TREATMENT OF UTERINE FIBROIDS BY INTRAVAGINAL ADMINISTRATION OF A LOW DOSE OF SELECTIVE PROGESTERONE RECEPTOR MODULATOR (SPRM), ANTI-PROGESTIN, OR ANTI-PROGESTATIONAL AGENT

Abstract

A method and intravaginal drug delivery device for reducing size of a uterine fibroid in a female in need thereof are provided. The method includes administering intravaginally to the female a therapeutically effective amount of an active agent, wherein the agent is delivered on a delivery device directly to uterine fibroid, wherein said amount is able to significantly reduce the size of the uterine fibroid, wherein the active agent is any one of selective progesterone receptor modulator (SPRM), an anti-progestin agent, and an anti-progestational agent.

Claims

1. A method for reducing size of a uterine fibroid in a female in need thereof comprising: administering intravaginally to the female a therapeutically effective amount of an active agent, wherein the agent is delivered on a delivery device directly to uterine fibroid, wherein a daily dose of the active agent does not exceed 500 mcg, wherein the active agent is mifepristone.

2. The method of claim 1, wherein the delivery device is any one of: a vaginal ring, a medicated intrauterine device (IUD), and a vaginal tablet.

3. The method of claim 2, wherein the active agent contained in the vaginal ring is mixed throughout the vaginal ring.

4. The method of claim 3, wherein the active agent is delivered at a daily dose ranging from 100 mcg to 400 mcg.

5. The method of claim 1, wherein the female has non-symptomatic or symptomatic uterine fibroids, wherein uterine fibroids symptom comprises at least one of: heavy menstrual bleeding, menstrual pain, pelvic pressure, abdominal pressure, pain during intercourse, urinary flow frequency, constipation, menorrhagia, anemia, and dysmenorrhea.

6. The method according to claim 1, wherein the active agent is administered: without interruption of drug delivery with duration of treatment period ranging from two weeks to six months, without interruption of drug delivery with duration of treatment period ranging from six months to three years, or in at least two periods of drug delivery ranging from approximately one month to approximately three months, separated by drug-free intervals when a drug delivery device is removed.

7. The method according to claim 1, wherein the active agent comprises any one of: mifepristone and metabolites thereof.

8. The method of claim 7, wherein the daily dose of each of the active agents ranging from 100 mcg to 500 mcg.

Description

DETAILED DESCRIPTION

[0025] The embodiments disclosed herein are only examples of the many possible advantageous uses and implementations of the innovative teachings presented herein.

[0026] In general, statements made in the specification of the present application do not necessarily limit any of the various claimed embodiments. Moreover, some statements may apply to some inventive features but not to others.

Definitions:

[0027] A vaginal ring (also known as an intravaginal ring) is a polymeric drug delivery device providing controlled release of drug(s) to the vagina and adjacent organs, including uterine fibroids over an extended period of time.

[0028] An Intrauterine Device (also known as an IUD) is an object placed in the uterus to prevent pregnancy. In the method of the present invention, the medicated IUD is considered as a drug delivery device providing controlled release of drugs to the vagina and adjacent organs, including uterine fibroids over an extended period of time.

[0029] A therapeutically effective amount of SPRM, or anti-progestin, or anti-progestational agent is defined as the amount of a drug that results in a significant (preferably, at least 15%) reduction in size of uterine fibroids when compared to the pre-treatment levels.

[0030] This invention provides for intravaginal delivery of a therapeutically effective amount of Selective Progesterone Receptor Modulator (SPRM), anti-progestin, or anti-progestational agent for the reduction in size of the uterine fibroids or the uterus and improvement in related symptoms.

[0031] In the method of the present invention, the SPRM, anti-progestin, or anti-progestational agent can be delivered using any intravaginal delivery device known in the art. Non-limiting examples of useful delivery devices include vaginal ring, intrauterine device, and vaginal tablet.

[0032] In a preferred embodiment, the drug delivery device is a vaginal ring. In another preferred embodiment, the drug delivery device is a medicated intrauterine device (IUD). In one embodiment, the agent can be mixed throughout the vaginal ring. In another embodiment, the agent can be distributed uniformly throughout the vaginal ring. In yet another embodiment, the agent can be encapsulated in a part of the vaginal ring. In a further embodiment, the agent can be located at the center of the vaginal ring. In yet another embodiment, a membrane of the agent can be placed between an un-medicated core and a metering layer of appropriate material.

[0033] The use of a vaginal drug delivery device delivering the agent directly to the affected tissues (e.g., vagina and adjacent organs, including uterine fibroids) is expected to enhance the agent's efficacy in the reduction in size of the fibroids and the uterus and improvement in related symptoms; it may also result in a shorter duration of therapy compared to other routes of drug administration.

