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USOO922.0692B2

(12) United States Patent (10) Patent No.: US 9.220,692 B2 DiLiberti et al. (45) Date of Patent: Dec. 29, 2015

(54) METHODS OF REDUCING SYMPTOMISIN (56) References Cited SUBJECTS USING SINGLE DOSAGE FORMS WITH TAPERING RELEASE RATES U.S. PATENT DOCUMENTS 4,822,616 A 4, 1989 Zimmermann et al. (75) Inventors: Charles E. DiLiberti, Montclair, NJ 5,486,362 A * 1/1996 Kitchell et al...... 424/426 (US); Anu Mahashabde, Kendall Park, 5,788,980 A 8, 1998 Nabahi NJ (US) 6,165,497 A * 12/2000 Osborne et al...... 424/448 2003/0216366 A1 11/2003 Leonard et al. (73) Assignee: TEVA WOMENS HEALTH, INC., 2010.0040671 A1 2/2010 Ahmed et al...... 424/432 Woodcliff Lake, NJ (US) 2011/0182977 A1* 7, 2011 Fossel ...... 424/450 (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 RU 2320331 C2 3, 2008 U.S.C. 154(b) by 482 days. WO WO 2006/026844 A1 3, 2006 (21) Appl. No.: 13/101.929 OTHER PUBLICATIONS International Search Report and the Written Opinion for PCT/ (22) Filed: May 5, 2011 US2011/0354.02 mailed on Jul. 26, 2011. Cutler et al., "Slow-release and injected treatments (65) Prior Publication Data enhance acute recovery after traumatic brain injury'. Pharmacology, Biochemistry and Behavior, PBB-69954, pp. 1-9, 2006. US 2011 FO27474.0 A1 Nov. 10, 2011 Physician's Desk Reference 2005 “Nicoderm CQ, PDR Network LLC, Montvale, NJ. Estring R, Physician's Leaflet, revised Aug. 2008, Pharmacia & Related U.S. Application Data Upjohn Company, NY, NY. MirenaR), Patient Information Booklet, 2004, Berlex, Montville, NJ. (60) Provisional application No. 61/331,775, filed on May Norplant(R) System, Product Sheet, revised Aug. 2003, Wyeth Labo 5, 2010. ratories, Philadelphia, PA. The Eurasian International Search Report for Eurasian Application (51) Int. Cl. No. 201290.972, completed on Jul. 7, 2013. Prilepskaya, V.N., "Hormone levonorgestrel-releasing intrauterine A6 IF 6/06 (2006.01) system.” Consilium medikum, Gynecology, 4:1:21-28, 2002. A6 IK3I/00 (2006.01) An English abstract translation of RU 2320331C2. A6 IK3I/37 (2006.01) A6 IK3 L/46.5 (2006.01) * cited by examiner A6 IK3I/55 (2006.01) A6 IK3I/522 (2006.01) Primary Examiner — Suzanne Ziska A6 IK3I/55 (2006.01) (74) Attorney, Agent, or Firm — Fanelli Haag. PLLC A61M 31/00 (2006.01) A61M 37/00 (2006.01) (57) ABSTRACT (52) U.S. C. The present invention is directed to methods of reducing CPC ...... A6 IK3I/00 (2013.01); A61 K3I/I37 symptoms associated with an abrupt reduction in an endog (2013.01); A61 K3I/465 (2013.01); A61 K enous or exogenous chemical in Subjects, the methods com 31/515 (2013.01); A61 K3I/522 (2013.01); prising: (a) administering to the Subject a single dosage form A6 IK3I/551 (2013.01); A61M31/002 comprising an active agent, wherein the release rate of the (2013.01); A61M 37/00 (2013.01) active agent from the single dosage form tapers throughout (58) Field of Classification Search the administration; and (b) removing the single dosage form CPC ... A61K 31/00; A61 K31/137; A61K 31/465; from the subjects after the release rate of the active agent is at A61 K31/522; A61 K31/551: A61K 3 1/515; or below a terminal symptom threshold level. A61M 37/00; A61M31/002 See application file for complete search history. 19 Claims, 1 Drawing Sheet U.S. Patent Dec. 29, 2015 US 9.220,692 B2

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Time (arbitrary units) US 9.220,692 B2 1. 2 METHODS OF REDUCING SYMPTOMISIN in each dosage is decreased in a step-down manner to alleviate SUBJECTS USING SINGLE DOSAGE FORMS the symptoms associated with withdrawal. However, WITH TAPERING RELEASE RATES with both the constant dosage regimens and the step-down regimens, there are one or more periods in which there is an This application claims the benefit of the filing date of U.S. 5 abrupt reduction in the amount of active agent administered. Application No. 61/331,775, filed May 5, 2010, the contents In the case of a constant regimen, the abrupt reduction in of which are hereby incorporated by reference in its entirety. active agent occurs when the treatment period ends. In the case of the step-down regimen, the abrupt reduction in active BACKGROUND OF THE INVENTION agent occurs whenever there is a “step-down to the next 10 1. Field of the Invention lower dosage, as well as when the treatment ends. The abrupt The present invention is directed to methods of reducing reduction of a regular dosage regimen of a substance can symptoms associated with an abrupt reduction in an endog result in the development of withdrawal symptoms in a sub enous or exogenous chemical in Subjects, the methods com ject, and potentially, in an adverse health condition. Thus, prising: (a) administering to the Subjects a single dosage form 15 there is a need for a single dosage form containing an active comprising an active agent, wherein the release rate of the agent, and methods of administering an active agent wherein active agent from the single dosage form tapers throughout the release rate of the active agent tapers during administra the administration; and (b) removing the single dosage form tion that avoid such problems. from the subjects after the release rate of the active agent is at or below a terminal symptom threshold level. BRIEF SUMMARY OF THE INVENTION 2. Background Art Continual administration of an active agent often involves The present invention is directed to a method of reducing a either a "constant dosage” regimen or a 'step-down dosage” symptom associated with an abrupt reduction in an endog regimen. A "constant dosage” regimen requires administer enous or exogenous chemical in a subject, the method com ing an unvarying amount of an active agent at regular time 25 prising: (a) administering to the Subject a single dosage form intervals, e.g., in a daily dosage. For example, hormone comprising an active agent, wherein the release rate of the replacement therapy often requires administering a constant active agent from the single dosage form tapers throughout daily dosage of an , thereby restoring the estrogenic the administration; and (b) removing the single dosage form hormones to their normal endogenous levels (see U.S. Pat. from the subject after the release rate of the active agent is at Nos. 5.210,081: 5,547,948: RE36,247; and see also physi 30 or below a terminal symptom threshold level. cians leaflet for ESTRING(R) ( vaginal ring, Pfizer, In some embodiments, the single dosage form IS adminis Inc., New York, N.Y., August 2008). Hormone replacement tered vaginally, subcutaneously, intramuscularly, transder therapy to treat can be administered for a period mally or buccally. In some embodiments, the single dosage of several months to several years. form is administered to the subject for about one week to Alternatively, for Some conditions, a step-down regimen is 35 about one year. In some embodiments, the single dosage form used. A “step-down dosage” regimen requires administering is administered to the subject for about at least three days. an active agent in an amount that decreases over time in a In some embodiments, the symptom is associated with step-wise or tiered manner. For example, nicotine replace menopause. In some embodiments, the active agent is a hor ment therapy is a stepdown dosage regimen indicated to mone. In some embodiments, the hormone is selected from reduce withdrawal symptoms, including nicotine cravings, 40 the group consisting of an estrogenic compound, a proges associated with quitting smoking. For example, NICODERM tinic compound, an androgenic compound, a , CQR. (see U.S. Pat. Nos. 5,004,610; 5,342,623: 5,344,656: and combinations thereof. 