibitors are described in U.S. Patent 5,643,873, which is incorporated herein by reference, and include: (2S,3S,5S)-5-((S)-2-formamido-4-methyl-valeryloxy)-2-hexyl-3-hydroxy-hexadecanoic 1,3 acid lactone, also known as tetrahydrolipstatin; (2S,3S,5S,7Z,10Z)-5-((S)-2-formamido-4-methyl-valeryloxy)-2-hexyl-3-hydroxy-7,10-hexadecanoic 1,3 acid lactone, also known as lipstatin; 1-(trans-4-isobutylcyclohexyl)-2-(phenylsulfonyloxy)ethanone, also known as FL-386; 4-methylpiperidine-1-carboxylic acid 4-phenoxyphenyl ester, also known as WAY121898; N-(3-chloro-4-(trifluoromethyl)phenyl-)N'-(3-(trifluoromethyl)-phenyl)urea, also known as BAY-N-3176; N-formyl-Lvaline-(S)-1-(((2S,3S)-3-hexyl-4-oxo-2-oxetanyl)methyl)hexyl ester, also known as valillactone; (2S,3S,5S,7Z,10Z)-5-((S)-2-acetamido3-carbamoylpropionyloxy)-2-hexyl-3-hydroxy-7,10-hexadecadienyl lactone, also known as esterastin; (3S,4S)-4-((1S,5R,7S,8R,9R,E)8-hydroxy-1,3,5,7,9-pentamethyl-6-oxo-3-undecenyl)-3-methyl-2oxetanone, also known as ebelactone A; (3S,4S)-3-ethyl-4((1S,5R,7S,8R,9R,E)-8-hydroxy-1,3,5,7,9-pentamethyl-6-oxo-3-undecenyl)-2-oxetanone, also known as ebelactone B; and 1,6-di(O(carbamoyl)cyclohexanone oxime)hexane, also known as RHC 80267.

Examples of bile salt inhibitors that are coenzymes of lipolytic enzymes and are suitable lipase inhibitors in said absorbent composition include, among others, cationic compounds described in patent application EP 97/120,700 filed November 26, 1997, incorporated herein by reference. The formulas of these compounds are: ³

Ra — N — r,

RM (I) or

R.

^R 1

4r ₅ ~n —r^ •R«

MΓ

Rtm or amphoteric compound preferably of acidic origin, which has at its isoelectric point the formula:

clay M

R^ —N ⁺ —A —BH ^R io (III) for the preparation of a compound for treating, preventing or controlling lipolytic dermatitis, wherein R1, R2, R3 and R4 are independently C1-C22 alkyl, alkenyl, aryl, arylalkyl, amidoalkyl, (poly)alkoxy, hydroxyalkyl or acyl groups or two or more of R1, _R2 , R3 and _R4 together form one or more ring structures;

• 4 • 9 9

4··

R ₅ , R ₆ and A are independently C1-C22 alkylene, alkenylene, (poly)alkoxylene, hydroxy alkylene, arylalkylene or amidoalkylene groups; R ₇ and R ₈ are independently C1-C4 alkyl, alkenyl, alkoxyl groups or hydroxyl groups or a hydrogen atom; R ₉ and R ₁₀ are independently C1-C22 alkyl, alkenyl, aryl, arylalkyl, amidoalkyl, (poly)alkoxyl, hydroxyalkyl or acyl groups or two or more of R 1 , R ₉ and R 10 together form one or more ring structures; the BH group is a proton donor; x is from 2 to 4; and M' is a counterion.

Another example of a suitable bile salt inhibitor is cholestyramine, described in C. Michael White et al., entitled "Cholestyramine Ointment to Treat Buttocks Rash and Anal Excoriation in an Infant", The Annals of Pharmacotherapy 30:954956, Sept. 1996.

Derivatives of p-guanidinebenzoic acid, particularly its esters, have been described as esterase inhibitors. Such inhibitors are suitable for the dermatological component of the absorbent composition of the present invention and are described in U.S. Patent 5,376,655 to Imaki et al. 27.

12. 1994, which is incorporated herein by reference.

Suitable amylase inhibitors and/or glucosidase amylase inhibitors include those described in U.S. Patent 5,643,874, which is incorporated herein by reference, and include O-4,6-dideoxy-4-(((1S(1α,4α,5β,6α))-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-yl)amino)-α-D-glucopyranosyl-(1-4)O-α-D-glucopyranosyl-(1-4)D-glucose, also known as acarbose; 2(S),3(R),4(S),5(S)tetrahydroxy-N-(2-hydroxy-1-(hydroxymethyl)-ethyl)-5-(hydroxy20 • · · · · · · · « ·

1,5-dideoxy-1,5-(2-(4-ethoxycarbonylphenoxy)-ethylimino)-Dglucitol, known as emiglitate; 2,6-dideoxy-2,6-imino-7-(β-D-glucopyranosyl)-D-glycero-L-guloheptitol, also known as MDL-25637;

1.5- dideoxy-1,5-(6-deoxy-1-0-methyl-α-D-glucopyranosyl-6-imino)D-glucitol, also known as camiglibose; 1,5,9,11,14-pentahydroxy3-methyl-8,13-dioxo-5,6,8,13tetrahydrobenzonaphthacene-2-carboxylic acid, known as pradimicin Q; or also as adiposin; and 1,2dideoxy-2-(2(S),3(S),4(R)-trihydroxy-5-hydroxy-methyl-5-cyclohexene-1(S)-amino)-L-glucopyranose, known as salbostatin. Other suitable amylase inhibitors include tendamistat, trestatins, and substances obtained from plants, particularly wheat, rice, corn, barley and other cereal grains, beans, and seaweed.

III. Absorbent materials

The term “absorbent article” is used herein to refer to a product that absorbs and contains bodily exudates. The term “disposable” is used herein to describe an absorbent article that is not intended to be washed or otherwise reprocessed or reused. Examples of disposable absorbent articles include feminine hygiene products such as sanitary napkins, sanitary pads and tampons, diapers, incontinence pads and pads, exercise pants, etc.

A typical disposable absorbent article consists of a liquid-permeable top layer, a liquid-impermeable bottom layer, and an absorbent core disposed between the top and bottom layers. Disposable absorbent articles and their components, including • 9 • · 9

99 99 »

99 9 9 9 the topsheet, the backsheet, the absorbent core and any individual layers of these parts have a body-facing surface and a garment-facing surface. As used herein, the term "body-facing surface" means that this surface of the device or a portion thereof is intended to be worn toward the wearer's body, while the "garment-facing surface" is on the opposite side and should be worn toward the garment.

The following section generally describes absorbent core, topsheet, and backsheet materials that are suitable for disposable absorbent articles. This general description applies to portions of the specific absorbent article shown in Figure 1 and described below, in addition to other absorbent articles generally described herein.

The absorbent core is typically capable of absorbing or retaining fluids (e.g., blood, urine, and/or other body exudates). The absorbent core is typically compressible, conformable, and non-irritating to the user's skin. The absorbent core can be manufactured in a variety of sizes and shapes (e.g., rectangular, oval, hourglass, "T" shape, dog bone shape, asymmetrical, etc.). Additionally, the absorbent core may also include, in addition to the absorbent components, any of a wide variety of fluid-absorbent materials, such as cellulose. Examples of other suitable absorbent materials used for the absorbent core include cellulose wadding; blended polymers such as coform; chemically strengthened, modified, or crosslinked cellulose fibers; synthetic fibers such as corrugated polyester fibers, peat, laminated paper, absorbent foams, absorbent sponge materials, superabsorbent polymers including composites, absorbent gelling agents, and the like.

4 4 • · • · · 4 • 4 4 4 4 4 4 • 44 · · materials or any similar material, combination of materials or mixtures thereof.

The arrangement and construction of the absorbent core may vary (e.g. the absorbent core may have different straddle zones and/or a profile that is thicker in the center; hydrophilic gradients; gradients of absorbent components; superabsorbent gradients or areas of lower average density or lower average base weight, e.g. acquisition areas or may be composed of one or more layers or structures). However, the overall absorbent capacity of the absorbent core should be appropriate for the proposed load and intended use of the absorbent article. Furthermore, the size and absorbent capacity of the absorbent core must be adequate for various uses, such as diapers, incontinence pads, menstrual pads, sanitary napkins and must be adapted to a range of users from children to adults. The absorbent core may also contain other absorbent components that are often used in absorbent articles, e.g. a backer layer, an absorbent layer for urine retention or another top layer to increase the comfort of the user.

The topsheet is typically pliable, soft, and non-irritating to the wearer's skin. Furthermore, the topsheet is liquid permeable, allowing liquids (e.g., blood and/or urine) to pass through it easily. Suitable topsheets can be made from a variety of materials, such as fleece and nonwoven materials (e.g., nonwoven webs of fibers), including nonwoven materials with apertures; polymers such as porous thermoplastic film, porous plastic film, and hydroformable thermoplastic films; porous foams; reticulated foams; reticulated thermoplastic films, and thermoplastic scrims. Suitable fleece and nonwoven materials include natural fibers (e.g., wood or cotton fibers), synthetic fibers (e.g., polymer fibers such as polyester, polypropylene, or polyethylene fibers), or materials formed by a combination of natural and synthetic fibers. If the topsheet is made from a nonwoven material, the material can be processed by a variety of known techniques. The net may be made, for example, by spinning, carding, hot-blown, wet-knitting, wet-forming, a combination of the above or the like. The top layer should contain a dermatological component with an enzyme inhibitor, regardless of whether it is made of wool or non-wool material, see below.

The backsheet is impermeable to liquids (e.g., blood and/or urine) and typically comprises a thin plastic layer, although other impermeable flexible materials may be used. The term "flexible" is used to refer to materials that are pliable and readily conform to the shape and contours of the human body. The backsheet prevents exudates absorbed and retained in the absorbent core from wetting articles in contact with the absorbent, such as sheets, underpants, pajamas, and undergarments. The backsheet may therefore comprise a fleece or nonwoven material, a polymer coating, such as a thermoplastic layer of polyethylene or polypropylene, or composite materials, such as a coated nonwoven material. A suitable backsheet is a polyethylene film having a thickness of from 0.012 mm to about 0.051 mm. Suitable polyethylene films are manufactured by Clopay Corporation of Cincinnati, Ohio, under the designation PI8-1401, and Tredegar Film Products of Terre Haute, Indiana, under the designation XP-39385. The backsheet is typically embossed and/or matted to give a textile appearance. Furthermore, the backsheet should be permeable to vapors from the absorbent core (i.e., the backsheet is breathable) while being impermeable. The size of the backsheet is determined by the size of the absorbent core and its chosen shape.

The backsheet and the topsheet are positioned, respectively, adjacent the garment and body-facing surfaces of the absorbent core. The absorbent core is typically attached to the topsheet, the backsheet, or both layers by one of the fastening elements (not shown in Figure 1) commonly used in the art. However, embodiments of the absorbent device may be apparent if parts or all of the absorbent core is not attached to either the topsheet or the backsheet, or both layers.

The backsheet and/or topsheet may be attached to the absorbent core or to each other by a continuous layer of adhesive, a patterned layer of adhesive, or a series of individual lines, spirals, or dots of adhesive. Suitable adhesives are manufactured by H.B. Fuller Company of St. Paul, Minnesota under the designation HL-1258 or H-2031. The bonding means preferably comprises a network of adhesive fibers as described in U.S. Patent 4,573,986, issued to Minetola et al. on March 4, 1986, which is incorporated herein by reference. An example of a bonding method is a network of fibers formed by multiple adhesive lines wound into a spiral, as described in U.S. Patent 3,911,173, issued to Sprague, Jr. on October 7, 1975, U.S. Patent 4,785,996, issued to Zwieker et al. on November 22, 1978 and U.S. Patent 4,482,666 to Werenicz on June 27, 1989. Each of these patents is incorporated herein by reference. Thermal bonds, pressure bonds, ultrasonic • · · · · · · · · • · · · · « * · · · ·

9 9 9 · · 9 9 9 9

Λζ 9 9 9999 9 9 ·«···· ··· ·· 9999 * ··· 9999 99 99 joints, dynamic mechanical joints or other suitable connecting means or combinations thereof known in the art.

The proposed disposable absorbent article is a diaper, which contains at least in one part an enzyme inhibitor and more preferably its surface contacting the user is treated with a dermatological composition containing an enzyme inhibitor. As used herein, the term diaper means an absorbent article which is generally used by children and incontinent persons and which is worn around the lower torso. In other words, the term diaper includes baby diapers, training pants, adult incontinence articles, etc.

Figure 1 is a diagram of a diaper 50, which is shown in an expanded state (i.e., not pulled down by elastic portions) and without certain parts so that its structure is clearly visible and is turned with its outer surface towards the viewer. The diaper 50 of Figure 1 is typically composed of a permeable topsheet 520, an impermeable backsheet 530 connected to the topsheet 520, an absorbent core 540 having a garment facing surface 542, a body facing surface 544, a side edge 546, waist edges 548 and tabs 549. The diaper 50 typically further includes elastic thigh cuffs 550 and a variously shaped elastic waist portion 560 and, typically, variously shaped fastening means 570.

The diaper 50 shown in Figure 1 has an outer surface 52, an inner surface 54, which corresponds to the body-facing surface opposite the outer surface 52, a first waist region 56, a second waist region 58, and a perimeter 51, which is defined by the outer edges of the diaper 50, where the longitudinal edges are designated 55 and the end edges 57. (V • · • · ·

9 9 9

9 9 9

99999 9

9 9

9 9 9

99

9 · · • 9 9 9

9 9 9

9 9 9 • · · 9 In the art, it is common to divide a diaper into two waist regions and a crotch region located therebetween, but in this application, for simplicity, only the division of the diaper 50 into waist regions containing the original crotch region is used. The body-facing surface 54 of the diaper 50 is that portion of the diaper 50 that is adjacent to the wearer's body during wear. The body-facing surface 54 is typically formed by at least a portion of the topsheet 520 and other portions that may be attached to the topsheet 520, such as the thigh cuffs 550, as well as areas that are not part of the topsheet but that contact the wearer, such as the waist portion 560, side portions, and the like. The outer surface 52 includes the portion of the diaper 50 that faces away from the wearer's body (i.e., the outer surface 52 is typically formed by at least a portion of the backsheet 530 and other portions that may be attached thereto). A first waist region 56 and a second waist region 58 extend between the end edges 57 of the circumference 51 and a transverse centerline 53 of the diaper 50. A longitudinal centerline 59 is also shown in FIG. 1 .

