|||||||||||| USOO5098714A United States Patent (19) 11 Patent Number: 5,098,714 Wright et al. (45) Date of Patent: Mar. 24, 1992 54) OSMOTIC, ORAL DOSAGE FORM FOR 4,309,996 l/1982 Theeuwes ........................... 28/260 FERTILITY CONTROL 4,320,759 3/1982 Theeuwes ........................... 128/260 o 4,449,983 5/1983 Cortese et al. ...................... 604/892 75 Inventors: Jeri D. Wright, Dublin; Jerry D. 4,772,474 9/1988 Eckenhoff et al. ................. 424/465 Childers, Fremont; Brian L. Barclay, 4,814,182 3/1989 Graham et al. ..................... 424/484 Sunnyvale; Patrick S. Wong, Palo Alto; Linda E. Atkinson, Portola OTHER PUBLICATIONS Valley, all of Calif. Wurster, Dale E.; J. Am. Pharm. Assn., Sci. Ed., vol. 49 73)73 AssiAssignee : ALZA Corporation,ion, Palo Alto, Calif.Cali Wurster,(1960), pp. Dale 82-4. E.; J. An. Pharm. Assoc., Sci. Ed., vol. 48 21 Appl. No.: 437,480 (1959), pp. 451-54. 22 Filed: Nov. 16, 1989 - The Pharmacological Basis of Therapeutics, by Goodman & Gilman, 7th Ed., (1985), pp. 1430-39. 5) Int. C.’................................................ A61K 9/24 52 U.S. Cl. .................................... 424/473; 424/471; Primary Examiner-Thurman K. Page 424/472 Assistant Examiner-Leon R. Horne 58 Field of Search ........................ 424/473, 471, 472 Attorney, Agent, or Firm-Paul L. Sabatine; Edward L. (56) References Cited Mandell; Jacqueline S. Larson U.S. PATENT DOCUMENTS (57) ABSTRACT 2,799,241 7/1957 Wurster ................................ 1824. An osmotic device is disclosed comprising an exterior 3,133,132 5/1964 Loeb et al. ............ 264/49 coat comprising an estrogenic and a progestogenic ste 3,845,770 1 1/1974 Theeuwes et al. .... ... 28/30 roid that are delivered immediately as a contraceptive 3,916,899 11/1975 Theeuwes et al..... ... 28/260 pair for fertility regulation in a female, and a compart 4,063,064 12/1977 Saunders et al. ..... a - 21/12 ment comprising an estrogenic steroid that is delivered 4,088,864 5/1978 Theeuwes et al..... 4,160,020 7/1979 Ayer et al............. - a a 219/260 at a controlled rate over a prolonged period of time for 4,177,256 12/1979 Michaels et al... r 3.2 fertility regulation in a female. 4,200,098 4/1980 Ayer et al..... ..125/260 4,285,987 8/1981 Ayer et al.. 427/3 9 Claims, 2 Drawing Sheets U.S. Patent Mar. 24, 1992 Sheet 1 of 2 5,098,714 FG. 4-2 U.S. Patent Mar. 24, 1992 Sheet 2 of 2 5,098,714 FG4 200.00 0. O O 0.00 6.00 TIME (HOURS) FG5 500 O O O 0.00 TIME (HOURS) 6.00 FIG6 5. 0.00 TIME (HOURS) 800 5,098,714 1. 2 progestogen in a pulsed dose followed by the rate-con OSMOTIC, ORAL DOSAGE FORM FOR trolled delivery of an estrogen over a prolonged period FERTILITY CONTROL of time for fertility control in a warm-blooded female. Another object of the invention is to provide a phar DESCRIPTION OF TECHNICAL FIELD 5 maceutically acceptable dosage form manufactured as This invention pertains to an osmotic oral dosage an osmotic dosage form that makes available initially an form useful for fertility control. The dosage form pro estrogen and a progestogen followed by sustained and vides an initial pulsed delivery of a progestogen and an controlled delivery of an estrogen. estrogen followed by a prolonged delivery of an estro Another object of the invention is to provide a novel gen. The invention concerns also a method of adminis 10 dosage form manufactured as an osmotic device that tering orally the dosage form for providing a pulsed can administer the steroids estrogen and progestogen delivery of a progestogen and an estrogen followed by immediately on entering the gastrointestinal tract for the controlled delivery of an estrogen over an extended passage to a biological receptor site to produce the period of time. desired contraceptive effect, followed by administering 15 estrogen only to the biological receptor site for the DISCLOSURE OF BACKGROUND OF THE intended effect. INVENTION Another object of the invention is to provide an os A continuous need exists for fertility control for pro motic dosage form that comprises two regimens of viding freedom for women to chose when they want to steroid administration in the same dosage form, com have children. Efforts were made, in the early 1960's, to 20 prising (1) a first regimen that administers a steroid pair satisfy the need for fertility control with the introduc comprising an estrogen and a progestogen and (2) a tion of the oral contraceptive pill comprising an estro second regimen that administers an estrogen, and genic steroid and a progestational steroid. The contra wherein the osmotic dosage form substantially elimi ceptive pill used by the prior art comprises a tablet form nates the unwanted influences of the gastrointestinal that delivers the steroids in a bulk, nonrate, uncon 25 trolled dose. In one prior art contraceptive regimen, a environment on the