United States Patent (19) 11 Patent Number: 4,628,051 Pasquale (45) Date of Patent: * Dec. 9, 1986

(54) TRIPHASIC ORAL CONTRACEPTIVE 56) References Cited U.S. PATENT DOCUMENTS 75) Inventor: Samuel A. Pasquale, Basking Ridge, 4,530,839 7/1985 Pasquale ...... 514/171 N.J. 4,544,554 10/1985 Pasquale ...... 514/170 73 Assignee: Ortho Pharmaceutical Corporation, Primary Examiner-Elbert L. Roberts Raritan, N.J. Attorney, Agent, or Firm-Benjamin F. Lambert 57 ABSTRACT * Notice: The portion of the term of this patent A method of contraception in which an and a subsequent to Oct. 1, 2002 has been are administered daily in a three phase disclaimed. sequence for 21 days is disclosed. In the first phase a combination of an estrogen and a progestogen in a low 21 Appl. No.: 743,344 but contraceptively effective daily dosage correspond ing in estrogenic activity to 0.02-0.05 mg of 17a (22 Filed: Jun, 11, 1985 and in progestogenic activity to 0.065-0.75 mg of norethindrone is administered for 5-8 days; followed by the administering of the same dosage Related U.S. Application Data of estrogen and a progestogen corresponding in proges 63 Continuation-in-part of Ser. No. 607,038, May 4, 1984, togenic activity to 0.25-1.0 mg of norethindrone for Pat. No. 4,544,554, which is a continuation-in-part of 7-11 days; followed by the administering of the same Ser. No. 536,135, Sep. 26, 1983, Pat. No. 4,530,839. dosage of estrogen and a progestogen corresponding in progestogenic activity to 0.35-2.0 mg of norethindrone 51) Int. Cl...... A61K 31/56; A01N 45/00 for 3-7 days; followed by 6-8 days without administer 52 U.S. C...... 514/170; 514/177; ing either an estrogen or a progestogen. 514/182 58 Field of Search ...... 514/170 25 Claims, No Drawings 4,628,051 1. 2 progestogen, for the first 5-8 days in a contraceptively TRIPHASIC ORAL CONTRACEPTIVE effective daily dosage a progestogen equivalent in effect to about 0.065-0.75 mg of norethindrone in combination This is a continuation-in-part of application Ser. No. with an estrogen equivalent in effect to about 0.02-0.05 607,038, filed May 4, 1984, now U.S. Pat. No. 4,544,554 5 mg of ethinyl ; followed by the administration which in turn is a continuation-in-part of application for 7-11 days, of a daily dosage of a progestogen equiv Ser. No. 536,135 filed Sept. 26, 1983. now U.S. Pat. No. alent in effect to about 0.25-1.0 mg of a norethindrone 4,530,839. together with an estrogen equivalent in effect to about This invention relates to a method of effecting contra 0.02-0.50 mg of ethinyl estradiol; and followed by the ception in the human female. More particularly, this 10 administration for 3-7 days of a daily dosage of a pro invention relates to a method of effecting contraception gestogen equivalent in effect to about 0.35-2.0 mg of comprising the oral administration of a low but con norethindrone in combination with an estrogen equiva traceptively effective daily dosage of a combination of lent in effect to about 0.02-0.05 mg of ethinyl estradiol, an estrogen and a progestogen for 21 successive days. provided that the dosage of estrogen is kept constant in Oral contraceptives first became available in the early 15 each phase during the 21-day cycle. The actual weight 1960's. Since that time, a number of regimens for con amount of the dosage at each dosage level will depend trolling ovulation and conception by the administration upon the estrogenic and progestogenic activity, respec of hormones have become known and are readily avail tively, of the components selected for the dosage units. able. The oral administration of combination type prep The total number of days during which the progesto arations containing both an estrogen and a progestogen 20 gen and estrogen combinations are administered daily is has been known for some time. Some