[0034] The use of a vaginal drug delivery device delivering the agent directly to the affected tissues is also expected to significantly reduce the agent's daily dose when compared to other routes of drug administration; this may result in a lower systemic drug circulation, possibly below detectable levels, and a lower incidence of drug-related adverse events.

[0035] In all embodiments, the agent is from a class of drugs called selective progesterone receptor modulators (SPRM), or from the class of drugs called anti-progestins, or from the class of drugs called anti-progestational agents. Non-limiting examples of useful agents include, e.g., mifepristone, ulipristal acetate, asoprisnil, onapristone, CDB-2914, CDB-4124, and metabolites thereof.

[0036] In one embodiment, daily agent doses useful in the method of the present invention do not exceed 1.4 mg. In a preferred embodiment, daily agent doses useful in the method of the present invention range from 50 mcg to 1 mg. In another preferred embodiment, the agent is mifepristone with a daily drug delivery dose ranging from 100 mcg to 500 mcg. In yet another preferred embodiment, the agent is CDB-4124 with a daily drug delivery dose ranging from 150 mcg to 600 mcg. In a further preferred embodiment, the agent is ulipristal acetate with a daily drug delivery dose ranging from 200 mcg to 700 mcg.

[0037] In certain embodiments, the method of the invention is used to treat females with symptomatic uterine fibroids. Non-limiting examples of symptoms include, e.g., heavy menstrual bleeding, menstrual pain, pelvic and abdominal pressure, pain during intercourse and obstructive symptoms, such as urinary flow frequency and constipation. In certain embodiments, the method of the invention is used to treat females with non-symptomatic uterine fibroids. In certain other embodiments, the method of the invention is used to treat females with uterine fibroids clinically diagnosed with menorrhagia. In certain additional embodiments, the method of the invention is used to treat females with uterine fibroids clinically diagnosed with anemia. In certain further embodiments, the method of the invention is used to treat females with uterine fibroids clinically diagnosed with dysmenorrhea. In certain other embodiments, the method of the invention is used to treat females without interruption of drug delivery with a treatment period ranging from two weeks to six months. In certain additional embodiments, the method of the invention is used to treat females without interruption of drug delivery with a treatment period ranging from six months to three years. In a preferred embodiment, the method of the invention is used to treat females without interruption of therapy with a treatment period ranging from approximately one month to approximately three months. In certain other embodiments, the method of the invention is used to treat females with the periods of drug delivery (ranging from approximately one month to approximately three months) followed by the drug-free intervals when the drug delivery device is removed. In certain further embodiments, upon administration of the agent according to the method of the invention, the amount of the agent in the female's systemic circulation is below detection levels.

[0038] The present invention is also described and demonstrated by way of the following examples. However, the use of these and other examples anywhere in the specification is illustrative only and in no way limits the scope and meaning of the invention or of any exemplified term. Likewise, the invention is not limited to any particular preferred embodiments described here. Indeed, many modifications and variations of the invention may be apparent to those skilled in the art upon reading this specification, and such variations can be made without departing from the invention in spirit or in scope. The invention is therefore to be limited only by the terms of the appended claims along with the full scope of equivalents to which those claims are entitled.

[0039] Example 1: The vaginal ring serving as a drug delivery device comprises a supporting ring free of active drug. The next (second) layer contains medication selected for treatment of uterine fibroids (selective progesterone receptor modulator, or anti-progestin, or anti-progestational agent). This layer is coated with the third, drug-free layer. Detailed description of such vaginal ring and suitable manufacturing methods can be found in U.S. Pat. No 4,822,616.

[0040] Per U.S. Pat. No 4,822,616, the supporting ring is made from a physiologically acceptable synthetic resin, such as, e.g., polyethylene, RTV silicone elastomers, LTV silicone elastomers, polyamides and polytetrafluoroethylene. The second layer with active medication comprises a pharmaceutically acceptable resin from which the drug is released. A preferred embodiment consists of the combination of drug and LTV silicone elastomer with a composition also described in the patent. Any LTV silicone elastomer is used in the third layer. The proposed vaginal ring ensures release of the active drug within the limits of the dosage required for the desired reduction in size of both uterine fibroids and the uterus.

[0041] In one embodiment, the second layer is medicated with mifepristone in an amount adequate to release the drug in a rate of 250-300 mcg/day. In another embodiment, the second layer is medicated with CDB-4124 in an amount adequate to release the drug in a rate of 300-400 mcg/day. In yet another embodiment, the second layer is medicated with ulipristal acetate in an amount adequate to release the drug in a rate of 300-500 mcg/day.

[0042] In all described embodiments, the treatment is continuous without interruption. A preferred duration of therapy (following insertion of the ring) ranges from approximately one month to approximately three months.

