Physiological vehicle compositions containing higher alkyl substituted azacyclopentan-2-ones

There is disclosed an improved method for topically administering a physiologically active agent to a human or animal by dissolving an effective amount of the agent in a carrier containing suitable amounts of 1-alkyl substituted-azacyclopentan-2-one, as defined herein, and contacting the skin or other membranes of the human or animal with the resulting composition, whereby penetration of the skin or membranes is enhanced.

BACKGROUND OF THE INVENTION 
Many physiologically active agents are best applied topically to obtain 
desirable results. Topical application, as contrasted to systemic 
application, largely avoids side effects of the agents and permits high 
local concentrations of the agents. 
The greatest problem in applying physiologically active agents topically is 
that the skin is such an 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 inflamation, acne, psoriasis, herpes 
simplex, eczema, infections due to fungus, virus or other microorganisms, 
or other disorders or 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 repellants 
and the like. 
Physiologically active agents may be applied to locally affected parts of 
the body through the vehicle 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, which is described in U.S. Pat. No. 3,551,554. In this 
description, the term "animal" includes human beings as well as other 
forms of animal life, and especially domesticated animals and pets. 
A number of 1-substituted-azacyclopentan-2-one compounds are known. The 
1-lower alkyl substituted azacyclopentane-2-ones having 1-4 carbon atoms 
are known to moderately enhance percutaneous absorption of chemicals, 
e.g., drugs. It would be desirable to obtain the same or higher level of 
percutaneous absorption with substantially lower concentrations of the 
penetration-enhancing compound. 
SUMMARY OF THE INVENTION 
This invention is a method for carrying physiologically active agents 
through body membranes such as skin and for retaining these agents in body 
tissues. The invention also relates to compositions for use in the method. 
More specifically, the invention relates to a method for topically 
administering a physiologically active agent to a human or animal 
comprising administering topically to a human or animal an effective 
amount of a composition containing the agent and an effective, non-toxic 
amount of a compound having the structural formula 
##STR1## 
wherein R' is H or a lower alkyl group having 1-4 carbon atoms and R is a 
straight or branch chain alkyl group having 7-12 carbon atoms. In the 
preferred embodiment, R' is H and R is a straight chain alkyl group having 
8-10 carbon atoms. 
It has been found that the physiologically active agents are carried 
through body membranes by the claimed vehicles and are retained in body 
tissue.

DETAILED DESCRIPTION OF THE INVENTION 
The claimed 1-higher alkyl-azacyclopentan-2-ones are made by methods as 
will be known to those of skill in the art, as further shown in the 
Examples below. 
The compounds covered by the general formula above may be prepared, for 
example, by treating azacyclopentan-2-one with an alkyl halide or alkyl 
mesylate in the presence of a base e.g. sodium hydride. The reaction is 
carried out under anhydrous conditions in a hydrocarbon solvent, for 
example, dry toluene at reflux temperature for 20 to 72 hours in an inert 
atmosphere, for example, nitrogen. This method is outlined below: 
##STR2## 
In another method gamma-dialkylaminobutyric acid may be treated with 
phosphorus trihalide and the resulting acid halide (which need not be 
isolated) is heated, resulting in the formation of 
N-alkylazacyclopentan-2-one. Suitable acid halide forming agents include 
phosphorous trichloride, phosphorous tribromide, thionyl chloride, etc. 
The acid halide is formed at room temperature and then the reaction 
temperature is raised to 70.degree.-90.degree. C. One of the alkyl groups 
on the amino nitrogen of the parent acid is eliminated as alkyl halide. If 
the alkyl groups on the amino nitrogen are different, the smaller of the 
two alkyl groups is eliminated preferentially. This method is described 
below: 
##STR3## 
Alternatively, butyrolactone may be heated with an alkyl amine for 24 to 48 
hours at 250.degree. C to obtain the corresponding 
N-alkyl-azacyclopentan-2-one as shown below: 
##STR4## 
The amount of 1-higher alkyl-azacyclopentan-2-one which may be used in the 
present invention is an effective, non-toxic amount for enhancing 
percutaneous absorption. Generally, this amount ranges between about 0.1 
to about 5 and preferably 0.1 to 2 percent by weight of the composition. 
