CA1072009A - Potentiated medicaments containing antimicrobial agents - Google Patents
Potentiated medicaments containing antimicrobial agentsInfo
- Publication number
- CA1072009A CA1072009A CA265,435A CA265435A CA1072009A CA 1072009 A CA1072009 A CA 1072009A CA 265435 A CA265435 A CA 265435A CA 1072009 A CA1072009 A CA 1072009A
- Authority
- CA
- Canada
- Prior art keywords
- cyclohexyl
- group
- propanol
- potentiator
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
Abstract of the Disclosure Antimicrobial compositions are provided wherein there is obtained an enhancement of the activity of an anti-microbial agent exemplified by quaternary ammonium compounds, bisdiguamides, anti-fungal agents, phenols, hydroxydiphenyls, carbanilides, salicylanilides, organo-metalic antiseptics, antibiotics, halogens, organic halogen derivatives and iodo-phores derived from monionic surface active agents and from polyvinylpyrrolidone by combining the antimicrobial agent with an effective amount of a potentiator. the potentiator is an alcohol or phenol derivative selected from the group consisting of (a) aliphatic straight or branched chain primary, secondary and tertiary monohydric alcohols wherin the straight chain alcohols have from about 5 to about 10 carbon atoms;
and the branched chain alcohols have up to about 17 carbon atoms, their longest straight chain of carbon to carbon bonds having from about 5 to about 10 carbon atoms; (b) a primary, secondary or tertiary cyclohexylalkanol or alkylcyclohexyl-alkanol where the alkanol is as more fully defined herein-after; (c) a primary, secondary or tertiary phenylalkanol, halophenylalkanol or C1 to C3 alkylphenylalkanol where the alkanol has from about 3 to about 9 carbon atoms; and (d) a cyclohexyl phenol which may have a substituent on the phenyl ring selected form the group consisting of C1 to C3 alkyl and alkoxy, hydroxy, halo, amino and alkyl and dialkyl amino-substituents.
and the branched chain alcohols have up to about 17 carbon atoms, their longest straight chain of carbon to carbon bonds having from about 5 to about 10 carbon atoms; (b) a primary, secondary or tertiary cyclohexylalkanol or alkylcyclohexyl-alkanol where the alkanol is as more fully defined herein-after; (c) a primary, secondary or tertiary phenylalkanol, halophenylalkanol or C1 to C3 alkylphenylalkanol where the alkanol has from about 3 to about 9 carbon atoms; and (d) a cyclohexyl phenol which may have a substituent on the phenyl ring selected form the group consisting of C1 to C3 alkyl and alkoxy, hydroxy, halo, amino and alkyl and dialkyl amino-substituents.
Description
lO~Z009 Background o~ the Invention In one aspect, this invention relates to antimicrobial compositions. More particularly, it relates to the discovery that a broad group of known antimicrobial agents have increased activity, either in terms of spectrum, killing power, or both when used in combination with the potentiating agents of this invention Ordinarily, the activity or killing power of known antimicrobial agents are inh~bited in the presence of blood~
would exudates and other proteinaceous matter including æerum proteins, together with saliva, sebaceous secretions, nasal and other muceous secretions.
; Although it has been raaliæed for some time that antibacterial agents lose their efficacy in the presence of blood~ bodily secretions such as milk serum and wou~d exudates the cause of this loss of efficacy or inactivation is not as yet fully understood~ It has been postulated, however~ that the lipophilic character of the antimicrobial agent is responsible for both protein binding and antimicrobial activity. In the presence of such extraneous proteinaceous matter as blood, the antimicrobial agent preferentially binds ~ to the serum proteins or other proteinaceo~s matter rather ,/! than to the bacterial cells Under oonditions where this desired preferential binding can occur, the antimicrobial agent is either ineffective or its efficacy is so reduced that greatly increased dosage levels are re~uired ~ .
, ~ .
;` J&J ~31 ~lV7'Z0~9 The ext~nt of this loss in actlvlty can app~o~ch 90 percentor more . F~r example, the antlmicrobial ac l;iv~ty of' quaternary ammonium compoun~ls can be so suppressed i.n the pres~nce of protelnaceous body fiuids that activity loss~s in excess o~ 96 percent have been recorded.
~ lle the lack of preslse knowledge und under-~tanding of t~e inactivation mechanism has hampered the development of topical antimtcroblal preparatlons which are effectlve in the presence o~ the in~ctivating materials above re~erred to, it has long been a desired and sought ~or goal to develop antlmicrobial compos~tions that could over~
come this inactivation.
Therefore9 an important feature o~ the present ~nvention is to provide compositions which include known ant~bacterlal, ~ntiviral or anti~un~al agents together with a potentiator ~or such a~ents so as to overcome the descti~ating ef~ect o~ proteinaceQus substances and to ~ignifîcan~ly increase the k~lling e~ficacy ~r to extend the antimicrobial spectrum of the antlmicrobial agent, i~.) or to have both enhancing e~ects, Enhancement o~ drug absorption through the intact skin has been pursued b~ many ~n~estigators in recent tlmes.
Most of these studies showed that the stratum corneum of the skln, the uppermost or horny layer, acts as a protectlve barrier a~ainst the extsrior environment. The stratum corneum consists of dead cells that are extensively ker~tinized and dehydrated. ~ue to the nature o~ the , highly crossllnked and insoluble keratin~ the barrier -~ pr~perty of this layer changes little upon exposure to various environmental condltlons.
Because o~ the lmpermeable nature o~ the ~tratum corneum, it has been a long deslred goal to temporarily .' ' ' .
~ - 4 -. .
~J ~31 ~ 2~g modir~r the barr~er property o~ this layer in order to enhance the penetrat~on o~ topically appl~ed drugs.
Espec~lly in der~tological condi~ions, topical ~pplic~tion of medicaments i~ pre~erred o~er systemic administration9 because the topically applied drug direc~ly attacks the a~ected target cells, Furthermore~ topical treatment eliminates ~ystem~c side e~ec~ that are ~requently associated with long term oral therapy.
Pre~ous studies h~e shown that dimethylsul~oxide tDM~O~ can enhance the ~bsorption of topically applied drugs through the stratwm corneumO Simllarly~ dimethyl ~ormamide tDMFA) and N3N-dlmethyl-acetamide (DMA) and their derivatlves are claimed to do the same. Some o~ these comb~nations are described i~ U.S. Patents Nos. 3,551,554 and 3,472,931.
` Other recent ~tudies on the phy~ico-chemical properties o~ the stratum corneum and the absorptlon o~
topicall~ applied drugs therethrough include: Scheuplein, R.J., J. Invest, Dermatol. 45, 334 (1966)~ Blank, I.~., J. Invest.
.~ Dermatol. 43, 415 (1964), Hadgra~t3 ~,W. and ~omers, &~F "
J, Pharm, Pharmacol. 8, 625 (1956); and Grasso, P. and Iansdowng A,B.G., J. Soc. Cosmet. Chem. 23~ 481-521 (1972).
~hu~, in accordance with another ~eature o~ the ; present invention, there are provided topical composition~
comprislng a known medicament9 exempli~ied by the anesthetics~
; and a potent~ator, whereby the pene~ratlon o~ topically applied anesthetic or other agents through the ~tratum corneum are substantially enhanced, As an example, enhanced penetration o~ the a~e~thetic agent by the aetion o~ the ~otentiator or acceler~tor re~ults in ~ ~uicker onset and deeper anesthesia at the treated site, than that which ls `:
.
~ 5 ~
,~
. . .
J&J 831 107X0~9 obtained without the acceler~tor, Furthermore, anesthesia ~t t,he ~ite o~ application le~ts up to several hours~
Conventional preparat~ons elicit only ~ur~ace anesthesia and onset times sometimeR extend to hours. Most con~entional preparations, moreov~r~ ha~e been reported to be ine~ectlve on intact skin [~drlani, ~0 and Dal~ nesthesia and Analges~a, Current Re~earche~, Vol. ~0, ~o. 5 (Sept.-Oct.
197~1 ) ] .
Summar~ ____he Inve~ ~on lQ It hQ6 no~ been disco~ered that the ~oregoing and other advant~ges which will become apparent upon ~urther reading are achieYed, in one em~odiment o~ the lnvention, by pro~id~ng an antimicrobial composition which includes~
tQgether with an antimicrobial agent~ a potenti~tor therefor as de~ined herein. The antimicrobial agent can be selected from the group consi~ting o~ quaternary ammonium compounds, bisdiguan~des, anti-~ungal agents, phenols, hydroxydiphenyls, ca~banilides, salicylanilides, organomet~lllc ant~ept~cs, antibiotics, iodine and organ~c iodine der~a~ves an~ ~odophores deri~ed ~rom nonionic wetting agents and from polyvinyl~yrrolidone~
and 1~ use~ in accordance with the present in~ention in combinatlon with a potent~ator o~ the type hereina~ter . de cribed.
It has also been d~sco~ered, in accordance with another embod~ment o~ the present ln~ention, that enhanced penetrat~on through the sk~n of known medlcament~ and ; lncreased topical actlvity thereof is pro~ided by a com-position compris~ng a known medicP~ent i~ combinatlon with a ~elected penetration accelerating potentiator thereror, ~ 831 :1072~0~
q~ med~ ~ament may be ~elec~ed ;~rom the group conslsting o~ anest;~letics3 antiinflammatory ~ents 7 antlmlcrobial a~nts including antibacterlal and arltiYir~l agents ~ cell regulatory agcn~s and the like. The potentiators for this aspect of the invent~on, as hereina~ter de~inedg include many o~ the compounds which are use~ul ~s potent~ators ~n the antimicrobial compositions o~ the pr~sen~ i~ventio~.
As used herein, the term "potentiator" i mean~
to indicate on the one hand, that the compound enhances t~e acti~ity of an antimicrobial agent o~er whQt lt ordinarily would be i~ otherwise u~ed al~ne. It ~lso w~ll be seen later th~t a num~er o~ combinat~ons Or antimicrobial agents and potentiators of the in~ention can be considered to ha~e a 3ynergistic ef~ect $n that the spectrum o~ the antlmicrobial COmpOSitiQn ~S extended to organism~ w~lch are not susceptible to either the anti-microbial agent or the potentiator when each is $ndi~idually employed at an equi~alent concentration, ~sr example griseo~ul~in when combinea with the potentiator 2,3-dimethyl~
would exudates and other proteinaceous matter including æerum proteins, together with saliva, sebaceous secretions, nasal and other muceous secretions.
; Although it has been raaliæed for some time that antibacterial agents lose their efficacy in the presence of blood~ bodily secretions such as milk serum and wou~d exudates the cause of this loss of efficacy or inactivation is not as yet fully understood~ It has been postulated, however~ that the lipophilic character of the antimicrobial agent is responsible for both protein binding and antimicrobial activity. In the presence of such extraneous proteinaceous matter as blood, the antimicrobial agent preferentially binds ~ to the serum proteins or other proteinaceo~s matter rather ,/! than to the bacterial cells Under oonditions where this desired preferential binding can occur, the antimicrobial agent is either ineffective or its efficacy is so reduced that greatly increased dosage levels are re~uired ~ .
, ~ .
;` J&J ~31 ~lV7'Z0~9 The ext~nt of this loss in actlvlty can app~o~ch 90 percentor more . F~r example, the antlmicrobial ac l;iv~ty of' quaternary ammonium compoun~ls can be so suppressed i.n the pres~nce of protelnaceous body fiuids that activity loss~s in excess o~ 96 percent have been recorded.
~ lle the lack of preslse knowledge und under-~tanding of t~e inactivation mechanism has hampered the development of topical antimtcroblal preparatlons which are effectlve in the presence o~ the in~ctivating materials above re~erred to, it has long been a desired and sought ~or goal to develop antlmicrobial compos~tions that could over~
come this inactivation.
Therefore9 an important feature o~ the present ~nvention is to provide compositions which include known ant~bacterlal, ~ntiviral or anti~un~al agents together with a potentiator ~or such a~ents so as to overcome the descti~ating ef~ect o~ proteinaceQus substances and to ~ignifîcan~ly increase the k~lling e~ficacy ~r to extend the antimicrobial spectrum of the antlmicrobial agent, i~.) or to have both enhancing e~ects, Enhancement o~ drug absorption through the intact skin has been pursued b~ many ~n~estigators in recent tlmes.
Most of these studies showed that the stratum corneum of the skln, the uppermost or horny layer, acts as a protectlve barrier a~ainst the extsrior environment. The stratum corneum consists of dead cells that are extensively ker~tinized and dehydrated. ~ue to the nature o~ the , highly crossllnked and insoluble keratin~ the barrier -~ pr~perty of this layer changes little upon exposure to various environmental condltlons.
Because o~ the lmpermeable nature o~ the ~tratum corneum, it has been a long deslred goal to temporarily .' ' ' .
~ - 4 -. .
~J ~31 ~ 2~g modir~r the barr~er property o~ this layer in order to enhance the penetrat~on o~ topically appl~ed drugs.