Figure 1 shows a proposed embodiment of a diaper 50 in which the topsheet 520 and the backsheet 530 have a length and width greater than the dimensions of the absorbent core 540. The elastic thigh cuffs 550 and the backsheet 530 extend beyond the edges of the absorbent core 540, thereby forming a perimeter 51 of the diaper 50.

The diapers of the present invention can be made in a number of known embodiments in which the absorbent cores are adapted to the present invention. Examples of embodiments are generally described in U.S. Patent 3,860,003 (Buell) filed January 14, 1975, U.S. Patent 5,151,092 (Buell et al.) issued September 29, 1992, and U.S. Patent 5,221,274 (Buell et al.) issued January 22, 1993. All of these patents are incorporated herein by reference. Other φφ * φφφ φφ · φ φφφφ • · · φ · φ φφφφ · φ«φ·* · · φφ φφ φ

A diaper embodiment to which the present invention can be readily adapted is described in U.S. Patent No. 5,554,145 to Roe et al., the disclosure of which is incorporated herein by reference.

The topsheet 520, which is particularly suitable for use in the diaper 50, is carded and thermally bonded in a manner conventional in the art. A suitable topsheet is composed of long polypropylene fibers having a denier of about 2.2. The term long fibers as used herein means those fibers having a length of at least 15.9 mm. The weight of the topsheet should be from about 14 to about 25 grams per square meter. A suitable topsheet is manufactured by Veratec, Inc., Division of International Paper Company, Mass. under the designation P-8.

The topsheet 520 of the diaper 50 is typically made of a hydrophilic material that will facilitate the rapid passage of fluids (e.g., urine) through the topsheet. If the topsheet is made of a hydrophobic material, at least portions of the topsheet must be modified to be hydrophilic and allow fluids to pass rapidly through the topsheet. This will reduce the likelihood that bodily exudates will drain from the topsheet rather than being absorbed from the topsheet by the absorbent core. The topsheet can be rendered hydrophilic by impregnation with a surfactant. Suitable methods of impregnation with a surfactant include spraying the surfactant onto the topsheet and dipping the fabric in the surfactant. A more detailed description of such modification and hydrophilicity is provided in U.S. Patents 4,988,344 and 4,988,345, both issued to Reising et al.

January 29, 1991, which are incorporated herein by reference.

The topsheet may also be in the form of an apertured film, which is preferred in feminine hygiene absorbent articles.

4 · 4 4

Aperture films are suitable because they are permeable to body fluids but are non-absorbent and have less tendency to backflow with subsequent wetting of the skin. This means that the surface of the film that contacts the body remains dry, thereby reducing body soiling and creating a better user experience. Suitable films are described in U.S. Patent 3,929,135 (Thompson) filed December 30, 1975, U.S. Patent 4,324,246 (Mullane et al.) filed April 13, 1982, U.S. Patent 4,342,314 (Radel et al.) filed August 3, 1982, U.S. Patent 4,463,045 (Ahr et al.) filed July 31, 1984, and U.S. Patent 5,006,394 (Baird) filed September 9, 1984.

4, 1991. Each of these patents is incorporated herein by reference.

Preferred microaperture films for topsheets are described in U.S. Patent 4,609,518 (Curro et al.) filed September 2, 1986 and U.S. Patent 4,629,643 (Curro et al.) filed December 16, 1986, which are incorporated herein by reference. A proposed topsheet for use in feminine hygiene products is a film described in one or more of the above-referenced patents and marketed by The Procter & Gamble Company of Cincinnati, Ohio under the designation DRIWEAWE®.

The body-facing surface of the film may be hydrophilic, allowing body fluids to permeate through the topsheet more rapidly than if it were not hydrophilic, thereby reducing the likelihood that the fluid will drain from the topsheet instead of being absorbed. In a preferred embodiment, a surfactant is incorporated into the polymeric material of the topsheet film as described in U.S. Statutory Invention Registration No. H1670 (Aziz et al.) issued July 1, 1997, which is incorporated herein by reference. In other embodiments (not shown) of the preferred invention, the absorbent article may be provided with additives to improve contact between the topsheet and the wearer's skin. V • 4 • 4 4

44444 4

4 ·

4 4

4 4 4

4 4 In one embodiment, the absorbent means is provided with elastic parts, as described in U.S. Patent 4,892,536 (DesMarais et al.)

9. 1. 1990, in U.S. Patent 4,990,147 (Freeland) 5. 2. 1991 and U.S. Patent 07,993,198 (Freeland et al.) 18. 12. 1992, which raise the topsheet, thereby improving contact with the perianal region of the wearer. In another embodiment, which is described in U.S. Patent 5,171,236 (Drier et al.) filed 15. 12. 1992, the diaper is provided with a series of joints that raise the topsheet. In yet another embodiment, which is described in U.S. Statuory Invention Registration H1687, filed in the name of Roe et al on 7. 10. 1997, the absorbent article is provided with a buttock protection portion that raises the topsheet into the gluteal groove of the wearer.

In the proposed diaper embodiment described herein, the backsheet 530 has an hourglass shape and extends beyond the absorbent core by at least 1.3 cm to 6.4 cm around the entire circumference of the diaper.

The absorbent core 540 may be of any size or shape that is compatible with the diaper 50. One proposed embodiment of the diaper 50 has an asymmetrical T-shaped absorbent core 540 with tabs in the first waist region, but a generally rectangular shape in the second waist region. Examples of absorbent materials that can be used to form absorbent cores of devices are described, for example, in U.S. Patent 4,610,678 (Weisman et al.) filed September 9, 1986, U.S. Patent 4,673,402 (Weisman et al.) filed June 16, 1987, U.S. Patent 4,888,231 (Angstadt) filed December 19, 1989, and U.S. Patent 4,834,735 (Alemany et al.) filed May 30, 1989. The absorbent core may further comprise a dual absorbent core system consisting of an absorbent/distribution core of chemically stiffened fibers that is positioned above the absorbent core.

2Λ · 9 9999 9 9 · 99 99 9

J\J 9 9 9 9 9 9 9 9 9 9 · 99 9 9999 99 99 retention core, this system is described in more detail in U.S. Patent 5,234,423 (Alemany et al.) filed August 10, 1993 and U.S. Patent 5,147,345 (Young, LaVon and Taylor) filed September 15, 1992. All of these patents are incorporated herein by reference.

In the proposed embodiment, the diaper 50 further includes elastic thigh cuffs 550 to provide improved containment of fluids and body exudates, an elastic waist portion 560 to provide improved fit and hold, and a fastening means 570 that creates a lateral connection that maintains the first waist region 56 and the second waist region 58 so that they overlap, thereby creating a lateral pull around the circumference of the diaper that maintains the diaper on the wearer. The diaper 50 may also include, in the waist regions 56 and 58, elastic waist strips (not shown) and/or elastic side sections (also not shown) to provide greater comfort and fit, as well as more efficient use of the diaper 50.

Elastic thigh cuffs 550 may have a variety of different embodiments, including those described in U.S. Patent 3,860,003, U.S. Patent 4,909,803 (Aziz et al.) filed March 20, 1990, U.S. Patent 4,695,278 (Lawson) filed September 22, 1987, and U.S. Patent 4,795,454 (Dragoo) filed January 3, 1989, the disclosures of which are incorporated herein by reference. Absorbent devices having elastic cuffs treated with a component that may be useful herein are described in U.S. Patent Applications 08/766,386 and 08/840,039, filed March 3, 1990.

12. 1996 and 24. 4. 1997, which are incorporated herein by reference.

The elastic waistband element is comprised of an elastic waistband strip (not shown) which can be formed in a number of different embodiments, including those described in U.S. Patent 4,515,595 (Kievit et al.) • ···>

• · · ·· · filed May 7, 1985, U.S. Patent 5,026,364 (Robertson) filed June 25, 1991, and the aforementioned U.S. Patent 5,151,092 (Buell et al.) filed September 29, 1992, the disclosures of which are incorporated herein by reference.

The elastic side panels can be formed in a variety of different embodiments. Examples of diapers with elastic side panels located in the diaper tabs are disclosed in U.S. Patent 4,857,067 (Wood et al.) filed August 15, 1989, U.S. Patent 4,383,781 (Sciaraffa et al.) filed March 3, 1983, U.S. Patent 4,938,753 (Van Gompel et al.) filed July 3, 1990, and U.S. Patent 5,151,092 (Buell et al.) filed September 29, 1992, which are incorporated herein by reference.

Examples of clamping means 570 are described in U.S. Patent 4,846,815 (Scripps) July 11, 1989, U.S. Patent 4,894,060 (Nestegard) filed January 16, 1990, U.S. Patent 4,946,527 (Battrell) filed August 7, 1990, U.S. Patent 3,848,594 (Buell) filed November 19, 1974, U.S. Patent 4,662,875 (Hirotsu et al.) filed May 5, 1987, and U.S. Patent 5,151,092 (Buell et al.) filed September 29, 1992, the disclosures of which are incorporated herein by reference.

The diaper 50 is typically applied by placing one of the waistband regions of the diaper, preferably the second waistband region 58, across the wearer's back and pulling the remainder of the diaper between the wearer's legs with the second waistband region, preferably the waistband region 56, positioned in front. Fastening means are then used to secure the diaper at the sides.

It is understood that any type of absorbent device may be used to utilize the enzyme inhibitor and/or the delivery system to transfer the inhibitor to the skin of the user while the device is being worn. The above description is therefore for illustrative purposes only.

The present invention may also utilize training pants as an absorbent comprising an enzyme inhibitor. As used herein, the term training pants refers to a disposable garment having fixed sides and leg openings and adapted for use by children or adults. The training pants are donned by the wearer inserting the wearer's legs into the leg openings and the pants are pulled up to the wearer's lower torso. Suitable training pants are described in U.S. Patent 5,246,433 (Hasse et al.) filed September 21, 1993, U.S. Patent 5,569,234 (Buell et al.) filed October 29, 1996, U.S. Patent 4,940,464 (Van Gompel et al.) filed July 10, 1990, and U.S. Patent 5,092,861 (Nomura et al.) filed March 3, 1992, the disclosures of which are incorporated herein by reference.

Other disposable absorbent articles which may be used in the present invention are incontinence articles. The term incontinence article is used to refer to pads, undergarments, absorbent pads, bed liners and the like, whether used by adults or other incontinent persons. Suitable incontinence articles are described in U.S. 4,253,461 (Strickland et al.) filed March 3, 1981, U.S. 4,597,760 and 4,597,761 (Buell), the aforementioned U.S. 4,704,115, U.S. 4,909,802 (Ahr et al.), U.S. 4,964,860 (Gipson et al.) filed October 23, 1990, and U.S. 5,304,161 (Noel et al.) filed April 19, 1994. The disclosures of these patents are incorporated herein by reference.

• · • · · • · · ·

Other disposable absorbent articles that can be used in the present invention are feminine hygiene articles, such as a sanitary napkin. Suitable feminine hygiene articles are described in U.S. Patent 4,556,146 (Swanson et al.) filed December 3, 1985, U.S. Patent 4,589,876 (Van Tilberg) filed April 27, 1993, U.S. Patent 4,687,478 (Van Tilburg) filed August 18, 1997, U.S. Patent 4,950,264 (Osborn) filed August 21, 1997. 1990, U.S. Patent 5,009,653 (Osborn) filed April 23, 1991, U.S. Patent 5,267,992 (Van Tilburg) filed December 7, 1993, U.S. Patent 5,389,094 (Lavash et al.) filed February 14, 1995, U.S. Patent 5,413,568 (Roach et al.) filed May 9, 1995, U.S. Patent 5,460,623 (Emenaker et al.) filed October 24, 1995, U.S. Patent 5,489,283 (Van Tilburg) filed February 6, 1996, U.S. Patent 5,569,231 (Emenaker et al.) filed October 29, 1997. 1996 and U.S. Patent 5,620,430 (Bamber) filed April 15, 1997. The disclosures of these patents are incorporated herein by reference.

IV. Enzyme inhibition testing

Standard in vitro enzyme activity and enzyme inhibition assays are well known. Reagents for performing these assays are readily available commercially. In general, a simple system consists of a substrate specific for the enzyme which, upon hydrolysis by the enzyme, forms a colored product. Enzyme activity is measured spectrophotometrically as the degree of development of the colored product (i.e., the level of color change) over a specified period of time. Inhibition of enzyme activity is manifested as a measurable reduction in the level of color change over the same period of time in the presence of an inhibitor. The following are examples of methods that can be used to determine the inhibitory activity of enzyme inhibitors on a) purified enzymes known from feces and b) enzyme activity in feces alone. However, these methods are not exclusive, and therefore other methods, other substrates, other inhibitors, and the like can be used to test for activity against a wide range of enzymes in feces.

For each of the following sample purified protease assays, stool protease assays, purified lipase assays, stool lipase assays, purified urease assays, stool urease assays, purified amylase assays, and stool amylase assays, the IC ₅₀ for each inhibitor tested can be determined according to the following equation:

IC ₅₀ = [I]/[(v/v1)-1)J, where [I] is the concentration of the inhibitor being tested, v is the level of substrate cleavage in the absence of inhibitor, and Vj is the level of substrate cleavage in the presence of inhibitor.

v and Vj are measured as changes in absorbance (optical density, OD) at a given wavelength/time (e.g. minutes).

