Transdermal Contraceptive Formulations

This invention relates to transdermal drug delivery. More particularly, this invention relates to contraceptive delivery and still more particularly, but without limitation thereto, this invention relates to the transdermal delivery of ethinyl estradiol and levonorgestrel, in combination, at therapeutically effective rates.

This invention is related to the inventions disclosed in the copending, coassigned patent applications of Gale, et al for Transdermal Administration of Progesterone, Estradiol Esters and Mixtures Thereof, of Cheng, et al for Skin Permeation Enhancer Compositions using Glycerol Monolaurate, and for Cheng, et al for Skin Permeation Enhancer Compositions, all of like date herewith.

The transdermal route of parenteral delivery of drugs provides many advantages and transdermal systems for delivering a wide variety of drugs or other beneficial agents are described in U.S. Pat. Nos. 3,598,122, 3,598,123, 4,379,454, 4,286,592, 4,314,557 and 4,568,343, for example, all of which are incorporated herein by reference.

Oral combination pills and intrauterine devices for purposes of contraception have been well documented for their problems such as inconvenience and side effects. Transdermal delivery of contraceptives as disclosed herein, is an attempt to eliminate or reduce those problems.

An object of the present invention is to provide delivery of contraceptives by means of transdermal systems.

A further object is to co-administer ethinyl estradiol and levonorgestrel at contraceptively effective rates.

A still further object of the present invention is to deliver contraceptives transdermally using skin permeation enhancers such as glycerol monooleate.

An even further object is to provide a method for the transdermal administration of ethinyl estradiol and levonorgestrel, in combination.

These and other objects have been demonstrated by the present invention wherein a transdermal system is designed using a polymer matrix containing glycerol monooleate as a permeation enhancer and ethinyl estradiol and levonorgestrel, in combination, as a contraceptive formulation.

The invention will be described in further detail with reference to the accompanying drawings wherein:

FIG. 1 is a cross-sectional view of one embodiment of the transdermal drug delivery system according to this invention.

FIG. 2 is a cross-sectional view of another embodiment of the transdermal drug delivery system of this invention.

This invention utilizes principles of transdermal drug delivery to provide a novel system for effectively administering contraceptives. Of particular significance is the use of a codelivered permeation enhancer, glycerol monooleate (GMO), to aid in drug delivery across the skin. The present invention provides continuous co-administration of ethinyl estradiol and levonorgestrel for up to seven days. GMO is used as a suitable permeation enhancer.

Referring now to FIG. 1, a transdermal therapeutic system 1 according to this invention is shown which comprises a drug/permeation enhancer reservoir 2 in the form of a matrix containing the drug formulation and the permeation enhancer. The reservoir 2 is covered by an impermeable backing 3 which is preferably sized slightly larger in circumference than reservoir 2. Means 4 for maintaining the system 1 on the skin may either be fabricated together with or provided separately from the remaining elements of the system, which means in the embodiment of FIG. 1 takes the form of an adhesive overlay. The use of an adhesive overlay with this invention is preferred to the use of an in-line adhesive applied to the skin proximal surface of reservoir 2 because glycerol monoleate adversely affects the adhesive properties of most pharmaceutically acceptable contact adhesives. For this reason, impermeable backing layer 3 is preferably sized slightly larger than the reservoir 2 to provide a peripheral area around reservoir 2, free of any glycerol monoleate adjuvant, to prevent adverse interaction between the adhesive in the overlay 4 and any of the enhancer which may seep from under the base of reservoir 2 in use. A strippable release liner 5, adapted to be removed prior to application would normally be included in the packaged product.

Various materials suited for the fabrication of the various layers are disclosed in the aforementioned patents.

The polymer matrix is preferably anhydrous and suitable materials include, without limitation, natural and synthetic rubbers or other polymeric material, thickened mineral oil or petroleum jelly, for example. The preferred embodiment according to this invention is fabricated from an ethylene vinylacetate (EVA) co-polymer of the type described in U.S. Pat. No. 4,144,317, preferably those having a vinylacetate (VA) content in the range of about 28 to 60% VA. Particularly good results have been obtained using 40% vinylacetate content (EVA 40).

A preferred embodiment is basically a monolith having the following composition by weight: 20-50% polymer, 10-50% tackifier, 0.01-1% ethinyl estradiol, 0.1-5% levonorgestrel and 10-50% permeation enhancer.