Espec~lly in der~tological condi~ions, topical ~pplic~tion of medicaments i~ pre~erred o~er systemic administration9 because the topically applied drug direc~ly attacks the a~ected target cells, Furthermore~ topical treatment eliminates ~ystem~c side e~ec~ that are ~requently associated with long term oral therapy.
Pre~ous studies h~e shown that dimethylsul~oxide tDM~O~ can enhance the ~bsorption of topically applied drugs through the stratwm corneumO Simllarly~ dimethyl ~ormamide tDMFA) and N3N-dlmethyl-acetamide (DMA) and their derivatlves are claimed to do the same. Some o~ these comb~nations are described i~ U.S. Patents Nos. 3,551,554 and 3,472,931.
` Other recent ~tudies on the phy~ico-chemical properties o~ the stratum corneum and the absorptlon o~
topicall~ applied drugs therethrough include: Scheuplein, R.J., J. Invest, Dermatol. 45, 334 (1966)~ Blank, I.~., J. Invest.
.~ Dermatol. 43, 415 (1964), Hadgra~t3 ~,W. and ~omers, &~F "
J, Pharm, Pharmacol. 8, 625 (1956); and Grasso, P. and Iansdowng A,B.G., J. Soc. Cosmet. Chem. 23~ 481-521 (1972).
~hu~, in accordance with another ~eature o~ the ; present invention, there are provided topical composition~
comprislng a known medicament9 exempli~ied by the anesthetics~
; and a potent~ator, whereby the pene~ratlon o~ topically applied anesthetic or other agents through the ~tratum corneum are substantially enhanced, As an example, enhanced penetration o~ the a~e~thetic agent by the aetion o~ the ~otentiator or acceler~tor re~ults in ~ ~uicker onset and deeper anesthesia at the treated site, than that which ls `:
.
~ 5 ~
,~
. . .
J&J 831 107X0~9 obtained without the acceler~tor, Furthermore, anesthesia ~t t,he ~ite o~ application le~ts up to several hours~
Conventional preparat~ons elicit only ~ur~ace anesthesia and onset times sometimeR extend to hours. Most con~entional preparations, moreov~r~ ha~e been reported to be ine~ectlve on intact skin [~drlani, ~0 and Dal~ nesthesia and Analges~a, Current Re~earche~, Vol. ~0, ~o. 5 (Sept.-Oct.
197~1 ) ] .
Summar~ ____he Inve~ ~on lQ It hQ6 no~ been disco~ered that the ~oregoing and other advant~ges which will become apparent upon ~urther reading are achieYed, in one em~odiment o~ the lnvention, by pro~id~ng an antimicrobial composition which includes~
tQgether with an antimicrobial agent~ a potenti~tor therefor as de~ined herein. The antimicrobial agent can be selected from the group consi~ting o~ quaternary ammonium compounds, bisdiguan~des, anti-~ungal agents, phenols, hydroxydiphenyls, ca~banilides, salicylanilides, organomet~lllc ant~ept~cs, antibiotics, iodine and organ~c iodine der~a~ves an~ ~odophores deri~ed ~rom nonionic wetting agents and from polyvinyl~yrrolidone~
and 1~ use~ in accordance with the present in~ention in combinatlon with a potent~ator o~ the type hereina~ter . de cribed.
It has also been d~sco~ered, in accordance with another embod~ment o~ the present ln~ention, that enhanced penetrat~on through the sk~n of known medlcament~ and ; lncreased topical actlvity thereof is pro~ided by a com-position compris~ng a known medicP~ent i~ combinatlon with a ~elected penetration accelerating potentiator thereror, ~ 831 :1072~0~
q~ med~ ~ament may be ~elec~ed ;~rom the group conslsting o~ anest;~letics3 antiinflammatory ~ents 7 antlmlcrobial a~nts including antibacterlal and arltiYir~l agents ~ cell regulatory agcn~s and the like. The potentiators for this aspect of the invent~on, as hereina~ter de~inedg include many o~ the compounds which are use~ul ~s potent~ators ~n the antimicrobial compositions o~ the pr~sen~ i~ventio~.
As used herein, the term "potentiator" i mean~
to indicate on the one hand, that the compound enhances t~e acti~ity of an antimicrobial agent o~er whQt lt ordinarily would be i~ otherwise u~ed al~ne. It ~lso w~ll be seen later th~t a num~er o~ combinat~ons Or antimicrobial agents and potentiators of the in~ention can be considered to ha~e a 3ynergistic ef~ect $n that the spectrum o~ the antlmicrobial COmpOSitiQn ~S extended to organism~ w~lch are not susceptible to either the anti-microbial agent or the potentiator when each is $ndi~idually employed at an equi~alent concentration, ~sr example griseo~ul~in when combinea with the potentiator 2,3-dimethyl~
2-hexanol is e~ecti~e against the otherwl~e resistant Candida albicans.
Enhanced actiYity, or potentiation, is also exhibited by the various potentiator-ant~microbial ~ combi~ tions of the present invention not ~nly when the , ~5 spectrum of activity o~ the combin~tions of this in~ent~on is broader than when either component o~ the combinations is : used alone, but also in substant~ally greater ac~ ty of the csmbination ag~inst a gi~en org~nism than could be accounted ~or by a simple addltive e~fect. Potentiatio~ o~ . 30 the topical compositi~ns of the present inventlon may be ~,0,7Z~o9 exhibited by either or both of enhanced penetration through skin or a like biological barrier and greater activity than could be expected from any additive effects of the active compound and the potentiator.
Description of the Preferred Embodiments Antimicrobial Compositions ,: ~
The antimicrobi~l compositions of the invention comprise an antimicrobial agent and a potentiator therefor. In use, the combination of antimicrobial agent and potentiator is preferably dissolved, suspended or dispersed in a suitable carrier. Although generally not as desirable as employing a ~
separate carrier, it has been found suitable to employ the same -chemical compound as both the potentiator and the carrier, thus eliminating the need for a separate carrier or vehicle.
Antimicrobial Agents Examples of antimicrobial agents which may be employed in the potentiated antimicrobial compositions of this invention include the antibiotics such as tetracycline, oxytetracycline, chlorotetracycline, neomycin, erythromycin and its derivatives, bacitracin, streptomycin, rifampicin and its derivatives, such as N-demethylrifampicin, kanamycin and chloromycetin; the anti-fungal agents such as griseofulvin, mycostatin, miconazole, and its derivatives as described in U.S. Patent No. 3,717,655;
bisdiguanides such as chlorhexidine; quaternary ammonium compounds such as domiphen bromide, domiphen chloride, domiphen fluoride, benzalkonium `
chloride, cetyl pyridinium chloride, dequalinium chloride, the cis isomer of 1-(3-chloroallyl~-3,5,7-triaza-l-azoniaadamantane ` chloride (available . ~ :
-~ ' .'', " ~&J 831 ~ 009 con~ercially ~rom the Dow Che~lical Company under the trademark Dowicil 200) and its analogues ~ descr~bed ~n U.S. P~tent No. 3,22~,~29, ce~yl trimethyl ammon~um bromide as well as ben2ethonium chloride and metblbenzethonium chloride such as descr$bed ~n U.S. Patents Nos, 2,170,111, 2,115~250 and 2,229,024; the carbanilides and salicylanilides such as 39494'-tr~chlorocarbanllide, ~nd 3,~'5~
tribromosal~cylanllide; the hydroxydiphenyls such as dichlorophene, tetrachlorophene, hexachloropheneg and ~,4,4'-trichloro-2'-hydroxydiphenylether; and organometallic and halogen ~ntiseptics ~uch as zinc pyrithione, sil~er sul~adiaz~ne, s~lver uracil, iodine, and the iodophores derived ~rom non-ionic sur~ace active agents such as are descrlbed in U.S, Patent~ I~os. 2,710,277 and 2,977~315 and from polyvinylpyrrolidone such as described in U~S.
Patents Nos0 2,706,701, 2,8269532 and 2~900,305.
Potentiat,ors The potentiators which can be sulta~ly employed in the antim~crobial composi~$ons o~ this invention include members selected from t~e group consisting vf:
-, I. Primary, secondary and tertiary straight or branched chain monohydric aliphatic alcohol~, wherein the s~raight chain alcohols have from about 5 to about 10 carbon atoms and the branched chain alcohols ha~e up to ab~ut 17 carb~n atoms, the~r longest chain of carbon to carbon bonds ha~ing ~rom about 5 to about 10 carbon atoms;
_ g ~
- J&~ 831 l~qz~as II, A cyclohexyl substituted alkanol of the structure . - R?--Rl~a ic3 CH
wherein Rl is Cl to C4 al~ halogen or hydro~;en; R2 andR3 are ~ndependen~ly selected ~rom hydrogen, Cl to C3 alkyl, and cyclopropyl; and n i s 1 to 4, provided that only one 10 of said R2 and R3 of a .. -- C --moiety may be propyl or cy;clopropyl;
III. Phenyl alkanols o~ the structure R4~ ~ - C- ~OH
; : 5R5 m wherein m is O or l; R4 is hydrogen, halogen, Cl to C4 0 alkyl, or cyclopropyl; R59 R6 and R7 are ~ndependently :~ selected ~rom hydro~en, Cl to C3 allcyl and cyclopropyl, -` provided~ however that only one of` R5, R~; and R7 is a propyl or cyclopropyl group, and ~ when m i8 0~ at least one R5 is other than hydro~;en3 and the total of the carbon ~5 atoms in the structure :. R5R5 P~6 C - t:--C----OH
R5R5 ~7 m i~ ~rom 3 to 9 carbon atoms 9 and - 10 _ ' .
~W 831 OOg IV. Phenol derlvative~ of the structure ' ~8 ~
where R8 i~ hydrogen~ Cl to C3 alkyl, Cl to C3 alkoxy, hydroxyl halogen, am~no, or mono or di Cl to C3 alkyl am~no, providea that the total number of carbon atoms in the ~lkyl gl`OUpS substituted on the amino does not exceed 5 carbcn at~ms. Pre~erably, when R8 is halogen, dl-Cl to C3 alkylamlno9 or Cl to C3 alkoxy, then R8 i~
to the phenolic hydroxyl group.
Examples o~ the p~eferred aliph~t~c alcohol potentiators. from Group I include: n-hexanol5 n-heptanol;
n-octanol; n-nonanol; n-decan~l; 2,3-dimethy1-2-hexanol;
2~5-dimethyl-2-hexanol; 2-methyl-3-hexanol; 2-heptanol;
:j
Enhanced actiYity, or potentiation, is also exhibited by the various potentiator-ant~microbial ~ combi~ tions of the present invention not ~nly when the , ~5 spectrum of activity o~ the combin~tions of this in~ent~on is broader than when either component o~ the combinations is : used alone, but also in substant~ally greater ac~ ty of the csmbination ag~inst a gi~en org~nism than could be accounted ~or by a simple addltive e~fect. Potentiatio~ o~ . 30 the topical compositi~ns of the present inventlon may be ~,0,7Z~o9 exhibited by either or both of enhanced penetration through skin or a like biological barrier and greater activity than could be expected from any additive effects of the active compound and the potentiator.
Description of the Preferred Embodiments Antimicrobial Compositions ,: ~
The antimicrobi~l compositions of the invention comprise an antimicrobial agent and a potentiator therefor. In use, the combination of antimicrobial agent and potentiator is preferably dissolved, suspended or dispersed in a suitable carrier. Although generally not as desirable as employing a ~
separate carrier, it has been found suitable to employ the same -chemical compound as both the potentiator and the carrier, thus eliminating the need for a separate carrier or vehicle.
Antimicrobial Agents Examples of antimicrobial agents which may be employed in the potentiated antimicrobial compositions of this invention include the antibiotics such as tetracycline, oxytetracycline, chlorotetracycline, neomycin, erythromycin and its derivatives, bacitracin, streptomycin, rifampicin and its derivatives, such as N-demethylrifampicin, kanamycin and chloromycetin; the anti-fungal agents such as griseofulvin, mycostatin, miconazole, and its derivatives as described in U.S. Patent No. 3,717,655;
bisdiguanides such as chlorhexidine; quaternary ammonium compounds such as domiphen bromide, domiphen chloride, domiphen fluoride, benzalkonium `
chloride, cetyl pyridinium chloride, dequalinium chloride, the cis isomer of 1-(3-chloroallyl~-3,5,7-triaza-l-azoniaadamantane ` chloride (available . ~ :
-~ ' .'', " ~&J 831 ~ 009 con~ercially ~rom the Dow Che~lical Company under the trademark Dowicil 200) and its analogues ~ descr~bed ~n U.S. P~tent No. 3,22~,~29, ce~yl trimethyl ammon~um bromide as well as ben2ethonium chloride and metblbenzethonium chloride such as descr$bed ~n U.S. Patents Nos, 2,170,111, 2,115~250 and 2,229,024; the carbanilides and salicylanilides such as 39494'-tr~chlorocarbanllide, ~nd 3,~'5~
tribromosal~cylanllide; the hydroxydiphenyls such as dichlorophene, tetrachlorophene, hexachloropheneg and ~,4,4'-trichloro-2'-hydroxydiphenylether; and organometallic and halogen ~ntiseptics ~uch as zinc pyrithione, sil~er sul~adiaz~ne, s~lver uracil, iodine, and the iodophores derived ~rom non-ionic sur~ace active agents such as are descrlbed in U.S, Patent~ I~os. 2,710,277 and 2,977~315 and from polyvinylpyrrolidone such as described in U~S.
