MXPA98002349A - Intravaginal rings with insertable drug-containing core - Google Patents

Abstract

Disclosed is a vaginal ring containing a ring body made of a first polymeric material having at least one hollow internal channel defining an opening to the exterior of said body and which channel is adapted to receive a drug-containing core through said opening, and a core containing at least one intravaginally administerable drug dispersed in a second polymeric material disposed in the channel. The core is positioned in the vaginal ring body suitably prior to use in order to substantially avoid initial bursts of drug into the tissues of the subject and resultant side effects such as nausea and vomiting. Representative drugs include contraceptive agents and other steroidal substances for use in hormone replacement therapy. Also disclosed are methods for preparing the vaginal rings, kits for assembling the vaginal rings, and methods of using the vaginal rings to achieve intravaginal delivery of drugs to a female.

Description

INTRAVAGINAL RINGS WITH AN INSERTABLE NUCLEUS THAT CONTAINS DRUG TECHNICAL FIELD The present invention is directed to intravaginal drug delivery devices and methods for the intravaginal administration of drugs, and more particularly, to the intravaginal administration of contraceptive agents and agents for hormone replacement therapy.

BACKGROUND OF THE INVENTION Vaginal rings are toroidal shaped devices designed to deliver a relatively constant dose of drug to the vagina, usually over a period of weeks to months. Typically, these are made of a silicone elastomer and contain a drug released through diffusion through the elastomer. The most common commercial applications have been to provide low doses of steroids for post-menopausal vaginal conditions. They have also been under development for use in contraception and hormone replacement therapy. Vaginal rings have also been used to administer spermicides, as well as a variety of locally or systemically active medications. Vaginal rings have provided several advantages, since their use is controlled by women; they allow a better regulated dose of drugs in the user's attention; and they prevent the destruction (through the intestine and through the first passage through the liver) of an appreciable portion of the daily dose of some steroids compared to their orally administered counterparts. The use of a vaginal ring to deliver drugs requires a ring design that regulates the release rate in order to provide the user with the appropriate daily dose. Among the important factors governing the release are the solubility of the drug in the ring elastomer, the surface area of the drug reservoir, the distance of the drug that must diffuse towards the ring body to reach its surface and the molecular weight of the drug If very high release rates are desired, these can be obtained through a drug loading on the ring surface as is characteristic of the homogeneous matrix ring design. However, this design has rapidly declining release rates, since the distance that the drug must travel to reach the surface of the ring increases as the drug load near the surface is exhausted. If moderately high release rates are needed to provide the appropriate dose, a design that modulates the rate of release by imposing a layer of drug-free elastomer between the drug reservoir and the outside of the ring is appropriate. This can be achieved by coating a homogeneous ring, or to preserve the drug, incorporating a drug-free core, and a shell design can be used. If an even lower release rate is desired, the drug can be confined to a small diameter at the center of the ring ("core ring"). Finally, the drug loaded nucleus may not enclose the ring, but rather may be of short length. Numerous types of vaginal rings have been described in the patent and non-patent literature. See, for example, the patents of E. U.A. Nos. 4,012,496 and 4, 155,991 (both by Schopflin and others), 4,292, 965 (Nash), 3,545,439 (Duncan), 3, 920,805 (Roseman), 3, 991, 760 and 3,995,634 (both by Drobish and others), 3,995,633 (Gougen), 4,250.61 1 and 4,286,587 (both of Wong), 4,596,576 (of Nijs); WO95 / 00199 (Lehtinen et al.), NL 8500-470-A; and Apter et al., Contraception 42: 285-295 (1990), Burton et al., Contraception 1_7: 221-230 (1978), Burton et al., Contraception 1_9: 507-516 (1979), Jackanicz, Contraception 24,323-339 ( 1981), Sivin et al., Contraception 24: 341-358 (1981), Timmer et al., Contraception 43: 629-642 (1990), and Toivonen, Contraception 20: 51 1 -518 (1979). The vaginal rings have been used experimentally to supply the contraceptive agent, ethinylestradiol. However, an unwanted percentage of women who have to use vaginal rings for this purpose have complained of nausea and vomiting, particularly from the first cycle of use of the rings due to an initial sudden increase in steroid release. The manufacture of the so-called "core" rings presents additional problems. One problem is the physical aspect of placing the nuclei in the ring body through techniques adapted to facilitate their manufacture. Another is that drugs with reactive groups such as ethynyl, amino groups, or sulfhydryl groups can prevent vulcanization of preferred silicone polymers. One method for introducing short stretches of drug loaded nuclei is to mold one half of the ring with a central groove, place the core in the groove, change the molds and inject the second half of the ring. This technique, while reliable, requires two molding steps to fabricate the ring body. It also limits the choice of elastomer when it relates to reactive drugs such as ethinylestradiol. Therefore, the need remains for a vaginal ring that does not cause nausea and vomiting, and other problems associated with some devices, as long as it continues to provide the other benefits that vaginal rings have offered.

