U.S. patent application number 13/070205 was filed with the patent office on 2011-07-14 for dosace form for hormonal contraceptive.
This patent application is currently assigned to Grunenthal GmbH. Invention is credited to Eric-Paul PAQUES, Georg SCHRAMM.
Application Number | 20110172197 13/070205 |
Document ID | / |
Family ID | 35456153 |
Filed Date | 2011-07-14 |
United States Patent
Application |
20110172197 |
Kind Code |
A1 |
SCHRAMM; Georg ; et
al. |
July 14, 2011 |
Dosace Form For Hormonal Contraceptive
Abstract
A dosage form for hormonal contraception containing a given
number of hormone-containing daily units and a given number of
hormone-free daily units for daily, oral administration, where the
hormone-containing daily units each contain at most the minimum
effective daily amount of folic acid for women and the hormone-free
daily units contain at least a multiple of this amount up to the
maximum permissible amount of folic acid for women.
Inventors: |
SCHRAMM; Georg; (Stolberg,
DE) ; PAQUES; Eric-Paul; (Aachen, DE) |
Assignee: |
Grunenthal GmbH
Aachen
DE
|
Family ID: |
35456153 |
Appl. No.: |
13/070205 |
Filed: |
March 23, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11244974 |
Oct 6, 2005 |
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13070205 |
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11009817 |
Dec 10, 2004 |
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11244974 |
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Current U.S.
Class: |
514/170 |
Current CPC
Class: |
A61K 31/57 20130101;
A61K 31/565 20130101; A61P 15/18 20180101; A61P 5/30 20180101; A61P
5/34 20180101 |
Class at
Publication: |
514/170 |
International
Class: |
A61K 31/57 20060101
A61K031/57; A61P 15/18 20060101 A61P015/18 |
Foreign Application Data
Date |
Code |
Application Number |
May 28, 2004 |
DE |
10 2004 026 670.0 |
May 28, 2004 |
DE |
10 2004 026 671.0 |
Claims
1-15. (canceled)
16. A hormonal contraceptive dosage form for uninterrupted daily
oral administration to women, said dosage form comprising
hormone-containing daily units and hormone-free daily units,
wherein each of the hormone-containing daily units does not
comprise any folic acid and each of the hormone-free daily units
comprises folic acid in a daily amount of >200 .mu.g up to the
maximum permissible amount of folic acid for women.
17. A dosage form according to claim 16, wherein the hormone-free
daily units each comprises more than 200 .mu.g and up to 5 mg of
folic acid.
18. A dosage form according to claim 16, wherein the hormone-free
daily units each comprises the same amount of folic acid.
19. A dosage form according to claim 16, wherein the dosage form
comprises at least 21 hormone-containing daily units and 7 to 3
hormone-free daily units.
20. A dosage form according to claim 19, wherein the number of
hormone-containing daily units is sufficient for administration for
a maximum of 2 years, and the number of hormone-free daily units is
sufficient for administration for 7 to 3 days.
21. A dosage form according to claim 19, comprising up to
730-hormone-containing daily units and 7 to 3 hormone-free daily
units.
22. A dosage form according to claim 19, which comprises 21 to 25
hormone-containing daily units and 7 to 3 hormone-free daily
units.
23. A dosage form according to claim 19, which comprises 42 to 52
hormone-containing daily units and 7 to 3 hormone-free daily
units.
24. A dosage form according to claim 19, which comprises 77 to 193
hormone-containing daily units and 7 to 3 hormone-free daily
units.
25. A dosage form according to claim 19, wherein the dosage form
comprises up to 365 hormone-containing daily units and 7 to 3
hormone-free daily units.
26. A dosage form according to claim 16, wherein the
hormone-containing daily units each comprises at least one
contraceptive active hormone component.
27. A dosage form according to claim 26, wherein the
hormone-containing daily units each comprises a hormone-combination
consisting of an oestrogen and a gestagen.
28. A dosage form according to claim 16, wherein the
hormone-containing daily units correspond to a monophasic
contraceptive.
29. A kit comprising at least one dosage form for hormonal
contraception according to claim 16.