A. Testing of purified proteases

1. Purified Trypsin

To test the effectiveness of protease inhibitors against purified trypsin, 0.05 ml of the putative inhibitor and 0.125 ml of 32 nM trypsin (e.g. Sigma, St. Louis, MO, cat. no. T6424) in trypsin buffer (50 mM TRIS, 20 mM CaCl ₂ , pH 8.2) are placed in a microcuvette. The cuvette is allowed to incubate at 25°C for about 10 minutes. To this mixture is added 0.025 ml of substrate (4 mM Cbz-arginine-pnitroanilide, e.g. Sigma, St. Louis, MO, cat. no. C4893) in

4 4 44 44 44

444 44 44 4444

4444 4 4 4444

4 4444 4 4 444444 j*> ··· 4 4 4444

4 444 4444 44 44 trypsin buffer, mix and after 10 minutes measure the absorbance at 25°C at 405 nm. The level of substrate cleavage in the presence of inhibitor (v) is the slope of the absorbance curve at 405 nm versus time. The same procedure is repeated without adding the putative inhibitor. The level of substrate cleavage in the absence of inhibitor (v) is the slope of the absorbance curve at 405 nm versus time. The values of Vj and the inhibitor concentration are used to calculate the IC ₅₀ according to the above equation.

2. Purified chymotrypsin

To test the effectiveness of protease inhibitors against purified chymotrypsin, 0.05 ml of the putative inhibitor and 0.125 ml of 16 nM chymotrypsin (e.g. Sigma, St. Louis, MO) are placed in a microcuvette.

MO, cat. no. C8946) in chymotrypsin buffer (50 mM TRIS, 10 mM CaCl ₂ , pH 7.6). The cuvette is allowed to incubate at 25°C for about 10 minutes. To this mixture, 0.025 ml of substrate (0.6 mM N-succ-ala-ala-pro-phe-p-nitroanilide, e.g. Sigma, cat. no. S7388) in chymotrypsin buffer is added to the cuvette, mixed and after 10 minutes the absorbance is measured at 25°C at 405 nm. The level of substrate cleavage in the presence of inhibitor (v) is the slope of the absorbance curve at 405 nm versus time. The same procedure is repeated without the addition of the putative inhibitor. The level of substrate cleavage in the absence of inhibitor (v) is the slope of the absorbance curve at 405 nm versus time. The Vj values and inhibitor concentration are used to calculate the IC ₅₀ according to the above equation.

3. Purified leucine aminopeptidase ·· * · ·· ·· *· • · « »· · · · · · ·

9 9 9 9 9 9 9 9 9 ar · · 9999 9 9 9 9 9 9 9 9 · 9 « · · · · · · ·« · ··· 9999 99 99

To test the efficacy of protease inhibitors against purified leucine aminopeptidase (LAP), 0.05 ml of the putative inhibitor and 0.125 ml of 0.06 U/ml LAP (e.g. Sigma,

St. Louis, MO, cat. no. L5006) in LAP buffer (50 mM sodium phosphate, pH 7.2). The cuvette is allowed to incubate at 25°C for about 10 minutes. To this mixture is added 0.025 ml of substrate (2.4 mM L-leucine-pnitroaniline, e.g. Sigma, St. Louis, MO, cat. no. L9125) in LAP buffer, mixed, and after 10 minutes the absorbance is measured at 25°C at 405 nm. The level of substrate cleavage in the presence of inhibitor (vj) is the slope of the absorbance curve at 405 nm versus time. The same procedure is repeated without the addition of the putative inhibitor. The level of substrate cleavage in the absence of inhibitor (v) is the slope of the absorbance curve at 405 nm versus time. The values of Vi and v and the inhibitor concentration are used to calculate the IC50 according to the above equation.

B. Testing for specific proteases from stool

The following is a general description of how to obtain a stool sample suitable for use in stool protease testing. However, anyone skilled in the art will be able to obtain appropriate stool samples for use in any of the specific protease (i.e. lipase, urease and amylase) tests from stool.

For the purpose of creating positive controls to ensure that the stool sample pool exhibits the enzymatic activity required for the evaluation of protease inhibitor activity, the following procedure is performed for each of the stool protease assays. The child's stool pool (at least five different samples) is collected so that it is free of urine and contamination and mixed with water in a weight ratio of

4 · ·· 44 ·4 i 4 4 «4 44 4 4 4 4

4 4 4 4 · 4 · 4 ·

4 4444 4 4 444444

3/ 4 · 4 44 444 4

4 444 4444 44 44 (w/w) e.g. 1:50. This mixture is then mixed thoroughly to obtain a homogeneous suspension by homogenization or sonication. The stool suspension is used as a source of protease activity as described below and will have a substrate conversion level in the absence of inhibitor in the range of 0.005 OD405 per minute to 0.020 OD405 per minute. (To ensure perfect linearity, the final absorbance should not exceed 1.5 _OD405 units). If the activity of the child's stool is outside this range, then it is not possible to accurately determine the IC50 values for the putative protease inhibitors. However, the range of enzyme activity can be adjusted by increasing or decreasing the dilution factor for each enzyme. If this is not possible, a different group should be selected for sample collection.

1. Trypsin activity in stool

To test the effectiveness of protease inhibitors against trypsin in feces, the inhibitor and trypsin buffer (50 mM TRIS, mM CaCl, pH 8.2) are placed in a cuvette so that the final volume is 0.8 ml. To this mixture, 0.1 ml of substrate (3 mM Cbz-arginine-pnitroanilide) is added to the cuvette. The cuvette is mixed by rotation and incubated at 25°C for 5 minutes. About 0.1 ml of stool suspension is added to the cuvette, everything is mixed and after 5 minutes the absorbance at 405 nm minus the absorbance at 490 nm is measured at 25°C. (The absorbance at 490 nm is a correction factor for the background absorbance caused by stool particles, i.e. interference). The level of substrate cleavage in the presence of inhibitor (v i ) is the slope of the absorbance difference curve (i.e., absorbance at 405 nm minus absorbance at 490 nm) versus time. The same procedure is repeated without the addition of the putative inhibitor. The level of substrate cleavage in the absence of inhibitor (v ) is the slope of the absorbance difference curve versus time. The values of v ; and v and the inhibitor concentration [I] are used to calculate the IC50 according to the above equation.

2. Chymotrypsin activity in stool

To test the effectiveness of protease inhibitors against chymotrypsin in stool, the inhibitor and chymotrypsin buffer (50 mM TRIS, 10 mM CaCl ₂ , pH 7.6) are placed in a cuvette so that the final volume is 0.92 ml. To this mixture, 0.04 ml of substrate (1.25 mM N-succala-ala-pro-phe-p-nitroanilide) is added to the cuvette. The cuvette is mixed by rotation and incubated at 25°C for 5 minutes. About 0.04 ml of stool suspension is added to the cuvette, everything is mixed and after 5 minutes the absorbance at 405 nm minus the absorbance at 490 nm is measured at 25°C. The level of substrate cleavage in the presence of the inhibitor (ví) is the slope of the curve of the difference in absorbance (i.e. absorbance at 405 nm minus absorbance at 490 nm) with respect to time. The same procedure is repeated without the addition of the putative inhibitor. The level of substrate cleavage in the absence of inhibitor (v) is the slope of the absorbance difference versus time curve. The values of v, a and the inhibitor concentration [I] are used to calculate the IC ₅₀ according to the above equation.

3. LAP activity in stool

To test the efficacy of protease inhibitors against LAP in stool, the inhibitor and LAP buffer (50 mM sodium phosphate, pH 7.2) are placed in a cuvette so that the final volume is 0.95 ml. To this mixture, 0.03 ml of substrate (6 mM L-leucine-p-nitroanilide) is added to the cuvette. The cuvette is mixed by rotation and incubated at 25°C for 5 minutes. About 0.02 ml of stool suspension is added to the cuvette, everything is mixed and after 5 minutes it is measured at ·· * r

25°C absorbance at 405 nm minus absorbance at 490 nm. The level of substrate cleavage in the presence of inhibitor (vj) is the slope of the curve of the difference in absorbance (i.e. absorbance at 405 nm minus absorbance at 490 nm) versus time. The same procedure is repeated without the addition of the putative inhibitor. The level of substrate cleavage in the absence of inhibitor (v) is the slope of the curve of the difference in absorbance versus time. The values of vj and the inhibitor concentration [I] are used to calculate the IC ₅₀ according to the above equation.

Using the purified protease and fecal protease assays described above, the protease inhibitory activity of selected protease inhibitors used in the absorbent compositions of the present invention was determined, and the test results are shown in Table 1.

Table 1

IC50 (μM) Purified proteases Specific stool tests TrvDsin Chvmotrvosin LAP* TrvDsin Chvmotrvosin LAP* Inhibitor soybean trypsin inhibitor 0.25 0.026 >10 <0.01 0.06 >20 aprotinin 0.168 1 >20 0.01 0.22 >20 hexamidine diisothionate 2.5 >1000 256 2.3 >1000 130 p-amino-benzamidine 13.8 >500 >500 20 >500 >500 leupeptin 0.14 >500 >500 0.11 >500 >500 pepstatin A 324 4.9 >500 >500 300 >500 chymostatin >500 <0.12 >500 >500 0.02 >500 TLCK 78.3 >500 >500 200 >500 >500 glycyrrhizic acid 45 >500 >500 >300 >300 >300 EDTA >125,000 >125,000 >1250 00 100 100 >3000 4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride 45.7 190 >500

*LAP = leucine aminopeptidase **TLCK = L-1-chloro-3-(4-tosylamido)-7-amino-2-heptanone-HCl ***EDTA - ethylenediaminetetraacetic acid

Table 1 shows that each of the compounds listed inhibits at least one protease tested using the purified protease and/or fecal protease method.

D. Testing of purified lipase

To test the efficacy of lipase inhibitors, 0.05 ml of the putative inhibitor and 0.125 ml of 160 nM pancreatic lipase (e.g. Sigma, St. Louis, MO, cat. no. L0382) in 50 mM TRIS buffer containing 1 mM CaCl ₂ at pH 8.0 are added to a microcuvette. The cuvette is incubated at 25°C for 10 minutes. Approximately 0.025 ml of substrate (1.25 mM p-nitrophenol caprylate, e.g. Sigma, St. Louis, MO, cat. no. N0752) is added to the cuvette and the mixture is allowed to incubate for a further 5 minutes. After 10 minutes, the absorbance at 405 nm is measured at 25°C. The level of substrate cleavage in the presence of the inhibitor (v1) is the slope of the absorbance curve at 405 nm versus time. The same procedure is repeated without the addition of the putative inhibitor. The level of substrate cleavage in the absence of inhibitor (v) is the slope of the absorbance curve at 405 nm versus time. The Vj values and inhibitor concentration [I] are used to calculate the IC ₅₀ according to the above equation.

E. Fecal lipase testing

To test the efficacy of lipase inhibitors against fecal lipases, the inhibitor and lipase buffer (50 mM TRIS buffer containing 1 mM CaCl ₂ , pH 8.0) are added to a cuvette to make a final volume of 0.8 ml. To this mixture, 0.1 ml of substrate (1.25 mM p-nitrophenol caprylate) is added to the cuvette. The cuvette is mixed by inversion and allowed to ...

1 · ····· · · ····· τΊ ··· · The values of Vj and v and the inhibitor concentration [I] are used to calculate the IC50 according to the above equation.

F Testing the activity of purified urease.

To test for urease inhibitor activity, 0.05 ml of the putative inhibitor and 0.125 ml of 0.08 U/ml Jack Bean urease (Sigma catalog U2125) in 45 mM sodium phosphate buffer, pH 6.8, are added to a microcuvette. The cuvette is allowed to incubate at 25°C for approximately 10 minutes. To this mixture is added 0.025 ml of substrate (300 mM urea, e.g. Sigma U0631) and the mixture is allowed to incubate for an additional 5 minutes. Ammonia release is immediately measured using a commercial ammonia detection kit (Sigma Diagnostics, St. Louis, MO, procedure 171).

G. Urease activity testing

To test the effectiveness of urease inhibitors against fecal urease, add the inhibitor and urease buffer (45 mM sodium phosphate, pH 6.8) to a cuvette to make a final volume of 0.8 ml. Add 0.1 ml of substrate (375 mM urea) to this mixture. Mix the cuvette

by inversion and incubated at 25°C for about 5 minutes. To this mixture, 0.1 ml of stool suspension is added, the mixture is mixed and incubated for a further 5 minutes. Ammonia release is then measured immediately using a commercial ammonia detection kit (Sigma Diagnostics, procedure 171).

H. Testing the activity of purified amylase

Amylase activity is determined using Sigma Diagnostics procedure 577. To test the effectiveness of amylase inhibitors, 0.010 ml of the putative inhibitor and 0.010 ml of human salivary amylase (Sigma No. A0521, 100 to 2000 U/l, measured by Sigma Diagnostics procedure 577) in water are added to a cuvette. The cuvette is incubated at 37°C for 10 minutes. To this mixture is added 1.00 ml of amylase substrate and the mixture is incubated for a further 2 minutes. After 2 minutes at 37°C, the absorbance at 405 nm is measured. The level of substrate cleavage in the presence of the inhibitor (v1) is the slope of the absorbance curve at 405 nm versus time. The same procedure is repeated without the addition of the putative inhibitor. The level of substrate cleavage in the absence of inhibitor (v) is the slope of the absorbance curve at 405 nm versus time. The Vj values and inhibitor concentration [I] are used to calculate the IC ₅₀ according to the above equation.

I. Testing of amylase activity from stool

Amylase activity is determined using Sigma Diagnostics procedure 577. To test the effectiveness of amylase inhibitors against fecal amylases, 0.010 ml of the putative inhibitor and 0.010 ml of stool suspension (100 to 2000 U/l, measured by Sigma Diagnostics, • » « ·

4Q · · ···· · · ··♦··· *+-} ·

X absorbance at 405 nm minus absorbance at 490 nm. The level of substrate cleavage in the presence of inhibitor (v i ) is the slope of the curve of absorbance at 405 nm versus time. The same procedure is repeated without the addition of putative inhibitor. The level of substrate cleavage in the absence of inhibitor (v ) is the slope of the curve of absorbance at 405 nm versus time. The values of v ; and v and the inhibitor concentration [I] are used to calculate the IC50 according to the above equation.

