AU628344B2 - N-dodecyl-pyrrolidone penetration enhancers - Google Patents

N-dodecyl-pyrrolidone penetration enhancers Download PDF

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AU628344B2
AU628344B2 AU35616/89A AU3561689A AU628344B2 AU 628344 B2 AU628344 B2 AU 628344B2 AU 35616/89 A AU35616/89 A AU 35616/89A AU 3561689 A AU3561689 A AU 3561689A AU 628344 B2 AU628344 B2 AU 628344B2
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hydrogen
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physiologically active
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Gevork Minaskanian
James V. Peck
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Whitby Research Inc
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/46—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom rings with more than six members
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    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07—ORGANIC CHEMISTRY
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
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    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Description

-nww- _1 i ANNOUNCEMNT OF THE LATER PUBLICATION OFAMENDED CLAIMS S (AND, WHERE APPLICABLE, STATEMENT UNDER ARTICLE 19) pTTT n1U 'W Itl.l 'I-ll; ir\l l\ IUr tlI IMl i1%JIN f lInternational Bureau INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 4 (11) International Publication Number: WO 89/09800 CO9B 67/00, A01N 25/00 Al A61K 31/70, 31/505, 31/56 (43) International Publication Date: 19 October 1989 (19.10.89) (21) International Application Number: PCT/US89/01381 (74) Agent: BOSTICH, June, Nelson Research Development Co., 1001 Health Sciences Road West, Irvine, CA (22) International Filing Date: 5 April 1989 (05.04.89) 92715 (US).
Priority data: (81) Designated States: AT (European patent), AU, BE (Euro- 179,144 8 April 1988 (08.04.88) US pean patent), CH (European patent), DE (European patent), DK, FR (European patent), GB (European patent), IT (European patent), JP, KR, LU (European pa- Parent Application or Grant tent), NL (European patent), NO, SE (European patent), (63) Related by Continuation US.
US 179,144 (CIP) Filed on 8 April 1988 (08.04.88) Published l 6 i I4- Z jctQ'l-R L l\C With international search reporL (71) Applicant (for all designated States except US)-NEL-SN- With amended claims.
-RESEARCH-&-DEVELOPMENT CO> [US/US]; 1001 Health Sciences Road West, Irvine, CA 92715 Date of publication of the amended claims: 2 November 1989 (02.11.89) (72) Inventors; and Inventors/Applicants (for US only) PECK, James, V. [US/ t L4.
US]; 2524 Bowdoin Place, Costa Mesa, CA 92626 (US).
MINASKANIAN, Gevork [US/US]; 8 Havenwood, Ir- T vine, CA 92714 (US).
6283 44 (54) Title: NOVEL TRANSDERMAL PENETRATION ENHANCERS R11' (CH2)x "tX-(CH 2 )n-R (Cu 2 (57) Abstract This invention relates to compounds and a method for their use in carrying physiologically active agents through body membranes such as skin and for retaining these agents in body tissues. More specifically, the invention relates to carboxylic acid derivatives and salts thereof, which compounds are useful in topically administering a physiologically active agent to a human or animal via a composition comprising the agent and an effective amount of a compound represented in one embodiment by general formula wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen, sulfur, or -CH 2 wherein R represents alkyl optionally substituted with one to three double or triple bonds, -CH3, or
COOR
1 and wherein R 1 represents hydrogen or lower alkyl; wherein represents alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, -(CH2)yCOOR I and with y being between zero and 3, inclusive; and wherein R" represents hydrogen or -(CH2)yCOORi such that when R" is hydrogen, then W is two hydrogen radicals and R' is not hydrogen; and when R' is hydrogen, then R" is not hydrogen; and wherein m is between 1 and 5, preferably 2, 3, or 4, while n is between 1 and 24, preferably between 5 and 12, and x is zero or 1, inclusive. It has been found that physiologically active agents are carried through body membranes by the above penetration-enhancing agents and are retained in body tissue.
The invention further relates to the penetration-enhancing agents themselves and the method of making such penetrationenhancing agents.
1 NOVEL TRANSDERMAL PENETRATION ENHANCERS 1. Field of the Invention This invention relates to compositions comprising a physiologically active agent and a novel transdermal penetration enhancer in an amount effective to enhance the penetration of the physiologically-active agent through the skin or other membrane of the body of an animal.
20 2. Background of the Art As hereinabove indicated, the present invention includes a number of uses in which it provides an "advantage. Each of these uses will be hereinafter addressed in the order of their recital beginning with the use of the composition of the present invention in S. the enhancement of the penetration of a physiologicallyactive agent through the skin or other membranes of body.
It is well known that in many physiologically active agents are best applied topically to obtain desirable results. Topical application, as contrasted to systemic application, can avoid metabolic degradation of the agents, largely avoids side effects of the agents, and permits high local concentrations of the agents.
920624,dbspec.019,35616.res,1 SO
I
-2- The greatest problem in applying physiologically active agents topically is that the skin is a very effective barrier to penetration. The epidermis of the skin has an exterior layer of dead cells called the stratum corneum, which is tightly compacted and oily and which provides an effective barrier against gaseous, solid or liquid chemical agents, whether used alone or in water or oil solutions. If a physiologically active agent penetrates the stratum corneum, it can readily pass through the basal layer of the epidermis and into the dermis.
Although the effectiveness of the stratum corneum .as a barrier provides great protection, it also frustrates efforts to apply beneficial agents directly to local areas of the body. The inability of physiologically active agents to penetrate the stratum corneum prevents their effective use to treat such conditions as inflammation, acne, psoriasis, herpes simplex, eczema, infections due to fungus, virus or other microorganisms, or other disorders and conditions of the skin or mucous membranes, or of conditions beneath the exterior surface of the skin or mucous membranes. The stratum corneum also prevents the skin from absorbing and retaining cosmetic-type materials such as sunscreens, perfumes, mosquito repellents and the like.
Physiologically active agents may be applied to locally affected parts of the body through the vehicles system described herein. Vehicles such as USP cold cream, ethanol and various ointments, oils, solvents, and emulsions have been used heretofore to apply physiologically active ingredients locally. Most such vehicles are not effective to carry significant amounts of physiologically active agants through the skin. One such vehicle is dimethyl sulfoxide.
The 1-lower alkyl substituted azacyclopentan-2-onas having 1-4 carbon atoms in the alkyl group are known to 17y iff4 T\ <~y -3moderately enhance percutaneous absorption of chemicals, e.g. drugs. It was earlier recognized that it would be desirable to obtain the same or higher level of percutaneous absorption with substantially lower concentrations of the penetration-enhancing compound. Therefore, various Nsubstituted azacycloalkan-2-ones were invented having the desired properties. These new penetration-enhancing agents are described in U.S. Patents 3,989,815; 3,989,816; 3,991,203; 4,122,170; 4,316,893; 4,405,616; 4,415,563; 4,423,040; 4,424,210; and 4,444,762, which are hereby incorporated by reference.
It is an object of this invention to provide new penetration-enhancing agents having the desirable property of enhancing the percutaneous absorption of physiologicallyactive agents at concentrations lower than the 1-lower alkyl substituted azacyclopentan-2-ones.
