WO2001018181A2 - Enzyme inhibitors - Google Patents
Enzyme inhibitors Download PDFInfo
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- WO2001018181A2 WO2001018181A2 PCT/US2000/024713 US0024713W WO0118181A2 WO 2001018181 A2 WO2001018181 A2 WO 2001018181A2 US 0024713 W US0024713 W US 0024713W WO 0118181 A2 WO0118181 A2 WO 0118181A2
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- 0 CC12C(CC*3)(CC4)C3C4CC1C2 Chemical compound CC12C(CC*3)(CC4)C3C4CC1C2 0.000 description 2
- LQNXSMLXSOPDKU-UHFFFAOYSA-N O=C1OC=NCC1 Chemical compound O=C1OC=NCC1 LQNXSMLXSOPDKU-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- 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
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- 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
Definitions
- the present invention relates to novel functional polymer conjugates which inhibit one or more proteolytic and/or lipolytic enzymes.
- the polymer conjugates described herein are suitable for use in any context wherein proteolytic and/or lipolytic 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 lipolytic enzymes, inter alia, trypsin, chymotrypsin, elastase, pancreatic lipase, which comprise human feces.
- endogenic proteolytic and/or lipolytic enzymes inter alia, trypsin, chymotrypsin, elastase, pancreatic lipase, which comprise human feces.
- skin irritation is not limited to enzymes which comprise feces, for example, menstrual fluids, nasal fluids, colostomy fluids, dandruff, wound healing may all provide a source of enzymes which produce irritation.
- Proteolytic and lipolytic enzyme inhibitors are known.
- An example of effective 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 catabolism can be interrupted.
- the present invention meets the aforementioned needs in that it has been surprisingly discovered that proteolytic and/or lipolytic enzyme inhibitors can be effectively delivered to human skin where said inhibitors can function as a barrier to enzyme activity thereby preventing diaper rash or other unwanted skin conditions.
- 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 an acyl unit which reversibly reacts with a protease or lipase enzyme.
- the inhibitor components of the present invention function as broadly specific enzyme inhibitors, that is the inhibitors do not bind so specifically to one type of enzyme that the inhibitors are not available for interaction with other enzymes which are present. It has been surprisingly discovered that non-specific protease inhibitors provide broader protection against skin irritation than enzyme-specific inhibitors, because these enzyme specific inhibitors are ineffective against other enzymes which may be present and which contribute to skin irritation.
- a first aspect of the present invention relates to polymer conjugate which inhibits protease or lipase enzyme, said polymer conjugate comprising a polymer component bonded to an enzyme inhibitor component having an acyl unit capable of inhibiting the activity of one or more protease or lipase enzymes, wherein said inhibitor component is directly bonded to said polymer component or is attached thereto by a linking unit, said linking unit optionally capable of modulating the interaction between a target enzyme and said inhibitor component, and wherein further said polymer component remains bonded to said inhibitor component after said acyl unit interacts with said target enzyme.
- the inhibitor component is either bonded directly to said polymer component or connected by way of a linking unit, said linking unit also preferably capable of modulating the interaction between the target enzyme and said inhibitor component.
- said linking unit also interacts with said enzyme, the polymer component also remains bonded to the inhibitor component.
- the inhibitors of the present invention interact with the target enzymes by way of an acyl unit.
- this interaction between a target enzyme and acyl group does not result in the enzyme inhibitor portion being cleaved from the polymeric backbone to which it is attached. Instead, even after the enzyme inhibitor component and target enzyme have formed an enzyme/substrate pair, the inhibitor component remains linked to the polymer component.
- the present invention further relates to a functionahzed polymer component comprising 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 functionahzed polymer component by one or more linking groups.
- 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 lipolytic 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 lipolytic enzymes with skin.
- skin conditions inter alia, rash, irritation
- proteolytic and/or lipolytic enzymes with skin.
- 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 an enzyme inhibitor component and a functionahzed polymer component.
- the primary means by which the enzyme inhibitor component interacts with an enzyme is by way of an acyl unit, however, other moieties which comprise the conjugate can serve to modulate enzyme/substrate interaction.
- the acyl unit can be activated towards interaction with the enzyme or the acyl unit can be masked which results in reduced availability of the acyl unit and therefore reduced interaction with unwanted substrates.
- the enzyme inhibitors of the present invention are preferably broad spectrum in their ability to inhibit enzymes.
- the term "broad spectrum” is defined herein as "an inhibitor which will bind to more than one enzyme and which does not bind to one particular enzyme in so strongly a manner as to exclude the binding of said inhibitor with other enzymes which are present.
- acyl unit is defined herein as "a carbonyl comprising unit which may be in one or more precursor forms, inter alia, as a member of a ring, as an anhydride. " Preferred acyl units are esters and aldehydes, more preferably esters.
