EP1212034A1 - Inhibiteurs d'enzymes - Google Patents

Inhibiteurs d'enzymes

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Publication number
EP1212034A1
EP1212034A1 EP00960051A EP00960051A EP1212034A1 EP 1212034 A1 EP1212034 A1 EP 1212034A1 EP 00960051 A EP00960051 A EP 00960051A EP 00960051 A EP00960051 A EP 00960051A EP 1212034 A1 EP1212034 A1 EP 1212034A1
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EP
European Patent Office
Prior art keywords
mixtures
substituted
alkyl
hydrogen
unsubstituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00960051A
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German (de)
English (en)
Inventor
Todd Laurence Underiner
Timothy Bates
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Procter and Gamble Co
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Procter and Gamble Co
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Publication date
Application filed by Procter and Gamble Co filed Critical Procter and Gamble Co
Publication of EP1212034A1 publication Critical patent/EP1212034A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/86—Polyethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/57—Compounds covalently linked to a(n inert) carrier molecule, e.g. conjugates, pro-fragrances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/75—Anti-irritant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
    • A61K2800/782—Enzyme inhibitors; Enzyme antagonists
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings

Definitions

  • the present invention relates to novel functional polymer conjugates which inhibit one or more proteolytic and/or Hpolytic enzymes.
  • the polymer conjugates described herein are suitable for use in any context wherein proteolytic and/or Hpolytic enzyme inhibition is indicated, inter alia, treatment of diaper rash.
  • Diaper rash is ubiquitous. It was once believed that contacting the skin with urine produced diaper rash, however, it is now understood that the irritation of tissue which manifests itself in "diaper rash" is primarily caused by endogenic proteolytic and/or Hpolytic enzymes, inter alia, trypsin, chymotrypsin, elastase, pancreatic Hpase, which comprise human feces.
  • endogenic proteolytic and/or Hpolytic enzymes inter alia, trypsin, chymotrypsin, elastase, pancreatic Hpase, which comprise human feces.
  • skin irritation is not limited to enzymes which comprise feces, for example, menstrual fluids may provide a source of enzymes which produce irritation.
  • Proteolytic and Hpolytic enzyme inhibitors are known.
  • inhibitors are "suicide inhibitors" which irreversibly react with the active site of the target enzyme thereby destroying the enzyme's ability to function.
  • Reversible enzyme inhibitors although not permanently inactivating the target enzyme, are also considered sufficiently effective to inhibit the effects of unwanted enzyme exposure.
  • One drawback of low molecular weight enzyme inhibitors is their propensity to be readily absorbed through skin tissue, thereby entering into human cells wherein normal cell cataboHsm can be interrupted.
  • the present invention meets the aforementioned needs in that it has been surprisingly discovered that proteolytic and/or Hpolytic enzyme inhibitors can be effectively delivered to human skin wherein said inhibitors can function as a barrier to enzyme activity thereby preventing diaper rash.
  • the enzyme inhibitors of the present invention are polymer conjugates which have an enzyme inhibitor component and a functionalized polymer component.
  • the enzyme inhibitor component comprises a heterocyclic ring template and an enzyme targeting unit.
  • the functionalized polymer component comprises a moiety which acts as an anchoring template for one or more enzyme inhibitors while providing a means for delivering the conjugate molecule to human skin.
  • the enzyme inhibitor component is optionally, but preferably, linked to the functionalized polymer component by a linking group. As described herein below, preferably said linking units function by interacting with the enzyme, as a leaving group, inter alia, which can potentially unmask an electrophile in the enzyme active site which leads to effectively irreversibly inhibiting the target enzyme.
  • a first aspect of the present invention relates to an enzyme inhibiting polymer conjugate having the formula:
  • T is a saccharin ring-comprising inhibitor component
  • L is a linking unit
  • [Poly] is a polymer component
  • z is 0 or 1 ; preferably a polymer conjugate having the formula:
  • a linking group, L is directly bonded to the nitrogen atom of the heterocyclic ring.
  • linking unit L also serves as a leaving group which facilitates irreversible binding to the target enzyme.
  • the present invention further relates to a process for preventing the formation of skin irritation which is due to the presence of proteolytic and/or Hpolytic enzymes, said process comprises the step of contacting an effective amount of a polymer conjugate as described herein below to human skin.
  • the present invention relates to the prevention of pernicious and otherwise unwanted skin conditions, inter alia, rash, irritation, which is caused by the contact of proteolytic and/or Hpolytic enzymes with skin.
  • skin conditions inter alia, rash, irritation
  • proteolytic and/or Hpolytic enzymes which are the cause of said unwanted skin condition.
  • the present invention achieves the desired result by applying to the skin by a suitable means a sufficient amount of a polymer conjugate which inhibits the activity of one or more enzymes which are the cause of said unwanted skin condition.
  • the polymer conjugates of the present invention comprise a saccharin enzyme inhibitor component.
  • the saccharin component is substituted by one or more units which activate or de- activate the enzyme inhibiting component towards one or more proteolytic or Hpolytic enzymes.
  • One or more saccharin enzyme inhibiting components may be present in the polymer conjugates of the present invention.
  • the conjugates of the present invention further comprise a functionalized polymer component which acts as an anchoring template for one or more enzyme inhibitors while providing a means for delivering the conjugate molecule to human skin.
  • the functionalized polymer component is typically an amphiphilic polymer which is capable of being directly attached to the enzyme inhibitor component or of being attached thereto by a linking unit.
  • the polymer component also provides the conjugate with a source of increased molecular weight which acts to inhibit the absorption of the enzyme inhibitor into skin tissue.