It is also an object of this invention to provide penetration-enhancing agents that are equivalent to the aforesaid new penetration-enhancing agents described in the above U.S. patents.
Other objects and advantages of the instant invention will be apparent from a careful reading of the specification below.
In this description, the term "animal" includes human beings as well as other forms of animal life, and especially domesticated animals and pets.
.o SUMMARY OF THE INVENTION This invention relates to compounds and a method for their use in carrying physiologically active agents through body membranes such as skin and for retaining these agents in body tissues. More 'specifically, the invention relates to carboxylic acid derivatives and salts thereof, which 1 compounds are useful in topically administering a
C_
,oJ 7 -4physiologically active agent to a human or animal via a composition comprising the agent and an effective amount of a compound represented by the general formula: (C 2)x -C-(CH 2 )n-R
H
Z
(CH2)m wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen; wherein R represents alkyl optionally substituted with one to three double or triple bonds,
-CH
3 or COOR 1 and wherein R 1 represents hydrogen or lower alkyl; wherein represents alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; 20 wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, -(CH2)yCOOR 1 and with y being between zero and 3, inclusive; and wherein R represents hydrogen or -(CH 2 )yCOOR 1 such that when is hydrogen, then W is two hydrogen radicals; and when R' is hydrogen, then is not S**hydrogen; and when is hydrogen, then R' is not "hydrogen; and wherein m is between one and 5, preferably 2, 3, or 4, while n is between 1 and 24, preferably between and 12, and x is zero or 1, inclusive.
In an alternative embodiment, the novel penetration enhancers include compounds represented by the general formula: 920624,dbspec,019,35616.res,4
R''
R
2
H-(CH
2 )n-R
-R
(C 2)m
R
3 wherein B represents oxygen, sulfur, or two hydrogen radicals; wherein A represents oxygen, sulfur, or wherein R, R 2 and R 3 independently represent alkyl optionally substituted with 1 to 3 double or triple bonds,-
-CH
3 or COOR 1 wherein R" represents hydrogen, alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl, or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, o acyloxy, alkylthio, hydroxy, or -(CH2)yCOORI; wherein represents hydrogen, or -(CH2)yCOORi; wherein R 1 represents a hydrogen or lower alkyl radical and y is between zero and 3, inclusive.
wherein m is between zero and 5, preferably 1 or 2; while n is between 1 and 24, preferably between 5 and 12, inclusive; And in yet another embodiment the compound is represented by the formula:
B"
1! (CH2)m
-C-(CH
2 )n-R 2 ~nr
I-I'
-6wherein R 2 is COOR 1 or an alkyl radical, optionally substituted with between 1 and 3 double or triple bonds; wherein R' is a hydrogen radical, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH 2 )yCOOR 1 wherein B' represents oxygen, sulfur, or two hydrogen radicals; wherein represents oxygen, sulfur, or two hydrogen radicals such that when is not hydrogen, B' is two hydrogen radicals, and R 2 is alkyl, then R' is
(CH
2 )yCOOR 1 where y cannot be zero; wherein y is between zero and three, inclusive, and
R
1 represents a lower alkyl or hydrogen radical.
and wherein m is between 3 and 6, preferably 3,4 or while n is between 1 and 24, preferably between 5 and 23, inclusive.
It has been found that physiologically active agents are carried through body membranes by the above S 2 penetration-enhancing agents and are retained in body 20 tissue.
S: The invention further relates to the penetrationenhancing agents themselves and the method of making such penetration-enhancing agents.
*ee *oo oO* *e go 920624,dbspec-019,35616.res,6
I
DETAILED DESCRIPTION OF THE INVENTION Novel transdermal penetration enhancers useful in the method of the present invention include carboxylic acid derivatives and their salts, which are compounds represented by the general formula: (CH2)x IH-(CH2)n-R
(CH
2
)X
Z R'
(CH
2 )m wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen; wherein R represents alkyl optionally substituted with one to three double or triple bonds, -SR'
-CH
3 or COOR 1 and wherein R 1 represents hydrogen or lower alkyl; 20 and wherein represents alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; S"wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, -(CH 2 )yCOOR 1 and with y being between zero and 3, inclusive; wherein represents hydrogen or -(CH 2 yCOOR 1 such that when is hydrogen, then W is two hydrogen radicals and when R' is not hydrogen; and when R' is hydrogen, then is not hydrogen; and wherein m is between one and 5, preferably 2, 3, o* 920624,dbspec,019,35616.res,7 8 or 4 while n is between 1 and 24, preferably between 5 and 12, inclusive, and x is zero or 1, inclusive.
In an alternative embodiment, the compounds useful as penetration enhancers include those represented by the general formula: R2 -CH-(CH 2 )n-R
-RI
(C 2)m R3 wherein B represents oxygen, sulfur, or two hydrogen radicals; wherein A represents oxygen, sulfur or -(CH 2 wherein R, R 2 and R 3 independently represent alkyl optionally substituted with 1 to 3 double or triple bonds,-
-CH
3 or COOR 1 wherein R' represents hydrogen, alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl, or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH2)yCOOR 1 wherein represents hydrogen or -(CH2)yCOORI; wherein m is between zero and 5, preferably 1 or 2; while n is between 1 and 24, preferably between 5 and 12, S• inclusive; and wherein R 1 represents a hydrogen or lower alkyl radical and y is between zero and 3, inclusive.
And in yet another embodiment the compound is represented by the formula:
B''
(CH
2 )m N-C-(CH 2 )n-R 2
R'
wherein R 2 is COOR 1 or an alkyl radical, optionally substituted with between 1 and 3 double or triple bonds; wherein R' is a hydrogen radical, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH 2 )yCOORi; wherein B' represents oxygen, sulfur, or -two hydrogen radicals; wherein represents oxygen, sulfur, or two hydrogen radicals such that when is not hydrogen, B' is two hydrogen radicals, and R 2 is alkyl, then R' is
-(CH
2 )yCOOR 1 where y is not zero; wherein y is between zero and three, inclusive, and
R
1 represents a lower alkyl or hydrogen radical.