The preferred system uses the EVA polymer as the elastomer. Typical suitable tackifiers are fully hydrogenated aromatic hydrocarbon resins. Successful results have been achieved with use of the Hercules, Inc. (Wilmington, Delaware) product line sold under the trade name Staybelite Ester.TM.. Specifically, Staybelite Ester #5 and #10 have been used.

The drugs are preferably dispersed through the matrix at a concentration in excess of saturation, i.e. at unit activity. The amount of excess is determined by the intended useful life of the system. The drugs, however, may be present at initial levels below saturation without departing from this invention. The permeation enhancer, preferably GMO, is dispersed through the matrix, preferably at a concentration sufficient to provide permeation enhancing concentrations of GMO in the reservoir throughout the anticipated administration time.

Referring now to FIG. 2, another embodiment of the invention is shown in place upon the skin 17 of a patient. In this embodiment the transdermal therapeutic system 10 comprises a multilaminate drug formulation/enhancer reservoir 11 having at least two zones 12 and 14. Zone 12 consists of a drug reservoir substantially as described with respect to FIG. 1. Zone 14 comprises a permeation enhancer reservoir which is preferably made from substantially the same matrix as is used to form zone 12 and which is substantially free of any undissolved drug. A rate-controlling membrane for controlling the release rate of the GMO from zone 12 to the skin may also be utilized between zones 12 and 14 if desired. Suitable rate-controlling membranes may be formed from polymers having a permeability to GMO lower than that of zone 12.

An advantage of the system described in FIG. 2 is that the drug loaded zone 12 is concentrated at the skin surface rather than throughout the entire mass of the reservoir. This functions to reduce the amount of drug in the system while maintaining an adequate permeation enhancer supply.

Superimposed over the drug formulation/enhancer reservoir 11 is an impermeable backing 15 and adhesive overlay 16 as described above with respect to FIG. 1. In addition, a strippable release liner (not shown) would preferably be provided on the system prior to use as described with respect to FIG. 1 and removed prior to application to the skin 17.

In the embodiments of FIGS. 1 and 2, the carrier or matrix material has sufficient viscosity to maintain its shape without oozing or flowing. If the matrix or carrier is a low viscosity flowable material, the composition can be fully enclosed in a pouch or pocket between the impermeable backing and a permeable or microporous skin contacting membrane, as known to the art from U.S. Pat. No. 4,379,454, noted above, for example.

The transdermal therapeutic systems of this invention may be fabricated by state of the art methods such as solution casting and melt blending. The main design criteria is that the active (drug formulation containing) layer be about 5-10 mils thick.

The required transdermal flux for effective contraception as provided by this invention, is at least 15 .mu.g/day of ethinyl estradiol and at least 50 .mu.g/day of levonorgestrel. For a 20 cm.sup.2 system, these daily flux values translate to be at least 0.04 g/cm.sup.2 /hr for ethinyl estradiol and at least 0.14 .mu.g/cm.sup.2 /hr for levonorgestrel.

The systems of this invention can be designed to effectively deliver ethinyl estraiiol and levonorgestrel for an extended time period of up to 7 days. The drug delivery must be continuous in order to provide effective contraception. Therefore, when one system has been in place on the skin for its effective time period, it is replaced with a fresh system. For example, for a 7 day system maintenance would involve replacing the system every 7 days with a fresh system and continuing said replacement for as long as contraception was desired.

The embodiments and applications of this invention are best understood in light of the following examples.

A transdermal therapeutic system as described with respect to FIG. 1 for the administration of ethinyl estradiol and levonorgestrel was formulated from: 5% levonorgestrel, 0.5% ethinyl estradiol, 37.8% EVA 40, 26.6% Staybelite Ester #5 and 30.1% GMO. The in vitro skin flux was measured over a seven day period, at 37.degree. C. The following table shows the flux data (averaged for thirteen samples) for both drugs and GMO:

The transdermal (in vivo) fluxes of ethinyl estradiol and levonorgestrel were estimated, based upon the following relationships:

and

where

Q=cumulative amount permeated

L=amount of drug loading in the formulation

S=drug solubility in GMO

Therefore, since the Q value for GMO is 5 mg/cm.sup.2 (5.times.10.sup.-3 g/cm.sup.2) over a seven day period, and the amount of ethinyl estradiol and levonorgestrel loaded is 5.times.10.sup.3 .mu.g/g each, the amount of each drug which permeates the skin is:

This invention has been described in detail with particular reference to certain preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of the invention.