of these regimens 21. These are followed by 6-8 days which are free of are based upon consistent dosage of either an estrogen hormone administration to approximate the natural or progestogen or both throughout the period of admin 28-day menstrual cycle of the female. Day one of the istration while others are directed to regimens wherein cycle is defined as the first day of menstruation and the the amount of estrogen or progestogen or both is in 25 days are numbered sequentially thereafter until men creased or decreased during the menstrual cycle. struation occurs again. The cycle usually lasts 28 days One disadvantage inherent in the administration of but it may be slightly longer or shorter. In actual prac the aforementioned pure and modified sequential prod tice a placebo or any other hormone-free agent such as, ucts involving the administration of relatively high for example, iron supplements, may be administered doses of estrogen, in addition to the usual symptoms due 30 during this period. Thus, in a preferred regimen, phase to excessive estrogen, i.e., gastrointestinal disturbances, one would commence sometime between day 4 and day nausea, weight gain with formation of edema, etc., is an 6 of the menstrual cycle and last 5-8 days but preferably increase in the risk of thromboembolic disease. Many of 7 days, phase two would last 7-11 days, preferably 7 these disadvantages can be avoided by the administra days, while phase three would last 3 to 7 days, prefera tion of two-stage or biphasic combination contracep 35 bly 7 days. tives, but even in the biphasic products it would be The contraceptive composition employed in the pres desirable if the ability to control the cycle could be ent invention comprises 21 separate daily dosage units improved. which are adapted for successive daily oral ingestion. The administration of three-stage or triphasic combi The composition consists essentially of, as the first nation type oral contraceptives is also known. Triphasic phase, 5-8 dosage units containing, in admixture with a combinations of various types are described in U.S. Pat. pharmaceutically acceptable carrier, a combination of Nos. 4,390,531; 4,066,757; 3,957,982; 3,795,734; and an estrogen in combination with a progestogen, fol 2,431,704. lowed by, as the second phase, 7-11 dosage units con In recent years data collected on the use of various taining, a combination of an estrogen and a progesto oral contraceptive regimens have indicated that in 45 gen, followed by, as the third phase, 3-7 dosage units creased blood pressure and decreased glucose tolerance containing a combination of an estrogen and a progesto are associated with the progestogen content or proges gen followed by 6-8 dosage units free of estrogen and tational activity of oral contraceptives. In addition, the progestogen. The estrogen daily dosage is kept constant progestogen activity is associated with a decrease in in all three phases. serum high density lipoprotein values. These findings 50 Any conventional estrogen may be employed as a have prompted a greater emphasis on a reduction of the suitable component in the contraceptive regimen of this progestogen dosage in oral contraceptives. invention. The particular regimen employed in a daily There is a need, therefore, for a combination type dosage should be equal in contraceptive activity in each contraceptive which contains low concentrations of phase to a daily dosage of about 0.020-0.050 mg of estrogen and progestogen but is still effective for the 55 17a-ethinylestradiol. The preferred dosage is one equal prevention of pregnancy. to a daily dosage of about 0.035 mg of 17a-ethinyles By the present invention a triphasic oral contracep tradiol. tive regimen is provided wherein the estrogen dosage is In addition to 17a-ethinylestradiol, esters