Compositions and method for enhancement of the transdermal flux of albuterol with a combination of 1-dodecyl-azacyclopheptan-2-one and urea

A topical albuterol composition having superior transdermal flux containing various amounts of albuterol, 1-dodecyl-azacycloheptan-2-one and urea in a non-aqueous environment. The enhancement observed in albuterol skin penetration indicates that a therapeutically effective amount of albuterol can be delivered through skin using these formulations. The compositions can be administered topically as a cream, lotion or via a transdermal device.

BACKGROUND OF THE INVENTION 
This invention relates to a method for increasing the transdermal flux of 
albuterol and to compositions for effecting the method. The compositions 
of the invention, which greatly increase the transdermal flux of 
albuterol, comprise albuterol with a combination of 
1-dodecyl-azacycloheptan-2-one and urea. 
1-Dodecyl-azacycloheptan-2-one is registered under the U.S. Trademark 
"Azone" and is commercially available from Nelson Research and Development 
Company, Irvine, Calif. 
Compositions and the method for preparation of the compound are disclosed 
in U.S. Pat. Nos. 3,989,815, and 4,316,893. 
1-Dodecyl-azacycloheptan-2-one has properties which enhance the 
percutaneous absorption of certain chemical agents with which it is 
incorporated. 
The use of suitable amounts of 1-dodecyl-azacycloheptan-2-one as a 
physiological carrier for topically administering an active agent to a 
human or animal is also disclosed in these patents, and discussed in 
Stoughton, Azone.RTM. (1-dodecyl-azacycloheptan-2-one) Enhances 
Percutaneous Penetration, III International Symposium on Psoriasis, 
Stanford, (Jul. 13-17, 1981). 
UK Pat. No. 1,468,815 discusses the use of urea in the treatment of skin 
conditions and restrictions on its use because it is unstable in neutral 
aqueous solution and decomposes, liberating carbon dioxide and ammonia. 
Urea buffered at a pH of about 2.0 has been tried, however, this very high 
acid level causes the cream containing said buffered urea to sting on 
application. 
Further, urea, in an aqueous solution when adsorbed onto particles of an 
inert powder has been found to be sufficiently stable to be formulated 
into skin creams and other pharmaceutical preparations. U.S. Pat. No. 
3,666,863 indicates that urea in aqueous solution has been used to enhance 
the topical absorption of compounds which have been known to have poor 
absorption. 
The use of urea as a therapeutic agent for the treatment of hyperkeratotic 
skin conditions is disclosed in U.S. Pat. No. 3,666,863 and UK Pat. No. 
1,468,815. In particular, urea is disclosed as being capable of hydrating 
the skin so as to allow the percutaneous transportation of medication, 
thus acting as a drug delivery system. A. C. Allenby, et al, Mechanism of 
Action of Accelerants on Skin Penetration, Brit. J. Dermatol., Suppl. 81 
(4), 47-55 (1969). 
.alpha..sup.1 -[Tert-butylamino)methyl]-4-hydroxy-m-xylene 
.alpha.,.alpha.'-diol, also known as albuterol, is useful as a relatively 
selective beta-2 adrenergic bronchodilator. The rate and extent of 
albuterol diffusion through skin is slow and insufficient to be 
therapeutic from simple conventional formulations. This is so because 
albuterol does not possess the necessary physical-chemical characteristics 
of a molecule which is best suited for absorption from systemic topical 
application. 