- the enzyme inhibitor component of the present invention is bonded to a polymer component.
- the enzyme inhibitor component can be bonded directly to the polymer component or it can be bonded to the polymer component by means of a linking unit, preferably a linking unit which participates in the interaction of the inhibitor component with a target enzyme.
- the linking unit facilitates interaction of the enzyme and inhibitor by "modulating" the interaction between the enzyme and inhibitor.
- modulating or modulate can have one or more meanings, however, one non-limiting example of this term is "facilitating the alignment of the inhibitor component into the enzyme active site”. Another equally suitable meaning for these terms relates to "providing a means by which the interaction between the inhibitor component and a target enzyme is modified, inter alia, strengthened, weakened, abated, prolonged".
- the enzyme inhibitor component of the present invention further comprises a unit or moiety which enhances the "broadness” or “range” of the enzyme inhibition or has the capacity to strengthen the interaction between the parent inhibitor and the target enzyme.
- the conjugates of the present invention further comprise a functionahzed polymer component which acts as a delivery template for one or more enzyme inhibitor components while serving other important function, inter alia, providing a means for anchoring the conjugate molecule to human skin, solublizing the conjugate into a carrier.
- the functionahzed 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 "selected" linking unit.
- a “selected” linking unit is one which when coupled with a particular enzyme inhibitor component, enhances the desired activity of said inhibitor.
- the polymer component also provides the conjugate with a source of increased molecular weight which acts to inhibit the abso ⁇ tion 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 directly to skin or by way of a substrate, diaper top sheet, inter alia, to which the conjugate is applied.
- 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 tests which differentiate the specificity of said enzyme inhibitor, for example, which differentiate the particular proteases obstructed by said inhibitor.
- the enzyme inhibitor component of the present invention comprises one or more units which have at least one acyl unit, preferably the acyl unit is a masked acyl unit.
- the preferred acyl units of the present invention are ester units and aldehyde units, more preferred are esters whether linear or part of a ring (cyclic esters).
- the term "masked acyl unit" is understood to be an acyl unit which is reactive towards an enzyme, for example, the serine hydroxyl unit of protease enzyme active sites, but not to common substrates, inter alia, water, alcohol.
- Linear Enzyme Inhibitors for example, the serine hydroxyl unit of protease enzyme active sites, but not to common substrates, inter alia, water, alcohol.
- One embodiment of the present invention relates to "linear" enzyme inhibitors having the general formula:
- [Inhibitor],, • (L) z -[Poly] y wherein [Inhibitor] is an enzyme inhibiting functionality; L is a linking unit; [Poly] is a polymer component; the indices have the following values: x is from 1 to 50, y is from 1 to 10, z is 0 or 1.
- the polymer conjugates of the present invention may comprise a single enzyme inhibiting unit having multiple polymer units attached thereto, multiple inhibiting functionalities attached to a single polymer component, or mixtures thereof.
- the preferred linear polymer conjugates of the present invention comprise an inhibitor wherein an acyl unit, [Acyl], is attached to a template, T.
- the template, T may serve one or more functions as described herein below.
- the preferred linear polymer conjugates have the formula:
- the acyl units of the present invention comprise one or more enzyme modulating units [Mod]- which serve to modulate the reactivity of the acyl unit towards a target enzyme.
- a preferred example of a linear enzyme inhibitor acyl unit which does not comprise a [Mod] unit is -C0 2 " (carboxylate).
- Non-limiting examples of acyl units which also comprise a [Mod] unit include: a) esters; b) aldehydes; c) acetals; d) ketones; e) ketals; f) thioesters; g) thioacetals; h) anhydrides; i) and mixtures thereof.
- [Mod] units are preferably C C ⁇ 2 alkyl units, more preferably C C alkyl units.
- Further examples include polymer conjugates having the formula:
- [Mod] is hydrogen for aldehydes acyl units and [Mod] is an alkyl unit for ketone acyl units.
- acyl units include masked acyl units, inter alia, acetals, orthoesters having the formula:
- the preferred linear polymer conjugates of the present invention have the formula:
- each [Mod] is independently selected from: a) hydrogen; b) Ci-Cjg substituted or unsubstituted, linear or branched alkyl; preferably CpCg linear unsubstituted alkyl; more preferably C C 4 alkyl, inter alia, methyl and ethyl; c) C 3 -C 1 8 substituted or unsubstituted, cycloalkyl; preferably C 6 -C ⁇ o unsubstituted cycloalkyl; d) C 2 -C 18 substituted or unsubstituted, linear or branched alkenyl; e) C 2 -C 18 substituted or unsubstituted, linear or branched alkynyl; f) C 6 -C 18 substituted or unsubstituted aryl; and g) a unit which is tied back to said T unit to form a ring comprising from 1 to 5 carbon atoms; and h) mixtures thereof; wherein
- the inhibitor component, T may comprise one or more units, as described herein below, which also serve to modulate the specificity of the inhibitor for a particular substrate.
