Note: Descriptions are shown in the official language in which they were submitted.
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
~ .
-3-
, ~ .
;` 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,
- 6
~ 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
-- 7 --
~,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
- 72
.. -- C --
R3
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-
.
13 -
..
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
-18-
, ',: '
:~ ,'' '',,
... . ... ....... ~".... .. .... . .. - .... --: . ~ ..
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
-20-
:' .. ',.',' ''
:,. .
~ "' - ','.':: ., .
.~ ~',.. ".
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
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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.
.
.
- 26 -
~&~ 831
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- 28
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~&J 83~
' .
, ~:
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. .
- 32
9 t~
- 1.0'7ZOO~ J~ 831
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- - 33 -
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~J 831 ~
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9 . ~-~
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~
- 34
~ .
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` ~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~
- 35
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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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