V. Dermatological component

Dermatological ingredients suitable for use in the absorbent articles of the present invention are described in U.S. Patent Nos. 08/926,532 and 08/926,533, both filed September 10, 1997, U.S. Patent No. 5,607,760 filed March 4, 1997, U.S. Patent No. 5,609,587 filed March 11, 1997, U.S. Patent No. 5,635,191 filed June 3, 1997, and U.S. Patent No. 5,643,588 filed July 1, 1997, the disclosures of which are incorporated herein by reference. The dermatological ingredient is said to be transferred to the skin of a wearer of the treated article during normal contact, movement of the wearer, and/or exposure to body heat. That is, transfer of the enzyme inhibitor-containing dermatological ingredient begins after application of the article to the wearer and continues for the duration of wear. As a result, the enzyme inhibitor is usually present on the user's skin before exposure to bodily secretions.

In addition to its function of ensuring a minimum inhibitory concentration of the enzyme inhibitor on the skin of the user, the dermatological component may also contain ingredients that, for example, reduce stool adherence to the skin, create a skin/stool barrier (e.g., cover the skin to prevent stool adhesion) while remaining relatively impermeable but breathable, or have other beneficial effects on the skin (e.g., soften the skin, improve or maintain skin quality), etc. The dermatological component may take a variety of forms, such as an emulsion, solution, cream, ointment, balm, suspension, gel, etc.

The transfer of an effective concentration of enzyme inhibitor from the absorbent composition to the skin and the effective amount of dermatological component applied or transferred to the surfaces of the composition contacting the user depend primarily on the dermatological component used. The amount of component should be at least on the part of the surface contacting the user from 0.0078 mg/cm ² to 12 mg/cm ² , more preferably from 0.16 mg/cm ² to 6 mg/cm ² and most preferably from 0.6 mg/cm ² to 4 mg/cm ² . However, these ranges are only illustrative and the skilled artisan will recognize that the nature of the component determines the amount that must be applied to transfer a sufficient concentration of enzyme inhibitor and that the required amount is determinable by routine experimentation.

The amount of dermatological component applied to the absorbent article is an important factor in the present invention, but more important is the amount of component transferred to the skin of the user during use of one or more of the compositions so prepared. Although the amount of dermatological component containing the enzyme inhibitor transferred to the skin depends to some extent on the nature of the component used and the potency of the enzyme inhibitor, relatively small amounts can be transferred that are still sufficient to produce a minimum inhibitory concentration of the enzyme inhibitor on the skin. This is particularly true for the proposed components described in Example 1.

Given the level of dermatological component that is transferred to the user during the wearing of one modified absorbent article for 3 hours (a typical wearing time) and especially for the proposed dermatological components described in Example 1, it is proposed that at least 0.0016 mg/cm ² , more preferably at least 0.0078 mg/cm ² and most preferably at least 0.016 mg/cm ² of dermatological component is transferred to the skin during the three hour wearing time. The typical amount of dermatological component transferred by one modified article during the three hour wearing time ranges from 0.0016 mg/cm ² to 0.78 mg/cm ² , more preferably from 0.0078 mg/cm ² to 0.47 mg/cm ² and most preferably from 0.016 mg/cm ² to 0.31 mg/cm ² .

For long-term use of the modified compositions (usually changed every 3 to 4 hours during the day and also before sleeping at night), such as for 24 hours, it is preferred to use components that are transferred to the skin of the user in an amount of at least 0.0047 mg/cm ² , more preferably at least 0.016 mg/cm ² and most preferably at least 0.047 mg/cm 2 . The amount of component transferred in 24 hours is usually from 0.0047 mg/cm ² to 2.79 mg/cm ² , more often from 0.016 mg/cm ² to 10 mg/cm ² and most often from 0.047 mg/cm ² to 0.93 mg/cm ² . The procedure for determining the amount of dermatological component transferred to the skin during wearing of the modified composition is described below.

It is apparent that from the numerous substances suitable for the skin-transmitting enzyme inhibitor dermatological components of the invention, those substances which are considered safe and effective dermatological agents have been logically selected. These substances are in Category I as defined by the U.S. Food and Drug Administration (FDA), (21 C.F.R. § 347), which now includes: allantoin, aluminum hydroxide gel, calamine, cocoa butter, dimeticone, fish oil (in combination), glycerin, kaolin, petrolatum, lanolin, mineral oil, shark oil, white petrolatum, talc, starch, zinc acetate, zinc carbonate, zinc oxide, etc. Other suitable substances are in Category III as defined by the U.S. Food and Drug Administration (FDA), which now includes: live yeast derivatives, aldiox, aluminum acetate, microporous cellulose, cholecalciferol, colloidal oatmeal, cysteine hydrochloride, dexpanthenol, Peruvian balsam oil, protein hydrolysates, racemic methionine, sodium bicarbonate, vitamin A, etc.

A number of FDA-listed dermatological ingredients are now commonly used in commercially available dermatological products, such as A and D Ointment®, Vaseline®, Petroleum Jelly, Desitin® Diaper Rash Ointment and Daily Care® ointment, Gold Bond® Medicated Baby Powder, Aquaphor® Healing Ointment, Baby Magie® Baby Lotion, Johnson's Ultra Sensitive® Baby Cream. Any of these commercial products can be incorporated with an effective concentration of the enzyme inhibitor and applied to an absorbent device to form a modified composition according to the present invention.

It will be further described that dermatological ingredients suitable for delivering enzyme inhibitors to the skin of a user are preferably, but not necessarily, ingredients with a melting profile that allows them to remain immobile at room temperature on a surface contacting the user, to readily transfer to the user at body temperature, and yet not to liquefy during storage under extreme conditions. In this regard, the ingredients are at least partially transferable to the skin by contact, user movement, and/or body heat. Since the ingredient is typically immobilized on the surface of the composition contacting the user, relatively low levels of the ingredient are sufficient to produce the desired effects on the skin. Furthermore, it may be necessary to use special packaging materials for the modified compositions of the present invention.

In the proposed embodiment, the dermatological components are water-in-oil emulsions, where the enzyme inhibitor is in the aqueous phase. However, the dermatological component itself may be solid or more often semi-solid at 20°C, i.e. ambient temperature. The term semi-solid means that the component has rheological properties typical of pseudo-solid or ductile liquids. In the absence of friction, the components may have the appearance of a semi-solid, but may liquefy when friction is increased. This is because the component primarily contains both solid and liquid parts. The viscosity of the dermatological component containing the enzyme inhibitor should be from 1.0 x 10 ⁴ to 1.0 x 10 ⁶ g/cm.s at zero friction, but more preferably from 5.0 x 10 ⁴ to 5.0 x 10 ⁶ g/cm.s. The term zero friction viscosity refers to the viscosity measured at very low friction levels (e.g., 1.0 s- ¹ ) using a suitable viscometer (e.g., model CSL 100 from TA Instruments of New Castle, DE). One skilled in the art will recognize that components other than those with a high melting point (see below) may be used which will have a comparable viscosity, which can be measured by extrapolating the viscosity versus friction curve for such a component to a zero friction level at a temperature of about 20°C. The proposed components are at least semi-solid at room temperature to prevent the component from migrating into the absorbent prior to use. In addition, they have • 4 ·

• · 4 • 44 44 · components final melting point (100% liquefaction) above possible adverse storage conditions, which may be higher than 45°C (e.g., warehouse in Arizona, truck in Florida, etc.). Examples of components having these features are described in detail in U.S. Patent 5,643,588, U.S. Patent 5,607,760, U.S. Patent 5,609,587, and U.S. Patent 5,635,191. The proposed components have the following melting profiles:

Property Suggested range The most suitable range % liquid at room temperature (20°C) 2-50 3-25 % of liquid at body temperature (3 7°C) 25-95 30-90 final melting point (°C) >38 >45

The proposed enzyme inhibitor-containing components do not tend to flow at ambient temperatures and migrate to a greater extent into undesirable areas of the composition to which they have been applied. This means that a smaller amount of the dermatological component is required to achieve the expected therapeutic and protective effect.

To prevent the components from migrating to unwanted locations within the composition, the components must be immobilized by making their viscosity as high as possible. Unfortunately, in some cases, higher viscosity can reduce the transfer of the component to the user's skin. Therefore, a balance must be achieved that allows both the component to be retained on the surface of the composition and its transfer to the user's skin. Suitable viscosities of these components are in the range of 0.05 to 5 g/cm.s, more preferably 0.05 to 3 g/cm.s and most preferably 0.05 to 1 g/cm.s, measured at • ·

60°C using a rotational viscometer (a suitable viscometer is a model 4357 from Lab Line Instruments, Inc. of Melrose Park, IL). The viscometer is operated at 60 rpm using shaft #2.

In addition to the dermatological ingredients adapted to have a therapeutic and/or protective effect on the skin and the positive effect of enzyme inhibitors, the other active ingredients of these ingredients are one or more preservatives or emollients. The term emollient as used herein is reserved for a substance that protects against moisture and irritation, softens, soothes, smoothes, coats, lubricates, moisturizes, protects and/or cleanses the skin. (It will be apparent that many of the substances mentioned above are emollients.) In the proposed embodiment, these emollients are malleable or liquid at ambient temperature, i.e. 20°C.

Examples of suitable emollients for use in the present invention include, but are not limited to, emollients derived from petroleum, sucrose esters of fatty acids, polyethylene glycol and its derivatives, humectants, fatty acid esters, alkyl ethoxylates, fatty acid ethoxylate esters, fatty alcohol, polysiloxane, propylene glycol and its derivatives, glycerin and its derivatives, including glyceride, acetoglyceride and ethoxylate glycerides of C ₂ C ₂ 8 fatty acids, triethylene glycol and its derivatives, spongin and or other waxes, fatty acids, fatty alcohol esters, especially those having 12 to 28 carbon atoms in their chain, such as stearic acid, propoxylated fatty alcohols, other fatty esters of polyhydroxy alcohols, lanolin and its derivatives, kaolin and its derivatives, any dermatological agent mentioned above or mixtures of these emollients. Suitable petroleum-derived emollients include those hydrocarbons or mixtures thereof having a chain length of from 16 to 32 carbons. Petroleum hydrocarbons having this chain length include mineral oil and petrolatum. The term mineral oil generally refers to a less viscous mixture of hydrocarbons having from 16 to 20 carbons. The term petrolatum generally refers to a more viscous mixture of hydrocarbons having from 16 to 32 carbons. Petrolatum and mineral oil are preferred emollients for use in the dermatological composition of the present invention.

Suitable fatty acid ester plasticizers include those derived from C ₁₂ -C ₂₈ fatty acids, more preferably C ₁₆ -C ₂₂ saturated fatty acids and short chain alcohols (C 1-C ₈ , more preferably C 1-C ₃ ). Suitable examples of such esters are methyl palmitate, methyl stearate, isopropyl laurate, isopropyl myristate, isopropyl palmitate, ethylhexyl palmitate and mixtures thereof. Suitable fatty acid ester plasticizers can also be derived from esters of long chain fatty alcohols (C ₁₂ -C ₂₈ , more preferably C _{12 -C} 16 ) and shorter chain fatty acids, e.g. lactic acid, such as lauryl lactate and cetyl lactate.

Suitable alkyl ethoxylate-type plasticizers are C ₂ -C ₂₂ fatty alcohol ethoxylates having an average degree of ethoxylation of from 2 to 30. These plasticizers are selected from the group consisting of lauryl, cetyl and stearyl ethoxylates or mixtures thereof having an average degree of ethoxylation of from 2 to 23. Illustrative examples of such alkyl ethoxylates are laureth-3 (lauryl ethoxylate with an average degree of ethoxylation of 3), laureth-23 (with an average degree of ethoxylation of 23), ceteth-10 (cetyl alcohol ethoxylate with an average degree of ethoxylation of 10) and steareth-10 (stearyl alcohol ethoxylate with an average degree of ethoxylation of 10). These alkyl ethoxylate plasticizers are typically used in combination with petroleum-derived plasticizers, such as petroleum jelly, in a weight ratio of alkyl ethoxylate plasticizer to petroleum-derived plasticizer of from 1:1 to 1:5, more preferably from 1:2 to 1:4.

Suitable fatty alcohol plasticizers are C ₂ -C ₂₂ fatty alcohols, more preferably C ₆ -C ₈ fatty alcohols. Illustrative examples are cetyl alcohol, stearyl alcohol and mixtures thereof. These plasticizers are generally used in combination with petroleum-derived plasticizers, such as petrolatum, in a weight ratio of fatty alcohol plasticizer to petroleum-derived plasticizer of from 1:1 to 1:5, more preferably from 1:1 to 1:2.

Other suitable types of plasticizers are polysiloxane compounds. In general, those polysiloxane substances suitable for use in the present invention are those whose monomeric siloxane unit has the following structure:

R*

Sil ² where R ¹ and R ² can be, independently for each monomer unit, hydrogen or alkyl, aryl, alkenyl, alkaryl, arakyl, cycloalkyl, halohydrocarbon or other radical. All of these radicals can be replaced by each other. The radicals R ¹ and R ² of each individual monomer unit can be different from the respective groups of the adjacent unit. In addition, the polysiloxane can have a linear chain structure, a branched chain or a cyclic structure. The radicals R ¹ and ·« · ··

R can independently be other groups such as siloxanes, polysiloxanes, silanes and polysilanes. The radicals R ¹ and R ² can contain any of a variety of organic groups including alcohol, carboxylic acid, phenyl and amine groups.

Examples of alkyl radicals are methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, decyl, octadecyl, etc. Examples of alkenyl radicals are vinyl, allyl, etc. Examples of aryl radicals are phenyl, diphenyl, naphthyl, etc. Examples of alkaryl radicals are toyl, xylyl, ethylphenyl, etc. Examples of aralkyl radicals are benzyl, alphaphenylethyl, beta-phenylethyl, alpha-phenylbutyl, etc. Examples of cycloalkyl radicals are cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of halogenated hydrocarbon radicals are chloromethyl, bromoethyl, tetrafluoroethyl, fluoroethyl, trifluoroethyl, trifluorooyl, hexafluorooxylyl, etc.