- the polymer conjugates of the present invention may comprise one or more inhibitor components. When multiple inhibitors are present, they are preferably not suicide inhibitors, but reversible inhibitors. If an inhibitor irreversibly binds to an enzyme, the size of the bound enzyme may serve to occlude the binding of other enzymes to the remaining inhibitor components.
- T units which comprise the linear polymer conjugates according to the present invention are selected from the group consisting of: a) substituted or unsubstituted, linear or branched C -C 22 alkylene; b) substituted or unsubstituted, linear or branched C -C 22 alkenylene; c) substituted or unsubstituted C6-C 22 cycloalkylene; d) substituted or unsubstituted C6-C 22 heterocyclic alkylene; e) substituted or unsubstituted C 6 -C 22 arylene; f) substituted or unsubstituted C7-C 22 alkylarylene; g) esters, carbonates, amides, ureas, or carbamates having the formula:
- R— (X)a-C— (X) a -R 2 wherein R 1 is selected from the group consisting of: i) substituted or unsubstituted, linear or branched C 1 -C 2 alkylene; ii) substituted or unsubstituted, linear or branched C 2 -C 22 alkenylene; iii) substituted or unsubstituted C -C 22 cycloalkylene; iv) substituted or unsubstituted C 6 -C 22 heterocyclic alkylene; v) substituted or unsubstituted C 6 -C 22 arylene; vi) substituted or unsubstituted C7-C 22 alkylarylene; R 2 is selected from the group consisting of: i) substituted or unsubstituted, linear or branched C C 22 alkyl; ii) substituted or unsubstituted, linear or branched C 2 -C 22 alkenyl;
- the carbonyl unit of said ester, carbonate, amide, urea, or carbamate is not the acyl unit which comprises the [Acyl] unit which is the point of primary interaction with the target enzyme, but said carbonyl unit would have the capacity to provide enzyme interaction if designed to do so by the formulator.
- D is oxygen which when taken together with the two adjacent carbonyl units forms a linear anhydride which after interaction with a target enzyme, releases a second, un-associated, polymer conjugate.
- each T, L, and [Poly] be the same for both polymer conjugates which form the dimer.
- the formulator can make use of the differential reactivity of enzymes and acyl units to deliver protease and/or lipase inhibitors of differing inhibition characteristics by using the linear "enzyme inhibition dimer" polymer conjugates of the present invention.
- Protease and/or lipase inhibitors which have the acyl unit as part of a ring are a preferred embodiment of the present invention.
- an acyl unit which is part of a ⁇ -lactone is used to exemplify "acyl unit-containing rings".
- acyl unit which is part of a ring.
- the units R', R", or R'" may represent a bond to the inhibitor component, a linking unit, or a polymer component.
- the inhibitor component remains bound to the polymer component after the acyl unit has interacted with the target enzyme thereby providing a polymer component bonded enzyme inhibitor.
- a ⁇ -lactone polymer conjugate of the present invention having the general formula:
- This same 4-guan ⁇ d ⁇ nobenzoate enzyme inhibition unit can be su ⁇ singly inco ⁇ orated into a polymer conjugate according to the present invention wherein the inhibitor is free to interact with the enzyme via the acyl unit, but the inhibitor remains tethered to the polymer component
- the inhibition unit can be formed into a heterocycle having the formula
- the formulator may make further use of this acyl unit containing ring Any T unit which comprises the ring system having the formula
- Non-limiting examples of other fused rings wherein X is selected from the group consisting of X is CH 2 , NH, O, S, CF 2 , and mixtures thereof; and each D, E, F, and G is independently selected from the group consisting of CH, CH 2 , N, NH, O, S, CF 2 , and mixtures thereof include: i)
- Preferred T units include: i)
- the T units may be linked to the polymer component in any manner which the formulator prefers, for example the most preferred units are the 4H-3,l-benzoxazin-4-one heterocycles having the formula:
- the formulator can equally well attach more than one polymer component to an inhibitor component, for example the polymer conjugate having the formula:
- acyl unit comprising ring systems which are suitable for use in the present invention include: i)
- the enzyme inhibition components of the present invention further comprises one or more enzyme differentiating units, R.
- R units are: a) hydrogen; b) C 1 -C 18 substituted or unsubstituted, linear or branched alkyl; preferably -Cs linear unsubstituted alkyl, inter alia, methyl and ethyl, especially when the enzyme inhibitor component comprises a benzoxazin-4-one moiety.
