Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1 334646
NOVEL TRANSDERMAL PENETRATION ENHANCERS
1. Field of the Invention
This invention relates to compositions comprising a
physiologically active agent and a novel transdermal pene-
tration enhancer in an amount effective to enhance the
penetration of the physiologically-active agent through the
skin or other membrane of the body of an animal.
Other such compositions and their uses relate to an
improved method of dyeing fibers, improved delivery of plant
nutrients, improved plant pest control, improved delivery of
plant growth regulations, improved acid-catalyzed conversion
of a reactant into a reaciton product and an improved insect
repellant.
2. Background of the Art
As hereinabove indicated, the present invention
includes a number of uses in which it provides an advantage.
Each of these uses will be hereinafter addressed in the
order of their recital beginning with the use of the
ocmposiion of the present invention in the enhancement of
the penetration of a physiologically-active agent through
the skin or other membranes of body.
It is well known that in many physiologically active
agents are best applied topically to obtain desirable
results. Topical application, as contrasted to systemic
application, can avoid metabolic degradation of the agents,
largely avoids side effects of the agents, and permits high
local concentrations of the agents.
~ ",
1 334646
--2--
The greatest problem in applying physiologically
active agents topically is that the skin is a very effective
barrier to penetration. The epidermis of the skin has an
exterior layer of dead cells called the stratum corneum,
which is tightly compacted and oily and which provides an
effective barrier against gaseous, solid or liquid chemical
agents, whether used alone or in water or oil solutions. If
a physiologically active agent penetrates the stratum
corneum, it can readily pass through the basal layer of the
epidermis and into the dermis.
Although the effectiveness of the stratum corneum as
a barrier provides great protection, it also frustrates
efforts to apply beneficial agents directly to local areas
of the body. The inability of physiologically active agents
to penetrate the stratum corneum prevents their effective
use to treat such conditions as inflammation, acne,
psoriasis, herpes simplex, eczema, infections due to fungus,
virus or other microorganisms, or other disorders and
conditions of the skin or mucous membranes, or of conditions
beneath the exterior surface of the skin or mucous
membranes. The stratum corneum also prevents the skin from
absorbing and retaining cosmetic-type materials such as
sunscreens, perfumes, mosquito repellents and the like.
Physiologically active agents may be applied to
locally affected parts of the body through the vehicles
system described herein. Vehicles such as USP cold cream,
ethanol and various ointments, oils, solvents, and emulsions
have been used heretofore to apply physiologically active
ingredients locally. Most such vehicles are not effective
to carry significant amounts of physiologically active
agents through the skin. One such vehicle is dimethyl
sulfoxide.
The l-lower alkyl substituted azacyclopentan-2-ones
having 1-4 carbon atoms in the alkyl group are known to
1 334646
moderately enhance percutaneous absorption of chemicals,
e.g. drugs. It was earlier recognized that it would be
desirable to obtain the same or higher level of percutaneous
absorption with substantially lower concentrations of the
penetration-enhancing compound. Therefore, various N-
substituted azacycloalkan-2-ones were invented having the
desired properties. These new penetration-enhancing agents
are described in U.S. Patents 3,989,815; 3,989,816;
3,991,203; 4,122,170; 4,316,893; 4,405,616; 4,415,563;
4,423,040; 4,424,210; and 4,444,762
It is an object of this invention to provide new
penetration-enhancing agents having the desirable property
of enhancing the percutaneous absorption of physiologically-
active agents at concentrations lower than the l-lower alkyl
substituted azacyclopentan-2-ones.
It is also an object of this invention to provide
penetration-enhancing agents that are eguivalent to the
aforesaid new penetration-enhancing agents described in the
above U.S. patents.
Other objects and advantages of the instant
invention will be apparent from a careful reading of the
specification below.
In this description, the term "animal" includes
human beings as well as other forms of animal life, and
especially domesticated animals and pets.
SUMMARY OF THE INVENTION
This invention relates to compounds and a method for
their use in carrying physiologically active agents through
body membranes such as skin and for retaining these agents
in body tissues. More specifically, the invention relates
to carboxylic acid derivatives and salts thereof, which
compounds are useful in topically administering a
"
, j, ..
-4- l 3 3 4 6 4 6
physiologically active agent to a human or animal via a
composition comprising the agent and an effective amount of
a compound represented by the general formulae:
~''
(CH/) -C-(CH2)n-R
Z ~ R'
\(CH2)m
wherein W represents oxygen, sulfur, or two hydrogen
radicals;
wherein Z represents oxygen, sulfur, or -CH2-;
wherein R represents alkyl optionally substituted
with one to three double or triple bonds, -SR''', -OR''',
-NHR''', -CH3, or COOR1, and wherein R1 represents hydrogen
or lower alkyl;
wherein R''' represents alkyl, alkylthioalkyl,
alkoxyalkyl, substituted aminoalkyl, optionally substituted
with a phenyl, benzoyl or heterocyclic group;
wherein R' represents hydrogen, alkyl, alkoxy,
acyloxy, alkylthio, hydroxy, -(CH2)yCOOR1 and with y being
between zero and 3, inclusive;
and wherein R'' represents hydrogen or -(CH2)yCOOR
such that when R " is hydrogen, then W is two hydrogen
radicals and R' is not hydrogen; and when R' is hydrogen,
then R'' is not hydrogen;
and wherein m is between one and 5, preferably 2, 3,
or 4, while n is between 1 and 24, preferably between 5 and
12, and x is zero or 1, inclusive.
In an alternative embodiment, the novel penetration
enhancers include compounds represented by the general
formula:
~ 334646
B R''
R2 ~ -cH-(cH2~n-R
----R'
(C:I2)m
~3
wherein B represents oxygen, sulfur, or two hydrogen
radicals;
wherein A represents oxygen, sulfur, or -(CH2)-;
wherein R, R2 and R3 independently represent alkyl
optionally substituted with 1 to 3 double or triple bonds,-
SR''', -OR''', -NHR''', -CH3, or COOR1;
wherein Rl'l represents hydrogen, alkyl,
alkylthioalkyl, alkoxyalkyl, substituted aminoalkyl,
optionally substituted with a phenyl, benzoyl, or
heterocyclic group;
wherein R' represents hydrogen, alkyl, alkoxy,
acyloxy, alkylthio, hydroxy, or -(CH2)yCOOR1;
wherein R'' represents hydrogen, or
-(CH2)yCOOR1;
wherein R1 represents a hydrogen or lower alkyl
radical and y is between zero and 3, inclusive.
wherein m is between zero and 5, preferably 1 or 2;
while n is between 1 and 24, preferably between 5 and 12,
inclusive;
And in yet another embodiment the compound is
represented by the formula:
(CH2)m ~-c-(CH2)n-R2
__ X R I
~ 334646
--6--
wherein R2 is COOR1 or an alkyl radical, optionally
substituted with between 1 and 3 double or triple bonds;
wherein R' is a hydrogen radical, alkyl, alkoxy,
acyloxy, alkylthio, hydroxy, or -(CH2)yCOOR1;
wherein B' represents oxygen, sulfur, or two
hydrogen radicals;
wherein B'' represents oxygen, sulfur, or two
hydrogen radicals such that when B'' is not hydrogen, B' is
two hydrogen radicals, and R2 is alkyl, then R' is
-(CH2)yCOOR1 where y cannot be zero;
wherein y is between zero and three, inclusive, and
R1 represents a lower alkyl or hydrogen radical.
and wherein m is between 3 and 6, preferably 3, 4 or
5 while n is between 1 and 24, preferably between 5 and 12,
inclusive;
and wherein y is between zero and three, inclusive,
and R1 represents a lower alkyl or hydrogen radical.
It has been found that physiologically active agents
are carried through body membranes by the above penetration-
enhancing agents and are retained in body tissue.
The invention further relates to the penetration-
enhancing agents themselves and the method of making such
penetration-enhancing agents.
It has been found that the hereinabove described 1-
substituted azacycloalkanes are also useful in the
enhancement of dye penetration in fibers by utilizing in a
dyeing process an effective amount of the 1-substituted
azacyloalkane. The invention also includes a compound
comprising an effective amount of dye and an effective
amount of the l-substituted azacyloalkane.
When combined with a plant nutrient, 1-substituted
azacycloaklane provides an improved method of delivery of
such plant nutrients by enhancing the uptake and
_7_ 1 3 3 4 6 4 6
assimilation of the plant nutrients in the plant. The
invention also includes a compound comprising an effective
amount of a plant nutrient and an effective, delivery-
enhancing amount of a novel penetration enhancer.
It has been found that the hereinablve described
novel penetration enhancers are also useful in an improved
method of plant pest control by enhancing the delivery of
pesticides to plant pests and the present invention includes
a compound comprising an effective amount of a plant
pesticide and an effective, delivery-enhancing amount of a
novel penetration enhancer.
