Title:  Intravaginal rings with insertable drug-containing core

United States Patent:  6,126,958

Inventors:  Saleh; Saleh Ismail (Assuit, EG); Nash; Harold A. (Harrington Park, NJ); Bardin; C. Wayne (New York, NY); Harmon; Troy (Lansdale, PA)

Appl. No.:  316640

Disclosed is a vaginal ring intended for the release of at least one drug over a prolonged time period. The vaginal ring contains 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 an intravaginally administerable drug-containing core 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. The core contains a pharmaceutically effective amount of at least one intravaginally administerable drug dispersed in a second polymeric material. The first and second polymeric materials may be the same or different. 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.

SUMMARY OF THE INVENTION

One 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 said body and which channel is adapted to receive a core containing an intravaginally administerable drug through the opening, and a core positioned in the channel, wherein the core contains a pharmaceutically effective amount of at least one intravaginally administerable 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 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 administerable drug, which may be the same or different from the drug contained in the core. Preferred drugs include contraceptive agents such as progestational compounds (e.g., norethindrone acetate and NESTORONE.TM. (i.e., 16-methylene-17.alpha.-acetoxy-19-norpregnene-3,20-dione)), and estrogenic substances (e.g., ethynylestradiol) and other steroidal compounds useful in hormone replacement regimens. In a more preferred embodiment, the core contains two drugs, more preferably two contraceptive agents, e.g., the first being the NESTORONE.TM. progestin or norethindrone acetate, and the second being ethynylestradiol. In another preferred embodiment, the vaginal ring body contains estradiol, and the core contains a progestin such as the NESTORONE.TM. progestin, and is used in hormone replacement therapy. In yet other preferred embodiments, the vaginal ring contains a plurality (e.g., two or three) of 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 from about 1% to about 65% of the weight of the core. The vaginal ring has an overall diameter of from about 4 mm to about 10 mm. The core has a cross-sectional diameter of from about 1.5 mm to about 5 mm, and a length of from about 5 mm to about 40 mm, and is positioned in the vaginal ring body such that the cross-sectional diameter of the ring body exceeds the cross-sectional 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 silicone medical grade adhesive (e.g., a polymethylsiloxane having methyldiacetoxysilyl end groups) for securing the core in the hollow channel of the ring body and/or separating the core from the exterior environment so as to prevent passage or diffusion of the drug to the exterior environment directly from the core.

Another aspect of the present invention is directed to a method of intravaginally administering a drug to a female over a predetermined time period, which involves the steps of:

(a) providing a vaginal ring body containing 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 intravaginally administerable drug-containing core through the opening;

(b) providing a core containing a pharmaceutically effective amount of the intravaginally administerable drug dispersed in a second polymeric material, wherein the first and second polymeric materials may be the same or different;

(c) positioning the core in the channel to thereby assemble the vaginal ring; and

(d) inserting the vaginal ring into the vagina so that the drug will be intravaginally delivered to the female for the predetermined period of time. In preferred embodiments, the vaginal ring is assembled (e.g., the core is positioned in the channel) within about four days prior to use, more preferably within about 24 hours prior to use, and most preferably substantially immediately prior to use, such that upon administration, there is no (i.e., negligible) initial burst of drug that otherwise tends to cause undesirable side effects such as nausea or vomiting. In addition, the vaginal ring body may be provided by molding the first polymeric material having the at least one hollow internal channel in a single step.

Yet another aspect of the present invention is directed to a kit which contains a suitably shaped vaginal ring body comprising 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 an intravaginally administerable drug-containing core through the opening, and at least one core to be positioned in the channel, wherein the core contains a pharmaceutically effective amount of an intravaginally administerable 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 for sealing the hollow channel after positioning the drug-containing core therein, and/or applicators for positioning the core in the channel and applying the sealant to the channel. The sealant is preferably a medical grade adhesive such as a polymethylsiloxane having methyldiacetoxysilyl end groups. The applicator is preferably a syringe.

The vaginal rings and the methods of the present invention offer several additional advantages over prior art drug delivery mechanisms. They provide for a substantially constant release of drug as compared to oral or injectable modes of drug administration, and they maintain the potency of drugs that are susceptible to destruction as they pass from the intestine through the liver immediately after absorption from the gut.

A further aspect of the present invention is directed to a method for the preparation of a vaginal ring by 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 vulcanizing the vaginal ring body and inserting the drug-containing core in the hollow internal channel, thereby 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 a continuous, annular ring body 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 vulcanizing. In another preferred embodiment, the core may be vulcanized in situ in the ring body, depending upon whether the drug is one in which the initial burst is to be avoided. For example, in cases where initial drug bursts are to be avoided, the ring body and core are vulcanized separately, and the cores are introduced into the channels suitably prior to use. In embodiments where an initial drug burst is not a problem, the core may be vulcanized in situ in the ring body subsequent to its introduction into the channel. In these embodiments, the drug-containing core may 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 situ.

In preferred embodiments, the diameter of the core relative to the channel may vary slightly; it may be substantially equal to or slightly greater or smaller than the channel diameter. In preferred embodiments, the core diameter is substantially equal to or even slightly greater than that of the channel, such that following insertion or formation of the core into the channel, surface contact is maintained between the outer longitudinal surfaces of the core and the surface of the channel. The method is less time consuming and more easily mechanized than current methods. Therefore, the core may be inserted into the ring body during the manufacturing process, or packaged separately and inserted suitably prior to use, in accordance with other aspects of the present invention.

Claim 1 of 4 Claims

We claim:

1. A vaginal ring body for making a vaginal ring, comprising a suitably shaped, inert, 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 an intravaginally administerable drug-containing core through said opening; such that upon assembly of said vaginal ring by positioning said drug-containing core into said hollow internal channel and sealing said channel, no portion of said drug-containing core is exposed to said exterior of said ring body.

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