The process of this invention may find use with many physiologically active 
agents which are soluble in the vehicles disclosed. 
Fungistatic and fungicidal agents such as, for example, thiabendazole, 
chloroxine, amphotericin, candicidin, fungimycin, nystatin, chlordantoin, 
clotrimazole, ethonam nitrate, miconazole nitrate, pyrrolnitrin, salicylic 
acid, fezatione, ticlatone, tolnaftate, triacetin and zinc and sodium 
pyrithione may be dissolved in the vehicles 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 higher 
concentrations and are retained for substantially longer time periods 
whereby a far more successful treatment is effected. 
For example, the method of this invention 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 vehicles and 
applying it to the affected area. 
The invention is also useful in treating skin problems, such as for 
example, herpes simplex, which may be treated by a solution of 
iododeoxyuridine dissolved in one of the vehicles, or such problems as 
warts which may be treated with agents such as podophylline dissolved in 
one of the vehicles. Skin problems such as psoriasis may be treated by 
topical application of a solution of a conventional topical steroid in one 
of the vehicles or by treatment with theophylline or antagonists of 
.beta.-adrenergic blockers such as isoproterenol in one of the vehicles. 
Scalp conditions such as alopecia areata may be treated more effectively 
by applying steroids such as triamcinolone acetonide dissolved in one of 
the vehicles of this invention directly to the scalp. 
The present invention is 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 vehicles 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, fludrocortisone, difluorsone diacetate, 
flurandrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone 
and its esters, chloroprednisone, clocortelone, descinolone, desonide, 
dexamethasone, dichlorisone, difluprednate, flucloronide, flumethasone, 
flunisolide, fluocinonide, flucortolone, fluoromethalone, fluperolone 
fluprednisolone, meprednisone, methylmeprednisolone, paramethasone, 
prednisolone and prednisone. 
This invention is also useful in antibacterial chemotherapy, e.g., in the 
treatment of skin conditions involving pathogenic bacteria. Typical 
antibacterial agents which may be used in this invention include 
sulfonomides, 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. 
This invention is also useful in protecting ultra-sensitive skin or even 
normally sensitive skin from damage or discomfort due to sunburn. Thus, 
dermatitis actinica may be avoided by application of a sunscreen, such as 
para-aminobenzoic acid or its well-known derivatives dissolved in one of 
the vehicles, to skin surfaces that are to be exposed to the sun; and the 
protective para-aminobenzoic acid or its derivatives will 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. 
This invention may also find use in treating scar tissue by applying agents 
which soften collagen, such as aminoproprionitrile or penicillamine 
dissolved in one of the vehicles of this invention topically to the scar 
tissue. 
Agents normally applied as eye drops, ear drops, or nose drops are more 
effective when dissolved in the vehicles of this invention. 
Agents used in diagnosis may be used more effectively when applied 
dissolved in one of the vehicles 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 vehicles of this invention. 
This invention is also useful for topical application of cosmetic or 
esthetic agents. For example, compounds such as melaninstimulating hormone 
(MHS) or dihydroxy acetone and the like are more effectively applied to 
skin to simulate a suntan when they are dissolved in one of the vehicles 
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 vehicles of this invention. 
The effectiveness of such topically applied materials as insect repellants 
or fragrances, such as perfumes and colognes, can be prolonged when such 
agents are applied dissolved in one of the vehicles 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 vehicles of the present invention may also be used to 
produce therapeutic effects which were not previously known. That is, by 
use of the vehicles 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 saturation of the entire body with 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 conditions because there was not 
heretofore known any formulation which could be delivered topically which 
would cause sufficient retention of griseofulvin in the skin to be useful 
therapeutically. 
However, it has now been discovered that griseofulvin, in a range of 
therapeutic concentrations between about 0.1% and about 10% may be used 
effectively topically if combined with one of the vehicles 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 the systemic antibiotic treatment 
are known to be partially effective, the topical treatments are generally 
not effective. 