Patents Nos0 2,706,701, 2,8269532 and 2~900,305.
Potentiat,ors The potentiators which can be sulta~ly employed in the antim~crobial composi~$ons o~ this invention include members selected from t~e group consisting vf:
-, I. Primary, secondary and tertiary straight or branched chain monohydric aliphatic alcohol~, wherein the s~raight chain alcohols have from about 5 to about 10 carbon atoms and the branched chain alcohols ha~e up to ab~ut 17 carb~n atoms, the~r longest chain of carbon to carbon bonds ha~ing ~rom about 5 to about 10 carbon atoms;
_ g ~
- J&~ 831 l~qz~as II, A cyclohexyl substituted alkanol of the structure . - R?--Rl~a ic3 CH
wherein Rl is Cl to C4 al~ halogen or hydro~;en; R2 andR3 are ~ndependen~ly selected ~rom hydrogen, Cl to C3 alkyl, and cyclopropyl; and n i s 1 to 4, provided that only one 10 of said R2 and R3 of a .. -- C --moiety may be propyl or cy;clopropyl;
III. Phenyl alkanols o~ the structure R4~ ~ - C- ~OH
; : 5R5 m wherein m is O or l; R4 is hydrogen, halogen, Cl to C4 0 alkyl, or cyclopropyl; R59 R6 and R7 are ~ndependently :~ selected ~rom hydro~en, Cl to C3 allcyl and cyclopropyl, -` provided~ however that only one of` R5, R~; and R7 is a propyl or cyclopropyl group, and ~ when m i8 0~ at least one R5 is other than hydro~;en3 and the total of the carbon ~5 atoms in the structure :. R5R5 P~6 C - t:--C----OH
R5R5 ~7 m i~ ~rom 3 to 9 carbon atoms 9 and - 10 _ ' .
~W 831 OOg IV. Phenol derlvative~ of the structure ' ~8 ~
where R8 i~ hydrogen~ Cl to C3 alkyl, Cl to C3 alkoxy, hydroxyl halogen, am~no, or mono or di Cl to C3 alkyl am~no, providea that the total number of carbon atoms in the ~lkyl gl`OUpS substituted on the amino does not exceed 5 carbcn at~ms. Pre~erably, when R8 is halogen, dl-Cl to C3 alkylamlno9 or Cl to C3 alkoxy, then R8 i~
to the phenolic hydroxyl group.
Examples o~ the p~eferred aliph~t~c alcohol potentiators. from Group I include: n-hexanol5 n-heptanol;
n-octanol; n-nonanol; n-decan~l; 2,3-dimethy1-2-hexanol;
2~5-dimethyl-2-hexanol; 2-methyl-3-hexanol; 2-heptanol;
:j
3-heptanol, 4-heptanoI and 2-ethyl-1-hexanol, Examples ~r the:pre~erred potentiators ~rom Group II include: cyclQhexylmethanol; l-cyclohexylethanol, 2-cyclohexy~ethanol; l-cyclohexyl-l-propanol; (cycl~hexyl)-~0 d~me~hyl-carbinol; t4-isopropylcyclo~exyl)-dimethylcarb~nol;
( 3-cyclohexyl-1-propanol; 2-cyclohexyl-1-propanol;
l-cyclohexyl-2-propanol; ?-cyclohexyl~ dimethylethanol;
2-cyclohexyl-2-methylprop~nol; 2-cyc1ohexyl-l~metbglpropansl;
~;~, 2-cyclohexyl~1,2-dimethylpropanol; 2-cyclohexyl~l 3 1-25 dimethylpropanol; 3-cyclohexyl-2-methylpropanol, 3~cycl~-hexyl-l methylpropanol; 3-cyclohexylbu~anol, 3-cyclohexyl-2-methylbutanol; and 3-cyclohexyl-132-dimethylbut~nol~
.
~; Pre~er~ed examples from Group III include: 3-phenyl-l-propanol; benzyl-t-but~nol~ l-(p-~hlorophenyl) 30 2-methyl-2-propanola 1-phenyl-2-methyl-2-propanol, l-phenyl-' 10~0~9 ~
"' ,'~';
:' 3-butanol; 2-methyl-3-phenyl-propanol; 2,2-dimethyl-3-phenyl~
propanol; 3~-p-chlorophenyl) propanol; 4(-p-chlorophenyl)-2- ~`
"..:.
butanol; 2,2-dimethyl-3(p-chlorophenyl)-propanol, 2-methyl-3(p-chlorophenyl)-propanol; l-phenyl-2-propanol; and l-(p-chloro~
phenyl)-2-propanol. ~ ; ;
Preferred examples ~rom Group IV include: 2-cyclo-hexylphenol; 4-cyclohexylresorcinol; 2-chloro-6-cyclohexyl-phenol; 4-amino~2-cyclohexylphenol hydrochloride; o-cyclohexyl- ~ ~
p-methoxyphenyl; o-cyclohexyl-p-cresol; o-(4-methylcyclohexyl)- ` ~;
10 p-cresol; and 4-chloro-2-cyclohexylphenol.
Illustrative Antimicrobial Compositions The antimicrobial compositions of this invention include at least one antimicrobial agent and at least one of the potentiators selected from Groups I, II, III and IV. In general, the composition comprises at least 0.1 percent of the ~¦ potentiator and at least 0.001 percent of the antimicrobial ~ agent. However amounts of as little as 0.05 percent potentiator ri have been found to be effective when the potentiator is selected from compounds of Group IV. The balance of the composition, if `~
' 20 any, is supplied by a suitable carrier as is hereinafter des-.~ ,.
cribed. Generally, the antimicrobial agent is employed in a " :.
quan~ity less than that of the potentiator. It is entirely suit- ; ~
,; , ~
able that up to 99.999~ of the composition be potentiator~ thus ... . . .
~!, obviating the need for using as additional component as a carrier. ~ ;
However, if desired, a carrier, preferably ethanol, can be employed. The more desirable compositions comprise from 0.1 to `
~; 90.0 percent potentiator and 0.001 to about 10.0 percent anti- ~ ~
`':'.' ::.:
microbial agent, and preferably from 0.1 to 10.0 percent poten- `~
~- tiator and from 0.001 to 0.5 percent antimicrobial ~:~
-12- ~ ~
; ,'' , .
:' .
J&~ 83 lO~Z009 ~gent, depen~ing on the pa rticular materi~ls used, ~rith the balance c~f th- composition co;.~prisin~; a suitable carrier, or combination of` carriers~ Ex~mples of such. compositions are ethanol solutions of: 0 , 05% micona 70le and 0, 50~ l-cyclo-~; hexylethanol; 0.05~ neomycin sul~te and 0,t~0% 2-cyclo-hexylethanol, 0O05~ tetracycline ~nd 0.75% n-hexanol, 0.05%
tetracycline and o.50% l-c~clohexylc~hanol; 0005% neomycin ~ul~ate and 0~75~ X,3-dimethyl-2-hexanol; 0~05~ neomycin sul~a~e and 0.75% l-cyclohexylethanol; 0,75~ iodine and 0,40~ 2-cyclohexylethanol3 and 0,05~ 3,3',4,5'-tetrachloro-salicylanil~de and 0.5~% l-cyclohexylethanol.
Examples o~ the Qntimicroblal composittons o~ this invention where there is a synergistic e~ect provided by the combin~t1on of the antimicroblal agent and the potenti~tor include ethanol s~lutions of: 0.05% 3,3'~l~35-tetrachloro-salicylanilide and 0.50% n-hexanol~ 0.025% dequalin~um chloride and 0.50~ chlorophenyl)-2-methyl-?-propanol;
0.025% domiphen bromide and 1.0% n-pentanol; 0.025% domlphen bromide and 0,75$ ~-heptan~l, 0.025~ domiphen bromide and 0 0.50% 2g3-d~methyl-2-hexanol, 0.025% domiphen bromide and 0.75~ 2,3-dimethyl-2-hexanol; 0.0125~ dom~phen bromide and o.6~ hexanol; 0.05~ hibitane and 0.10% 2-cyclohexylphenol;
0,05% griseo~ulv~n and 0,75% hexanol; 0.0~% griseo~ul~in ~nd 0.5~ 2,3-dimethyl-2-hexanol3 0.05% griseofu~v~n and " 25 0.75% 2,3-dimethyl-?-hexanol; 0.05% grlseo~ul~in a~d 005%
l-cyclohexylethanol; 0.05% griseo~ul~n and 0.75% 1-cyclohexyl-ethanol; 0.05% ~etra~ycline and 0.~% 1-( -chlorophe~yl)-2-methyl-2-propanol; 0.1% zinc pyrith~one and 0~5~
- cyc~ohexylethanol; 0~1% zlnc pyrlthione and 0,75~ 2,3-dimethyl-2-hexanol; loO~ zlnc pyrlthione ~nd 0.5% 1-.
..
J~ ~31 1~7Z~Og ( -chlorophen~ methyl~2-propanol; and 0.5~ zinc p~ithiolle and o.6~ ~-c~cloh~xylethallOl.
. In use, the antimic~obial agcnt and the ~otentlator &re conveniently dissol~ed or dispersed in an lner~ f~uid medium whlch serves as a carrier. The term inert means that khe carrier does n~t ha~e a del~terious e~fect on the anti-microb~al agent upon storage, nor substanti~lly diminish its acti~ty, nor ad~ersely react w~th any other component of the composition o~ this invention. Suitable carrier lnclude water, l~er alkanol~ such as ethanol3 the known pharmaceutlcal Yehicles such as cc~n~entionally employed ~or topical applica-atlons such, for example, as olntments, creams, lotions, aerosols, suspen~ions snd solutions. The pre~erred carriers ~re ethanol and water.
~
The top~cal compositions of the present invention exhibiting enhRnced penetration through the intac~ skin or enhanced to~lcal activity comprise~ ~n admixture, a medicament, ~or example~ an anesthetic compound, su~h as lidocalne, benzocalne, tetracain, carbocaine~ rodocaine, etc., with a potentiatorO This ma~ be employed in any of the known forms ~or applying medicaments topically~ including 801ut~0ns, cream~, gels and the like. Preferably both the known med~cament and the potentiator are dissol~ed~ suspended or dispersed in ~ suitab~e carrier. As in the case of the antlmlcrobial compositions of thP present invention, the potentiator may al80 serve as the carrler, alth~u~h, generally, a separate pharmaceutically a~ceptable carrler ~s preferred~ and an aqueous carrier ~s partlcularly pre~erred.
~ ~ 14 -, ..
J8~J 831 `` :lOqZ009 Potentiators __ .
For the ~opical compositions of the present l~ent$on9 the potentiator is selected ~rom the grc~up con ~t~n~; o~:
I. Prim~ryg second~ry and tertiary ~tr~i~sht or brarlched chain monohydri-~ aliphatic alcoh~ls whereln the ~traight cha~n alcohols ha~re rrc~m about 5 to about 10 car~on atoms and the branched chain alcohols haYe up to about 17 carbon atoms, ~helr longe~t chain o~ carbon to c~rbon bondæ
h2~ n~s ~rom abou~ 5 to a~out 10 carboll atoms 3 II. A cyclohexyl æubstituted alkanol Df` the ~tructure 1~
R~ - C----OR
~herein ~1 is Cl to C4 alkyl, ha ogen or hydrogen; R2 and R3 are ~ndependently selected ~rom hydrogen, Cl to C3 ~ij al~cyl, and cyclopropyl, and ~ ls 1 to 4, pro~rid~d that ~;; o~ly one of' said R2 and R3 of a : R2 . j ~ C
: -3 moiety may be propyl or cyclopropyl; and III. Phenyl alkanols o~ the Rtructure l 5~5 R~;
R,4~--C lC tC~
~rhereln m i8 0 or ~; R4 i~ hydrogen, halogen, Cl to C4 - allcyl3 or c~clc)propyl; R5, R6 and R7 are ~ ndependently selected f`rom hydrvgen, Cl to C3 alkyl and eyclopropyl3 .
J&3 ~31 ~20~9 provided, h~wever, that only one of R5. Rh and R7 is ~
propyl or cyclopropyl ~I`OUp ~ and when m is O, ~t least one R5 i~ ~ther than hydro~en; and the total o~. the carbon atoms $n the structure l5~5 l~ . .
_f f_ I --OH
, 5 5 _ 7 m is ~rom 3 to 9 carbon atoms.
Examples o~ the p eferred aliphatlc alcohol potentiators from ~roup ~ include: n-pentanol; n-hexanol, n-heptanol; n-octanol; n-nonanol; n-dec~nol; ~,3-dimethyl-2~hexanol, 2,5-dimethyl-2-hexanol~ 2-methy1-3 hexanol; 2 heptanol; 3-heptanol; 4heptanol and 2-ethyl-1-hexanol.