- R 4 is hydrogen, -C 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; 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 12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR 10 , and mixtures thereof; v) -C(X)NR 10 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 10 is hydrogen,
- R 12 is C 2 -C linear or branched alkylene, substituted or unsubstituted phenylene;
- R 13 is -(CH ) P -, wherein p is from 0 to 12; q is from 1 to 4; xxii) -S-; xxiii) -(R"),S(R") r ; wherein R 11 is C r C 12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxiv) -(R u ) t S(0)(R n ) r ; wherein R" is -C 12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; t is 0 or 1 ; xxv) -(R 11 ) t S0 2 (R 11 ) t -; wherein R 11 is C ⁇ -C, 2 alkylene, substituted or unsubstitute
- R 9 is: i) hydrogen; ⁇ ) C 1 -C 18 substituted or unsubstituted, linear or branched alkyl; iii) C 3 -C 18 substituted or unsubstituted, linear or branched cycloalkyl iv) C 2 -C 18 substituted or unsubstituted, linear or branched alkenyl; v) C 2 -C 18 substituted or unsubstituted, linear or branched alkynyl; vi) C ⁇ -Cis substituted or unsubstituted aryl; vii) C 2 -C 18 substituted or unsubstituted heterocyclic alkyl; viii) C 3 -C 18 substituted or unsubstituted heterocyclic alkenyl; ix) -OH; x) -SO,M; xi) -OSO 3 M; xii) -N0 2 ; xiii) halogen selected from fluorine
- R 4 is hydrogen, C 1 -C 4 alkyl, or mixtures thereof
- R 5 is hydrogen, C C 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, CpC 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
- xix) -NHOR 16 wherein R 16 is hydrogen; C 1 - 2 linear or branched alkyl; acyl having the formula -COR 17 , wherein R 17 is C C 4 alkyl; or mixtures thereof;
- xx a unit having the formula:
- R is hydrogen; CpC ⁇ linear or branched alkyl; C7-C22 linear or branched alkylenearyl; acyl having the formula -COR 17 , R 17 is C 1 -C4 alkyl; or mixtures thereof; xxi) an amino unit having the formula: (CH 2 ) m N(R 3 ) 2 wherein each R 3 is independently Cj-C 18 substituted or unsubstituted, linear or branched alkyl; m is from 0 to 10; xxii) a quaternary ammonium unit having the formula: (CH 2 ) m N(R 3 ) 3 Y - wherein each R 3 is independently C C ⁇ g substituted or unsubstituted, linear or branched alkyl; Y is an anion of sufficient charge to provide electronic neutrality; m is from 0 to 10; o) two R units on the same carbon atom can be taken together to form a carbonyl unit or carbony
- Preferred R units according to the present invention include: a) hydrogen; b) Cj-Cs 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.
- R 2 phenyl, substituted phenyl, pyridinyl, substituted pyridinyl; j) an amino unit having the formula: — N(R J ) 2 wherein each R 3 is independently hydrogen, methyl, ethyl, 2-hydroxyethyl, cyclopropyl; for example, methylamino, dimethylamino, ethylamino, diethylamino, dicyclopropyl; a unit having the formula:
- NR 5 wherein 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 -C 6 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) cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 2,5-dimethylcyclopentyl; v) phenyl, 4-methoxyphenyl, 4-nitrophenyl, 3-chlorophenyl, 4- chlorophenyl, 3,5-dichlorophenyl, 4-aminobenzyl, 4-guanidinobenzyl; vi) N-aziridinyl, 2-pyrrolindinyl, 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl; viii) -OH, when the index p is from 1 to 4, preferably when p is 1 ; ix) -SO 3 M when the index p is from 1 to 4, preferably when p is
- 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: — ( Rl )n " R 2 wherein R 1 is C 1 - 2 linear or branched alkylene, C 2 -C 12 linear or branched alkenylene, or mixtures thereof; R 2 C 6 -C ⁇ 8 substituted or unsubstituted aryl, C3-C 18 heteroaryl, or mixtures thereof; n is from 1 to 16.
- suitable heteroaryl units are 5-member rings which have the formula: or a 6-member ring having 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 inco ⁇ orated 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.