  • the polymer component also acts to facilitate formulation of the enzyme inhibitor into carriers or facilitates deposition of the conjugate on to either skin or a substrate to which said conjugate is applied.
  • the conjugates of the present invention also optionally comprise a linking unit which serves to tether the enzyme inhibitor portion of the conjugate to the polymeric component.
  • a linking group is present to facilitate preparation and attachment of the polymer thereto.
  • the linking group is preferably a unit which also has an interaction with the target enzyme or other enzymes which may be present, said interaction may increase selectivity for the target enzyme or aid in decreasing the affinity for a non-targeted enzyme.
  • the linking group therefore serves a dual role; acting in a manner which modulates the specificity of the polymer conjugate while providing a means for linking the enzyme inhibitor portion to the polymer backbone.
  • linking units may serve a purpose not related to the enzyme activity of the polymer conjugate.
  • the linking unit may serve to provide hydrogen bonding with the solvent affording increased compatibility of the inhibitor portion with the carrier.
  • the polymer conjugates of the present invention are utilized in an effective amount.
  • effective amount is defined herein as the amount necessary to provide a reduction in enzyme activity in at least one inhibition assay.
  • Preferred assays which are described herein are, inter alia, "Fecal Protease Inhibition Assay", “Skin Test of Inhibition of IL-l ⁇ Production”. Suitable tests also include test which differentiate the specificity of said enzyme inhibitor, for example, which proteases are obstructed by said inhibitor.
  • the enzyme inhibitor component of the present invention comprises a saccharin moiety having the formula:
  • polymer component is linked to the nitrogen of the heterocyclic ring, or a saccharin moiety having the formula:
  • the polymer component is linked to the benzene ring.
  • a linking group which also serves as a leaving group is present.
  • R' is preferably a unit which serves as a leaving group facilitating irreversible binding to the target enzyme.
  • the saccharin enzyme inhibitor component of the latter embodiment remains attached to the polymer component during and after interaction with the target enzyme, it is not a requirement that these inhibitors irreversibly bind to the target enzyme.
  • sacharin ring is defined herein as a l,2-benzisothiazol-3(2H)-one 1,1 -dioxide ring or named alternatively, 2,3-dihydro-3-oxobenzisosulfonazole, and is used interchangeably with each of these chemical terms.
  • the enzyme inhibition component optionally comprises one or more enzyme differentiating units, R.
  • R units serve to attenuate the interaction of the saccharin inhibitor component with the target enzyme.
  • R units are: a) hydrogen; b) CpCis substituted or unsubstituted, linear or branched alkyl; preferably C Cg linear unsubstituted alkyl, inter alia, methyl and ethyl, especially when the enzyme inhibitor component comprises a benzoxazin-4-one moiety.
  • each R 3 is independently hydrogen, CpCig substituted or unsubstituted, linear, cyclic, or branched alkyl; Y is an anion of sufficient charge to provide electronic neutrality; m is from 0 to 10; 1) a unit having the formula:
  • R 4 is hydrogen, C 1 -C 4 alkyl, or mixtures thereof
  • R 5 is hydrogen, -C 4 alkyl, or mixtures thereof
  • R 4 and R 5 can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; preferred is amidine
  • m a unit having the formula:
  • R 6 is hydrogen, C 1 -C 4 alkyl, or mixtures thereof;
  • R 7 is hydrogen, C C 4 alkyl, or mixtures thereof;
  • R 6 and R 7 can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; preferred are guanidine units and cyclic units, inter alia, imidazolinyl; n) a unit having the formula:
  • R 8 -R 9 wherein R 8 is: i) -(CH 2 ) P -, wherein p is from 0 to 12; ⁇ ) -C(O)-; iii) -C(X)NR 10 -, wherein R 10 is hydrogen, C C 4 alkyl, or mixtures thereof; X is oxygen, sulfur, NR 10 , and mixtures thereof; iv) -C(X)R' 'C(X)-, wherein R 1 ' is C,-C ⁇ 2 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR 10 , and mixtures thereof; v) -C(X)NR ,0 C(X)-, wherein R 10 is hydrogen, C,-C 4 alkyl, or mixtures thereof; X is oxygen, sulfur, NR 10 , and mixtures thereof; vi) -C(X)NR 10 R' 'NR 10 C(X)-, wherein
  • R 9 is: i) hydrogen; ⁇ ) Ci-Cis substituted or unsubstituted, linear or branched alkyl; i ⁇ ) C 3 -C is substituted or unsubstituted, linear or branched cycloalkyl iv) C 2 -C is substituted or unsubstituted, linear or branched alkenyl; v) C 2 -C is substituted or unsubstituted, linear or branched alkynyl; vi) C 6 -C is substituted or unsubstituted aryl; vii) C 2 -C is substituted or unsubstituted heterocyclic alkyl; viii) C 3 -C is substituted or unsubstituted heterocyclic alkenyl; ix) -OH; x) -S0 3 M; xi) -OSO 3 M; xii) -N0 2 ; xiii) halogen selected from fluorine,
  • R 4 is hydrogen, CpC 4 alkyl, or mixtures thereof
  • R 5 is hydrogen, C 1 -C 4 alkyl, or mixtures thereof
  • R 4 and R 5 can be taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms
  • R 6 is hydrogen, C C 4 alkyl, or mixtures thereof; R 7 is hydrogen,
  • Preferred R units according to the present invention include: a) hydrogen; b) CpCg linear unsubstituted alkyl, for example, methyl, ethyl, propyl, isopropyl, n- butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, 2-methyl hexyl, 2-ethyl, hexyl.
  • Methyl and ethyl are especially preferred when the enzyme inhibitor component comprises a benzoxazin-4-one moiety.