5,364,630; 5,462,745; 5,508,038; 5,633,008; and 6,165,497, In some embodiments, the symptom is associated with Glaxo SmithKline, United Kingdom) administers a once drawal due to a cessation in the administration of an endog daily dosage of nicotine for a period of 10 weeks in a decreas 45 enous or exogenous chemical to the Subject. In some embodi ing series of dosage levels. During the first six weeks of the ments, the active agent is selected from the group consisting regimen, 21 mg of nicotine is administered per day, followed ofa stimulant, a beta-blocker, an , an opioidantagonist, by two weeks of administering 14 mg of nicotine per day, and a , a barbituate, and a selective serotonin ending with administering 7 mg of nicotine per day for the (SSRI). final two weeks of the regimen. These doses of nicotine are 50 In some embodiments, the symptom is associated with an not sufficient to raise the systemic circulating level of nicotine addiction to an exogenous chemical. In some embodiments, to that attained while Smoking tobacco products, but are Suf the active agent is selected from the group consisting of ficient to alleviate the symptoms associated with nicotine nicotine, , and . withdrawal, and thus helps Subjects in the cessation of In some embodiments, the single dosage form is selected tobacco use. 55 from the group consisting of an intravaginal ring, an intrau Step-down dosage regimens can also be administered to terine dosage form, and a vaginal pessary. In some embodi Subjects in need of hormone replacement therapy. For ments, the single dosage form is an intravaginal ring. In some example, see U.S. Appl. Pub. No. 2003/0216366 AI. Step embodiments, the single dosage form is an implant. In some down dosage regimens are also frequently administered to embodiments, the single dosage form is selected from the Subjects discontinuing the use of a , a beta-adren 60 group consisting of a transdermal adhesive patch, a transder ergic antagonist, or an . For example, with mal reservoirdosage form, a transdermal matrix dosage form, drawal symptoms associated with addiction to heroin can be a non-occlusive transdermal patch dosage form, a bioadhe greatly reduced by administering multiple dosage forms of a sive , a bioadhesive plaster, and a buccal patch dosage long-acting opioid such as methadone (see labeling for form. METHADOSE(R), Mallinckrodt, Hazelwood, Mo., February 65 In some embodiments, the release rate of the active agent 2008). These regimens typically last about three to seven tapers linearly throughout the administration. In some days, or longer, during which time the amount of methadone embodiments, the release rate of the active agent tapers bipha US 9.220,692 B2 3 4 sically throughout the administration. In some embodiments, of an endogenous or exogenous chemical in a Subject over a the release rate tapers first order exponentially throughout the period of about 1 week to about 4 weeks. In some embodi administration. ments, an abrupt reduction can be about 75% to about 100% In some embodiments the active agent is passively released reduction in the systemic concentration of an endogenous or from the single dosage form. In some embodiments, the exogenous chemical in a Subject over a period of about 1 hour active agent is actively released from the single dosage form. to about 24 hours. In some embodiments, an abrupt reduction The present invention is also directed to atherapeutic pack can be about 75% to about 100% reduction in the systemic age comprising: (a) a single dosage form of the present inven concentration of an endogenous or exogenous chemical in a tion; and (b) a label comprising directions for use of the single subject over a period of about 1 day to about 7 days. In some dosage form for reducing a symptom associated with the 10 embodiments, an abrupt reduction can be about 75% to about abrupt reduction in an endogenous or exogenous chemical in 100% reduction in the systemic concentration of an endog a subject, wherein the directions describe the method of enous or exogenous chemical in a Subject over a period of reducing a symptom in a Subject with anyone of the single about 1 week to about 4 weeks. In some embodiments, an dosage forms of the present invention. abrupt reduction can be about 25% to about 75% reduction in 15 the systemic concentration of an endogenous or exogenous BRIEF DESCRIPTION OF THE DRAWINGS chemical in a subject over a period of about 1 hour to about 24 hours. In some embodiments, an abrupt reduction can be FIG. 1 is a graphical description of the release rate of an about 25% to about 75% reduction in the systemic concen active agent from a single dosage form of the present inven tration of an endogenous or exogenous chemical in a subject tion. The initial release rate of the active agent, 101, can be over a period of about 1 day to about 7 days. In some embodi above a symptom threshold level, 104. Once the release rate ments, an abrupt reduction can be about 25% to about 75% of the active agent reaches the symptom threshold level, the reduction in the systemic concentration of an endogenous or release rate tapers throughout the administration, 102. After exogenous chemical in a Subject over a period of about 1 week the release rate of the active agent is at or below a terminal to about 4 weeks. In some embodiments, an abrupt reduction symptom threshold level, 105, the single dosage form can be 25 can be about 25% to about 50% reduction in the systemic removed from the subject, 103. concentration of an endogenous or exogenous chemical in a subject over a period of about 1 hour to about 24 hours. In DETAILED DESCRIPTION OF THE INVENTION some embodiments, an abrupt reduction can be about 25% to about 50% reduction in the systemic concentration of an The present invention is directed to methods of reducing 30 endogenous or exogenous chemical in a subject over a period symptoms associated with an abrupt reduction in an endog of about 1 day to about 7 days. In some embodiments, an enous or exogenous chemical in a subject, the method com abrupt reduction can be about 25% to about 50% reduction in prising: (a) administering to the Subject a single dosage form the systemic concentration of an endogenous or exogenous comprising an active agent, wherein the release rate of the chemical in a subject over a period of about 1 week to about active agent from the single dosage form tapers throughout 35 4 weeks. In some embodiments, an abrupt reduction can be the administration, and (b) removing the single dosage form about 10% to about 25% reduction in the systemic concen from the subject after the release rate of the active agent is at tration of an endogenous or exogenous chemical in a subject or below a terminal symptom threshold level. over a period of about 1 hour to about 24 hours. In some As used herein, “symptom” refers to adverse or undesired embodiments, an abrupt reduction can be about 10% to about effects associated with an abrupt reduction in an endogenous 40 25% reduction in the systemic concentration of an endog or exogenous chemical in a Subject. A symptom can be an enous or exogenous chemical in a Subject over a period of undesired physiological or psychological effect caused by a about 1 day to about 7 days. In some embodiments, an abrupt condition, disorder or disease. As used herein, “reducing a reduction can be about 10% to about 25% reduction in the symptom' can comprise preventing the symptom, inhibiting systemic concentration of an endogenous or exogenous the symptom, diminishing the symptom, alleviating the 45 chemical in a subject over a period of about 1 week to about symptom, stabilizing the symptom (i.e., not worsening), 4 weeks. In some embodiments, an abrupt reduction can be delaying the onset of the symptom, slowing the progression about 1% to about 10% reduction in the systemic concentra of the symptom, reducing the likelihood of occurrence of the tion of an endogenous or exogenous chemical in a subject symptom, or eliminating the symptom. over a period of about 1 hour to about 24 hours. In some As used herein, "abrupt reduction” refers to a decline in the 50 embodiments, an abrupt reduction can be about 1% to about systemic concentration of an endogenous or exogenous 10% reduction in the systemic concentration of an endog chemical in a subject over a period of time. Rates of reduction enous or exogenous chemical in a Subject over a period of of an endogenous or exogenous