It has long been known that systemic treatment of acne is not preferred 
because of side effects resulting from saturation of the entire body with 
antibiotics and the fact that only the affected skin need by treated. 
However, despite a long-felt need for a topical treatment for acne, 
antibiotics generally have been used only systemically to treat acne 
because there was not heretofore known an antibacterial formulation which 
could be used topically which would be effective therapeutically in the 
treatment of acne. However, it has now been discovered that antibiotics, 
especially those of the lincomycin and erythryomycin families of 
antibiotics, may be used in the treatment of acne topically if combined 
with one of the vehicles described herein. 
The antibiotics composition so applied is carried into and through the 
epidermis and deeper layers of the skin as well as into follicles and 
comedones (sebum-plugged 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 
repellants, 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 carrier which make up the foregoing dosage forms 
include water, acetone, isopropyl alcohol, freons, ethyl alcohol, 
polyvinyl pyrrolidone, propylene glycol, fragrances, gel-producing 
materials, mineral oil, stearyl alcohol, stearic acid, spermaceti, 
sorbitan monooleate, "Polysorbates," "Tweens," sorbital, methylcellulose, 
etc. 
The amount of the composition, and thus of the physiologically active agent 
therein, 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 agent 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, as in the routine procedure of the physician. 
The examples which follow illustrate the compositions of the present 
invention. Temperatures are given in degrees Centigrade. 
EXAMPLE 1 
Preparation of 1-n-Octylazacyclopentan-2-one having the following 
structure: 
##STR5## 
A suspension of 5.44 g of 57% sodium hydride/mineral oil (actually 3.10 g 
NaH, 0.13 mole) in 200 ml of petroleum ether was allowed to settle and the 
residue washed with 2 .times. 200 ml of petroleum ether. After the excess 
petroleum ether was removed, 150 ml of dry toluene was added and the 
mixture stirred as 10 g (0.1174 mole) of azacyclopentan-2-one in 25 ml of 
dry toluene was added dropwise over one hour. After the addition was 
complete, the mixture was refluxed for one hour then 25.1 g (0.13 mole) of 
1-bromooctane in 25 ml of dry toluene was added dropwise over one hour to 
the refluxing mixture. After the addition was complete, the mixtures was 
refluxed for 3 days. The reaction mixture was filtered twice (the latter 
time through celite), and the solvent evaporated to yield a yellow oil. 
Vacuum distillation yeilded a fraction b.p. 128.degree.-132.degree. at 0.3 
mm, weighing 13.6 g (59%). 
______________________________________ 
Chromatography: 
GLC: On 7' 5% SE-30 column at 150.degree. shows 1 peak of 
97% purity. 
Infrared: Neat liquid 
.lambda. max cm.sup.-1 
3500 (broad), 2960, 2930, 2860, 1690, 1495, 1460, 1430, 
1380, 1330, 1310 (shoulder); 1220, 1170, 1120, 1060, 
850, 720. 
Nuclear Magnetic Resonance: 
(CCl.sub.4 + TMS) 
Multiplet at 3.3 .delta. 
Multiplet at 2.15 .delta. 
Broad singlet at 1.3 .delta. 
Broad triplet at 0.9 .delta. 
______________________________________ 
EXAMPLE 2 
Preparation of 1-n-Nonylazacyclopentan-2-one having the following 
structure: 
##STR6## 
A suspension of 5.44 g of 57% sodium hydride/mineral oil (actually 3.0 g 
NaH, 0.13 mole) in 200 ml of petroleum ether was allowed to settle and the 
residue washed with 2 .times. 200 ml of petroleum ether. After the excess 
petroleum ether was removed, 150 ml of dry toluene was added and the 
mixture stirred under nitrogen as 10 g (0.1174 mole) of 
azacyclopentan-2-one in 25 ml of dry toluene was added dropwise over one 
hour. After the addition was complete, the mixture was refluxed for one 
hour, then 27 g (0.13 mole) of 1-bromononane in 25 ml of dry toluene was 
added dropwise over one hour. After the addition was complete, the mixture 
was refluxed for 3 days, filtered twice (the latter through celite), then 
was concentrated to yield a yellow oil. Distillation of this oil under 
vacuum yielded a fraction b.p. 139.degree.-143.degree. at 0.5 mm, weighing 
13.4 g (56%). 