and wherein m is between 3 and 6, preferably 3,4,or while n is between 1 and 24, preferably between 5 and 12, inclusive; These novel transdermal penetration-enhancing :additives may be made by the methods illustrated in the Examples below. Typical examples of compounds represented by the above general formulae include: acid l. -N-butyl-2-pyrrolidone-5-carboxylic acid l1-N-pentyl-2-pyrrolidone-5-carboxylic acid acid 1-N-octyl-2-pyrrolidone-5-carboxylic acid acid acid acid 1-N-hexadecyl-2-pyrrolidone-5-carboxylic acid 'Nr 10 l-N-hepty Lf-2-pyrro'Lidone-5-carboxylic acid 1-N- f-oIe tyl-2- piperidone-6-carboxylic acid l-N-butyl-2-piperidone-6-carboxylic acid l-N-pentyl-2-piperidone-6-carboxylic acid l-N-hexyl-2 -piperidorie-6-carboxylic acid 1-N-octyl-2-piperidorie-6-carboxylic acid l-N-nonyl-2-piperidone-6-carboxylic acid 1-N--decyl-2-piperidone-6-carboxylic acid 1-N-tetradecyl-2-piperidone-6-carboxylic acid l-N-hexadecyl-2-piperidone-6-carboxylic acidl-N-heptyl-2 -piperidone-6 -carboxylic acid 1- (n-dodecylthio) ethyl) carboxylic acid 1- (n-butylthio) ethyl) carboxylic acid 1- (n-pentylthio) ethyl) carboxylic acid 1- (n-hexylthio) ethyl) .00% carboxylic acid i- (n-octylthio) ethyl) carboxylic acid 1- (2-(n-rionylthio) ethyl) carboxylic acid So' a1- (n-decylthio) ethyl) carboxylic acid 1- (n-tetradecylthio) ethyl) -2pyrrolidorie-5-carboxylic acid 1- (r-hexadecylthio) ethyl) carboxylic acid l-(2-(n'-heptylthio) ethyl) carboxylic acid 1- (n-dodecylthio) ethyl) -piperidine-3carboxylic acid 1- (n-butylthio) ethyl) -piperidine-3carboxylic acid 1- (2-(n-pentylthio) ethyl) -piperidine-3carboxylic acid 1- (n-hexylthio) ethyl) -piperidine-3carboxylic acid 1- (n-octylthio) ethyl) -piperidine-3carboxylic acid 1- (n-nonylthio) ethyl) -piperidine-3carboxylic acid 1- (n-decylthio) ethyl) -piperidine-3carboxylic acid 1- (n-tetradecylthio) ethyl) -piperidine-3carboxylic acid 1- (r-hexadecylthio) ethyl) -piperidine-3carboxylic acid 1- (r-heptyl'lthic) ethyl) -piperidine-3carboxylic acid 2-dodecyl, 2-N- (2-pyrrolidone) -acetic acid 2-butyl, 2-N- (2-pyrrolidone) -acetic acid 2-pentyl, 2-N- (2-pyrrolidone) -acetic acid 2-hexyl, 2-N- (2-pyrrolidone) -acetic acid Se 2-octyl, 2-N- (2-pyrrolidone) -acetic acid 2-nonyl, 2-N-(2-pyrrolidone) -acetic acid 2-decyl, 2-N- (2-pyrrolidone) -acetic acid 2-erdcl2N(-yroioe-ctcai 2-tetradecyl, 2-N- (2-pyrrolidone) -acetic acid 2-hexadeyl,--2--(pyrrolidoe) -acetic acid 2-hoetyl, 2-N- (2-pprroidone) -acetic acid 2-dodecyl, 2-N- (2-piperioene ne-acetic acid 2-dodeyl, 2-N- (azacycloheptane-2-ore) -acetic acid 2-butyl, 2-N- (azacycloheptane-2-oie) -acetic acid 2-penyl,2-N-(azacycloheptane-2-one) -acetic acid 2-hexyl,2-N-(azacycloheptane-2-one) -acetic acid i i -i.
12 2-nonyl,2-N-(azacycloheptane-2-one)-acetic acid 2-decyl,2-N-(azacycloheptane-2-one)-acetic acid 2-tetradecyl,2-N-(azacycloheptane-2-one)-acetic acid 2-hexadecyl,2-N-(azacycloheptane-2-one)-acetic acid 2-heptyl,2-N-(azacycloheptane-2-one)-acatic acid 6-(N-pyrrolidine)-hexanoic acid 8-(N-pyrrolidine)-octanoic acid acid 12-(N-pyrrolidine)-dodecanoic acid 12-diethylaminododecanoic acid acid 6-diethylaminohexanoic acid 8-diethylaminooctanoic acid 2-(N-morpholine)-2-dodecylacetic acid 2-(N-morpholine)-2-decylacetic acid 2-(N-morpholine)-2-octylacetic acid 2-(N-morpholine)-2-hexylacetic acid 2-(N-morpholine)-2-butylacetic acid It has also been found that the penetration enhancers herein also themselves possess antiviral activity and can be used alone to combat viral infections.
When used in compositions comprising a second physiologically active agent, the amount of the novel transdermal penetration enhancers used in the present invention is an effective amount for enhancing percutaneous absorption. Generally, this amount ranges between about 0.01 to about 5 and preferably about 0.1 to 2 percent by weight of the composition.
The subject compositions may find use with many physiologically active agents which are soluble in the vehicles disclosed. The penetration enhancer can be applied before, after, or in combination with the physiologically active agent. The order of application is immaterial.
ITS
-s- 13 Fungistatic and fungicidal agents such as, for example, thiabendazole, chloroxine, amphotericin B, candicidin, fungimycin, nystatin, chlordantoin, clotrimazole, miconazole nitrate, pyrrolnitrin, salicyclic acid, fezatione, tolnaftate, triacetin and zinc and sodium pyrithione may be dissolved in the penetration-enhancing agents described herein and topically applied to affected areas of the skin. For example, fungistatic or fungicidal agents so applied are carried through the stratum corneum, and thereby successfully treat fungus-caused skin problems.
These agents, thus applied, not only penetrate more quickly than when applied in the vehicles of the prior art, but additionally enter the animal tissue in high concentrations and are retained for substantially longer time periods whereby a far more successful treatment is effected.
For example, the subject compositions may also be employed in the treatment of fungus infections on the skin S"caused by candida and dermatophytes which cause athletes foot or ringworm, by dissolving thiabendazole or similar antifungal agents in one of the above-described penetrationenhancing agents and applying it to the affected area.
.The subject compositions are also useful in treating skin problems, for example, herpes simplex, which may be treated by a solution of iododeoxyuridine dissolved in one of the penetration-enhancing agents or such problems as warts which may be treated with agents such as podophylline S. dissolved in one of the penetration-enhancing agents. Skin problems such as psoriasis may be treated by topical application of a solution of a conventional topical steroid in one of the penetration-enhancing agents or by treatment with theophylline or antagonists of 3-adrenergic blockers such as isoproterenol in one of the penetration-enhancing agents. Scalp conditions such as alopecia areata may be treated more effectively by applying steroids such as 14 triamcinolone acetonide dissolved in one of the penetrationenhancing agents of this invention directly to the scalp.
The subject compositions are also useful for treating mild eczema, for example, by applying a solution of fluocinolone acetonide or its derivatives; hydrocortisone, triamcinolone acetonide, indomethacin, or phenylbutazone dissolved in one of the penetration-enhancing agents to the affected area.
Examples of other physiologically active steroids which may be used with the vehicles include corticosteroids such as, for example, cortisone, cortodoxone, flucetonide, fluorocortisone, diflursone diacetate, flurandrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and its esters, chloroprednisone, clocortelone, descinolone, desonide, dexamethasone, dichlorisone, defluprednate, flucloronide, flumethasone, flunisolide, fluocinonide, flucortolone, fluoromethalone, fluperolone, fluprednisolone, meprednisone, methylmeprednisolone, paramethasone, predisolone and prednisone.
The subject compositions are also useful in antibacterial chemotherapy, e.g. in the treatment of skin conditions involving pathogenic bacteria. Typical antibacterial agents which may be used in this invention include sulfonamides, penicillins, cephalosporins, penicillinase, erythromycins, lincomycins, vancomycins, tetracyclines, chloramphenicols, streptomycins, etc. Typical examples of the foregoing include erythromycin, erythromycin ethyl carbonate, erythromycin estolate, erythromycin glucepate, erythromycin ethylsuccinate, erythromycin lactobionate, lincomycin, clindamycin, tetracycline, chlortetracycline, demeclocycline, doxycycline, methacycline, oxytetracycline, minocycline, etc.