SUMMARY OF THE INVENTION 
The present invention provides a method for enhancing skin penetration of 
albuterol in a mammal which comprises the administration of a composition 
comprising, a therapeutically effective amount of albuterol and a 
transdermal flux enhancing amount of a combination of 
1-dodecyl-azacycloheptan-2-one and urea, with a pharmaceutically 
acceptable thickening agent. The composition of this invention comprises 
the following weight percent based on the total weight of the 
compositions: 
(a) about 5 to 50 percent albuterol, preferably about 10 to 30 percent, 
(b) about 5 to 50 percent 1-dodecyl-azacycloheptan-2-one, preferably about 
10 to 50 percent, 
(c) 5 to 50 percent urea, preferably 10 to 25 percent, 
(d) sufficient pharmaceutically acceptable thickening agent to cause the 
formation of a homogeneous solid or semi-solid preparation, preferably 
polyvinyl chloride/vinyl acetate copolymer; mineral oil containing about 5 
to 20 percent polyethylene; caprylic/capric triglyceride containing about 
0.5 to 5 percent aluminum monostearate; isopropyl myristrate containing 
about 5 to 20 percent polyethylene. 
The following compositions are preferred: 
I. about 10% of albuterol; about 30% of 1-dodecyl-azacycloheptan-2-one; 
about 20% of urea; and about 40% polyvinyl chloride/vinyl acetate 
co-polymer. 
II. about 30% of albuterol; about 35% of 1-dodecyl-azacycloheptan-2-one; 
about 20% of urea; and about 15% polyvinyl chloride/vinyl acetate 
co-polymer. 
III. about 25% of albuterol; about 20% of 1-dodecyl-azacycloheptan-2-one; 
about 25% of urea; and about 30% polyvinyl chloride/vinyl acetate 
co-polymer. 
IV. about 25% of albuterol; about 20% 1-dodecyl-azacycloheptan-2-one; about 
20% of urea; and about 35% mineral oil containing about 5 to 20 percent 
polyethylene. 
V. about 10% of albuterol; about 50% of 1-dodecyl-azacycloheptan-2-one; 
about 20% of urea; and about 20% caprylic/capric triglyceride containing 
about 0.5 to 5 percent aluminum monostearate. 
VI. about 20% of albuterol; about 50% of 1-dodecyl-azacycloheptan-2-one; 
about 10% of urea; and about 20% isopropyl myristrate containing about 5 
to 20 percent polyethylene. 
VII. about 15% of albuterol; about 35% of 1-dodecyl-azacycloheptan-2-one; 
about 25% of urea; and about 25% polyvinyl chloride/vinyl acetate 
co-polymer. 
The following compositions are most preferred: 
VIII. about 20% of albuterol; about 35% of 1-dodecyl-azacycloheptan-2-one; 
about 20% of urea; and about 25% polyvinyl chloride/vinyl acetate 
co-polymer. 
XI. about 20% of albuterol; about 35% of 1-dodecyl-azacycloheptan-2-one; 
about 20% urea; and about 25% polyvinyl chloride/vinyl acetate co-polymer. 
DETAILED DESCRIPTION OF THE INVENTION 
The invention provides a composition which can be administered topically as 
a cream, ointment or via a transdermal device, e.g., a patch. The patch is 
conveniently applied to the skin to provide transdermal albuterol 
administration over a prolonged period of time, e.g., about 24 hours to 
168 hours. For reasons of convenience, effectiveness and controlled blood 
levels, the transdermal delivery via a patch of albuterol is preferred. 
Preferably, the transdermal composition of this invention is utilized in a 
"reservoir type" or "matrix type" patch which is applied to the skin and 
worn for a specific period of time to permit the absorption of a desired 
amount of albuterol through the skin. The compositions of this invention 
can be packaged to produce a "reservoir type" transdermal patch with or 
without a rate-limiting patch membrane. The size of the patch and/or the 
rate limiting membrane can be chosen to deliver the transdermal flux rates 
desired. The therapeutically desired transdermal amount of albuterol has 
been determined to be about 3 to 4 milligrams per day. Drug Delivery 
Systems Characteristics and Biomedical Application; R. L. Juliano, ed., 
Oxford University, N.Y. (1980); and Controlled Drug Delivery Vol. 1 Basic 
Concepts, Stephen D. Bruck (1983) describe the theory and application of 
methods useful for preparation of transdermal delivery systems. The 
relevant teachings of these texts are herein incorporated by reference. 