30. A kit form according to claim 29, wherein the kit comprises a
plurality of dosage forms for hormonal contraception according to
claim 16.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation in Part Application of
U.S. patent application Ser. No. 11/009,817, still pending.
[0002] This application claims priority from German Patent
Application No. 10 2004 026 671.9 filed May 28, 2004, German Patent
Application No. 10 2004 026 670.0 filed May 28, 2004, pending U.S.
application Ser. No. 11/009,817 and pending U.S. application Ser.
No. 11/009,938.
BACKGROUND OF THE INVENTION
[0003] 1. Field of the Invention
[0004] The present invention relates to a dosage form for hormonal
contraception containing a given number of hormone-containing daily
units and a given number of hormone-free daily units for
uninterrupted daily oral administration to women, characterized in
that the hormone-containing daily units contain folic acid in a
daily amount of at most 200 .mu.g and the hormone-free daily units
in each case contain folic acid in a daily amount of >200 .mu.g
up to the maximum permissible amount of folic acid for women.
[0005] It is suspected that long-term taking of gestagen-based
hormonal contraceptives may lead to a deficiency of folic acid.
This deficiency may lead to cardiovascular diseases, for
example.
[0006] It is also known that if pregnancy occurs a short time after
stopping taking such hormonal contraceptives, there is a risk that
the deficiency of folic acid may lead to neural tube defects in the
embryo. Since the neural tube develops in the first weeks of
pregnancy, it is particularly advantageous to ensure that folic
acid is taken prior to conception.
[0007] If, therefore, a woman stops taking hormonal contraceptives
because she wants to have a child and she falls pregnant in the
first cycle after stopping the hormonal contraceptives, it is
particularly important to ensure an appropriately high level of
folic acid in the period directly after stopping taking the "Pill",
as hormonal contraceptives are known.
[0008] There is therefore a need to add folic acid to hormonal
contraceptives in such a way that the added folic acid is adapted
to a woman's varying needs over the period during and after a
tablet-taking cycle.
[0009] 2. Brief Description of Related Developments
[0010] The combination of hormonal contraceptives and folic acid is
already known from WO 99/53910. The amount of folic acid per daily
dose of hormones merely matches the changes in a woman's folic acid
requirements as she ages, and does not take account of the changes
in folic acid requirements over a contraceptive-taking cycle.
SUMMARY OF THE INVENTION
[0011] It was therefore the object of the present invention to
provide a dosage form for hormonal contraception which takes
account of the changes in folic acid requirements during a
hormone-taking cycle and subsequent hormone-free daily units.
[0012] This object was achieved by providing the dosage form
according to the invention for hormonal contraception containing a
given number of hormone-containing daily units and a given number
of hormone-free daily units for uninterrupted daily oral
administration to women, characterized in that the
hormone-containing daily units contain folic acid in a daily amount
of at most 200 .mu.g and the hormone-free daily units in each case
contain folic acid in a daily amount of >200 .mu.g up to the
maximum permissible amount for women of folic acid.
[0013] Women of child-bearing age have a daily folic acid
requirement which may be adequately met by a healthy diet. Long
term taking of hormonal contraceptives containing gestagens may
lead to an additional folic acid requirement, which may likewise be
met by a healthy diet. However, it is advisable to provide women
with a daily dose of the minimum effective daily amount of folic
acid.
[0014] Accordingly, hormone-containing daily units of the dosage
form according to the invention may each comprise a daily amount of
folic acid corresponding to this minimum effective daily amount of
folic acid. Preferably, the hormone-containing daily units of the
dosage form according to the invention contain 0 to 200 .mu.g of
folic acid, particularly preferably 5 to 200 .mu.g of folic
acid.
[0015] The hormone-containing daily units of the dosage form
according to the invention may also not contain any additional
folic acid, however.
[0016] To ensure that a woman consumes the necessary amount of
folic acid or that her increased folic acid requirement at least at
the beginning of pregnancy is met as quickly as possible if she
decides to try for a baby, so avoiding possible damage to the
embryo due to a folic acid deficiency, the hormone-free daily units
of the folic acid dosage form according to the invention contain
folic in an amount of more that 200 .mu.g up to the maximum
permissible daily amount of folic acid for women, preferably up to
5 mg of folic acid per daily unit, particularly preferably of more
than 200 .mu.g to 5 mg folic acid, very particularly preferably up
to the maximum permissible daily amount of folic add for women of
reproductive age.
