MXPA98002799A - System of delivery of medication for two or massubstancias acti - Google Patents

Abstract

The present invention relates to a delivery system of medicament, preferably in a ring 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 at a relatively low degree of oversaturation

Description

Delivery system of medication for two c plus active substances The present invention relates to a delivery system of medication for the simultaneous release of two or more active substances and more particularly to a delivery system of vaginal medicament in the form of a ring, said system releases the active substances in a substantially constant proportion over a prolonged period of time. Such a release system is for example known from US Pat. Nos. 3,995,633 and 3,995,634, where deposits, preferably spherical or cylindrical, separately, containing different active substances are assembled on specially constructed supports. Such a release system is also described in U.S. Patent No. 4,237,885, where a tube or coil of polymeric material is divided into portions by means of a plurality of "separators" provided in the tube, after each of the tube portions. The separated one is filled with a different active substance in a silicone fluid and the two ends of the tube are subsequently connected to each other. However, in this release system, the transport (diffusion) of the active material from one reservoir to the other takes place through the wall of the tube, especially over prolonged storage, so that the rate of fixed release predisposed between the substances active in question will change over a period of time. A two-layer vaginal ring has been described in European Patent Publication 0,050,867, which ring comprises a pharmacologically acceptable support ring covered by two layers preferably of silicone elastomers, by means of which the inner layer is a silicone elastomer loaded with an active substance. A similar ring-shaped vaginal delivery system has been described in US Patent 4,292t965. The use of silicone elastomers is now considered to be less safe and clearly is no longer the material of choice. In U.S. Patent 4,596,576 a two compartment vaginal ring has been described, wherein each compartment contains a different active substance. However, to achieve a suitable ring with a constant release rate between the various active substances, it was necessary, however, to join the final portions of the compartments with inert plugs, preferably glass plugs. Patent publication WO 97/02015 discloses a two-compartment device, consisting of a first compartment of a core, a medicated intermediate layer and a non-medicated outer layer, and a second compartment consisting of a medicated core and a non-medicated outer layer. . Release systems, which over a long period release two or more active substances in a substantially constant proportion between one and the other are extremely useful for certain applications. For example, in the field of contraception and in the field of hormone replacement therapy, extensive use is made of the simultaneous administration of an agent having a progestogenic activity and an agent having an estrogenic activity, preferably in a substantially constant proportion. The simultaneous introduction of these two drugs into a reservoir can, however, only lead purely accidentally to the desired release rate. In fact, the release per unit of time is determined by the solubility of the active substance in the outer layer of the polymeric material (which forms the wall of the reservoir) and by the diffusion coefficient of the active substance in the outer layer. In this type of release system, in fact, the choice of the material of the outer layer of the reservoir determines the release rate of the active substances contained in the reservoir to a large extent. Although theoretically it is possible to choose from a very large variety of polymeric materials, it is found in practice that only a relatively small number of polymers appear to be able to function satisfactorily as an outer layer determining the release of the deposit. Not only medical use imposes certain requirements on the polymer but also a large number of polymers are inadequate in that, for example, they have insufficient rigidity, are insufficiently inert, provide insufficient solubility of the active substance (s). ), etc.

Moreover, the composition of the tank containing the active substances is also important, because the material of the tank is responsible for an adequate supply of the active substances for the inner side of the outer layer. The material of the tank may not shrink upon the release of the active substances, it must be capable of taking a large quantity of the active substances, etc. In most cases, one is forced to choose a release system with a plurality of separate reservoirs as a release system, which is capable of releasing two or more active substances in a particular proportion as is clearly demonstrated in the aforementioned references - Apart from a not always satisfactory release, the release rate and the release time in some cases, all the vaginal rings described suffer from being relatively complicated, making them more expensive to manufacture. Surprisingly, the Applicant has found that a reliable release rate over a prolonged period of time can be achieved by using a drug delivery system, preferably in the form of a ring, of a compartment, for at least two steroidal compounds (such as as progestogen and estrogen) and more preferably for etonogestrel and ethinylestradiol when selecting and carefully treating the reservoir and outer layer materials. The preferred drug delivery system in the form of a ring according to the present invention (hereinafter called a vaginal ring) comprises at least one compartment comprising a thermoplastic polymer core containing at least one progestogenic steroidal compound and the estrogenic steroidal compound in a proportion by weight that allows a direct release of said polymer from 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, being preferably 1 to about 6 times the amount by weight necessary to obtain the saturation concentration of said progestogenic steroid in said core polymer at 25 ° C, said estrogenic compound being initially dissolved in the core polymer at a concentration qu e is less than those of said progestogenic compound, and a thermoplastic skin (outer layer) which is permeable for 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-vinyl acetate copolymer (poly-EVA) containing at least etonogestrel (3-keto desogestrel) as the progestogenic compound and ethinylestradiol as the estrogenic compound in a weight ratio of about 10 parts of etonogestrel and about 1.5-5 parts of ethinylestradiol, by means of which the etonogestrel compound is dissolved in the nucleus of poly-EVA in a weight amount of at least 1 but not more than about 6 times, and more preferably between 2 and 5 times the amount needed to obtain its saturation concentration at 25CC, and a poly-EVA thermoplastic skin which it is permeable for both etonogestrel and ethinylestradiol. As can already be derived 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 greater) at temperatures between 4 ° C and 25 ° C. ° C, provided that the steroid concentration does not exceed the solubility at 25 ° C 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 (co-solvent effect). NeverthelessIf this excess exceeds the allowable limits, the steroid crystallizes on the outer surface of the vaginal ring. This finding allows a vaginal ring, which can be easily manufactured, and which provides reliable and predictable release of steroid compounds. In contrast to the vaginal ring comprising a fluid core containing steroids, the solid thermoplastic core of the present vaginal ring does not carry the risk of leaking fluid comprising steroids, for example due to a failing seal. In addition, the present vaginal rings can be manufactured with easy extrusion techniques and inexpensively. The manufacture of a complicated device, that is, comprising compartments that differ in both the number of layers and the steroid composition, is avoided.