The viscosity of suitable polysiloxanes can vary widely, as can the viscosity of siloxanes in general, and therefore the siloxanes can be flowable or can be modified to become flowable. This means that their viscosity ranges from 5 centistokes (measured at 37°C using a glass viscometer) to 20,000,000 centistokes, but is not limited to these values. The polysiloxanes should have a viscosity at 37°C in the range of 5 to 5,000 centistokes, more preferably 5 to 2,000 centistokes, and most preferably 100 to 1,000 centistokes. High viscosity polysiloxanes that are not flowable can be effectively applied to the absorbent article by, for example, forming an emulsion of the polysiloxanes in a surfactant or by forming a solution of the siloxanes using a solvent such as hexane, which is mentioned only by way of example.

The individual methods of applying polysiloxane plasticizers to absorbent articles will be discussed in more detail below.

Polysiloxane compounds proposed for use in the present invention are described in U.S. Patent No. 5,059,282. The most suitable polysiloxane compounds include polymethylsiloxane compounds with a phenyl group (e.g., Dow Corning 556 Cosmetic-Grade Fluid: polymethylphenylsiloxane) and/or demethicones with a cetyl or stearyl group, such as Dow 2502 and Dow 2503 polysiloxane fluids. In addition to these phenyl or alkyl group substitutions, effective substitution with amine, carboxyl, hydroxyl, ether, polyether, aldehyde, ketone, amide, ester, and thiol groups can also be made. Of this range of effective substituents, phenolic, amino, alkyl, carboxyl, and hydroxyl groups are preferred, but phenolic groups are most preferred.

Suitable fatty ester plasticizers are polyol polyesters, which are described in U.S. Patent No. 5,609,587. Examples of polyols include, but are not limited to, polyhydric compounds such as pentaerythritol, sugars such as raffinose, maltodextrose, galactose, sucrose, glucose, lactose, mannose, and erythrose, and sugar alcohols such as erythritol, xylitol, maltitol, mannitol, and sorbitol. Such polyols are formed from esters of fatty acids and/or other organic moieties having from 2 to 30 carbons. While it is not necessary that all of the hydroxyl groups of the polyols be esterified, the proposed polyol polyester plasticizers have substantially all (e.g., at least 85%) of the hydroxyl groups esterified. Sucrose polyol polyesters, such as sucrose polycotonate, sucrose polysoate and « · · · · · · · • · · · · • · · · · · · · · ··· · « · * ·· · · · • · · · · e · · · · · · · · · i· ·· sucrose polybehenate are very suitable. Mixtures of these polyol polyesters are also suitable plasticizers for the present invention.

Suitable moisturizing ingredients are glycerin, propylene glycol, sorbitol, trihydroxystearin, etc.

The amount of emollient that may be included in a dermatological composition depends on a number of factors, e.g. the type of emollient in question, the desired effect on the skin, other components of the composition, etc. The composition contains emollients from 0 to 100% by weight. However, a suggested range is from 10 to 95%, more preferably from 20 to 80%, and most preferably from 40 to 75% by weight.

Another useful component of the enzyme inhibitor-containing dermatological composition may be a substance that is capable of immobilizing the component (including the enzyme inhibitor, the proposed emollient and/or other protective agent) in a desired area within or on the treated article. Since some of the proposed components of the composition are malleable or liquid at 20°C, they will tend to flow or migrate even when subjected to only slight friction. If they are applied to a user-contacting surface or other area of the absorbent article in a dissolved or liquid state, they will generally not remain in that area because they tend to migrate and overflow into an undesired area of the article.

If any of the components of the dermatological component migrate into the interior of the composition, this may have an undesirable effect on the absorbency of the core of the composition due to the hydrophobic properties, e.g., plasticizers or other components used in the dermatological component of the composition of the present invention. This also means that a larger amount of the dermatological component must be applied to the composition to achieve the desired effect. Increasing the content of the dermatological component not only increases the cost, but also increases the undesirable effect on the absorbency of the core of the composition and the undesirable carryover of the component during processing of the modified composition.

The immobilizing agent counteracts the tendency of the components of the dermatological composition to migrate or flow away by retaining them on the surface or in the area of the composition to which they have been applied. This is due in part to the immobilizing agent raising the melting point and/or viscosity of the component above that of the mobile components.

It is advantageous to lock the immobilizing agent on the surface that touches the user or in the area of the device to which it is applied. This can be achieved by using immobilizing agents that solidify rapidly after application to the device. Furthermore, external cooling of the device using fans, blowers, etc. can be used to accelerate the crystallization of the agent.

The immobilizing agent should have a melting profile such that the component is solid or semi-solid at ambient temperature. Thus, proposed immobilizing agents should have a melting point of at least 35°C. At this temperature, the immobilizing agent will not tend to migrate or flow. Proposed immobilizing agents have melting points of at least 40°C. Typically, the immobilizing agent will have a melting point in the range of 50°C to 150°C.

The immobilizing agents may be selected from a wide variety of substances, provided that the inhibitory properties of the dermatological component have the beneficial effect on the skin described herein. It is found that certain emollients or classes of emollients have such melting properties that they are suitable as immobilizing agents. Such substances may serve both the functions of an emollient and an immobilizing agent. The proposed immobilizing agent will belong to the group consisting of C14-C22 fatty alcohols, C12-C22 fatty acids, C12-C22 fatty alcohol ethoxylates and mixtures thereof, having an average degree of ethoxylation of from 2 to 30. The proposed immobilizing agents include _C16 -C18 fatty alcohols, preferably crystalline high melting point substances selected from the group consisting of cetyl alcohol, stearyl alcohol, behenyl alcohol and mixtures thereof. (The linear structure of these substances may accelerate solidification on the treated absorbent.) Mixtures of cetyl alcohol and stearyl alcohol are preferred. Other proposed immobilizing agents are C ₆ -C ₁₈ fatty acids, preferably from the group consisting of palmitic acid, stearic acid and mixtures thereof. Mixtures of palmitic acid and stearic acid are preferred. Other proposed immobilizing agents include C ₆ -C 18 fatty alcohol ethoxylates with an average degree of ethoxylation of from 5 to 20. The fatty alcohols and fatty acids should be linear. Importantly, these proposed immobilizing agents, such as C 16 -C 18 fatty alcohols, increase the level of crystallization of the component, thereby accelerating crystallization on the substrate surface.

Other types of immobilizing agents that can be used herein are polyhydroxy fatty acid esters, polyhydroxy fatty acid amides, and mixtures thereof. The proposed esters and amides have three or more free hydroxyl groups on the polyhydroxy fatty acid chain.

group and are usually non-ionic in nature. Given the possible skin hypersensitivity of users of products to which the ingredient has been applied, these esters and amides should be relatively mild and non-irritating to the skin.

O

II

R—CPolyhydroxy fatty acid esters suitable for use in the proposed invention have the following formula:

_γ n

where R is a C5-C31 hydrocarbon group, typically a linear chain of C7 _- C19 alkyl or alkenyl, more preferably a linear chain of _C9 - _C17 alkyl or alkenyl, most preferably a linear chain of Cn- _C17 alkyl or alkenyl or mixtures thereof. Y is a polyhydroxy hydrocarbon group with a hydrocarbon chain having at least 2 free hydroxyls directly attached to the chain and n is at least 1. Suitable Y groups can be derived from polyols such as glycerol, pentaerythritol, sugars such as raffinose, maltodextrose, galactose, sucrose, glucose, xylose, fructose, maltose, lactose, mannose and erythrose, sugar alcohols such as erythritol, xylitol, maltitol, mannitol and sorbitol and anhydrides of sugar alcohols such as sorbitan.

One class of suitable polyhydroxy fatty acid esters includes certain sorbitan esters, particularly sorbitan esters of saturated C ₆ -C ₂ 2 fatty acids. These sorbitan esters typically contain, due to the method by which they are produced, mixtures of mono-, di-, tri-, etc. esters. Illustrative examples of suitable sorbitan esters are sorbitan palmitates (e.g., SPAN 40), sorbitan stearates (e.g., SPAN 60), and sorbitan behenates, which include one or more mono-, di-, and tri-ester variants of these sorbitan esters, e.g., sorbitan mono-, di-, and tri-palmitate, sorbitan mono-, di-, and tri-stearate, sorbitan mono-, di-, and tri-behenate, as well as mixtures of sorbitan mono-, di-, and tri-esters of fatty acids. Mixtures of various sorbitan esters may also be used, such as sorbitan palmitates with sorbitan stearates. Particularly suitable sorbitan esters are sorbitan stearates, typically as mixtures of mono-, di-, and triesters (plus some tetraesters), such as SPAN 60 and the sorbitan stearates sold under the trade name GLYCOMUL-S by Lonza, Inc. Although these sorbitan esters typically contain mixtures of mono-, di-, and triesters, plus some tetraesters, the mono- and di-esters usually predominate in these mixtures.

Another class of suitable polyhydroxy fatty acid esters includes certain glyceryl monoesters, particularly glyceryl monoesters of saturated C ₆ -C ₂ 2 fatty acids, such as glyceryl monostearate, glyceryl monopalmitate and glyceryl monobehenate. Mixtures of glyceryl monoesters, as well as sorbitan esters, usually include some di- and triesters. However, to be useful in the present invention, these mixtures should primarily contain glyceryl monoesters.

Another class of suitable polyhydroxy fatty acid esters includes sucrose esters of fatty acids, especially sucrose esters of C12-C22 fatty acids. Particularly suitable are sucrose monoesters and diesters, as well as sucrose mono- and distearates and sucrose mono- and dilaurates.

Polyhydroxy fatty acid amides suitable for use in the present invention have the following formula:

OR ¹ «2 HIR—C—N—Z where R ¹ is H, C1-C4 hydrocarbon, 2-hydroxyethyl, 2-hydroxypropyl, methoxyethyl, methoxypropyl or mixtures thereof, especially C1-C4 alkyl, methoxyethyl or methoxypropyl, more preferably C1 or C2 alkyl or methoxypropyl, most preferably C1 alkyl (i.e. methyl) or methoxypropyl and R ² is a C5-C31 hydrocarbon group, usually a linear chain of C7- _C19 alkyl or alkenyl, more preferably a linear chain of C9-C17 alkyl or alkenyl, most preferably a linear chain of C11-C17 alkyl or alkenyl or mixtures thereof and Z is a polyhydroxy hydrocarbon having a linear chain with at least 3 hydroxyl groups directly attached to the chain. See US Patent 5,174,927 which describes these polyhydroxy fatty acid amides and their preparation.

The Z group is derived from a reducing sugar in a reductive amination reaction, preferably glycityl. Suitable reducing sugars are glucose, fructose, maltose, lactose, galactose, mannose and xylose. In addition to these sugars, high dextrose corn syrup, high fructose corn syrup and high maltose corn syrup can also be used. A mixture of sugar components for the Z group can be formed from these corn syrups.

The group Z is selected from the group consisting of -CH ₂ -(CHOH) _n CH ₂ OH, -CH ₂ (CH ₂ OH)-[(CHOH) _n _i]-CH ₂ OH, -CH ₂ OH-CH ₂ (CHOH) ₂ (CHOR ³ )-(CHOH)-CH 2 OH, where n is an integer from 3 to 5 and R ³ is H or a cyclic or aliphatic monosaccharide. Glycityls where n is 4 are particularly suitable, especially -CH 2 -(CHOH) ₄ -CH ₂ OH.

In the above formula, R ¹ may be, for example, N-methyl, N-ethyl, N-propyl, N-isopropyl, N-butyl, N-2-hydroxyethyl, N-methoxypropyl or N-2-hydroxypropyl. R ² may be chosen, for example, to form cocamides, stearamides, oleamides, lauramides, myristamides, capricamides, palmitamides, tallowamides and the like. The group Z may be 1-deoxyglucityl, 2-deoxyfructityl, 1-deoxymaltityl, 1-deoxylactityl, 1-deoxygalactityl, 1-deoxymannityl, 1-deoxymaltotriotityl and the like.

The most suitable polyhydroxy fatty acid amides have this general formula:

About R1

OH

AND

CH

R2—C—N—CH ₂

CH ₂ —OH where R ¹ is methyl or methoxypropyl, R ² is a Cn-C ₁₇ alkyl or alkenyl group with a linear chain. These include N-lauryl-Nmethyl glucamide, N-lauryl-N-methoxypropyl glucamide, N-cocoyl-Nmethyl glucamide, N-cocoyl-N-methoxypropyl glucamide, N-palmityl• · • »

N-methoxypropyl glucamide, N-tallowyl-N-methyl glucamide or N-tallowyl-N-methoxypropyl glucamide.

As previously mentioned, some immobilizing agents require an emulsifier to dissolve in the plasticizer. This applies in particular to some glucamides, such as N-alkyl-N-methoxypropyl glucamides with an HLB value of at least 7. Suitable emulsifiers are generally those with an HLB value of less than 7. In this regard, it has been found that sorbitan esters, such as sorbitan stearate, which have an HLB value of 4.9 and lower are suitable for dissolving glucamide immobilizing agents in petrolatum. Other suitable emulsifiers are steareth-2 (polyethylene glycol ethers of stearyl alcohol, which are formed according to the formula CH ₃ (CH 2 ) i7 (OCH ₂ CH 2 ) _n OH, where the average value of n is 2, sorbitan tristearate, isosorbide laurate and glyceryl monostearate. The emulsifier may be present in an amount that allows the immobilizing agent to dissolve in the plasticizer and form a homogeneous mixture. For example, a mixture of about 1.1 N-cocoyl-N-methyl glucamide and petrolatum, which does not normally dissolve into a single-phase mixture, dissolves into a single-phase mixture after the addition of 20% Steareth-2 and sorbitan tristearate as emulsifier.

Other types of additives that can be used as immobilizing agents, either alone or in combination with the immobilizing agents mentioned above, are waxes such as carnauba wax, beeswax, beeswax, candelilla, paraffin, ceresin, esparto, ouricuri, reswax, isoparaffin and other known mined and mineral waxes. The high melting point of these substances allows the component to be immobilized on the desired surface or area of the composition. Microcrystalline waxes are also good immobilizing agents. Microcrystalline waxes help to lock the low molecular weight hydrocarbons within the dermatological component. Paraffin wax is suitable. An example of an alternative immobilizing agent is paraffin wax, such as Parrafin S.P. 434 from Strahl and Pitsch lne.