COMPENDIUM OF THE INVENTION An aspect of the present invention is directed to a vaginal ring, which contains a vaginal ring body of a first polymeric material having at least one hollow internal channel defining an opening to the exterior of the body, said channel being adapted for received a core containing a drug intravaginally administrable through the opening, and a core placed in the channel, wherein the core contains a pharmaceutically effective amount of at least one intravaginally administrable drug dispersed in the second polymeric material. The first and second polymeric materials may be the same or different. In preferred embodiments, the first and / or the second polymeric material is a silicone elastomer such as polydimethylsiloxane or a copolymer of dimethylsiloxane and methylvinylsiloxane, or a polyurethane. The vaginal ring body may also contain a particulate filler material and / or a pharmaceutically effective amount of a vaginally administrable drug, which may be the same as or different from the drug contained in the core. Preferred drugs include contraceptive agents such as progestational compounds (e.g., norethindrone acetate and NESTORONE ™ (ie, 16-methylene-17a-acetoxy-19-norpregneno-3,20-dione)), and estrogenic substances (e.g. , ethinylestradiol) and other steroidal compounds useful in hormone replacement regimen. In a particularly preferred embodiment, the core contains two drugs, most preferably two contraceptive agents, for example the first being the progestin or norethindrone acetate N ESTORONE ™, and the second feels ethinylestradiol. In another preferred embodiment, the vaginal ring body contains estradiol, and the core contains a progestin such as the progestin NESTORONE ™, and is used in hormone replacement therapy. In still other preferred embodiments, the vaginal ring contains a plurality of (eg, two or three) drug-containing cores, wherein each core may contain the same or a different drug, or more than one drug. In other preferred embodiments, the drug is present in the core in an amount of about 1% to about 65% of the weight of the core. The vaginal ring has a total diameter of about 4 mm to about 10 mm. The core has a cross-sectional diameter of about 1.5 mm to about 5 mm, and a length of about 5 mm to about 40 mm, and is placed in the vaginal ring body so that the transverse diameter of the ring body exceeds the Transverse diameter of the core by an average of 1 mm in all directions. The hollow channel of the vaginal ring may also contain a sealant, such as a medical grade adhesive, silicone, (eg, a polydimethylsiloxane having end groups of methyldiacetoxysilyl) to secure the core in the hollow channel of the ring body and / or to separate the nucleus from the external environment, in order to avoid the passage or diffusion of the drug to the external environment directly from the nucleus. Another aspect of the present invention is directed to a method for intravaginally administering a drug to a woman for a predetermined period, which involves the steps of: (a) providing a vaginal body containing a first polymeric material that it has at least one hollow internal channel defining an opening towards the outside of the body and said channel is adapted to receive an intravaginally administrable drug-containing core, through the opening; (b) providing a core containing a pharmaceutically effective amount of the intravaginally administrable drug dispersed in a second polymeric material, wherein the first and second polymeric materials may be the same or different; (c) place the nucleus in the canal to assemble the vaginal ring; and (d) inserting the vaginal ring into the vagina, so that the drug will be intravaginally delivered to the woman for a predetermined period. In preferred embodiments, the vaginal ring is assembled (e.g., the core is placed in the channel) in about four days before use, most preferably in about 24 hours before use, and particularly preferably substantially immediately before use. , so that after administration, there is no initial (ie, negligible) sudden increase in drug that otherwise tends to cause unwanted side effects, such as nausea or vomiting. In addition, the vaginal ring body can be provided through the molding of the first polymeric material having at least one hollow internal channel in a single pass. In a further aspect of the present invention is directed to a device, which contains a properly configured vaginal ring body comprising a first polymeric material having at least one hollow internal channel defining an opening towards the outside of said body and said The channel is adapted to receive a core containing an intravaginally administrable drug through the opening, and at least one core to be placed in the channel, wherein the core contains a pharmaceutically effective amount of an intravaginally administrable drug dispersed in a second. polymeric material, wherein the first and second polymeric materials may be the same or different. In preferred embodiments, the kit also contains a sealant to seal the hollow channel after placement of the drug-containing core therein, and / or applicators to place the core in the channel and apply the sealant to the channel. The sealant is preferably a medical grade adhesive, such as a polydimethylsiloxane, having methyldiacetoxysilyl end groups. The applicator is preferably a syringe. The vaginal rings and methods of the present invention offer several additional advantages over the prior art drug delivery mechanisms. These provide a substantially constant release of the drug as compared to oral or injectable modes of drug administration, and maintain the potency of drugs that are susceptible to destruction as they pass from the intestine through the liver immediately after absorption. to part of the intestines. A further aspect of the present invention is directed to a method for the preparation of a vaginal ring through a relatively simple procedure, in which the first polymeric material is molded in a single step to form the vaginal ring body with at least one hollow internal channel, followed by vulcanization of the vaginal ring body and insertion of the drug-containing core into the hollow internal channel, thus assembling the vaginal ring. In a preferred embodiment, the first polymeric material is an elastomeric material, which is molded with at least one removable rod or other suitable device to produce an annular ring body, contiguous with a corresponding predetermined number of channels. In preferred embodiments, the molding step is conducted in the presence of a catalyst. The core is prepared by mixing the drug with an elastomeric material, followed by molding and then vulcanization. In another preferred embodiment, the core can be vulcanized in situ? in the ring body, depending on whether the drug is one in which the initial sudden increase can be avoided. For example, in cases where the initial drug surges are avoided, the ring body and the core are vulcanized separately, and the nuclei are properly introduced into the channels before use. In modalities where a sudden increase in initial drug is not a problem, the core can be vulcanized in situ in the ring body subsequent to its introduction into the channel. In these embodiments, the core containing the drug can be effectively introduced by injecting a mixture of the drug, the second polymeric material and a suitable catalyst into the hollow internal channel of the vaginal ring body, so that the drug-containing core is formed in if you. In preferred embodiments, the diameter of the core relative to the channel may vary slightly; it can be substantially equal to or slightly larger or smaller than the diameter of the channel. In preferred embodiments, the diameter of the core is substantially equal to or slightly greater than that of the channel, so that after the insertion or formation of the core in the channel, contact of the surfaces is maintained between the outer longitudinal surfaces of the core. and the surface of the channel. The method consumes less time and is more easily mechanized than current methods. Therefore, the core can be inserted into the ring body during the manufacturing process, or packaged separately and properly inserted before use, according to other aspects of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1A is a cutaway view of a "breastplate" vaginal ring of the prior art. Figure 1 B is a cross-sectional view of a vaginal ring of the previous "cuirass" design technique.

