FIELD OF THE INVENTION

The present invention relates to monolithic intravaginal rings comprising progesterone, methods of making, and uses thereof. The intravaginal rings comprise progesterone, a polysiloxane elastomer, and a pharmaceutically acceptable hydrocarbon or glycerol esters of a fatty acid.

BACKGROUND OF THE INVENTION

Progesterone is a C-21 steroid hormone and belongs to a class of hormones called progestogens. It is the major naturally occurring steroid and is a precursor in the biosynthesis of other steroids, particularly glucocorticoids, androgens and estrogens.

Progesterone stimulates the growth of the uterus and also stimulates a number of specific changes in the endometrium and myometrium. Progesterone is essential for the development of decidual tissue and the differentiation of luminal and glandular epithelial tissue. It also plays several roles in gestation, including breast enlargement, inhibition of uterine contractility, maintenance of gestation, immunological protection of the embryo, and inhibition of prostaglandin synthesis.

Progesterone has been used in the treatment of a number of clinical disorders such as luteal phase defects, dysfunctional uterine bleeding, endometriosis, endometrial carcinoma, benign breast disease, pre-eclampsia, and regimens of in vitro fertilization. The luteal phase of a natural cycle is characterized by the formation of a corpusluteum, which secretes steroid hormones, including progesterone. After fertilization and implantation, the developing blastocyst secretes human chorionic gonadotropin (“hCG”), which maintains the corpusluteumand its secretions. Normal luteal function is essential for maintaining pregnancy and data suggest that progesterone is necessary for the maintenance of early pregnancy. Penzias, A. S.,Fertility and Sterility77:318-323 (2002).

Unfortunately, not all women of reproductive age are able to become pregnant, or maintain a pregnancy; indeed, about twelve to fifteen percent of women of reproductive age in the United States have received an infertility service at some time in their lives. Assisted Reproductive Technology (“ART”) generally involves the surgical removal of eggs from a woman's ovaries, fertilizing them with sperm in the laboratory, and then returning them to either the donor woman's or another woman's uterus (Centers for Disease Control, Assisted Reproductive Technology Success Rates, National Summary and Fertility Clinic Reports. U.S. Department of Health and Human Services, 2004). There are three types of ART: (a) IVF (in vitro fertilization) involves extracting the eggs, fertilizing them in the laboratory, and transferring resulting embryos to the uterus through the cervix, (b) GIFT (gamete intrafallopian transfer) involves placing unfertilized eggs and sperm into the woman's fallopian tubes using a laparoscope through an abdominal incision, and (c) ZIFT (zygote intrafallopian transfer) involves extracting the eggs, fertilizing them in the laboratory, and using a laparoscope to place the fertilized egg(s) into a woman's fallopian tubes.

ART is also further classified by whether a woman's own eggs were used (nondonor), or eggs were donated from another woman (donor). In addition, the embryos used can be newly fertilized (fresh), or previously fertilized, frozen, and then thawed (frozen). For many women, in conjunction with ART, steps must be taken to prime the uterus for implantation, and to sustain the pregnancy after implantation. There have been many tools developed to aid in this process.

In the mid-1980s, gonadotrophin releasing hormone (“GnRH”) agonists were incorporated into ovarian stimulation regimens and are associated with improved outcomes after IVF and other assisted reproductive technologies. GnRH agonists work by suppressing the pituitary and preventing premature surges of endogenous luteinizing hormone (“LH”) during IVF cycles, allowing time for a larger number of oocytes to reach maturity prior to harvesting as well as increasing follicular growth. However, GnRH agonists inhibit the corporaluteain these cycles and may create an iatrogenic luteal phase defect.

Use of a GnRH agonist causes suppression of pituitary LH secretion for as long as 10 days after the last dose and pituitary function may not return completely until 2-3 weeks after the end of therapy. Without this LH signal, the corpusluteummay be dysfunctional, and subsequent progesterone and estrogen secretion may be abnormal, compromising endometrial receptivity, and potentially leading to decreased implantation and pregnancy rates. Pritts et al.,Human Reproduction17:2287-2299 (2002).

Various hormones, including estrogens, progesterone, and hCG, have been used during the luteal phase and beyond in IVF cycles for luteal phase support. A 1994 meta-analysis showed that the use of hCG or progesterone led to significantly higher pregnancy rates than placebo. Soliman et al.,Fertility and Sterility61:1068-76 (1994). Progesterone in numerous forms (oral, vaginal, intramuscular (“IM”)) is considered to be the agent of choice because hCG is associated with a higher risk of ovarian hyperstimulation syndrome (“OHSS”), a potentially life-threatening condition associated with an increased risk of thromboembolism.

Most treatment protocols advocate the use of progesterone throughout the first trimester of pregnancy, since corpusluteumactivity has been demonstrated up to week 10 of pregnancy, although progesterone supplementation continuing beyond a positive serum pregnancy test may not be needed. The goal of progesterone supplementation is therefore to assist a corpusluteumthat may have become compromised during ovulation induction or oocyte retrieval.