[0017] By adding folic acid to the hormone-free daily units of the
dosage form according to the invention in amounts of up to the
maximum permissible amount, it is possible to increase the folic
acid concentration in a woman's body while she is taking the
hormone-free daily units to the extent that the her body's
increased folic acid requirement is met as quickly as possible if
she stops taking a hormone-containing contraceptive and then falls
pregnant.
[0018] The hormone-containing daily units of the dosage form
according to the invention preferably each contain the same amount
of folic acid. This also applies to the hormone-free daily units,
which likewise each contain the same amount of folic acid, this
being greater than the amount contained in the hormone-containing
daily units however.
[0019] The folic acid may also be present in the dosage form
according to the invention as a pharmaceutically safe salt,
preferably as sodium, potassium or magnesium salt, or as a
corresponding derivative.
[0020] Suitable derivatives of folic acid are mono- or diesters,
wherein the diesters may be differently or identically esterified.
Suitable ester groups are preferably C.sub.1-C.sub.8 low alkyl
groups, such as methyl, ethyl, propyl or butyl, branched
C.sub.1-C.sub.8 low alkyl groups, such as isopropyl, isobutyl or
sec.-butyl, cycloalkyl groups, such as cyclopentyl or cyclohexyl,
aryl groups, such as phenyl or substituted phenyl with 1-2
substituents, such as low alkyl or haloalkoxyl groups, or arylalkyl
groups with C.sub.1-C.sub.8 alkyl and aryl groups, such as phenyl
or substituted phenyl.
[0021] In addition, the hormone-free daily units and optionally the
hormone-containing daily units may contain further vitamins or
minerals in addition to the folic acid.
[0022] The number of daily units of a dosage form according to the
invention may correspond to a natural, monthly menstrual cycle. In
this case, the dosage form according to the invention contains 21
to 25 hormone-containing daily units and 7 to 3 hormone-free daily
units.
[0023] However, it is also possible for the total number of
hormone-containing daily units to correspond to more than a woman's
natural monthly cycle, such that a dosage form according to the
invention may contain hormone-containing daily units to be taken
without interruption for up to 2 years, preferably up to 1 year,
and 7 to 3 hormone-free daily units. However, it is also possible
for the dosage form according to the invention to comprise 42 to 52
or 77 to 193 hormone-containing daily units alongside 7 to 3
hormone-free daily units.
[0024] The hormone-containing daily units of the dosage form
according to the invention may each contain at least one
contraceptively acting hormone component, preferably a combination
of hormone components such as an oestrogen and a gestagen.
[0025] Oestrogens which are suitable for the hormone-containing
daily units of the dosage form according to the invention are
preferably selected from the group comprising oestradiol,
oestradiol valerate, ethinyloestradiol and mestranol.
Ethinyloestradiol is particularly preferred as the oestrogen for
the dosage form according to the invention.
[0026] Gestagens which are suitable for the hormone-containing
daily units of the dosage form according to the invention are
preferably selected from the group comprising norethisterone,
norethisterone acetate, norethisterone enantate, norgestimate,
norgestrel, levonorgestrel, gestodene, hydroxyprogesterone
caproate, medroxyprogesterone acetate, megestrol acetate,
chlormadinone acetate, lynestrenol, cyproterone acetate,
drospirenone, dienogest, desogestrel, progesterone, dydrogesterone,
medrogestone, ethynodiol, promegestone, nomegestrol acetate and
trimegestone.
[0027] The hormones are preferably used in the amounts stated
below.