Figure 2A is a cross-sectional view of a "homogeneous" vaginal ring of the prior art. Figure 2B is a cross-sectional view of a vaginal "core" ring of the prior art. Figure 3 is a cross-sectional view of a modified "core" ring of the prior art. Figure 4A is a schematic view of a vaginal ring body according to the present invention. Figure 4B is a schematic view of a drug-containing core according to the present invention. Fig. 4C is a schematic view of an assembled vaginal ring according to the present invention. Figure 5 is a schematic view of another assembled ring according to the present invention. Figure 6 illustrates graphically the in vitro release of ethinylestradiol from vaginal rings illustrated in Figure 3.

Figure 7 illustrates graphically the in vitro release of ethylestradiol from vaginal rings of the present invention. Figure 8 graphically illustrates the progestin release N ESTORO N E ™ from vaginal rings of the present invention.

Figures 9 and 1 0 graphically illustrate the release of ethylestradiol and N ESTORON E ™, respectively, from the different vaginal rings of the present invention, which are assembled 1 7 hours before the in vitro release measurement. Figure 1 1 graphically illustrates the effect of storage time on the amount of initial release of ethinylestradiol from the vaginal rings of the present invention. Figures 12 and 13 graphically illustrate the release of ethinylestradiol and N ESTORONE ™ from the same core, and ethinylestradiol only, respectively, from the vaginal rings of the present invention assembled 6 days before initiating release rate measurements. Figures 14 and 15 graphically illustrate the release of ethinylestradiol and N ESTORONE ™ from the same core, and from N ESTORONE ™ only, respectively, of the vaginal rings of the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION The representative prior art vaginal rings are illustrated in Figures 1 A, 1 B, 2A, 2B, and 3. The armor ring 10, illustrated in Figures 1 A and 1 B, contains an inert core 12 surrounded by a drug-containing layer (e.g., steroid) 14, which in turn is surrounded by a drug release control layer 16. In this manner, the steroid loading is in an area below the ring surface, but it does not extend towards the center of the ring. The shell rings were developed to provide a lower dose than that which could have been initially supplied by a homogeneous ring 20, illustrated in Figure 2A. In the homogeneous ring, the drug is substantially and uniformly dispersed throughout the volume of the vaginal ring. If even lower doses are desired, the drug or steroid load can be delivered through a so-called core ring, as illustrated in Figure 2B. The drug loading is contained entirely in the core 24 of the ring 26. In FIG. 3, a modification of the core ring is illustrated. The vaginal core ring 30, which has a total diameter of 58 mm, and a cross-sectional diameter of 7.6 mm, contains a first, non-extensive core 32 containing I progestational compound, norethindderone acetate, and a second non-extensive core 34, which contains the estrogenic compound, ethinylestradiol. Each of the cores 32 and 34 has a cross-sectional diameter of 2 mm. Applicants have unexpectedly found that the vomiting and nausea that have typically been found in some women shortly after beginning the use of a vaginal ring with a core containing ethylestradiol, is due to the initial sudden increase of drug from the ring caused by the accumulation of drug in the ring body between the core and the outer surface of the ring and during post-fabrication storage. These experimental results are described in detail in Example 1. The vaginal rings of the present invention, on the other hand, eliminate or substantially mitigate unwanted side effects, such as nausea and vomiting, usually associated with the use of estrogen-containing vaginal drug delivery systems. Figures 4A, 4B, and 4C illustrate a preferred embodiment of the present invention. Returning to Figure 4A, the vaginal ring body 40 is configured in the form of a continuous annular ring, and is composed of a first polymeric material containing at least one hollow internal channel 42, which opens or is open to the outside environment, and which is adapted to receive at least one drug-containing core 44 (Figure 4B) through the opening. As illustrated in Figure 4A, the hollow channel is in communication with the outside of the ring body through an opening in the ring body. By the term "ring" is meant any curved or continuous toroidal shape that does not compromise ease of administration (insertion), comfort, aesthetic appearance, or efficacy. By the term "internal", it is meant that there is no portion of the core that is exposed to or in contact with the outer surface of the ring body once the vaginal ring is fully assembled (and the opening is sealed), so that when administered, the drug will diffuse from the nucleus directly into the tissue of the subject. In preferred embodiments, the core is inserted into the channel suitably before use (i.e., administration or insertion of the vaginal ring through the patient). The phrase "suitably before use" means that the drug-containing core is placed in the hollow channel at a time so that the accumulation of the drug in the ring body 40 (i.e., in the ring body between the core and the external surface) and the resulting initial sudden increase of the drug after subdermal administration are insignificant (ie, side effects such as nausea and vomiting that occur with some steroids are minimized). In preferred embodiments, the core is placed in the channel no more than about 4 days before use, preferably about 24 hours before use, and most preferably substantially and immediately before use. In some unusual situations, however, the insertion of the nucleus can be conducted more than a week before administration of the drug ring of the present invention. For example, fully assembled vaginal rings at least 10 days before use, in which they are stored at a temperature substantially below room temperature, for example, around 5 ° C, will not cause an initial sudden increase or effects. indicated laterals. The vaginal ring may also contain a pharmaceutically effective amount of at least one vaginally administrable drug, preferably uniformly dispersed in the first polymeric material. The core 