and ethers kept constant throughout the 21-day cycle while the of 17a-ethinylestradiol such as, for example, 17a progestogen dosage is gradually increased in successive ethinylestradiol 3-dimethylamino propionate, 17a doses. The purpose of the invention is to lower the total ethinylestradiol 3-cyclopentyl ether (quinestrol) and monthly dose in the oral contraceptive while 17a-ethinylestradiol 3-methyl ether () may still obtaining equivalent bleeding patterns and protec also be employed as the estrogen component. Natural tion against pregnancy as found with conventional oral such as , , estrone sulfate contraceptives. 65 piperazine salt, estradiol and , and their esters, as According to the present invention, reliable contra well as the synthetic estrogens, may also be employed. ception is achieved by administering for 21 successive The preferred estrogens are 17a-ethinylestradiol and days to a female a combination of an estrogen and a 17a-ethinylestradiol 3-methyl ether. 4,628,051 3 As the progestogen component, any progestationally -continued active compound may be employed. The progestogen is 88.9 mg. lactose anhydrous preferably administered in a daily dosage in the first 10.0 mg. pregelatanized starch N.F. phase corresponding in progestogenic activity to 0.5 mg. stearate N.T. 0.065-0.75 mg of norethindrone per day, during the 99.935 mg. total weight next phase a daily dosage corresponding in progesto 2nd Stage 7 Tablets genic activity to 0.25-1.0 mg of norethindrone per day 0.035 mg. 17a-ethinylestradiol and during the third phase a daily dosage corresponding 0.75 mg. norethindrone 88.70 mg. lactose anhydrous in progestogenic activity to 0.35-2.0 mg of norethindr 10.02 mg. pregelatanized starch N.F. ione per day. 10 0.5 mg. magnesium stearate N.F. which may be employed as a compo 100.005 mg. total weight nent in the present invention include and 3rd Stage 7 Tablets its derivatives such as, for example, 17-hydroxyprogest 0.035 mg. 17a-ethinylestradiol erone esters and 19-nor-17-hydroxyprogesterone esters, 1.0 mg. norethindrone 17a-ethinyltestosterone, 17a-ethinyl-19-nortestosterone 15 88.5 mg. lactose anhydrous and derivatives thereof, norethindrone, D-, 10.0 mg. pregelatanized starch N.F. A15 , A15 levonorgestrel , Allevo 0.5 mg. magnesium stearate N.F. norgestrel acetate oxime, and D-1713-acetoxy-136 100.035 mg. total weight ethyl-17a-ethinyl-gon-4-en-3-one oxime. The preferred progestogens are norethindrone, D-norgestrel and D 20 176-acetoxy-1313-ethyl-17a-ethinyl-gon-4-en-3-one EXAMPLE 2 oxime (). Composition of a tablet for each stage: The estrogen and progestogen components are pref erably administered together orally in a pharmaceuti 1st Stage 7 Tablets cally acceptable nontoxic carrier, but they can also be 25 0.035 mg. 17a-ethinylestradiol administered separately or parenterally. In general, the 0.50 mg. D-176-acetoxy-13,3-ethyl-17a-ethinyl-gon-4-en effective agents are processed, together with the usual 3-one oxime additives, vehicles and/or flavor-ameliorating agents 87.9 mg. lactose anhydrous normally employed in Galenic pharmacy, in accor 11.1 mg. pregelatanized starch N.F. 30 0.5 mg. magnesium stearate N.F. dance with generally accepted pharmaceutical prac 100.035 mg. total weight tices. For the preferred oral administration, tablets, 2nd Stage 7 Tablets dragees, capsules, pills, suspensions or solutions are 0.035 mg. 17a-ethinylestradiol particularly suitable; for parenteral application, oily 0.75 mg. D-17g-acetoxy-13,3-ethyl-17a-ethinyl-gon-4-en 3-one oxime solutions such as, for example, sesame oil or castor oil 35 89.70 mg. lactose anhydrous solutions which can optionally additionally contain a 9.02 mg pregelatanized starch N.F. diluent such as, for example, benzyl benzoate or benzyl 0.5 mg. magnesium stearate N.F. alcohol. 