steroids while they reside in the tablet comprising both an estrogen and a progestin are dosage form, and also provides for instant administra administered for about three weeks, while in another tion of the steroid by the first regimen and the con modification a tablet comprising an estrogen is adminis trolled, low-dose administration or the steroid during tered for about two weeks and a tablet comprising an the second regimen. estrogen and progestin are administered for about a Another object of the invention is to provide an os week. The contraceptive steroids were delivered as an motic dosage form that can deliver a progestational oral tablet devoid of rate-controlled delivery properties steroid at a pulsed rate of delivery for substantially because the contraceptive steroids are practically insol lessening liver metabolism of the steroid. uble in aqueous fluids and, accordingly, they do not 35 Another object of the invention is to provide an os lend themselves for manufacture into a dosage form that notic dosage form that can deliver an estrogen steroid administers the steroids at a controlled and known rate in small amounts for substantially lessening the inci per unit time. dence of side effects. The contraceptive steroids, moreover, were deliv Another object of the present invention is to provide ered by the prior art in a dose unprotected from the an osmotic dosage form that can deliver a substantially changing environment of the gastrointestinal tract, with aqueous insoluble estrogen and progestogen pair at a little consideration for the steroid's pharmacological pulsed rate, and then deliver an aqueous insoluble estro and physiological effects and the accompanying disad gen at a controlled and continuous rate over time. vantages on a recipient. For example, one disadvantage Another object of the present invention is to provide associated with the prior art tablet accompanies the 45 an osmotic dosage form adapted for oral administration dose-dumping of estrogen which can lead to gastroin of an estrogen and a progestogen, which dosage form testinal disturbances, nausea, weight-gain, edema, and comprises an external pulse released coat comprising an an increase in the incidence of thrombophelibitis and estrogen and a progestogen, and a compartment con associated cardiovascular disorders. Also, the prior art prising a first composition comprising an estrogen and a tablet does not provide for the fast release of a progesta 50 contacting second expandable composition, which com tional steroid for avoiding liver metabolism of the ste positions operate together for the controlled administra roid and the subsequent delivery of an estrogen in small tion of an estrogen over time. continuous doses for lessening the incidence of side Another object of the present invention is to provide effects in the recipient. The oral contraceptives are a complete oral contraceptive regimen useful for disclosed in The Pharmacological Basis of Therapeutics, 55 women of childbearing age which regimen comprises by Goodman and Gilman, 7th Ed., pages 1430 to 1439 an osmotic dosage form and a method of contraception, (1985), published by Macmillian Publishing Company. the use of which osmotic dosage form and method of contraception requires intervention only for initiation DISCLOSURE OF OBJECTS OF THE of the contraceptive regimen. INVENTION Another object of the invention is to provide a com Accordingly, in view of the above presentation, it is position of matter comprising an estrogen, a progesto an immediate object of this invention to provide a dos gen and a cellulose polymer, which composition can be age form comprising an estrogen and a progestogen that externally stored on and dispensed from an osmotic can be administered for fertility control, and which device for the purpose of fertility control. dosage form substantially overcomes the disadvantages 65 Another object of the invention is to provide a and omissions associated with the prior art. method for producing contraception by orally adminis Another object of the present invention is to provide tering an estrogen and a progestogen to a warm a dosage form for co-administering an estrogen and a blooded animal desiring fertility control. 5,098,714 3 4. Another object of the invention is to provide a con 14 that connects internal compartment 13 with the exte traceptive regimen comprising eighteen to twenty-three rior of dosage form 10. Dosage form 10 can comprise dosage forms, which dosage forms deliver a pulsed dose more than one exit means 14. Wall 12 of dosage form 10 of a progestational and estrogenic steroid followed by a comprises in at least a part a semipermeable composi continuous dose of an estrogenic steroid. tion that is permeable to the passage of an exterior fluid Other objects, features, and advantages of the inven present in the environment of use.