Examples o~ the pre~erred potentiators ~rom 1~ Group II include: cyclohexylmethanol, l-cyclohexylethanol, 2-cyclohexylethanol; l-cyclohexyl-l-propanol~ (cyclohexyl)-dimethyl carbinol; (4-isopropylcyclohexyl )-dimethylcarbinol;
3-cyclohexyl-l~propanol; 2-cyclohexyl-1-propanol; l-cyclo-hexyl-2-prop~nol; 2~-cyclohexyl-1~1-dimethylethanol; 2 cyclo-hexyl-2 methylpropan~l; 2-cyclohexyl-1-methylpr~panol;
2-cyclohexyl-1,2-dlmethylpropanol; 2-c~clohe~yl-191-dimethylpropanol, 3 cyclohex~l-2-methylpropan~l; 3-cyclohexyl-l-methylpropanol; 3-cyclohexylbutanol; 3-cyclohexyl-2-methyl-butanol; and 3-cyclohexyl-192-d1methylbutanol.
Prererred examples ~rom Group III include: 3-phenyl-l-propanol; ~enzyl-t-butanol3 1-phenyl-2-methyl~2-propanol3 1-pheny1-3-butanol; 2-methy1-3-phenyl-propanol3 2~2-dimethy~3pheny1propanol, and 1-phenyl-2-propanol~
It will be seen tha~ many o~ the ~oregoing pot ntiators r~r use in the topical compositions o~ the , - 16 -J&J 831 0~20~9 . .
present invention ~re al~o useful as potentiators for the antlmicroblal compositions. ~ndeed, as ~ill bcco;ne more appal~ent from the fol~owing discussion~ many of the antimicrobial compositions dlsclosed above are also useful topically, and fall within ~he scope o~ ~he topical compositions ~ the present invention. Thu~, the main difference between the two sets o~ potentiat~rs is that the potentiators o~
Group IV for the antimicrob~al compo~itions ha~e not been round to be partlcularly e~ective ~or enhancing penetration o~ medicaments thrQugh lntact slcin.
. The med~caments of which may ~e used in the ~opical composltions of the lnvention include antimicrobial agents, such a~ the antibiotics~ for example, tetracycline, oxytetracycline, chlorotetracyclineg neomycin~ erythromycin and its deri~a~ives, cycloserine, bacitrac1n, streptomycin, rifamp~cin and its derivatives, such as N-demethylri~arnpicin, ~anamycin and chloromy~etln; the anti-fungal agents such as griseofulvin~ mycostatin~ ~iconazole, and its deri~ati~es as described in U.S, Patent No. 3~717,655; quaternary ammonium compounds such as dom~phen bro~ide, domiphen chloride~ domlphen rluo~ide, benzalkonium chloride, cet~l pyridinium chloride~
dequalinium chloride; and organometallic and halogen antiseptics such as zinc pyrithionP, sodium pyrithione, silver sul~adiazine9 sil~er uracil, lodine, and the iodophores derlved from non-ionic sur~ace active ~ents such as are described ln U.S~
Patents Nos. 2,710~277 and 2,~77,315 and ~rom polyv~nyl-pyrrolidone such as described in U.S. Patents Nos. 2,706,7019 2,826,532 and 2,900,305~ Other medicaments whose penetratlon through the ~kin and topical acti~ity are enhanced, and may - 17 ~
~9 thus be used in the topical compositions of the present inven-tion include antiviral and cell regulatory agents such as 5-iodo-2'-deoxyuridine, 5-iodo-2'-deoxyuridine triphosphate, 5-bromouracyl, 5-fluorouracyl, cyclic adenosine monophosphate (c-AMP), cyclic adenosine monophosphate dibutyrate (c-AMP-dibutyrate), cyclic adenosine monophosphate succinate, cyclic guanosine monophosphate (c-~MP), methotrexate,6-azauridine triacetate (azaribin~, epinsphrine, phenephrine, L-dihydroxy-phenyl alanine (l-DOPA) and dopamine.
A particularly preferred application of the topical compositions of the present invention is as topical anesthetic compositions, and much of the remainder of the discussion of the topical compositions of the present invention will be directed to such compositions for illustrative purposes. Suitable anesthetic agents for use in the topical anesthetic compositions of the present invention include lidocaine, benzocaine, tetra- -~
:. .:. .:
cain, carbocain, rodocain and the like.
Illustrative Topical Compositions The topical compositions of this invention include at ;~
least one medicament, e.g. an anesthetic agent, and one or more of the potentiators selected from Groups I, II and III above.
The anesthetic compositions comprise at least 0.05~ (by weight) of the potentiator and at least 0.5% of the anesthetic agent, ~ -with the rest of the composition, if any, comprising one or more of ethanol, water and other conventional vehicles. Generally, `
beyond a concentration of about 15 to 18% by weight of potentia-tor no further enhancement of the penetration or activity of the anesthetic is observed. Thus, while more potentiator could be used, for example as the vehicle, there is no particular advantage in using a concentration , ',: ' :~ ,'' '',, ... . ... ....... ~".... .. .... . .. - .... --: . ~ ..
8~1 10 ~z~og - . .. .
o~ potentifit~r ln excess of' about 15% by ~reight. A pref'erred ranee for the c~ncen~ration o~ potentiator is ~rom about ~ to about 12,~ by weight ~ the compositton. A preferred range for the concentratt on of anesthetic is from about 1% to about 10 by weight, althouE~h as much as 12~ by wei~sht or more may be employed, Suitable vehicles include water, lower alcohols such as ethanol and t sopropanol, propyl~ne gl~rcol, and other conventiona~:Lly employed pharmaceutical ~reh~cles ~or topical appl~cation such as ointments, creams~ lotions, aerosols, ~uspensions and solutions. Preferably the topical composlt~ on contains ~rom about 10% to about 50% by we~ht o~ water, more pre~erably, ~rom about 20~ to about 40% water.
Examples o~ 8UC~ com~ositlons are ethanol ~olutions 1~ o~ 4% lidocaine and 12% 2-cycloher.ylethanol; 4~ lodocaine and 6~ 2-cyclohexyl l,l-dimethylethanol; 4% carbocaine and 6%
2-cyclohexyl~2-methyl-propanol; 3% tetracaine and 8~o 2-cyclohexyl-~-methylpropansl; 6% benzocaine and 6% l-cyclohexyl 1-propanol3
( 3-cyclohexyl-1-propanol; 2-cyclohexyl-1-propanol;
l-cyclohexyl-2-propanol; ?-cyclohexyl~ dimethylethanol;
2-cyclohexyl-2-methylprop~nol; 2-cyc1ohexyl-l~metbglpropansl;
~;~, 2-cyclohexyl~1,2-dimethylpropanol; 2-cyclohexyl~l 3 1-25 dimethylpropanol; 3-cyclohexyl-2-methylpropanol, 3~cycl~-hexyl-l methylpropanol; 3-cyclohexylbu~anol, 3-cyclohexyl-2-methylbutanol; and 3-cyclohexyl-132-dimethylbut~nol~
.
~; Pre~er~ed examples from Group III include: 3-phenyl-l-propanol; benzyl-t-but~nol~ l-(p-~hlorophenyl) 30 2-methyl-2-propanola 1-phenyl-2-methyl-2-propanol, l-phenyl-' 10~0~9 ~
"' ,'~';
:' 3-butanol; 2-methyl-3-phenyl-propanol; 2,2-dimethyl-3-phenyl~
propanol; 3~-p-chlorophenyl) propanol; 4(-p-chlorophenyl)-2- ~`
"..:.
butanol; 2,2-dimethyl-3(p-chlorophenyl)-propanol, 2-methyl-3(p-chlorophenyl)-propanol; l-phenyl-2-propanol; and l-(p-chloro~
phenyl)-2-propanol. ~ ; ;
Preferred examples ~rom Group IV include: 2-cyclo-hexylphenol; 4-cyclohexylresorcinol; 2-chloro-6-cyclohexyl-phenol; 4-amino~2-cyclohexylphenol hydrochloride; o-cyclohexyl- ~ ~
p-methoxyphenyl; o-cyclohexyl-p-cresol; o-(4-methylcyclohexyl)- ` ~;
10 p-cresol; and 4-chloro-2-cyclohexylphenol.
Illustrative Antimicrobial Compositions The antimicrobial compositions of this invention include at least one antimicrobial agent and at least one of the potentiators selected from Groups I, II, III and IV. In general, the composition comprises at least 0.1 percent of the ~¦ potentiator and at least 0.001 percent of the antimicrobial ~ agent. However amounts of as little as 0.05 percent potentiator ri have been found to be effective when the potentiator is selected from compounds of Group IV. The balance of the composition, if `~
' 20 any, is supplied by a suitable carrier as is hereinafter des-.~ ,.
cribed. Generally, the antimicrobial agent is employed in a " :.
quan~ity less than that of the potentiator. It is entirely suit- ; ~
,; , ~
able that up to 99.999~ of the composition be potentiator~ thus ... . . .
~!, obviating the need for using as additional component as a carrier. ~ ;
However, if desired, a carrier, preferably ethanol, can be employed. The more desirable compositions comprise from 0.1 to `
~; 90.0 percent potentiator and 0.001 to about 10.0 percent anti- ~ ~
`':'.' ::.:
microbial agent, and preferably from 0.1 to 10.0 percent poten- `~
~- tiator and from 0.001 to 0.5 percent antimicrobial ~:~
-12- ~ ~
; ,'' , .
:' .
J&~ 83 lO~Z009 ~gent, depen~ing on the pa rticular materi~ls used, ~rith the balance c~f th- composition co;.~prisin~; a suitable carrier, or combination of` carriers~ Ex~mples of such. compositions are ethanol solutions of: 0 , 05% micona 70le and 0, 50~ l-cyclo-~; hexylethanol; 0.05~ neomycin sul~te and 0,t~0% 2-cyclo-hexylethanol, 0O05~ tetracycline ~nd 0.75% n-hexanol, 0.05%
tetracycline and o.50% l-c~clohexylc~hanol; 0005% neomycin ~ul~ate and 0~75~ X,3-dimethyl-2-hexanol; 0~05~ neomycin sul~a~e and 0.75% l-cyclohexylethanol; 0,75~ iodine and 0,40~ 2-cyclohexylethanol3 and 0,05~ 3,3',4,5'-tetrachloro-salicylanil~de and 0.5~% l-cyclohexylethanol.
Examples o~ the Qntimicroblal composittons o~ this invention where there is a synergistic e~ect provided by the combin~t1on of the antimicroblal agent and the potenti~tor include ethanol s~lutions of: 0.05% 3,3'~l~35-tetrachloro-salicylanilide and 0.50% n-hexanol~ 0.025% dequalin~um chloride and 0.50~ chlorophenyl)-2-methyl-?-propanol;
0.025% domiphen bromide and 1.0% n-pentanol; 0.025% domlphen bromide and 0,75$ ~-heptan~l, 0.025~ domiphen bromide and 0 0.50% 2g3-d~methyl-2-hexanol, 0.025% domiphen bromide and 0.75~ 2,3-dimethyl-2-hexanol; 0.0125~ dom~phen bromide and o.6~ hexanol; 0.05~ hibitane and 0.10% 2-cyclohexylphenol;
0,05% griseo~ulv~n and 0,75% hexanol; 0.0~% griseo~ul~in ~nd 0.5~ 2,3-dimethyl-2-hexanol3 0.05% griseofu~v~n and " 25 0.75% 2,3-dimethyl-?-hexanol; 0.05% grlseo~ul~in a~d 005%
l-cyclohexylethanol; 0.05% griseo~ul~n and 0.75% 1-cyclohexyl-ethanol; 0.05% ~etra~ycline and 0.~% 1-( -chlorophe~yl)-2-methyl-2-propanol; 0.1% zinc pyrith~one and 0~5~
- cyc~ohexylethanol; 0~1% zlnc pyrlthione and 0,75~ 2,3-dimethyl-2-hexanol; loO~ zlnc pyrlthione ~nd 0.5% 1-.
..
J~ ~31 1~7Z~Og ( -chlorophen~ methyl~2-propanol; and 0.5~ zinc p~ithiolle and o.6~ ~-c~cloh~xylethallOl.
. In use, the antimic~obial agcnt and the ~otentlator &re conveniently dissol~ed or dispersed in an lner~ f~uid medium whlch serves as a carrier. The term inert means that khe carrier does n~t ha~e a del~terious e~fect on the anti-microb~al agent upon storage, nor substanti~lly diminish its acti~ty, nor ad~ersely react w~th any other component of the composition o~ this invention. Suitable carrier lnclude water, l~er alkanol~ such as ethanol3 the known pharmaceutlcal Yehicles such as cc~n~entionally employed ~or topical applica-atlons such, for example, as olntments, creams, lotions, aerosols, suspen~ions snd solutions. The pre~erred carriers ~re ethanol and water.