The amount of immobilizing agent to be included in the composition depends on a number of factors, including the content of active ingredients (e.g., plasticizers), the type of immobilizing agent, if used, the other components of the composition, whether an emulsifier is needed to dissolve the immobilizing agent in the other components, and other similar factors. If an immobilizing agent is used, then its content in the composition is generally from 5 to 90%. More preferably, the content of the immobilizing agent in the composition is from 5 to 50%, most preferably from 10 to 40%.

It is desirable that at least a portion of the topsheet of the device be made of a hydrophilic material that facilitates the transfer of fluids (e.g., urine). It is also desirable that the dermatological component be sufficiently wettable to permit rapid transfer of fluids through the topsheet. Hydrophobic dermatological components may also be used, but only to the extent that the desired properties of the topsheet are not compromised. (One option is, for example, to apply the component to only a portion of the topsheet.) This will reduce the likelihood that body exudates will drain from the thus modified topsheet before they can be absorbed through the topsheet into the absorbent core.

If a hydrophilic component is required, it may be necessary to add a hydrophilic surfactant (or a mixture of hydrophilic surfactants) to improve wettability.

surfactants), depending on the respective components used in the composition. However, some immobilizing agents, such as N-cocoyl-N-methoxypropyl glucamide, have HLB values above 7 and are sufficiently wetting even without the addition of a hydrophilic surfactant. Other immobilizing agents, such as C ₆ -C ₈ fatty alcohols with HLB values below 7, may require the addition of a hydrophilic surfactant to improve wettability. Similarly, a hydrophilic surfactant must be added to a hydrophobic emollient, such as petrolatum, if the composition is required to be hydrophilic. Of course, there is no point in considering wettability if the surface contacting the user is not the top layer of the composition or if the desired properties of the top layer are provided in another way (e.g. by partial coating).

Suitable hydrophilic surfactants should be miscible with the other components of the dermatological component to form mixtures. Due to the possible hypersensitivity of the skin of users of absorbent articles with a dermatological component applied, these surfactants should be relatively mild and non-irritating. These hydrophilic surfactants should be non-ionic in order not to irritate the skin, but also to avoid undesirable effects on other parts of the treated article. For example, reduction in tensile strength, quality of adhesive bonds, etc.

Suitable nonionic surfactants should be immobile after application of the component to the composition and their HLB values should be in the range of 4 to 20, more preferably 7 to 20. In order to be immobile, these nonionic surfactants typically have a melting point higher than the temperatures to which the absorbent compositions are exposed during storage, transport, sale and use, e.g. at least 30°C. In this respect, w · · <9 · « ·» nonionic surfactants typically have melting points similar to the previously described immobilizing agents.

Suitable nonionic surfactants for use in the components applied to the composition, at least in the outlet region, are alkyl glycosides, alkyl glycoside ethers as described in U.S. Patent 4,011,389, alkyl polyethoxylate esters such as Pegosperse 1000MS from Lonza, Inc., Fair Lawn, New Jersey, ethoxylated sorbitan mono-, di- and/or tri-esters of _C1- C18 fatty acids with an average degree of ethoxylation of from 2 to 20, preferably from 2 to 10, such as TWEEN 60 (sorbitan esters of stearic acid with an average degree of ethoxylation of 4), and condensation products of aliphatic alcohols with 1 to 54 moles of ethylene oxide. The alkyl chain of the aliphatic alcohol is generally linear in configuration and contains from 8 to 22 carbon atoms. Particularly suitable are the condensation products of alcohols with an alkyl group containing from 11 to 22 carbon atoms with 2 to 30 moles of ethylene oxide per mole of alcohol. Examples of such ethoxylated alcohols are the condensation products of myristyl alcohol with 7 moles of ethylene oxide per mole of alcohol, the condensation products of coconut alcohol (a mixture of fatty alcohols with alkyl chains of 10 to 14 carbon atoms) with 6 moles of ethylene oxide. A number of suitable ethoxylated alcohols are commercially available, including Tergitol 15-S-9 (a condensation product of linear Cn-Cis alcohols with 9 moles of ethylene oxide) sold by Union Carbide Corporation, KYRO EOB (a condensation product of linear C13-C15 alcohols with 9 moles of ethylene oxide) from The Procter & Gamble Co., NEODOL surfactants from Shell Chemical Co., notably NEODOL 25-12 (a condensation product of linear C12-C15 alcohols with 12 moles of ethylene oxide) and NEODOL 23-6.5T (a condensation product of linear C12-C13 alcohols

B ···« B

Β · » * Β Β Β Β • · «ΒΒΒ * * * Β Β « Β • Β Β Β Β Β Β ΒΒΒΒ • · Β ΒΒΒΒΒΒΒΒ ΒΒ β Β with 6.5 moles of ethylene oxide, which has been distilled to remove impurities) and in particular the PLURAFAC surfactants to BASF Corp., in particular PLURAFAC A-38 (a condensation product of a linear Cis alcohol with 27 moles of ethylene oxide). (Some hydrophilic surfactants, in particular ethoxylated alcohols, such as NEODOL 25-12, can act as alkyl ethoxylate plasticizers). Other suitable examples of ethoxylated alcohol surfactants are the Brij surfactants and mixtures thereof, in particular Brij 72 (i.e., Steareth-2) and Brij 76 (i.e., Steareth-10). Furthermore, mixtures of ethoxylated cetyl alcohol and stearyl alcohol with an average degree of ethoxylation of 10 to 20 can also be used as hydrophilic surfactants.

Another surfactant suitable for use in the composition is Aerosol OT, dioctyl ester of sodium sulfosuccinic acid sold by American Cyanamid Company.

Other suitable surfactants are silicone copolymers such as General Electric SF 1188 (polydimethylsiloxane polyoxyalkylene ether copolymer) and General Electric SF 1228 (silicone polyether copolymer). These silicone surfactants can be used in combination with other types of hydrophilic surfactants mentioned above, such as ethoxylated alcohols. These silicone surfactants have been found to be effective at concentrations as low as 0.1%, but more preferably up to 0.25 to 1.0% by weight of the component.

If a hydrophilic component is required, the amount of hydrophilic surfactant required to increase the wettability of the component to the desired level depends in part on the HLB value and the amount of immobilizing agent, if used, on the HLB value used • · · 1 * < · * · · ··· · » · · 9 9 9 9 • · · 9 9 9 9 9 9 9

9 9 9 99 9 9 9 « « » · »

W · · · · · · 9 9

9 9 999 9999 99 9 9 surfactant and other similar factors. To increase wettability, the component may contain from 0.1 to 50% hydrophilic surfactant. However, to increase wettability, the component usually contains from 1 to 25%, more preferably from 10 to 20% hydrophilic surfactant.

The composition may contain other components commonly present in emulsions, ointments, solutions, suspensions, etc., of this type. These components include water, viscosity modifiers, perfumes, disinfectant antibacterial agents, antiviral agents, vitamins, pharmaceutical agents, film-forming agents, deodorants, opacifiers, astringents, solvents, preservatives, etc. In addition, stabilizers such as cellulose derivatives, proteins and lecithin may be added to extend the expiration of the composition. All of these substances are well known in the art as additives and may be used in appropriate amounts in these compositions.

If a water-based dermatological component is used, a preservative must be used. Suitable preservatives are propylparaben, methylparaben, benzyl alcohol, benzylkonium, tribasic calcium phosphate, BHT or acids such as citric, tartaric, maleic, lactic, malic, benzoic, salicylic, etc. Suitable viscosity-increasing agents include some of the substances described as effective immobilizing agents. Other suitable viscosity-increasing agents are, for example, alkylgalactomannan, silicon dioxide, talc, magnesium silicate, sorbitol, colloidal silicon dioxide, magnesium aluminum silicate, zinc stearate, wool wax alcohol, sorbitan sesquioleate, cetylhydroxyethyl cellulose and other modified celluloses. Suitable solvents are propylene glycol, glycerin, cyclomethicone, • · · < · » « · · · · · · ♦ · · r · ·

999999 9 9

9 9 9 9 9 9 9 9

9 9 999 9999 99 9 polyethylene glycols, hexylene glycol, diol and solvents with multiple hydroxyl groups. Suitable vitamins are A, D ₃ , E, B ₅ and E acetate.

VI. Application of the component to the device

The absorbent device must be modified so that the dermatological component containing the enzyme inhibitor is at least partially transferred from the modified device to the user's skin during wear.

Therefore, the dermatological component is applied either directly to one or more surfaces that contact the wearer or is applied at other locations or in another manner so that it is readily available for transfer from one or more surfaces that contact the wearer during wear, independently of the wearer. (For example, substances placed under the surface that contacts the wearer, encapsulated components, etc.) It goes without saying that in order to make the transfer of the component to the areas most exposed to stress more effective, it is necessary to apply the component to the parts of the top layer and the cuff that are in contact with the buttocks, genitals, groin area and anal area. Additionally, the component may be applied to other areas of the composition to provide transfer to the hips, abdomen, back, waist, thighs, etc. Suitable methods include spraying, printing (e.g., flexographic printing), coating (e.g., slot coating, screen coating), extrusion, or a combination of these application methods, e.g., spraying the dermatological component onto a rotating surface, such as a press roll, which then transfers the component to the desired portion of the composition. The enzyme inhibitor-containing dermatological component may be applied as a solid by any of a number of methods, e.g., extrusion.

»» ·»

9 9 • ·

9 • » • · · · • · · · »· • · · · « « 9 *

« · ♦··♦··

If the component is hydrophobic in nature, it may happen that when applied to the top layer of the composition, the layer will not be completely saturated with the component in the area corresponding to the outlet area of the composition. If the top layer is saturated with the component in the outlet area, then there is a great risk that the component will block the openings of the top layer, thereby reducing the ability of the top layer to transfer fluids to the absorbent core below. Saturation of the top layer is also undesirable for achieving a therapeutic and/or protective effect. Similarly, saturation of other components of the composition may not be desirable. Suitable methods of application are those in which the component is applied primarily to the outer surface of the top layer of the composition.

The minimum amount of enzyme inhibitor-containing component applied to the user-contacting surface of the invention corresponds to an amount sufficient to provide a therapeutic, protective and/or skin-condition-improving effect. The amount of component applied depends on various factors, including the substance of the composition being treated, the relative portion of the user-contacting surface not covered by the component, the composition of the component, etc. Generally speaking, if relatively hydrophobic components are used and are applied to the entire top layer, then the amount of component applied is in the range of 0.016 mg/cm ² to 2.33 mg/cm ² , more preferably from 0.16 mg/cm ² to 1.55 mg/cm ² . It is clear that a larger amount of dermatological component can be applied to other parts of the composition where fluid distribution is not impaired (e.g. cuffs, waist portion, side panels, etc.). It is also clear that relatively hydrophilic components can be applied to the top layer in larger quantities without significantly affecting the distribution properties. Conversely, a larger amount of hydrophilic component may be undesirable if it is applied to parts (e.g. cuff, waist)

4 ·

4 «44 4

4 4 4 4 ·

44444« 4 4

4 4 4 4 • · * 4444444

4 4 4 4 4 4 4 other than the top layer, where secretions could be sucked to the edges and subsequent fluid leakage.

Because the component is completely immobilized on the surface, only a small amount of it is required to transfer an effective amount of the enzyme inhibitor. We believe that these small amounts are sufficient to achieve the desired effect on the skin, as the component is continuously, spontaneously released during wear. This means that the ability to use relatively low levels of the dermatological component means that the top layer of the composition is able to maintain its transfer properties in the area of fluid outflow.

The component may be applied to the user-contacting surface non-uniformly. By non-uniformly is meant that the amount, location, distribution pattern, etc., of the component may be different on the user-contacting surface and may also be different in other areas of the device. For example, to maintain the distribution properties of the top layer, it may be necessary to apply the component non-uniformly, especially if it is hydrophobic in nature. For this reason, some parts of the treated surface of the device (and its areas) must have a greater or lesser amount of the component, including parts to which the component is not applied. In one such embodiment, where the component is relatively hydrophobic, the surface of the top layer has areas to which the component has not been applied, particularly in the area of the top layer that corresponds to the crotch area. The crotch area of the device, as used herein, is a rectangle, as defined below, which is centered longitudinally and transversely at the crotch point. The crotch point is determined by putting on the device with the user standing and pulling the thread around the legs in a figure eight shape. The point of the device that corresponds to the intersection of the fibers is considered to be the crotch point. (It is clear that the crotch point is determined by placing the absorbent device on the user in a specified manner and determining the location where the crossed fibers touch the device.) For incontinence devices (e.g. diapers, adult incontinence devices), the length of the crotch area corresponds to 40% of the total length of the absorbent device (i.e. in the y dimension). For menstrual pads, the length of the crotch area corresponds to 80% of the total length of the absorbent device. The width of the crotch area is the same as the width of the widest part of the absorbent core measured at the crotch point. (The absorbent core components are the materials that participate in the absorption, transfer, distribution and/or storage of body fluids. The term absorbent core does not include the topsheet or backsheet of the absorbent article.) An example would be an incontinence article with a length of 50 cm and a core width in the crotch area of 10 cm, the crotch area being rectangular, centered on the crotch area and having a length of 20 cm and a width of 10 cm.

It is surprising that when the component is applied non-uniformly to the top layer or part thereof (e.g. microscopic or macroscopic areas where no component is applied), the component is transferred to the user even in areas of the skin that correspond to the untreated areas of the top layer or part thereof. The amount and uniformity of the component transferred to the skin depends on a number of influences, including, for example, the method of application of the dermatological component, the contact of the user's skin and the treated area, the friction that occurs during wear between the user's skin and the treated area, the heat generated by the user that enhances the transfer of the component, the properties of the component, the substances that make up the component, etc.

