Patent Publication Number: US-4544554-A

Title: Triphasic oral contraceptive

Description:
This is a continuation-in-part of application Ser. No. 536,135, filed Sept. 26, 1983. 
    
    
     This invention relates to a method of effecting contraception in the human female. More particularly, this invention relates to a method of effecting contraception comprising the oral administration of a low but contraceptively effective daily dosage of a combination of an estrogen and a progestogen for 21 successive days. 
     Oral contraceptives first became available in the early 1960&#39;s. Since that time, a number of regimens for controlling ovulation and conception by the administration of hormones have become known and are readily available. The oral administration of combination type preparations containing both an estrogen and a progestogen has been known for some time. Some of these regimens are based upon consistent dosage of either an estrogen or progestogen or both throughout the period of administration while others are directed to regimens wherein the amount of estrogen or progestogen or both is increased or decreased during the menstrual cycle. 
     One disadvantage inherent in the administration of the aforementioned pure and modified sequential products involving the administration of relatively high doses of estrogen, in addition to the usual symptoms due to excessive estrogen, i.e., gastrointestinal disturbances, nausea, weight gain with formation of edema, etc., is an increase in the risk of thromboembolic disease. Many of these disadvantages can be avoided by the administration of two-stage or biphasic combination contraceptives, but even in the biphasic products it would be desirable if the ability to control the cycle could be improved. 
     The administration of three-stage or triphasic combination type oral contraceptives is also known. Triphasic combinations of various types are described in U.S. Pat. Nos. 4,390,531; 4,066,757; 3,957,982; 3,795,734; and 2,431,704. 
     In recent years data collected on the use of various oral contraceptive regimens have indicated that increased blood pressure and decreased glucose tolerance are associated with the progestogen content or progestational activity of oral contraceptives. In addition, the progestogen activity is associated with a decrease in serum high density lipoprotein values. These findings have prompted a greater emphasis on a reduction of the progestogen dosage in oral contraceptives. 
     There is a need, therefore, for a combination type contraceptive which contains low concentrations of estrogen and progestogen but is still effective for the prevention of pregnancy. 
     By the present invention a triphasic oral contraceptive regimen is provided wherein the estrogen dosage is kept constant throughout the 21-day cycle while the progestogen dosage is gradually increased in successive doses. The purpose of the invention is to lower total monthly steroid dose in the oral contraceptive while still obtaining equivalent bleeding patterns and protection against pregnancy as found with conventional oral contraceptives. 
     According to the present invention, reliable contraception is achieved by administering for 21 successive days to a female a combination of an estrogen and a progestogen, for the first 5-8 days in a contraceptively effective daily dosage a progestogen equivalent in effect to about 0.065-0.75 mg of norethindrone in combination an estrogen equivalent in effect to about 0.02-0.05 mg of ethinyl estradiol; followed by the administration for 7-11 days, of a daily dosage of a progestogen equivalent in effect to about 0.25-1.0 mg of a norethindrone together with an estrogen equivalent in effect to about 0.02-0.50 mg of ethinyl estradiol; and followed by the administration for 3-7 days of a daily dosage of a progestogen equivalent in effect to about 0.35-2.0 mg of norethindrone in combination an estrogen equivalent in effect to about 0.02-0.05 mg of ethinyl estradiol, provided that the dosage of estrogen is kept constant in each phase during the 21-day cycle. The actual weight amount of the dosage at each dosage level will depend upon the estrogenic and progestogenic activity, respectively, of the components selected for the dosage units. 
     The total number of days during which the progestogen and estrogen combinations are administered daily is 21. These are followed by 6-8 days which are free of hormone administration to approximate the natural 28-day menstrual cycle of the female. Day one of the cycle is defined as the first day of menstruation and the days are numbered sequentially thereafter until menstruation occurs again. The cycle usually lasts 28 days but it may be slightly longer or shorter. In actual practice a placebo or any other hormone-free agent such as, for example, iron supplements, may be administered during this period. Thus, in a preferred regimen, phase one would commence sometime between day 4 and day 6 of the menstrual cycle and last 5-8 days but preferably 7 days, phase two would last 7-11 days, preferably 7 days, while phase three would last 3 to 7 days, preferably 7 days. 