The compound containing the delivery-enhancing
compound and pesticide may be applied directly to the plant
pest by topical applicaiton or indirectly by topical
application to the plant to be protected. The latter
indirect method of application enables the pesticide to
reach its ultimate site of action, namely, the plant pest,
after the plant pest has come into contact with the treated
plant.
It has been found that the hereinabove described
novel penetration enhancers are also useful in an improved
method of delivery of plant growth regulators and the
present invention includes a compound comprising an
effective amount of a plant growth reglator and an effective
delivery-enhancing amount of the novel penetration
enhancers. The plant gorwth regulators and penetration
enhancer may be applied to the plant in a conventional
manner.
It has been found that the hereinabove described
novel penetration enhancers are also useful as insepct
repellants, the application and/or delivery of penetratioOn
enhancers for such use being by conventional means.
The present invention also provides a process fo rht
econversion of a reactant into a reaction product in the
-8- 1 3 3 4 6 4 6
presence of an acid catalyst which comprises contacting said
reactant with an acid catalyst comprising a salt of the
hereinabove described novel penetration enhancers.
DETAILED DESCRIPTION OF THE INVENTION
Novel transdermal penetration enhancers useful in
the method of the present invention include carboxylic acid
derivatives and their salts, which are compounds represented
by the general formulae:
R"
\ C
(CH~2)x N- H-(CH2)n~R
Z ~ R'
~(CH2)m
wherein W represents oxygen, sulfur, or two hydrogen
radicals;
wherein Z represents oxygen, sulfur, or -CH2-;
wherein R represents alkyl optionally substituted
with one to three double or triple bonds, -SR''', -OR''',
-NHR''', -CH3, or COOR1, and wherein R1 represents hydrogen
or lower alkyl;
and wherein R''' represents alkyl, alkylthioalkyl,
alkoxyalkyl, substituted aminoalkyl, optionally substituted
with a phenyl, benzoyl or heterocyclic group;
wherein R' represents hydrogen, alkyl, alkoxy,
acyloxy, alkylthio, hydroxy, -(CH2)yCOOR1 and with y being
between zero and 3, inclusive;
wherein R'' represents hydrogen or -(CH2)yCOOR1 such
that when R'' is hydrogen, then W is two hydrogen radicals
and R' is not hydrogen; and when R' is hydrogen, then R'' is
not hydrogen;
and wherein m is between one and 5, preferably 2, 3,
-9- 1 3 3 4 6 4 6
or 4 while n is between 1 and 24, preferably between 5 and
12, inclusive, and x is zero or 1, inclusive.
In an alternative embodiment, the compounds useful
as penetration enhancers include those represented by the
general formula:
B ~''
R ~ ~tJ-CH- ( CH2 ) n~R
----R'
- (C~2)m
~3
wherein B represents oxygen, sulfur, or two hydrogen
radicals;
wherein A represents oxygen, sulfur or -(CH2)-;
wherein R, R2 and R3 independently represent alkyl
optionally substituted with 1 to 3 double or triple bonds,-
SR' ", -OR'", -NHR' ", -CH3, or COOR1;
wherein R' " represents hydrogen, alkyl, alkylthio-
alkyl, alkoxyalkyl, substituted aminoalkyl, optionally
substituted with a phenyl, benzoyl, or heterocyclic group;
wherein R' represents hydrogen, alkyl, alkoxy,
acyloxy, alkylthio, hydroxy, or -(CH2)yCOOR1;
wherein R'' represents hydrogen or -(CH2)yCOOR1;
wherein m is between zero and 5, preferably 1 or 2;
while n is between 1 and 24, preferably between 5 and 12,
inclusive;
and wherein R1 represents a hydrogen or lower alkyl
radical and y is between zero and 3, inclusive.
And in yet another embodiment the compound is
represented by the formula:
1 334546
--10--
(CH2)m N-C~(CH2)n~R2
~ R'
wherein R2 is COOR1 or an alkyl radical, optionally
substituted with between 1 and 3 double or triple bonds;
wherein R' is a hydrogen radical, alkyl, alkoxy,
acyloxy, alkylthio, hydroxy, or -(CH2)yCOORl;
wherein B' represents oxygen, sulfur, or two
hydrogen radicals;
wherein B'' represents oxygen, sulfur, or two
hydrogen radicals such that when B'' is not hydrogen, B' is
two hydrogen radicals, and R2 is alkyl, then R' is
-(CH2)yCOORl where y is not zero;
wherein y is between zero and three, inclusive, and
Rl represents a lower alkyl or hydrogen radical.
and wherein m is between 3 and 6, preferably 3,4,or
5, while n is between 1 and 24, preferably between 5 and 12,
inclusive;
These novel transdermal penetration-enhancing
additives may be made by the methods illustrated in the
Examples below. Typical examples of compounds represented
by the above general formulae include:
l-N-dodecyl-2-pyrrolidone-5-carboxylic acid
1-N-butyl-2-pyrrolidone-5-carboxylic acid
l-N-pentyl-2-pyrrolidone-5-carboxylic acid
l-N-hexyl-2-pyrrolidone-5-carboxylic acid
l-N-octyl-2-pyrrolidone-5-carboxylic acid
l-N-nonyl-2-pyrrolidone-5-carboxylic acid
l-N-decyl-2-pyrrolidone-5-carboxylic acid
l-N-tetradecyl-2-pyrrolidone-5-carboxylic acid
l-N-hexadecyl-2-pyrrolidone-5-carboxylic acid
-11- 1 3 3 4 6 4 6
1-N-heptyl-2-pyrrolidone-5-carboxylic acid
1-N-dodecyl-2-piperidone-6-carboxylic acid
1-N-butyl-2-piperidone-6-carboxylic acid
1-N-pentyl-2-piperidone-6-carboxylic acid
1-N-hexyl-2-piperidone-6-carboxylic acid
1-N-octyl-2-piperidone-6-carboxylic acid
1-N-nonyl-2-piperidone-6-carboxylic acid
l-N-decyl-2-piperidone-6-carboxylic acid
l-N-tetradecyl-2-piperidone-6-carboxylic acid
1-N-hexadecyl-2-piperidone-6-carboxylic acid
1-N-heptyl-2-piperidone-6-carboxylic acid
1-(2-(n-dodecylthio)ethyl)-2-pyrrolidone-5-
carboxylic acid
1-(2-(n-butylthio)ethyl)-2-pyrrolidone-5-
carboxylic acid
1-(2-(n-pentylthio)ethyl)-2-pyrrolidone-5-
carboxylic acid
1-(2-(n-hexylthio)ethyl)-2-pyrrolidone-5-
carboxylic acid
1-(2-(n-octylthio)ethyl)-2-pyrrolidone-5-
carboxylic acid
1-(2-(n-nonylthio)ethyl)-2-pyrrolidone-5-
carboxylic acid
1-(2-(n-decylthio)ethyl)-2-pyrrolidone-5-
carboxylic acid
1-(2-(n-tetradecylthio)ethyl)-2-
pyrrolidone-5-carboxylic acid
1-(2-(n-hexadecylthio)ethyl)-2-pyrrolidone-5-
carboxylic acid
1-(2-(n-heptylthio)ethyl)-2-pyrrolidone-5-
carboxylic acid
1-(2-(n-dodecylthio)ethyl)-piperidine-3-
carboxylic acid
1 334646
1-(2-(n-butylthio)ethyl)-piperidine-3-
carboxylic acid
1-(2-(n-pentylthio)ethyl)-piperidine-3-
carboxylic acid
1-(2-(n-hexylthio)ethyl)-piperidine-3-
carboxylic acid
1-(2-(n-octylthio)ethyl)-piperidine-3-
carboxylic acid
1-(2-(n-nonylthio)ethyl)-piperidine-3-
carboxylic acid
- 1-(2-(n-decylthio)ethyl)-piperidine-3-
carboxylic acid
1-(2-(n-tetradecylthio)ethyl)-piperidine-3-
carboxylic acid
- 1-(2-(n-hexadecylthio)ethyl)-piperidine-3-
carboxylic acid
1-(2-(n-heptyllthio)ethyl)-piperidine-3-
carboxylic acid
2-dodecyl,2-N-(2-pyrrolidone)-acetic acid
2-butyl,2-N-(2-pyrrolidone)-acetic acid
2-pentyl,2-N-(2-pyrrolidone)-acetic acid
2-hexyl,2-N-(2-pyrrolidone)-acetic acid
2-octyl,2-N-(2-pyrrolidone)-acetic acid
2-nonyl,2-N-(2-pyrrolidone)-acetic acid
2-decyl,2-N-(2-pyrrolidone)-acetic acid
2-tetradecyl,2-N-(2-pyrrolidone)-acetic acid
2-hexadecyl,2-N-(2-pyrrolidone)-acetic acid
2-heptyl,2-N-(2-pyrrolidone)-acetic acid
2-dodecyl,2-N-(2-piperidone)-acetic acid
2-dodecyl,2-N-(azacycloheptane-2-one)-acetic acid
2-butyl,2-N-(azacycloheptane-2-one)-acetic acid
2-pentyl,2-N-(azacycloheptane-2-one)-acetic acid
2-hexyl,2-N-(azacycloheptane-2-one)-acetic acid
2-octyl,2-N-(azacycloheptane-2-one)-acetic acid
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-13- l 334646
2-nonyl,2-N-(azacycloheptane-2-one)-acetic acid
2-decyl,2-N-(azacycloheptane-2-one)-acetic acid
2-tetradecyl,2-N-(azacycloheptane-2-one)-acetic acid
2-hexadecyl,2-N-(azacycloheptane-2-one)-acetic acid
2-heptyl,2-N-(azacycloheptane-2-one)-acetic acid
6-(N-pyrrolidine)-hexanoic acid
8-(N-pyrrolidine)-octanoic acid
10-(N-pyrrolidine)-decanoic acid
12-(N-pyrrolidine)-dodecanoic acid
12-diethylaminododecanoic acid
10-diethylaminodecanoic acid
6-diethylaminohexanoic acid
8-diethylaminooctanoic acid
2-(N-morpholine)-2-dodecylacetic acid
2-(N-morpholine)-2-decylacetic acid
2-(N-morpholine)-2-octylacetic acid
2-(N-morpholine)-2-hexylacetic acid
2-(N-morpholine)-2-butylacetic acid
It has also been found that the penetration
enhancers herein also themselves possess antiviral activity
and can be used alone to combat viral infections.