The thermoplastic polymer that can be used to practice the invention can, in principle, be any elastomeric material or thermoplastic polymer suitable for pharmaceutical use, such as low density polyethylene, ethylene-vinyl acetate copolymers and styrene-butadiene-styrene copolymers . The ethylene-vinyl acetate copolymer (poly-EVA) is highly preferred due to its excellent mechanical and physical properties (eg solubility of steroids in the material). The poly-EVA material can be preferably used for both the core and the skin and can be any commercially available ethylene-vinyl acetate 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. However, in practice, the ring has an outer diameter of between 50 and 60 mm and more preferably between 52 and 56 mm; the diameter of the cross section is preferably between approximately 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 normally be in the order of 1700-2000 mm2, although significantly larger surfaces are possible, provided that the design (physical dimensions) of the ring vaginal avoid 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 medications. Such an extra compartment may be necessary, for example, to practice hormone replacement therapy, where the ratio between progestogen and estrogen is different from the proportion 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 excellent and adjustable release pattern. The vaginal ring according to the invention is designed primarily for contraceptive use, but - as said before - it can also be used under certain conditions in HRT (hormone replacement therapy). The progestogenic steroidal compound can be any suitable progestogen, such as desogestrel, etonogestrel, levonorgestrel, norgestimate, gestodena 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, while estradiol is the preferred estrogen for HRT. For human contraception, the vaginal ring according to the present invention is preferably characterized in that the body of the poly-EVA core comprises etonogestrel and ethinylestradiol at about 0.2-0.4, more preferably at 1 to 0.2-0.3, weight ratio, by means of which the etonogestrel is dissolved in the poly-EVA material to a relatively low degree of supersaturation, preferably from 1 to 6 times its saturation concentration at 25 ° C, in order to allow a period of 21 days, an average release rate of 95 to 145 μg, preferably 120 μg of etonogestrel and 10-20 μg, preferably 15 μg of eti-estradiol for 24 hours in situ. In an advantageous embodiment of a vaginal ring, the skin is a skin of ethylene-vinyl acetate copolymer having a thickness ranging from 40 to 300 μm and a content of vinyl acetate ranging from 5 to 15%, and more particularly the skin of the compartment has a thickness of 10 μm and is comprised of ethylene-vinyl acetate copolymer with a vinyl acetate content of 9% to 10%. Such skin has an excellent solubility and diffusion properties of steroids, allowing the combined release of etonogestrel and ethinylestradiol in the proper proportion at moderate concentrations of the steroids in the vaginal ring for a prolonged period of time. In addition, the core body is advantageously comprised of an ethylene-vinyl acetate copolymer with 25 to 35%, preferably 26 to 30% of vinyl acetate content. The percentage of vinyl acetate can be established using potentiometric titration, as described in several textbooks on this subject. As said before, an essential element of the present invention is to have the progestogenic steroid dissolved in the core material in a relatively low degree of supersaturation. This "relatively low degree of supersaturation" can be broadly defined as the amount of progestogenic steroid which is one to about six times the amount necessary to obtain the saturation concentration of the steroid in the polymer at 25 ° C and more preferably at 2 ° C. to 5 times. The saturation concentration of the steroid can be determined by various methods known per se in the art. For example, the thermoplastic polymer is introduced into a saturated solution of the steroid (provided with additional steroid crystals) at 25 ° C and kept in this saturated solution until the concentration of the steroid in the polymer remains constant. Another suitable method for determining the saturation concentration is the so-called time delay method. In a more preferred embodiment of the invention, wherein the progestogenic steroidal compound is etonogestrel, the estrogenic compound is ethinylestradiol and the core material is poly-EVA, a "low supersaturation degree" is obtained by using an amount of etonogestrel in said poly-EVA core material from about 0.3 to about 1% by weight, the amount of ethinylestradiol then being from about 0.05 to about 0.3% by weight. With such an initial low degree of supersaturation, the etonogestrel containing the vaginal ring is surprisingly stable. The poly-EVA core can 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 ethinylestradiol. At these preferred steroid concentrations in the core material, the skin specified above allows the combined release of etonogestrel and ethinylestradiol at the appropriate physiological rate for a prolonged period of time, by means of which the drug delivery device - the ring Vaginal - shows excellent stability (no crystallization on the outer surface of the ring) over storage for 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 coextrusion of the medicated core and the non-medicated outer layer. The fibers thus obtained are cut into pieces of the required length and each piece is assembled to the ring-shaped device in any suitable manner. The rings are then packaged, for example in a suitable sack, optionally after having been sterilized or disinfected. The invention is further illustrated by the following examples, describing the manufacture of a vaginal ring according to the invention.