- 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 18 ) x - wherein R 18 is C 2 -C 12 linear alkylene, C 3 -C 12 branched alkylene, phenylene, C7- 2 alkylenearylene, and mixtures thereof; R 19 is hydrogen, C ⁇ -C ⁇ 8 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 -Cj 8 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 -C 12 branched alkylene, phenylene, C 7 -C 12 alkylenearylene, and mixtures thereof;
- R 19 is hydrogen, -Cig substituted or unsubstituted, linear or branched alkyl; C 3 -C ⁇ s substituted or unsubstituted, linear or branched cycloalkyl; C 2 -C 18 substituted or unsubstituted, linear or branched alkenyl; C 2 -C 18 substituted or unsubstituted, linear or branched alkynyl; C ⁇ -Cis substituted or unsubstituted aryl; and mixtures thereof;
- 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
- 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 mco ⁇ orate 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 in) a polysaccha ⁇ de unit having the formula
- the polysaccha ⁇ de units of the present invention can be any mixture of 5 and 6-member ring sugar units, inter aha, sucrose, glucose, mannose, fructose in) a polyamine unit having the formula
- R is C 2 -C 12 linear alkylene, C 3 - 2 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 polyammes does not exceed about 30,000 daltons
- the index k is equal to 13 and j is equal to 0
- the index j is equal to 7 (This combination of indices results in a material having an average molecular weight of about 646 daltons, which, for the pu ⁇ oses of the present invention is a low molecular weight polyalkyleneimine )
- the enzyme inhibiting component may be linked or directly
- the polymeric component of the present mvention 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. Gnanou, et al, Makromolecular Chemistry, Vol. 189 (1988) pp. 2885-2892, U.S. 5,648,506 Desai et al., issued July 15, 1997, each of which is inco ⁇ orated herein by reference.
- the preferred polymer or copolymer unit [Poly] of the present invention are polyalkyleneoxy unit having the formula:
- R 19 (OR 18 ) x - and co-polymeric polyalkyleneoxy units having the formula:
- R ⁇ OR ⁇ MOR 20 wherein R 19 is preferably methyl for conjugates which comprise one enzyme inhibitor component, R 1 is preferably hydroxyethyl for conjugates comprising two enzyme inhibitor components.
- R 19 is preferably methyl for conjugates which comprise one enzyme inhibitor component
- R 1 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 ), ⁇ (OR 20 ) y - units are copolymer having random polymer units, for example, using EO for ethyleneoxy and PO for propyleneoxy, units having a formula:
- x' + x" + x'" + y' + y" + y'" represent a copolymer having 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.
- Non-limiting examples of suitable polyalkyleneoxy polymers for use in the present invention include polyethyleneglycol having an average molecular weight of 1500 daltons (PEG 1500), 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. Also preferred are EO/PO/EO and PO/EO/PO co-polymers.
- One important embodiment of the present invention relates to 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 copolymerization, 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:
- R 1 1 is C Ci 2 substituted or unsubstituted alkylene; C 2 -C 12 substituted or unsubstituted alkenylene; C3- 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, mo ⁇ holine, oxazole, tetrazole, lH-indenedione, ox
- 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 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:
- any combination of repeatable units can be taken together to form a linking unit, for example, a linking unit having the 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 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 12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; X is oxygen, sulfur, NR 10 , and mixtures thereof; v) -C(X)NR 10 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(
- R 11 is C 1 -C 12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof;
- X is oxygen, sulfur, NR 10 , and mixtures thereof;
- R 11 is C 1 -C 12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof;
- X is oxygen, sulfur, NR 10 , and mixtures thereof;
- R 11 is C 1 -C 12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof;
- X is oxygen, sulfur, NR 10 , and mixtures thereof;
- R 1 1 is C 1 -C 12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof;
- X is oxygen, sulfur, NR 10 , and mixtures thereof;
- R 1 ' is C 1 -C 12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof;
- X is oxygen, sulfur, NR 10 , and mixtures thereof;
- R 1 1 is C 1 -C 12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof;
- X is oxygen, sulfur, NR 10 , and mixtures thereof;
- R 11 is C C ⁇ 2 alkylene, substituted or unsubstituted phenylene, or mixtures thereof;
- t
- More preferred L units according to the present invention include: i) -C(O)-; ii) -C(0)NH-; iii) -C(0)R u C(0)-, wherein R 11 is methylene, ethylene, propylene, butylene, or mixtures thereof; iv) -C(0)NHC(0)-; v) -C(0)NHR' 'NHC(O)- wherein R 1 ' is methylene, ethylene, propylene, butylene, or mixtures thereof; vi) -NHC(O)-; vii) -NHC(0)NH-; viii) -C(0)R ⁇ NH-, R 1 1 is C 1 -C 12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; ix) -NHR ⁇ C(0) -, R 1 1 is C 1 -C 12 alkylene, substituted or unsubstituted phenylene, or mixtures thereof; ix) -
- ketothiazole polymer conjugate having the formula:
- the polymer component being a random block copolymer of ethyleneoxy and propyleneoxy units.
- a further example of a preferred linear polymer conjugate has the formula:
- linear polymer conjugate is the ⁇ -ketoester having the formula: HNk ⁇ NH 2
- the [Poly] unit is an MPEG unit having the formula: wherein x has a value such that the molecular weight of the polymer component is from about 500 daltons to about 10,000 daltons.