When used in compositions comprising a second
physiologically active agent, the amount of the novel
transdermal penetration enhancers used in the present
invention is an effective amount for enhancing percutaneous
absorption. Generally, this amount ranges between about
0.01 to about 5 and preferably about 0.1 to 2 percent by
weight of the composition.
The subject compositions may find use with many
physiologically active agents which are soluble in the
vehicles disclosed. The penetration enhancer can be applied
before, after, or in combination with the physiologically
active agent. The order of application is immaterial.
1 334646
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Fungistatic and fungicidal agents such as, for
example, thiabendazole, chloroxine, amphotericin B,
candicidin, fungimycin, nystatin, chlordantoin, clotrima-
zole, miconazole nitrate, pyrrolnitrin, salicyclic acid,
fezatione, tolnaftate, triacetin and zinc and sodium
pyrithione may be dissolved in the penetration-enhancing
agents described herein and topically applied to affected
areas of the skin. For example, fungistatic or fungicidal
agents so applied are carried through the stratum corneum,
and thereby successfully treat fungus-caused skin problems.
These agents, thus applied, not only penetrate more quickly
than when applied in the vehicles of the prior art, but
additionally enter the animal tissue in high concentrations
and are retained for substantially longer time periods
whereby a far more successful treatment is effected.
For example, the subject compositions may also be
employed in the treatment of fungus infections on the skin
caused by candida and dermatophytes which cause athletes
foot or ringworm, by dissolving thiabendazole or similar
antifungal agents in one of the above-described penetration-
enhancing agents and applying it to the affected area.
The subject compositions are also useful in treating
skin problems, for example, herpes simplex, which may be
treated by a solution of iododeoxyuridine dissolved in one
of the penetration-enhancing agents or such problems as
warts which may be treated with agents such as podophylline
dissolved in one of the penetration-enhancing agents. Skin
problems such as psoriasis may be treated by topical
application of a solution of a conventional topical steroid
in one of the penetration-enhancing agents or by treatment
with theophylline or antagonists of ~-adrenergic blockers
such as isoproterenol in one of the penetration-enhancing
agents. Scalp conditions such as alopecia areata may be
treated more effectively by applying steroids such as
-15- l 3 3 4 6 4 6
triamcinolone acetonide dissolved in one of the penetration-
enhancing agents of this invention directly to the scalp.
The subject compositions are also useful for
treating mild eczema, for example, by applying a solution of
fluocinolone acetonide or its derivatives; hydrocortisone,
triamcinolone acetonide, indomethacin, or phenylbutazone
dissolved in one of the penetration-enhancing agents to the
affected area.
Examples of other physiologically active steroids
which may be used with the vehicles include corticosteroids
such as, for example, cortisone, cortodoxone, flucetonide,
fluorocortisone, diflursone diacetate, flurandrenolone
acetonide, medrysone, amcinafel, amcinafide, betamethasone
and its esters, chloroprednisone, clocortelone,
descinolone, desonide, dexamethasone, dichlorisone,
defluprednate, flucloronide, flumethasone, flunisolide,
fluocinonide, flucortolone, fluoromethalone, fluperolone,
fluprednisolone, meprednisone, methylmeprednisolone,
paramethasone, predisolone and prednisone.
The subject compositions are also useful in antibac-
terial chemotherapy, e.g. in the treatment of skin condi-
tions involving pathogenic bacteria. Typical antibacterial
agents which may be used in this invention include sul-
fonamides, penicillins, cephalosporins, penicillinase,
erythromycins, lincomycins, vancomycins, tetracyclines,
chloramphenicols, streptomycins, etc. Typical examples of
the foregoing include erythromycin, erythromycin ethyl
carbonate, erythromycin estolate, erythromycin glucepate,
erythromycin ethylsuccinate, erythromycin lactobionate,
lincomycin, clindamycin, tetracycline, chlortetracycline,
demeclocycline, doxycycline, methacycline, oxytetracycline,
minocycline, etc.
The subject compositions are also useful in pro-
tecting ultra-sensitive skin or even normally sensitive skin
- 1 3 3 4 6 4 6
-16-
from damage or discomfort due to sunburn. Thus, dermatitis
actinica may be avoided by application to the skin surfaces
that are to be exposed to the sun of a sunscreen, such as
para-aminobenzoic acid or its well-known derivatives in
combination with one of the above-described penetration-
enhancing agents. The protective para-aminobenzoic acid or
its derivatives will thereby be carried into the stratum
corneum more successfully and will therefore be retained
even when exposed to water or washing for a substantially
longer period of time than when applied to the skin in
conventional vehicles. This invention is particularly
useful for ordinary suntan lotions used in activities
involving swimming because the ultraviolet screening
ingredients in the carriers of the prior art are washed off
the skin when it is immersed in water.
The subject compositions may also find use in
treating scar tissue by applying topically to the scar
tissue agents which soften collagen, such as aminopropionit-
rile or penicillamine dissolved in one of the penetration-
enhancing agents of this invention.
Agents normally applied as eye drops, ear drops, or
nose drops are more effective when dissolved in the
penetration-enhancing agents of this invention.
Agents used in diagnosis may be used more
effectively when applied dissolved in one of the
penetration-enhancing agents of this invention. Patch tests
to diagnose allergies may be effected promptly without
scratching the skin or covering the area subjected to an
allergen when the allergens are applied in one of the
penetration-enhancing agents of this invention.
The subject compositions are also useful for topical
application of cosmetic or esthetic agents. For example,
compounds such as melanin-stimulating hormone (MSH) or
dihydroxyacetone and the like are more effectively applied
-
-17- 1 3 3 4 6 4 6
to skin to stimulate a suntan when they are dissolved in one
of the penetration-enhancing agents of this invention. The
agent is carried into the skin more quickly and in greater
quantity when applied in accordance with this invention.
Hair dyes also penetrate more completely and effectively
when dissolved in one of the penetration-enhancing agents of
this invention.
The effectiveness of such topically applied
materials as insect repellents or fragrances, such as
perfumes and colognes, can be prolonged when such agents are
applied in combination with one of the penetration-enhancing
agents of this invention.
It is to be emphasized that the foregoing are simply
examples of physiologically active agents including
therapeutic and cosmetic agents having known effects for
known conditions, which may be used more effectively for
their known properties in accordance with this invention.
In addition, the penetration-enhancing agents of the
present invention may also be used to produce therapeutic
effects which were not previously known. That is, by use of
the penetration-enhancing agents described herein,
therapeutic effects heretofore not known can be achieved.