  • each R 3 is independently hydrogen, methyl, ethyl, 2-hydroxyethyl, cyclopropyl; for example, methylamino, dimethylamino, ethylamino, diethylamino, dicyclopropyl;
  • R 4 and R 5 are each hydrogen, R 4 and R 5 is taken together to form a heterocyclic ring comprising from 3 to 5 carbon atoms; preferably amidine, 2- pyridinyl, pyrimidinyl, imidazolyl; m) a unit having the formula:
  • R 8 -R 9 wherein R 8 is: i) -(CH 2 ) P -, wherein p is from 0 to 12; ⁇ ) -C(O)-; xvi) -NR 10 -, wherein R 10 is hydrogen, C C 4 alkyl, or mixtures thereof; xvii) -0-; xxi) alkyleneoxyalkylene having the formula: (R 12 0) q R 13 - wherein R 12 is C 2 -C6 linear or branched alkylene, substituted or unsubstituted phenylene; R 13 is -(CH 2 ) P -, wherein p is from 0 to 12; q is from 1 to 4; xxii) -S-; xxvi) or mixtures thereof; R 9 is: i) methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl; preferably methyl when R 8 is -0-; ii
  • substituted or unsubstituted, linear or branched is defined herein as the following.
  • Alkyl chains which comprise, for example, a -Cis alkyl unit will have any combination of carbon atoms arranged in linear form or with one or more branching chains provided the total number of carbons is from 1 to 18 carbon atoms.
  • substituted is meant any unit which suitably replaces a hydrogen atom of a linear or branched chain, non-limiting examples of which include halogen, hydroxyl, nitro, amino, cyano, -CO 2 M, - SO 3 M, -OSO 3 M, wherein M is a water soluble cation.
  • alkenyl units one or more double bonds may be present and said bonds may be conjugated or non-conjugated.
  • Alkenyl units also include allenes.
  • substituents may comprise alkyl units as will as halogen, etc.
  • R units can take any form which modulates the enzyme inhibition properties of the T unit.
  • R units under (i) above are alkylenearyl having the formula: (R')n-R 2 wherein R 1 is -C 12 linear or branched alkylene, C 2 - 2 linear or branched alkenylene, or mixtures thereof; R 2 C ⁇ -Cis substituted or unsubstituted aryl, C 3 -C 18 heteroaryl, or mixtures thereof; n is from 1 to 16.
  • suitable heteroaryl units are 5-member rings which have the formula:
  • Non-limiting examples of heterocyclic units suitable for use in the present invention include thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, triazolyl, tetrazolyl, benzothiazolyl, benzofuryl, indolyl, indenyl, azulenyl, fluorenyl, oxazolyl, isoxazolyl, isotriazolyl, imidazolyl, pyraxolyl, oxadiazolyl, indolizinyl, indolyl, isoindolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, and mixtures.
  • the heterocyclic ring can be substituted, for example, 2-pyridinecarboxylic acid (picolinyl)
  • the heterocyclic ring can be incorporated in any manner, for example, as a 2-pyridinyl unit (picolyl) or bonded to the heteroatom, for example, N-aziridinyl, N-pyrrolidinyl.
  • Conjugates of the present invention which are salts or salt- forming compounds will preferably have counter ions which facilitate delivery or formulation.
  • preferred cations include sodium, potassium, lithium, ammonium, alkylammonium, and the like.
  • Preferred anions include halogen, preferably chlorine, methylsulfate, and the like.
  • di-basic acids inter alia, oxalic, fumaric, succinic, may be used to form deliverable salts as well.
  • Polymeric Component The polymeric component of the present invention comprises units which provide the herein described conjugates with one or more properties which facilitate the delivery of the enzyme inhibitor to the required substrate.
  • the polymeric unit or the present invention represented by [Poly]- can be bonded directly to the enzyme inhibiting component or can be attached by way of a linking unit.
  • the polymeric materials of the present invention comprise: i) a polyalkyleneoxy unit having the formula:
  • R 19 (OR ,8 ) x - wherein R 18 is C 2 - 2 linear alkylene, C3- 2 branched alkylene, phenylene, C7- 2 alkylenearylene, and mixtures thereof; R 19 is hydrogen, Cr substituted or unsubstituted, linear or branched alkyl; C 3 -C 18 substituted or unsubstituted, linear or branched cycloalkyl; C 2 -C 18 substituted or unsubstituted, linear or branched alkenyl; C 2 -Ci 8 substituted or unsubstituted, linear or branched alkynyl; C 6 -C 18 substituted or unsubstituted aryl; and mixtures thereof.
  • the index x has the value of from about 10 to about 500.
  • the polyalkyleneoxy unit may be a homopolymer, (e.g., all ethyleneoxy units), co-polymer (e.g., a mixture of ethyleneoxy and propyleneoxy units), or a block co-polymer.
  • the average molecular weight of a polyalkyleneoxy polymeric unit according to the present invention is from about 400 daltons, preferably from about 1500 daltons, more preferably from about 3400 daltons to about 35,000 daltons, preferably to about 20,000 daltons, more preferably to about 10,000 daltons, most preferably to about 8000 daltons.
  • R 18 is C 2 -C 12 linear alkylene, C 3 - 2 branched alkylene, phenylene, C 7 -C 12 alkylenearylene, and mixtures thereof;
  • R 19 is hydrogen, -Cig substituted or unsubstituted, linear or branched alkyl; C3-C 1 8 substituted or unsubstituted, linear or branched cycloalkyl;
  • C 2 -C 18 substituted or unsubstituted, linear or branched alkenyl;
  • R 20 is a unit selected from: a) a unit having the formula:
  • the index x has the value of from about 10 to about 500.