Oral, IM, and intravaginal progesterone preparations are available. Oral formulations appear to be inferior for luteal support. Serum progesterone levels are highest with IM administration, but because of the uterine first pass effect with IM administration, vaginal administration results in higher endometrial progesterone levels. Bulletti et al.,Human Reproduction12:1073-9 (1997).

IM progesterone (50-100 mg daily) is widely used, but requires daily injections and is painful, uncomfortable, and inconvenient for patients; some patients may even develop a sterile abscess or an allergic response to the oil vehicle. Toner J. P., Human Reproduction 15 Supp. 1:166-71 (2000). Vaginal progesterone gel (Crinone®/Prochieve® 8%; Columbia Laboratories, Livingston, N.J.) is less painful and easier to use than IM, but also requires daily dosing, may be messy, and due to potential leakage, may not provide a full dose with every application. Crinone® is a bioadhesive vaginal gel containing micronized progesterone in an emulsion system. The carrier vehicle is an oil in water emulsion containing the water swellable, but insoluble, polymer polycarbophil.

The use of a progesterone vaginal insert (Endometrin®) 3 times daily has recently been approved by the U.S. Food and Drug Administration (“FDA”) to support embryo implantation and early pregnancy by supplementation of corpus luteal function as part of an ART treatment program for infertile women. In addition, vaginal use multiple times daily of micronized progesterone capsules has been reported and is used clinically, but luteal phase supplementation or replacement is not an FDA-approved indication for this product.

There is also published information comparing a vaginal progesterone ring to IM progesterone for use in both IVF and oocyte donation. Zegers-Hochschild et al.,Human Reproduction15:2093-2097 (2000).

Intravaginal devices for delivering progesterone and/or intravaginal devices comprising polysiloxane elastomers are discussed in U.S. Pat. Nos. 3,545,439; 3,948,262; 4,012,496; 5,869,081; 6,103,256; 6,056,976; and 6,063,395.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to a method for treating a luteal phase defect in a patient in need thereof, the method comprising administering to the patient a monolithic intravaginal ring comprising (a) a therapeutically effective amount of progesterone, (b) a polysiloxane elastomer, and (c) a pharmaceutically acceptable hydrocarbon or glycerol esters of a fatty acid, wherein the polysiloxane elastomer is present in a concentration of about 55% to about 90% by total weight of the ring.

The present invention is directed to a method for treating a luteal phase defect in a patient in need thereof, the method comprising administering to the patient a monolithic intravaginal ring comprising (a) a therapeutically effective amount of progesterone, (b) a polysiloxane elastomer, and (c) a pharmaceutically acceptable oil, wherein the polysiloxane elastomer is present in a concentration of about 55% to about 90% by total weight of the ring.

The present invention is directed to a monolithic intravaginal ring for treating a luteal phase defect in a patient in need thereof, the ring comprising (a) about 5% to about 40% by weight of progesterone, (b) about 55% to about 90% by weight of polysiloxane elastomer, and (c) about 0.1% to about 10% by weight of a pharmaceutically acceptable hydrocarbon or glycerol esters of a fatty acid, wherein the progesterone is homogeneously dispersed in the elastomer.

The present invention is directed to a monolithic intravaginal ring for treating a luteal phase defect in a patient in need thereof, the ring comprising (a) about 5% to about 40% by weight of progesterone, (b) about 55% to about 90% by weight of polysiloxane elastomer, and (c) about 0.1% to about 10% by weight of a pharmaceutically acceptable oil, wherein the progesterone is homogeneously dispersed in the elastomer.

The present invention is directed to a process for making a monolithic intravaginal ring, the process comprising (a) mixing progesterone, a pharmaceutically acceptable hydrocarbon or glycerol esters of a fatty acid, and a polysiloxane to form a homogeneous mixture, (b) placing the homogeneous mixture into a mold, and (c) curing the mold at about 60° C. to about 180° C., wherein the polysiloxane is present in a concentration of about 55% to about 90% by total weight of the ring.

The present invention is directed to a process for making a monolithic intravaginal ring, the process comprising (a) mixing progesterone, a pharmaceutically acceptable oil, and a polysiloxane to form a homogeneous mixture, and (b) placing the homogeneous mixture into a mold, wherein the polysiloxane is present in a concentration of about 55% to about 90% by total weight of the ring.

The present invention is directed to a method for treating a luteal phase defect in a patient in need thereof, the method comprising administering to a patient a monolithic intravaginal ring comprising (a) progesterone, (b) a dimethylpolysiloxane elastomer, and (c) a pharmaceutically acceptable hydrocarbon or glycerol esters of a fatty acid, wherein the ratio of progesterone to elastomer is about 1:1 to about 1:10, the progesterone is homogeneously dispersed in the elastomer, the ratio of progesterone to hydrocarbon or glycerol esters of a fatty acid is about 1:0.1 to about 1:100, and wherein the progesterone is released from the monolithic intravaginal ring for up to about 18 days after administration to the patient.