44, illustrated in Figure 4B, contains a pharmaceutically effective amount of a dispersed intravaginally administrable drug, preferably in the form of a substantially uniform dispersion, in a second polymeric material. The first and second polymeric materials may be the same or different. Figure 4C illustrates an assembled vaginal ring 48, wherein the core 44 is disposed or placed in a hollow channel 42, and secured in the channel through a sealant, which in a preferred embodiment is a medical grade adhesive silicone 49 The first and second polymeric materials suitable for use in the present invention are compatible with each other and the drug (e.g., the polymer can not inactivate the drug); they are non-toxic and non-absorbable in the subject; are capable of being properly configured for intravaginal administration; and allow the controlled diffusion of the drug from the nucleus, through the ring body and into the tissues of the subject. Examples include elastomers such as polysiloxanes, polyurethanes, ethylene / vinyl acetate copolymers, and copolymers of dimethylsiloxanes and methylvinyls. loxanes. Preferred polymeric materials are silicone elastomer, particularly polydimethylsiloxanes and derivatives thereof (eg, fluoro or ph containing groups). The structural integrity of the ring body can be improved through the addition of a particulate material such as smoked silica or diatomaceous earth. The sealant closes the channel after the placement of the core and can also be used to form a firm connection between the ring body and the core, and serves as a lubricant during core insertions. The diffusion of the drug through the axial ends of the core is also minimized. Preferred sealants include medical grade adhesives such as polydimethylsiloxanes and particularly those having methyldiacetoxysilyl end groups, which are vulcanized after exposure to moist air. The intravaginally administered drug contained in the nucleus and optionally the vaginal ring includes any pharmacologically active physiological substance which due to its potency and solubility in the ring elastomer, can be released in suitable doses from the ring bodies with central drug bearing nuclei, particularly cores of at least a cumulative length of 60 mm. Among the drugs that meet these criteria, those used chronically and those with a low acceptable dose scale are particularly suitable. Examples include contraceptive steroids, and certain steroids for hormone replacement therapy. Representative steroids include progesterone, N ESTORON E ™ (i.e., 16-methyl-17a-acetoxy-19-norpregnen-3,20-dione), N ESTORON E ™, norethindrone acetate, 3-ketodesogestrel, desogestrel, linestrenol, norgestrienone, nomegestrol acetate, medroxprogesterone acetate, gestodene, ethinodiol diacetate, norethindrone, ethinyl estradiol, mestranol, estradiol benzoate, estradiol cypionate, estrone and estradiol valerate. The term "pharmaceutically effective" means an amount that is sufficient to effect the desired physiological or pharmacological change in the subject. This amount will vary depending on such factors as the potency of the particular drug, the desired pharmacological physiological effect, and the length of time of the intended treatment. Those skilled in the art of pharmacists will be able to determine said amount for any given drug with normal procedures. See, for example, Chien et al., J. Pharm. Sci. 63, 365 (1974), and patent of E. U.A. No. 3, 710,795. In a preferred embodiment, wherein the drug is a contraceptive agent, the "pharmaceutically effective" amount is a sufficient amount that results in contraception for a predetermined period, which is generally from about 3 months to about 1 year. In general, this amount is on the scale of about 5.0 μg to about 200 μg / day. The amount of drug in the core will generally be on the scale of about 2-65% by weight of the core, depending on the daily dose and the duration of the desired treatment. Larger amounts of drug can advantageously be obtained by omitting the particulate filler materials in the polymeric material of the core. In another preferred embodiment, the vaginal ring is used in hormone replacement therapy and the vaginal ring body has estradiol or estrone, and the core contains a progestin such as N ESTORON E ™. The ring body may contain a plurality of drug-containing cores. Figure 5 illustrates another preferred embodiment of the present invention, wherein the intravaginal ring 50 contains the ring body 52 having cores 54, 56 and 58 disposed in hollow channels 53, 55 and 57, respectively, which are sealed with a medical grade silicone adhesive 59. The drug contained in each of the cores 54, 56 and 58 may be the same or different. In addition, one or two of the nuclei may contain a drug, an initial sudden increase of which may not cause unwanted side effects in a patient, so that the nuclei containing said drugs, may be inserted (such as by injection). in the ring body after molding the ring body and before packing and storing. The vaginal ring bodies of the present invention are prepared using a single molding step. In a preferred embodiment, the first polymeric material is cast into a mold having removable bar-type inserts, extending therein, which when removed form channels where the drug-containing core will be inserted. The ring body thus molded is then vulcanized according to normal techniques. The vulcanization can be conducted at room temperature or elevated temperatures, and, if necessary, in the presence of a suitable catalyst such as heavy metals (eg platinum), peroxides (2,4-dichlorobenzoyl peroxide), stannous octoate and dibutyl tin . The core containing the drug is also prepared with standard techniques such as extrusion and injection molding. In a preferred embodiment, the drug is mixed with the second polymeric material, and the mixture is injected into a suitably shaped mold, and then vulcanized. The vulcanization catalyst selects in order to be effective in the presence of the drug and does not interact chemically with the drug. The vulcanization of the ring bodies and the core can optionally be followed by a post-cure step. In another preferred modality, the vulcanization of the cores is carried out after the introduction of the drug into the hollow channel of the ring body. This modality is used when an initial sudden increase