U.S. patent application number 13/900790 was filed with the patent office on 2014-02-20 for pharmaceutical composition for use as a contraceptive.
The applicant listed for this patent is Bayer Pharma Aktiengesellschaft. Invention is credited to Wolfgang Heil, Renate Heithecker, Juergen Hilman, Michael Huempel, Ralph Lipp, Johannes W. Tack.
Application Number | 20140050794 13/900790 |
Document ID | / |
Family ID | 26933853 |
Filed Date | 2014-02-20 |
United States Patent
Application |
20140050794 |
Kind Code |
A1 |
Hilman; Juergen ; et
al. |
February 20, 2014 |
PHARMACEUTICAL COMPOSITION FOR USE AS A CONTRACEPTIVE
Abstract
A pharmaceutical composition comprises, as a first active agent,
6.beta.,7.beta.;15.beta.,16.beta.-dimethene-3-oxo-17.alpha.-pregn-4-ene-2-
1,17-carbolactone (drospirenone) in an amount corresponding to a
daily dosage, on administration of the composition, of from about 2
mg to about 4 mg, and, as a second active agent,
17.alpha.-ethinylestradiol (ethinylestradiol) in an amount
corresponding to a daily dosage of from about 0.01 mg to about 0.05
mg, together with one or more pharmaceutically acceptable carriers
or excipients. In a specific embodiment, the composition consists
of a number of separately packaged and individually removable daily
dosage units placed in a packaging unit and intended for oral
administration for a period of at least 21 consecutive days,
wherein said daily dosage units comprises the combination of
drospirenone and ethinylestradiol. The composition may further
comprise 7 or less daily dosage units containing no active agent or
containing ethinylestradiol alone.
Inventors: |
Hilman; Juergen; (Berlin,
DE) ; Heil; Wolfgang; (Berlin, DE) ; Lipp;
Ralph; (Berlin, DE) ; Heithecker; Renate;
(Berlin, DE) ; Huempel; Michael; (Berlin, DE)
; Tack; Johannes W.; (Berlin, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bayer Pharma Aktiengesellschaft |
Berlin |
|
DE |
|
|
Family ID: |
26933853 |
Appl. No.: |
13/900790 |
Filed: |
May 23, 2013 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11266395 |
Nov 4, 2005 |
|
|
|
13900790 |
|
|
|
|
10359069 |
Feb 6, 2003 |
|
|
|
11266395 |
|
|
|
|
09654227 |
Aug 31, 2000 |
6787531 |
|
|
10359069 |
|
|
|
|
60240953 |
Aug 31, 1999 |
|
|
|
Current U.S.
Class: |
424/490 ;
427/2.14; 514/170 |
Current CPC
Class: |
A61K 31/56 20130101;
A61K 2300/00 20130101; A61K 31/585 20130101; A61K 31/567 20130101;
A61K 31/56 20130101 |
Class at
Publication: |
424/490 ;
514/170; 427/2.14 |
International
Class: |
A61K 31/585 20060101
A61K031/585; A61K 31/567 20060101 A61K031/567 |
Claims
1.-35. (canceled)
36. A pharmaceutical composition comprising ethinylestradiol and
inert carrier particles containing drospirenone on their surface,
wherein drospirenone is present in the composition in an amount
corresponding to a daily dosage of from about 2 mg to about 4 mg;
ethinylestradiol is present in the composition in an amount
corresponding to a daily dosage of from about 0.01 mg to about 0.05
mg; and at least 70% of said drospirenone is dissolved from said
composition within 30 minutes, as determined by USP XXIII Paddle
Method II using water at 37.degree. C. as the dissolution media and
50 rpm as the stirring rate.
37. The composition according to claim 36, wherein said composition
comprises inert carrier particles containing ethinylestradiol on
their surface.
38. The composition according to claim 36 or 37, wherein said
composition further comprises a carrier or excipient which acts to
promote dissolution of both active substances.
39. The composition according to claim 38, wherein said carrier or
excipient is selected from the group consisting of carboxymethyl
cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
gelled starch, gelatin and polyvinylpyrrolidone.
40. The composition according to claim 39, wherein said carrier or
excipient is polyvinylpyrrolidone.
