United States Patent:  5,989,581

Assignee:  Akzo Nobel N.V. (Arnhem, NL)

Filed:  April 8, 1998

The present invention is dealing with a drug delivery system, preferably in a ring-shaped form suitable for vaginal administration, for the simultaneous release of a progestogenic steroid compound and an estrogenic steroid compound in a fixed physiological ratio over a prolonged period of time. The drug delivery system comprises at least one compartment comprising a thermoplastic polymer core containing the mixture of the progestogenic and estrogenic compounds and a thermoplastic polymer skin, the progestogenic compound being initially dissolved in the polymer core material in a relatively low degree of supersaturation.

SUMMARY OF THE INVENTION

Surprisingly, applicant has found that a reliable release ratio over a prolonged period of time can be achieved using a one-compartment, preferably ring shaped, drug delivery system for at least two steroidal compounds (such as a progestogen and an estrogen) and more preferably for etonogestrel and ethinylestradiol by carefully selecting and treating the reservoir and outer layer materials.

The preferably ring-shaped drug delivery system according to the present invention (hereinafter called vaginal ring) comprises at least one compartment comprising a thermoplastic polymer core containing at least the progestogenic steroidal compound and the estrogenic steroidal compound in a ratio by weight that allows a direct release from the said polymer of both the progestogenic compound and the estrogenic compound in physiologically required amounts, said progestogenic compound being initially dissolved in the core polymer in a relatively low degree of supersaturation, preferably being 1 to about 6 times of the amount by weight necessary for obtaining the saturation concentration of said progestogenic steroid in said core polymer at 25^oC., said estrogenic compound being initially dissolved in the core polymer in a concentration being lower than that of the said progestogenic compound, and a thermoplastic skin (outer layer) being permeable for the said progestogenic and estrogenic compounds.

More particularly a vaginal ring according to the invention preferably to be used for contraception comprises at least one compartment comprising a thermoplastic polymer core of ethylene-vinylacetate copolymer (poly-EVA) containing at least etonogestrel (3-keto desogestrel) as the progestogenic compound and ethinylestradiol as the estrogenic compound in a ratio by weight of about 10 parts of etonogestrel and about 1.5-5 parts of ethinylestradiol, whereby the compound etonogestrel is dissolved in the poly-EVA core in an amount by weight of at least 1 but not more than about 6 times and more preferably between 2 and 5 times the amount necessary for obtaining its saturation concentration at 25^oC., and a thermoplastic skin of poly-EVA being permeable for both etonogestrel and ethinylestradiol.

As may be derived already from the above description the present invention is based on the surprising finding that a steroid can be retained in a supersaturated state during prolonged storage (such as 6 months or longer) at temperatures between 4^oC. and 25^oC., provided that the steroid concentration does not exceed the solubility at 25^oC. excessively. Of course, the allowable excess is determined by the lowest storage temperature, the steroid compound, and the thermoplastic polymer including any additional compounds present (cosolvent effect). If however the said excess exceeds the allowable limits the steroid crystallises out on the exterior surface of the vaginal ring.

This finding allows for a vaginal ring which can be easily manufactured, and which provides for the reliable and predictable release of the steroid compounds. In contrast to known vaginal rings comprising a steroid-containing fluid core, the solid thermoplastic core of present vaginal ring does not bring with it the risk of leakage of steroid-comprising fluid, for example due to a failing seal. In addition, the present vaginal rings can be manufactured with extrusion techniques easily and cheaply. The manufacture of a complicated device, that is, comprising compartments differing both in the number of layers and in steroid composition, is circumvented.

The thermoplastic polymer that can be used in practising the invention, may in principle be any thermoplastic polymer or elastomer material suitable for pharmaceutical use, such as low density polyethylene, ethylene-vinylacetate copolymers and styrene-butadiene-styrene copolymers. The ethylene-vinylacetate copolymer (poly-EVA) is highly preferred due to its excellent mechanical and physical properties (e.g. solubility of the steroids in the material). The poly-EVA material may preferably be used for both the core as well as the skin and can be any commercially available ethylene-vinylacetate copolymer, such as the products available under the trade names: Elvax, Evatane, Lupolen, Movriton, Ultrathene and Vestypar.

The vaginal ring according to the invention can be manufactured in any size as required. In practice, however, the ring has an outer diameter of between 50 and 60 mm and more preferably between 52 and 56 mm; the cross sectional diameter is preferably between about 2.5 and 5 mm.

The surface of the core body is preferably more than 800 mm², more preferably at least 1000 mm² and will typically be in the order of 1700-2000 mm², though significantly larger surfaces are possible, provided that the design (physical dimensions) of the vaginal ring prevents inconvenience for the subject. Although not preferred it may sometimes be required to add a second compartment which is a placebo compartment or a compartment loaded with one or more other drugs. Such an extra compartment may be necessary for example in practising hormonal replacement therapy, where the ratio between progestogen and estrogen is different from the ratio suitable for contraception. A vaginal ring comprising only one compartment, however, is the preferred embodiment of this invention; it is easy to manufacture and shows an adjustable and excellent release pattern.