100.005 mg. total weight In the case of the preferred oral application, the 3rd Stage 7 Tablets three-phase combination-type contraceptives are pref 0.035 mg. 17a-ethinylestradiol 1.0 mg. D-17A-acetoxy-134-ethyl-17a-ethinyl-gon-4-en erably packaged in the form of a pharmaceutical kit or 3-one oxime package in which the daily dosages are arranged for 87.5 mg. lactose anhydrous proper sequential administration. This invention also 11.0 mg. pregelatanized starch N.F. relates, therefore, to a pharmaceutical unit which con 0.5 mg. magnesium stearate N.F. tains combination-type contraceptives in 28 dosage 100.035 mg. total weight units in a synchronized, fixed sequence, wherein the 45 sequence or arrangement of the dosage units corre sponds to the stages of daily administration. EXAMPLE 3 The pharmaceutical unit can be, e.g., in the form of a Composition of a tablet for each stage: transparent package having 28 dosage units arranged sequentially and consisting of 7 tablets for the first 50 phase, followed by 7 tablets for the second phase, fol 1st Stage 7 Tablets 0.035 mg. 17a-ethinylestradiol lowed by 7 tablets for the third phase, and finally foll 0.50 mg. D-norgestrel lowed by 7 placebos. A single tablet is to be taken each 90.0 mg. lactose anhydrous day over a period of 28 days. 55 9.0 mg. pregelatanized starch N.F. Without further elaboration it is believed that one 0.5 mg. magnesium stearate N.F. skilled in the art, using the preceding description, can 100,035 mg. total weight fully utilize the present invention. The following pre 2nd Stage 7 Tablets 0.035 mg. 17a-ethinylestradiol ferred specific embodiments are to be construed as 0.75 mg. D-norgestrel merely illustrative of the invention and are not meant to 60 87.70 mg. lactose anhydrous limit the invention in any way. 1.02 mg. pregelatanized starch N.F. - 0.5 mg. magnesium stearate N.F. EXAMPLE 1 100.005 mg. total weight Composition of a tablet for each stage: 3rd Stage 7 Tablets 0.035 mg. 17a-ethinylestradiol 65 1.0 mg. D-norgestrel 1st Stage 7 Tablets 89.5 mg. lactose anhydrous 0.035 mg. 17a-ethinylestradiol 9.0 mg. pregelatanized starch N.F. 0.50 mg. norethindrone 0.5 mg. magnesium stearate N.F. 4,628,051 6 -continued -continued 100.035 mg. total weight 0.5 mg. magnesium stearate N.F. 100,000 mg. total weight 3rd Stage 7 Tablets 5 0.035 mg. 17a-ethinylestradiol EXAMPLE 4 0.100 mg. D-norgestrel Composition of a tablet for each stage: 89.5 mg. lactose anhydrous 9.88 mg. pregelatanized starch N.F. 0.5 mg. magnesium stearate N.F. 1st Stage 7 Tablets 10 100.015 mg. total weight 0.035 mg. 17a-ethinylestradiol 0.180 mg. norgestimate 90.200 mg. lactose anhydrous EXAMPLE 7 9.085 mg. pregelatanized starch N.F. 0.500 mg. magnesium stearate N.F. Composition of a tablet for each stage: 100.000 mg. total weight 15 2nd Stage 7 Tablets 0.035 mg. 17a-ethinylestradiol 1st Stage 7 Tablets 0.215 mg. norgestimate 0.035 mg. 17a-ethinylestradiol 90.150 mg. lactose anhydrous 0.025 mg. D-norgestrel 9.100 mg. pregelatanized starch N.F. 90.00 mg. lactose anhydrous 0.500 mg. magnesium stearate N.F. 20 9.45 mg. pregelatanized starch N.F. 100.000 mg. total weight 0.50 mg. magnesium stearate N.F. 3rd Stage 7 Tablets 100.000 mg. total weight 0.035 mg. 17a-ethinylestradiol 2nd Stage 7 Tablets 0.250 mg. norgestimate 0.035 mg. 17a-ethinylestradiol 90.115 mg. lactose anhydrous 0.038 mg. D-norgestrel 9.100 mg. pregelatanized starch N.F. 25 87.70 mg. lactose anhydrous 0.500 mg. magnesium stearate N.F. 11.74 mg. pregelatanized starch N.F. 100.000 mg. total weight 0.50 mg. magnesium stearate N.F. 100.013 mg. total weight 3rd Stage 7 Tablets EXAMPLE 5 30 0.035 mg. 17a-ethinylestradiol 0.050 mg. D-norgestrel Composition of a tablet for each stage: 89.500 mg. lactose anhydrous 9.93 mg. pregelatanized starch N.F. 0.50 mg. magnesium stearate N.F. st Stage 7 Tablets 100.015 