Fig. 1 shows a flat cross-sectional view of a first embodiment of a vaginal ring according to the present invention; Fig. 2 shows a planar cross-sectional view of a second embodiment of a vaginal ring according to the present invention; Fig. 3 shows a flat cross-sectional view of a third non-circular embodiment of a vaginal ring according to the present invention; and Fig. 4 shows a partial planar cross-sectional view of a fourth embodiment of a vaginal ring according to the present invention provided with corrugations.

Fig. 1 shows a vaginal ring with a body of nucleus (1) and a skin (2) which covers the body of the core (1) and controls the rate of release. As shown in Fig- 3, the ring is not necessarily a perfectly circular object, while the section of a vaginal ring according to the invention shown in Fig. 4 demonstrates that the ring may involve a design that elongates the surface . Fig. 2 illustrates that another body (3) can be incorporated as part of the ring.

Example 1 57 parts of etonogestrel, 12 parts of ethininestradiol (EE), 5 parts of magnesium stearate and 9926 parts of Evatane® 28-25 are mixed. This mixture is co-constructed with Evatane® 1020 VN3 to form a ca-axial fiber with an outer diameter of 4.0 mm and a skin thickness of 80 μm. The fiber is cut into pieces of 157 mm. Subsequently, the ends of the pieces of the fiber are joined using an adhesive (Fig. 1). The obtained ring is stored at 25 ° C and relative humidity of the environment (RH) for 6 months, after which the amount of steroids on the outer surface is determined by rinsing with methanol and the subsequent HPLC analysis. The amount of steroid on the surface of the ring is less than 10 μg of etonogestrel and less than 2 μg of ethinylestradiol, which is considered very small and comparable to the situation at time zero. This example shows that even with etonogestrel at a relatively low degree of supersaturation, a stable dosage form can be obtained.

Example 2 75 parts of etonogestrel, 16 parts of ethinylestradiol, 5 parts of magnesium stearate and 9904 parts of Evatane® 28-25 are mixed. This mixture is co-extruded with Evatane® 1020 VN3 to form a coaxial fiber with an outer diameter of 3.5 mm and a skin thickness of 90 μm. The fiber is cut into pieces of 147 mm. Subsequently, the two ends of each piece of fiber are joined using an adhesive. The obtained ring is stored at 25 ° C / RH environment for 6 months after which the amount of steroids on the outer surface is determined by rinsing with methanol and the subsequent HPLC analysis. The amount of steroid on the surface of the ring is less than 10 μg of etonogestrel and less than 2 μg of ethinylestradiol, which is considered very small and comparable to the situation at time zero.

Example 3 According to the procedure of Example 1, the ring-shaped devices with the characteristics listed in Table 1 were prepared. It should be noted that the saturation concentration of etonogestrel was determined at 25 ° C, using a dissolution test, and is 0.35% In the dissolution test, the solubility of the active substances etonogestril and ethinylestradiol in the core polymer (Evatane® 28-25) is determined by saturating flat films (thickness 200 μm) with saturated aqueous solutions of said substances active, using an incubator (shaking). After 4 to 6 weeks, the films were analyzed for steroid content. The two time periods were chosen in order to ensure that the maximum saturation is reached (which can be concluded from the fact that no significant difference between weeks 4 and 6 is found). Values at 25 ° C are approximately 0.35% for etonogestrel and approximately 1.30 for ethinylestradiol.