The subject compositions are also useful in protecting ultra-sensitive skin or even normally sensitive skin CVr oi i I; II i: 15 from damage or discomfort due to sunburn. Thus, dermatitis actinica may be avoided by application to the skin surfaces that are to be exposed to the sun of a sunscreen, such as para-aminobenzoic acid or its well-known derivatives in combination with one of the above-described penetrationenhancing agents. The protective para-aminobenzoic acid or its derivatives will thereby be carried into the stratum corneum more successfully and will therefore be retained even when exposed to water or washing for a substantially longer period of time than when applied to the skin- in conventional vehicles. This invention is particularly useful for ordinary suntan lotions used in activities involving swimming because the ultraviolet screening ingredients in the carriers of the prior art are washed off the skin when it is immersed in water.
The subject compositions may also find use in treating scar tissue by applying topically to the scar tissue agents which soften collagen, such as aminopropionitrile or penicillamine dissolved in one of the penetrationenhancing agents of this invention.
Agents normally applied as eye drops, ear drops, or nose drops are more effective when dissolved in the penetration-enhancing agents of this invention.
Agents used in diagnosis may be used more effectively when applied dissolved in one of the penetration-enhancing agents of this invention. Patch tests to diagnose allergies may be effected promptly without oo 'scratching the skin or covering the area subjected to an allergen when the allergens are applied in one of the penetration-enhancing agents of this invention.
The subject compositions are also useful for topical application of cosmetic or esthetic agents. For example, compounds such as melanin-stimulating hormone (MSH) or dihydroxyacetone and the like are more effectively applied
C)J
L
16 to skin to stimulate a suntan when they are dissolved in one of the penetration-enhancing agents of this invention. The agent is carried into the skin more quickly and in greater quantity when applied in accordance with this invention.
Hair dyes also penetrate more completely and effectively when dissolved in one of the penetration-enhancing agents of this invention.
The effectiveness of such topically applied materials as insect repellents or fragrances, such as perfumes and colognes, can be prolonged when such agents are applied in combination with one of the penetration-enhancing agents of this invention.
It is to be emphasized that the foregoing are simply examples of physiologically active agents including therapeutic and cosmetic agents having known effects for known conditions, which may be used more effectively for their known properties in accordance with this invention.
In addition, the penetration-enhancing agents of the present invention may also be used to produce therapeutic effects which were not previously known. That is, by use of the penetration-enhancing agents described herein, therapeutic effects heretofore not known can be achieved.
As an example of thea foregoing, griseofulvin is *o known as the treatment of choice for fungus infections of the skin and nails. Heretofore, the manner of delivery of griseofulvin has been oral. However, it has long been known that oral treatment is not preferred because of side effects resulting from exposure of the entire body to griseofulvin and the fact that only the outer layers of affected skin need to be treated. Therefore, because fungal infections are generally infections of the skin and nails, it would be advantageous to utilize griseofulvin topically. However, despite a long-felt need for a topical griseofulvin, "A griseofulvin has been used orally to treat topical fungus i j 17 conditions because there was not heretofore known any formulation which could be delivered topically which would cause sufficient retention of griseofulvin in the skin to be useful therapeutically.
However, it has now been discovered that griseofulvin, in a range of therapeutic concentrations between about 0.1% and about 10% may be used effectively topically if combined with one of the penetration-enhancing agents described herein.
As a further example, acne is the name commonly applied to any inflammatory disease of the sebaceous glands; also acne vulgaris. The microorganism typically responsible for the acne infection is Corynebacterium acnes. Various therapeutic methods for treating acne have been attempted including topical antibacterials, e.g. hexachlorophene, and systemic antibiotics such as tetracycline. While systemic antibiotic treatments are known to be partially effective, S: topical treatments are generally not effective.
However, it has long been known that systemic treatment of acne is not preferred because of side effects resulting from exposure of the entire body to antibiotics and the fact that only the affected skin need be treated.
Heretofore, despite a long-felt need for a topical treatment for acne, antibiotics generally have been used only systemically to treat acne because an antibacterial formulation which could be used topically as an effective therapeutic in the treatment of acne was not known.
However, it has now been discovered that antibiotics, especially those of the lincomycin and erythromycin families of antibiotics, may be used topically in the treatment of acne if combined with one of the penetration-enhancing agents described herein.
The antibiotic compositions so applied are carried into and through the epidermis and deeper layers of the skin 7 t VT O 18 as well as into follicles, (which contain C. acnes) in therapeutically effective amounts and thereby successfully may be used to temporarily eliminate the signs and symptoms of acne.
The term "physiologically active agent" is used herein to refer to a broad class of useful chemical and therapeutic agents including physiologically active steroids, antibiotics, antifungal agents, antibacterial agents, antineoplastic agents, allergens, antihistaminic agents, anti-inflammatory agents, ultraviolet screening agents, diagnostic agents, perfumes, insect repellents, hair dyes, etc.
Dosage forms for topical application may include solution nasal sprays, lotions, ointments, creams, gels, suppositories, sprays, aerosols and the like. Typical inert carriers which make up the foregoing dosage forms include water, acetone, isopropyl alcohol, freons, ethyl alcohol, polyvinylpyrrolidone, propylene glycol, fragrances, gelproducing materials, mineral oil, stearyl alcohol, stearic acid, spermaceti, sorbitan monooleate, "Polysorbates", "Tweens", sorbital, methyl cellulose, etc.
The amount of the composition and/or of the physiologically active agent to be administered will S" obviously be an effective amount for the desired result expected therefrom. This, of course, will be ascertained by the ordinary skill of the practitioner. Due to enhanced activity which is achieved, the dosage of physiologically active agent may often be decreased from that generally applicable. In accordance with usual prudent formulating practices, a dosage near the lower end of the useful range of the particular physiologically active agent may be employed initially and the dosage increased as indicated from the observed response, as in the routine procedure of the physician.
OT
I
i ;l 19 The invention is further illustrated by the following examples which are illustrative of various aspects of the invention, and are not intended as limiting the scope of the invention as defined by the appended claims.
EXAMPLE 1 Preparation of 1-N-dodecyl-2-pyrrolidone-5-carboxylic acid A. To a stirred solution of 1.92 g NaH washed with pet ether) in dry THF at room temperature under N 2 was added dropwise a solution of 7.06 g of ethyl carboxylate in 20 mL of THF. The mixture was refluxed for 1 h, cooled to room temperature, followed by dropwise addition of 1.3 equivalents of 1-bromododecane. After additional reflux overnight and workup, the crude oil was subjected to flash chromatography (silica, 8:2 pet ether/EtOAC) to give 3.14 g of ethyl 1-N-dodecyl-2pyrrolidone-5-carboxylate as a clear oil: NMR (CDC1 3 6 3.68(m), 2.1(m) 1.6-1.0(m), 0.9(t).