~
The top~cal compositions of the present invention exhibiting enhRnced penetration through the intac~ skin or enhanced to~lcal activity comprise~ ~n admixture, a medicament, ~or example~ an anesthetic compound, su~h as lidocalne, benzocalne, tetracain, carbocaine~ rodocaine, etc., with a potentiatorO This ma~ be employed in any of the known forms ~or applying medicaments topically~ including 801ut~0ns, cream~, gels and the like. Preferably both the known med~cament and the potentiator are dissol~ed~ suspended or dispersed in ~ suitab~e carrier. As in the case of the antlmlcrobial compositions of thP present invention, the potentiator may al80 serve as the carrler, alth~u~h, generally, a separate pharmaceutically a~ceptable carrler ~s preferred~ and an aqueous carrier ~s partlcularly pre~erred.
~ ~ 14 -, ..
J8~J 831 `` :lOqZ009 Potentiators __ .
For the ~opical compositions of the present l~ent$on9 the potentiator is selected ~rom the grc~up con ~t~n~; o~:
I. Prim~ryg second~ry and tertiary ~tr~i~sht or brarlched chain monohydri-~ aliphatic alcoh~ls whereln the ~traight cha~n alcohols ha~re rrc~m about 5 to about 10 car~on atoms and the branched chain alcohols haYe up to about 17 carbon atoms, ~helr longe~t chain o~ carbon to c~rbon bondæ
h2~ n~s ~rom abou~ 5 to a~out 10 carboll atoms 3 II. A cyclohexyl æubstituted alkanol Df` the ~tructure 1~
R~ - C----OR
~herein ~1 is Cl to C4 alkyl, ha ogen or hydrogen; R2 and R3 are ~ndependently selected ~rom hydrogen, Cl to C3 ~ij al~cyl, and cyclopropyl, and ~ ls 1 to 4, pro~rid~d that ~;; o~ly one of' said R2 and R3 of a : R2 . j ~ C
: -3 moiety may be propyl or cyclopropyl; and III. Phenyl alkanols o~ the Rtructure l 5~5 R~;
R,4~--C lC tC~
~rhereln m i8 0 or ~; R4 i~ hydrogen, halogen, Cl to C4 - allcyl3 or c~clc)propyl; R5, R6 and R7 are ~ ndependently selected f`rom hydrvgen, Cl to C3 alkyl and eyclopropyl3 .
J&3 ~31 ~20~9 provided, h~wever, that only one of R5. Rh and R7 is ~
propyl or cyclopropyl ~I`OUp ~ and when m is O, ~t least one R5 i~ ~ther than hydro~en; and the total o~. the carbon atoms $n the structure l5~5 l~ . .
_f f_ I --OH
, 5 5 _ 7 m is ~rom 3 to 9 carbon atoms.
Examples o~ the p eferred aliphatlc alcohol potentiators from ~roup ~ include: n-pentanol; n-hexanol, n-heptanol; n-octanol; n-nonanol; n-dec~nol; ~,3-dimethyl-2~hexanol, 2,5-dimethyl-2-hexanol~ 2-methy1-3 hexanol; 2 heptanol; 3-heptanol; 4heptanol and 2-ethyl-1-hexanol.
Examples o~ the pre~erred potentiators ~rom 1~ Group II include: cyclohexylmethanol, l-cyclohexylethanol, 2-cyclohexylethanol; l-cyclohexyl-l-propanol~ (cyclohexyl)-dimethyl carbinol; (4-isopropylcyclohexyl )-dimethylcarbinol;
3-cyclohexyl-l~propanol; 2-cyclohexyl-1-propanol; l-cyclo-hexyl-2-prop~nol; 2~-cyclohexyl-1~1-dimethylethanol; 2 cyclo-hexyl-2 methylpropan~l; 2-cyclohexyl-1-methylpr~panol;
2-cyclohexyl-1,2-dlmethylpropanol; 2-c~clohe~yl-191-dimethylpropanol, 3 cyclohex~l-2-methylpropan~l; 3-cyclohexyl-l-methylpropanol; 3-cyclohexylbutanol; 3-cyclohexyl-2-methyl-butanol; and 3-cyclohexyl-192-d1methylbutanol.
Prererred examples ~rom Group III include: 3-phenyl-l-propanol; ~enzyl-t-butanol3 1-phenyl-2-methyl~2-propanol3 1-pheny1-3-butanol; 2-methy1-3-phenyl-propanol3 2~2-dimethy~3pheny1propanol, and 1-phenyl-2-propanol~
It will be seen tha~ many o~ the ~oregoing pot ntiators r~r use in the topical compositions o~ the , - 16 -J&J 831 0~20~9 . .
present invention ~re al~o useful as potentiators for the antlmicroblal compositions. ~ndeed, as ~ill bcco;ne more appal~ent from the fol~owing discussion~ many of the antimicrobial compositions dlsclosed above are also useful topically, and fall within ~he scope o~ ~he topical compositions ~ the present invention. Thu~, the main difference between the two sets o~ potentiat~rs is that the potentiators o~
Group IV for the antimicrob~al compo~itions ha~e not been round to be partlcularly e~ective ~or enhancing penetration o~ medicaments thrQugh lntact slcin.
. The med~caments of which may ~e used in the ~opical composltions of the lnvention include antimicrobial agents, such a~ the antibiotics~ for example, tetracycline, oxytetracycline, chlorotetracyclineg neomycin~ erythromycin and its deri~a~ives, cycloserine, bacitrac1n, streptomycin, rifamp~cin and its derivatives, such as N-demethylri~arnpicin, ~anamycin and chloromy~etln; the anti-fungal agents such as griseofulvin~ mycostatin~ ~iconazole, and its deri~ati~es as described in U.S, Patent No. 3~717,655; quaternary ammonium compounds such as dom~phen bro~ide, domiphen chloride~ domlphen rluo~ide, benzalkonium chloride, cet~l pyridinium chloride~
dequalinium chloride; and organometallic and halogen antiseptics such as zinc pyrithionP, sodium pyrithione, silver sul~adiazine9 sil~er uracil, lodine, and the iodophores derlved from non-ionic sur~ace active ~ents such as are described ln U.S~
Patents Nos. 2,710~277 and 2,~77,315 and ~rom polyv~nyl-pyrrolidone such as described in U.S. Patents Nos. 2,706,7019 2,826,532 and 2,900,305~ Other medicaments whose penetratlon through the ~kin and topical acti~ity are enhanced, and may - 17 ~
~9 thus be used in the topical compositions of the present inven-tion include antiviral and cell regulatory agents such as 5-iodo-2'-deoxyuridine, 5-iodo-2'-deoxyuridine triphosphate, 5-bromouracyl, 5-fluorouracyl, cyclic adenosine monophosphate (c-AMP), cyclic adenosine monophosphate dibutyrate (c-AMP-dibutyrate), cyclic adenosine monophosphate succinate, cyclic guanosine monophosphate (c-~MP), methotrexate,6-azauridine triacetate (azaribin~, epinsphrine, phenephrine, L-dihydroxy-phenyl alanine (l-DOPA) and dopamine.
A particularly preferred application of the topical compositions of the present invention is as topical anesthetic compositions, and much of the remainder of the discussion of the topical compositions of the present invention will be directed to such compositions for illustrative purposes. Suitable anesthetic agents for use in the topical anesthetic compositions of the present invention include lidocaine, benzocaine, tetra- -~
:. .:. .:
cain, carbocain, rodocain and the like.
Illustrative Topical Compositions The topical compositions of this invention include at ;~
least one medicament, e.g. an anesthetic agent, and one or more of the potentiators selected from Groups I, II and III above.
The anesthetic compositions comprise at least 0.05~ (by weight) of the potentiator and at least 0.5% of the anesthetic agent, ~ -with the rest of the composition, if any, comprising one or more of ethanol, water and other conventional vehicles. Generally, `
beyond a concentration of about 15 to 18% by weight of potentia-tor no further enhancement of the penetration or activity of the anesthetic is observed. Thus, while more potentiator could be used, for example as the vehicle, there is no particular advantage in using a concentration , ',: ' :~ ,'' '',, ... . ... ....... ~".... .. .... . .. - .... --: . ~ ..
8~1 10 ~z~og - . .. .
o~ potentifit~r ln excess of' about 15% by ~reight. A pref'erred ranee for the c~ncen~ration o~ potentiator is ~rom about ~ to about 12,~ by weight ~ the compositton. A preferred range for the concentratt on of anesthetic is from about 1% to about 10 by weight, althouE~h as much as 12~ by wei~sht or more may be employed, Suitable vehicles include water, lower alcohols such as ethanol and t sopropanol, propyl~ne gl~rcol, and other conventiona~:Lly employed pharmaceutical ~reh~cles ~or topical appl~cation such as ointments, creams~ lotions, aerosols, ~uspensions and solutions. Preferably the topical composlt~ on contains ~rom about 10% to about 50% by we~ht o~ water, more pre~erably, ~rom about 20~ to about 40% water.
Examples o~ 8UC~ com~ositlons are ethanol ~olutions 1~ o~ 4% lidocaine and 12% 2-cycloher.ylethanol; 4~ lodocaine and 6~ 2-cyclohexyl l,l-dimethylethanol; 4% carbocaine and 6%
2-cyclohexyl~2-methyl-propanol; 3% tetracaine and 8~o 2-cyclohexyl-~-methylpropansl; 6% benzocaine and 6% l-cyclohexyl 1-propanol3
4% rodocalne and 12% n hexanol; 4~0 l~docaine an~ ~% benzyl-t-butanol3 2% tetracaine and 8~ 3 phenyl-l-propanol, and the like.
Currently a~ailable topically used anesthetic preparations are generally inef~ective or only partially e~fective when applled onto intact skin. One preparation that has been shown to be e~ective to cause sur~ace 25 anesthe~ia contalns 20% benzocaine. Thi8 high concentr~tion oP benzocaine is believed to be undesirable and dangerous ~ecause of' po~sible toxic side e~f`ects.
- A sigrli~icant impro~ement in the ~peed o~ action ~nd ~n the duration o~ e~lcacy o~ the currently used -~ 30 anesthetics can be ~chie~red when they are combined with a .
-~ penetrant accelerator in ac~ordance with the present invention. Some o~ the accelerators themselves pos~esæ
; 19 -l~Z~Og ' ' ' .
...,~i anesthetic activity and it is conceivable that their combination with the conventional anesthetics (lidocaine, benzocaine, carbocaine, etc.) results in the potentiation of their anesthe- ;
tic activity. In addition, it is postulated that the potentia- ` -tors themselves alter membrane permeability and enhance the -penetration of the anesthetics into the receptor sites even through the intact skin and cell membranes~ Because of this unique ability of the accelerators to alter the permeability barrier of the skin and also of the cell membranes, low concen-~rations of the conventional anesthetics are sufficient to , achieve good anesthesia at the treated site. `~
; The following specific examples will further serve to `
; illustrate the compositions of this invention. -Example 1 .. . . .. .
~, The procedure described below together with the results obtained according to that procedure will further illustrate ~ -~, the antimicrobial compositions of this invention and their unusual degree of effectiveness. The procedure entails admixing (1) 3 ml citrated hùman blood, (2) 5 ml peptone water, (3) 1 ml cell suspension (bacteria, yeast or fungi), and (4) 1 ml of a test solution, which test solution comprises 40% ethanol and may include either or both of an antimicrobial agent and a -;~
potentiator. The first three components are admixed and pre-incubated at room temperature for ten minutes before the addition of the test solution.
After the ten minute preincubation period, the test solution comprising 40% ethanol, alone or ~ogether with the anti-microbial agent alone, the potentiato~. alone, or the combination of the two, is added. At intervals o one, ten :' .. ',.',' '' :,. .
~ "' - ','.':: ., .
.~ ~',.. ".
J&G~J 83-iO~21:1 09 and thirty minutes af'ter this ~inal additic:~n, one ml o~
the treat~d mixture is remt)ve~ and transferred to R dilutlon tube th~t contains 9,ml o~ a neutralizing composition com-prislng peptone water ~nd an ~ntim~ crobi al neutrallz~r .
Currently a~ailable topically used anesthetic preparations are generally inef~ective or only partially e~fective when applled onto intact skin. One preparation that has been shown to be e~ective to cause sur~ace 25 anesthe~ia contalns 20% benzocaine. Thi8 high concentr~tion oP benzocaine is believed to be undesirable and dangerous ~ecause of' po~sible toxic side e~f`ects.
- A sigrli~icant impro~ement in the ~peed o~ action ~nd ~n the duration o~ e~lcacy o~ the currently used -~ 30 anesthetics can be ~chie~red when they are combined with a .
-~ penetrant accelerator in ac~ordance with the present invention. Some o~ the accelerators themselves pos~esæ
; 19 -l~Z~Og ' ' ' .
...,~i anesthetic activity and it is conceivable that their combination with the conventional anesthetics (lidocaine, benzocaine, carbocaine, etc.) results in the potentiation of their anesthe- ;
tic activity. In addition, it is postulated that the potentia- ` -tors themselves alter membrane permeability and enhance the -penetration of the anesthetics into the receptor sites even through the intact skin and cell membranes~ Because of this unique ability of the accelerators to alter the permeability barrier of the skin and also of the cell membranes, low concen-~rations of the conventional anesthetics are sufficient to , achieve good anesthesia at the treated site. `~
; The following specific examples will further serve to `
; illustrate the compositions of this invention. -Example 1 .. . . .. .