- the [Mod] unit comprises a unit having the formula: and the [Acyl] unit has the formula:
- An example of a preferred polymer conjugate having an ester acyl unit masked in a ring comprises a 4H-benzoxazin-4-one heterocyclic unit wherein each R unit is hydrogen which is linked by an ethyleneimine unit to a polyethyleneglycol polymer component having an average molecular weight of about 5000 daltons having the formula:
- Another preferred polymer conjugate comprises a 4H-benzoxazin-4-one heterocyclic unit wherein each R unit is hydrogen which is linked by an N-ethylene-N'-phenylene urea unit to a polyethyleneglycol polymer component having an average molecular weight of about 5000 daltons having the formula:
- Another preferred polymer conjugate comprises a 4H-benzoxazin-4-one heterocyclic unit wherein one R unit is guanidinyl which is linked by an N-ethylene-N'-phenylene urea unit to a polyethyleneglycol polymer component having an average molecular weight of about 5000 daltons having the formula:
- Another preferred polymer conjugate comprises a 4H-benzoxazin-4-one heterocyclic unit wherein one R unit is methyl which is linked directly to a polyethyleneglycol polymer component having an average molecular weight of about 5000 daltons having the formula:
- Another preferred polymer conjugate comprises a thieno[3,2- ][l,3]oxazine-4-one heterocyclic unit wherein one R unit is methyl which is linked directly to a polyethylene-glycol polymer component having an average molecular weight of about 5000 daltons having the formula
- Methoxy polyethyleneglycol having an average molecular weight of about 5000 daltons (MPEG 5000) (50 g, 0.01 mol) is charged to a reaction vessel and dissolved in dichloromethane (125 mL). Under an inert atmosphere, a solution of phosgene in toluene (5.7 mL, 1.93 M) is added while cooling in ice. After addition, the ice bath is removed and the reaction mixture stirred for 12-18h under an inert atmosphere to form an MPEG 5000 chloroformate. In a separate flask, 2-amino-6-methylbenzoic acid (1.66 g, 0.011 mol) is dissolved in dichloromethane (100 mL) which is heated to 30°C.
- MPEG 5000 average molecular weight of about 5000 daltons
- MPEG 5000 (13.7g, 2.75mmol) is charged to a reaction vessel and dissolved in toluene (lOOmL) at 48°C. Under an inert atmosphere, a solution of phosgene in toluene (1.6mL, 1.93M) is added while cooling in ice. After the addition, the reaction mixture is stirred for 12-18h under an inert atmosphere at 48°C to form an MPEG 5000 chloroformate. In a separate flask, 2-amino- 6-methylbenzoic acid (457mg, 3.025mmol) is dissolved in toluene (70mL) that is heated to 75°C.
- Poly(N-vinylpyridine) (3.75 g, 0.033 mol) is added to the solution.
- the MPEG 5000 chloroformate is added dropwise to the anthranilate mixture.
- the reaction mixture is stirred for 12-24 h, then the temperature is raised to 80 °C and ethyl chloroformate (2.6 mL, 27.5mmol) is added and reaction mixture is stirred for another 12-24h.
- the solution is filtered to remove the polyfN-vinylpyridine) and the solution is precipitated onto 3.5 L of diethyl ether.
- the precipitate is filtered under nitrogen to yield 2-(MPEG 5000)-5-methyl-4H-3,l-benzoxazin-4-one as a white solid (12.4 g, 90%) which is dried under vacuum.
- Polyethylene glycol having an average molecular weight of about 4000 daltons (PEG 4000) (5 g, 1.25 mmol) is charged to a reaction vessel and dissolved in dichloromethane (16 mL). Under an inert atmosphere, a solution of phosgene in toluene (1.6 mL, 1.93 M) is added. After addition, the reaction mixture is stirred for 12-18h to form the PEG-4000 bis chloroformate. In a separate flask, 2-amino-6-methylbenzoic acid (416 mg, 2.75 mmol) is dissolved in dichloromethane (25 mL) which is warmed to 30°C.
- PEG 4000 Polyethylene glycol having an average molecular weight of about 4000 daltons
- the PEG 5000 urea from step one (2.2 g, 0.41 mol) is treated with concentrated sulfuric acid (4 mL) and allowed to stand for 4 hours.
- the reaction mixture is diluted with excess saturated sodium bicarbonate and held at 0° C. Extraction with dichloromethane affords the 4H- benzoxazin-4-one linked by an N-ethylene-N'-phenylene urea moiety to a polyethyleneglycol polymer component having an average molecular weight of about 5000 daltons.
- N-7- bis(Boc)-guanidino-2-(4-amino)phenyl-4H-3,l-benzoxazine-4-one-2-yl N' PEG 5000 urea from above (0.5 g, 0.1 mmol) is dissolved in glacial acetic acid (4 mL) and refluxed for 15 minutes The solvent is removed under reduced pressure to afford N-4-(7-guanidinyl-4H-3,l- benzoxazine-4-one-2-yl)phenylene N'-PEG 5000 urea.