Thus, the drug-matrix could be formed by conventional means utilizing 
various polymers, e.g. silicone, polyvinyl alcohol, polyvinyl 
chloride-vinyl acetate co-polymer. The drug matrix is then packaged into 
an appropriate transdermal patch. 
Pharmaceutically acceptable thickening agents are, for example, polyvinyl 
chloride/vinyl acetate copolymer, which is available under the trade name 
FPC 6338 from Occidental Chemical Corporation; mineral oil containing 
about 5 to 20 percent polyethylene (polyethylene which is available under 
the trade name A-C.RTM. Polyethylene from Allied Chemical Corporation); 
caprylic/capric triglyceride containing about 0.5 to 5 percent aluminum 
monostearate. Caprylic/capric triglyceride which is available under the 
tradename Miglyol.RTM. from Dynamit Nobel; and isopropyl myristrate 
containing about 5 to 20 percent polyethylene. 
These thickening agents result in a homogeneous semi-solid preparation and 
provide a medium through which the physiologically active agents can be 
applied to skin or be packaged into an appropriate "reservoir or matrix 
type" transdermal patch.

The following examples illustrate compositions of this invention and their 
preparation. All percentages therein are by weight. The definitions of 
components whose chemical compositions are not immediately clear from the 
name used, may be found in the CTFA Cosmetic Ingredients Dictionary, 3d 
Edition, published by the Cosmetic, Toiletry and Fragrance Association, 
Inc., Washington, D.C. It will be apparent to those skilled in the art 
that many modifications thereof may be practiced without departing from 
the purpose and intent of this invention. 
TABLE 1 
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Transdermal Pharmaceutical Compositions of the Present Invention 
(Examples 1-13) 
Percent By Weight 
Ingredients Ex 1 
Ex 2 
Ex 3 
Ex 4 
Ex 5 
Ex 6 
Ex 7 
Ex 8 
Ex 9 
Ex 10 
Ex 11 
Ex 
Ex 
__________________________________________________________________________ 
13 
Albuterol 5 20 50 40 25 10 20 20 15 10 30 25 20 
1-dodecylazacycloheptan-2-one 
35 35 15 5 20 50 50 35 35 30 35 20 50 
Urea 20 20 20 25 20 20 5 20 25 20 20 25 10 
Polyvinyl Chloride Vinyl Acetate 
40 25 15 30 0 0 0 25 25 40 15 30 0 
Co-polymer 
Mineral Oil containing 5 to 20 percent 
0 0 0 0 35 0 0 0 0 0 0 0 0 
polyethylene 
Caprylic/capric triglyeride containing 
0 0 0 0 0 20 0 0 0 0 0 0 0 
0.5 to 5 percent alumninum monostearate 
Isopropyl Myristrate containing 
0 0 0 0 0 0 25 0 0 0 0 0 20 
5 to 20 percent polyethylene 
__________________________________________________________________________ 
PROCEDURE FOR EXAMPLES 1-13 
1. Charge the 1-dodecyl-azacycloheptan-2-one to a suitable container. 
2. Add the urea to the 1-dodecyl-azacycloheptan-2-one with appropriate 
agitation and mix until uniformly dispersed. 
3. Add the albuterol with appropriate agitation and mix until uniformly 
dispersed. 
4. Charge the thickening agent and mix until uniformly dispersed. 
5. Cure the drug/polymer mixture, if necessary, and then form, fill and 
seal the formulation to yield a transdermal drug delivery system. 
SCREENING OF ALBUTEROL FOR TRANSDERMAL PENETRATION 
Compositions containing albuterol, Azone.RTM. and urea were screened for 
transdermal penetration as follows: 
The skin diffusion cells used were similar to those described by Franz, J. 
Invest. Derm., 64,190, (1975). Excised defatted human skin was stretched 
across a reservoir containing a phosphate buffer solution (pH 7.4, 0.02M) 
in direct contact with the dermal side of the skin. The temperature of 
this buffer solution was maintained at 37.degree..+-.0.5.degree. C. by 
circulating water at the appropriate temperature through a jacket which 
surrounds each assembly. Freshly made albuterol preparations were applied 
to the stratum corneum surface. The buffer solution was removed in its 
entirety and replaced with fresh solution at various time intervals and 
assayed for albuterol content in order to determine albuterol flux through 
skin. 