~, The procedure described below together with the results obtained according to that procedure will further illustrate ~ -~, the antimicrobial compositions of this invention and their unusual degree of effectiveness. The procedure entails admixing (1) 3 ml citrated hùman blood, (2) 5 ml peptone water, (3) 1 ml cell suspension (bacteria, yeast or fungi), and (4) 1 ml of a test solution, which test solution comprises 40% ethanol and may include either or both of an antimicrobial agent and a -;~
potentiator. The first three components are admixed and pre-incubated at room temperature for ten minutes before the addition of the test solution.
After the ten minute preincubation period, the test solution comprising 40% ethanol, alone or ~ogether with the anti-microbial agent alone, the potentiato~. alone, or the combination of the two, is added. At intervals o one, ten :' .. ',.',' '' :,. .
~ "' - ','.':: ., .
.~ ~',.. ".
J&G~J 83-iO~21:1 09 and thirty minutes af'ter this ~inal additic:~n, one ml o~
the treat~d mixture is remt)ve~ and transferred to R dilutlon tube th~t contains 9,ml o~ a neutralizing composition com-prislng peptone water ~nd an ~ntim~ crobi al neutrallz~r .
5 The neutralizer is requ~ red to :Snactivate the unadsorbed ant~ microl)ial ~gent that otherwi~e may give rise to ~al~e positilre result~ . After neutralization~ serial dilut~ ons are made ~qit~ peptone w~er, and each dllution i8 plated OU~ 1T1 a petr~ dish, and then co~ered with 15 ml o~ ~
10 trypticase soy or Mycophil agar media,. The plates are incuba~ed at appropr~ate temperature ~or tw~ to thr~e days, then the colonies are cvunted at ea~h d~lutlon.
The number Or sur~riving organisms are determined by multiplying the number o~ colonies that are counted at the 15 l~west dilutlon with the p~wer of that dilutlon.
A ~er~es o~ the ~ollowing ~our solut~ons was prepared ln accordan~e with the ~oregolng pr~cedure:
ethanol : 409 water ~ 60 II etha~ol 40 water antimicrobial agent;
III ethanol 40%
w~ter 57%
+
potentiator; and IY ethanol 405~
water ~7%
antimicrobial agent potentiator.
The results are reporged ~n Table I below .
. - 21 ` ` 1~i7;~)9 ` J~ 83 U~
a) o~ oco u~
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C~ ~ Q r~ O . rl CJ~DO ~ O
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' J&~ 83 10~20~9 Thus, lt can be seen that when the antimlcrobial com~ositions o~ this~invention are employed, the killing e~ficacy o~ the an~imlcrobial agent in the presenc~ o~ blood is greatly enhanced, In a slmllar manner, additional antimicroblal compositions of thi~ inventlon h~ve been testea and a summary o~ the test results appears ln Table II.
.
.
~&~ 831 , ~q a~ ~ ~ C-- ~ ~ ~ t_ ~ ~
o o o o o o o o o XO XO~ ~:o XO ~o ~o 'XO XO XO
~ . ,1o o o o O W ~D ~1 ~) ~I N ~) ~ 0 r-l 0 ~ 0~ 0 ~) ~ ~
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10 trypticase soy or Mycophil agar media,. The plates are incuba~ed at appropr~ate temperature ~or tw~ to thr~e days, then the colonies are cvunted at ea~h d~lutlon.
The number Or sur~riving organisms are determined by multiplying the number o~ colonies that are counted at the 15 l~west dilutlon with the p~wer of that dilutlon.
A ~er~es o~ the ~ollowing ~our solut~ons was prepared ln accordan~e with the ~oregolng pr~cedure:
ethanol : 409 water ~ 60 II etha~ol 40 water antimicrobial agent;
III ethanol 40%
w~ter 57%
+
potentiator; and IY ethanol 405~
water ~7%
antimicrobial agent potentiator.
The results are reporged ~n Table I below .
. - 21 ` ` 1~i7;~)9 ` J~ 83 U~
a) o~ oco u~
oo C~OO ooo o X X~D O ~ X X oO X K X O
N O C~l O ~ l ~1 0 O .. ... ....
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C~ ~ Q r~ O . rl CJ~DO ~ O
~ g ~1 ~ 00D~ ~
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C~l V ~ _ ~
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H ~1 H H H a)o~e~ a~ S a) p:; O H H ::~ H H b H H !~ ~ a) ~ Ll~ I ~
H H H 1--I H H H 1-1 H H H h ~ ~q~ ,1 c~l ~rl 0~ E3 0`--~ ~ O
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-- ~5 - .
' J&~ 83 10~20~9 Thus, lt can be seen that when the antimlcrobial com~ositions o~ this~invention are employed, the killing e~ficacy o~ the an~imlcrobial agent in the presenc~ o~ blood is greatly enhanced, In a slmllar manner, additional antimicroblal compositions of thi~ inventlon h~ve been testea and a summary o~ the test results appears ln Table II.
.
.
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, ~:
Ethanol 20 Glycerine USP 10%
Flavor 0.2 Domiphen Brom~de from 0.05 t~ 0.1~%
2-C~clohexylethanol ~r~m 0.1 to 30~%
Amaranth solution 0.04%
Dlstllled water q. 8 . to 100%
To use this mouth~ash solution~ the mouth is rin~ed wlth 5 to 20 ~1 ~or 30 to 60 reconds twlce daily. In v~tro models sh~w a reductlon of 85 to 95% in dental plaque ~ormation ~ -as compared to ~ontrols u~der ldentical experlmental conditlons.
' , . .
~ . ~^~
~ Potentlator, l-(p-chlorophenol)-2 methyl-2 prop~nol 3.0 to - 6.~% . `'~
Antl~icrobial, Irgasan DP 300~(2,~,4~-~richloro-2~-hydroxy-diphenyl~ether) 0.05 to 0.25 '~0 Surfactant, Emcol E607 2u~%
Glycerine USP 5. ~
P.E~G. 6000 distearate 1.5~ ::
;
Di tilled ~ater q.s, t~ 10~
To use th~s sur~ical scrub~ the hands are rubbed toeether ~5 wlth 10 to 15 ml o~ the above solution ~or o~e to three ~nute6 ~n the same manner a~ currently used ~urglca~ ~crub ~olu~ions~ ~ :
' ' - '''' ~",' ,-. .
~ ~ 3~ -a~;J 831 2~9 Hard Surface D~sin~ect~nt Pstentiator, 2,3-Dimethyl-2-hexanol 3,0 to 10~
Antimic~oblal, Dequallnium Cl 0.05 to 3.0%
. . . _ -5- ---~-Is~-propanol~ 40.0 Propylene glycol 50~
Distilled water q.s. to 100.00%
In us~ng th~s ~lsin~ectank~ ~he solutios is spread onto the 3ur~a~e with a so~t cloth, or by spraying ln the ~orm o~ an aerosol spray~ resulting in steriliæation of the sur~ace withln one to fi~e m~nute~O
h~timicrobial, Domiphen bromide 0.125%
15 Potentiator ~ l-Cyclohex~ pr~panol 3 . O %
Ethanol or isopropanol . 4000 % -Distilled water 56 . 87 %
In tests and operati~e technigues sarried out according to the procedure ~et ~orth ln F, Goldschmidt, Reproducible 20 Topical Staphylococcal Infection in Rats9 Applied Nicroblologyl 23, No. 1~ p~ 130 ~1972), established ~nf`ec~lons with absces~ formation were demon~trated in gl.4% o~ the inPected control anlmals with reco~rerab~e StaPhylococcus areus ln amounts of 105 cells ~r more per 25 gram o~ excised body wall.
In the experimsntal group composition Or this Esc~mple, infectlon was pr~rented, abscess d~d ~t de~relop;
and ~ ~ aureus could be recc~rered only ~rom ; 28.6% of the enimals ~n amouats of 105 or more cells per gr~m o~ excised body w~ll. Using 3.0~ l-cyclohexyl-l-propanol alone~ abscess ~ormatlon oc~urred ln lOG~ o~ the animal~
'-~&~ 831 ; ~
3L~q~O09 with recoverAble ~5~ aureus in amounts of 106 cells or morc per gram of excised body wall. With domiphen bromid e alotle , absc e~ s f orrr~t ~. on ~ccurred ln, and ~ o-o~cos aureus could be reeovered fromg ~2.3% o~
5 the animals in amounts o~ 105 or more cel~s per gram of excl~ed body wall.
In summar~, approxlmately f$~e out o~ se~ren a~lnal~
responded to the combination therapy, whereas neither agent alone was su~Picient to pre~rent the ln~ectlon~l -To ~llustrate the enhanced penetratil~n Or ~he topical compositions c~r the inventlon, the ~oll~wing formul~tion was employed to prepare compositions whi~h were then tested in a ~tand~rdized ~kin blanch1rlg test wherein 15 the degree o~ blanching corresponds to the degree Or penetr~tion.
- The results are shown ~n Table III.
FOBMULATION
Ethanol 50.ûO ~ w/w . Propylene glycol 10.00 Cetyl alcohol 0~.50 dl-Epinephri~e O .10 Di~hiothr~itol O. 001 Water 29.40 Penekrant potentiator 10.00 lOû.OO
No~e-- In formula (1) o~ Table III below the a'bo~re ~ormllat~on wa~ ~,rarled by sub~tituting ethanol ~or the penetrant potentîa~or, so that ~ormula ~13 contained a total o~
60% w/w ethan~l. .
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Top~cal ~nesthetic Solut.ion ~rr.lulation Eth~nol 10 - 80.0~ w/w Pen~t~-nnt ~ccelerator 1 - 12.
Anesthetic Agent1 - 10;0~
Water, q.s. to 100.0%
p~ 8.o ~
':
Ethanol . 50.~ w/w Penetrant Accelerat~r 12~0 Anesthetic Agent 4b~
; ~iater ~ 31.0%
Kluc el HF 3 . 0%
Ethanol 21.0% w/w . Penetrant Accelerator12.0 Anesthetic Agent 4 9 0 :'0 Dibutylphthalate 35,o% , Isopropylmyristate 23.
Cabosi~ 5. ~ ~ ~
~, -~;:
"~
Ethanol 50.0% w/w Propylene Glycol lOo ~ ~ '~
Anesthetic Agent 40 ~ :~ ;
Penetrant A~celerator 12.0%
Water 24~
~ .
, . . .
,. .~ , ` ~0~ 9 J&J 831 Example 11 Topica~. Anesthetlc Solutlon Fol;nulation Ethanol ~ 50.0~0 Propylene Glycol 10.0%
- 5 Cetyl Alcohol 0~5 Anesthetlc Agent 4.
' Penetra~t A~celerator 10.5 Water 2~.5~
When the ~ormulations of Examples 7-119 prepared using ~idoca~ne HCl as the anesthetic agent and 2-cyclohexyl-191-dimet~lyl ethanol as the penetr~nt acceleratolg were applied topically to intact ~uman skin ~rith a "BAND-AID"~
brand adhesive bandage, sur~ace to deep anesthesia was obtained within 15 to 60 minutes. The onset time of anesthes~a was 15 rapid (15 to 30 minutes) and anesthesia lasted ~or several hours ( 3 ~o 6 hours). me results o~ similar ~tudies are ~ummarized in Tables IV ~nd V~
Slmilar animal studies with guinea pigs ~ the 20 preparation being appl~ed onto ~he intact skin, showed that the combln2tlon o~ the anesthetic ~lth the penetrant accelerator elicits qulck and deep anesthesia at the t~eated ~ite (~5 min.), the anesthesia lasting up to se~eral hours. These results are summarized in T~ble VI.
"In ~itro" percutaneous absorption studle~ with intact guinea pig skln showed that the combination o~ lidocaine wlth a penetrant acceler~tor resul~s in 20 to 30 fold more lidocaine penetration thr~ugh the ~ntact skin than without the accelerator~
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Thus, it can be seen that when ~he anesthetic compositions o~ this in~ention are employed 9 the anesthetic acti~ty of the conventional anesthetic a~ents is greatly enhPnced even through the ~ntact skin.
As will be appare~t to those skilled ~n the art, many changes and modi~cations may be made which do not depart from the scope or spirit of the l~entlon.
H~-~ing now described sny ~nventi~n, what I de~ire to secure by Letter6 Putent and hereby claim is:
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Ethanol 20 Glycerine USP 10%
Flavor 0.2 Domiphen Brom~de from 0.05 t~ 0.1~%
2-C~clohexylethanol ~r~m 0.1 to 30~%
Amaranth solution 0.04%
Dlstllled water q. 8 . to 100%
To use this mouth~ash solution~ the mouth is rin~ed wlth 5 to 20 ~1 ~or 30 to 60 reconds twlce daily. In v~tro models sh~w a reductlon of 85 to 95% in dental plaque ~ormation ~ -as compared to ~ontrols u~der ldentical experlmental conditlons.
' , . .