[0043] Example 2: The vaginal ring serving as a drug delivery device comprises the active drug selected for treatment of excessive menstrual blood loss (tranexamic acid or another antifibrinolytic or hemostatic agent)and a delivery module. Delivery module comprises (a) reservoir for storing the active drug, (b) a rate controller or wall that is formed of styrene-butadiene copolymer that maintains the prescribed rate of drug release throughout the life of system, (c) energy source or the concentration of active drug in reservoir that provides the driving means for transferring the active drug from a higher amount in reservoir to the rate controller, (d) an inner mass transfer conductor for housing the active drug in reservoir, and (e) a portal that provides the exit from the drug delivery module to the tissues. Detailed description of such vaginal ring and its manufacturing process can be found, for example, in U.S. Pat. No 4,250,611.

[0044] In one embodiment, the delivery module of the vaginal ring contains mifepristone in an amount supporting the drug release at a rate of 250-300 mcg/day. In another embodiment, the delivery module of the vaginal ring contains CDB-4124 in an amount supporting the drug release at a rate of 300-400 mcg/day. In yet another embodiment, the delivery module of the vaginal ring contains ulipristal acetate in an amount supporting the drug release at a rate of 300-500 mcg/day.

[0045] In all described embodiments, the treatment is continuous without interruption. A preferred duration of therapy (following insertion of the ring) ranges from approximately one month to approximately four months.

[0046] Example 3: The vaginal ring serving as a drug delivery device is a ring-shaped solid carrier made of silicone rubber (polysiloxane) or other suitable material. The ring has a homogenous design with an active drug dispersed in the carrier. Detailed description of such vaginal ring can be found, for example, in U.S. Pat. No 5,869,081. Per U.S. Pat. No 5,869,081, the vaginal ring provides sustained release of the medication and results in low circulatory levels of the drug, while concentrating its biological effect on a regional level.

[0047] In one embodiment, the carrier contains mifepristone in an amount supporting the drug release at a rate of 250-300 mcg/day. In another embodiment, the carrier contains CDB-4124 in an amount supporting the drug release at a rate of 300-400 mcg/day. In yet another embodiment, the carrier contains ulipristal acetate in an amount supporting the drug release at a rate of 300-500 mcg/day.

[0048] In all described embodiments, the treatment is continuous without interruption. A preferred duration of therapy (following insertion of the ring) ranges from approximately two weeks to approximately one month.

[0049] Example 4: The medicated intrauterine device (IUD) serving as a drug delivery device is inserted into the uterus for a predetermined time period. The device comprises a body of the device in combination with an external surface contacting the uterus. The external surface is medicated and provides controlled drug release. Detailed description of such IUD can be found in U.S. Pat. No. 4,359,046.

[0050] In one embodiment, the IUD is medicated with mifepristone in an amount supporting the drug's release at a rate of 200-250 mcg/day. In another embodiment, the carrier contains CDB-4124 in an amount supporting the drug release at a rate of 250-300 mcg/day. In yet another embodiment, the carrier contains ulipristal acetate in an amount supporting the drug release at a rate of 250-300 mcg/day.

[0051] Contraceptive action of the IUD is considered as optional. In all described embodiments, the treatment is continuous without interruption. A preferred duration of therapy (following insertion of the IUD) is up to three years.

[0052] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

[0053] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entirety as if physically present in this specification.

REFERENCES

[0054] .sup.1 Shwalisz K., et al. Effectiveness of Asoprisnil, a Selective Progesterone Receptor Modulator (SPRM) in Treating Uterine Leiomyomata. Advances in Leiomyoma Research, 2.sup.nd NIH International Congress, Feb. 24-25, 2005, Bethesda, Md.

[0055] .sup.2 Kaunitz A M. Progestin-releasing intrauterine systems and leiomyoma. Contraception. 2007 June;75(6 Suppl):S130-3. Epub 2007 Mar. 9.

[0056] .sup.3 About Uterine Fibroids. Introduction. National Uterine Fibroids Foundation, accessed at http://www.nuff.org/health.htm (reference on file)

[0057] .sup.4Viswanathan M. et al. Management of uterine fibroids: an update of the evidence, Evid Rep Technol Assess (Full Rep). 2007 July;(154):1-122.

[0058] .sup.5 Rodriguez M I, Darney P D. Non-contraceptive applications of the levonorgestrel intrauterine system. International Journal of Women's Health. Volume 2010:2 P. 63-68.