As an example of the foregoing, griseofulvin is
known as the treatment of choice for fungus infections of
the skin and nails. Heretofore, the manner of delivery of
griseofulvin has been oral. However, it has long been known
that oral treatment is not preferred because of side effects
resulting from exposure of the entire body to griseofulvin
and the fact that only the outer layers of affected skin
need to be treated. Therefore, because fungal infections
are generally infections of the skin and nails, it would be
advantageous to utilize griseofulvin topically. However,
despite a long-felt need for a topical griseofulvin,
griseofulvin has been used orally to treat topical fungus
-18- l 3 3 4 6 4 ~
conditions because there was not heretofore known any
formulation which could be delivered topically which would
cause sufficient retention of griseofulvin in the skin to be
useful therapeutically.
However, it has now been discovered that griseo-
fulvin, in a range of therapeutic concentrations between
about 0.1% and about 10% may be used effectively topically
if combined with one of the penetration-enhancing agents
described herein.
As a further example, acne is the name commonly
applied to any inflammatory disease of the sebaceous glands;
also acne vulgaris. The microorganism typically responsible
for the acne infection is Corynebacterium acnes. Various
therapeutic methods for treating acne have been attempted
including topical antibacterials, e.g. hexachlorophene, and
systemic antibiotics such as tetracycline. While systemic
antibiotic treatments are known to be partially effective,
topical treatments are generally not effective.
However, it has long been known that systemic
treatment of acne is not preferred because of side effects
resulting from exposure of the entire body to antibiotics
and the fact that only the affected skin need be treated.
Heretofore, despite a long-felt need for a topical treatment
for acne, antibiotics generally have been used only
systemically to treat acne because an antibacterial
formulation which could be used topically as an effective
therapeutic in the treatment of acne was not known.
However, it has now been discovered that antibiotics,
especially those of the lincomycin and erythromycin families
of antibiotics, may be used topically in the treatment of
acne if combined with one of the penetration-enhancing
agents described herein.
The antibiotic compositions so applied are carried
into and through the epidermis and deeper layers of the skin
1 33~646
--19--
as well as into follicles, (which contain C. acnes) in
therapeutically effective amounts and thereby successfully
may be used to temporarily eliminate the signs and symptoms
of acne.
The term "physiologically active agent" is used
herein to refer to a broad class of useful chemical and
therapeutic agents including physiologically active
steroids, antibiotics, antifungal agents, antibacterial
agents, antineoplastic agents, allergens, antihistaminic
agents, anti-inflammatory agents, ultraviolet screening
agents, diagnostic agents, perfumes, insect repellents, hair
dyes, etc.
Dosage forms for topical application may include
solution nasal sprays, lotions, ointments, creams, gels,
suppositories, sprays, aerosols and the like. Typical inert
carriers which make up the foregoing dosage forms include
water, acetone, isopropyl alcohol, freons, ethyl alcohol,
polyvinylpyrrolidone, propylene glycol, fragrances, gel-
producing materials, mineral oil, stearyl alcohol, stearic
acid, spermaceti, sorbitan monooleate, "Polysorbates",
"Tweens", sorbital, methyl cellulose, etc.
The amount of the composition and/or of the
physiologically active agent to be administered will
obviously be an effective amount for the desired result
expected therefrom. This, of course, will be ascertained by
the ordinary skill of the practitioner. Due to enhanced
activity which is achieved, the dosage of physiologically
active agent may often be decreased from that generally
applicable. In accordance with usual prudent formulating
practices, a dosage near the lower end of the useful range
of the particular physiologically active agent may be
employed initially and the dosage increased as indicated
from the observed response, as in the routine procedure of
the physician.
-20- l 3 3 4 6 4 6
- The invention is further illustrated by the
following examples which are illustrative of various aspects
of the invention, and are not intended as limiting the scope
of the invention as defined by the appended claims.
EXAMPLE 1
Preparation of 1-N-dodecyl-2-Pyrrolidone-5-carboxYlic acid
A. To a stirred solution of 1.92 g NaH (60%, washed with pet
ether) in dry THF at room temperature under N2 was added
dropwise a solution of 7.06 g of ethyl 2-pyrrolidone-5-
carboxylate in 20 mL of THF. The mixture was refluxed
for 1 h, cooled to room temperature, followed by dropwise
addition of 1.3 equivalents of 1-bromododecane. After
additional reflux overnight and workup, the crude oil was
subjected to flash chromatography (silica, 8:2 pet
ether/EtOAC) to give 3.14 g of ethyl l-N-dodecyl-2-
pyrrolidone-5-carboxylate as a clear oil: NMR (CDCl3)
4.2(m), 3.68(m), 2.9(m), 2.6-2.2(m), 2.1(m), 1.6-l.O(m),
o.g(t)-
Basic hydrolysis of the product of example lA atroom temperature, followed by acidic workup resulted in
1.73 g of 1-dodecyl-2-pyrrolidone-5-carboxylic acid as a
white solid: NMR (CDCl3) ~ 4.29(m), 3.75(m), 3.00(m),
2.7-2.3(m), 2.2(m), 1.5(m), 1.3(s), O.9(t).
B. Example lA was repeated using Ethyl 12-Bromododecanoate,
followed by hydrolysis to give 12-(N-pyrrolidin-2-one-5-
carboxy)dodecanoic acid.
C. Example lA was repeated using Ethyl 2-Bromotetrade-
canoate, followed by hydrolysis to give 2-(N-pyrrolidin-
2-one-5-carboxy)-2-dodecylacetic acid.
-
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D. Example lA was repeated replacing ethyl 2-pyrrolidone-5-
carboxylic acid with proline ethyl ester, followed by
hydrolysis to give N-dodecylproline.
E. Example lA was repeated replacing ethyl-2-pyrrolidone-5-
carboxylic acid with N-Acetyl alanine ethyl ester,
followed by hydrolysis to give N-Acetyl-N-dodecylalanine.
F. Example lA was repeated, replacing starting materials
with N-ethyl alanine ethyl ester and dodecanoyl chloride
and followed by hydrolysis to give N-Ethyl-N-(1-
oxododecyl)alanine.
EXAMPLE 2
Preparation of 2-Pentyl-2-oxo-1-PYrrolidineacetic acid
A. Alkylation of 2.0 g 2-pyrrolidone, under the same
procedure described in Example lA, with 7.23 g ethyl-2-
bromoheptanoate resulted in 1.6 g Qf 2-pentyl-2-oxo-1-
pyrrolidineacetic acid ethyl ester as a light yellow oil:
NMR (CDCl3) ~ 4.75 (dd), 4.15 (q), 3.55(m), 3.35(m),
2.45(t), 2.2-1.6(m), 1.4-1.2(m), 0.9(m).
Basic hydrolysis of the product in Example 2A at room
temperature, followed by acidic workup resulted in 0.89 g
of 2-pentyl-2-oxo-1-pyrrolidineacetic acid as a white
solid: NMR (CDCl3) ~ 4.8(dd), 3.6(m), 3.4(m), 2.5(t),
2.2-2.05(m), 1.75(m), 1.4-1.2(s), 0.9(t).
B. Example 2A was repeated using 2-Oxazolidine, followed by
- hydrolysis to give 2-dodecyl-2-oxa-3-oxazolidineacetic
acid.
1 334646
C. Example 2A was repeated using ~-Caprolactam and ethyl 2-
bromotetra-decanoate, followed by hydrolysis to give 2-
(l-azacycloheptan-2-one)-2-dodecylacetic acid.
D. Example 2A was repeated using Morpholine, followed by
hydrolysis to give 2-dodecyl-4-morpholineacetic acid.
E. Example 2A was repeated using Pyrrolidine, followed by
hydrolysis to give 2-dodecyl-1-pyrrolidineacetic acid.
F. Example 2A was repeated using Proline ethyl ester,
followed by hydrolysis to give 2-(N-pyrrolidino-2-
carboxy)-2-dodecylacetic acid.
G. Example 2A was repeated using N-Ethyl acetamide, followed
by hydrolysis to give 2-(N-ethylacetamido)-2-
dodecylacetic acid.
H. Example 2A was repeated using Diethylamine, followed by
hydrolysis to give 2-(N,N-diethylamino)-2-dodecylacetic
acid.
I. Example 2A was repeated using ethyl 2-bromotetra-
decanoate, followed by hydrolysis to give 2-dodecyl-2-
oxo-1-pyrrolidineacetic acid.
EXAMPLE 3
Preparation of ll-(diethylamino)-undecanoic acid
A. According to the previously described basic hydrolysis
procedure of Example lB, 0.47 g of ethyl 11-
(diethylamino)-undecanoate resulted in the desired
product as a white solid: NMR (CDC13) ~ 3.1 (q),
2.95(m), 2.25(t), 1.7-1.6(m), 1.4-l.l(m).
-23- l 3 3 4 6 4 6
B. Example 3A was repeated using Pyrrolidine, followed by
hydrolysis, to give 11-(1-pyrrolidino)undecanoic acid.