Basic hydrolysis of the product of example 1A at room temperature, followed by acidic workup resulted in 1.73 g of l-dodecyl-2-pyrrolidone-5-carboxylic acid as a white solid: NMR (CDC13) 6 4.29(m), 3.75(m), 3.00(m), 0.9(t).
i B. Example 1A was repeated using Ethyl 12-Bromododecanoate, followed by hydrolysis to give 12-(N-pyrrolidin-2-one-5carboxy)dodecanoic acid.
C. Example 1A was repeated using Ethyl 2-Bromotetradecanoate, followed by hydrolysis to give 2-(N-pyrrolidin- 2-one-5-carboxy)-2-dodecylacetic acid.
C l 20 D. Example 1A was repeated replacing ethyl carboxylic acid with proline ethyl ester, followed by hydrolysis to give N-dodecylproline.
E. Example 1A was repeated replacing carboxylic acid with N-Acetyl alanine ethyl ester, followed by hydrolysis to give N-Acetyl-N-dodecylalanine.
F. Example 1A was repeated, replacing starting materials with N-ethyl alanine ethyl ester and dodecanoyl chloride and followed by hydrolysis to give N-Ethyl-N-(loxododecyl)alanine.
EXAMPLE 2 Preparation of 2-pentyl-2-oxo-l-pvrrolidineacetic acid A. Alkylation of 2.0 g 2-pyrrolidone, under the same procedure described in Example IA, with 7.23 g a thyl-2bromoheptanoate resulted in 1.6 g of 2-pentyl-2-oxo-lpyrrolidineacetic acid ethyl ester as a light yellow oil: NMR (CDC1 3 6 4.75 4.15 3.55(m), 3.35(m), 2.45(t), 0.9(m).
Basic hydrolysis of the product in Example 2A at room temperature, followed by acidic workup resulted in 0.89 g of 2-pentyl-2-oxo-l-pyrrolidineacetic acid as a white solid: NMR (CDC13) 6 4.8(dd), 2.2-2.05(m), 1.75(m), 0.9(t).
oi B. Example 2A was repeated using 2-Oxazolidine, followed by hydrolysis to give 2-dodecyl-2-oxa-3-oxazolidineacetic acid.
z j -i ri; 21 C. Example 2A was repeated using E-Caprolactam and ethyl 2bromotetra-decanoate, followed by hydrolysis to give 2- (l-azacycloheptan-2-one)-2-dodecylacetic acid.
D. Example 2A was repeated using Morpholine, followed by hydrolysis to give 2-dodecyl-4-morpholineacetic acid.
E. Example 2A was repeated using Pyrrolidine, followed by hydrolysis to give 2-dodecyl-l-pyrrolidineacetic acid.
F. Example 2A was repeated using Proline ethyl ester, followed by hydrolysis to give 2-(N-pyrrolidino-2carboxy)-2-dodecylacetic acid.
G. Example 2A was repeated using N-Ethyl acetamide, followed by hydrolysis to give 2-(N-ethylacetamido)-2dodecylacetic acid.
H. Example 2A was repeated using Diethylamine, followed by hydrolysis to give 2-(N,N-diethylamino)-2-dodecylacetic acid.
I. Example 2A was repeated using ethyl 2-bromotetradecanoate, followed by hydrolysis to give 2-dodecyl-2oxo-l-pyrrolidineacetic acid.
EXAMPLE 3 Preparation of ll-(diethylamino)-undecanoic acid A. According to the previously described basic hydrolysis procedure of Example 1B, 0.47 g of ethyl 11- (diethylamino)-undecanoate resulted in the desired product as a white solid: NMR (CDC13) 6 3.1 AT 2.95(m), 2.25(t), 1.4-1.1(m).
I i:.T i. ;i 22 B. Example 3A was repeated using Pyrrolidine, followed by hydrolysis, to give 11-(l-pyrrolidino)undecanoic acid.
C. Example 3A was repeated using Morpholine, followed by hydrolysis, to give ll-(4-Morpholino)undecanoic acid.
D. Example 3A was repeated using Piperazine, followed by hydrolysis, to give 11-(l-Piperazino)undecanoic acid.
E. Example 3A was repeated using 2-Pyrrolidinone, followed by hydrolysis, to give ll-(N-Pyrrolidino-2-one) undecanoic acid.
F. Example 3A was repeated using 2-Oxazolidone, followed by hydrolysis, to give l1-(3-Oxazolidin-2-one)undecanoic acid.
G. Example 3A was repeated using E-Caprolactam, followed by hydrolysis, to give ll-(l-hexamethylineimin-2-one) undecanoic acid.
H. Example 3A was repeated using Proline ethyl ester, followed by hydrolysis,' to give 11-(1-pyrrolidin-2carboxy)undecanoic acid.
I. Example 3A was repeated using N-Ethyl acetamide, followed by hydrolysis, to give 1l-(N-Ethyl acetamido)-undecanoic acid.
J. Example 3A was repeated using N-Acetyl alanine ethyl ester, followed by hydrolysis, to give carboxy-l-decyl)alanine.
7 0 r 23 EXAMPLE 4 To model the capacity of the carboxylic acid derivatives of 1-substituted azacycloalkanes for enhancing permeability of physiologically active agents through skin and mucous membranes, a series of experiments were conducted using either ethanol-C 14 or butanol-C 14 as a control. The amount penetrating was calculated as percent of penetration of the control. For comparison with each control, parallel tests were also conducted using a known penetration enhancer, 1-n-dodecylazacyclo-heptane-2-one.
Ethanol and butanol have known permeability coefficients for passage through hairless mouse skin via a diffusion cell. The permeability coefficient is expressed by the formula: DKm/v h h wherein D is the diffusivity (diffusion coefficient), Km/v is the partition coefficient between the membrane and medium vehicle), and h is the membrane thickness, S. respectively. See Kurihara.-Bergstrom, T, et al., "Physio- S: chemical Study of Percutaneous Absorption Enhancement by Dimethyl Sulfoxide: Kinetic and Thermodynamic Determinants of Dimethyl Sulfoxide Mediated Mass Transfer of Alkanols" in Journal of Pharmaceutical Sciences, Vol. 75, No. 5, May 1986, pp. 479-86. Full thickness abdominal and dorsal sections of mouse skin membranes were obtained from the hairless mouse strain (Skin Cancer Hospital, Temple University, Philadelphia, PA).
Formulations to be tested contained either one or five weight percent of a penetration enhancer, three weight Rpercent Tween 20, and the balance of nanopure water. A S\ trace amount of radio labelled ethanol C 14 or butanol C 14 24 was added to each formulation prior to assay and then of the labelled formulation was counted in a liquid scintillation counter to determine the number of disintegrations per minute (DPM).
The receptor cells of nine finite dose Franz diffusion cells were filled with isotonic saline and maintained at 37 0 C by submersion into a thermostatically controlled water jacket. The saline was stirred for minutes with a magnetic stir bar to achieve equilibrium.
Freshly excised full thickness mouse skin was tlhen mounted with an 0 ring between the donor and the receptor cells. After one hour of equilibration the saline was removed from the receptor cells and replaced by 4-5 ml of fresh saline solution at 37 0
C.