41. The composition according to claim 36, 37, 39 or 40, wherein at
least 80% of said drospirenone is dissolved from said composition
within 20 minutes, as determined by USP XXIII Paddle Method II
using water at 37.degree. C. as the dissolution media and 50 rpm as
the stirring rate.
42. The composition according to claim 36, 37, 39 or 40, wherein
drospirenone is present in an amount corresponding to a daily
dosage of from 2.5 mg to 3.5 mg.
43. The composition according to claim 42, wherein drospirenone is
present in an amount corresponding to a daily dosage of about 3
mg.
44. The composition according to claims 36, 37, 39 and 40, wherein
ethinylestradiol is present in an amount corresponding to a daily
dosage of from 0.015 mg to 0.03 mg.
45. The composition according to claim 36, 37, 39 or 40, wherein
said composition is in the form of an oral dosage unit.
46. The composition according to claim 45, wherein said oral dosage
unit is in the form of a tablet, a capsule or a pill.
47. The composition according to claim 41, wherein drospirenone is
present in an amount corresponding to a daily dosage of about 3
mg.
48. The composition according to claim 43, wherein ethinylestradiol
is present in an amount corresponding to a daily dosage of from
0.015 mg to 0.03 mg.
49. The composition according to claim 48, wherein said composition
is in the form of an oral dosage unit.
50. A pharmaceutical preparation comprising a number of separately
packaged and individually removable oral dosage units as defined in
claim 45 placed in a packaging unit and intended for oral
administration for a period of at least 21 consecutive days.
51. The preparation according to claim 50, wherein the number of
oral dosage units is 28, or a multiple of 28.
52. The preparation according to claim 51, wherein the number of
oral dosage units is 2 times 28, 3 times 38, or 4 times 28.
53. The preparation according to claim 50, which additionally
comprises 7 or less oral dosage units containing no active agent
intended for oral administration subsequent to the period of at
least 21 days, the total number of daily dosage units being at
least 28.
54. The preparation according to claim 52, wherein the number of
oral dosage units is 21, 22, 23, or 24, and wherein the number of
oral dosage units containing no active agent is 7, 6, 5 or 4.
55. A pharmaceutical preparation comprising a number of separately
packaged and individually removable oral dosage units placed in a
packaging unit and intended for oral administration for a period of
at least 28 consecutive days, wherein at least 21 of said oral
dosage units are as defined in claim 45, and wherein 7 or less of
said oral dosage units contain ethinylestradiol alone in an amount
from about 0.01 mg to about 0.05 mg.
56. The preparation according to claim 55, wherein the number of
oral dosage units is 21, 22, 23 or 24, and wherein the number of
oral dosage units containing ethinylestradiol alone is 7, 6, 5 or
4.
57. A pharmaceutical preparation comprising a number of separately
packaged and individually removable oral dosage units as defined in
claim 46 placed in a packaging unit and intended for oral
administration for a period of at least 21 consecutive days.
58. The preparation according to claim 57, wherein the number of
oral dosage units is 28, or a multiple of 28.
59. The preparation according to claim 58, wherein the number of
oral dosage units is 2 times 28, 3 times 38, or 4 times 28.
60. The preparation according to claim 57, which additionally
comprises 7 or less oral dosage units containing no active agent
intended for oral administration subsequent to the period of at
least 21 days, the total number of daily dosage units being at
least 28.
61. The preparation according to claim 59, wherein the number of
oral dosage units is 21, 22, 23, or 24, and wherein the number of
oral dosage units containing no active agent is 7, 6, 5 or 4.
62. A pharmaceutical preparation comprising a number of separately
packaged and individually removable oral dosage units placed in a
packaging unit and intended for oral administration for a period of
at least 28 consecutive days, wherein at least 21 of said oral
dosage units are as defined in claim 46, and wherein 7 or less of
said oral dosage units contain ethinylestradiol alone in an amount
from about 0.01 mg to about 0.05 mg.
63. The preparation according to claim 62, wherein the number of
oral dosage units is 21, 22, 23 or 24, and wherein the number of
oral dosage units containing ethinylestradiol along is 7, 6, 5 or
4.