Table 1: Characteristics of vaginal rings Example 4 57 parts of etonogestrel, 12 parts of ethinylestradiol, 5 parts of magnesium stearate and 9926 parts of Evatane® 28-25 are mixed. This mixture is co-extruded with Evatane® 1020 VN3 to form a coaxial fiber with an outer diameter of 4.0 mm and a skin thickness of 90 μm. The fiber is cut into pieces of 147 mm. The piece of fiber is placed in a mold at a temperature of 40 ° C, the ends of a piece of fiber are joined by injecting high density polyethylene (HPE) between the ends of the fiber and subsequently cooled. Fig. 2 shows the HDPE body (3) joining the ends of the core body (1) covered with the skin (2).

Example 5 69 parts of etonogestrel, 16 parts of ethinylestradiol, 5 parts of magnesium stearate and 9910 parts of Evatane® 28-25 are mixed. This mixture is co-extruded with Evatane® 1020 VN3 to form a coaxial fiber with an outer diameter of 4.0 mm and a skin thickness of 1 10 μm. The fiber is cut into pieces of 157 mm. Subsequently, the ends of the pieces of the fiber are joined by welding.

Reference example 500 parts of etonogestrel, 500 parts of ethinylestradiol and 9000 parts of Evatane® 28-25 are mixed. This mixture is co-extruded with Evatane® 1080 VN5 to form co-axial fibers with an outer diameter of 2.75 mm and different skin thicknesses. The fibers are stored at room temperature after which the amount of steroids from the outer surface is determined by rinsing with methanol and the subsequent HPLC analysis. The amounts of steroids on the surface of the fiber are given in Table 2. This example clearly shows that a non-stable, high-supersaturation dosage form can be obtained.

Table 2: Quantity of steroids on the surface of the fibers to be used in the manufacture of vaginal rings

Claims (10)

1. A medicine delivery system comprising at least one compartment, which comprises a thermoplastic polymer core and a skin of thermoplastic polymer covering the core, said core comprising a mixture of progestogenic steroidal compound and an estrogenic steroidal compound in a proportion by weight that allows a direct release of said polymer from 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 relatively low degree of supersaturation, said estrogenic compound being dissolved in said polymer core material at a concentration lower than that of said progestogenic compound, and said thermoplastic skin being permeable for said progestogenic and estrogenic compounds.

2. A medicine delivery system according to claim 1, characterized in that the delivery system has a substantially ring-shaped form and is intended for vaginal administration of the mixture of progestogenic and estrogenic compounds.

3. A medicine delivery system according to claim 1 or 2, characterized in that at least the skin, but preferably also the core material, comprises ethylene-vinyl acetate copolymer as the thermoplastic polymer.

4. A medicine delivery system according to any of the preceding claims characterized in that the compound is dissolved in the thermoplastic core material in a weight amount of at least about one but not more than 6 times the amount necessary to maintain its concentration of saturation (at 25 ° C).

5. A medicine delivery system according to claim 4, characterized in that the dissolved amount is 2 to 5 times the amount needed.

6. A delivery system of medicament in a substantially ring form and suitable for vaginal administration comprising at least one compartment, which comprises a core of thermoplastic polymer and a skin of thermoplastic polymer covering said core, said core comprising a mixture of a progestogenic steroidal compound and an estrogenic steroidal compound in a weight proportion of 10 parts of the progestogenic compound to 1.5-5 parts of the estrogenic compound, said progestogenic compound being initially dissolved in said polymer core in a relatively low degree of supersaturation, and said polymer skin being permeable for both the progestogenic compound and the estrogenic compound. A medicine delivery system according to claim 6, characterized in that the thermoplastic polymer used for the core material is an ethylene-vinyl acetate copolymer, the thermoplastic polymer used for the skin material is a copolymer of ethylene-vinyl acetate, said core comprising a mixture of the progestogenic compound etonogestrel and the estrogenic compound ethinylestradiol in a ratio of 10 parts to 2-4 parts, said core comprising from 0.3 to 1% by weight of etonogestrel and from about 0.05 to approximately 0.3% by weight of ethinylestradiol. 8. A medicine delivery system according to claim 7, characterized in that the ratio of etonogestrel to ethinylestradiol is 10 parts to 2-3 parts, the percentage by weight of etonogestrel being between 0.5% and 1.0%. 9. A medicine delivery system according to claim 7 or 8, characterized in that the skin is an ethylene-vinyl acetate copolymer skin having a thickness ranging from 40 to 300 μm and a content of vinyl acetate. which varies from 5 to 15%. 10. A medicine delivery system according to claim 9, characterized in that the thickness of the skin is 80 to 150 μm and the content of vinyl acetate is 9-10%. 1 1. A medicine delivery system according to any of claims 6 to 10, characterized in that the core material is composed of an ethylene vinyl acetate copolymer with a content of 25 to 35% vinyl acetate. 12. A medication delivery system according to any of claims 6-1 1, characterized in that the core material comprises 0.55 to 0.8% by weight of etonogestrel and 0.12 to 0.18% by weight of ethinylestradiol.