  • the index y has the value of from about 10 to about 100.
  • R'" is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenyl, a continuation of the chain by branching, or mixtures or mixtures; u has the value of from about 3 to 100.
  • the molecular weight of a polymeric component which comprises a co-polymeric polyalkyleneoxy unit is such that the desired viscosity and solubility of the entire molecule fits the needs of the formulator.
  • units from (a) which comprise one or more linking units to enzyme inhibiting components may incorporate one or more hydrophilic units into the chain to increase the solubility of the final conjugate polymer.
  • any of the polymers described herein can be random co-polymers or block co-polymers. iii) a polysaccharide unit having the formula:
  • R 21 is hydrogen, C 1 -C 4 alkyl, and mixtures thereof; the indices r and s are each independently from 0 to 100.
  • the polysaccharide units of the present invention can be any mixture of 5 and 6-member ring sugar units, inter alia, sucrose, glucose, mannose, fructose, iii) a polyamine unit having the formula:
  • R is C2-C 12 linear alkylene, C 3 -C 12 branched alkylene, and mixtures thereof; preferably R is ethylene, 1,3-propylene, and 1 ,6-hexylene, more preferred is ethylene.
  • the indices j and k are such that the molecular weight of said polyamines does not exceed about 30,000 daltons. For example, for an entirely linear polyethyleneimine having a molecular weight of about 600 daltons, the index k is equal to 13 and j is equal to 0. For an entirely branched polyethyleneimine having a molecular weight of approximately 600 daltons, the index j is equal to 7.
  • the enzyme inhibiting component may be linked or directly bonded to any of the backbone nitrogen units.
  • the polymeric component of the present invention may be a mixture of one or more of the polymeric units described herein above.
  • the formulator may attach to the polymeric component of the polymer conjugate as many linking units as necessary to deliver the required number of enzyme inhibiting components.
  • One preferred permutation of admixtures of different components are star polymers as described in "Synthesis of Star-Shaped Poly(ethylene oxide)", Y.
  • the preferred polymer or copolymer unit [Poly] of the present invention are polyalkyleneoxy unit having the formula: R 19 (OR I8 ) x - and co-polymeric polyalkyleneoxy units having the formula:
  • R 19 is preferably methyl for conjugates which comprise one enzyme inhibitor component, R 19 is preferably hydroxyethyl for conjugates comprising two enzyme inhibitor components.
  • the preferred [Poly] units have the formulae:
  • R 18 is preferably ethylene and R 20 is preferably 2-propylene and when R 18 , OR 19 , and OR 20 are taken together the [Poly] unit has a molecular weight of from about 500 daltons, preferably from about 1000 daltons, more preferably from about 2000 daltons, most preferably from about 3000 daltons to about 10,000 daltons, preferably to about 8,000 daltons, more preferably to about 7500 daltons.
  • R 19 (OR 18 )x(OR 20 ) v — units are copolymer having random polymer units, for example, using EO for ethyleneoxy and PO for propyleneoxy, units having a formula:
  • Non-limiting examples of suitable polyalkyleneoxy polymers for use in the present invention include polyethyleneglycol having an average molecular weight of 1500 daltons (PEG1500), 4000 daltons (PEG 4000), polyethyleneglycol having an average molecular weight of 5000 daltons (PEG 5000), polyethyleneglycol methyl ether having an average molecular weight of 1500 daltons (MPEG 1500), polyethyleneglycol methyl ether having an average molecular weight of 4000 daltons (MPEG 4000), polyethyleneglycol methyl ether having an average molecular weigh of 5000 daltons (MPEG 5000), block co-polymers of polyethylene glycol and polypropylene glycol (EO/PO co-polymers, wherein said PO unit can be 1 , 2-propylene, 1,3- propylene, or mixtures thereof), for example Pluronics ® available ex BASF.
  • PO unit can be 1 , 2-propylene, 1,3- propylene, or mixtures thereof
  • conjugates which comprise multiple enzyme inhibitor components. This can be done by the formulator to increase the relative amount of inhibitor on a per weight basis of conjugate or to deliver multiple inhibitors per conjugate.
  • the following are non-limiting examples of polyhydroxy units which are suitable for this embodiment.
  • the enzyme inhibiting polymer conjugates of the present invention optionally, but preferably, comprise one or more linking units, L.
  • the conjugate may comprise more than one linking unit.
  • more than one type of linking unit may be present.
  • one type of linking unit may be convenient for one particular inhibitor component whereas a second unit is more compatible with a second type of heterocyclic enzyme inhibiting unit.
  • the linking units of the present invention may comprise any units capable of linking the enzyme inhibitor component to the polymer backbone. If the backbone is formed by random co- polymerization, the linking unit may be included.
  • the linking group may be attached via "grafting" to the polymer backbone.
  • Units which may conveniently serve as linking units are amino acids which have a carboxyl end and an amine end and which are capable of easy assembly into polymeric units (peptides). One or more amino acids taken together are a preferred means for linking the polymer unit and the enzyme inhibitor unit.
  • Preferred linking units of the present invention have the formula:
  • ⁇ (X) J [C(X)] k (X) J (R 11 ) n (X) J [C(X)] k (X) J ⁇ — is preferably a repeatable unit, inter alia, amino acid, di-acid, wherein R 1 1 is Ci-C ⁇ substituted or unsubstituted alkylene; C 2 -C 12 substituted or unsubstituted alkenylene; C 3 -C ⁇ 2 cycloalkylene; substituted or unsubstituted aromatic; inter alia, 1 ,2-phenylene, 5-sulfo-l,3-phenylene, 1,4- phenylene; substituted or unsubstituted heterocyclic, non-limiting examples of which include benzimidazole, benzimidazolone, pyridine, piperazine, pyrroline, imidazoline, imidazole, morpholine, oxazole, tetrazole, lH-indenedione,
  • R 1 ' units can be substituted or unsubstituted with any of the herein above defined -R 8 R 9 units.