mg. total weight 0.035 mg. 17a-ethinylestradiol 35 0.250 mg. norethindrone 88.9 mg. lactose anhydrous 10.32 mg. pregelatanized starch N.F. EXAMPLE 8 0.5 mg. magnesium stearate N.F. Composition of a tablet for each stage: 100.005 mg. total weight 2nd Stage 7 Tablets 40 0.035 mg. 17a-ethinylestradiol 1st Stage 7 Tablets 0.375 mg. norethindrone 0.035 mg. 17a-ethinylestradiol 88.70 mg. lactose anhydrous 0.090 mg. norgestimate 10.39 mg. pregelatanized starch N.F. 90.200 mg. lactose anhydrous 0.5 mg. magnesium stearate N.F. 45 9.18 mg. pregelatanized starch N.F. 100.000 mg. total weight 0.50 mg. magnesium stearate N.F. 3rd Stage 7 Tablets 100.005 mg. total weight 0.035 mg. 17a-ethinylestradiol 2nd Stage 7 Tablets 0.500 mg. norethindrone 0.035 mg. 17a-ethinylestradiol 88.5 mg. lactose anhydrous 0.100 mg. norgestimate 10.47 mg. pregelatanized starch N.F. 50 90.150 mg. lactose anhydrous - 0.5 mg. magnesium stearate N.F. 9.23 mg. pregelatanized starch N.F. 100.005 mg. total weight 0.50 mg. magnesium stearate N.F. 100.015 mg. total weight 3rd Stage 7 Tablets EXAMPLE 6 55 0.035 mg. 17a-ethinylestradiol 0.125 mg. norgestimate Composition of a tablet for each stage: 90.115 mg. lactose anhydrous 9.230 mg. pregelatanized starch N.F. 0.500 mg. magnesium stearate N.F. 1st Stage 7 Tablets 100.005 mg. total weight 0.035 mg. 17a-ethinylestradiol 60 0.05 mg. D-norgestrel 90.0 mg. lactose anhydrous 9.43 mg. pregelatanized starch N.F. CLINICAL TESTS 0.5 mg. magnesium stearate N.F. EXAMPLE 9 100.015 mg. total weight 2nd Stage 7 Tablets 65 A preparation according to Example 1 was adminis 0.035 mg. 17a-ethinylestradiol 0.075 mg. D-norgestrel tered in three separate studies to a total of 656 women of 87.70 mg. lactose anhydrous child-bearing age. Subjects meeting the selection crite 11.69 mg. pregelatanized starch N.F. ria were administered the contraceptive formulation on 4,628,051 7 8 a regimen of 21 days on and 7 days off for up tradiol and norethindrone in a contraceptively effective to 12 cycles. daily dosage corresponding to 0.035 mg of 17a The preparation was shown to be highly efficacious ethinylestradiol and 0.50 mg of norethindrone for 7 in preventing pregnancy. In each study the bleeding daysa daily dosage equal to 0.035 mg of 17a-ethinyles pattern consistently showed a decrease in the incidence tradiol and 0.75 mg of norethindrone; and for the next 7 of mid-cycle breakthrough bleeding and/or spotting. days a daily dosage equal to 0.035 mg of 17a-ethinyles Having described the invention in specific detail and tradiol and 1.0 mg of norethindrone; followed by 7 days exemplified the manner in which it may be carried into without estrogen and progestogen administration. practice, it will be apparent to those skilled in the art 12. The contraception method of claim 1 which com that innumerable variations, applications, modifications, 10 prises administering for 21 successive days to a female and extensions of the basic principles involved may be of childbearing age a combination of 17a-ethinyles made without departing from its spirit or scope. It is to tradiol and D-173-acetoxy-13,3-ethyl-17a-ethinyl-gon be understood that the foregoing is merely exemplary 4-en-3-one oxime in a contraceptively effective daily and the present invention is not to be limited to the dosage corresponding to 0.035 mg of 17a-ethinyles specific form or arrangements of parts herein described 15 tradiol and 0.180 mg of D-1713-acetoxy-13,3-ethyl-17a and shown. I claim: ethinyl-gon-4-en-3-one oxime for 7 days; for the next 7 1. A method of contraception which comprises ad days a daily dosage equal to 0.035 mg of 17a-ethinyles ministering for 21 successive days to a female of tradiol and 0.215 mg of D-1743-acetoxy-13,3-ethyl-17a childbearing age a combination of an estrogen and a 20 ethinyl-gon-4-en-3-one oxime; and