Three of the nine donor cells were charged with 100 l of radio-labelled saline containing no penetration enhancer as the control, three were charged with 100 Jl of the one weight percent penetration enhancer formulation in labelled saline, and three cells were charged with equal amounts of the five weight percent penetration enhancer formulation in labelled saline.
At 45 minute intervals, 50 1l samples were taken from each receptor cell port with a micropipettor. The volume removed was replaced with a 50 ul sample of fresh 37 0 C saline formulation. Each sample was then placed into a liquid scintillation counting vial along with 4.0 41 of scintillation cocktail (Aquasol, New England Nuclear, Boston, MA).
Based upon the predetermined DPM for each formulation, the amount of alkanol carried through the mouse skin by each formulation was calculated using known methods.
Tables II and III below summarize the increase in .fS^wQ permeation of radio labelled alkanol achieved by addition of W$\Athe penetration enhancer. It will be noted that in every ev r l _9^ 25 test the penetration of ethanol was increased by at least 76 per cent over that achieved without aid of the penetration enhancers of this invention. The best results in these tests were achieved using a 1 weight percent concentration of N-0917 penetration enhancer, which yielded a penetration of ethanol through hairless mouse skin of 616% of that achieved without the penetration enhancer.
As shown in Table II, all of the penetration enhancers of this invention yielded penetration of butanol at least 119 percent of that achieved by the control.
TABLE I ETHANOL C 14 AS PERMEANT
PENETRATION
COEFFICIENT
COMPOUND CONC'N (X10 3 CM/NR) OF CONTROL S1% 19.42 616 1A 5% 17.20 546 1% 8.21 155 2A 5% 25.62 484 11.28 341 21 6.89 208 1% 2.38 76 2C 5% 4.82 155 1% 10.69 269 AZONE 5% 18.58 466 T I, r^ Sc- 26 TABLE 11 BUTANOL
C
14 AS PERI4EANT
PENETRATION
COEFFICIENT
(X10- 3 CM/NR) COMPOUND CONC'N OF CONTROL 37.39 40.74 14 .69 22.23 18.91 23 .68 10.80 11.65 24.83 23.29 297 324 135 204 204 255 119 128 0 a.
00 0 340 319 AZONE EXAMPLE The following formulation is prepared: Solution M%' Griseofulvin1 acid 1 Isopropyl myristate Fragrance 0.1 Ethanol 92.9 This formulation is effective in the treatment of fungus infections.
27 EXAMPLE 6 An aerosol form of the formulation of Example 7 is prepared by preparing the following mixture: Formulation Freon 1 1 Freon is 75/25 Freon 114/12.
EXAMPLE 7 The following cream formulation is prepared: a *o *a Clindamycin base Stearyl alcohol, U.S.P.
Ethoxylated cholesterol Synthetic spermaceti Sorbitan monooleate Polysorbate 80, U.S.P.
acid Sorbitol solution, U.S.P.
Sodium citrate Chemoderm #844 Fragrance Purified water 12.0 0.4 0.2 68.4 This formulation is effective in the treatment of acne.
0I 28- EXAMPLE 8 The following solution formulations are prepared: A B Clindamycin base Clindamycin phosphate acid Sodium hydroxide M Hydrochloric acid Disodium edetate 2H 2 0 Fragrances N-dodecyl-2 carboxylic acid Purified water T .nnonn~nI 1.3 0. 077 0.003 0.5 .0 20.0 77-1 2.27 0.003 17.73 77. 4Q7
B
B B B. B.
B.
B
B
B
B
U
B.
B
B B B B B. B B B *B eB B B
B
These solutions are effective for the treatment of acne in humans.
EXAMPLE 9 The following solution formulation is prepared: Neomycin sulfate Lidocaine. Hydrocortisone 0.25 acid Pro~vlene alvcol -98.25 This solution is effective for the treatment of otitis in domestic animals.
-29- EXAMPLE The following sunscreen emulsion is prepared: p-Aminobenzoic acid Benzyl alcohol acid Polyethylene glycol 500-MS 10.0 Isopropyl lanolate Lantrol Acetylated lanolin Isopropyl myristate Light mineral oil Cetyl alcohol Veegum *0Propylene glycol Purified water 64.0 EXML 11 Th folwn aniepatcsluini rprd N-oey00proioe--abxl0 cd 0.
Polethlen Purified water 89.9 0b9 Ujl~ 30 EXAMPLE 12 The following insect repellant atomizing spray is prepared: Diethyltoluamide 0.1 acid 0.1 Ethanol 99.8 EXAMPLE 13 The following lotion formulation may be prepared containing about 0.001 to 1 percent, with preferably 0.1 percent fluocinolone acetonide: Fluocinolone acetonide 0.001-1 Cetyl alcohol 15.0 Propylene glycol 10.0 Sodium lauryl sulfate 15.0 N-dodecyl-2-pyrrolidone-5-carboxylic acid S. Water (to make 100%) The steroid is dissolved in the vehicle and added to a stirred, cooling melt of the other ingredients. The preparation is particularly useful for the treatment of inflamed dermatoses by topical application to the affected skin area. The amount and frequency of application is in accordance with standard practice for topical application of this steroid. Penetration of the steroid into the inflamed S* tissue is enhanced and a therapeutic level is achieved more rapidly and sustained for longer duration than when the steroid is applied in conventional formulations.
1$t

Claims (54)

1. A composition comprising an effective amount of a physiologically active agent and an effective penetrating amount of a compound represented by the general formula (CH2 x (-CH-(CH 2 )n-R R (CH 2 )m and salts thereof wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen; wherein R represents alkyl optionally substituted with one to three double or triple bonds NHR' -CH 3 or -COOR 1 wherein R' represents alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH2)yCOORj; wherein R 1 represents hydrogen or lower alkyl and y is between zero and 3, inclusive. wherein represents hydrogen, or -(CH2)yCOOR 1 such that when is hydrogen, then W is two hydrogen radicals and R' is not hydrogen; and when R' is hydrogen, then is not hydrogen; and wherein m is between one and 5, n is between 1 and 24, and x is zero or 1, inclusive; 920623,dblet 127,35616.res,47 T\>"y r. i r j: A -32-
2. The composition of claim 1 wherein R is -CH 3 n is 4, 10 or 11, is hydrogen or -(CH 2 )yCOOR 1 with y being zero and R 1 being hydrogen, ethyl or methyl; W is oxygen or two hydrogen radicals, Z is -CH 2 m is one or three, x is one and R' is hydrogen or -(CH 2 )yCOOR.
3. The composition of claim 2 wherein R 1 is ethyl.
4. The composition of claim 2 wherein R 1 is methyl. The composition of claim 2 wherein n is eleven.
6. The composition of claim 2 wherein n is eleven,L and m is three.
7. The composition of claim 2 wherein n is ten, W "is two hydrogen radicals, is hydrogen, and R' is 20 -(CH2)yCOOR, with y being zero and R 1 being hydrogen.
8. The composition of claim 5 wherein W is oxygen, m is three and y is one. 25 9. The composition of claim 1 wherein m is three, is hydrogen, x is one, n is ten, W is two hydrogen radicals and R is COOR 1 with R 1 being hydrogen.