chemical is specific for that about 1 day to about 7 days. In some embodiments, an abrupt chemical, and can also be dependent on the Subject. As used reduction can be about 1% to about 10% reduction in the herein, a decline in the systemic concentration of the endog 55 systemic concentration of an endogenous or exogenous enous or exogenous chemical is “abrupt' if the rate of reduc chemical in a subject over a period of about 1 week to about tion results in the occurrence of an adverse or undesired 4 weeks. In some embodiments, an abrupt reduction can be symptom in the Subject. By way of example, in some embodi about 1% to about 25% reduction in the systemic concentra ments, an abrupt reduction can be about 50% to about 100% tion of an endogenous or exogenous chemical in a subject reduction in the systemic concentration of an endogenous or 60 over a period of about 1 hour to about 24 hours. In some exogenous chemical in the Subject over a period of about 1 embodiments, an abrupt reduction can be about 1% to about hour to about 24 hours. In some embodiments, an abrupt 25% reduction in the systemic concentration of an endog reduction can be about 50% to about 100% reduction in the enous or exogenous chemical in a Subject over a period of systemic concentration of an endogenous or exogenous about 1 day to about 7 days. In some embodiments, an abrupt chemical in a subject over a period of about 1 day to about 7 65 reduction can be about 1% to about 25% reduction in the days. In some embodiments, an abrupt reduction can be about systemic concentration of an endogenous or exogenous 50% to about 100% reduction in the systemic concentration chemical in a subject over a period of about 1 week to about US 9.220,692 B2 5 6 4 weeks. In some embodiments, an abrupt reduction can be ance. In some embodiments, the exogenous chemical can be about 5% to about 10% reduction in the systemic concentra administered by, or under the direction of a physician. In tion of an endogenous or exogenous chemical in a subject Some embodiments, the exogenous chemical is an addictive over a period of about 1 hour to about 24 hours. In some chemical. Alternatively, the exogenous chemical can be a embodiments, an abrupt reduction can be about 5% to about non-addictive chemical. For example, administration of an 10% reduction in the systemic concentration of an endog exogenous chemical Such as beta-blocker or corticosteroid enous or exogenous chemical in a Subject over a period of may not induce an addiction to a beta-blocker or corticoster about 1 day to about 7 days. In some embodiments, the abrupt oid, however, withdrawal symptoms may result once admin reduction results in the occurrence of a symptom. istration of the exogenous chemical is ceased. As used herein, "endogenous chemical” refers to a chemi 10 In some embodiments, the symptom is associated with the cal that is naturally present in the Subject or is naturally cessation of administration of an exogenous chemical, produced by the Subject. Examples of endogenous wherein the exogenous chemical is a stimulant. Symptoms chemicals can include hormones such as , associated with the abrupt reduction in stimulant levels in a progestins, , , or . Subject can vary, are known in the art, and can include, e.g., Thus, in Some embodiments, the symptom is associated with 15 depression, irritability, fatigue, drowsiness, insomnia, head a rapid hormone reduction, as experienced in menopause, or ache, loss of appetite, nausea, vomiting, muscle pain, stiff to the period of natural or induced cessation of ovarian func ness, and combinations thereof. tion. Symptoms associated with menopause can also be In some embodiments, the symptom is associated with the related to peri-menopause, post menopause or oophorecto cessation of administration of an exogenous chemical, mized women, or women whose endogenous wherein the exogenous chemical is a beta-blocker. Symptoms production has been Suppressed by a pharmaceutical chemi associated with the abrupt reduction in beta-blocker levels in cal composition, e.g., a GnRH agonist Such as leuprolide Subject can vary, are known in the art, and can include, e.g., sold under the tradename LUPRONR (TAP Pharma myocardial infarction, Ventricular arrhythmia, and combina ceutical Products, Inc., Lake Forest, Ill.) or acetate, tions thereof. sold under the tradename ZOLADEXR (AstraZeneca, Wilm 25 In some embodiments, the symptom is associated with the ington, Del.). cessation of administration of an exogenous chemical, Various symptoms associated with menopause can occur. wherein the exogenous chemical is an opioid. Symptoms In some embodiments, the symptom associated with meno associated with the abrupt reduction in opioid levels in a pause includes the occurrence of hot flashes. The symptom Subject can vary, are known in the art, and can include, e.g., associated with menopause can also include, but is not limited 30 severe dysphoria, anxiety, eye tearing, runny nose, fevers, to, night Sweats, emotional changes (mood Swings and gastrointestinal distress, nausea, insomnia, Sweating, goose changes in sexual interest), sleep disturbances (insomnia), bumps, cramps, deep pains, and combinations thereof. premature ovarian failure, natural or induced cessation of In some embodiments, the symptom is associated with the ovarian function, or combinations thereof. Thus in some cessation of administration of an exogenous chemical, embodiments, the present invention relates to methods of 35 wherein the exogenous chemical is a barbituate. Symptoms reducing symptoms associated with menopause, e.g., hot associated with the abrupt reduction in barbituate levels in a flashes, the method comprising administering to a Subject a Subject can vary, are known in the art, and can include, e.g., single dosage form comprising estrogen, e.g., ethinyl estra anxiety, irritability, elevated heart and/or respiration rate, diol, wherein the release rate of the active agent from the muscle pain, nausea, tremors, hallucinations, confusion, sei single dosage form tapers throughout the administration, and 40 Zures, and combinations thereof. removing the single dosage form from the Subject after the In some embodiments, the symptom is associated with the release rate of the active agent is at or below a terminal cessation of administration of an exogenous chemical, symptom threshold level, i.e., a level by which hot flashes wherein the exogenous chemical is a benzodiazepine. Symp would no longer occur. toms associated with the abrupt reduction in benzodiazipene In some embodiments, the symptom is due to abrupt reduc 45 levels in a subject can vary, are known in the art, and can tion in the systemic level of an endogenous chemical, e.g., include, e.g., anxiety, insomnia, depression, aggressive , that results from castration in a male Subject. behavior, nausea, gastrointestinal distress, blurred vision, In some embodiments, the symptom is associated with dizziness, ringing in the ears, headaches, muscle pain, chest drawal due to a cessation in the administration of an exog pain, decreased libido, hallucinations, irregular heartbeat, enous chemical to the Subject. As used herein, "exogenous 50 and combinations thereof. In some embodiments, the Symp chemical refers to a chemical that does not naturally occur in tom is associated with the cessation of administration of an the subject or is not naturally produced in vivo by the subject, exogenous chemical, wherein the exogenous chemical is a e.g., an exogenous chemical can include any drug, hormone, selective serotonin reuptake inhibitor (SSRI). Symptoms chemical or therapeutic agent administered to a subject. The associated with the abrupt reduction in SSRI levels in a sub symptoms can be associated with a physical addiction and/or 55 ject can vary, are known in the art, and can include, e.g., a psychological addiction to the exogenous chemical. In some apathy, nausea, drowsiness, headache, bruxism, dizziness, embodiments, the symptom is associated with the cessation fatigue, urinary retention, depression, Suicidal