64. A method for preparing a pharmaceutical composition as defined
in claim 36, comprising spraying a solution of drospirenone onto
the surface of inert carrier particles followed by incorporation of
the particles in the composition.
65. A method for preparing a pharmaceutical composition as defined
in claim 37, comprising spraying a solution of drospirenone onto
the surface of inert carrier particles and spraying a solution of
ethinylestradiol onto the surface of inert carrier particles
followed by incorporation of the particles in the composition.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a pharmaceutical
composition comprising drospirenone and ethinylestradiol, a method
of providing dissolution of drospirenone, methods of inhibiting
ovulation by administration of drospirenone and the use of
drospirenone and ethinylestradiol for inhibiting ovulation.
[0002] BACKGROUND OF THE INVENTION
[0003] Oral contraceptives containing a combination of a gestagen
and an estrogen component have been used since the 1960's. The
earliest contraceptive preparations consisted of 21 tablets
containing the combination of active agents and 7 tablets
containing no active agent, and the amount of each active agent was
the same in each tablet (the so-called one-phase preparations).
Subsequently, preparations were developed that consisted of tablets
containing different amounts and ratios of the active agents over
the cycle of administration (the so-called multiple-phase
preparations).
[0004] Contraceptive reliability is mainly provided by the gestagen
component. The daily dosage should be at least the minimum of what
is needed for the gestagen in question to inhibit ovulation
effectively. The estrogen component acts to increase the ovulation
inhibitory effect of gestagen and to ensure cycle stability. Since
the introduction of oral contraceptives, the daily dosage of
gestagen has been reduced through the development of new and more
efficient gestagens than were present in the earlier contraceptive
preparations. It has also been possible to reduce the daily dosage
of estrogen.
[0005]
6.beta.,7.beta.;15.beta.,16.beta.-dimethylene-3-oxo-17.alpha.-pregn-
-4-ene-21,17-carbolactone (drospirenone) is known from DE 26 52 761
in which its use as a diuretic compound is disclosed.
[0006] In DE 30 22 337, the gestagen-like activity of the compound
and its consequent utility as a contraceptive agent is described at
dosage levels of 0.5-50 mg of drospirenone per day. It is also
noted that the mechanism of action of the compound is very similar
to that of the natural corpus luteum hormone progesterone, and that
it does not give rise to increased blood pressure for which reason
it may be administrated to women who have or are at risk of
developing increased blood pressure. It is further described that
drospirenone may be administered together with ethinylestradiol in
an amount of 0.03-0.05 mg per day.
[0007] DE 30 51 166 discloses the use of the drospirenone for the
treatment of gynaecological irregularities and for contraception at
a dosage level of 0.5-50 mg per day.
[0008] EP 398 460 discloses the use Of drospirenone for the
treatment of androgen-induced disorders, aldosterone-induced
disorders and hormonal irregularities as well as for contraception
at dosage levels of 0.5-50 mg, preferably 1-10 mg per day.
Ethinylestradiol may be co-administered at a level of 0.02-0.04 mg
per day.
[0009] U.S. Pat. No. 5,756,490 discloses pharmaceutical combination
preparations comprising 23 or 24 dosage units containing a
combination of a gestagen and an estrogen and 4-10 dosage units
containing estrogen alone. Drospirenone is mentioned as a possible,
but not preferred, gestagenic compound and ethinylestradiol is
mentioned as a possible, but not preferred, estrogenic
compound.
SUMMARY OF THE INVENTION
[0010] In the course of research leading to the present invention,
it has surprisingly been found that a hitherto undisclosed minimum
dosage level of drospirenone is required for reliable contraceptive
activity. Similarly, a preferred maximum dosage has been identified
at which unpleasant side effects, in particular excessive diuresis,
may substantially be avoided.
[0011] Accordingly, in a first aspect, the present invention
relates to a pharmaceutical composition comprising, as a first
active agent,
6.beta.,7.beta.;15.beta.,16.beta.-dimethylene-3-oxo-17.alpha.-pregn-4-ene-
-21,17-carbolactone (drospirenone) in an amount corresponding to a
daily dosage, on, administration of the composition, of from about
2 mg to about 4 mg, and, as a second active agent,
17.alpha.-ethinylestradiol (ethinylestradiol) in an amount
corresponding to a daily dosage of from about 0.01 mg to about 0.05
mg, together with one or more pharmaceutically acceptable carriers
or excipients.