     The contraceptive composition employed in the present invention comprises 21 separate daily dosage units which are adapted for successive daily oral ingestion. The composition consists essentially of, as the first phase, 5-8 dosage units containing, in admixture with a pharmaceutically acceptable carrier, a combination of an estrogen in combination with a progestogen, followed by, as the second phase, 7-11 dosage units containing, a combination of an estrogen and a progestogen, followed by, as the third phase, 3-7 dosage units containing a combination of an estrogen and a progestogen followed by 6-8 dosage units free of estrogen and progestogen. The estrogen daily dosage is kept constant in all three phases. 
     Any conventional estrogen may be employed as a suitable component in the contraceptive regimen of this invention. The particular regimen employed in a daily dosage should be equal in contraceptive activity in each phase to a daily dosage of about 0.020-0.050 mg of 17α-ethinylestradiol. The preferred dosage is one equal to a daily dosage of about 0.035 mg of 17α-ethinylestradiol. 
     In addition to 17α-ethinylestradiol, esters and ethers of 17α-ethinylestradiol may also be employed as the estrogen component. Natural estrogens such as estrone, estradiol and estriol, and their esters, as well as the synthetic estrogens, may also be employed. The preferred estrogen is 17α-ethinylestradiol. 
     As the progestogen component, any progestationally active compound may be employed. The progestogen is preferably administered in a daily dosage in the first phase corresponding in progestogenic activity to 0.065-0.75 mg of norethindrone per day, during the next phase a daily dosage corresponding in progestogenic activity to 0.25-1.0 mg of norethindrone per day and during the third phase a daily dosage corresponding in progestogenic activity to 0.35-2.0 mg of norethindrone per day. 
     Progestogens which may be employed as a component in the present invention include progesterone and its derivatives such as, for example, 17-hydroxyprogesterone esters and 19-nor-17-hydroxyprogesterone esters, 17α-ethinyltestosterone, 17α-ethinyl-19-nortestosterone and derivatives thereof, norethindrone, and D-17β-acetoxy-13β-ethyl-17α-ethinyl-gon-4-en-3-one oxime. The preferred progestogens are norethindrone, D-norgestrel and D-17β-acetoxy-13β-ethyl-17α-ethinyl-gon-4-en-3-one oxime (norgestimate). 
     The estrogen and progestogen components are preferably administered together orally in a pharmaceutically acceptable nontoxic carrier, but they can also be administered separately or parenterally. In general, the effective agents are processed, together with the usual additives, vehicles and/or flavor-ameliorating agents normally employed in Galenic pharmacy, in accordance with generally accepted pharmaceutical practices. For the preferred oral administration, tablets, dragees, capsules, pills, suspensions or solutions are particularly suitable; for parenteral application, oily solutions such as, for example, sesame oil or castor oil solutions which can optionally additionally contain a diluent such as, for example, benzyl benzoate or benzyl alcohol. 
     In the case of the preferred oral application, the three-phase combination-type contraceptives are preferably packaged in the form of a pharmaceutical kit or package in which the daily dosages are arranged for proper sequential administration. This invention also relates, therefore, to a pharmaceutical unit which contains combination-type contraceptives in 28 dosage units in a synchronized, fixed sequence, wherein the sequence or arrangement of the dosage units corresponds to the stages of daily administration. 
     The pharmaceutical unit can be, e.g., in the form of a transparent package having 28 dosage units arranged sequentially and consisting of 7 tablets for the first phase, followed by 7 tablets for the second phase, followed by 7 tablets for the third phase, and finally followed by 7 placebos. A single tablet is to be taken each day over a period of 28 days. 
     Without further elaboration it is believed that one skilled in the art, using the preceding description, can fully utilize the present invention. The following preferred specific embodiments are to be construed as merely illustrative of the invention and are not meant to limit the invention in any way. 
    