in the drug does not cause unwanted side effects. In those cases, when an initial sudden increase of a drug will not cause unacceptable side effects, the same hollow channel of the ring body can serve as the mold, it "receives" the core containing the drug allowing the injection of a drug mixture. , the second polymeric material and a catalyst that then forms a nucleus in situ. The core is then vulcanized. The methods described for preparing the vaginal rings of the present invention offer several advantages in addition to avoiding the effects of sudden increase. They allow the production of the ring body in a single step. The placement of the nucleus is facilitated since it is simply pushed in a longitudinal channel, or in alternative modalities, it is left to form in situ. In addition, the method is less time consuming and more easily mechanized. Of course, these advantages are realized even when the cores are inserted immediately after the molding of the ring body, before packing and / or storage. In addition, in those embodiments wherein the curing of the drug body is conducted in the absence of the drug, interference with vulcanization due to the presence of the drug, which has some precluded drug / polymer combinations in the prior art, is avoided. In addition, the absence of the drug during manufacture of the ring body allows the use of higher temperatures and shorter molding times. In a preferred embodiment, the ring body and the core containing the drug are suitably packaged together so that the device can be assembled by a physician, pharmacist, or even the subject, suitably before use. In preferred embodiments, the vaginal ring is assembled no later than about 4 days prior to administration, in a more preferred embodiment, in about 24 hours before use, and in a particularly preferred embodiment, substantially and immediately before use. The kits preferably contain a sealant to secure the core containing the drug in the hollow channel of the ring body. Preferred sealants are medical grade adhesives as described above. The equipment may also contain an applicator, such as a syringe, for supplying or inserting the sealant into the hollow channel. In a preferred embodiment of the assembly, of the device, a small opening is made in the support at the closed end of the hollow channel, to allow air to escape when the core is introduced. The channel is then approximately half filled with the sealant, after insertion of the core, which ensures firm, uniform contact between the core containing the drug and the inner surface of the hollow channel. More sealant is added and the excess, which is also compressed from the open end of the channel, is removed while sealing the open end of the flooded channel with the other surface of the support. In a most preferred embodiment, an even simpler procedure is used to assemble the vaginal ring. The parameters that define the optimal difference between the core and channel diameters are: (1) the anticipation of the shrinkage amount of the core diameter that will occur as the drug is lost from the core during use; (2) the ease of insertion of the nucleus; (3) the prevention of distortion of the vaginal ring at the point of compromising the aesthetic appearance; and (4) the compromise of drug release due to the loss of contact between the nucleus and the body of the child. Accordingly, in this embodiment, the diameter of the core is substantially equal to, or even slightly greater than, that of the channel, so that the contact between the core and the ring body is maintained due to the elasticity of the ring body. In contrast to the previous mode, it is not necessary to apply adhesive to the channel before inserting the core. Rather, a suitable medical grade adhesive is applied after insertion of the core to seal the channel. The nucleus can be inserted into the canal with a suitable applicator, such as a thin-walled trocar. The vagi rings of the present invention have a total diameter of about 48 to about 60 mm, and a cross-sectional diameter of about 4 to about 10 mm, with the dimensions depending in part on the dimensions of the core. Preferably, the relevant dimensions of the ring and the core are established such that after assembly of the device, the transverse diameter of the support exceeds the transverse diameter of the core by an average of at least 1 mm in all directions. The dimensions of the nucleus are determined based on factors such as the amount of drug that will be delivered to the subject, the time during which it will be delivered, the diffusion characteristics of the drug, and the relative ease with which the channels supplementary dimensions can be formed on the support. In general, the core has a length of about 5 mm to about 40 mm. For example, to adapt a core having a length of about 26 mm, it is preferred that the ring body have a diameter of about 60 mm, and a cross-sectional diameter of about 9 mm. The corresponding hollow channel may be slightly curved. The core containing the drug has a diameter of about 1.5 to about 5 mm, and will vary in relation to the diameter of the hollow channel of the ring body depending on the method in which the vaginal ring is to be assembled. The inventors of the present have found that core diameters of about 3 mm are particularly well suited to deliver a drug for about 1 year, and thus offer the additional advantage of reducing the cost per cycle to use the vaginal ring. In the above embodiment, where a sealant is introduced into the hollow channel both before and after the insertion of the core, the core diameter is typically smaller than that of the channel, for example, a channel diameter of 3.18 mm will be easily adapted to a 3mm core. In the most preferred embodiment, the core diameter slightly exceeds that of the channel, for example, a 2.8 mm channel will be adapted to a 3.0 mm core. In general, the diameter of the core can vary about 10% of the diameter of the channel. The invention will now be further explained by reference to the following detailed examples. These examples are merely illustrative, and do not limit the applicant's invention in any way. Unless otherwise indicated, all percentages are by weight, and the storage temperature of the vaginal rings after assembly and before the measurement of release rates was at room temperature.