ideation, pho of the administration of the exogenous chemical Such as, for tosensitivity, and combinations thereof. example, withdrawal symptoms associated with the abrupt As used herein, “administering or “administration” refers cessation in administering an opiate, stimulant, or other 60 to the process of transferring an amount of an active agent chemical Substance. In some embodiments, the symptom can from a single dosage form to a subject. In some embodiments, be associated with the physical or psychological addiction to administering means releasing an amount of active agent a stimulant, an opiate, a benzodiazepine, a barbiturate, or a from a single dosage form to a Subject. selective serotonin reuptake inhibitor (SSRI). In some Various modes of administration can be used in the present embodiments, the symptom is an adverse reactionina Subject 65 invention. For example, single dosage forms administered by associated with ceasing the regular administration of an exog the methods of the present invention can be administered enous chemical to which the subject has developed a toler intravaginally, Subcutaneously, intramuscularly, transder US 9.220,692 B2 7 8 mally, or buccally. In some embodiments, a single dosage enous chemical which is abruptly reduced in the subject. form for use with the present invention is a monolithic intra Active agents include, but are not limited to, hormones, vaginal, transdermal, buccal, Subcutaneous, or intramuscular stimulants, beta-blockers, or , opioid antago single dosage form. In some embodiments, a single dosage nists, , , and selective serotonin form for use with the present invention is a multi laminate reuptake inhibitors (SSRIs). intravaginal, transdermal, buccal, Subcutaneous, or intramus Non-limiting examples of a “hormone' include an estro cular single dosage form. In some embodiments, a single genic compound, a progestinic compound, an androgenic dosage form for use with the present invention is a composite compound, a corticosteroid, and combinations thereof. intravaginal, transdermal, buccal, Subcutaneous, or intramus An “estrogenic compound” or “estrogen refers to any of cular single dosage form. As used herein, "composite' is 10 various natural or synthetic compounds that stimulate the defined as an article that is synthesized and derives its com development of female secondary sex characteristics and pro position and function from more than one material or com mote the growth and maintenance of the female reproductive pound. system; or any other compound that mimics the physiological “Intravaginally refers to administration of an active agent effect of natural estrogens, whether or not steroidal in struc through the vaginal, uterine, or cervical mucosa or tissue. 15 ture. Suitable estrogenic compounds for use with the present Non-limiting examples of suitable intravaginal single dosage invention include, but are not limited to, 17o-estradiol, 17 B forms for use with the methods of the present invention estradiol, , , estradiol includes an intravaginal ring, an intra-uterine dosage form, a cypionate, estradiol heptanoate, estradiol decanoate, estra vaginal pessary, and a vaginal tablet. diol acetate, , 17a-, ethi “Transdermally” refers to administration of an active agent nylestradiol-3-acetate, ethinylestradiol-3-benzoate, , across a dermal membrane. “Buccally” refers to administra , polyestrolphosphate, , estrone tion of an active agent across the mucosa or tissue of the acetate, , , piperazine estrone mouth. In some embodiments of the present invention, the Sulfate, , , , , active agent is administered via a transdermal or buccal uni delta-8,9-dehydro estrone, a sulfate of equilin, a sulfate tary dosage form. The transdermal or buccal dosage form can 25 ester of delta-8,9-dehydro estrone, and combinations thereof. be occlusive or non-occlusive. Non-limiting examples of suit Various conjugated estrogens can also be administered able transdermal or buccal single dosage forms for use with from a single dosage form of, or for use with, the present the present invention includes a patch, an adhesive patch, a invention. As used herein, the term "conjugated refers to the reservoir dosage form, a matrix dosage form, a multi-laminar Sulfate ester, glucuronide ester, or mixed Sulfate-glucuronide patch, a non-occlusive patch, a bioadhesive tablet, and a bio 30 , of an estrogen. Estrogens also include pharmaceuti adhesive plaster. Transdermal and buccal single dosage forms cally Suitable forms of a an estrogenic compound. In for use with the methods of the present invention can further some embodiments, the salt is a , potassium, or comprise a bio-adhesive layer useful to adhere the single 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris) salt. dosage form to the dermis or mucosa of a Subject. Suitable conjugated estrogens for use with the present “Subcutaneously” refers to administration of an active 35 invention include, but are not limited to, sodium estrone Sul agent to tissues or blood vessels immediately below the skin. fate, sodium equilin Sulfate, sodium 17C.-dihydroequilin Sul “Intramuscularly refers to administration of an active agent fate, sodium 17 B-dihydroequilin sulfate, sodium 17C.-estra through direct absorption by muscle tissues Surrounding a diol sulfate, sodium 17 B-, sodium Subcutaneous single dosage form without passing through a sulfate, sodium 17C.-dihydroequilenin sulfate, sodium 17 B mucosal or dermal membrane. Non-limiting examples of 40 dihydroequilenin sulfate or combination thereof. In some Suitable Subcutaneous or intramuscular single dosage forms embodiments, the composition of the present invention com for use with the methods of the present invention include prises a conjugated estrogen Such as, but not limited to, implantable dosage forms. Sodium estrone Sulfate, Sodium equilin Sulfate, sodium 17C.- As used herein, a “subject” refers to a human, or non dihydroequilin sulfate, sodium 17 B-dihydroequilin sulfate, human animal, to which a single dosage form of or for use 45 sodium 17C.-estradiol sulfate, sodium 17 B-estradiol sulfate, with, the present invention is administered. In some embodi Sodium equilenin Sulfate, sodium 17C-dihydroequileninsul ments, the Subject is a domesticated animal, a herd animal, or fate, sodium 17 B-dihydroequilenin sulfate, A8.9-dehy an animal in captivity, e.g., present in a Zoo, in some embodi droestrone sulfate, and combination thereof. ments, the Subject is a female human. In some embodiments, Non-limiting examples of suitable progestinic compounds the Subject is a male human. 50 for use with the present invention include acetoxypreg As used herein, the term “single dosage form' refers to not nenolone, allylestrenol, anagestone acetate, chlormadinone more than one unitary dosage form being administered to a acetate, cyproterone, , desogestrel, dihy Subject to reduce the symptom associated with an abrupt drogesterone, dimethisterone, 17O-ethinyltestosterone, reduction in an endogenous or exogenous chemical in a Sub ethynodiol diacetate, fluorogestone acetate, gestadene, ject. “Unitary” refers to a dosage form that consists of one part 55 hydroxyprogesterone, hydroxyprogesterone acetate, hydrox or unit. Thus, a “single dosage form' is administered to a yprogesterone caproate, hydroxymethylprogesterone, Subject in its entirety. In some embodiments, a single dosage hydroxymethylprogesterone acetate, 3-ketodesogestrel, is also removed from a subject in its entirety except for the levonorgestrel, , medrogestone, medroxyprogest endogenous or exogenous chemical released from the single erone acetate, megestrol, , melengestrol dosage form. In some embodiments, the single dosage form 60 acetate, norethindrone, norethindrone acetate, norethister does not change in size or shape during the administration. one, acetate, norethynodrel, norgestimate, An “active agent” refers to an endogenous or exogenous norgestrel, norgestrienone, normethisterone, progesterone, chemical that has a physiological or psychological effect on a