    
     EXAMPLE 1 
     Composition of a tablet for each stage: 
     
         ______________________________________                                    
1st Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
0.50      mg.       norethindrone                                         
88.9      mg.       lactose anhydrous DT                                  
10.0      mg.       pregelatinized starch N.F.                            
0.5       mg.       magnesium stearate N.F.                               
199.935   mg.       total weight                                          
2nd Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
0.75      mg.       norethindrone                                         
88.70     mg.       lactose anhydrous DT                                  
10.02     mg.       pregelatinized starch N.F.                            
0.5       mg.       magnesium stearate N.F.                               
100.05    mg.       total weight                                          
3rd Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
1.0       mg.       norethindrone                                         
88.5      mg.       lactose anhydrous DT                                  
10.0      mg.       pregelatinized starch N.F.                            
0.5       mg.       magnesium stearate N.F.                               
100.035   mg.       total weight                                          
______________________________________                                    
 
    
     EXAMPLE 2 
     Composition of a tablet for each stage: 
     
         ______________________________________                                    
1st Stage 7 Tablets                                                       
0.035 mg.     17α-ethinylestradiol                                  
0.50  mg.     D-17β-acetoxy-13β-ethyl-17α-ethinyl-gon-4-en
              -                                                           
              3-one oxime                                                 
87.9  mg.     lactose anhydrous DT                                        
11.1  mg.     pregelatinized starch N.F.                                  
0.5   mg.     magnesium stearate N.F.                                     
100.035                                                                   
      mg.     total weight                                                
2nd Stage 7 Tablets                                                       
0.035 mg.     17α-ethinylestradiol                                  
0.75  mg.     D-17β-acetoxy-13β-ethyl-17α-ethinyl-gon-4-en
              -                                                           
              3-one oxime                                                 
89.70 mg.     lactose anhydrous DT                                        
9.02  mg.     pregelatinized starch N.F.                                  
0.5   mg.     magnesium stearate N.F.                                     
100.005                                                                   
      mg.     total weight                                                
3rd Stage 7 Tablets                                                       
0.035 mg.     17α-ethinylestradiol                                  
1.0   mg.     D-17β-acetoxy-13β-ethyl-17α-ethinyl-gon-4-en
              -                                                           
              3-one oxime                                                 
87.5  mg.     lactose anhydrous DT                                        
11.0  mg.     pregelatinized starch N.F.                                  
0.5   mg.     magnesium stearate N.F.                                     
100.035                                                                   
      mg.     total weight                                                
______________________________________                                    
 
    
     EXAMPLE 3 
     Composition of a tablet for each stage: 
     
         ______________________________________                                    
1st Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
0.50      mg.       D-norgestrel                                          
90.0      mg.       lactose anhydrous DT                                  
9.0       mg.       pregelatinized starch N.F.                            
0.5       mg.       magnesium stearate N.F.                               
100.035   mg.       total weight                                          
2nd Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
0.75      mg.       D-norgestrel                                          
87.70     mg.       lactose anhydrous DT                                  
11.02     mg.       pregelatinized starch N.F.                            
0.5       mg.       magnesium stearate N.F.                               
100.005   mg.       total weight                                          
3rd Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
1.0       mg.       D-norgestrel                                          
89.5      mg.       lactose anhydrous DT                                  
9.0       mg.       pregelatinized starch N.F.                            
0.5       mg.       magnesium stearate N.F.                               
100.035   mg.       total weight                                          
______________________________________                                    
 
    
     EXAMPLE 4 
     Composition of a tablet for each stage: 
     
         ______________________________________                                    
1st Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
0.180     mg.       norgestimate                                          
90.200    mg.       lactose anhydrous DT                                  
9.085     mg.       pregelatinized starch N.F.                            
0.500     mg.       magnesium stearate N.F.                               
100.000   mg.       total weight                                          
2nd Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
0.215     mg.       norgestimate                                          
90.150    mg.       lactose anhydrous DT                                  
9.100     mg.       pregelatinized starch N.F.                            
0.500     mg.       magnesium stearate N.F.                               
100.000   mg.       total weight                                          
3rd Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
0.250     mg.       norgestimate                                          
90.115    mg.       lactose anhydrous DT                                  
9.100     mg.       pregelatinized starch N.F.                            
0.500     mg.       magnesiun stearate N.F.                               
100.000   mg.       total weight                                          
______________________________________                                    
 
    
     EXAMPLE 5 
     Composition of a tablet for each stage: 
     