The vaginal ring according to the invention is primarily designed for contraceptive use, but--as said above--may also be used under certain conditions in HRT (hormonal replacement therapy). The progestogenic steroidal compound can be any suitable progestogen, such as desogestrel, etonogestrel, levonorgestrel, norgestimate, gestodene or any other steroidal compound with progestogenic activity. The estrogenic steroidal compound can be any suitable estrogen, such as estradiol, estriol, mestranol and ethinylestradiol. The preferred progestogen is etonogestrel. The preferred estrogen for contraceptive use is ethinylestradiol whereas estradiol is the preferred estrogen for HRT.

For contraception in humans, the vaginal ring according to the present invention is preferably characterised in that the poly-EVA core body comprises etonogestrel and ethinyl estradiol in about a 1 to 0.2-0.4, more preferably in a 1 to 0.2-0.3, ratio by weight, whereby etonogestrel is dissolved in the poly-EVA material up to a relatively low degree of supersaturation, preferably 1 to 6 times its saturation concentration at 25^oC., so as to allow over a period of 21 days an average release rate of 95 to 145 .mu.g, preferably 120 .mu.g, etonogestrel and 10-20 .mu.g, preferably 15 .mu.g, ethinyl estradiol per 24 hours in situ.

In an advantageous embodiment of such a vaginal ring, the skin is an ethylene-vinylacetate copolymer skin having a thickness ranging from 40 to 300 .mu.m and a vinyl acetate content ranging from 5 to 15%, and more in particularly the skin of the compartment has a thickness of 110 .mu.m and is comprised of ethylene-vinylacetate copolymer with a 9% to 10% vinyl acetate content.

Such a skin has excellent solubility and steroid diffusion properties, allowing the combined release of etonogestrel and ethinyl estradiol in the proper ratio at moderate concentrations of the steroids in the vaginal ring during a prolonged period of time.

In addition, the core body is advantageously comprised of a ethylene-vinyl acetate copolymer with a 25 to 35%, preferably 26 to 30% vinyl acetate content. The percentage vinyl acetate can be established using potentiometric titration as described in various textbooks on this subject matter.

As said earlier it is an essential element of the present invention to have the progestogenic steroid dissolved in the core material in a relatively low degree of supersaturation. This "relatively low degree of supersaturation" may generally be defined as the amount of progestogenic steroid that is one to about six times the amount necessary to obtain the saturation concentration of the steroid in the polymer at 25^oC. and more preferably from 2 to 5 times.

The saturation concentration of the steroid can be determined by various methods known per se in the art. For instance the thermoplastic polymer is introduced in a saturated solution of the steroid (provided with additional steroid crystals) at 25^oC. and kept in that saturated solution until the concentration of the steroid in the polymer remains constant. Another suitable method for the determination of the saturation concentration is the so called time-lag method.

In a more preferred embodiment of the invention wherein the progestogenic steroidal compound is etonogestrel, the estrogenic compound is ethinyl estradiol and the core material is poly-EVA , a "low degree of supersaturation" is obtained by using a quantity of etonogestrel in said poly-EVA core material of from about 0.3 to about 1% by weight, the quantity of ethinyl estradiol then being from about 0.05 to about 0.3% by weight. With such initial low degree of supersaturation the etonogestrel containing vaginal ring is surprisingly stable.

The poly-EVA core may advantageously comprise 0.5 to 1%, preferably 0.55 to 0.8% by weight of etonogestrel and 0.10 to 0.23%, preferably 0.12-0.18% by weight of ethinyl estradiol.

At these preferred steroid concentrations in the core material, the skin specified above allows for the combined release of etonogestrel and ethinyl estradiol at the proper physiological rate for a prolonged period of time, whereby the drug delivery device--the vaginal ring--shows excellent stability (no crystallisation on the exterior surface of the ring) upon storage during a considerable period of time.

The vaginal ring according to the invention can be manufactured in any suitable manner. A preferred method of manufacture comprises co-extrusion of the drug-loaded core and the non-medicated outer layer. The fibres thus obtained are cut into pieces of the required length and each piece is assembled to a ring shaped device in any suitable manner. The rings are then packed for example in a suitable sachet, optionally after being sterilised or disinfected.

Claim 1 of 11 Claims

1. A drug delivery system comprising at least one compartment which comprises a thermoplastic polymer core and a thermoplastic polymer skin covering the core, said core comprising a mixture of a steroidal progestogenic compound and a steroidal estrogenic compound in a ratio by weight that allows a direct release of both said progestogenic compound and said estrogenic compound in physiologically required amounts, said progestogenic compound being initially dissolved in said polymer core material in a degree of supersaturation of 1 to about 6 times of the amount by weight necessary for obtaining saturation concentration of said progestogenic compound in said polymer core material at 25^oC., said estrogenic compound being dissolved in said polymer core material in a concentration lower than that of said progestogenic compound, and said thermoplastic skin being permeable for said progestogenic and estrogenic compounds.

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