·

4» 4

4 4 4

4 4 4 4 4 4 • 44

4 4 ·

A variety of patterns may be used in non-uniform application of the component, including, for example, the application of small droplets (e.g., by spraying), tiny dots (e.g., by gravure printing), longitudinal or transverse stripes (formed by contact slot coating), spirals that move transversely or longitudinally, etc., pattern printing, etc. In these embodiments, where the topsheet contains separate, unprocessed regions, the extent of the open portion of the topsheet area that corresponds to the crotch area may vary considerably. (The extent of the open portion of the topsheet is determined by (i) measuring the surface area of the topsheet that falls within the crotch area, (ii) measuring the total surface area of the unmodified area in that portion of the topsheet, and (iii) dividing the result of the measurement from (ii) by the result of the measurement from (i). The term unmodified as used herein means that the area of the topsheet contains less than 0.0016 mg/ ^cm2 of the ingredient. In this regard, the extent of the open portion may be from 1% to 99%, from 5% to 95%, from 10% to 90%, from 15% to 85%, from 20% to 80%, from 25% to 75%, from 30% to 70%, or from 35% to 65%. The extent of the open portion necessary to achieve the desired effects of the ingredient and the desired distribution properties of the topsheet is largely determined by the properties of the ingredient (primarily its composition and the ratio of hydrophobic to hydrophilic properties). The skilled person The skilled person will appreciate that the desired extent of the open portion can be easily determined by simple experiment.

Components that are relatively hydrophobic and are not to be applied to the top layer areas are first applied to the top layer of the composition in an amount of from 0.0078 mg/cm ² to 5.43 mg/cm ² , more preferably from 0.16 mg/cm ² to 3.88 mg/cm ² and most preferably from 0.62 mg/cm ² to 3.1 mg/cm 2 . It is clear that components that are relatively hydrophilic can be applied in larger amounts without significantly affecting the distribution properties of the top layer. Of course, compositions with a relatively high percentage of open areas in the crotch can also have larger amounts of the component applied without significantly affecting the distribution properties of the top layer.

In one proposed embodiment, the topsheet is coated with longitudinal strips of the component. These longitudinal strips (or spirals) are separated from each other by longitudinal strips where little or no component is applied. In these embodiments, each strip of component typically has a width of from 3 mm to 20 mm, preferably from 3 mm to 13 mm, and the width of the strips not containing the component is typically from 3 mm to 26 mm, preferably from 4 mm to 13 mm. These ranges are applicable for conventional baby diapers. For larger products, such as adult incontinence products, these ranges may be larger.

The dermatological component may also be applied in a non-uniform pattern to other parts of the device. In such cases, the open area may be calculated from a rectangle defined by the perimeter of the dermatological component.

The component may be applied to the device at any time during assembly. For example, the component may be applied to the finished absorbent article before it is packaged. The component may also be applied to a given part (e.g., topsheet, cuffs, side panels, waistband, etc.) at the point of exchange or by the fabric supplier before it is combined with other parts into the finished absorbent article. The component may also be applied to other areas of the article so that it may transfer to one or more user-contact surfaces during wear.

9 *'·

99 99

9 9 9 9

99999 9 • · • 9 9

9 9

9 9

9 9

9

The component is usually applied to the composition in its heated state, since its melting point is significantly higher than the ambient temperature. The component is usually heated to a temperature in the range of 35°C to 150°C, but preferably from 40°C to 100°C, before being applied to the composition. The enzyme inhibitor can be added to the component before or after heating. If it is added before heating, the temperature must be chosen so as not to denature it. Alternatively, the enzyme inhibitor can be added to the preheated component, which has already been partially cooled to a temperature that does not damage the enzyme inhibitor, but is sufficient to apply the component to the composition. The liquid component is allowed to cool and solidify after being applied to the composition. The process of applying the component is usually arranged so that cooling is active.

When applying the component to the device, slot coating, spray coating, gravure coating and extrusion are preferred. One of these methods is slot coating the top layer of the composite finished device.

VII. Testing methods

A. Transfer of dermatological ingredient and enzyme inhibitor to the user's skin

Overview

This method utilizes a removable skin analog that is placed on the skin of the user for a period of time. The skin analog is then removed and the amount of dermatological component or the amount of protease inhibitor in the solvent extract of the analog is determined using conventional analytical procedures. This method is described

9 9 9 9

9999

9 9

9 9 · 9 • 9999 for use in baby diapers containing a dermatological ingredient with an enzyme inhibitor. The skilled artisan will be able to determine appropriate changes for other dermatological ingredients, protease inhibitors, absorbents, or user types.

Tested individuals

Two approximately equal groups of male and female children should be selected according to the following characteristics. Sufficient numbers of children should be selected to ensure that at least 15 individuals complete all parts of each test.

Inclusion conditions

a. Healthy child.

b. Caregiver willing to refrain from using solutions, creams, powders, or other dermatological products in the diaper area for the duration of the test.

c. Children who wear diapers all day.

d. Caregiver willing to bathe the child the day before the test, but not before it is completed.

e. Caregiver willing to refrain from swimming the child from the evening before the test until its completion.

Conditions of separation

a. The child has been sick for the past four days.

b. Diarrhea (loose stools) within four days before the test.

c. Medications that may increase bowel movements (e.g. oral antibiotics, antifungals, corticosteroids).

d. Damaged skin at or around the testing site (e.g. burns, active skin lesions, etc.).

494 4494

9 9 9 * 9 9 9 9

9 9 9

9 9

e. Known allergies or irritations from adhesive or dermatological ingredients.

Substances

In vivo transmission

Skin analogue:

Sample container dermatological tape - TEGADERM Tape 1622W available from 3M Health Cares, St. Paul, MN glass with cap from VWR Scientific, West Chester, PA under the designation 15900242

Tape release powder: Baby powder (containing only talc and fragrance) to Johnson & Johnson, New Brunswick, NJ

Surgical gloves: from Best Manufacturing Co., Menlo GA, under the designation 6005PFM

Extraction and analysis of dermatological components

Solvent:

Stearyl alcohol: 1-hexadecanol: Preparation vial: Gas chromatograph:

dichloromethane from Louis, MO, 27056-3 Aldrich 25876-8 Aldrich 25874-1 10 ml suitable for ionization Packard model 5890

Sigma-Aldrich, St.

detector from Hewlett

·· · * ·« · · ·· ··· · · · · ···· _ - ···· · · ··«· /π · ·····♦ · · ·· ·♦ · ^{z ν} ··· ·· · · · ·· · ··· ···· ·♦ ·· Column: Chrompack CP Sil-5 capillary column CB, 2 meters x 0.25 mm silica

glass with a film thickness of 0.12 gm (without replacements)

Instrumentation data of the system: must allow repeated determination of the areas with the highest values

Extraction and analysis of a typical inhibitor (e.g. hexamidine) of an enzyme (e.g. protease)

Solvent:

dichloromethane from Sigma-Aldrich, St. Louis, MO, 27056-3

Preparation bottle: 10 ml

Column: Hewlett Packard Zorbax SB-CN narrow bore 5 gm, 2.1 x 150 mm with Waters Bondapack CN 10 gm, guard column

3.9 x 20 mm

Instrumentation data of the system: must allow repeated determination of the areas with the highest values

Way

In vivo transmission

A. Confirmation from the caregiver that the child has been bathed within the last 24 hours and that no solutions, powders, etc. have been applied to the diaper area since then.

B. Putting on surgical gloves, placing the child on the table, and removing their diaper.

C. Turning the baby onto his stomach.

D. Remove the TEGADERM tape release liner and lightly dust the adhesive surface with J&J Baby Powder (wearing surgical gloves to avoid contaminating the tape). Apply a sufficient amount of powder to the entire tape area, excluding the edges. (This step is done to prevent the tape from adhering too aggressively to the baby’s skin.)

E. Figures 2a and 2b illustrate the placement of the TEGADERM tape, designated herein as tape 700. Tape 700 is applied to the infant's right buttock. Tape 700 is applied to the highest point of the infant's buttock near the gluteal crease. To measure transfer at two time points or to measure the effect of another diaper, a second tape 700 may be applied. If a second tape 700 is used, it is applied to the left buttock in the same manner.

F. Diaper changes are performed according to the following protocol: 3 hour transfer time - 1 diaper, 6 hour transfer time - 2 diapers (change every 3 hours), 24 hour transfer time ad lib by caregiver. For 24 hour transfer time, the following additional instructions must be followed:

1. Use only water and a washcloth to clean the diaper area during the test. Do not use baby wipes. Do not touch the area around the straps with your hands or a cleaning tool.

• 4 • 4 4 • «444 4

4 4

4 4

4 4

444 44 4444

4· 4 444 4·»4 ·· 44

2. Do not use dermatological products (solutions, ointments, creams, soaps, etc.) during the test.

3. Do not bathe the child during the test.

4. Use only tested diapers.

5. Record the time of defecation and wash the child with water and a washcloth.

G. Record the application time of each tested diaper.

H. Call the child before the designated transmission time expires.

I. Remove the test diaper. If the child has had a bowel movement, the 700 strip should be removed and discarded (the child has completed the test and the data will not be included in the analysis). If the child has urinated, the 700 strip is acceptable for the analysis below.

J. The test operator removes the 700 strip by grasping its edge with tweezers and gently peeling it away from the skin, all while wearing surgical gloves.

K. Prepare a jar and carefully label the sample for later identification.

L. After completion of the test, store all samples in the analysis jars described below.

1. Extraction and analysis of tested samples of dermatological component *· Β • · « · • ····· • Β · ·· « • · • 9 • ···· ·· »» • Β Β · • · · · · • · Β ·

B B · ·

BB BB

This method is intended for testing the proposed dermatological component, the component from Table 4. The skilled artisan will know what adjustments are necessary for the extraction and analysis of other dermatological components. In general: 1) one of the major components of the dermatological component is extracted from the skin analog using an appropriate solvent, 2) a gas chromatograph or other suitable quantitative analytical technique is used to determine the amount of the major component in the extract, 3) the amount of the dermatological component is calculated from the unit area by the amount of the major component in the extract and the area of the tape.

Internal standard/solvent

Prepare the internal standard/solvent by accurately weighing 100±2 mg of 1-hexadecanol into a small beaker. Dissolve the 1-hexadecanol in dichloromethane and transfer to a graduated cylinder. Rinse the beaker 3 times with dichloromethane, transferring the contents to the graduated cylinder each time. Make up to volume and mix well. This solution will be used to create the internal standard and extract the dermatological component from the strips. The solvent container should be tightly closed to prevent evaporation.

Standard calibration

Prepare a calibration standard of known concentration by accurately weighing (±0.1 mg) 10 ± 1 mg of stearyl alcohol into a 100 ml graduated cylinder. Record the mass of stearyl alcohol used. Add the internal standard/solvent to the cylinder and mix until dissolved. Make up to volume and mix again. The solvent container should be tightly closed to prevent evaporation. This solution will be used in determining the relative ·· ·

Preparation and calibration of the gas chromatograph

Install the column and check the gas flow through the column while

100°C and the injection port and detector at operating temperatures. The flow chromatograph will operate under the following conditions:

Carrier gas: hydrogen (helium can also be used), flow rate 1.5 ml/min.

Injection port: 325°C, flow rate 30 ml/min, partition cleaning 2 ml/min, glass wool insert, Merlin microseal.

Injected volume: 2 μΐ divided.

FID detector: 350°C, gas flow set according to manufacturer's instructions. Typical gas flow is 400 ml/min for air, 30 ml/min for hydrogen and 30 ml/min for additive gas.

Column thermostat: 100°C with an increment of 15°C/min to 325°C, takes minutes.

Make sure all connections are tight and do not leak.

Turn on the detector and allow it to stabilize. Leave the column at 325°C for 30 minutes. Clean the syringe with dichloromethane. The syringe should also be flushed several times after each injection. Perform several blind runs with dichloromethane until you get a good baseline without spurious peaks. If spurious peaks appear or the baseline is not good, try to correct the problem.

• · • · • · · • ·

Set up the instrument according to the calibration standard previously prepared. Follow the manufacturer's recommendations to determine the correct sequence of operations. Calculations should be performed in a manner similar to that described below.

Sample analysis procedure

1) Remove the cap from the sample vial and add 10 ml of extraction solvent/internal standard solution using the pipette. Close the cap and swirl the contents so that the 700 strip is not stuck to the sides of the vial and is completely immersed in the solvent. Repeat with all samples.

2) Leave the samples for 16 hours (usually overnight).

3) Mix the contents of the vial. Using a pipette, transfer all of the sample extract into the labeled vial. Cap the vial. Close the vial and leave it until the analysis is complete. Repeat with all samples.

4) Load the vials in random order into the test machine and start the assay under the conditions described above. The first vial should be a dichloromethane blank. Several control standards should be included (about every 20th sample) to verify the accuracy of the measurement.

5) After the measurement is complete, check each chromatogram to confirm the correctness of the analysis. If there is a problem, try to identify and eliminate it. If necessary, re-analyze the samples.

Calculations

The number of micrograms of stearyl alcohol in the extract of each sample is calculated based on the relative response of the stearyl alcohol peak to the 1-hexadecanol internal standard peak. The ratio of the peak areas is multiplied by the relative response factor (determined during instrument calibration) and the micrograms of internal standard in the extract to obtain the total number of pg of stearyl alcohol in the sample.

Instrument calibration

Determination of the relative instrument response factor for stearyl alcohol and the internal standard, which are derived from the peak areas of stearyl alcohol and 1-hexadecanol in the chromatogram of the calibration standard.

Reaction factor (R _č ) = ^areavst mass _vst massa areaa where area _vst = peak area for internal standard.

area _sa = peak area for stearyl alcohol. mass _vs t ⁼ micrograms of internal standard used to prepare the internal standard/extraction solvent.

mass _S a ⁼ micrograms of stearyl alcohol used to prepare the calibration standard

Sample calculations

The number of micrograms of stearyl alcohol in each sample is calculated from the peak area on the sample chromatogram according to the following equation:

area and weight _V st

Number of pgs SA = area _vst

RF

100 c 4 ··· 4 4 4 4 · · · ·

4·· 4 · 4444 • 4444·· · 4 4 4 44 4

444 44 4444

4· 9 4444444 ·· ·· where area _vst = area of the peak of the internal standard.

area _sa = area of the stearyl alcohol peak. massvst ⁼ micrograms of internal standard used to prepare the internal standard/extraction solvent.