  • X is oxygen, sulfur, NR 10 wherein R 10 is hydrogen, C 1 -C 4 alkyl, phenyl, or R 10 can be taken as part of a ring bonded to another moiety in the linking group, for example, a propylene unit forming a ring between the nitrogen and R 1 ' as in the formula:
  • indices h, j, and k are each independently 0 or 1.
  • amino acids are a suitable and a preferred class of linking units, either alone, in combination with other amino acids, or other R 1 ' units.
  • the index f has the value from 0 to 10.
  • An example of a linking unit comprising a repeatable unit (amino acid) wherein the index f greater than 1 is a linking unit having the general formula:
  • the preferred linking units of the present invention comprise one or more units selected from the group consisting of: i) -(CH 2 ) P -, wherein p is from 0 to 12; ⁇ ) -C(O)-; iii) -C(X)NR 10 -, wherein R 10 is hydrogen, C ⁇ -C alkyl, or mixtures thereof; wherein
  • X is oxygen, sulfur, NR 10 , and mixtures thereof; iv) -C(X)R' 'C(X)-, wherein R 1 ' is C C ⁇ 2 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; wherein X is oxygen, sulfur, NR 10 , and mixtures thereof; v) -C(X)NR' °C(X)-, wherein R 1 ° is hydrogen, C , -C 4 alkyl, or mixtures thereof; wherein X is oxygen, sulfur, NR 10 , and mixtures thereof; vi) -C(X)NR 10 R' 'NR 10 C(X)-, wherein R 10 is hydrogen, C,-C 4 alkyl, or mixtures thereof; R ⁇ is -C 12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; wherein X is oxygen, sulfur, NR 10 , and mixtures thereof; vii) -NR 10 C
  • X is oxygen, sulfur, NR 10 , and mixtures thereof; viii) -NR 10 C(X)NR 10 -, wherein R 10 is hydrogen, C r C 4 alkyl, or mixtures thereof; wherein X is oxygen, sulfur, NR 10 , and mixtures thereof; ix) -NR 10 C(X)R' 'NR 10 -, wherein R 10 is hydrogen, C,-C 4 alkyl, or mixtures thereof; R 11 is C 1 -C 12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; wherein X is oxygen, sulfur, NR 10 , and mixtures thereof; x) -NR'V 'C(X)NR 10 -, wherein R 10 is hydrogen, C C 4 alkyl, or mixtures thereof; R 11 is C 1 -C 12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; wherein X is oxygen, sulfur, NR 10 , and mixtures thereof
  • R 11 is C 1 -C 12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; wherein X is oxygen, sulfur, NR 10 , and mixtures thereof; xv) -R 1 1 NR'°C(X)NR 10 R 1 '-, wherein R 10 is hydrogen, C,-C 4 alkyl, or mixtures thereof; R 11 is -C 12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; wherein X is oxygen, sulfur, NR 10 , and mixtures thereof; xvi) -NR 10 -, wherein R 10 is hydrogen, -C alkyl, or mixtures thereof; xvii) -0-; xviii) -(R 1 '),C(X)(R' '),-; wherein t is 0 or 1 ; wherein X is oxygen, sulfur, NR 10 , and mixtures thereof; xix) -(R 1 l ) t
  • More preferred L units according to the present invention include: i) -C(O)-; ii) -C(0)NH-; iii) -C(0)R ⁇ C(0)-, wherein R 11 is methylene, ethylene, propylene, butylene, or mixtures thereof; iv) -C(0)NHC(0)-; v) -C(0)NHR u NHC(0)- wherein R 11 is methylene, ethylene, propylene, butylene, or mixtures thereof; vi) -NHC(O)-; vii) -NHC(0)NH-; viii) -C(0)R u NH-, R ⁇ is C ⁇ -C ]2 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; ix) -NHR ⁇ C(0) -, R ⁇ is C 1 - 2 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; x) -NH-; x
  • Preferred enzyme inhibiting units are derivatives of N-hydroxymethylsaccharin.
  • an L unit serves as a leaving group which remains attached to the polymer component after the saccharin inhibitor component begins a series of reactions leading to irreversible binding to a target enzyme.
  • PEG 5000 is used to represent methoxy capped polyethylene glycol homopolymer having an average molecular weight of about 5000 daltons.
  • a preferred polymer conjugate having the approximate IUPAC name N-(PEG 5000)- terephthalamic acid l,l,3-trioxo-l,3-dihydro-l ⁇ 6 -benzo[ ⁇ i]isothiazol-2-ylmethyl ester, comprises an N-methylenesaccharin enzyme inhibiting component linked by a (xi) linking unit, - NR 10 C(X)R n C(X)O-, wherein R 10 is hydrogen; R 11 is unsubstituted phenylene; each X is oxygen; to a polyethyleneglycol polymer component having an average molecular weight of about 5000 daltons, said polymer conjugate having the formula:
  • Another preferred polymer conjugate exemplifying a preferred R unit and which comprises the same linking unit and polymer component has the formula:
  • Another preferred polymer conjugate having the approximate IUPAC name PEG 5000- carbamic acid 4-[5-(l,l,3-trioxo-l ,3-dihydro-l ⁇ 6 -benzo[ ⁇ jisothiazol-2-ylmethylsulfanyl)-tetrazol- l-yl]-phenyl ester, comprises a phenyl moiety and tetrazole moiety as the R 1 1 unit, said polymer conjugate having the formula:
  • Another preferred polymer conjugate having the approximate IUPAC name N-(PEG 5000 propanoyl)-tranexamic acid l,l,3-trioxo-l,3-dihydro-l ⁇ 6 -benzo[ ]isothiazol-2-ylmethyl ester, comprises a cyclohexylene and methylene moiety combination as the R 11 unit, said polymer conjugate having the formula:
  • the mono-PEG 5000 hemiamide from above (0.27 g, 0.05 mmol) is combined with N- bromomethyl saccharin (0.14 g, 0.5 mmol) in acetonitrile (10 mL).