trimegestone, norelgestromin, and combinations thereof. Subject. In some embodiments, the active agent can be the An "androgenic compound' or "' refers to any of same as the endogenous or exogenous chemical which is 65 various natural or synthetic compounds that stimulate the abruptly reduced in the subject. In some embodiments, the development of male secondary sex characteristics. Non-lim active agent can be different than the endogenous or exog iting examples of androgenic compounds for use with the US 9.220,692 B2 10 present invention include the naturally occurring androgens dine, , , , , ketobemi and derivatives thereof, and the following: , done, carfentanyl, propoxyphene, , dex androsterone acetate, androsterone propionate, androsterone tromoramide, , , , benzoate, , androstenediol-3-acetate, andros , , , nalbufine, dezo tenediol-17-acetate, androstenediol-3,17-diacetate, andros- 5 cine, , , , , diphenoxy tenediol-17-benzoate, androstenediol-3-acetate-17-ben late, and combinations thereof. “” refers to Zoate, , , sodium an agent that binds to opioid receptors but does not activate dehydroepiandrosterone Sulfate, 4-dihy the opioid receptors. Non-limiting examples of an opioid drotestosterone, 5C-, dromostanolone, antagonist for use with the present invention include nalox dromostanolone propionate, methandrostenolone, testolac- 10 one, , , and combinations thereof. tone, bolasterone, , , A “benzodiazepine” refers to anxiolytics that act on the phenpropionate, nandrolone decanoate, nandrolone furylpro central nervous system. Non-limiting examples of benzodi pionate, nandrolone cyclohexanepropionate, nandrolone azepines for use with the present invention include , benzoate, nandrolone cyclohexanecarboxylate, , lorazepam, prazepam, , , flu ethylestrenol, , stanozolol, testosterone, testosterone 15 razepam, oxazepam, triazolam, temazepam, midazolam, enanthate, testosterone propionate, testosterone cypionate, medazepam, chlordiazepoxide, alprazolam, estaZolam, testosterone phenylacetate, testosterone acetate, testosterone quazepam, cloraZepate, and combinations thereof. isobutyrate, testosterone buciclate, testosterone heptanoate, A “barbiturate” refers to a sedative drug related to barbi testosterone decanoate, testosterone undecanoate testoster turic acid. Non-limiting examples of barbiturates for use with one caprate and testosterone isocaprate, 4-dihydrotestoster- 20 the present invention include barbital, barbituric acid, phe one enanthate, 4-dihydrotestosterone propionate, 4-dihy nobarbital, butalbital, secobarbital, aprobarbital, amobar drotestosterone cypionate, 4-dihydrotestosterone phenyl bital, talbutal, and combinations thereof. acetate, 4-dihydrotestosterone acetate, 4-dihydrotestosterone A “selective serotonin reuptake inhibitor” or “SSRI” refers isobutyrate, 4-dihydrotestosterone buciclate, 4-dihydrotest to an antidepressant drug that blocks the neuronal uptake of osterone heptanoate, 4-dihydrotestosterone decanoate, 4-di- 25 serotonin, thereby resulting in increased extracellular levels hydrotestosterone undecanoate, 4-dihydrotestosterone of serotonin. Non-limiting examples of SSRIs for use with the caprate, 4-dihydrotestosterone isocaprate, methyl more present invention include citalopram, dapoxetine, escitalo thandrolone, esterolone, , oxymetholone, flu pram, fluvoxamine, paroxetine, Sertraline, Zimelidine, and oxymesterone, and combinations thereof. combinations thereof. A “corticosteroid’ refers to any of various adrenal-cortex 30 As used herein, "rate.” “release rate, and “rate of release' . Non-limiting examples of corticosteroids for use refer to the dose per unit time by which an active agent is with the present invention include , hydrocortisone, released from a single dosage form, e.g., the release rate refers prednisone, methylprednisolone acetate, betamethasone to the amount of an active agent released from the single dipropionate, fluocinolone actinide, betamethasone Valerate, dosage form divided by the period of time over which the triamcinolone actinide, clobetasol propionate, desoximeta- 35 releasing occurred. The units associated with rate generally Sone, diflorasone diacetate, amcinonide, flurandrenolide, correspond to an amount (i.e., moles, grams, milligrams, hydrocortisone Valerate, hydrocortisone butyrate, desonide, cubic centimeters, milliliters, etc.) per unit time (i.e., seconds, and combinations thereof. minutes, hours, days, weeks, months, years, etc.). A “stimulant” refers to any Substance that causes an The release rate can be determined by numerous methods increase in activity in various parts of the nervous system, or 40 either in vivo or , as known by those in the art. For directly increases muscle activity. Non-limiting examples of example, in vitro release rates can be determined by placing a stimulants for use with the present invention include nicotine, single dosage form in a reservoir containing a solution for a caffeine, theophylline, theobromine, amphetamine, metham first period of time and measuring a first release rate. The phetamine, dextroamphetamine, phendimetrazine, benzphet single dosage form is removed from the reservoir and the amine, methylene-dioxymethamphetamine, , 45 amount of active agent released into the Solution is measured pemoline, diethylpropion, 3.4-methylene-dioxyamphet (i.e., by chromatography, spectroscopy, or some other amine, , methylphenidate, dexmethylphenidate, method), giving a first rate. The single dosage form is then 1-amphetamine, and combinations thereof. placed in a reservoir containing a fresh Solution for a second A “beta-adrenergic blocking agent” or “beta-blocker' period of time. The single dosage form is removed and the refers to a drug that opposes the excitatory effects of norepi- 50 amount of active agent released into the second solution is nephrine released from sympathetic nerve endings at beta measured to give the second rate. Similarly, the release rate of receptors. Beta-blockers can slow the heart rate, reduce blood the active agent from the single dosage form can be measured pressure and reduce anxiety. Beta-blockers are typically used in vivo, e.g., the single dosage form can be administered to a in the treatment of angina, heart arrhythmias, high blood subject, and then the release rate of the active agent from the pressure (i.e., hypertension), mitral valve prolapse, migraine 55 dosage form can be determined indirectly by measuring the and other conditions. Non-limiting examples of beta-block plasma levels of the active agent over time. ers for use with the present invention include acebutolol, While in some embodiments, the onset of administration atenolol, betaxolol, bisoprolol, carteolol, esmolol, labetalol, can result in an initially increasing rate until the maximum metoprolol, nadolol, penbutolol, pindolol, propranolol. dosage rate, i.e., the V, is achieved, for the methods of the Sotalol, timolol, and combinations thereof. 