C. Example 3A was repeated using Morpholine, followed by
hydrolysis, to give 11-(4-Morpholino)undecanoic acid.
D. Example 3A was repeated using Piperazine, followed by
hydrolysis, to give 11-(1-Piperazino)undecanoic acid.
E. Example 3A was repeated using 2-Pyrrolidinone, followed
by hydrolysis, to give 11-(N-Pyrrolidino-2-one)
undecanoic acid.
F. Example 3A was repeated using 2-Oxazolidone, followed by
hydrolysis, to give 11-(3-Oxazolidin-2-one)undecanoic
acid.
G. Example 3A was repeated using ~-Caprolactam, followed by
hydrolysis, to give 11-(1-hexamethylineimin-2-one)
undecanoic acid.
H. Example 3A was repeated using Proline ethyl ester,
followed by hydrolysis, to give 11-(1-pyrrolidin-2-
carboxy)undecanoic acid.
I. Example 3A was repeated using N-Ethyl acetamide, followed
by hydrolysis, to give 11-(N-Ethyl acetamido)-undecanoic
acid.
J. Example 3A was repeated using N-Acetyl alanine ethyl
ester, followed by hydrolysis, to give N-acetyl-N-(10-
carboxy-1-decyl)alanine.
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EXAMPLE 4
To model the capacity of the carboxylic acid deriva-
tives of 1-substituted azacycloalkanes for enhancing
permeability of physiologically active agents through skin
and mucous membranes, a series of experiments were conducted
using either ethanol-C14 or butanol-C14 as a control. The
amount penetrating was calculated as percent of penetration
of the control. For comparison with each control, parallel
tests were also conducted using a known penetration
enhancer, l-n-dodecylazacyclo-heptane-2-one.
Ethanol and butanol have known permeability coeffi-
cients for passage through hairless mouse skin via a
diffusion cell. The permeability coefficient is expressed
by the formula:
p DKm/v
wherein D is the diffusivity (diffusion coefficient), Km/v
is the partition coefficient between the membrane (m) and
medium (v, vehicle), and h is the membrane thickness,
respectively. See Kurihara-Bergstrom, T, et al., "Physio-
chemical Study of Percutaneous Absorption Enhancement by
Dimethyl Sulfoxide: Kinetic and Thermodynamic Determinants
of Dimethyl Sulfoxide Mediated Mass Transfer of Alkanols" in
Journal of Pharmaceutical Sciences, Vol. 75, No. 5, May
1986, pp. 479-86. Full thickness abdominal and dorsal
sections of mouse skin membranes were obtained from the
hairless mouse strain (Skin Cancer Hospital, Temple
University, Philadelphia, PA).
Formulations to be tested contained either one or
five weight percent of a penetration enhancer, three weight
percent Tween 20, and the balance of nanopure water. A
trace amount of radio labelled ethanol C14 or butanol C14
Trade-mark
~,
1 334646
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was added to each formulation prior to assay and then lOml
of the labelled formulation was counted in a liquid
scintillation counter to determine the number of disin-
tegrations per minute (DPM).
The receptor cells of nine finite dose Franz
diffusion cells were filled with isotonic saline and
maintained at 37C by submersion into a thermostatically
controlled water jacket. The saline was stirred for 30
minutes with a magnetic stir bar to achieve equilibrium.
Freshly excised full thickness mouse skin was then
mounted with an O ring between the donor and the receptor
cells. After one hour of equilibration the saline was
removed from the receptor cells and replaced by 4-5 ml of
fresh saline solution at 37C.
Three of the nine donor cells were charged with 100
~1 of radio-labelled saline containing no penetration
enhancer as the control, three were charged with 100 ~1 of
the one weight percent penetration enhancer formulation in
labelled saline, and three cells were charged with equal
amounts of the five weight percent penetration enhancer
formulation in labelled saline.
At 45 minute intervals, 50 ~1 samples were taken
from each receptor cell port with a micropipettor. The
volume removed was replaced with a 50 ~1 sample of fresh
37C saline formulation. Each sample was then placed into a
liquid scintillation counting vial along with 4.0 ~1 of
scintillation cocktail (Aquasol*, New England Nuclear,
Boston, MA).
Based upon the predetermined DPM for each formula-
tion, the amount of alkanol carried through the mouse skin
by each formulation was calculated using known methods.
Tables II and III below summarize the increase in
permeation of radio labelled alkanol achieved by addition of
the penetration enhancer. It will be noted that in every
* Trade-mark
-
-26- l 3 3 4 6 4 6
test the penetration of ethanol was increased by at least 76
per cent over that achieved without aid of the penetration
enhancers of this invention. The best results in these
tests were achieved using a 1 weight percent concentration
of N-0917 penetration enhancer, which yielded a penetration
of ethanol through hairless mouse skin of 616% of that
achieved without the penetration enhancer.
As shown in Table II, all of the penetration
enhancers of this invention yielded penetration of butanol
at least 119 percent of that achieved by the control.
TABLE I
ETHANOL - C14 AS PERMEANT
PENETRATION
- COEFFICIENT
COMPOUNDCONC'N (X10-3CM/NR) % OF CONTROL
1% 19.42 616
lA 5% 17.20 546
1% 8.21 155
2A 5% 25.62 484
1% 11.28 341
2I 5% 6.89 208
1% 2.38 76
2C 5% 4.82 155
1% 10.69 269
AZONE 5% 18.58 466
-27- l 3 3 4 6 4 6
TABLE II
BUTANOL - C14 AS PERMEANT
PENETRATION
COEFFICIENT
COMPOUND CONC'N(X10-3CM/NR)% OF CONTROL
1% 37.39 297
lA 5% 40.74 324
1% 14.69 135
2A 5% 22.23 204
1% 18.91 204
2I 5% 23.68 255
1% 10.80 119
2C 5% 11.65 128
1% 24.83 340
AZONE 5% 23.29 319
EXAMPLE 5
The following formulation is prepared:
Solution (%)
Griseofulvin
N-dodecyl-2-pyrrolidone-5-carboxylic acid
Isopropyl myristate 5
Fragrance 0.1
Ethanol 92.9
This formulation is effective in the treatment of
fungus infections.
1 334646
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EXAMPLE 6
An aerosol form of the formulation of Example 7 is
prepared by preparing the following mixture:
Formulation 25%
Freonl* 75%
Freon is 75/25 Freon 114/12.
EXAMPLE 7
The following cream formulation is prepared:
%
Clindamycin base 1.0
Stearyl alcohol, U.S.P. 12.0
Ethoxylated cholesterol 0.4
Synthetic spermaceti 7.5
Sorbitan monooleate 1.0
Polysorbate 80, U.S.P. 3.0
N-dodecyl-2-pyrrolidone-5-carboxylic acid 0.5
Sorbitol solution, U.S.P. 5.5
Sodium citrate 0.5
Chemoderm #844 Fragrance 0.2
Purified water 68.4
This formulation is effective in the treatment of
acne.
* Trade-mark
~ ,,
-29- l 3 3 4 6 4 6
EXAMPLE 8
The following solution formulations are prepared:
A (%) B (%)
Clindamycin base -- 1.0
Clindamycin phosphate acid 1.3 --
Sodium hydroxide 0.077 --
1.0 M Hydrochloric acid -- 2.27
Disodium edetate 2H2O 0.003 0.003
Fragrances 0.5 0.5
N-dodecyl-2-pyrrolidone-5-
carboxylic acid .0 1.0
Purified water 20.0 17.73
Isopropanol 77.12 77.497
These solutions are effective for the treatment of
acne in humans.
EXAMPLE 9
The following solution formulation is prepared:
%
Neomycin sulfate 0.5
Lidocaine 0.5
Hydrocortisone 0.25
N-dodecyl-2-pyrrolidone-5-carboxylic acid 0.5
Propylene glycol 98.25
This solution is effective for the
treatment of otitis in domestic animals.