10. The composition of claim 1 wherein m is 1 or 2 and n is between 5 and 12, inclusive.
11. The composition of claim 1 wherein n is ten, R is CH 3 is hydrogen, R' is -(CH2)yCOOR 1 with y being zero and R 1 being hydrogen; W is oxygen, x is one and m is one. r, 920624,dbspec.019,35616.res,32 IV I -33-
12. The composition of claim 1 wherein Z is oxygen, is -(CH 2 )yCOOR 1 where y is zero and R 1 is hydrogen, W is oxygen, x is zero, R is -CH 3 n is eleven and, m is two.
13. The composition of claim 12 wherein W is two hydrogen radicals, x is one.
14. The composition of claim 1 wherein W is oxygen, R' is hydrogen, R is -CH 3 is -(CH 2 )yCOOR 1 where y is zero and R1 is hydrogen, n is eleven, x is one and m is three. The composition of claim 1 wherein Z is oxygen, is -(CH 2 )yCOORi where y is zero and R 1 is hydrogen, WL is oxygen, x is zero, R is -CH 3 n is eleven, m is two.
16. The composition of claim 15 wherein W is two S: *hydrogen radicals, x is one.
17. The composition of claim 1 wherein W is oxygen, Z is -CH 2 R' is hydrogen, R is -CH 3 is (CH 2 )yCOOR 1 where y is zero and R 1 is hydrogen, n is eleven, x is one and m is three.
18. The composition of claim 1 wherein the physiologically active agent is an antibacterial agent. *e
19. The composition of claim 18 wherein teh antibacterial agent is an antibiotic. The composition of claim 19 wherein the antibiotic is selected from the group consisting of lincomycin, clindamycin, erythromycin and pharmaceutically useful salts thereof. 920624,dbspecr-19,35616.res,33 1; I -34-
21. The composition of claim 1 wherein the physiologically active agent is a physiologically active steroid.
22. The composition of claim 1 wherein the physiologically active agent is an antifungal agent.
23. The composition of claim 1 wherein the physiologically active agent is iododeoxyuridine.
24. The composition of claim 1 wherein the physiologically active agent is A method for enhancing penetration of physiologically active agents through the skin or mucosal- membranes of humans and animals comprises the topical administration to the skin or mucosal membrane of humans and animals of effective amounts of a physiologically active agent and a membrane penetration enhancer having 20 the structural formula w Sx -CH-(CH 2 )n-R \\CH2)m *s and salts thereof S. wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen sulfur, or two hydrogen radicals; wherein R represents alkyl optionally substituted with one to three double or triple bonds, -CH 3 or COOR 1 wherein represents alkyl, alkylthioalkyl, i alkoxyalkyl, substituted aminoalkyl, optionally 24d 19 16.res ~lA' o 920624,dbspec.019,35616.res,34 substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, -(CH 2 )yCOOR 1 and wherein represents hydrogen or -(CH 2 )yCOOR 1 such that when is hydrogen, then W is two hydrogen radicals; and when R' is hydrogen, then is not hydrogen; and when is hydrogen, then R' is not hydrogen; wherein m is between one and 5 and n is between 1 and 24, inclusive and x is zero or 1; and wherein R 1 represents hydrogen or lower alkyl radical and y is between zero and three, inclusive.
26. The method of claim 25 wherein the physiologically active agent is an antibacterial agent.
27. The method of claim 26 wherein the antibacterial agent is an antibiotic. 20 28. The method of claim 25 wherein the •physiologically active agent is a physiologically active steroid.
29. The method of claim 28 wherein the 25 physiologically active agent is an antifungal agent. The method of claim 25 wherein the physiologically active agent is iododeoxyuridine.
31. The method of claim 25 wherein the physiologically active agent is
32. A composition comprising an effective amount of a physiologically active agent and an effective penetrating amount of a compound represented by the general formula 920624,dbspec.019,35616.res,35 -36- R 2 N-CH-(CH 2 )n-R 4 R' (c 2 )m :3 and salts thereof wherein B represents oxygen, sulfur, or two hydrogen radicals; wherein A represents oxygen, sulfur, or -(CH 2 wherein R, R 2 and R 3 independently represent alkyl optionally substituted with 1 to 3 double or triple bonds, -CH3, or COOR 1 wherein represents hydrogen, alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl optionally substituted with a phenyl, benzoyl, or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH2)yCOORI; wherein represents hydrogen, or -(CH2)yCOOR1; wherein R 1 represents a hydrogen or lower alkyl 25 radical and y is between zero and 3, inclusive; and wherein m is between zero and 5, while n is between 1 and 24, .inclusive. 3.o. The composition of claim 32 wherein A is -CH 2 R 2 is -CH3, R 3 is -CH 3 m is zero, R' is hydrogen, B is two hydrogen radicals, R is -COOR 1 where R 1 is hydrogen, methyl or ethyl, is hydrogen, and n is nine.
34. The composition of claim 33 where R 1 is ethyl. The composition of claim 33 where R 1 is methyl. 920624,dbspec.019,35616.res,36 -37-
36. The composition of claim 32 where A is -CH 2 R 2 is -CH 3 R 3 is -CH 3 m is zero, R' is hydrogen, R is -COOR 1 where R 1 is hydrogen, methyl or ethyl, R' is hydrogen, and n is nine.
37. The composition of claim 36 where R 1 is ethyl.
38. The composition of claim 36 where R 1 is methyl.
39. The composition of claim 32 wherein the antibacterial agent is an antibiotic. The composition of claim 39 wherein the antibiotic is selected from the group consisting of lincomycin, clindamycin, erythromycin and pharmaceutically useful salts thereof.
41. The composition of claim 32 wherein the :physiologically active agent is a physiologically active 20 steroid.
42. The composition of claim 32 wherein the physiologically active agent is an antifungal agent. 25 43. The composition of claim 32 wherein the physiologically active agent is iododeoxyuridine. C 44. The composition of claim 32 wherein the physiologically active agent is A method for enhancing penetration of topically administered active agents through the skin or mucosal membranes of humans and animals comprises the topical administration to the skin or mucosal membrane of humans and animals of effective amounts of a physiologically active agent and a membrane penetration enhancer having aREs the structural formula 920624,dbspec.019,35616.res,37 -38 R 2 N- H-(CH 2 )n-R -R' (C2)m A and salts thereof wherein B represents oxygen, sulfur, or two hydrogen radicals; wherein A represents oxygen, sulfur, or wherein R, R 2 and R 3 independently represent alkyl optionally substituted with 1 to 3 double or triple bonds, -CH 3 or COOR 1 wherein represents hydrogen, alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl optionally substituted with a phenyl, benzoyl, or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH 2 )yCOOR 1 wherein represents hydrogen, or -(CH2)yCOORI; wherein R 1 represents a hydrogen or lower alkyl radical and y is between zero and 3, inclusive; 25 and wherein m is between zero and 5, while n is between 1 end 24, inclusive.