         ______________________________________                                    
1st Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
0.250     mg.       norethindrone                                         
88.9      mg.       lactose anhydrous DT                                  
10.32     mg.       pregelatinized starch N.F.                            
0.5       mg.       magnesium stearate N.F.                               
100.006   mg.       total weight                                          
2nd Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
0.375     mg.       norethindrone                                         
88.70     mg.       lactose anhydrous DT                                  
10.39     mg.       pregelatinized starch N.F.                            
0.5       mg.       magnesium stearate N.F.                               
100.000   mg.       total weight                                          
3rd Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
0.500     mg.       norethindrone                                         
88.5      mg.       lactose anhydrous DT                                  
10.47     mg.       pregelatinized starch N.F.                            
0.5       mg.       magnesium stearate N.F.                               
100.005   mg.       total weight                                          
______________________________________                                    
 
    
     EXAMPLE 6 
     Composition of a tablet for each stage: 
     
         ______________________________________                                    
1st Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
0.05      mg.       D-norgestrel                                          
90.0      mg.       lactose anhydrous DT                                  
9.43      mg.       pregelatinized starch N.F.                            
0.5       mg.       magnesium stearate N.F.                               
100.015   mg.       total weight                                          
2nd Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
0.075     mg.       D-norgestrel                                          
87.70     mg.       lactose anhydrous DT                                  
11.69     mg.       pregelatinized starch N.F.                            
0.5       mg.       magnesium stearate N.F.                               
100.000   mg.       total weight                                          
3rd Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
0.100     mg.       D-norgestrel                                          
89.5      mg.       lactose anhydrous DT                                  
9.88      mg.       pregelatinized starch N.F.                            
0.5       mg.       magnesium stearate N.F.                               
100.015   mg.       total weight                                          
______________________________________                                    
 
    
     EXAMPLE 7 
     Composition of a tablet for each stage: 
     
         ______________________________________                                    
1st Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
0.025     mg.       D-norgestrel                                          
90.00     mg.       lactose anhydrous DT                                  
9.45      mg.       pregelatinized starch N.F.                            
0.50      mg.       magnesium stearate N.F.                               
100.000   mg.       total weight                                          
2nd Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
0.038     mg.       D-norgestrel                                          
87.70     mg.       lactose anhydrous DT                                  
11.74     mg.       pregelatinized starch N.F.                            
0.50      mg.       magnesium stearate N.F.                               
100.013   mg.       total weight                                          
3rd Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
0.050     mg.       d-norgestrel                                          
89.500    mg.       lactose anhydrous DT                                  
9.93      mg.       pregelatinized starch N.F.                            
0.50      mg.       magnesium stearate N.F.                               
100.015   mg.       total weight                                          
______________________________________                                    
 
    
     EXAMPLE 8 
     Composition of a tablet for each stage: 
     
         ______________________________________                                    
1st Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
0.090     mg.       norgestimate                                          
90.200    mg.       lactose anhydrous DT                                  
9.18      mg.       pregelatinized starch N.F.                            
0.50      mg.       magnesium stearate N.F.                               
100.005   mg.       total weight                                          
2nd Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
0.100     mg.       norgestimate                                          
90.150    mg.       lactose anhydrous DT                                  
9.23      mg.       pregelatinized starch N.F.                            
0.50      mg.       magnesium stearate N.F.                               
100.015   mg.       total weight                                          
3rd Stage 7 Tablets                                                       
0.035     mg.       17α-ethinylestradiol                            
0.125     mg.       norgestimate                                          
90.115    mg.       lactose anhydrous DT                                  
9.230     mg.       pregelatinized starch N.F.                            
0.500     mg.       magnesium stearate N.F.                               
100.005   mg.       total weight                                          
______________________________________                                    
 
    
     Clinical Tests 
     EXAMPLE 9 
     A preparation according to Example 1 was administered in three separate studies to a total of 656 women of child-bearing age. Subjects meeting the selection criteria were administered the contraceptive formulation on a regimen of 21 days on medication and 7 days off for up to 12 cycles. 
     The preparation was shown to be highly efficacious in preventing pregnancy. In each study the bleeding pattern consistently showed a decrease in the incidence of midcycle breakthrough bleeding and/or spotting. 
     Having described the invention in specific detail and exemplified the manner in which it may be carried into practice, it will be apparent to those skilled in the art that innumerable variations, applications, modifications, and extensions of the basic principles involved may be made without departing from its spirit or scope. It is to be understood that the foregoing is merely exemplary and the present invention is not to be limited to the specific form or arrangements of parts herein described and shown.