~ . ~^~
~ Potentlator, l-(p-chlorophenol)-2 methyl-2 prop~nol 3.0 to - 6.~% . `'~
Antl~icrobial, Irgasan DP 300~(2,~,4~-~richloro-2~-hydroxy-diphenyl~ether) 0.05 to 0.25 '~0 Surfactant, Emcol E607 2u~%
Glycerine USP 5. ~
P.E~G. 6000 distearate 1.5~ ::
;
Di tilled ~ater q.s, t~ 10~
To use th~s sur~ical scrub~ the hands are rubbed toeether ~5 wlth 10 to 15 ml o~ the above solution ~or o~e to three ~nute6 ~n the same manner a~ currently used ~urglca~ ~crub ~olu~ions~ ~ :
' ' - '''' ~",' ,-. .
~ ~ 3~ -a~;J 831 2~9 Hard Surface D~sin~ect~nt Pstentiator, 2,3-Dimethyl-2-hexanol 3,0 to 10~
Antimic~oblal, Dequallnium Cl 0.05 to 3.0%
. . . _ -5- ---~-Is~-propanol~ 40.0 Propylene glycol 50~
Distilled water q.s. to 100.00%
In us~ng th~s ~lsin~ectank~ ~he solutios is spread onto the 3ur~a~e with a so~t cloth, or by spraying ln the ~orm o~ an aerosol spray~ resulting in steriliæation of the sur~ace withln one to fi~e m~nute~O
h~timicrobial, Domiphen bromide 0.125%
15 Potentiator ~ l-Cyclohex~ pr~panol 3 . O %
Ethanol or isopropanol . 4000 % -Distilled water 56 . 87 %
In tests and operati~e technigues sarried out according to the procedure ~et ~orth ln F, Goldschmidt, Reproducible 20 Topical Staphylococcal Infection in Rats9 Applied Nicroblologyl 23, No. 1~ p~ 130 ~1972), established ~nf`ec~lons with absces~ formation were demon~trated in gl.4% o~ the inPected control anlmals with reco~rerab~e StaPhylococcus areus ln amounts of 105 cells ~r more per 25 gram o~ excised body wall.
In the experimsntal group composition Or this Esc~mple, infectlon was pr~rented, abscess d~d ~t de~relop;
and ~ ~ aureus could be recc~rered only ~rom ; 28.6% of the enimals ~n amouats of 105 or more cells per gr~m o~ excised body w~ll. Using 3.0~ l-cyclohexyl-l-propanol alone~ abscess ~ormatlon oc~urred ln lOG~ o~ the animal~
'-~&~ 831 ; ~
3L~q~O09 with recoverAble ~5~ aureus in amounts of 106 cells or morc per gram of excised body wall. With domiphen bromid e alotle , absc e~ s f orrr~t ~. on ~ccurred ln, and ~ o-o~cos aureus could be reeovered fromg ~2.3% o~
5 the animals in amounts o~ 105 or more cel~s per gram of excl~ed body wall.
In summar~, approxlmately f$~e out o~ se~ren a~lnal~
responded to the combination therapy, whereas neither agent alone was su~Picient to pre~rent the ln~ectlon~l -To ~llustrate the enhanced penetratil~n Or ~he topical compositions c~r the inventlon, the ~oll~wing formul~tion was employed to prepare compositions whi~h were then tested in a ~tand~rdized ~kin blanch1rlg test wherein 15 the degree o~ blanching corresponds to the degree Or penetr~tion.
- The results are shown ~n Table III.
FOBMULATION
Ethanol 50.ûO ~ w/w . Propylene glycol 10.00 Cetyl alcohol 0~.50 dl-Epinephri~e O .10 Di~hiothr~itol O. 001 Water 29.40 Penekrant potentiator 10.00 lOû.OO
No~e-- In formula (1) o~ Table III below the a'bo~re ~ormllat~on wa~ ~,rarled by sub~tituting ethanol ~or the penetrant potentîa~or, so that ~ormula ~13 contained a total o~
60% w/w ethan~l. .
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Top~cal ~nesthetic Solut.ion ~rr.lulation Eth~nol 10 - 80.0~ w/w Pen~t~-nnt ~ccelerator 1 - 12.
Anesthetic Agent1 - 10;0~
Water, q.s. to 100.0%
p~ 8.o ~
':
Ethanol . 50.~ w/w Penetrant Accelerat~r 12~0 Anesthetic Agent 4b~
; ~iater ~ 31.0%
Kluc el HF 3 . 0%
Ethanol 21.0% w/w . Penetrant Accelerator12.0 Anesthetic Agent 4 9 0 :'0 Dibutylphthalate 35,o% , Isopropylmyristate 23.
Cabosi~ 5. ~ ~ ~
~, -~;:
"~
Ethanol 50.0% w/w Propylene Glycol lOo ~ ~ '~
Anesthetic Agent 40 ~ :~ ;
Penetrant A~celerator 12.0%
Water 24~
~ .
, . . .
,. .~ , ` ~0~ 9 J&J 831 Example 11 Topica~. Anesthetlc Solutlon Fol;nulation Ethanol ~ 50.0~0 Propylene Glycol 10.0%
- 5 Cetyl Alcohol 0~5 Anesthetlc Agent 4.
' Penetra~t A~celerator 10.5 Water 2~.5~
When the ~ormulations of Examples 7-119 prepared using ~idoca~ne HCl as the anesthetic agent and 2-cyclohexyl-191-dimet~lyl ethanol as the penetr~nt acceleratolg were applied topically to intact ~uman skin ~rith a "BAND-AID"~
brand adhesive bandage, sur~ace to deep anesthesia was obtained within 15 to 60 minutes. The onset time of anesthes~a was 15 rapid (15 to 30 minutes) and anesthesia lasted ~or several hours ( 3 ~o 6 hours). me results o~ similar ~tudies are ~ummarized in Tables IV ~nd V~
Slmilar animal studies with guinea pigs ~ the 20 preparation being appl~ed onto ~he intact skin, showed that the combln2tlon o~ the anesthetic ~lth the penetrant accelerator elicits qulck and deep anesthesia at the t~eated ~ite (~5 min.), the anesthesia lasting up to se~eral hours. These results are summarized in T~ble VI.
"In ~itro" percutaneous absorption studle~ with intact guinea pig skln showed that the combination o~ lidocaine wlth a penetrant acceler~tor resul~s in 20 to 30 fold more lidocaine penetration thr~ugh the ~ntact skin than without the accelerator~
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~o I ~ 3 ~ 1 3 3 ~ 3 ,. . .
.
..
~, .
~:`' , .
,-, . . .
.
J~ 831 ~O~J2~0~ .
Thus, it can be seen that when ~he anesthetic compositions o~ this in~ention are employed 9 the anesthetic acti~ty of the conventional anesthetic a~ents is greatly enhPnced even through the ~ntact skin.
As will be appare~t to those skilled ~n the art, many changes and modi~cations may be made which do not depart from the scope or spirit of the l~entlon.
H~-~ing now described sny ~nventi~n, what I de~ire to secure by Letter6 Putent and hereby claim is:
'' . ~ .
. .
, ~, , - 3g
Claims (37)
1. An antimicrobial composition comprising an antimicrobial agent and a potentiating amount of at least one potentiator selected from the group consisting of:
(a) the primary, secondary and tertiary straight or branched chain monohydric aliphatic alcohols, wherein the straight chain alcohols have from about 5 to about 10 carbon atoms and the branched chain alcohols have up to about 17 carbon atoms, their longest chain of carbon to carbon bonds having from about 5 to about 10 carbon atoms;
(b) the primary, secondary and tertiary cyclohexyl-alkanols and alkylcyclohexyl alkanol having the structure:
wherein R1 is C1 to C4 alkyl, halogen or hydrogen; R2 and R3 are independently selected from hydrogen, C1 to C3 alkyl, and cyclopropyl; and n is 1 to 4, provided that only one of said R2 and R3 of a moiety may be propyl or cyclopropyl;
(c) the primary, secondary and tertiary phenyl alkanols having the structure:
wherein m is 0 or 1; R4 is hydrogen, halogen, C1 to C4 alkyl, or cyclopropyl; R5, R6 and R7 are independently selected from hydrogen, C1 to C3 alkyl and cyclopropyl, provided, however that only one of R5, R6 and R7 is a propyl or cyclopropyl group, and, when m is 0, at least one R5 is other than hydrogen; and the total of the carbon atoms in the structure is from 3 to 9 carbon atoms; and (d) the cyclohexyl phenols having the structure:
where R8 is hydrogen, C1 to C3 alkyl, C1 to C3 alkoxy, hydroxy, halogen, amino, or mono or di C1 to C3 alkyl amino, provided that the total number of carbon atoms in the alkyl groups substituted on the amino does not exceed 5.
(a) the primary, secondary and tertiary straight or branched chain monohydric aliphatic alcohols, wherein the straight chain alcohols have from about 5 to about 10 carbon atoms and the branched chain alcohols have up to about 17 carbon atoms, their longest chain of carbon to carbon bonds having from about 5 to about 10 carbon atoms;
(b) the primary, secondary and tertiary cyclohexyl-alkanols and alkylcyclohexyl alkanol having the structure:
wherein R1 is C1 to C4 alkyl, halogen or hydrogen; R2 and R3 are independently selected from hydrogen, C1 to C3 alkyl, and cyclopropyl; and n is 1 to 4, provided that only one of said R2 and R3 of a moiety may be propyl or cyclopropyl;
(c) the primary, secondary and tertiary phenyl alkanols having the structure:
wherein m is 0 or 1; R4 is hydrogen, halogen, C1 to C4 alkyl, or cyclopropyl; R5, R6 and R7 are independently selected from hydrogen, C1 to C3 alkyl and cyclopropyl, provided, however that only one of R5, R6 and R7 is a propyl or cyclopropyl group, and, when m is 0, at least one R5 is other than hydrogen; and the total of the carbon atoms in the structure is from 3 to 9 carbon atoms; and (d) the cyclohexyl phenols having the structure:
where R8 is hydrogen, C1 to C3 alkyl, C1 to C3 alkoxy, hydroxy, halogen, amino, or mono or di C1 to C3 alkyl amino, provided that the total number of carbon atoms in the alkyl groups substituted on the amino does not exceed 5.
2. An antimicrobial composition of Claim 1 in which said antimicrobial agent is a member selected from the group consisting of the antibiotics, anti-fungal agents, bisdiguanides, quaternary ammonium compounds, carbanilides, salicylanilides, phenols, hydroxydiphenyls, organo-metallic and halogen antiseptics, and iodophores derived from nonionic surface active agents and from polyvinylpyrrolidone.
3. An antimicrobial composition of Claim 2 wherein the antibiotic is selected form the group consisting of tetracycline, oxytetracycline, chlorotetracycline, neomycin, erythromycin, bacitracin, streptomycin, rifampicin, N-demethyl-rifampicin, kanamycin and chloromycetin.
4. An antimicrobial composition of Claim 2 wherein the antifungal agent is selected form the group consisting of griseofulvin, mycostatin and miconazole.
5. An antimicrobial composition of Claim 2 wherein the bisdiguanidine is chlorhexidine.
6. An antimicrobial composition of Claim 2 wherein the quaternary ammonium compound is selected from the group consisting of domiphen bromide, domiphen chloride, domiphen fluoride, benzalkonium chloride, cetyl pyridinium chloride, dequalinium chloride, the cis isomer of 1-(3-chloro-allyl)-3,5,7-triaza-1-azoniaadamantane chloride, cetyl trimethylammonium bromide, benzethonium chloride and methyl-benzethonium chloride.
7. An antimicrobial composition of Claim 2 wherein the antimicrobial agent is selected from the group consisting of 3,3', 4,5'-tetrachlorosalicylanilide, 2,4,4'-trichloro-2'-hydroxydiphenylether, 3,4,4'-trichlorocarbanilide, 3,4,4'-tribromosalicylanilide, and 3,4',5-tribromosalicylanilide.
8. An antimicrobial composition of Claim 2 in which the antimicrobial agent is selected from the group consisting of zinc pyrithione, silver sulfadiazine, silver uracil, iodine, and the iodophores derived from a non-ionic surface active agent or from polyvinylpyrrolidone.
9. An antimicrobial composition of Claim 1 in which the potentiator is selected from the group consisting of n-hexanol, n-heptanol, n-octanol, n-nonanol, n-decanol, 2,3-dimethyl-2-hexanol, 2,5-dimethyl-2-hexanol, 2-methyl-3-hexanol, 2-heptanol, 3-heptanol, 4-heptanol and 2-ethyl-1-hexanol.
10. An antimicrobial composition of Claim 1 in which the potentiator is selected from the group consisting of cyclohexylmethanol, 1-cyclohexylethanol, 2-cyclohexyl-ethanol, 1-cyclohexy1-1-propanol, (cyclohexyl)-dimethylcarbinol, (4-isopropylcyclohexyl)-dimethylcarbinol, 3-cyclohexyl-1-propanol, 2-cyclohexyl-1-propanol, 1-cyclohexyl-2-propanol, 2-cyclohexyl-1,1-dimethylethanol, 2-cyclohexyl-2-methylpropanol, 2-cyclohexyl-1-methylpropanol, 2-cyclohexyl-1,2-dimethylpropanol, 2-cyclohexyl,1-dimethylpropanol, 3-cyclohexyl-2-methyl-propanol, 3-cyclohexyl-1-methylpropanol, 3-cyclohexylbutanol, 3-cyclohexyl-2-methylbutanol and 3-cyclohexyl-1,2-dimethyl-butanol.
