United States Patent (10) Patent No.: US 7,297,688 B2 Grubb (45) Date of Patent: Nov
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US007297.688B2 (12) United States Patent (10) Patent No.: US 7,297,688 B2 Grubb (45) Date of Patent: Nov. 20, 2007 (54) STARTER KIT FOR LOW DOSE ORAL 5,552,394 A * 9/1996 Hodgen ...................... 514,178 CONTRACEPTIVES 5,898,032 A 4/1999 Hodgen 6,027,749 A 2/2000 Schmidt-Gollwitzer et al. (75) Inventor: Gary S. Grubb, Newtown Square, PA 6,133,251 A 10/2000 Dittgen et al. (US) FOREIGN PATENT DOCUMENTS (73) Assignee: Wyeth, Madison, NJ (US) WO WO 9741870 11, 1997 WO WO 98 04268 2, 1998 (*) Notice: Subject to any disclaimer, the term of this WO WO 99.12531 3, 1999 patent is extended or adjusted under 35 WO WO 99,53910 10, 1999 U.S.C. 154(b) by 502 days. OTHER PUBLICATIONS Nordette R monograph, Physicians' Desk Reference, 50th edition, (21) Appl. No.: 09/872,250 1996, p. 2755-2758.* (22) Filed: Jun. 1, 2OO1 AlesseR)s monograph, electronicCOC Physicians'ySicians DeskS Ref.CC , Apr.pr O O Katzung Basic & Clinical Pharmacology, 6th edition, 1995, p. 620.* (65) Prior Publication Data Endrikat et al., Contraception, 1997:55(3): 131-137.* Goodman and Gilman's the Pharmacological Basis of Therapeutics, US 2002/0010167 A1 Jan. 24, 2002 9th ed., p. 1420-1421.* O O J. Endrikat et al., Contraception, 1997. 131-137, 55. Related U.S. Application Data M. Akerlund et al., Br. J. Obstetrics and Gynaecology, 1993, 832-8, (60) Provisional application No. 60/210.310, filed on Jun. 100(9). 8, 2000. * cited by examiner (51) Int. Cl. Primary Examiner San-ming Hui A6 IK33/56 (2006.01) (74) Attorney, Agent, or Firm—Arnold S. Milowsky; (52) U.S. Cl. ....................................... 514/171; 514/182 Michael A. Patané; Pepper Hamilton LLP (58) Field of Classification Search ................514/178, 514/170,172, 182 (57) ABSTRACT See application file for complete search history. The present invention provides a contraceptive kit which (56) References Cited helps to overcome or ameliorate the problem of break through bleeding and spotting associated with lowest dose U.S. PATENT DOCUMENTS (15-20 ug EE) estrogen contraceptives. 4,530,839 A 7/1985 Pasquale 5,418,228 A 5, 1995 Bennink 11 Claims, No Drawings US 7,297,688 B2 1. 2 STARTER KT FOR LOW DOSE ORAL in the form of tablets or capsules may also contain excipients CONTRACEPTIVES Such as binders, diluents, disintegrating agents and lubricat ing agents. Placebos of the cycle pack may contain non This application claims the benefit of U.S. Provisional hormonal active agents such as iron or folic acid. Application No. 60/210,310, filed Jun. 8, 2000. Effective dose refers to the combined amount of steroid in a daily dosage unit taking into account the potency of a BACKGROUND OF THE INVENTION given steroid. The effective dose of a given steroid can be determined by one skilled in the art. Since the introduction of oral contraceptives (OCs) over Hormonal active ingredients useful as oral contraceptives a quarter-century ago, research has been directed toward 10 are well known in the art. Generally oral contraceptives developing preparations that minimize the potential for side contain an estrogen and a progestin. Hormonal active ingre effects while maintaining efficacy and normal menstrual dients may be formulated as monophasic, biphasic or tripha patterns. S1C. During the first three to four months oral contraceptive Suitable estrogens include 17-B estradiol, estrone, or a salt use, the incidence rate of breakthrough bleeding and spot 15 thereof, estriol, ethinylestradiol and mestranol. ting rates in the first cycle are about two times higher than Suitable progestins include trimegestone, nomegestrol, the rate that remains generally steady after cycle 4. This is dienogest, norgestrel, levonorgestrol, cyproterone acetate, due to the change in endometrial histology over several 3-ketodesogestrel (or etonogestrel), desogestrel, gestodene, months of OC use that is due to a progestin effect from an norethindrone, drospirenone, medroxy progesterone acetate, OC. Several months of OC use produces a more secretory megestrol acetate, norgestimate, 17B deactyl norgestimate, endometrium which is less prone to breakthrough bleeding. oSaterone, norethindrone acetate, lynestrenol, norethyno Breakthrough bleeding and spotting are the most common drel, and ethynodiol diacetate. Combination oral contracep complaint by women first using OCs and is a common tives (containing estrogen and progestins) are commercially reason for discontinuing use of OCs. Breakthrough bleeding available such as those sold under the tradenames AlesseR), and spotting rates are higher with OCs containing amounts 25 Brevicon(R), Demulen R, Desogen R, Estrostep(R), Harmo of estrogen less than about 30 ug, particularly in the first net(R), Levlen R, Levlite(R), Levora