for the next 7 days a progestogen in a low but contraceptively effective daily daily dosage equal to 0.035 mg of 17a-ethinylestradiol dosage corresponding in estrogenic activity to and 0.250 mg of D-1743-acetoxy-136-ethyl-17a-ethinyl 0.02-0.05 mg of 17a-ethinylestradiol and in progesto gon-4-en-3-one oxime; followed by 7 days without es genic activity to 0.065-0.75 mg of norethindrone for 5-8 trogen and progestogen administration. days; for the next 7-11 days an estrogen daily dosage 25 13. A triphasic oral contraceptive unit consisting of equal to 0.02-0.05 mg of 17a-ethinylestradiol and in 21 separate dosage units, adapted for successive daily progestogenic activity to 0.250-1.0 mg of norethin oral administration comprising: drone; and for the next 3-7 days an estrogen daily dos 7 dosage units containing, in admixture with a phar age equal to 0.02-0.05 mg of 17a-ethinylestradiol and in maceutically acceptable carrier, a combination of progestogenic activity 0.35-2.0 mg of norethindrone; 30 an estrogen and a progestogen at contraceptively followed by 6-8 days without estrogen and progestogen effective dosages corresponding in activity to administration, provided that the estrogen daily dosage 0.02-0.05 mg of 17a-ethinylestradiol and in proges is the same for each period. togenic activity to 0.065-0.75 mg of norethindrone 2. The method of claim 1 wherein the estrogen and as the first phase; followed by 7 dosage units con progestogen are administered orally and the period 35 taining in admixture with a pharmaceutically ac specified in each phase is seven days. ceptable carrier, a combination of an estrogen at a 3. The method of claim 2 wherein the estrogen and contraceptively effective dosage corresponding in progestogen are administered in admixture. activity to 0.02-0.05 mg of 17a-ethinylestradiol 4. The method of claim 1 wherein the progestogen is and in progestogenic activity to 0.25-1.0 mg of selected from the group consisting of D-norgestrel, A15 40 norethindrone as the second phase; followed by 7 levonorgestrel, Al levonorgestrel acetate, A15 levo dosage units containing in admixture with a phar norgestrel acetate oxime, norethindrone, progesterone maceutically acceptable carrier, a combination of and D-176-acetoxy-136-ethyl-17a-ethinyl-gon-4-en an estrogen at a contraceptively effective dosage 3-one oxime. corresponding to 0.02-0.05 mg of 17a-ethinyles 5. The method of claim 1 wherein the estrogen is 45 tradiol and in progestogenic activity to 0.35-2.0 mg selected from the group consisting of 17a-ethinyles of norethindrone as the third phase, and optionally tradiol, mestranol, estrone, estrone sulfate piperazine containing 7 dosage units free of estrogen and pro salt, estradiol and estriol. gestogen; provided that the estrogen daily dosage 6. The method of claim 3 wherein the estrogen is is the same in all three phases. 17a-ethinylestradiol and the progestogen is norethin 50 drone. 14. The unit according to claim 13 wherein the dos 7. The method of claim 3 wherein the estrogen is age units are in the form of tablets. 17a-ethinylestradiol 3-methyl ether and the progesto 15. The unit according to claim 13 wherein the estro gen is norethindrone. gen is selected from the group consisting of 17a 8. The method of claim 1 wherein the estrogen is 55 ethinylestradiol, mestranol, estrone, estrone sulfate, 17a-ethinylestradiol and the progestogen is D-1713 estrone sulfate piperazine salt, estradiol and estriol. acetoxy-13,3-ethyl-17a-ethinyl-gon-4-en-3-one oxime. 16. The unit according to claim 14 wherein the estro 9. The method of claim 1 wherein the estrogen is gen is 17a-ethinylestradiol. 17a-ethinylestradiol 3-methyl ether and the progesto 17. The unit according to claim 13 wherein the estro gen is D-17B-acetoxy-13,3-ethyl-17a-ethinyl-gon-4-en 60 gen is 17a-ethinylestradiol 3-methyl ether. 