[0059] .sup.6 ADAM Mobile Encyclopedia Uterine Fibroids. Accessed at http://pfizer.adam.com/content.aspx?productId=101&pid=1&gid=000914 (reference on file)

[0060] 7 Preglem licenses additional rights for ulipristal acetate from HRA Pharma. Accessed at http://www.preglem.com/files newspdf/PR_Preglem%20NA%20Rights%20to%20Uliprist al%20Acetate.pdf (reference on file)

[0061] .sup.8 David Chelmow Non-surgical Options for Menorrhagia. OBG Management November 2005 (Vol. 17, No.11)

[0062] .sup.9 National Collaborating Centre for Women's and Children's Health. Heavy menstrual bleeding. London (UK): Royal College of Obstetricians and Gynaecologists (RCOG); 2007 January.

[0063] .sup.10Rossetti A, Sizzi O, Soranna L, et al. Long-term results of laparoscopic myomectomy: recurrence rate in comparison with abdominal myomectomy. Hum Reprod 2001;16:770-774.

[0064] .sup.11Uterine Artery Embolization. Wikipedia. Assessed at http://en.wikipedia.org/wiki/Uterine_artery_embolization (reference on file)

[0065] .sup.12 Spitz I M., Mifepristone: where do we come from and where are we going? Clinical development over a quarter of a century. Contraception. Corrected Proof. 1 Feb. 2010.

[0066] .sup.13 Preglem announces positive Phase III results for Esmya as an effective treatment for uterine fibroids. Accessed at http://www.preglem.com/files/newspdf/PR_PregLem%20PEARLII_Phase%20III%20results_%20FINAL%20.pdf (reference on file)

[0067] .sup.14Steinauer, J, Pritts, E A, Jackson, R, Jacoby A F. Systematic review of mifepristone for the treatment of uterine leiomyomata. Obstet Gynecol 2004; 103:1331.

[0068] .sup.15Spitz I M. Pharmacology and mechanisms of action of progesterone receptor antagonists and selective progesterone receptor modulators. UpToDate. Online 18. 2, May 2010.

[0069] .sup.16Mifepristone. Wikipedia. Accessed at http://en.wikipedia.org/wiki/Mifepristone (reference on file)

[0070] .sup.17Eisinger S H., et al. Twelve-month safety and efficacy of low-dose mifepristone for uterine myomas. J Minim Invasive Gynecol 2005; 12:227.

[0071] .sup.18Gommier B, Magning G. Mifepristone for treatment of myomas [meeting abstract]. Third Symposium. Misoprostol and mifepristone in obstetrics and gynecology. Valencia, Spain, Oct. 4-5, 2007).

[0072] .sup.19Fiscella K, et al. Effect of mifepristone for symptomatic leiomyomata on quality of life and uterine size: a randomized controlled trial. Obstet Gynecol 2006;108:1381-7.

[0073] .sup.20Esteve C J L, et al. Mifepristone for the treatment of uterine leiomyomas: a randomized controlled trial. Obstet Gynecol 2008;112:1029-36.

[0074] .sup.21Eisinger, S H, et al. Open-label study of ultra low-dose mifepristone for the treatment of uterine leiomyomata. Eur J Obstet Gynecol Reprod Biol 2009, 0ct. 1;146(2):215-8;

[0075] .sup.22Fiscella K. Use of antiprogestins for treatment of uterine fibroids: clinical trials (presentation). Advances in Uterine Leiomyoma Research. 2.sup.nd NIH International Congress. Feb. 24-25, 2005. Bethesda Md. (reference on file)

[0076] .sup.23Kingsberg S A., et al. Treating dyspareunia caused by vaginal atrophy: a review of treatment options using vaginal estrogen therapy. International Journal of Women's Health. August 2009 , Volume 2009:1 Pages 105-111

[0077] .sup.24Ballagh S A. Vaginal Ring Hormone Delivery Systems in Contraception and Menopause. CLINICAL OBSTETRICS AND GYNECOLOGY/VOLUME 44/NUMBER 1/MARCH 2001

[0078] .sup.25Iyer V., et al. Vaginal drug delivery. ExpressPharma, 1-15 Jul. 2008

[0079] .sup.26Igarashi M. Novel vaginal danazol ring therapy for pelvic endometriosis, in particular deeply infiltrating endometriosis. Hum Reprod. 1998 July;13(7):1952-6.

[0080] .sup.27Ficicioglu C. et al. High local endometrial effect of vaginal progesterone gel. Gynecological Endocrinology, Volume 18, Issue 5 May 2004, pages 240-243.

[0081] .sup.28Kuhl H. Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005; 8 (Suppl 1)3-63.

[0082] .sup.29 Center for Drug Evaluation and Research. Application Number 21-225. Mirena NDA

[0083] Medical review; accessed at Mirena NDA Medical review. Accessed at http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-225.pdf_Mirena_Medr.pdf (reference on file)