EXAMPLE 1 Illustration of the sudden increase effect and the effects of storage conditions on it. The vaginal rings illustrated in Figure 3, but containing only a single core were prepared using polydimethylsiloxane vulcanizable at room temperature. Stannous octoate (stannous 2-ethylexanoate) was used as a catalyst to effect the cure. The dimensions of the ring body were a total diameter of 56 mm and a cross-sectional diameter of 9 mm. The core was made from the same polymer mixed with ethylestradiol to give a concentration of 7% steroid in the core. The dimensions of the core were 2.2 by 20 mm. The ring body was made in 2 stages, the core being centered in the first half of the ring, which was then overlapped with polydimethylsiloxane to complete the ring body. In vitro measurements were made of the rate of release after storage as indicated in Table 1, and graphically illustrated in Figure 6. The measurements were made on four rings in a combination of time and temperature.

TABLE 1 In vitro release of ethinylestradiol in storage periods after ring manufacture μg EE / day + SD (N = 4) Storage Time Temperature Day 1 2 3 1 day Environment 26 + 2 2 weeks 5o 45 + 5 22 + 6 20 + 7 2 weeks Environment 60 + 6 23 + 4 17 + 3 2 weeks 37 ° 1 16 + 7 24 6 20 + 3 2 months 5o 56 + 3 33 + 2 28 + 4 2 months Environment 74 + 3 24 + 2 32 + 5 2 months 37 ° 136 + 19 33 + 4 19 + 2 6 months 5 ° 50 + 1 0 30 + 6 24 + 6 6 months Environment 126 + 6 39 + 6 27 + 6 6 months 37 ° 135 + 5 35 + 5 20 + 1 The release results indicate that the magnitude of the first sudden increase of the first day increases with the storage time, with even greater and faster increases exhibited at higher storage temperatures. As illustrated in Figure 6, the sudden increase is greatly confined to the first day after insertion of the vaginal ring.

EXAMPLE 2 Illustration of the use of the intravaginal drug delivery devices of the present invention to avoid a sudden increase in steroid release.

Vaginal rings of the present invention were prepared with two channels. The ring body had a total diameter of 56 mm and a cross-sectional diameter of 8.4 mm. The elastomer used to mold the rings was a platinum catalyzed dimethylsiloxane / methylvinylsiloxane copolymer manufactured by Applied Silicone Corp. of Ventura, CA. The elastomer was identified as LSR 25-10: 1. This was packed in two parts, which were mixed together in the ratio of 10: 1 to effect vulcanization. The mixture was injected into a mold with a removable steel bar to produce channels for core insertion. The cure was conducted at 105 ° C for 30 minutes. Nuclei were prepared by mixing the steroid with a vulcanizable polydimethylsiloxane at room temperature (MED 6382, obtained from NuSil Silicone Technology of Carpintería, CA.). Two cores were prepared and each was inserted into each ring. Each one was 3 x 15 mm. One contained 50% of N ESTORON E ™ and one contained 40% of N ESTORONE ™ and 12% ethinylestradiol. The channels in the ring body were partially filled with medical adhesive, polydimethylsiloxane, and the nuclei were inserted 17 hours before starting the in vitro release measurements. The release patterns are shown in Figures 7 and 8. Only an insignificant sudden increase in release of ethinylestradiol, and no sudden increase in release of N ESTORON E ™ are shown.

EXAMPLE 3 Illustrating the use of the present invention to avoid a sudden increase in release of the steroid. Vaginal rings of the present invention were prepared using a platinum-catalyzed dimethylsiloxane / methylvinylsiloxane copolymer manufactured by Applied Silicone Corp. of Ventura CA, identified as LSR 25-10: 1. The ring bodies had a total diameter of 56 mm and a transverse diameter of 8.4 mm. The two parts of the elastomer composition were mixed together in a ratio of 10: 1, and injected into a mold with a removable steel bar to produce a channel for core insertion. The cure was carried out by heating 30 minutes at 105 ° C. The cores were made by mixing the ethinylestradion N ESTORONE ™ with polydimethylsiloxane catalyzed with stannous octoate (R-2602 manufactured by NuSil Silicone Technology of Carpintería, CA). The nuclei contained 12% ethinylestradiol and 40% N ESTORONE ™. The cores had a diameter of 3 mm and a length of 15 mm or 20 mm. The channels in the rings were partially filled with medical adhesive, polydimethylsiloxane, and the cores were inserted 17 hours before the start of the in vitro measurements. The release patterns are illustrated in Figures 9 and 10. The data show that there was no initial sudden increase in ethinylestradiol or NESTORON E ™, when the core placement was made 17 hours before the measurement of the rate of release. The results also illustrate the example of the core length on the rate of release.

EXAMPLE 4 The ring bodies were of the same dimension, composition and method of manufacture as in Example 3. The cores had a length of 20 mm, a diameter of 3 mm, and were made by mixing steroid with a polydimethylsiloxane catalyzed with stannous octoate (MED. -6382, manufactured by NuSil Silicone Technology of Carpintería, CA). The nuclei in the rings, designated 818 and 848, contained 12% ethinylestradiol. Those in the rings designated 846, 847, 816 and 817 contained 12% of ethinylestradiol and 40% of NESTORONE ™. The nuclei were placed either 3 hours or 24 hours before the in vitro release measurements. One ring from each group (818 and 846) was stored for two months at room temperature after the initial 10 days of in vitro release before re-measuring the initial release rate. The results are shown graphically in Figure 1 1. These illustrate the release pattern of ethinylestradiol after short periods between the insertion of the nuclei and the measurement of the release and the formation of a sudden potential increase of release in two months of storage at room temperature.