3-one oxime. 18. The unit according to claim 13 wherein the pro 10. The method of claim 6 wherein the estrogen daily gestogen is selected from the group consisting of D dosage is 0.035 mg for each 7 day period and the proges norgestrel, A5 levonorgestrel, Al levonorgestrel ace togen daily dosage is 0.5 mg for the first 7 days, 0.75 mg tate, Al levonorgestrel acetate oxime, norethindrone, for the second 7 days and 1.0 mg for the third 7 days. 65 progesterone and D-17.6-acetoxy-13?-ethyl-17a-ethi 11. The contraception method of claim 1 which com nyl-gon-4-en-3-one oxime. prises administering for 21 successive days to a female 19. The unit according to claim 18 wherein the pro of childbearing age a combination of 17a-ethinyles gestogen is norethindrone. 4,628,051 10 20. The unit according to claim 18 wherein the pro 25. A triphasic oral contraceptive unit consisting of gestogen is D-17G-acetoxy-13,3-ethyl-17a-ethinyl-gon 21 separate dosage units, adapted for successive daily 4-en-3-one oxime. oral administration comprising: 21. The unit according to claim 13 wherein the estro 5-8 dosage units containing, in admixture with a gen is 17a-ethinylestradiol 3-methyl ether and the pro 5 pharmaceutically acceptable carrier, a combination gestogen is norethindrone. of an estrogen and a progestogen at contracep 22. The unit according to claim 13 wherein the estro tively effective dosages corresponding in activity gen is 17a-ethinylestradiol 3-methyl ether and the pro to 0.02-0.05mg of 17a-ethinylestradiol and in pro gestogen is D-17A-acetoxy-13,3-ethyl-17a-ethinyl-gon gestogenic activity to 0.065-0.75 mg of norethin 4-en-3-one oxime. 10 drone as the first phase; followed by 7-11 dosage 23. A composition according to claim 13 wherein the units containing in admixture with a pharmaceuti estrogen daily dosage in all three phases is equivalent to cally acceptable carrier, a combination of an estro 0.035 mg of 17a-ethinylestradiol; and the progestogen gen at a contraceptively effective dosage corre daily dosage is equivalent to 0.50 mg of norethindrone sponding in activity to 0.02-0.05 mg of 17a in the first phase, 0.75 mg of norethindrone in the sec 5 ethinylestradiol and in progestogenic activity to ond phase and 1.0 mg of norethindrione in the third 0.25-1.0 mg of norethindrone as the second phase; phase. followed by 3-7 dosage units containing in admix 24. A composition according to claim 13 wherein the ture with a pharmaceutically acceptable carrier, a estrogen daily dosage in all three phases is equivalent to combination of an estrogen at a contraceptively 0.035 mg of 17a-ethinylestradiol; and the progestogen 20 effective dosage corresponding to 0.02-0.05 mg of daily dosage is equivalent to 0.180 mg of D-1743 17a-ethinylestradiol and in progestogenic activity acetoxy-13,3-ethyl-17a-ethinyl-gon-4-en-3-one oxime in to 0.35-2.0 mg of norethindrone as the third phase, the first phase, 0.215 mg of D-176-acetoxy-13,3-ethyl and optionally containing 6-8 dosage units free of 17a-ethinyl-gon-4-en-3-one oxime in the second phase estrogen and progestogen; provided that the estro and 0.250 mg of D-17 (3-acetoxy-136-ethyl-17a-ethinyl 25 gen daily dosage is the same in all three phases. gon-4-en-3-one oxime in the third phase. k k

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65 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 4, 628 O 51 DATED December 9, 1986 INVENTOR(S) : Samuel A. PASQUALE It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

On the title page, after item 73, 's Notice" should read as follows: -- The portion of the term of this patent subsequent to July 23, 2002 has been disclaimed. --.

Signed and Sealed this Sixth Day of July, 1993 2-4./rizé MECHAEL K. KIRK Attesting Officer Acting Commissioner of Patents and Trademarks