-
-30- 1 3 3 4 ~ ~ 6
EXAMPLE 10
The following sunscreen emulsion is prepared:
%
p-Aminobenzoic acid 2.0
Benzyl alcohol 0.5
N-dodecyl-2-pyrrolidone-5-carboxylic acid 1.0
Polyethylene glycol 500-MS 10.0
Isopropyl lanolate 3.0
Lantrol 1.0
Acetylated lanolin 0.5
Isopropyl myristate 5.0
Light mineral oil 8.0
Cetyl alcohol 1.0
Veegum 1.0
Propylene glycol 3.0
Purified water 64.0
EXAMPLE 11
The following antineoplastic solution is prepared:
%
5-Fluorouracil 5.0
N-dodecyl-2-pyrrolidone-5-carboxylic acid 0.1
Polyethylene glycol 5.0
Purified water 89.9
-
1 334646
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EXAMPLE 12
The following insect repellant atomizing spray is
prepared:
%
Diethyltoluamide 0.1
N-dodecyl-2-pyrrolidone-5-carboxylic acid 0.1
Ethanol 99.8
EXAMPLE 13
The following lotion formulation may be prepared
containing about 0.001 to l percent, with preferably 0.1
percent fluocinolone acetonide:
%
Fluocinolone acetonide 0.001-1
Cetyl alcohol 15.0
Propylene glycol 10.0
Sodium lauryl sulfate 15.0
N-dodecyl-2-pyrrolidone-5-carboxylic acid 1.0
Water (to make 100%)
The steroid is dissolved in the vehicle and added to
a stirred, cooling melt of the other ingredients. The
preparation is particularly useful for the treatment of
inflamed dermatoses by topical application to the affected
skin area. The amount and frequency of application is in
accordance with standard practice for topical application of
this steroid. Penetration of the steroid into the inflamed
tissue is enhanced and a therapeutic level is achieved more
rapidly and sustained for longer duration than when the
steroid is applied in conventional formulations.
The pentration enhancers of the present invention
can also be used in combination with fabric dyes for the
dyeing of fibers, additives, or textile auxiliaries, useful
in improving or enhancing the dyeing process by enabling the
dyeing of fibers at lower temperatures and in shorter times
1 334646
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than without the use of the composition. Dyeable fibers
include both natural and man-made fibers.
Natural fibers suitable for use in the method of the
present invention include cotton, linen, wood, and silk and
others such as kapok, hemp, jute and ramie. Man-made fibers
include rayon (fibers composed of regenerated cellulose),
acetate (fibers composed of cellulose approximately di- or
tri-acetate) and synthetic fibers which are composed of non-
natural fiber-forming substances manufactured by chemical
methods, such as polyamide, acrylic, polyester and
polyolefin.
Typical polyamide fibers include nylons, such as,
for example, poly (hexamethylene-adipamide), poly (mxylylene
adipamide), poly (xylylene sebacamide), polycaprolactam and
the like. Typical acrylic fibers are synthetic consisting
wholly of polyacrylonitrile or a copolymer of a mixture of
acrylonitrile and another vinyl compound, such as Orlon*
Dynel, Verel, Creslan, Acrilan, Courtelle and Vinyon.
Typical polyester fibers include Terylene, Dacron and Kodel.
Typical polyolefin fibers include polyethylene,
polypropylene, Vinylon, Rhouyl, Zefran and Darvan.
Various dyestuffs are available and may be
classified as substantive or direct dyes, asoic or naphthol
dyes, vat dyes and sulfur dyes, acid dyes and mordant or
metalized dyes, basic or cationic dyes, disperse dyes and
fiber reactive dyes.
Direct dyes are soluble in water and are applied
primarily to cellulosic fibers and occasionally to protein
fibers and polyamides, azoic or naphthol dyes are somewhat
similar to developed direct dyes and are used on the same
fiber group. Acid dyes and mordant or metalized dyes are
used in protein fibers, acrylic fibers, nylon fibers and
some modified polyester fibers. Cationic or basic dyes are
used especially for coloring acrylic fibers and may be
r- - * Trade-mark
-33- 1 3 3 4 6 4 6
useful with nylon and polyester fibers. Disperse dyes were
originally developed for use on acetate fibers and are now
used for coloring acetate, polyester, acrylic and polyamide
fibers. Reactive dyes are used primarily on cotton,
cellulosis, wool, silk and acrylics.
While it is usual to dye most natural fibers in dye
liquors at temperatures up to 100C, these conditions are
generally not sufficient to allow the production of deep
shades on synthetic fiber materials. Furthermore, while
some natural fibers, such as wool, can be satisfactorily
dyed in boiling aqueous dye liquors, it usually takes 1-1/2
to 2 hours for the dye to be fully absorbed to produce a
deep shade. Wool dyes more slowly than cotton and viscose
rayon. For this reason, it is generally not practical to
dye wool fabrics by conventional continuous dyeing methods.
However, at temperatures above 100C., wool and synthetic
fibers absorb dyes more quickly and thus the continuous
dyeing of wool would be possible, except that such high
temperature dyeing conditions can result in deterioration of
the fiber.
With the use of the compounds described herein, the
dyeing process can often be carried out at lower
temperatures and completed in a shorter time than without
the use of such compounds. Furthermore, use of the
compounds described herein enhances the penetration of the
dyes into the fiber being dyed and improves fastness. The
compounds described herein are especially useful in the
dyeing of synthetic fibers for carpet.
The amount of the compounds described herein which
may be used in the present invention varies with the desired
fiber and dye, the desired time and temperature of dyeing,
and the dyeing process that is used. Generally, the
compounds described herein may be used in amounts of about
0.1 to about 50% by weight and preferably about 1 to about
1 334646
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10% by weight of the dye liquor.
The textile materials with which the compounds of
the present invention may be used may be of any type
including, but not limited to, a yarn or fabric of any of
the known fabric types including woven, knitted, or non-
woven. An especially suitable fabric is a tufted or looped
pile carpet.
As used herein, the term "effective amount" in
reference to the textile auxiliary disclosed herein has
reference to that amount of the disclosed compound
sufficient to improve dye penetration by swelling the fibers
to be dyed or dispersing the dye being used in the dyeing
process into smaller particles for improving dye fastness,
or facilitating the use of lower temperatures and shorter
times in the dyeing process.
The subject composition is useful in the treatment
of plants, in particular for an improved method of the
delivery of plant nutrients.
The supply and absorption of chemical compounds
needed for growth and metabolism may be defined as nutrition
and the chemical compounds required by an organism termed
nutrients. The mechanisms by which nutrients are converted
to cellular material or used for energetic purposes are
metabolic processes. The term 'metabolism' encompasses the
various reactions occurring in a living cell in order to
maintain life and growth. Nutrition and metabolism are thus
very closely interrelated.
The essential nutrients required by green plants are
exclusively of inorganic nature. In this respect, green
plants differ fundamentally from man, animals and a number
of microorganisms, which additionally need organic compounds
as foodstuffs. An essential element may be defined as one
which is required for the normal life cycle of an organism
and whose functions cannot be substituted by other chemical
1 334646
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compounds. In addition, the element must be shown to be
directly involved in nutrition, as for example as a
constituent of an essential enzyme system. Based on this
definition, the following chemical elements are now known to
be essential for higher plants:
Carbon C Potassium K Zinc Zn
Hydrogen H Calcium Ca Molybdenum Mo
Oxygen O Magnesium Mg Boron B
Nitrogen N Iron Fe Chlorine Cl
Phosphorus P Manganese Mn Sodium Na
Sulfur S Copper Cu Silicon Si
Cobalt Co
The list of essential elements shown above may well
not be complete and other elements, in very low
concentrations, may yet be shown to be essential for higher
plants. For some microorganisms, for example, vanadium (V)
has now been established as an essential element.
The plant nutrients may be divided into macro-
nutrients and micronutrients. Macronutrients are found and
needed in plants in relatively higher amounts than micro-
nutrients. The plant tissue content of the macronutrient N,
for example, is over a thousand times greater than the
content of the micronutrient Zn. Following the classifi-
cation based on the element content in plant material, the
following elements may be defined as macronutrients: C, H,
O, N, P, S, K, Ca, Mg, Na and Si. The micronutrients are:
Fe, Mn, Cu, Zn, Mo, B and Cl. This division of the plant
nutrients into macro and micronutrients is somewhat
arbitrary and in many cases differences between the contents
of macronutrients and micronutrients are considerably lower
than the example cited above.
The process of nutrient uptake and assimilation by
plants is not fully understood, although a number of
theories of ion uptake and transport are known, see for
-36- l 3 3 4 6 4 6
example, Mengel, et al, Principles of Plant Nutrition,
Chapter 3, "Nutrient Uptake and Assimilation", International
Potash Institute, Bern (1978).
The amount of the subject composition which may be
used in the present invention is an amount effective for
enhancing the delivery of a plant nutrient to a plant.
Generally, an effective amount ranges between about 0.01 to
about 99.9 and preferably about 0.1 to 10 percent by weight
of the composition.
Plant nutrients which may be used in this invention
include conventional macronutrients and micronutrients
previously described including essential as well as non-
essential plant nutrients. Examples of nutrients include,
but are not limited to, the primary plant foods: nitrogen
including ammonia and nitrate ions, phosphorous (phosphoric
acid), potassium (potash); the secondary plant-food
elements: calcium, magnesium and sulfur; and the trace
elements: manganese, boron, copper, zinc, iron molybdenum
and chlorine. The form of the foregoing nutrients may be in
any conventional form, see, for example, McVickar, et al.,
Using Commercial Fertilizer, The Interstate Publishers,
Danville, Illinois (1978).