Calculate the transferred amount of dermatological component in mg/cm ² where:

Transferred component = _ο,οοϊ x pg stearyl alcohol_ (SA concentration in component) x (tape area)

In the method described above, the concentration of stearyl alcohol in the composition is 41% and the dimensions of the tape are 4.4 cm x 4.4 cm.

Transferred component = (0.001 x pg stearyl alcohol in component)/(0.41 x

4.4 cm x 4.4 cm) = 0.000126 x pg stearyl alcohol (mg/cm ² )

2. Extraction and analysis of protease inhibitor in the test sample

This method is adapted for use with a dermatological composition containing a protease inhibitor from Table 1. The skilled artisan will know what adjustments are necessary for the extraction and analysis of other protease inhibitors. In general: 1) the protease inhibitor is released from the skin analog by the action of an appropriate solvent, 2) HPLC or other quantitative analytical technique is then used to determine the level of inhibitor in the extract, 3) the amount of protease inhibitor is calculated as a unit area per the amount of inhibitor in the extract and the area of the tape.

Preparation of standards

To prepare a 10 μg/mL hexamidine standard solution, weigh out 0.10 grams +/- 0.02 grams of hexamidine diisothionate and dissolve it in the mobile phase (10% crystalline acetic acid and 17.5% methanol) of the HPLC solution. Prepare additional hexamidine standards from the 10 pg/mL standard solution, see Table 2, and make up to 100 mL with the HPLC mobile phase solution.

Table 2

Preparation of standards*

standard hexamidine standard solution (ml) final volume (ml) nominal concentration (pg/ml) 1 5.0 100 0.5 2 10.0 100 1.0 3 25.0 100 2.5 4 50.0 100 5.0

Sample preparation

1. Place the tested transfer strip into a 40 ml glass vial.

2. Add 10 ml of dichloromethane and close the bottle tightly.

3. Let the bottle shake for 30 minutes.

4. Remove the vial from the shaker, remove the vial cap and add 10 ml of HPLC mobile phase solution. Close the vial and shake again.

5. Shake the sample for 30 minutes to dissolve the hexamidine in the aqueous phase.

6. Allow the sample to settle for at least 30 minutes and the layers to separate.

• 4 » 4 4 · · 4 4 4 4

4 4 4 · · 4 · · · • 444444 4 · «· · 4 ·

2< ··· ·♦ »,··· «4 ν» ««····» ·· «4

7. After sample separation, remove the aqueous (top) layer with a syringe and filter it through a 0.45 pm filter.

Sample analysis

Chromatograph the standards and samples according to the conditions described in Table 3.

Table 3

Chromatographic conditions

Mobile phase flow: 0.25 ml/min Mobile phase: 10% crystalline acetic acid, 17.5% methanol Injected volume: 10ml UV detector wavelength: 254 nm UV detector sensitivity: 1,000 AUFS UV detector filter: 2.0 seconds Time: 10.0 minutes

Calculations

1. Standard concentration (mg/ml):

Si(mg/ml) = W(mg)/100*(Vi/100) (1)

W = mass of hexamidine for the stock standard solution

Vi = volume of hexamidine stock solution used for standard preparation (Table I) • ·

2. Calibration curve

A. Create a table of mg/mL hexamidine in each standard (Si) and the responses (peak area or peak height), R _Í5 for each of the solutions.

B. Create a calibration curve according to equation (2).

Ri = mSi + b (2)

3. Tested samples

A. Calculate the amount of hexamidine (Hi) in the sample extracts using the measured response R and the calibration equation:

Hi = (R-b)/m (3)

B. Calculate the amount of hexamidine (H) in the samples in mg according to Equation 4.

H = Hi * 10 (4)

C. Divide the amount of hexamidine (H) by the area of the tape to determine the concentration of hexamidine per unit area of the skin analog.

VIIL Examples of embodiments of the invention

The following are examples of (a) applying a dermatological component to a diaper topsheet and (b) methods of the present invention that utilize compositions containing such topsheets. A similar approach can be used to modify other parts of such a composition.

• 4 44 4 4 • 4 4 ·· 4 « · 4 · 4

4 I » 9 9 4

9 9 9

Example 1

Preparation and testing of an absorbent article with a top layer containing a dermatological ingredient and an enzyme inhibitor

A. Preparation of dermatological components

Folder 1

The dermatological component is formed by mixing the following components: 99 parts of a warmed (i.e., liquid) base composition containing 85 parts of SEFA cottonate (sucrose polycotonate from Procter & Gamble Co., Cincinnati, OH) and 15 parts of SEFA behenate (sucrose polybehenate from Procter & Gamble Co., Cincinnati, OH) with 1 part of acetohydroxamic acid (Sigma Chemicals, St. Louis, MO).

Folder 2

The dermatological component is formed by mixing the following components: 99 parts of a warmed (i.e., liquid) base composition containing 58 parts petrolatum (from Witco Corp., Greenwich, CT as White Protopet), 41 parts stearyl alcohol (from Procter & Gamble Co., Cincinnati, OH as CO 1897), and 1 part aloe extract (from Madis Botanicals, Inc., S. Hackensack, NJ as Veragel Lipoid in Kaydol) with 1 part tranexamic acid (Sigma Chemicals).

Folder 3

The dermatological component is prepared in the same way as component 2, except that triacetin is used instead of tranexamic acid.

« · 9 • · • · · · t·

Folder 4

The dermatological component is formed by mixing the following components: 9 parts of a heated (i.e., liquid) base composition containing 58 parts petrolatum (from Witco Corp., Greenwich, CT as White Protopet), 41 parts stearyl alcohol (from Procter & Gamble Co., Cincinnati, OH as CO 1897), and 1 part aloe extract (from Madis Botanicals, Inc., S. Hackensack, NJ as Veragel Lipoid in Kaydol) with 1 part of a heated (i.e., 60°C) inhibitor component containing 9 parts Tween 60 (ICI Surfactants) and 1 part hexamidine diisothionate (from Laboratories Serobilogiques, Pulnoy, France as Elestab HP100).

B. Preparation of the composition by contact slot coating

The component from Table 1 is placed in a heating tank with an operating temperature of 77°C. The component is then applied with a contact applicator (e.g. Meltex EP45) to the top layer of the composition in strips that run lengthwise. Exactly 5 strips are applied, each of which has a width of 0.54 cm. (i.e. in the transverse dimension of the composition) and a length of 25.4 cm and the applied amount is 1.19 mg/cm ² . The distance between the strips is 0.67 cm.

Example 2

Ways to improve skin condition

An incontinent adult weighing 82.5 kg, using absorbents and suffering from mild erythema, wears an adult incontinence device similar to the diaper of Example 1 for at least 5 days. The device is changed in the manner usual for the user (usually every 4 to 5 hours during the day and before bedtime).

«· *

During this period, no user intervention is required (e.g. application of dermatological products). Towards the end of these 5 days, a reduction or disappearance of the erythema is observed.

Example 3

Ways to improve skin condition

A child weighing 16 kg and suffering from diaper rash and erythema wears the diapers from Example 1 at night for at least 5 days (i.e. uses the untreated composition during the day). The diapers are changed by the caregiver in the usual way. During this time, no interventions by the caregiver (e.g. application of dermatological preparations) occur. Towards the end of these 5 days, a reduction or disappearance of the rash and erythema is observed.

Example 4

How to maintain skin condition

A child weighing 12.5 kg and without diaper rash or erythema is evaluated for otitis media and prescribed systemic antibiotics. Based on experience with conventional (untreated) diapers, the caregiver expects the child to develop erythema and/or diaper rash due to looser stools. The diapers described in Example 1 are worn continuously during the course of antibiotics. No user intervention (e.g., application of dermatological preparations) occurs during this time. No erythema or diaper rash is observed in the child during the administration of antibiotics.

The descriptions of all patents, patent applications (and all patents relating to the subject matter, as well as relevant published foreign patent applications) and publications mentioned in this specification are hereby incorporated by reference. However, we do not admit that any of the documents mentioned herein describe the proposed invention.

While particular embodiments of the present invention have been shown and described, it will be apparent to those skilled in the art that various other changes and modifications may be made without departing from the scope of the invention. It is our intention, therefore, to cover in the appended claims all such changes and modifications that fall within the scope of the invention.

Claims (13)

PATENT CLAIMS An absorbent composition, a portion of which comprises a dermatological component with an enzyme inhibitor, wherein the dermatological component containing the enzyme inhibitor is at least partially transferred from the composition to the skin of the user of the composition during normal contact, movement of the user and / or body heat. The composition of claim 1, wherein the enzyme inhibitor is selected from a protease inhibitor, a lipase inhibitor, a bile salt inactivator, an elastase inhibitor, a urease inhibitor, an amylase inhibitor, or a mixture thereof. Composition according to claim 1 or 2, characterized in that the dermatological component is solid or semi-solid at 20 ° C. Composition according to claim 1, 2 or 3, characterized in that the dermatological component comprises 5% to 95% of a plasticizer, which is malleable or liquid at 20 ° C and further preferably comprises 5% to 95% of an agent capable of immobilizing the plasticizer in the plasticizer. and having a melting point of at least 35 ° C. The device according to claims 1-4, characterized in that the portion provides a surface contacting the user, preferably a topsheet. A composition according to claims 1-4, characterized in that the dermatological component containing the enzyme inhibitor is applied to the topsheet such that one or more regions of the topsheet are untreated by the dermatological component and the dermatological component with the enzyme inhibitor is preferably applied. onto a topsheet in the form of strips separated by a row of strips without a dermatological component. Composition according to claims 1-6, characterized in that the dermatological component comprises from 0.001% to 50% of an enzyme inhibitor, preferably from 0.1% to 10%. The composition of claims 1-7, wherein the IC ₅₀ of the enzyme inhibitor is not greater than 500 µΜ. polysiloxane plasticizers, 9. The composition of claim 1 wherein the dermatological component further comprises a compound selected from the group consisting of a plasticizer of petroleum origin, a fatty acid ester plasticizer, an alkyl ethoxylate plasticizer, a fatty acid ester ethoxylate plasticizer, a fatty alcohol type, a sucrose ester plasticizer fatty acids, polyesters of ethylene glycol and its derivatives, sorbitol and its derivatives, trihydroxystearin and its derivatives, hydrating agents, demethicone, petrolatum, propylene glycol and its derivatives, glycerin and its derivatives, triethylene glycol and its derivatives, sperm fat and other waxes, fatty acids, fatty alcohol ethers, propoxylated fatty alcohols, polyhydroxy alcohol fatty esters, lanolin and its derivatives, kaolin and its derivatives, lanolin, mineral oil, shark liver oil, white petrolatum, talc, starch, zinc acetate, zinc carbonic acid ester, zinc oxide Derivatives of live yeast, aldioxa, aluminum acetate, microporous cellulose, cholecalciferol, colloidal oatmeal, cysteine hydrochloride, dexpanthanol, Peruvian balsam • · oil, protein hydrolysates, methionine, sodium bicarbonate, acetates vitamins A, D _3, E, B _5, and E and mixtures thereof. Composition according to claim 1, characterized in that at least 0.0016 mg / cm ² , more preferably at least 0.0078 mg / cm ^2, and most preferably from 0.0016 mg / cm ^{2, is} transferred to the skin of the user during wear of the treated composition. up to 0.78 mg / cm ^{2 of the} dermatological component. An absorbent composition, at least a portion of which comprises a dermatological component that is solid or semi-solid at 20 ° C and comprises (i) 0.001% to 50% enzyme inhibitor, (ii) 5% to 95% plasticizer, which is malleable or liquid at 20 ° C. And (iii) 5% to 95% of an agent capable of immobilizing the emollient in the composition, wherein the immobilizing agent has a melting point of at least 35 ° C. The composition of claim 1, wherein the enzyme inhibitor is selected from the group consisting of: soybean trypsin inhibitor and other trypsin inhibitors of plant origin, ovomucoids, chymostatin, aprotinin, leupeptin and analogs thereof, bestatin and analogs thereof, antipain, antithrombin III, hirudin, cystatin, and ₂ macroglobulin, α-antitrypsin, pepstatin and its analogues, TLCK, TPCK, tranexamic acid and its salts, glycyrhizic acid and its salts, stearylglycyrretinate, 18-3-glycyrrhizic acid and its salts, colloidal oat extracts , elhibin, 4- (2-aminoethyl) benzenesulfonyl fluoride HCl, quercetin, phytolic acid and its salts, ethylenediaminetetraacetic acid (EDTA) and its salts, hexamidine and its salts, pentamidine and its salts, benzamidine and its salts and derivatives, p-aminobenzidine and its salts and derivatives, guanidinobenzoic acid 99 9 9 9 9 9 9 9 99 9 9 9 9 9 9 9 And its salts and derivatives, including polymer derivatives, alkylhydroxamic acids and their respective salts and derivatives, phosphoramidate and its derivatives, water-soluble metal salts, zinc salts of saturated and unsaturated monocarboxylic acids, glycerol fatty acid esters, such as triacetin, copolymers of propylene oxide and ethylene oxide, chlorhexidine, cholestyramine, acarbose, voglibose, miglitol, emiglitate, camiglibose, pradimicin Q, salbostatin, tendamistat, alcohols, inhibitors of plant origin, mainly from wheat, rice, corn, barley , beans and seaweed, tetrahydrolipstatin, lipstatin, valilactone, esterastine, ebelactone A and B, 1,6-di (O- (carbamoyl) cyclohexanone oxime) hexane and mixtures thereof. A method for reducing the enzymatic activity of stool enzymes on a skin portion of an absorbent user comprising the steps of (i) forming an absorbent composition at least a portion of which comprises an enzyme inhibitor dermatological component and (ii) transferring a portion of the dermatological component to the skin of the wearer.