[0012] Apart form the active substances themselves, it is envisaged
that an ester or prodrug of drospirenone may be employed in the
present composition, e.g. an oxyiminopregnane carbolactone as
disclosed in WO 98/24801. Likewise, it is envisaged that esters or
ethers of ethinylestradiol may be included in the composition.
[0013] In a further aspect, the invention relates to a method of
inhibiting ovulation in a mammal, in particular a human, comprising
administering, to said mammal, drospirenone in an amount in the
range of from about 2 mg to about 4 mg of per day, together with
ethinylestradiol in,.an amount of from about 0.01 mg to about 0.05
mg per day, said amounts being effective to inhibit ovulation in
said mammal.
[0014] In a still further aspect, the invention relates to the use
of drospirenone combined with ethinylestradiol for preparing a
pharmaceutical preparation for the inhibition of ovulation in a
mammal, in particular a human, the composition comprising an amount
of drospirenone corresponding to a daily dosage, on administration
of the composition, of from about 2 mg to about 4 mg, and
`comprising an amount of ethinylestradiol corresponding, to a daily
dosage, on administration of the composition, of from about 0.01 to
about 0.05 mg.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] The invention is further described with reference to the
drawings in which
[0016] FIG. 1 is a graph showing the in vitro dissolution rate of
drospirenone from tablet cores, V1-V7 being batches containing
micronized drospirenone, and V8 being a batch containing
macrocrystalline drospirenone;
[0017] FIG. 2 is a graph showing the in vitro dissolution rate of
drospirenone from tablet cores, different lines representing
different test batches;
[0018] FIG. 3 is a graph showing the in vitro dissolution rate of
drospirenone from film-coated tablets, different lines representing
different test batches;
[0019] FIG. 4 is a graph showing the in vitro dissolution rate of
ethinylestradiol from tablet cores, different lines representing
different test batches; and
[0020] FIG. 5 is a graph showing the in vitro dissolution rate of
ethinylestradiol from film-coated tablets, different lines
representing different test batches.
DETAILED DISCLOSURE OF THE INVENTION
[0021] Drospirenone, which may be prepared substantially as
described in, e.g., U.S. Pat. No. 4,129,564 or WO 98/06738, is a
sparingly soluble substance in water and aqueous buffers at various
pH values. Furthermore, drospirenone is rearranged to an inactive
isomer under acid conditions and hydrolysed under alkaline
conditions. To ensure good bioavailability of the compound, it is
therefore advantageously provided in a form that promotes rapid
dissolution thereof.
[0022] It has surprisingly been found that when drospirenone is
provided in micronized form (so that particles of the active
substance'have a surface area of more than 10,000 cm.sup.2/g, and
the following particle size distribution as determined under the
microscope: not more than 2 particles in a given batch with a
diameter of more than 30 .mu.m, and preferably .ltoreq.20 particles
with a diameter of .gtoreq.10 .mu.m and .ltoreq.30 .mu.m) in a
pharmaceutical composition, rapid dissolution of the active
compound from the composition occurs in vitro ("rapid dissolution"
is defined as the dissolution of at least 70% over about 30
minutes, in particular at least 80% over about 20 minutes, of
drospirenone from a tablet preparation containing 3 mg of
drospirenone in 900 ml of water at 37.degree. C. determined by the
USP XXIII Paddle Method using a USP dissolution test apparatus 2 at
50 rpm). Instead of providing the drospirenone in micronized form,
it is possible to dissolve it in a suitable solvent, e.g. methanol
or ethyl acetate, and spray it onto the surface of inert carrier
particles followed by incorporation of the particles containing
drospirenone on their surface in the composition.
[0023] Without wishing to be limited to any particular theory, it
appears that the in vitro dissolution rate of drospirenone is
connected to the dissolution rate in vivo resulting in rapid
absorption of drospirenone in vivo on oral administration of the
compound. This is an advantage because isomerization of the
compound in the gastric environment and/or hydrolysis in the
intestine is substantially reduced, leading to a high
bioavailability of the compound.