EXAMPLE 5 Ring bodies with a cross-sectional diameter of 8.4 mm and a total diameter of 56 mm were made with MED-6382, polydimethylsiloxane catalyzed with stannous octoate. The ring bodies were formed in a mold containing removable bars to establish the channels for the insertion of the core. The nuclei had dimensions of 3 x 20 mm. The nuclei in rings designated 641 and 642 obtained both ethinylestradiol and NESTORONE ™; those for the nuclei in rings designated 643 and 644 contained only ethinylestradiol. Steroid concentrations in the nuclei were 12% for ethylestradiol and 40% for NESTORONE ™. The elastomer used in all the cores was NED-6382. The nuclei were inserted into the ring bodies 6 days before initiating release rate measurements. The results are presented in Figures 12 and 13. These show a small sudden increase followed by an almost constant release rate during the 8 months in which the measurements were made. The small normal deviations within the groups that contained both rings with ethinylestradiol nuclei and rings with nuclei containing both steroids, illustrate that the presence of N ESTORON E ™ had no significant effect on the release of ethinylestradiol.

EXAMPLE 6 Ring bodies were made using the LSR 25: 10 elastomer, molding the elastomer around the metal bars. The removal of the metal bars produced two channels, each having a diameter of 2.8 mm. The cores having a diameter of 3.0 mm, and containing either 12% by weight of ethinylestradiol and 40% by weight of N ESTORONE ™ or 50% of NESTORONE ™ alone, were prepared through injection molding, using the silicone elastomer R-2602. After mixing the R-2602 and the steroid, four drops of the stannous octoate catalyst were reacted with every 6 g of the steroid / elastomer mixture, which was then injected into the mold. The nuclei containing both steroids were cut into lengths of 18 mm, and those containing only NESTORON E ™ were cut into 20 mm lengths. One channel of each ring body was loaded with a core of N ESTORON E ™ only, and the second channel was loaded with a core of the combination type, each inserting the nucleus into the channel using a trocar, and then sealing the end Open the canal by applying a medical adhesive. The pattern of in vitro release of the assembled vaginal rings was comparable with the release rate of similar rings, containing nuclei that have diameters slightly smaller than those of the corresponding channels, and where the adhesive was applied to the channels before and after of the insertion of the nuclei. (Data not revealed).

EXAMPLE 7 Ring bodies were made from LSR elastomer 25: 10 Applied Silicone, through injection molding at 120 ° C for 3 minutes. The removal of the two metal bars produced two channels (with a diameter of approximately 3.8 mm) in each ring. A channel from each of the three rings was filled with a paste composed of N usil elastomer R-2602 containing 50% N ESTORONE ™ and 0.5% stannous octoate as the curing agent. The second channel of each of the three rings was filled with a paste composed of the Nusil R-2602 elastomer containing 40% N ESTORON E ™, 14% ethinylestradiol (EE) and 0.5% stannous octoate as the curing agent . The length of the dough in each channel was approximately 1 8 mm. After injecting the paste, the opening of the channel was sealed with silicon adhesive M ED-1 137. Figures 14 and 15 show the in vitro release of the N ESTORON E ™ and EE, respectively, from these rings. . The pattern is one of an initial sudden increase lasting 1 or 2 days, followed by an almost constant release.

INDUSTRIAL APPLICABILITY The vaginal dials of the present invention have numerous industrial uses. These can be used to deliver low doses of steroids for post-menopausal vaginal conditions. They can also be used for contraception and hormone replacement therapy. They can also be used to administer spermicides, as well as a variety of locally or systemically active medications to treat vaginal infections, etc. All publications cited in the specification are indicative of the level of experience of those skilled in the art to which this invention pertains. All of these publications are incorporated herein by reference to the same degree as if each individual publication was specific and individually indicated as incorporated by reference. Although the invention has been described with reference to particular embodiments, it should be understood that these embodiments are merely illustrative of the principles and applications of the present invention. Therefore, it should be understood that numerous modifications may be made to the illustrative embodiments and that other provisions may be observed without departing from the spirit and scope of the present invention, as defined by the appended claims.

Claims (4)