60 present invention the maximum dosage rate occurs rapidly “Opioid. “opiate,” or “opioid agonist” refers to any agent relative to the length of time the active agent is administered that binds to opioid receptors, which are found principally in at a tapering rate. For example, in the methods of the present the central nervous system. Non-limiting examples of opioids invention V can occur within the first 10%, 5%, or 2% of for use with the present invention include methadone, mor the total administration time. phine, , thebaine, diamorphine, , hydroc- 65 As used herein, the terms “tapers' and “tapering rate” refer odone, , , , to the general inverse trend of the release rate of the active , levomethadyl acetate hydrochloride, pethi agent from the single dosage form, i.e., the release rates of the US 9.220,692 B2 11 12 active agent from the dosage form diminish gradually as the that the release rate of the active agent is at or below a terminal time of administration increases. If plotted on a graph of units symptom threshold level when the administration is discon of active ingredient delivered versus time, a "tapering tinued. release rate of the present invention would produce a plot in As used herein, “terminal symptom threshold level” refers which the rate of administering an active agent (the y-axis to a release rate of an active agent to a subject at or below variable) versus time (the x-axis variable) would display a which the administration can be discontinued without induc negatively sloped line or curve. In some embodiments, a ing a symptom associated with an abrupt reduction in an statistically relevant fit of the release rate of the active agent endogenous or exogenous chemical in the Subject. In some from the dosage form measured at various times once the embodiments, a terminal symptom threshold level refers to a 10 release rate of the active agent in which removal of the single release rate is at or below the symptom threshold level, will dosage form from the Subject will not cause significant produce a negatively, or tapering, sloped line or curve. In adverse effects. In some embodiments, a terminal symptom Some embodiments, if plotted on a graph, a tapering release threshold level refers to a release rate of the active agent in rate of the present invention would produce a plot similar to which abrupt disruption or cessation of the administration FIG.1. In some embodiments, a statistically relevant fit of the 15 will not result in a symptom in the Subject. negatively sloped portion of the plot results in a fit with a first For example, a terminal symptom threshold level for order exponentially gradually tapering slope, i.e., a “first reducing a symptom associated with menopause can include order exponentially tapering rate. In some embodiments, a administering an equivalent conjugated estrogen (PRE statistically relevant fit of the negatively sloped portion of the MARINR) at a release rate of about 0.1 mg/day to about 2.0 plot results in a biphasic linear curve, i.e., a “biphasically mg/day, a release rate of about 0.2 mg/day to about 1.0 linearly tapering rate.” mg/day, or a release rate of about 03 mg/day to about 0.8 In some embodiments, if plotted on a graph, a "tapering mg/day. release rate of the present invention would produce a plot in For example, a terminal symptom threshold level for which the cumulative amount of active agent released from reducing a symptom associated with an addiction to nicotine the single dosage form (the y-axis variable) versus time (the 25 can include administering nicotine at a release rate of about x-axis variable) would display a positively sloped line or 5.0 mg/day to about 20 mg/day, a release rate of about 2.5 curve. In some embodiments, the slope of the line gradually mg/day about 10 mg/day, or a release rate of about 0.1 mg/day approaches Zero. to about 3.0 mg/day. For example, a terminal symptom In some embodiments, there is a correlation between the threshold level for reducing a symptom associated with an 30 addiction to heroin, or another opiate substance, can include tapering release rate from the single dosage form and a reduc administering methadone at a release rate of about 1.0 mg/day tion in the systemic level of the active agent within the sub to about 100 mg/day, or a release rate of about 20 mg/day to ject. In some embodiments, the tapering rate does not corre about 40 mg/day. late with the systemic level of active agent within the subject While not being bound by any particular theory, reducing a because of for example, the pharmacokinetics of the active 35 symptom by a method of the present invention is achieved by agent, a first-pass of the active agent, etc., or administering an amount of an active agent from a single because the active agent is delivered directly to the organs, dosage form, wherein the release rate of the active agent from largely or completely bypassing systemic administration. the single dosage form is above the symptom threshold level. In some embodiments, the single dosage form is adminis and wherein the release rate of the active agent tapers tered without any breaks, discontinuities, or interruptions. In 40 throughout the administration. By administering the active Some embodiments, the administration is lacking steps or agent at a tapering release rate, the Subject can respond to the tiers. Thus, if plotted on a graph, the release rate of the present administration by requiring a decreasing amount of the active invention versus time could be fit by a single, continuous line agent to reduce the symptom. Thus, the symptom threshold with Substantially no breaks, discontinuities, interruptions, level can also decrease throughout the administration. While and/or abrupt changes in the slope of the line. 45 not being bound by any particular theory, because the admin In some embodiments, the release rate of the active agent istration of the active agent tapers over time, there is no from the single dosage form is initially above a symptom inducement or reoccurrence of the symptom in the Subject threshold level and tapers throughout the administration. In that can result from a break, interruption, abrupt reduction, or Some embodiments, the release rate of the active agent tapers discontinuity in the administration. In some embodiments, once the release rate of the active agent is at or below the 50 the release rate of the active agent tapers until discontinuing symptom threshold level. As used herein, a “symptom thresh the administration will not result in a reduction of a symptom old level” refers to the minimum release rate of active agent associated with an abrupt reduction in an endogenous or needed to reduce a symptom in a subject. Thus, if the release exogenous chemical in a Subject. rate of the active agent abruptly falls below the symptom The methods of the present invention can be used in con threshold level, a symptom can occur in the Subject. 55 junction with other methods and dosage forms. For example, In some embodiments, the methods of the present inven administering an active agent at a constant dosage regimen tion can include discontinuing administration of the single results in a discontinuity at the conclusion of the regimen. dosage form of the present invention by removing the single Additionally administering an active agent by a step-down dosage form from the subject after the release rate of the dosage regimen results in discontinuous administering during active agent is at or below a terminal symptom threshold 60 and at the conclusion of the regimen, which can result in a level. “Removing the single dosage form can include reoccurrence of the condition, or the symptoms thereof, extracting an intravaginal single dosage form, Surgically thereby diminishing the effectiveness of the regimen. Thus, removing a Subcutaneous or intramuscular single dosage the methods of the present invention can be administered at form, and peeling off a transdermal or buccal single dosage the conclusion of either a constant dosage or step-down dos form. In some embodiments, the administration can be dis 65 age regimento improve the effectiveness of these regimens in continued after a pre-determined amount of time, if the pre treating the condition, and preventing a reoccurrence of a determined amount of time is sufficiently long enough Such condition or the symptoms thereof. US 9.220,692 B2 13 14 The intravaginal, transdermal, buccal, Subcutaneous, or active agent to a Subject at a release rate that tapers for about intramuscular dosage form for use with the present invention three days to about ten days. In some embodiments, single can comprise an excipient. An "excipient” refers to a phar dosage forms for use with the present invention transdermally macologically inert Substance that enables the active agent to or buccally administer an active agent to a subject at a release be released from the single dosage form at a tapering rate. In 5 rate that tapers for about four days to about ten days, in some Some embodiments, an excipient can be contained in, or embodiments, single dosage forms for use with the present comprise, a bio-adhesive layer of a transdermal or buccal invention