  • Triethylamine (0.11 g, 1 mmol) is added and the reaction gently heated to 40 °C for 2 hours then stirred at room temperature for 18 hours.
  • the reaction solution is diluted with ether and the resulting solid collected by filtration. Recrystallization from ethanol yields the desired terephthalate amide-ester which is used without further purification.
  • the solvent is removed under reduced pressure, the residue partitioned between ethyl acetate and water, and the organic phase concentrated to afford the saccharin tranexamic acid condensation product.
  • the condensate from the preceding step is charged to a 25% solution of trifluoroacetic acid in methylene chloride (5 mL) and is stirred for 2 hours.
  • the solvent is removed under reduced pressure and the resulting oil digested in and HCl/ether solution to afford the de-protected condensation product.
  • the de-protected condensation product as the HCl salt (0.035 g, 0.1 mmol), PEG 5000 propionic acid (1 g, 0.2 mmol) and DMF (5 mL) are combined in a reaction vessel together with triethylamine (0.015 mL, 0,01 lg, 0.1 1 mmol).
  • Dicyclohexylcarbodiimide (0.021 g, 0.1 mmol) is added.
  • the reaction is stirred 18 hours after which time cold ether is added and the resulting precipitate is collected by filtration. Recrystallization from ethanol affords the desired saccharin polymer conjugate.
  • the polymer conjugates of the present invention are effective in treating and/or preventing one or more skin conditions, including irritation, resulting from the contact of enzymes with skin, inter alia, diaper rash.
  • One effective means for delivering the stable conjugates to skin is via an article of manufacture, preferably an "absorbent article".
  • absorbent articles include sanitary napkins, panty liners, diapers, incontinence briefs, training briefs.
  • the polymer conjugates of the present invention are formulated into a skin- compatible carrier which serves to solublized the conjugate in addition to providing a vehicle for uniform delivery of the enzyme inhibitor to the skin surface.
  • a skin- compatible carrier which serves to solublized the conjugate in addition to providing a vehicle for uniform delivery of the enzyme inhibitor to the skin surface.
  • the formulator of articles of manufacture which employ the enzyme inhibiting conjugates of the present invention will recognize the vehicle may take any form, inter alia, aqueous, non-aqueous, dry powder.
  • the amount of polymer conjugate which is present in the formulation depends upon the embodiment chosen by the formulator.
  • the polymer component of the conjugate itself may have properties which allow for the direct application of the conjugate without the need for a vehicle.
  • the conjugate when incorporated as part of a composition, will comprise from about 0.01%o, preferably from about 1% to about 20%, preferably to about 10% by weight, of the delivery vehicle.
  • the compounds of the present invention may be tested in a standard enzyme assay for protease activity, as follows:
  • Infant feces are collected in a manner to keep them free from urine contamination and mixed with water to obtain a weight by weight (w/w) mixture (e.g., 1 :4 w/w). This mixture is then mixed thoroughly to obtain a homogeneous suspension by homogenization or sonication. The feces are then diluted with a reaction buffer, described below, to obtain a fecal concentration which, when added to a protease substrate, hydrolyzes the substrate over a 5 to 60 minute period.
  • w/w weight by weight
  • fecal trypsin activity may be determined at pH 8.2 in a 50 nM Tris-HCl buffer with 20 mM CaCl2, containing 0.3 mM of the composition to be tested; fecal chymotrypsin activity at pH 7.6 in a 50 mM Tris-HCl buffer with 20 mM CaCl2, containing 0.05 mM of the composition to be tested; and fecal leucine aminopeptidase activity at pH 7.2 in 50 mM sodium phosphate containing the composition to be tested.
  • each putative inhibitory composition is added to duplicate feces-containing reaction buffers, and the inhibition of the enzyme activity is measured.
  • Compounds having an IC50 of 100 ⁇ M or less are preferred compounds of the invention. More preferred are compounds having an IC50 to IC90, and most preferably an ICso to IC90, of 100 ⁇ M or less.
  • An in vitro method to determine the efficacy of the compounds of the present invention in preventing the proinflammatory response of the skin to feces and fecal enzymes may be performed as follows:
  • Human keratinocytes are obtained from epidermal tissue and cultured in serum-free medium in plastic culture vessels containing a nylon mesh surface for a period of time until they are confluent. The mesh surface is then raised to the liquid air interface in order to promote differentiation and formation of multilayered organized layers analogous to those found in vivo, including a well defined stratum corneum barrier. Any cell culture system that promotes the growth and differentiation of keratinocytes, as described, may be employed. A commercially
  • Infant feces are collected in a manner to keep them free of urine contamination and diluted with phosphate-buffered saline (PBS) (pH 7.2 - 7.4). The mixture is then mixed thoroughly to obtain a homogenous suspension by homogenization or sonication.
  • PBS phosphate-buffered saline
  • To assay for IL- 1 ⁇ production due to fecal enzyme activity an aliquot of the homogenate is diluted with PBS and added to the surface of a control culture in a culture vessel.