The method of application of the plant nutrient
compositions described herein is conventional. See, for
example, McVickar, et al., Using Commercial Fertilizers,
Chapter XIV, "Methods of Applying Fertilizers".
The precise amount of the plant nutrient composition to
be delivered to the plant will obviously be an effective
amount for the desired result expected therefrom. This, of
course, will be ascertained by the ordinary skill of the
practitioner. Due to enhanced activity which is achieved,
the amount of plant nutrients may often be decreased from
that generally applicable. In accordance with the usual
prudent formulating practices, a dosage near the lower end
~37~ 1 3 3 ~ 6 ~ 6
of the useful range of the particular agent may be employed
initially and the dosage increased as indicated from the
observed response.
The subject composition as hereinabove described in
combination with a pesticide, provides a method and
composition for plant pest control.
Pesticides are chemicals designed to combat the
attacks of various pests on agricultural and horticultural
crops. They fall into three major classes: insecticides,
fungicides and herbicides (or weed killers). There are also
rodenticides (for control of vertebrate pests), nematicides
(to kill microscopic eelworms), mollusicides (to kill slugs
and snails) and acaricides (to kill mites).
Pesticides may also be divided into two main types,
namely contact or nonsystemic pesticides and systemic
pesticides. Contact or surface pesticides do not
appreciably penetrate plant tissues and are consequently not
transported or translocated, within the plant vascular
system. The earlier insecticides, fungicides and herbicides
were of this type; their disadvantages are that they are
susceptible to the effects of weathering (wind, rain and
sunlight) over long periods and new plant growth will be
left unprotected and hence open to attack by insect and
fungal pests. The early agricultural fungicides were,
therefore, protectant fungicides--in other words, they are
designed ot prevent the development of the fungal spores,
but once the fungus has become established and infection
starts to ramify through the plant tissues, such nonsystemic
fungicides possess little eradicant action and usually
cannot halt the infection.
In contrast, many of the more recent pesticides are
systemic in character -- these can effectively penetrate the
plant cuticle and move through the plant vascular system.
Examples are provided by the phenoxyacetic acid selective
1 3346~6
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herbicides, certain organophosphorus insecticides and the
more recently discovered systemic fungicides like benomyl.
Systemic fungicides are also sometimes termed plant
chemotherapeutants and can not only protect the plant from
fungal attack, but also cure or inhibit an established
infection. They are little affected by weathering and will
also confer immunity on all new plant growth.
Pests can be divided into various groups. In the
plant kingdom, characterized by the ability of the organism
to photosynthesize carbohydrates from air and water with the
aid of the green pigment chlorophyll, higher plants growing
where man does not want them are termed weeds and are
important pests. Of the lower plants, algae are not
generally of as great importance as pests, although in some
circumstances, e.g., in lakes and other slow-moving water,
excessive algal growth of "bloom" may cause considerable
damage and require treatment with chemicals (algicides).
Fungi or nonphotosynthetic plants cannot obtain
their nutrients from air and water since they do not have
chlorophyll; consequently, they feed directly on decaying
plant or animal matter (saprophytic fungi) or on living
plants or animals (parasitic fungi). There are thousands of
different species of fungi mainly found in soil -- some,
like yeasts, are unicellular while others are composed of a
network of branched filaments (hyphae). A number of fungi
are serious pests attacking both living crop plants and also
crops in storage.
Several bacteria are causal agents of plant
diseases, although they are not nearly as important as the
phytopathogenic fungi. Bacteria can be observed under the
microscope and can be classified according to their shape;
thus a spherical bacterium is termed a coccus while a rod-
shaped one is a bacillus.
1 334646
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Viruses, like bacteria and fungi, attack plants and
animals and some species cause significant plant diseases.
Viruses form a distinct category of living organism because
they are not true cells. Unlike bacteria, they are too
small (100-300 A) in diameter to be observed with an
ordinary microscope, but they can be revealed under the
electron microscope -- each virus consists of a single
strand of DNA or RNA surrounded by a protective coat of
protein.
Several higher animals (vertebrates) are important
pests, e.g., mice, rats and rabbits; another group of pests
is represented by the true insects (arthropods) which are
invertebrates. The latter possess three pairs of legs and
the adult body has three parts; the arachnids (mites and
ticks) differ from true insects in having no distinct
division of the body into three parts; also they usually
have four pairs of legs. In the lower orders of animals,
certain nematodes, parasitic worms often with unsegmented
bodies, are important crop pests.
If pesticides are to be active, they must reach the
ultimate site of action within the target organism. Thus,
even surface fungicides, like Bordeaux mixture, must be able
to penetrate the fungal spore; similarly, contact
insecticides have to penetrate the insect cuticle, and
contact herbicides penetrate the plant cuticle when they
impinge on it. The requirements if the pesticides are to be
systemic in action are much more stringent because, in
addition, they must have the capacity to be absorbed by the
roots or leaves or seeds of plants and be delivered to other
parts of the plant. In this way, the whole plant, including
new growth, is protected from fungal attack, or rendered
poisonous to any insect that eats or sucks it.
-
1 3346~6
-40-
The amount of the s~bject composition which may be
used in the present invention is an amount effective for
enhancing the delivery of a pesticide to a plant pest. In
the case of indirect application of the active materials to
a plant, the enhanced delivery achieved through the use of
l-substituted azacycloalkane includes improved substantivity
and systemic effects of the pesticide. Generally, an
effective amount ranges between about O.O1 to about 99.9 and
preferably about O.l to 10 percent by weight of the
pesticide composition.
Suitable pesticides include botanical insecticides
such as, for example, nicotine, derris (rotenone) and
pyrethrum; synthetic insecticides including dinitrophenols,
such as, for example, DNOC; organic thiocyanates such as,
for example, lethane and thanite, organochlorine
insecticides including DDT and related compounds; containing
the cyclodiene group such as, for example, aldrin and
dieldren, organosphosphorous insecticides;
hexachlorocyclohexane; insecticides including malathion,
mevinphos, rogar, dimethtoate, nenozan, miral, diazinon,
dursbon, bay-rusil; organocarbonate insecticides including
pirimicarb, carbaryl, baygon, propoxur, zectron, carbofuran,
aldicarb (Temik), methomul (Lonnate); fungicides including
phenylmercury compounds, naban, metham, sodium, thiron;
compounds containing the n-trichloromethylthio group, such
as, for example, captan, folpet and oifolatan;
dinitrophenols, including dinocap (Karathane);
chlorobenzynes and related compounds, quinones such as, for
example, dodine and roural, sulphonamides, benzimidazoles;
thiophonates; oxathinns; pyrimadines; piperozine, morpholine
and azepine derivatives; organophosphorous compounds
including wepsyn, kitazin and conen, herbicides including
carboxylic acid herbicides, such as, for example, 2, 4-D
MCPA, 2, 3, 6-TBA, IAA, picloram and dichlobenil;
* Trade-mark
,~ ~
1 334646
chloroaliphatic acids such as dalapan and TCA, and
heterocyclic compounds such as atrozine (Gesaprim);
triazales such as amitrole, pyrazon, bromacil, endothal;
bipyridinum herbicides including paraquat and diquat;
benzonitriles; diphenyl ethers; organosphosphorous compounds
such as, for example, phosphorothiolates such as bensullide;
phosphoramidates such as DMPA (Zyron); phosphonates such as
glyphosate; plant growth regulators; fumigants; rodenticides
including anticoagulants such as warfarin, pidone and
norbormide (Raticote); sleep-inducing narcotic drugs such as
chloralose; gophacide, silatrane and crimidine, nematicides
such as dazomet and nellite; molusicides such as
metaldehyde, methiocasb and frescon; repellants, antifeeding
compounds such as ZIP; chemosterilants, hormones and growth
inhibitors. Further examples ~f pesticides suitable for use
in the present invention are known in the art (see, for
example, R. Cremyln, Pesticides Pre~aration and Mode of
Action, John Wiley and Sons, 1979; F. McEwan, et al., The
Use of Siqnificance of Pesticides in the Environment, John
Wiley and Sons, 1979; D. Roberts, Fundamentals of Plant Pest
Control, E. H. Freeman and Company, 1978.
The method of application of the pesticide
composition described herein is conventional. See, for
example, G. Hartley, et al., Chemicals for Pest Control,
Chapter 15, "Application of Pesticides," Pergamon Press,
1969.
The precise amount of the pesticide composition to
be delivered to the plant or pest will obviously be an
effective amount for the desired result expected therefrom.