R, Loestrin R, Loette R, several months of use. LoOvral(R), Micronor R, Minesse R, Minulet(R), Mircette R, Using a constant dose of progestin, Endrikat et al., 1997 Modicon R, Necon R, Nordette R, Norinyl(R), Ortho-cept(R), found that the breakthrough bleeding/spotting rate for 30 ug Ortho-Cyclen R, Ortho-Novum(R, Ortho-Tri-Cyclen(R), ethinyl estradiol (EE) OC as compared to 20 ug EEOC was 30 68% in cycle 1, 85% in cycle 2 and 67% in cycle 3. Ovcon R, Ovral(R), Ovrette(R), Trilevlen R, Trimiron(R), Similarly, Akerlund et al. (1993) found that the BTB/S rate TriMinulet(R), Tri-Norinyl(R), Triphasil R., Trivora R, and for 30 ug EEOC as compared to 20 ug EEOC was 77% in Zovia(R). cycle 1, 60% in cycle 2 and 67% in cycle 3. These results are Kits of the present invention may contain multiple cycles consistent with the conversion to a secretory endometrium 35 dosages of various combination oral contraceptive arranged occuring more quickly with an OC containing higher EE to appropriately decrease the effective dosage of total steroid doses. from the penultimate cycle pack to the last cycle pack. For The present invention provides a contraceptive kit which instance, a kit of the present invention might combine as a helps to overcome or ameliorate the problem of break first cycle Nordette(R), as a second cycle Triphasil.R and as a through bleeding and spotting associated with lowest dose 40 third cycle Alesse?R). Alternatively, a kit of the present (15-20 ug EE) estrogen contraceptives. invention might combined first and second cycles of Nor dette R, third and fourth cycles of Triphasil.R and a fifth DETAILED DESCRIPTION OF THE cycle of Alesse R. In another embodiment of the invention, INVENTION the kit might present a first cycle of Levora R, a second cycle 45 of Trilevora(R) or Trilevlen(R) and a third cycle of LevliteR). In accordance with the present invention is provided an In yet another embodiment of the invention, a first cycle of oral contraceptive starter kit comprising two or more cycle LoestrinR 1.5/30, a second cycle of Estrostep(R) and a third packs of oral contraceptives containing an estrogen and a cycle of LoestrinR) 1/20 might be combined. Similarly, a first progestin, and having a first and a last cycle pack, the cycle of Ortho-Novum(R) 1/35, a second cycle of Ortho effective dosage of Steroid in the first cycle pack being 50 NovumR 7/7/7 and a third cycle of an OC containing greater than in Subsequent cycle packs, the last cycle pack norethindrone and an EE dose of less than or equal to 30 ug providing the Smallest amount of effective steroid dosage, are combined in a starter kit. More detailed examples of and no more than about 20 ug EE per dosage unit. The starter cycles and dosages are described in the Examples. kit provides a means to gradually decrease the dose of Although not required, in Some preferred embodiments of estrogen over a number of cycles, thereby decreasing inci 55 the present invention the progestin and estrogen should be dences of breakthrough bleeding and spotting that are often the same, although the dosages are varied throughout the associated the lose-dose estrogen contraceptives. Thus, a cycles of the kit. first cycle may contain, for example, 30 ug of estrogen per Each cycle may range in duration from 21-25 consecutive dosage unit. A second cycle may contain 30 ug of estrogen days of steroid, followed by non-contraceptive placebos for per dosage unit. A third cycle may contain 20 ug of estrogen 60 the remainder of each cycle (i.e. 3-7 days). The kit may per dosage unit. Following the completion of the starter kit, contain daily dosages arranged in dispensers such as blister standard cycle packs of lowest dose EEOC may be used. packs or dial pack dispensers. Cycle pack, as used herein, refers to an oral contraceptive The starter kit may contain 2 or more single cycle dosage pill pack generally containing from 21-25 consecutive days arrangements, or the cycles may be combined to form a of active ingredient-containing dosage units and may also 65 multi-cycle dosage arrangement. The starter kit may also contain placebos for the remainder of the cycle (3 to 7 days), contain instructional materials, markings or arrangements which are free of hormonal active ingredient. Dosage units which explain the use and order of the cycle packs. US 7,297,688 B2 3 4 In multi-cycle dosage arrangements the cycles may be separated from one another spatially and/or by other mark EXAMPLE 4-continued ings. Alternatively, blister packs containing individual cycles may be separated by perforations in the base of the Compound Amount Duration Cycle blister pack or other means suitable for separation. NET 1 mg 7 days EE 35 ug EXAMPLES NET 1 mg 21 days 3 EE 25 ug The following examples are illustrative but are not meant to be limiting of the present invention.