transdermally or buccally administer an active dosage form. Suitable excipients include Solubilizing agents, agent to a subject at a release rate that tapers for about five permeation enhancers and penetration enhancers. days to about ten days. In some embodiments, the present invention is directed to 10 In some embodiments, single dosage forms for use with the a single dosage form for intravaginally, transdermally, buc present invention Subcutaneously or intramuscularly admin cally, Subcutaneously, or intramuscularly administering an ister an active agent to a subject for a release rate that tapers active agent to a Subject to reduce a symptom associated with for about one month to about one year. In some embodiments, an abrupt reduction in an endogenous or exogenous chemical single dosage forms for use with the present invention Sub in a Subject, the dosage form comprising a carrier and an 15 cutaneously or intramuscularly administer an active agent to active agent. As used herein, “a carrier refers to a material a subject at for a release rate that tapers for about one month that is miscible with that active agent, a material in which the to about three months. In some embodiments, single dosage active agent is soluble, or a solid material that can be uni forms for use with the present invention subcutaneously or formly blended with the active agent, (e.g., polymeric mate intramuscularly administer an active agent to a subject for a rials such as polyacrylic and poly(alkyl)acrylic acids, elasto release rate that tapers for about one month to about six meric , hydrophilic and hydrophobic cellulose months. In some embodiments, single dosage forms for use derivatives, etc.) A carrier can comprise anyone of a , with the present invention Subcutaneously or intramuscularly an emulsion, a plaster, a gel, an epoxy, an oil, a Surfactant, and administer an active agent to a Subject for a release rate that combinations thereof, that can be used to contain or solubilize tapers for about one year or longer. an active agent. In some embodiments, the carrier can com 25 In some embodiments, the active agent can be passively prise a matrix, reservoir, film, ring, laminar or multilaminate released from the single dosage form. As used herein, "pas structure, plaster, or gel useful for containing or storing, and sively released refers to release of the active agent through then releasing an active agent. non-mechanical means. In some embodiments, the active The single intravaginal, transdermal, buccal, or subcutane agent is passively released from the single dosage form ous dosage forms of the present invention for use with the 30 through, but not limited to, diffusion, secretion, or osmosis. In methods of the present invention can further comprise one or Some embodiments, the active agent is actively released from more rate-controlling layers, membranes, or films that sur the single dosage form. As used herein, “actively released” round the active agent or that the active agent must pass refers to the release of the active agent through mechanical through to be released from the single dosage form. A rate means. In some embodiments, the active agent is actively controlling layer can control the rate of release of the active 35 released from the single dosage form through, but not limited agent from the single dosage form, and ensure that the rate of to, osmotic pumps, electrically driven pumps, or piezoelectric release tapers over an extended period of time. elements that release active agents in response to an applied The single dosage forms for use with the present methods Current. of the invention release an active agent for a period of time to The total amount of an active agent administered to a reduce a symptom associated with an abrupt reduction in an 40 subject can be varied, but must be sufficient to administer the endogenous or exogenous chemical in a Subject. The period active agent at the desired rates throughout the administration of time for which a single dosage form is administered can period. The amount of the active agent to be administered to depend on the method by which the dosage form is adminis a subject can be determined by the nature of the symptom tered (i.e., intravaginally, transdermally, buccally, intramus and/or the characteristics of the Subject, e.g., weight, age, cularly, or Subcutaneously). In some embodiments, dosage 45 health, etc. In some embodiments the amount of the active forms of the present invention are capable of releasing an agent administered to a subject can be determined by a person active agent for extended periods of time. The period of time of skill in the art. One of skill in the art can perform pharma a dosage form is administered can vary depending on the cokinetic studies and use the results thereof to adjust the method of administering the dosage form, the type of an dosage amount to a suitable level, or determine an appropriate active agent, the amount of an active agent, and the symptom 50 dosage amount based on systematically varying the dosage that is being reduced. amount administered to a Subject and monitoring the Symp in Some embodiments, single dosage forms for use with the toms of the Subject after the administration. Appropriate ani present invention intravaginally administer an active agent to mal studies can be performed to determine an appropriate a subject a release rate that tapers for about one week to about dosage amount. As used herein, "one of skill in the art one year, or greater than one year, up to about four years. In 55 includes, for example, a physician, a physicians assistant, a Some embodiments, single dosage forms for use with the nurse practitioner, a pharmacist, pharmacologist, phamiaco present invention intravaginally administer an active agent to kineticist and a customer service representative. a subject at a release rate that tapers for about one week to The present invention is directed to a kit, or “therapeutic about six months. In some embodiments, single dosage forms package comprising a single dosage form and a label com for use with the present invention intravaginally administeran 60 prising directions for the use of the package for reducing a active agent to a Subject at a release rate that tapers for about symptom associated with an abrupt reduction in an endog one week to about three months. In some embodiments, enous or exogenous chemical in a subject. In some embodi single dosage forms for use with the present invention intra ments, a therapeutic package can comprise a cardboard or vaginally administer an active agent to a subject at a release paper package with printed instructions. A kit or therapeutic rate that tapers for about one week to about one month. 65 package can contain a single dosage form. In some embodi In some embodiments, single dosage forms for use with the ments, a kit or therapeutic package can contain a single dos present invention transdermally or buccally administer an age form of a given strength. A “label' or “printed instruc US 9.220,692 B2 15 16 tions' can be in a form prescribed by a governmental agency mm to 60 mm, an inner diameter of 10 mm to 40 mm, and a regulating the manufacture, use or sale of pharmaceuticals or cross-sectional diameter of 5 mm to 8 mm. The support of the biological products, which notice reflects approval by the intravaginal ring has a cross-sectional diameter of 2 mm to 4 agency of the manufacture, use or sale for human administra . tion to reduce a symptom. The kit can further comprise printed matter, which, e.g., provides information on the use of Example 4 the single dosage form to reduce a symptom, or a pre-re corded media device which, e.g., provides information on the Reduction of Symptoms Associated with Heroin use of the single dosage form to reduce a symptom. “Printed Addiction matter can be, for example, one of a book, booklet, brochure 10 or leaflet. The printed matter can describe the use of the single A female Subject suffering from Symptoms associated with dosage form of the present invention