Most modern pesticides are used in agriculture at a dosage
of less than one pound per acFe. This, of course, will be
ascertained by the ordinary skill of the practitioner. Due
to enhanced activity which is achieved, the dosage of agent
may often be decreased from t~at generally applicable. In
* Trade-mark
- 1 3 3 4 6 46
-42-
accordance with the usual prudent formulating practices, a
dosage near the lower end of the useful range of the
particular agent may be employed initially and the dosage
increased as indicated from the observed response.
The subject composition as hereinabove described, in
combination with a plant growth regulator, is a method and
composition for plant growth.
Plant growth regulators are organic compounds, other
than nutrients, that, in low concentrations, affect the
morphological structure and/or physiological processes of
plants. Plant hormones or phytohormones, are naturally
occurring growth regulators that in low concentrations
control physiological processes in plants. The synthetic
growth regulators are used by Man to control such processes
as fruit development, fruit thinning, defoliation, growth
stimulation and retardation, rooting of cuttings and many
other processes. Over the past 30 years, the investigation
and development of plant growth regulators has been one of
the most active areas of fundamental and applied botanical
research. The PANS Plant Growth Regulator Index (P.J.
Kempt, 25 (2), 211 and 213) under the list of Common and
Trade Names and Code Numbers has 492 entries (excluding
herbicides except where these are used specifically for some
growth regulatory purpose other than weed killing).
Plant growth regulators that are currently in use at
the present time affect a great variety of plant growth
processes, including the following (some of the growth
regulators in common use are in brackets): rooting of
cuttings (indole-butyric acid); promotion of flowering in
pineapples (1-naphthaleneacetic acid; B-hydroxyethyl-
hydrazine; ethephon); prevention of preharvest drop of
apples (NAA; daminozide); inhibition of turf growth (maleic
hydrazide; mefluididediethanolamine); prevention of
sprouting of potatoes (maleic hydrazide); floral induction
-- 1 3 3 4 6 4 6
-43-
in apple, pear, peach (succinic acid-2, 2-dimethylhydrazine;
2, 3, 5-triodobenzoic acid); early flowering of 'long day'
plants, e.g., lettuce radish, mustard, dill (gibberellins);
flowering of many biennials which normally require low
temperatures to flower (gibberellins); improvement of yield
of sugar-cane and prevention of flowering (diuron; diquat);
delay in flowering in almond and peach to avoid adverse
weather conditions (diaminozide); induction of abscission of
mature citrus fruits (cyclohexim; 5-chloro-3-methyl-4-nitro-
1-H-pyrazole); defoliation of cotton leaves to aid
harvesting of bolls (ethephon); thinning of fruit, e.g.,
grapes, peaches, (gibberellic acid; ethephon, 3-
chlorophenoxy-~-propionamide); prevention of pre-harvest
drop of citrus (2, 4-dichlorophenoxyacetic acid); induction
of fruit set, e.g., in tomato, squash, eggplant, fig (4-
chloro-phenoxyacetic acid; 2-naphthyloxyacetic acid);
increase in size and quality of grapes (gibberellins);
induction of amylase in barley for malting (gibberellins);
stimulation of growth of sugar-cane (gibberellins);
reduction of stem length in cereals (2-chloroethyl
trimethyl-ammonium chloride); development of female flowers,
e.g., in pumpkins (NAA; ethephon; daminozide); promotion of
male flowers, e.g., in hops (gibberellins); bioregulation of
plant composition, e.g., colour in citrus, sugar in sugar-
cane, vitamin content in vegetables, increase in dry weight,
timing of crop development, increased latex from rubber
trees (various growth regulators).
The amount of the subject composition which may be
used in the present invention is an amount effective for
enhancing the delivery of a plant growth regulator to a
plant. Generally, an effective amount ranges between about
0.01 to about 99.9 and preferably about 0.1 to 10 percent by
weight of the composition.
1 33~646
-44-
Suitable plant growth regulators include both
natural and synthetic auxins, such as IAA (indolyl-3-acetic
acid), IBA (4-(indol-3 yl) butyric acid), NAO (alphanaphthy-
lacetic acid), NOA (2-naphthyloxy-acetic acid) and NAD (1-
naphthylacetamide); phenoxyalkanoic acids, gibberellins,
cytokinins, abscisic acid, maleic hydrazide, propham and
cloropopham, S,S,S-tributyl phosphorotrithioate, S,S,S,-
Tributyl phosphorotrithioite, chloromequat, daminozide,
glyphosine, ancymidol, chlorphonium chloride, dikegulac
sodium, morpholinium chloride, fosamine, mefulidide, 4-
methoxybenzophenones, PP 528 (ethyl-5-(4-chlorophenyl)-2H-
tetrazol-2-yl acetate), piproctanyl bromide, 2-(3-aryl-5-
pyrazoyl) benzoic acids, BTS 34723 (1-(N-2-phenoxyethyl)-N-
propylcarbamoy)-N-imidazole), BTS 34442 (1-(N-2,4-
dichlorobenzyl)-N-isopropyl-carbamoyl)-lN-imidazole), UBI
P293 (2,3,-dihydro-5, 6-diphenyl-1, 4-oxathiin), M&B 25, 105
(propyl 3-t-butyl phenoxyacetate), thidaizuron (N-phenyl-N'-
(1,2,3-thiadiazol-5-yl) urea), mepiguat (l,l-
dimethylpiperidinium chloride), BAS 09800W (mepiquat
chloride plus ethephan), IZAA* (5-chloroindazole-8-acetic
ethyl ester), MON 8000, DOWCO 242 (tetraisopentyl-ammonium
bromide), quarternary ammonium iodides; morphactins
including chloroflurecol-methyl, flurecol-butyl, TIBA
(2,3,5-tri-iodobenzoic acid; gametocides including RH 531
(sodium 1-(4-chlorphenyl)-1,2-dihydro-4, 6-dimethyl-2-
oxonicotinate), DPX-3778 (3-(4-chlorophenyl)-6-methoxy-
1,3,5-triazine-2, 4-dione triethanolamine) and allelo-
pathins. Additional plant growth regulators are known in
the literature, see, for example, Fletcher, et al.,
Herbicides and Plant Growth Requlators, Chapter 2.
opportunities for use of plant growth regulators
include treatments for seed or seedlings for transplanting
which will promote early growth and root developmenti
substances to improve quality (usually protein levels and
* Trade-mark
1 334~4~
-45-
amino acid balance) of grain crops; substances to improve
yield and quality of forages; opportunities in forestry,
such as seeling survival and growth, early seed production
and accelerated growth rates; systems to reduce energy costs
by r~;r; zing response to cultivation, fertilizers (i.e.,
uptake, mobilization, etc.) and irrigation water; compounds
to inhibit ethylene action or production and thus reduce
young fruit abscission in indeterminately fruiting crops;
new gibberellins with species- or function specific effects,
new applications of known substances based on understanding
hormone interactions and storage/inactivation systems ('slow
release' compounds) and substances to manipulate natural
conjugation reactions; substances to alleviate or minimize
effects of plant diseases and insects, or to facilitate
systems of integrated pest management; substances to modify
productivity by reducing photorespiration, dark respiration,
or by promoting nitrogen metabolism/fixation, photo-
synthesis, translocation; substances that intensify
synthesis of specific highly desired end-products (oil,
protein, cellulose); substance to increase productivity by
shifting developmental patterns, such as extending the
period of inflorescence differentiation or seed development.
The foregoing serves to illustrate the wide range of
opportunities available to agricultural chemists.
Plant tissue culture pioneered by White, Steward,
Skoog and others, beginning almost as a botanical curiosity,
has with the help of growth-regulatory chemicals become a
powerful tool in the hands of the plant breeder. It is now
possible to tissue culture almost any plant and to develop
uniform plantlets from such cultures. Even pollen grains
can be used and the subsequent haploid plants made polyploid
by the use of suitable chemical agents. Together with
apical meristem culture, there is an unending supply of
material.
1 334646
-46-
The method of application of the plant growth
regulator composition described herein is conventional.
See, for example, W.W. Fletcher and R.C. Kirkwood,
Herbicides and Plant Growth Regulators, Granada Publishing
Limited, New York, 1982.
The precise amount of the plant growth regulator
composition to be delivered to the plant will obviously be
an effective amount for the desired result expected
therefrom. This, of course, will be ascertained by the
ordinary skill of the practicioner. Due to enhanced
activity which is achieved, the amount of plant growth
regular may often be decreased from that generally
applicable. In accordance with the usual prudent
formulating practices, a dosage near the lower end of the
useful range of the particular agent may be employed
initially and the dosage increased as indicated from the
observed response.
While particular embodiments of the invention have
been described, it will be understood, of course, that the
invention is not limited thereto since many obvious
modifications can be made and it is intended to include with
this invention any such modifications as will fall within
the scope of the appended claims.