46. The method of claim 45 wherein the physiologically active agent is an antibacterial agent.
47. The method of claim 46 wherein the antibacterial agent is an antibiotic.
48. The method of claim 46 wherein the antibiotic is selected from the group consisting of lincomycin, clindamycin, erythromycin and pharmaceutically useful c salts thereof. 92624dbsp 1935616.res38 920624,dbspec019,35616.res,38 1 -39-
49. The method of claim 45 wherein the physiologically active agent is a physiologically active steroid.
50. The method of claim 45 wherein the physiologically active agent is an antifungal agent.
51. The method of claim 45 wherein the physiologically active agent is iododeoxyuridine.
52. The method of claim 45 wherein the physiologically active agent is
53. A composition comprising an effective amount of a physiologically active agent and an effective penetrating amount of a compound represented by the general formula 20 S" (CH 2 m (CH 2 )n-R2 and salts thereof wherein R 2 is COOR 1 or an alkyl radical optionally substituted with between 1 and 3 double or triple bonds; S* wherein R' is a hydrogen radical, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH 2 )yCOOR; wherein B' is represents oxygen, sulfur, or two hydrogen radicals; wherein represents oxygen or sulfur such that when is oxygen or sulfur, B' is two hydrogen radicals, and R 2 is alkyl, then R' is -(CH 2 )yCOOR 1 where .y is not zero; wherein y is between zero and three, inclusive, and 920624,dbspec0O19,35616.res,39 i a W.J A R 1 represents a lower alkyl or hydrogen radical; and wherein m is between 3 and 6, while n is between 1 and 24, inclusive.
54. The composition of claim 53 wherein teh physiologically active agent is an antibiotic. The composition of claim 54 wherein the antibiotic is selected from the group consisting of lincomycin, clindamycin, erythromycin and pharmaceutically useful salts thereof.
56. The composition of claim 53 wherein the physiologically active agent is a physiologically active steroid.
57. The composition of claim 53 wherein the physiologically active agent is an antifungal agent. 20 58. The composition of claim 53 wherein the physiologically active agent is iododeoxyuridine.
59. The composition of claim 53 wherein the physiologically active agent is
60. A method for enhancing penetration of physiologically active agents through the skin or mucosal membranes of humans and animals comprises the topical administration of effective amounts of a physiologically active agent and a membrane penetration enhancer having the structural formula B' dbspec 920624,dbspec.019,3616.res,40 r -4 41 and salts thereof wherein R 2 is COOR 1 or an alkyl radical optionally substituted with between 1 and 3 double or triple bonds; wherein R' is a hydrogen radical, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, or -(CH 2 )yCOOR 1 wherein B' is represents oxygen, sulfur, or two hydrogen radicals; wherein represents oxygen or sulfur such that when is oxygen or sulfur, B' is two hydrogen radicals, and R 2 is alkyl, then R' is -(CH 2 )yCOOR 1 where y is not zero; wherein y is between zero and three, inclusive, and R 1 represents a lower alkyl or hydrogen radical; and wherein m is between 3 and 6, while n is between Sr1 and 24, inclusive.
61. The method of claim 60 wherein the .rs: physiologically active agent is an antibacterial agent.
62. The method of claim 61 wherein the antibacterial agent is an antibiotic.
63. The method of claim 62 wherein the antibiotic 25 is selected from the group consisting of lincomycin, clindamycin, erythromycin and pharmaceutically useful salts thereof.
64. The method of claim 60 wherein the physiologically active agent is a physiologically active steroid. The method of claim 60 wherein the physiologically active agent is an antifungal agent.
66. The method of claim 60 wherein the FA physiologically active agent is iododeoxyuridine. 920624,dbspec,019,35616.res,41 -42-
67. The method of claim 60 wherein the physiologically active agent is
68. The method of claim 60 wherein m is 1 to 2 and n is 5 to 12, inclusive.
69. A method for causing antiviral activity in humans and animals comprising the topical administration to the skin or mucosal membrane of humans and animals of an effective amount of a composition having the structural formula R" (CH 2 x -CH-(CH2)n-R I R' (CH2)m 20 and salts thereof wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen, sulfur or two hydrogen radicals; 25 wherein R represents alkyl substituted with one to three double or triple bonds -NHR'', -CH 3 or -COOR 1 wherein represents alkyl, alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl, optionally substituted with a phenyl, benzoyl or heterocyclic group; wherein R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy, -(CH 2 )yCOOR 1 wherein represents hydrogen, -(CH 2 )yCOOR 1 such that when is hydrogen, then W is two hydrogen radicals; and when R' is hydrogen, then is not hydrogen; and when is hydrogen, then R' is not Shydrogen; -9 A 920624,dbspec.019,35616.res,67 -7 S1., *1. -43 and wherein m is between one and 5 and n is between 1 and 24, inclusive and x is zero or 1; and wherein R 1 represents hydrogen or lower alkyl radical and y is between zero and three, inclusive. A composition substantially as hereinbefore described with reference to the Examples.
71. A method for enhancing penetration of physiologically active agents through the skin or mucosal membrane of humans and animals substantially as hereinbefore described with reference to the Examples. DATED this 25th day of June, 1992 Whitby Research, Inc. By Its Patent Attorneys DAVIES COLLISON CAVE S S S 920624,dbspec.019,35616.res,43 4, cC 'W~ INTERNATIONAL SEARCH REPORT International Application No. PCT/US89/0 1351 I. CLASSIFICATION OF SUBJECT MATTER (II several classification symbols apply, indicate all) 6 According to International Patent Classification (IPC) or to both National Classification and IPC IPC(4): C09B 67/00; A01N 25/00; A61K 31/70, 31/505, 31/5E U.S.C1: 8/565,568,570;514/24,29,44,169,247,602 71/65. II. FIELDS SEARCHED Minimum Documentation Searched 7 Classification System Classification Symbols U.S. Ci. 65, 5 8, 570, 571, 572, 574, 5 4,602,607; 71/65,11,DIG 1; 514/24,26,29,44,49, ,50,167,169,247 Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included in the Fields Searched 8 III. DOCUMENTS CONSIDERED TO BE RELEVANT 9 Category Citation of Document, 1 with indication, where appropriate, of the relevant passages 12 Relevant to Claim No. 13 A Chemical Abstracts, volume 92, no. 24, 71-75 issued 16 June 1975 (Columbus, Ohio, and K. Shiozawa et. al., "High level- ':2-95 dyed printings," see page 77, column 1, the abstract No. 157718f, Japanese patent 74 36,077, 27 September 1974. A US, A, 4,613,359 (YAMAZAKI et al) 23 76-81 September 1986, see column 2, lines 15-23. And ':6-101 X EP, A, 0241,050 (TSUJI et al) 14 October 1-71 1987, see pages 4 and 9. Special categories of cited documents: 10 later document published after the international filing date document defining the general state of the art which is not or priority date and not in conflict with the application but A consderedfnbeof peargnraevancthe art hch cited to understand the principle or theory underlying the considered to be of particular relevance invention earlier document but published on or after the international document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or involve an inventive step which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other suLh docu. other means ments, such combination being obvious to a person skilled document published prior to the international filing date but in the art, later than the priority date claimed document member of the same patent family IV. CERTIFICATION Date 0 th Actual Crpt n of the International Search Date of Mailing of this International Search Report u 21 JUL 1989 Int ational Searching Authority Signature of Authorized Officer ibA/US Elli Peselev Form PCT/lSA210 (second het) (Rev.11-87)
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