TABLE-US-00001 Oestrogens: Oestradiol, oestradiol valerate 0.5 to 4
mg Ethinyloestradiol 5 to 50 .mu.g Mestranol 8 to 70 .mu.g
TABLE-US-00002 Gestagens: Norethisterone, norethisterone acetate
0.5 to 1.0 mg Norgestimate 0.1 to 0.25 mg Norgestrel 0.3 to 1.0 mg
Levonorgestrel 0.05 to 0.15 mg Gestodene 0.05 to 0.12 mg
Hydroxyprogesterone caproate 10 to 800 mg Medroxyprogesterone
acetate 2.5 to 40 mg Megestrol acetate 1.0 to 10 mg Chlormadinone
acetate 0.5 to 10 mg Lynestrenol 0.4 to 3 mg Cyproterone acetate
0.5 to 10 mg Drospirenone 1.0 to 10 mg Dienogest 1.0 to 10 mg
Desogestrel 0.06 to 0.30 mg Progesterone 100 to 1000 mg
Dydrogesterone 5 to 50 mg Medrogestone 2 to 30 mg Ethynodiol,
ethynodiol diacetate 0.4 to 3 mg Promegestone 0.5 to 10 mg
Nomegestrol acetate 0.5 to 10 mg Trimegestone 1 to 10 mg
Etonogestrel 0.1 to 1 mg Norelgestromin 0.1 to 2 mg Norethynodrel
0.3 to 3 mg Tibolone 1 to 10 mg
[0028] The dosage forms according to the invention, especially the
hormone-containing daily units, preferably comprise the following
hormone combinations:
1. 0.015 mg ethinyloestradiol+0.06 mg gestodene 2. 0.02 mg
ethinyloestradiol+0.15 mg desogestrel 3. 0.02 mg
ethinyloestradiol+0.5 mg norethisterone 4. 0.02 mg
ethinyloestradiol+1 mg chlormadinone acetate or 2 mg or 3 mg
chlormadinone acetate 5. 0.02 mg ethinyloestradiol+1 mg
norethisterone 6. 0.03 mg ethinyloestradiol+1 mg norethisterone 7.
0.02 mg ethinyloestradiol+4 mg chlormadinone acetate 8. 0.02 mg
ethinyloestradiol+5 mg chlormadinone acetate 9. 0.02 mg
ethinyloestradiol+0.1 mg levonorgestrel 10. 0.02 mg
ethinyloestradiol+0.15 mg desogestrel 11. 0.02 mg
ethinyloestradiol+0.1 mg levonorgestrel 12. 0.03 mg
ethinyloestradiol+3 mg drospirenone 13. 0.02 mg ethinyloestradiol+3
mg drospirenone 14. 0.03 mg ethinyloestradiol+2 mg chlormadinone
acetate 15. 0.035 mg ethinyloestradiol+0.25 mg norgestimate 16.
0.03 mg ethinyloestradiol+0.5 mg norethisterone 17. 0.03 mg
ethinyloestradiol+0.15 mg desogestrel 18. 0.03 mg
ethinyloestradiol+0.075 mg gestodene 19. 0.03 mg
ethinyloestradiol+0.15 mg levonorgestrel 20. 0.03 mg
ethinyloestradiol+0.15 mg desogestrel 21. 0.03 mg
ethinyloestradiol+0.15 mg levonorgestrel 22. 0.03 mg
ethinyloestradiol+0.125 mg levonorgestrel 23. 0.0375 mg
ethinyloestradiol+0.75 mg lynestrenol 24. 0.03 mg
ethinyloestradiol+1 mg norethisterone 25. 0.03 mg
ethinyloestradiol+0.5 mg norethisterone 26. 0.03 mg
ethinyloestradiol+0.15 mg levonorgestrel 27. 0.04 mg
ethinyloestradiol+2 mg lynestrenol 28. 1st phase=7 days [0029]
0.050 mg desogestrel+0.035 ethinyloestradiol [0030] 2nd phase=7
days [0031] 0.100 mg desogestrel+0.030 ethinyloestradiol [0032] 3rd
phase=7 days [0033] 0.150 mg desogestrel+0.030 ethinyloestradiol
29. 1st phase=6 days [0034] 0.03 mg EE+0.05 mg levonorgestrel
[0035] 2nd phase=5 days [0036] 0.04 mg EE+0.075 mg levonorgestrel
[0037] 3rd phase=10 days [0038] 0.03 mg EE+0.125 mg levonorgestrel
30. 1st phase=7 days [0039] 0.035 mg EE+0.180 mg norgestimate
[0040] 2nd phase=7 days [0041] 0.035 mg EE+0.215 mg norgestimate
[0042] 3rd phase=7 days [0043] 0.035 mg EE+0.250 mg norgestimate
31. 1st phase=6 days [0044] 0.03 mg EE+0.05 mg levonorgestrel
[0045] 2nd phase=5 days [0046] 0.04 mg EE+0.075 mg levonorgestrel