1. CLAIMS 1 .- A vaginal ring, comprising: a vaginal ring body comprising a first polymeric material having at least one hollow internal channel defining an opening towards the outside of the body and said channel is adapted to receive a core containing a intravaginally administrable drug through said opening; in combination with a nucleus placed in said channel, the core containing a pharmaceutically effective amount of at least one intravaginally administrable drug dispersed in a second polymeric material, wherein the first and second polymeric materials may be identical or different.
2. 2. The vaginal ring according to claim 1, wherein the first polymeric material, the second polymeric material, or both the first and the second polymeric material comprise a silicone elastomer.
3. 3. The vaginal ring according to claim 1, wherein the first polymeric material, the second polymeric material, or both the first and the second polymeric material comprise a polyurethane.
4. 4. The vaginal ring according to claim 1, wherein the drug is a hormone replacement steroid. 5 - The vaginal ring according to claim 1, wherein the drug is a contraceptive agent. 6. The vaginal ring according to claim 4, wherein the steroid is an estrogenic compound. 7. The vaginal ring according to claim 5, wherein the contraceptive agent is a progestational compound. 8. The vaginal ring according to claim 1, wherein the core contains a first drug and second drug. 9. The vaginal ring according to claim 8, wherein the first and second drugs are contraceptive agents. 10. The vaginal ring according to claim 9, wherein the first contraceptive agent is an estrogenic compound and the second contraceptive agent is a progestational compound. 1. The vaginal ring according to claim 10, wherein the estrogen compound is ethinylestradiol and the progestational compound is 16-methylene-17a-acetoxy-19-norpregnen-3-20-dione. 12. - The vaginal ring according to claim 10, wherein the estrogenic compound is ethinylestradiol and the progestational compound is norethindrone acetate. 13. The vaginal ring according to claim 1, comprising first and second hollow channels, and first and second nuclei placed in the first and second channels, respectively. 14. The vaginal ring according to claim 1, comprising first, second, and third hollow channels, and first, second and third nuclei placed in the first, second and third channels, respectively. 15. The vaginal ring according to claim 1, wherein the pharmaceutically effective amount of the drug is from about 1% to about 65% of the weight of the core. 16. The vaginal ring according to claim 1, having a total diameter of about 48 mm to about 60 mm. 17. The vaginal ring according to claim 1, having a transverse diameter of about 4 mm to about 10 mm. 18. The vaginal ring according to claim 1, wherein the core has a cross-sectional diameter of about 1.5 mm to about 5 mm. 19. The vaginal ring according to claim 1, wherein the core has a length of about 5 mm to about 40 mm. 20. The vaginal ring according to claim 1, wherein the core is placed in the vaginal ring body, so that the transverse diameter of the vaginal ring body exceeds the transverse diameter of the core by an average of about 1 mm. in all directions. 21. The vaginal ring according to claim 1, wherein said opening of the internal channel is sealed. 22. The vaginal ring according to claim 1, further comprising a sealant. 23. - The vaginal ring according to claim 22, wherein the sealant comprises a medical grade silicone adhesive. 24. The vaginal ring according to claim 23, wherein the adhesive comprises a polydimethylsiloxane having methyldiacetoxysilyl end groups. 25. The vaginal ring according to claim 1, wherein the vaginal ring body further comprises an intravaginally administrable drug. 26. - The vaginal ring according to claim 25, wherein the vaginally administrable drug in said vaginal ring body is estradiol. 27. - The vaginal ring according to claim 25, wherein the vaginally administrable drug in said nucleus is a progestin. 28. The vaginal ring according to claim 27, wherein the progestin is 16-methylene-17a-acetoxy-1-9-norpregnen-3, 20-dione. 29. A vaginal ring body, comprising a polymer material, inert, suitably configured, having at least one hollow internal channel defining an opening towards the outside of the body and the channel is adapted to receive a core containing an intravaginally administrable drug through said opening. 30 - A device comprising: a vaginal ring body comprising a first polymeric material having at least one hollow internal channel defining an opening towards the outside of said body, and the channel is adapted to receive a core containing a drug intravaginally administrable through the opening; and at least one core to be placed in the hollow channel, said core comprising a pharmaceutically effective amount of an intravaginally administrable drug disposed in a second polymeric material, wherein the first and second polymeric materials may be the same or different. 31 - The equipment according to claim 30, further comprising a sealant. 32. A method for administering a drug to a woman for a predetermined period, comprising the steps of: providing a vaginal ring body comprising a first polymeric material, having at least one hollow internal channel defining an opening toward the exterior of the body, said channel being adapted to receive a core containing drug through the opening; providing a core comprising a pharmaceutically effective amount of an intravaginally administrable drug disposed in a second polymeric material, wherein the first and second polymer materials may be identical or different; and place the nucleus in the canal to assemble a vaginal nipple properly before use of the vaginal ring. 33.- A method for preparing a vaginal ring comprising a vaginal ring body comprising a first polymeric material having at least one hollow internal channel defining an opening towards the body exterior, and said channel is adapted to receive a core that contains a drug intravaginally administrable through the opening, and a core placed in the channel, in core containing a pharmaceutically effective amount of at least one drug intravaginally administrable in a second polymeric material, wherein the first and second polymeric materials can be same or different, comprising the steps of: molding the first polymeric material in the shape of the vaginal ring body in a single step; vulcanize the vaginal ring body; and insert the core into the hollow internal channel. 34.- A method for preparing a vaginal ring comprising a vaginal ring body comprising a first polymer material having at least one hollow internal channel defining an opening towards the outside of the body and said channel is adapted to receive a core that contains a drug intravaginally administrable through the opening, and a nucleus placed in the channel, the core containing a pharmaceutically effective amount of at least one intravaginally administrable drug disposed in a second polymeric material, wherein the first and second polymeric materials can be the same or different, comprising the steps of: molding the first polymeric material in a single step to form said vaginal ring body; and providing said drug containing core in the hollow internal channel thereby assembling the vaginal ring. The method according to claim 34, wherein the step of providing the core containing the drug comprises injecting a mixture of said drug, the second polymeric material and a suitable catalyst into the hollow internal channel so that said Core is formed in situ. 36. The method according to claim 35, further comprising the step of vulcanizing the core thus formed.