11. An antimicrobial composition of Claim 1 in which the potentiator is selected from the group consisting of 3-phenyl-1-propanol, benzyl-t-butanol, 1-(p-chlorophenyl)-2-methyl-2-propanol, 1-phenyl-2-methyl-2-propanol, 1-phenyl-3-butanol, 2-methyl-3-phenyl-propanol, 2,2-dimethyl-3-phenyl-propanol, 3(p-chlorophenyl)-propanol, 4(p-chlorophenyl)-2-butanol, 2,2-dimethyl-3(p-chlorophenyl)-propanol, 2-methyl-3(p-chlorophenyl)-propanol, 1-phenyl-2-propanol and 1-(p-chlorophenyl)-2-propanol.
12. An antimicrobial composition of Claim 1 in which the potentiator is selected from the group consisting of 2-cyclohexylphenol, 4-cyclohexylresorcinol, 2-chloro-6-cyclohexylphenol, 4-amino-2-cyclohexylphenol hydrochloride, o-cyclohexyl-p-methoxyphenol, o-cyclohexyl-p-cresol, o-(4-methylcyclohexyl)-p-cresol, and 4-chloro-2-cyclohexylphenol.
13. An antimicrobial composltion of Claim 1 whlch contains at least about 0.001 percent by weight of the anti-microbial agent and at least about 0.05 percent by weight of the potentiator.
14. An antimicrobial composition of Claim 13 which further comprises a pharmaceutically acceptable carrier.
15. An antimicrobial composition of Claim 14 which contains from about 0.001 to about 10 percent of the anti-microbial agent, from about 0.05 to about 90.0% of the potentiator, and a carrier selected from the group consisting of water, and the lower alkanols.
16. A composition of Claim 15 which contains from about 0.001 to about 5% antimicrobial agent and from about 0.1 to about 10% potentiator.
17. An antimicrobial composition of Claim 15 in wherein the said carrier is ethanol.
18. An antimicrobial composition of Claim 1 wherein the antimicrobial agent comprises at least 0.001% of domiphen bromide and the potentiator comprises at least 0.1%
of 1-cyclohexyl-1-propanol.
of 1-cyclohexyl-1-propanol.
19. A potentiated topical composition comprising an effective amount of a topical medicament selected from the group consisting of antibiotics, anti-fungal agents, quaternary ammonium compounds, organo-metallic and halogen antiseptics, antiviral and cell regulatory agents, and anesthetic agents and a potentiating amount of potentiator selected from the group consisting of:
(a) primary, secondary and tertiary straight or branched chain monohydric aliphatic alcohols wherein the straight chain alcohols have from about 5 to about 10 carbon atoms and the branched chain alcohols have up to about 17 carbon atoms, their longest chain of carbon to carbon bonds having from about 5 to about 10 carbon atoms;
(b) cyclohexyl substituted alkanols of the structure wherein R1 is C1 to C4 alkyl, halogen or hydrogen; R2 and R3 are independently selected from hydrogen, C1 to C3 alkyl, and cyclopropyl; and n is 1 to 4, provided that only one of said R2 and R3 of a moiety may be propyl or cyclopropyl; and (c) phenyl alkanols of the structure wherein m is 0 or 1; R4 is hydrogen, halogen, C1 to C4 alkyl, or cyclopropyl; R5, R6 and R7 are independently selected from hydrogen, C1 to C3 alkyl and cyclopropyl, provided, however, that only one of R5, R6 and R7 is a propyl or cyclopropyl group, and , when m is 0, at least one R5 is other than hydrogen; and the total of the carbon atoms in the structure.
is from 3 to 9 carbon atoms.
(a) primary, secondary and tertiary straight or branched chain monohydric aliphatic alcohols wherein the straight chain alcohols have from about 5 to about 10 carbon atoms and the branched chain alcohols have up to about 17 carbon atoms, their longest chain of carbon to carbon bonds having from about 5 to about 10 carbon atoms;
(b) cyclohexyl substituted alkanols of the structure wherein R1 is C1 to C4 alkyl, halogen or hydrogen; R2 and R3 are independently selected from hydrogen, C1 to C3 alkyl, and cyclopropyl; and n is 1 to 4, provided that only one of said R2 and R3 of a moiety may be propyl or cyclopropyl; and (c) phenyl alkanols of the structure wherein m is 0 or 1; R4 is hydrogen, halogen, C1 to C4 alkyl, or cyclopropyl; R5, R6 and R7 are independently selected from hydrogen, C1 to C3 alkyl and cyclopropyl, provided, however, that only one of R5, R6 and R7 is a propyl or cyclopropyl group, and , when m is 0, at least one R5 is other than hydrogen; and the total of the carbon atoms in the structure.
is from 3 to 9 carbon atoms.
20. A topical composition of claim 19 wherein the antibiotic is selected from the group consisting of teteracycline, oxytetracycline, chlorotetracycline, neomycin, erythromycin, cycloserine, bacitracin, streptomycin, rifampicin, N-demethylrifampicin, kanamycin and chloromycetin.
21. A topical composition of claim 19 wherein the antifungal agent is selected from the group consisting of griseofulvin, mycostatin and miconazole.
22. A topical composition of claim 19 wherein the quaternary ammonium compound is selected from the group consisting of domiphen bromide, domiphen chloride, domiphen fluoride, benzalakonium chloride, cetyl pyridinium chloride and dequalinium chloride.
23. A topical composition of claim 19 wherein the antiseptic agent is selected form the group consisting of zinc pyrithione, silver sulfadiazine, silver uracil, iodine, and an iodophore derived form a non-ionic surface active agent or from polyvinylpyrrolidone.
24. A topical composition of claim 19 wherein the topical medicament is selected from the group consisting of 2'-deoxyuridine, 5-iodo-2'-deoxyuridine triphosphate, 5-bromouracyl, 5-fluorouracyl, cyclic adenosine monophosphate ?-AMP), cyclic adenosine monophosphate dibutyrate (c-AMP-dibutyrate), cyclic adenosine monophosphate succinate, cyclic guanosine monophosphate (c-GMP), methotrexate, 6-azauridine triacetate (azaribin), epinephrine, phenephrine, L-dihydroxyphenyl alanine (l-DOPA) and dopamine.
25. A topical composition of claim 19 wherein the anesthetic agent is selected from the group consisting of lidocaine, benzocaine, tetracaine, carbocaine and rodocaine.
26. A topical composition of claim 19 in which the potentiator is selected form the group consisting of n-pentanol, n-hexanol, n-heptanol, n-octanol, n-nonanol, n-decanol, 2,3-dimethyl-2-hexanol, 2,5-dimethyl-2-hexanol, 2-methyl-3-hexanol, 2-heptanol, 3-heptanol, 4-heptanol and 2-ethyl-1-hexanol.
27. A topical composition of claim 19 in which the potentiator is selected form the group consisting of cyclohexylmethanol, 1-cyclohexylethanol, 2-cyclohexyl-ethanol, 1-cyclohexyl-1-propanol, (cyclohexyl)-dimethyl carbinol, (4-isopropylcyclohexyl)-dimethylcarbinol, 3-cyclohexyl-1-propanol, 2-cyclohexyl-1-propanol, 1-cyclohexyl-2-propanol, 2-cyclohexyl-1, 1-dimethylethanol, 2-cyclohexyl-2-methylpropanol, 2-cyclohexyl-1-methylpropanol, 2-cyclohexyl-1,2-dimethylpropanol, 2-cyclohexyl-1, 1-dimethylpropanol, 3-cyclohexyl-2-methylpropanol, 3-cyclohexyl-1-methylpropanol, 3-cyclohexylbutanol, 3-cyclohexyl-2-methylbutanol and 3-cyclohexyl-1,2-dimethyl-butanol.
28. A topical composition of claim 19 in which the potentiator is selected from the group consisting of 3-phenyl-1-propanol, benzyl-t-butanol, 1-phenyl-2-methyl-2-propanol, 1-phenyl-3-butanol, 2-methyl-3-phenyl-propanol, 2,2-dimethyl-3-phenylpropanol, and 1-phenyl-2-propanol.
29. A topical composition of claim 19 in which the amount of potentiator is from about 0.05% by weight to about 15% by weight of the composition.
30. A topical composition of claim 29 in which the amount of potentiator is from about 1 to about 12% by weight of the composition.
31. A topical composition of claim 19 which contains at least about 0.05% by weight of the topical medicament and at least about 0.05% by weight of the potentiator.
32. A topical composition of claim 29 which includes from about 0.5 to about 12% by weight of an anesthetic agent.
33. A topical composition of claim 32 wherein the amount of anesthetic agent is from about 1% to about 10% by weight.
34. A topical composition of claim 19 which further includes a pharmaceutically acceptable carrier.
35. A topical composition of claim 34 in which the carrier is selected from the group consisting of water, the lower alkanols and propylene glycol.
36. A topical composition of claim 35 in which said carrier comprises water.
37. The topical composition of claim 19 in the form of an ointment, cream, lotion, aerosol preparation, suspension or solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA265,435A CA1072009A (en) | 1976-11-12 | 1976-11-12 | Potentiated medicaments containing antimicrobial agents |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA265,435A CA1072009A (en) | 1976-11-12 | 1976-11-12 | Potentiated medicaments containing antimicrobial agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1072009A true CA1072009A (en) | 1980-02-19 |
Family
ID=4107245
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA265,435A Expired CA1072009A (en) | 1976-11-12 | 1976-11-12 | Potentiated medicaments containing antimicrobial agents |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1072009A (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0129284A2 (en) | 1983-06-21 | 1984-12-27 | THE PROCTER & GAMBLE COMPANY | Improved penetrating topical pharmaceutical compositions containing 1-dodecyl-azacycloheptan-2-one |
| US4537776A (en) * | 1983-06-21 | 1985-08-27 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions containing N-(2-hydroxyethyl) pyrrolidone |
| US4552872A (en) * | 1983-06-21 | 1985-11-12 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions containing corticosteroids |
| US4663077A (en) * | 1984-06-11 | 1987-05-05 | Morton Thiokol Inc. | Microbiocidal compositions comprising an aryl alkanol and a microbiocidal compound dissolved therein |
| US4683080A (en) * | 1984-06-11 | 1987-07-28 | Morton Thiokol, Inc. | Microbiocidal compositions comprising an aryl alkanol and a microbiocidal compound dissolved therein |
| US4711914A (en) * | 1985-04-22 | 1987-12-08 | Morton Thiokol, Inc. | Microbiocidal compositions comprising an aryl alkanol and a microbiocidal compound dissolved therein |
| US4895877A (en) * | 1984-06-11 | 1990-01-23 | Morton Thiokol, Inc. | Microbiocidal compositions comprising an aryl alkanol and a microbiocidal compound dissolved therein |
| US4954487A (en) * | 1979-01-08 | 1990-09-04 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions |
| WO2005018585A1 (en) * | 2003-08-25 | 2005-03-03 | Bioequal Ag | Pharmaceutical and cosmetic formulations for treating fingernails |
-
1976
- 1976-11-12 CA CA265,435A patent/CA1072009A/en not_active Expired
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4954487A (en) * | 1979-01-08 | 1990-09-04 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions |
| EP0129284A2 (en) | 1983-06-21 | 1984-12-27 | THE PROCTER & GAMBLE COMPANY | Improved penetrating topical pharmaceutical compositions containing 1-dodecyl-azacycloheptan-2-one |
| US4537776A (en) * | 1983-06-21 | 1985-08-27 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions containing N-(2-hydroxyethyl) pyrrolidone |
| US4552872A (en) * | 1983-06-21 | 1985-11-12 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions containing corticosteroids |
| US4557934A (en) * | 1983-06-21 | 1985-12-10 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions containing 1-dodecyl-azacycloheptan-2-one |
| US4663077A (en) * | 1984-06-11 | 1987-05-05 | Morton Thiokol Inc. | Microbiocidal compositions comprising an aryl alkanol and a microbiocidal compound dissolved therein |
| US4683080A (en) * | 1984-06-11 | 1987-07-28 | Morton Thiokol, Inc. | Microbiocidal compositions comprising an aryl alkanol and a microbiocidal compound dissolved therein |
| US4895877A (en) * | 1984-06-11 | 1990-01-23 | Morton Thiokol, Inc. | Microbiocidal compositions comprising an aryl alkanol and a microbiocidal compound dissolved therein |
| US4711914A (en) * | 1985-04-22 | 1987-12-08 | Morton Thiokol, Inc. | Microbiocidal compositions comprising an aryl alkanol and a microbiocidal compound dissolved therein |
| WO2005018585A1 (en) * | 2003-08-25 | 2005-03-03 | Bioequal Ag | Pharmaceutical and cosmetic formulations for treating fingernails |
| AU2004266053B2 (en) * | 2003-08-25 | 2011-06-09 | Bioequal Ag | Pharmaceutical and cosmetic formulations for treating fingernails |
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