[0047] 3rd phase=10 days [0048] 0.03 mg EE+0.125 mg levonorgestrel
32. 1st phase=7 days [0049] 0.035 mg EE+0.5 mg norethisterone
[0050] 2nd phase=9 days [0051] 0.035 mg EE+1 mg norethisterone
[0052] 3rd phase=5 days [0053] 0.035 mg EE+0.5 mg norethisterone
33. 1st phase=6 days [0054] 0.03 mg EE+0.05 mg levonorgestrel
[0055] 2nd phase=5 days [0056] 0.04 mg EE+0.075 mg levonorgestrel
[0057] 3rd phase=10 days [0058] 0.03 mg EE+0.125 mg levonorgestrel
34. 1st phase=7 days [0059] 0.035 mg-EE+0.5 mg norethisterone
[0060] 2nd phase=7 days [0061] 0.035 mg EE+0.75 mg norethisterone
[0062] 3rd phase=7 days [0063] 0.035 mg EE+1 mg norethisterone 35.
1st phase=6 days [0064] 0.03 mg EE+0.05 mg levonorgestrel [0065]
2nd chase=5 days [0066] 0.04 mg EE+0.075 mg levonorgestrel [0067]
3rd phase=10 days [0068] 0.03 mg EE+0.125 mg levonorgestrel 36. 1st
phase=6 days [0069] 0.03 mg EE+0.05 mg levonorgestrel [0070] 2nd
phase=6 days [0071] 0.04 mg EE+0.075 mg levonorgestrel [0072] 3rd
phase=9 days [0073] 0.03 mg EE+0.125 mg levonorgestrel 37. 1st
phase=6 days [0074] 0.03 mg EE+0.05 mg levonorgestrel [0075] 2nd
phase=5 days [0076] 0.05 mg EE+0.05 mg levonorgestrel [0077] 3rd
phase=10 days [0078] 0.04 mg EE+0.125 mg levonorgestrel 38. 1st
phase=6 days [0079] 0.03 mg EE+0.05 mg levonorgestrel [0080] 2nd
phase=5 days [0081] 0.04 mg EE+0.075 mg levonorgestrel [0082] 3rd
phase=10 days [0083] 0.03 mg EE+0.125 mg levonorgestrel 39. 0.035
mg ethinyloestradiol+2 mg cyproterone acetate 40. 0.05 mg
mestranol+2 mg chlormadinone acetate 41. 1st phase=11 days [0084]
0.05 mg ethinyloestradiol+1 mg chlormadinone acetate [0085] 2nd
phase=11 days [0086] 0.05 mg ethinyloestradiol+2 mg chlormadinone
acetate 42. 0.08 mg mestranol+2 mg chlormadinone acetate 43. 0.03
mg ethinyloestradiol+2 mg dienogest 44. 0.05 mg
ethinyloestradiol+0.5 mg norgestrel 45. 0.05 mg
ethinyloestradiol+0.125 mg levonorgestrel 46. 0.05 mg
ethinyloestradiol+0.25 mg levonorgestrel 47. 0.05 mg
ethinyloestradiol+0.125 mg levonorgestrel 48. 0.05 mg
ethinyloestradiol+1 mg norethisterone acetate 49. 0.05 mg
ethinyloestradiol+0.25 mg levonorgestrel 50. 1st phase=7 days
[0087] 0.04 mg ethinyloestradiol+0.025 mg desogestrel [0088] 2nd
phase=15 days [0089] 0.03 mg ethinyloestradiol+0.125 mg desogestrel
51. 1st phase=11 days [0090] 0.05 mg ethinyloestradiol+0.05 mg
levonorgestrel [0091] 2nd phase=10 days [0092] 0.05 mg
ethinyloestradiol+0.125 mg levonorgestrel 52. 1st phase=11 days
[0093] 0.05 mg ethinyloestradiol+0.05 mg levonorgestrel [0094] 2nd
phase=10 days [0095] 0.05 mg ethinyloestradiol+0.125 mg
levonorgestrel 53. 1st phase=7 days [0096] 0.05 mg
ethinyloestradiol+ [0097] 2nd phase=15 days [0098] 0.05 mg
ethinyloestradiol+2.5 mg lynestrenol 54. 1st phase=7 days [0099]
0.05 mg ethinyloestradiol+ [0100] 2nd phase=15 days [0101] 0.05 mg
ethinyloestradiol+0.125 mg desogestrel 55. 1st phase=6 days [0102]
0.05 mg ethinyloestradiol+ [0103] 2nd phase=15 days [0104] 0.05 mg
ethinyloestradiol+1 mg norethisterone acetate
[0105] Where the dosage form according to the invention provides a
multiphasic hormone combination, it is recommended that the
hormone-containing daily units be taken without interruption only
for a period of 21 to 25 days, followed by 7 to 3 days of taking
hormone-free daily units.