  • a predetermined quantity of a putative inhibitor (compound) is added to an otherwise identical diluted aliquot of the homogenate prior to adding it to the surface of a test culture.
  • the cultures are allowed to incubate in a controlled atmosphere. At selected times, the control cultures and inhibitor-treated test cultures, and the underlying culture media are harvested. The culture media are assayed for the presence of IL-l ⁇ by known methods. For example, a suitable assay for IL- 1 ⁇ is an enzyme-linked immunoabsorbent method
  • the percent reduction in IL- 1 ⁇ production due to the presence of the compound (inhibitor) is calculated as follows:
  • the polymer conjugates of the present invention are effective in treating and/or preventing one or more skin conditions, including irritation, resulting from the contact of enzymes with skin, inter alia, diaper rash.
  • One effective means for delivering the stable conjugates to skin is via an article of manufacture, preferably an "absorbent article".
  • absorbent articles include sanitary napkins, panty liners, diapers, incontinence briefs, training briefs.
  • the formulator can add to the compositions of the present invention one or more "adjunct biologically active ingredients" to adjust the properties of the composition or to serve as an aid, inter alia, to healing of skin, booster to enzyme inhibition.
  • the adjunct biologically active ingredients comprise from about 0.01%, preferably from about 0.05%, more preferably from about 0.1% to about 5%, preferably to about 2%, more preferably to about 1% by weight, of said composition.
  • a non-limiting example of a biologically active adjunct ingredient is hexamidine, 4,4'-
  • Hexamidine is preferred as an adjunct to the polymer conjugates of the present invention. Without being limited by theory or application, hexamidine has multiple properties ascribed thereto, inter alia, as a topical antiseptic: Bordeaux Med., M. J. Fenelon, 3, 867 (1970); as an antibacterial: J. Int. Med. Res., G. Micheal et al., 14, 205 (1986).
  • Hexamidine is preferably delivered as the diisethionate as Elestab HP 100 ® available ex Rhone-Poulenc; inter alia, as RF 2535, Desomedine, Esomedine, Hexomedine, Ophtamedine.
  • the conjugates of the present invention may be formulated as ointments, creams, lotions, etc. which can be directly applied or delivered via an article of manufacture, inter alia, a diaper.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or colorizing agents.
  • the polymer conjugates of the present invention are formulated into a skin- compatible carrier which serves to solublized the conjugate in addition to providing a vehicle for uniform delivery of the enzyme inhibitor to the skin surface.
  • a skin- compatible carrier which serves to solublized the conjugate in addition to providing a vehicle for uniform delivery of the enzyme inhibitor to the skin surface.
  • the formulator of articles of manufacture which employ the enzyme inhibiting conjugates of the present invention will recognize the vehicle may take any form, inter alia, aqueous, non-aqueous, dry powder.
  • the amount of polymer conjugate which is present in the formulation depends upon the embodiment chosen by the formulator.
  • the polymer component of the conjugate itself may have properties which allow for the direct application of the conjugate without the need for a vehicle.
  • the conjugate when incorporated as part of a composition which comprises only polymer conjugate and a delivery vehicle, the conjugate will typically comprise from about 0.01%, preferably from about 1% to about 20%, preferably to about 10% by weight, of the delivery vehicle.
  • compositions of the present invention will preferably comprise one or more adjunct ingredients which include carriers.
  • carriers is used interchangeably with the term “emollients", "lotion base”, etc.
  • the formulator will recognize that certain carriers will have an emollient property or can serve more than one function.
  • the compositions of the present invention comprise from about 1%, preferably from about 5%, more preferably from about 10% to about 99%, preferably to about 95%, more preferably to about 80%, most preferably to about 50% by weight, of one or more carriers.
  • Non- limiting examples of carriers include petroleum-based emollients, sucrose ester fatty acids, polyethylene glycol and derivatives thereof, humectants, fatty acid ester type, alkyl ethoxylate type, fatty acid ester ethoxylates, fatty alcohol type, polysiloxane type, propylene glycol and derivatives thereof, glycerin and derivatives thereof, including glyceride, acetoglycerides, and ethoxylated glycerides of C ⁇ 2 -C 22 fatty acids, triethylene glycol and derivatives thereof, spermaceti or other waxes, fatty acids, fatty alcohol ethers, propoxylated fatty alcohols, other fatty esters of polyhydroxy alcohols, lanolin, kaolin, any of the Federally monographed commercially available skin care.
  • Suitable petroleum-based emollients include C 1 -C 32 hydrocarbons, including paraffins, include mineral oil and petrolatum
  • compositions of the present invention typically comprises, other than carriers, other adjunct ingredients.
  • other preferred adjunct ingredients include water, viscosity modifiers, perfumes, disinfectant antibacterial actives, antiviral agents, vitamins, pharmaceutical actives, film formers, deodorants, opacifiers, astringents, solvents, preservatives, viscosity modifiers, and mixtures thereof.
  • Water-based skin care carriers and compositions may optionally comprise a preservative, non-limiting examples or which include propyl paraben, methyl paraben, benzyl alcohol, benzalkonium, tribasic calcium phosphate, BHT, or acids such as citric, tartaric, maleic, lactic, malic, benzoic, salicylic, and mixtures thereof.
  • a preferred use of the polymer conjugates of the present invention is for treatment or prevention of skin irritation from exposure to human feces as it relates to diaper rash and other articles of manufacture used to contain human waste.
  • the polymer conjugates of the present invention inhibit proteolytic and/or Hpolytic enzymes whether endogenous or exogenous. Therefore the formulator can employ the conjugates of the present invention in any embodiment which has the purpose of modulating or prevent the effects of exposure to said enzymes.