to reduce a symptom heroin addiction is administered a vaginal ring comprising associated with an abrupt reduction in an endogenous or methadone as described in Example 3. Upon administration exogenous chemical in a Subject. Possible formats included, of the methadone vaginal ring to the Subject, methadone is but are not limited to, a bullet point list, a list of frequently 15 released from the Vaginal ring at a rate sufficient to reduce the asked questions (FAQ) or a chart. Additionally, the informa symptoms associated with heroin, wherein the release rate of tion to be imparted can be illustrated in non-textual terms methadone tapers over about 30 days. After about 30 days, the using pictures, graphics or other symbols. release rate of methadone has tapered to, or below, a terminal All of the various embodiments or options described herein symptom threshold level. The methadone vaginal ring is then can be combined in any and all variations. removed from the subject without inducement or reoccur The following examples are further illustrative of the rence of symptoms associated with heroin addiction in the present invention, but are not to be construed to limit the Subject. Scope of the present invention. Example 5 Example 1 25 Preparation of a Vaginal Ring Comprising Nicotine Preparation of an Estradiol Vaginal Ring A vaginal ring comprising trifluoropropylmethyl/dimethyl A vaginal ring containing estradiol, silicone polymers and siloxane is made as described in U.S. Pat. No. 6,436,428, barium Sulfate is prepared according to methods known in the 30 except nicotine is added as an active agent instead of oxybu art. See physicians leaflet for ESTRING(R) (estradiol vaginal tynin. The ring is given 24 hours at ambient conditions to ring, Pfizer, Inc., New York, N.Y., August 2008). The vaginal allow the ring to fully cure, resulting in a vaginal ring com ring demonstrates release kinetics for an estradiol over a prising nicotine. period of time. A plot of the release rate will show a release rate of about 0.3 ug/hour one hour after administration. The 35 Example 6 vaginal ring continues to release estradiol from the ring over the course of about nine months. The release rate of estradiol Reduction of Symptoms Associated with Nicotine from the ring tapers, without abrupt changes, until the release Addiction rate is at or below a terminal symptom threshold level in Subject. 40 A female Subject suffering from Symptoms associated with nicotine addiction is administered a vaginal ring as described Example 2 in Example 5. Upon administration of the nicotine Vaginal ring to the Subject, nicotine is released from the vaginal ring Reduction of Symptoms Associated with Menopause at a rate Sufficient to reduce the symptoms associated with 45 nicotine addiction, wherein the release rate of nicotine tapers A female Subject Suffering from Symptoms associated with over about six months. After about six months, the releaserate menopause, e.g., hot flashes, is administered a vaginal ring of nicotine has tapered to, or below, a terminal symptom comprising ethinyl estradiolas described in Example 1. Upon threshold level. The nicotine vaginal ring is then removed administration of the ethinyl estradiol vaginal ring to the from the subject without inducement or reoccurrence of the Subject, ethinyl estradiol is released from the vaginal ring at a 50 symptoms associated with nicotine addiction in the Subject. rate sufficient to reduce the occurrence of hot flashes in the These examples illustrate possible embodiments of the subject, wherein the release rate of ethinyl estradiol tapers present invention. While the invention has been particularly over about 1 year. After one year, the release rate of ethinyl shown and described with reference to some embodiments estradiol has tapered to, or below, a terminal symptom thresh thereof, it will be understood by those skilled in the art that old level. The vaginal ring is then removed from the subject 55 they have been presented by way of example only, and not without inducement or reoccurrence of hot flashes in the limitation, and various changes in form and details can be Subject. made therein without departing from the spirit and scope of the invention. Thus, the breadth and scope of the present Example 3 invention should not be limited by any of the above-described 60 exemplary embodiments, but should be defined only in accor Preparation of a Vaginal Ring Comprising dance with the following claims and their equivalents. Methadone All documents cited herein, including journal articles or abstracts, published or corresponding U.S. or foreign patent An intravaginal ring is prepared as described in U.S. patent applications, issued or foreign patents, or any other docu application Ser. No. 12/539,568, except methadone is placed 65 ments, are each entirely incorporated, by reference herein, in the vaginal ring instead of estrogen and progestin. The including all data, tables, figures, and text presented in the resulting intravaginal ring has an outer diameter of about 40 cited documents. US 9.220,692 B2 17 18 What is claimed is: 9. The method of claim 1, wherein the symptom is associ 1. A method of reducing a symptom associated with an ated with an addiction to an exogenous chemical. abrupt reduction in an endogenous or exogenous chemical in 10. The method of claim 9, wherein the active agent is a subject, the method comprising: (a) Vaginally administering to the Subject a single admin selected from the group consisting of nicotine, caffeine, and istration of a single dosage form comprising an active methadone. agent, wherein the release rate of the active agent from 11. The method of claim 1, wherein the single dosage form the single dosage form tapers throughout the adminis is selected from the group consisting of an intravaginal ring, tration; and an intrauterine dosage form, and a vaginal pessary. (b) removing the single dosage form from the Subject after 12. The method of claim 1, wherein the single dosage form the release rate of the active agent is at or below a 10 is an intravaginal ring. terminal symptom threshold level. 13. The method of claim 1, wherein the dosage form is an 2. The method of claim 1, wherein the single dosage form implant. is administered to the subject for about one week to about one 14. The method of claim 1, wherein the release rate of the year. 15 active agent tapers linearly throughout the administration. 3. The method of claim 1, wherein the single dosage form 15. The method of claim 1, wherein the release rate of the is administered to the subject for about at least three days. active agent tapers biphasically throughout the administra 4. The method of claim 1, wherein the symptom is associ ated with menopause. tion. 5. The method of claim 1, wherein the active agent is a 16. The method of claim 1, wherein the release rate of the hormone. active agent tapers first order exponentially throughout the 6. The method of claim 5, wherein the hormone is selected administration. from the group consisting of an estrogenic compound, a 17. The method of claim 1, wherein the active agent is progestinic compound, an androgenic compound, a corticos passively released from the single dosage form. teroid, and combinations thereof. 18. The method of claim 1, wherein the active agent is 7. The method of claim 1, wherein the symptom is associ 25 actively released from the single dosage form. ated with withdrawal due to a cessation in the administration 19. A therapeutic package comprising: of an endogenous or exogenous chemical to the Subject. (a) the single dosage form of claim 1; and 8. The method of any one of claim 7, wherein the active (b) a label comprising directions for use of the single dos agent is selected from the group consisting of a stimulant, a age form for reducing a symptom associated with the beta-blocker, an opioid, an opioid antagonist, a benzodiaz 30 abrupt reduction in an endogenous or exogenous chemi epine, a barbiturate, and a selective serotonin reuptake inhibi cal in a subject. tor (SSRI).