[0106] The dosage form according to the invention preferably
comprises at least 21, preferably 21 to 25, hormone-containing
daily units which preferably include 5 to 30 .mu.g of
ethinyloestradiol and 0.5 to 5 mg of chlormadinone acetate, and 3
to 7 hormone-free daily units. However, the dosage form according
to the invention may also comprise hormone-containing daily units
for several years, preferably of 42 to 365 units, which contain the
stated hormone combination in the stated ranges, wherein the
corresponding uninterrupted tablet-taking periods are followed by 7
to 3 hormone-free daily units with an elevated amount of folic acid
stated according to the invention.
[0107] As already stated, the hormone-containing daily units of the
dosage form according to the invention may take the form of a
monophasic (one-phase) or multiphasic contraceptive. In the case of
a multiphasic contraceptive, a two-phase or a three-phase pill may
be present, which is not usually suitable, however, to be taken for
a period longer than a woman's natural cycle.
[0108] The dosage form according to the invention may also be a
constituent of a kit, wherein the kit according to the invention
may comprise a plurality of the dosage forms according to the
invention, especially if one dosage form comprises only one monthly
cycle.
[0109] The kit may optionally include a calendar or a diary.
EXAMPLES
Example 1
a) Composition
TABLE-US-00003 [0110] Per tablet Ethinyloestradiol 0.020 mg
Chlormadinone acetate 2.000 mg Povidone K30 3.000 mg Lactose 31.980
mg Maize starch 12.000 mg Magnesium stearate 0.500 mg Highly
disperse silicon dioxide 0.500 mg
[0111] Ethinyloestradiol (EE) and povidone K30
(polyvinylpyrrolidone) were dissolved in 600 ml of ethanol.
Chlormadinone acetate (particle size 90%<50 .mu.m), lactose and
maize starch were mixed in a mixer/pelletiser (Diosna P25) for 5
mins. and then moistened thoroughly and mixed with the ethanolic
EE/PVP solution. The moist composition was forced through a 3 mm
screen and dried in a vacuum drying cabinet. The dried granular
product was disagglomerated through a 0.6 mm screen, mixed with
magnesium stearate and highly disperse silicon dioxide and pressed
on a tablet press with 5 mm punches into tablets with a weight of
50 mg.
[0112] b) As indicated under a), hormone-free, folic
acid-containing tablets with a weight of 50 mg were produced,
wherein the sodium salt of the folic acid was dissolved in 600 ml
of aqueous ethanol.
TABLE-US-00004 Per tablet Sodium folate 3.000 mg Povidone K30 3.000
mg Lactose 31.000 mg Maize starch 12.000 mg Magnesium stearate
0.500 mg Highly disperse silicon dioxide 0.500 mg
[0113] The tablets were coated with a
methylhydroxypropylcellulose-based coating (e.g. Opadry YS-1-2184
made by Colorcon), coating composition 2 mg per tablet, and
packaged into a dosage form comprising 120 hormone-containing daily
units without folic acid and 7 hormone-free daily units with folic
acid.
* * * * *