- 6-Methyl anthranilic acid (0.15 g, 1 mmol) is dissolved in a mixture of 1% sodium bicarbonate (2.5 mL) and THF (0.5 mL).
- the PEG 5000 chloroformate from above (1 g, 0.2 mmol) is dissolved in THF and added dropwise to the reaction solution and is stirred for 18 hours.
- the reaction solution is extracted with dichloromethane, the extracts combined and the solvent removed under reduced pressure to yield the PEG 5000 benzoxazine carbamate.
- the carbamate from above (0.05 g, 0.01 mmol) is dissolved in pyridine (3 mL) and ethyl chloroformate (0.004 mL, 4.0 mmol) is added followed by activated molecular sieves. After stirring 18 hours the solvent is removed under reduced pressure to afford the desired product.
- 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.
- 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. In some instances, 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. However, when inco ⁇ orated as part of a composition, the conjugate will comprise from about 0.01%, 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.
- 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.
- 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
- ® available cell culture system suitable for use is Epiderm (MatTek Co ⁇ oration).
- IL-l ⁇ 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.
- 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.
- a suitable assay for IL-l ⁇ is an enzyme-linked immunoabsorbent method
- 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.
- 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 (1 70); 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. In some instances, 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. However, when inco ⁇ orated as part of a composition, 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 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 16 -C 32 hydrocarbons, including paraffins, include mineral oil and petrolatum (also
- 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.
- stabilizers can be added to enhance the shelf life of the composition such as cellulose derivatives, proteins and lecithin
- 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 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 lipolytic enzymes whether endogenous or exogenous.
- the formulator can employ the conjugates of the present invention in any embodiment which has the pu ⁇ ose 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.
- compositions according to the present invention 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 which inhibit protease or lipase enzyme, said polymer conjugate comprising a polymer component bonded to an enzyme inhibitor component having an acyl unit capable of inhibiting the activity of more than one protease or lipase enzymes, wherein said inhibitor component is directly bonded to said polymer component or is bonded by a linking unit, said linking unit capable of modulating the interaction of a target enzyme and said inhibitor component wherein said polymer component remains bonded to said inhibitor component after said acyl unit interacts with said target enzyme; and b) the balance carriers and adjunct ingredients.
- a composition for application to human skin said composition inhibiting proteolytic and/or lipolytic 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 which inhibit protease or lipase enzyme, said polymer conjugate comprising a polymer component bonded to an enzyme inhibitor component having an acyl unit capable of inhibiting the activity of more than one protease or lipase enzymes, wherein said inhibitor component is directly bonded to said polymer component or is bonded by a linking unit, said linking unit capable of modulating the interaction of a target enzyme and said inhibitor component wherein said polymer component remains bonded to said inhibitor component after said acyl unit interacts with said target enzyme; b) from about 0.01%, preferably from about 0.05%, more preferably from about 0.1% to about 5%, preferably to about 2%, more
- a composition for application to human skin, said composition inhibiting proteolytic and/or lipolytic 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 which inhibit protease or lipase enzyme, said polymer conjugate comprising a polymer component bonded to an enzyme inhibitor component having an acyl unit capable of inhibiting the activity of more than one protease or lipase enzymes, wherein said inhibitor component is directly bonded to said polymer component or is bonded by a linking unit, said linking unit capable of modulating the interaction of a target enzyme and said inhibitor component wherein said polymer component remains bonded to said inhibitor component after said acyl unit interacts with said target enzyme; b) from about 0.01%, preferably from about 0.05%, more preferably from about 0.1% to about 5%, preferably to about 2%,
- the present invention further relates to a method for inhibiting skin irritation comprising the step of contacting human skin with one or more enzyme inhibitor polymer conjugates according to the present invention.
- the present invention further relates to a method for inhibiting skin irritation comprising the step of contacting human skin with a composition which comprises: 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 which inhibit protease or lipase enzyme, said polymer conjugate comprising a polymer component bonded to an enzyme inhibitor component having an acyl unit capable of inhibiting the activity of more than one protease or lipase enzymes, wherein said inhibitor component is directly bonded to said polymer component or is bonded by a linking unit, said linking unit capable of modulating the interaction of a target enzyme and said inhibitor component wherein said polymer component remains bonded to said inhibitor component after said
- compositions of the present invention can also be delivered to skin via compositions which provide other primary benefits.