______________________________________ 
Chromatography: 
GLC: On 7' 5% SE-30 at 150.degree. shows 1 peak of &gt;99% purity. 
Infrared: Neat film 
.lambda. max cm.sup.-1 
2960, 2430, 2860, 1690, 1495, 1460, 1430, 1380, 1285, 1270; 
1220, 1160, 1120, 1050, 930, 850, 720. 
Nuclear Magnetic Resonance: (CCl.sub.4 + TMS) 
Multiplet centered 3.3 .delta. 
Multiplet centered at 2.2 .delta. 
Broad singlet at 1.3 .delta. 
Broad triplet at 0.9 .delta. 
______________________________________ 
EXAMPLE 3 
The following solution formulation is prepared: 
______________________________________ 
Solution (%) 
______________________________________ 
Griseofulvin 1 
1-octyl-azacyclopentan-2-one 
1 
Isopropyl myristate 5 
Fragrance 0.1 
Ethanol qs. ad 
______________________________________ 
This formulation is effective in the treatment of fungus infections. 
EXAMPLE 4 
An aerosol form of the formulation of Example 3 is prepared by preparing 
the following mixture: 
______________________________________ 
Formulation 25% 
Freon.sup.1 75% 
______________________________________ 
.sup.1 Freon is 75/25 Freon 114/12. 
EXAMPLE 5 
The following cream formulation is prepared: 
______________________________________ 
% 
______________________________________ 
Clindamycin (base) 1.0 
Stearyl alcohol, U.S.P. 12.0 
Ethoxylated cholestrol 0.4 
Synthetic spermaceti 7.5 
Sorbitan monooleate 1.0 
Polysorbate 80, U.S.P. 3.0 
1-nonyl-azacyclopentan-2-one 
0.5 
Sorbitol solution, U.S.P. 
5.5 
Sodium citrate 0.5 
Chemoderm #844 Fragrance 0.2 
Purified water qs. ad 
______________________________________ 
This formulation is effective in the treatment of acne. 
EXAMPLE 6 
The following solution formulations are prepared: 
______________________________________ 
A(%) B(%) 
______________________________________ 
Clindamycin base -- 1.0 
Clindamycin phosphate acid 
1.3 -- 
Sodium hydroxide 0.077 -- 
1.0 Molar hydrochloric acid 
-- 2.27 
Disodium edetate . 2H.sub.2 O 
0.0033 0.0033 
Fragrances 0.5 0.5 
1-nonyl-azacyclopentan-2-one 
1.0 1.0 
Purified water 20.0 17.73 
Isopropanol qs. ad. 
______________________________________ 
These solutions are effective for the treatment of acne in humans. 
EXAMPLE 7 
The following solution formulation is prepared: 
______________________________________ 
% 
______________________________________ 
Neomycin sulfate 0.5 
Lidocaine 0.5 
Hydrocortisone 0.25 
1-decyl-azacyclopentan-2-one 
0.5 
Propylene glycol qs. ad. 
______________________________________ 
This solution is effective for the treatment of otitis in domestic animals. 
EXAMPLE 8 
The following sunscreen emulsion is prepared: 
______________________________________ 
% 
______________________________________ 
p-amino benzoic acid 2.0 
Benzyl alcohol 0.5 
1-octyl-azacyclopentan-2-one 
1.0 
Polyethylene glycol 400-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 qs. ad 
______________________________________ 
EXAMPLE 9 
The following antineoplastic solution is prepared: 
______________________________________ 
% 
______________________________________ 
5-Fluorouracil 5 
1-nonyl-azacyclopentan-2-one 
0.1 
Polyethylene glycol 5 
Purified water qs. ad 
______________________________________ 
EXAMPLE 10 
The following insect repellant atomizing spray is prepared: 
______________________________________ 
% 
______________________________________ 
Diethyltoluamide 0.1 
1-octyl-azacyclopentan-2-one 
0.1 
Ethanol qs. ad 
______________________________________ 
EXAMPLE 11 
The following lotion formulation may be prepared containing about 0.001 to 
1 percent, with preferably 0.1 percent fluocinolone acetonide: 
______________________________________ 
% 
______________________________________ 
Fluocinolone acetonide 0.001 - 1 
Cetyl alcohol 15 
Propylene glycol 10 
Sodium lauryl sulfate 15 
1-octyl-azacyclopentan-2-one 
1 
Water qs. ad. 