  • the formulations can have a variety of other uses, non-limiting examples of which include applying the compositions to cotton swabs wherein the compositions are applied to area where enzyme activity is to be inhibited or modulated (i.e., nasal canal, throat), applying the compositions to facial tissues or wipes for application to any skin surface or orifice, inter alia, nasal passage, ocular region.
  • area where enzyme activity is to be inhibited or modulated i.e., nasal canal, throat
  • facial tissues or wipes for application to any skin surface or orifice, inter alia, nasal passage, ocular region.
  • a composition for inhibiting enzymes on human skin comprising: a) from about 0.01%, preferably from about 0.5%, more preferably from about 1%, most preferably from about 1.5% to about 10%, preferably to about 7.5%, more preferably to about 5% by weight, of one or more polymer conjugates having the formula:
  • a composition for application to human skin comprising: a) from about 0.01%, preferably from about 0.5%, more preferably from about 1%, most preferably from about 1.5% to about 10%, preferably to about 7.5%, more preferably to about 5% by weight, of one or more polymer conjugates having the formula: T— (L) z — [Poly] wherein T is a saccharin ring-comprising enzyme inhibitor component, L is a linking unit, [Poly] is a polymer component, z is 0 or 1 ; b) from about 0.01%, preferably from about 0.05%), more preferably from about 0.1%) to about 5%, preferably to about 2%, more preferably to about 1% by weight, of an adjunct biologically active ingredient, preferably hexamidine; and c) the balance carriers and adjunct ingredients.
  • T is a saccharin ring-comprising enzyme inhibitor component
  • L is a linking unit
  • [Poly] is a polymer component
  • z is 0
  • a composition for application to human skin comprising: a) from about 0.01%, preferably from about 0.5%, more preferably from about 1%, most preferably from about 1.5% to about 10%, preferably to about 7.5%, more preferably to about 5% by weight, of one or more polymer conjugates having the formula:
  • a composition for inhibiting enzymes on human skin comprising: a) from about 0.01%, preferably from about 0.5%, more preferably from about 1%, most preferably from about 1.5% to about 10%, preferably to about 7.5%, more preferably to about 5% by weight, of one or more polymer conjugates having the formula:
  • composition comprising a polymer conjugate according to the present invention which is suitable for use in an absorbent article.
  • compositions of the present invention can also be delivered to skin via compositions which provide other primary benefits.
  • Skin Cleansers
  • the present invention also comprises a method for the treatment and prevention of diaper rash and diaper dermatitis caused by the prolonged contact of human skin with body waste.
  • the present invention also ameliorates and serves as a prophylactic means to prevent the occurrence of said skin irritation by providing a barrier against unwanted protease or lipolase enzymes.
  • the method of the present invention comprises the step of contacting human skin with a composition comprising: a) an effective amount, preferably from about 0.1%, more preferably from about 1% by weight, of a polymer conjugate according to the present invention; and b) the balance carriers and adjunct ingredients; wherein said composition is optionally, but preferably, applied to a substrate, inter alia, diaper topsheet, sanitary napkin.
  • the methods of the present invention are carried out a pH which is compatible with the skin of the user.
  • the methods of the present invention also include contacting human skin with an ingredient which provides an additional benefit to the user, inter alia, provides conditioning to the exposed skin.
  • the methods of the present invention deliver an "effective amount" of the compositions, which is the minimum inhibitory concentration of the selected enzyme inhibitor, to the skin.
  • an effective amount of the compositions, which is the minimum inhibitory concentration of the selected enzyme inhibitor, to the skin.
  • any amount may be delivered by the formulator.

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Abstract

La présente invention concerne des conjugués polymères inhibiteurs d'enzymes, de préférence un conjugué polymère ayant la formule (I) dans laquelle R représente une unité dont le rôle est d'atténuer l'interaction entre le constituant inhibiteur saccharine avec une enzyme ciblée, L représente un groupe de liaison; [Poly] représente une unité polymère, i indique le nombre desdites unités de saccharine constituant ledit conjugué et ayant une valeur comprise entre 1 et 100; z représente 0 ou 1; lesdits conjugués polymères étant adaptés à une utilisation dans la prévention de l'irritation de la peau résultant de l'exposition de la peau aux liquides biologiques, inter alia, les matières fécales, le fluide menstruel. Les conjugués de la présente invention sont utiles dans des couches, des pansements, des serviettes hygiéniques et analogue.
EP00960051A 1999-09-10 2000-09-08 Inhibiteurs d'enzymes Withdrawn EP1212034A1 (fr)

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JP5020451B2 (ja) * 1999-09-10 2012-09-05 ザ プロクター アンド ギャンブル カンパニー 酵素インヒビター
WO2001018181A2 (fr) * 1999-09-10 2001-03-15 The Procter & Gamble Company Inhibiteurs d'enzymes
DE60233315D1 (de) * 2001-03-23 2009-09-24 Enzon Inc Prodrugs von krebsmitteln mit substituierten aromatischen säuren
US8907154B2 (en) 2001-10-01 2014-12-09 The Procter & Gamble Company Sanitary napkins with hydrophobic lotions
GB0129987D0 (en) * 2001-12-14 2002-02-06 Zylepsis Ltd Skin compositions

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US5306818A (en) * 1990-11-01 1994-04-26 Sterling Winthrop Inc. Tetrahydro 2-saccharinylmerthyl aryl carboxylates
AU656027B2 (en) * 1991-11-15 1995-01-19 Sanofi Saccharin derivative proteolytic enzime inhibitors
US6066673A (en) * 1998-03-12 2000-05-23 The Procter & Gamble Company Enzyme inhibitors

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