- 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 hpase 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
Description
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JP2001522393A JP2003509538A (en) | 1999-09-10 | 2000-09-08 | Enzyme inhibitor |
EP00960050A EP1212098A2 (en) | 1999-09-10 | 2000-09-08 | Enzyme inhibitors |
AU71270/00A AU7127000A (en) | 1999-09-10 | 2000-09-08 | Enzyme inhibitors |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003020282A1 (en) * | 2001-08-30 | 2003-03-13 | Alizyme Therapeutics Limited | Thieno-(1,3)-oxazin-4-ones with lipase inhibiting activity |
WO2003041744A2 (en) * | 2001-11-13 | 2003-05-22 | The Procter & Gamble Company | Protease enzyme inhibitors |
WO2005020970A2 (en) * | 2003-08-29 | 2005-03-10 | Smith & Nephew, Inc. | Protease inhibitor compositions for prevention and treatment of skin conditions |
JP2005518383A (en) * | 2001-12-20 | 2005-06-23 | オーエスアイ・ファーマスーティカルズ・インコーポレーテッド | Pancreatic lipase inhibiting compounds, their synthesis and use |
US8907154B2 (en) | 2001-10-01 | 2014-12-09 | The Procter & Gamble Company | Sanitary napkins with hydrophobic lotions |
US9035123B2 (en) | 2002-10-01 | 2015-05-19 | The Procter & Gamble Company | Absorbent article having a lotioned topsheet |
Families Citing this family (1)
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PE20010586A1 (en) * | 1999-09-10 | 2001-06-23 | Procter & Gamble | CONJUGATES OF FUNCTIONAL POLYMERS INHIBITING LIPOLYTIC AND / OR PROTEOLYTIC ENZYMES |
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DE4342154A1 (en) * | 1993-12-10 | 1995-06-14 | Behringwerke Ag | Amidinophenylalanine derivatives, process for their preparation, their use and agents containing them as anticoagulants |
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2000
- 2000-09-08 PE PE2000000930A patent/PE20010588A1/en not_active Application Discontinuation
- 2000-09-08 AU AU71270/00A patent/AU7127000A/en not_active Abandoned
- 2000-09-08 JP JP2001522393A patent/JP2003509538A/en active Pending
- 2000-09-08 EP EP00960050A patent/EP1212098A2/en not_active Withdrawn
- 2000-09-08 WO PCT/US2000/024713 patent/WO2001018181A2/en not_active Application Discontinuation
- 2000-09-11 AR ARP000104758A patent/AR023272A1/en not_active Application Discontinuation
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Cited By (13)
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AU2002321536B2 (en) * | 2001-08-30 | 2007-05-17 | Norgine Bv | Thieno-(1,3)-oxazin-4-ones with lipase inhibiting activity |
WO2003020282A1 (en) * | 2001-08-30 | 2003-03-13 | Alizyme Therapeutics Limited | Thieno-(1,3)-oxazin-4-ones with lipase inhibiting activity |
JP2010159260A (en) * | 2001-08-30 | 2010-07-22 | Norgine Bv | Thieno-(1,3)-oxazin-4-ones with lipase inhibiting activity |
US7407954B2 (en) | 2001-08-30 | 2008-08-05 | Alizyme Therapeutics Limited | Thieno-(1,3)-oxazin-4-ones with lipase inhibiting activity |
US8907154B2 (en) | 2001-10-01 | 2014-12-09 | The Procter & Gamble Company | Sanitary napkins with hydrophobic lotions |
WO2003041744A3 (en) * | 2001-11-13 | 2004-02-19 | Procter & Gamble | Protease enzyme inhibitors |
WO2003041744A2 (en) * | 2001-11-13 | 2003-05-22 | The Procter & Gamble Company | Protease enzyme inhibitors |
JP2005518383A (en) * | 2001-12-20 | 2005-06-23 | オーエスアイ・ファーマスーティカルズ・インコーポレーテッド | Pancreatic lipase inhibiting compounds, their synthesis and use |
US9035123B2 (en) | 2002-10-01 | 2015-05-19 | The Procter & Gamble Company | Absorbent article having a lotioned topsheet |
US9737446B2 (en) | 2002-10-01 | 2017-08-22 | The Procter & Gamble Company | Absorbent article having a lotioned topsheet |
US10687991B2 (en) | 2002-10-01 | 2020-06-23 | The Procter & Gamble Company | Absorbent article having a lotioned topsheet |
WO2005020970A3 (en) * | 2003-08-29 | 2005-07-07 | Smith & Nephew Inc | Protease inhibitor compositions for prevention and treatment of skin conditions |
WO2005020970A2 (en) * | 2003-08-29 | 2005-03-10 | Smith & Nephew, Inc. | Protease inhibitor compositions for prevention and treatment of skin conditions |
Also Published As
Publication number | Publication date |
---|---|
WO2001018181A3 (en) | 2001-12-13 |
JP2003509538A (en) | 2003-03-11 |
AR023272A1 (en) | 2002-09-04 |
AU7127000A (en) | 2001-04-10 |
EP1212098A2 (en) | 2002-06-12 |
PE20010588A1 (en) | 2001-06-23 |
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