______________________________________ 
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 inflammed 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 inflammed 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. 
EXAMPLE 12 
The percutaneous penetration of the claimed vehicles were compared to prior 
art vehicles by means of a diffusion cell using excised hairless mouse 
skin as the membrane. Skin specimens were obtained from male mice 8-9 
weeks old. Each test solution contained 0.5% .sup.3 
H-3',5'-cyclic-adenosine monophosphate. The compounds tested are shown in 
Table 1; the results of the tests are shown in Table 2. 
Table 1 
______________________________________ 
Identified in 
Compound Table 2 as 
______________________________________ 
1-methyl-azacyclopentan-2-one 
A 
1-ethyl-azacyclopentan-2-one 
B 
1-propyl-azacyclopentan-2-one 
C 
1-n-butyl-azacyclopentan-2-one 
D 
1-n-hexyl-azacyclopentan-2-one 
E 
1-n-octyl-azacyclopentan-2-one 
F 
1-n-nonyl-azacyclopentan-2-one 
G 
dimethyl formamide H 
phosphate buffer, 0.1 M, pH 6.98 
PB 
propylene glycol PG 
______________________________________ 
Table 2 
______________________________________ 
Influence of Organic Liquids on the Penetration 
of cAMP through Mouse Skin 
Steady-state 
Permea- 
Cumulative Penetration 
bility 
Penetration.sup.b 
of .sup.3 H-cAMP 
Constant.sup.e 
Vehicle (n moles cm.sup.-2) 
(n moles (.mu.cm 
Composition.sup.a 
5 hr 14 hr 30 hr cm.sup.-2 min.sup.-1) 
min.sup.-1) 
______________________________________ 
1. PB 0.0 2.5 4.7 --.sup.c -- 
2. PB/PG 0.0 0.5 1.3 --.sup.c -- 
3. H/PB 0.8 2.8 6.0 --.sup.c -- 
4. A/PB 1.0 3.8 7.5 --.sup.c -- 
5. B/PB 1.7 4.8 9.5 --c -- 
6. C/PB 2.2 5.8 22.3 0.027 1.78 
7. D/PB 5.5 30.0 90.0 0.056 3.70 
8. D/PB/PG 0.5 13.7 61.8 0.063 4.16 
9. E/PB/PG 0.7 17.5 69.0 0.063 4.16 
10. F/PB/PG 20.0 1800 3950.sup.d 
3.470 229.19 
11. G/PB/PG 50.0 2150 4050.sup.d 
3.470 229.19 
______________________________________ 
.sup.a Each solution contains 0.5% .sup.3 H-cAMP, 2-7 are 50/50 mixtures 
(by volume), 7 and 8 contain equal volumes of D, 8-11 contain equi molar 
amounts of test compounds and varying amounts of propylene glycol. 
.sup.b Results represent average values obtained from two skin cells. 
.sup.c Steady-state penetration not reached in 30 hours. 
.sup.d Value signifies &gt;95% penetration 
.sup.e Ratio of the steady-state penetration rate to concentration of 
.sup.3 H-cAMP in the donar solution. Values for skin penetrating capacity 
range from "very slow" (&lt;0.1) to "very fast" (&gt;100). 
The foregoing tests show that the higher alkyl substituted 
azacyclopentan-2-ones having 8 and 9 carbon atoms respectively, in the 
alkyl substituent, i.e., 1-octyl and 1-nonyl, are far more potent 
(.apprxeq.50 times) in their ability to enhance percutaneous penetration 
than are the 1-lower alkyl-azacyclopentan-2-ones having 1-6 carbons in the 
alkyl substituent.