The present invention is directed to a method for treating a luteal phase defect in a patient in need thereof, the method comprising administering to a patient a monolithic intravaginal ring comprising (a) progesterone, (b) a dimethylpolysiloxane elastomer, and (c) a pharmaceutically acceptable oil, in a ratio of about 4:15:1, respectively, wherein the progesterone is homogeneously dispersed in the elastomer, and wherein the progesterone is released from the monolithic intravaginal ring for up to about 18 days after administration to the patient.

The present invention is directed to a method for treating a luteal phase defect in a patient in need thereof, the method comprising administering to the patient a monolithic intravaginal ring comprising (a) about 15% to about 25% by weight of progesterone, (b) about 70% to about 80% by weight of a dimethylpolysiloxane elastomer, and (c) about 1% to about 10% by weight of a pharmaceutically acceptable hydrocarbon or glycerol esters of a fatty acid, wherein the progesterone is homogeneously dispersed in the elastomer, and wherein the progesterone is released from the monolithic intravaginal ring for up to about 18 days after administration to the patient.

The present invention is directed to a method for treating a luteal phase defect in a patient in need thereof, the method comprising administering to the patient a monolithic intravaginal ring comprising (a) about 15% to about 25% by weight of progesterone, (b) about 70% to about 80% by weight of a dimethylpolysiloxane elastomer, and (c) about 1% to about 10% by weight of a pharmaceutically acceptable oil, wherein the progesterone is homogeneously dispersed in the elastomer, and wherein the progesterone is released from the monolithic intravaginal ring for up to about 18 days after administration to the patient.

The present invention is directed to a method for treating a luteal phase defect in a patient in need thereof, the method comprising administering to the patient a monolithic intravaginal ring comprising (a) progesterone, (b) a dimethylpolysiloxane elastomer, and (c) mineral oil, in a ratio of about 4:15:1, respectively, wherein the progesterone is homogeneously dispersed in the elastomer, and released from the intravaginal ring at about 15 mg/day to about 25 mg/day in vivo and wherein the intravaginal ring is replaced after about every 7 days following administration to the patient.

The present invention is directed to a method for treating a luteal phase defect in a patient in need thereof, the method comprising administering to the patient a monolithic intravaginal ring comprising (a) about 20% progesterone, (b) about 75% MED-4840, and (c) about 5% mineral oil, wherein the progesterone is homogeneously dispersed in the elastomer, and released from the intravaginal ring at about 15 mg/day to about 25 mg/day in vivo and wherein the intravaginal ring is replaced after about every 7 days following administration to the patient.

In some embodiments, the progesterone is homogeneously dispersed in the polysiloxane elastomer.

In some embodiments, the polysiloxane elastomer is a diorganopolysiloxane elastomer. The diorganopolysiloxane elastomer can be a dimethylpolysiloxane elastomer. The dimethylpolysiloxane elastomer can further comprise a dimethylmethylhydrogen polysiloxane crosslink.

In some embodiments, the pharmaceutically acceptable hydrocarbon or glycerol esters of a fatty acid is present in a concentration of about 0.1% to about 10% by total weight of the ring.

In some embodiments, the pharmaceutically acceptable hydrocarbon or glycerol esters of a fatty acid is selected from mineral oil, silicone oil and combinations thereof. In some embodiments, the pharmaceutically acceptable hydrocarbon or glycerol esters of a fatty acid is mineral oil.

In some embodiments, the progesterone is present in a concentration of about 15% to about 30% by total weight of the ring.

In some embodiments, the progesterone is released at a steady rate for about 1 day to about 14 days. In some embodiments, the progesterone is released at a steady rate for about 1 day to about 10 days. In some embodiments, the progesterone is released at a steady rate for about 1 day to about 7 days.

In some embodiments, the progesterone is released from the monolithic intravaginal ring at a steady rate for up to about 10 days after administration to the patient. In some embodiments, the progesterone is released from the monolithic intravaginal ring at a steady rate for up to about 14 days after administration to the patient. In some embodiments, the progesterone is released from the monolithic intravaginal ring at a steady rate for up to about 18 days after administration to the patient.

In some embodiments, the polysiloxane is vinyl end blocked. In some embodiments, the polysiloxane is dimethylpolysiloxane.

In some embodiments, the process further comprises mixing a second polysiloxane into the homogeneous mixture prior to placing into the mold. In some embodiments, the second polysiloxane is a crosslinker. In some embodiments, the crosslinker is dimethylmethylhydrogen polysiloxane.

In some embodiments, the placing of the homogeneous mixture is by injection.

In some embodiments, the progesterone is released from the intravaginal ring at about 10 mg/day to about 40 mg/day in vivo. In some embodiments, the progesterone is released from the intravaginal ring at about 10 mg/day to about 30 mg/day in vivo. In some embodiments, the progesterone is released from the intravaginal ring at about 15 mg/day to about 25 mg/day in vivo.

In some embodiments, the intravaginal ring is replaced after about 14 days following administration to the patient. In some embodiments, the intravaginal ring is replaced after about 7 days following administration to the patient.