Table II shows that 1-dodecyl-azacycloheptan-2-one when incorporated into 
an albuterol non-aqueous polymeric matrix, enhances the transdermal flux 
of albuterol through human cadaver skin in a dose dependent manner. 
Table III shows that a 1-dodecyl-azacycloheptan-2-one and urea combination 
enhances the transdermal flux of albuterol to a greater extent than do 
equivalent concentrations of 1-dodecyl-azacycloheptan-2-one or urea used 
alone. 
In particular, urea and 1-dodecylazacycloheptan-2-one in combination within 
an albuterol:non-aqueous vehicle, when applied to skin or membrane 
surfaces, causes an absorption rate of albuterol greater than that 
resulting from its use with urea or 1-dodecyl-azacycloheptan-2-one alone 
and greater than an additive effect of the urea and Azone. In fact, 
greater absorption of albuterol has been achieved than has heretofore been 
possible. It is also surprising that urea is effective for this use when 
in non-aqueous form. 
The result is that the albuterol:1-dodecyl-azacycloheptan-2-one:urea 
composition having enhanced skin absorption properties, delivers a 
therapeutically effective amount of albuterol through the skin. 
TABLE II 
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IN VITRO SKIN PENETRATION 
Cumulative Albuterol Flux.sup.a 
(mg/cm.sup.2) 
Formulation n.sup.b 24 hour 48 hour 
______________________________________ 
Alb:PVC/VA.sup.c 
4 0 0 
(30:70) 
Alb:Azone:PVC/VA 
3 0.01 0.04 
(30:10:60) 
Alb:Azone:PVC/VA 
3 0.02 0.14 
(30:25:45) 
Alb:Azone:PVC/VA 
3 0.04 0.36 
(30:50:20) 
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.sup.a Flux through human cadaver skin. Skin:female, nonwhite, 79. Mean o 
n diffusion cells 
.sup.b Number of skin diffusion cells. 
.sup.c PVC/VA:polyvinyl chloride/vinyl acetate copolymer. 
Table II shows cumulative albuterol flux rates when varying levels of 
Azone.RTM. are incorporated into an albuterol: non-aqueous polymeric 
matrix, e.g., polyvinyl chloride/vinyl acetate co-polymer. These data show 
the enhancement of albuterol flux by Azone.RTM. through human cadaver shin 
in a dose dependent manner. 
TABLE III 
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In Vitro Skin Penetration 
Cumulative Albuterol Flux.sup.a 
(mg/cm.sup.2) 
Formulation n.sup.b 
24 hour 48 hour 
______________________________________ 
Alb:Urea:PVC/VA.sup.c 
3 0.05 0.28 
(20:20:60, w:w:w) 
Alb:Azone:PVC/VA 
3 0.08 0.65 
(20:50:30, w:w:w) 
Alb:Azone:Urea:PVC/VA 
3 0.13 0.53 
(20:15:20:45, w:w:w:w) 
Alb:Azone:Urea:PVC/VA 
3 0.13 0.64 
(20:25:20:35, w:w:w:w) 
Alb:Azone:Urea:PVC/VA 
4 0.37 1.32 
(20:35:20:25, w:w:w:w) 
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.sup.a Flux through human cadaver skin. Skin:female, white, 62. Mean of n 
diffusion cells 
.sup.b Number of skin diffusion cells. 
.sup.c PVC/VA:polyvinyl chloride/vinyl acetate copolymer. 
Table III illustrates a more than additive increased enhancement of 
albuterol transdermal absorption when urea is incorporated into the 
albuterol:Azone.RTM.; polymeric matrix. This Azone.RTM./urea combination 
enhances the transdermal absorption of albuterol to a greater extent than 
do comparable concentrations of Azone.RTM. or urea when used alone.