[0024] With respect to ethinylestradiol which is also a sparingly
soluble substance, though less sensitive to degradation than
drospirenone under conditions prevailing in the gastrointestinal
tract, it is also an advantage to provide it in micronized form or
sprayed from a solution, e.g. in ethanol, onto the surface of inert
carrier particles. This has the added advantage of facilitating a
more homogenous distribution of the ethinylestradiol throughout the
composition which might otherwise be difficult to obtain because
ethinylestradiol is incorporated in extremely small amounts. When
ethinylestradiol is provided in micronized form, it preferably has
the following particle size distribution as determined under the
microscope: 100% of the particles have a diameter of .ltoreq.15.0
.mu.m, 99% of the particles have a diameter of .ltoreq.12.5 .mu.m,
95% of the particles have a diameter of .ltoreq.5 10.0 .mu.m, and
50% of the particles have a diameter of .ltoreq.3.0 .mu.m.
Furthermore, no particle is larger than 20 .mu.m, and .ltoreq.10
particles have a diameter of .gtoreq.15 .mu.m and .ltoreq.20
.mu.m.
[0025] To obtain a more rapid rate of dissolution, it is preferred
to include carriers or excipients which act to promote dissolution
of both active substances. Examples of such carriers and excipients
include substances that are readily soluble in water such as
cellulose derivatives, carboxymethylcellulose, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, gelled starch, gelatin or
polyvinylpyrrolidone. In particular, it appears as though
polyvinylpyrrolidone might be particularly helpful to promote
dissolution.
[0026] The composition of the invention preferably comprises
drospirenone in an amount corresponding to a daily dosage of from
about 2.5 mg to about 3.5 mg, in particular about 3 mg. The amount
of ethinylestradiol preferably corresponds to a daily dosage of
from about 0.015 mg to about 0.04 mg, in particular from about
0.015 mg to about 0.03.mg. More particularly, the present
composition comprises an amount of drospirenone corresponding to a
daily dosage of from about 3.0 to about 3.5 mg and ethinylestradiol
in an amount corresponding to from about 0.015 to about 0.03
mg.
[0027] Apart from its ability to inhibit ovulation, the composition
of the invention has been found to possess pronounced
anti-androgenic properties and may therefore be used in the
prevention or treatment of androgen-induced disorders, in
particular acne. Such use may be independent from or concomitant
with the use as a contraceptive disclosed above. Furthermore, since
drospirenone is an aldosterone antagonist, it has diuretic
properties and is therefore suitable for counteracting the
water-retentive properties of ethinylestradiol.
[0028] In a particular embodiment, the invention relates to a
pharmaceutical preparation consisting of a number of separately
packaged and individually removable daily dosage units placed in a
packaging unit and intended for oral administration for a period of
at least 21 consecutive days, wherein each of said daily dosage
units comprises a combination Of drospirenone in an amount of from
about 2 mg to about 4 mg and ethinylestradiol in an amount from
about 0.01 to about 0.05 mg.
[0029] In one embodiment, the preparation further comprises 7 or
less said daily dosage units containing no active agent.
Alternatively, it is possible to include, in the dosage regimen, a
period of 7 days or less during which no dosage units are ingested.
For compliance reasons, however, it may be preferred to include an
appropriate number of blanks in the preparation; in which case the
total number of daily dosage units in the preparation is at least
28. The inclusion of blanks, or the pill-free days, will then
trigger withdrawal bleeding.
[0030] The preparation may be a one-phase composition, i.e. a
preparation wherein the amounts of either active agent remains
constant for the entire at least 21-day period, or the amounts of
either or both active agents may be varied over the at least 21-day
period to generate a multiple-phase preparation, e.g. a two- or
three-phase preparation, substantially as disclosed in, e.g., EP
148 724. In case of multiple-phase preparation, it may be possible
to include a natural estrogen such as estradiol, e.g. in an amount
of from about 0.5 mg to about 4 mg per day, instead of
ethinylestradiol.
[0031] In suitable embodiments of the present preparation, the
number of daily dosage units comprising the combination of
drospirenone and ethinylestradiol may be 21, 22, 23 or 24, and the
number of daily dosage units containing no active agent may then be
7, 6, 5 or 4, as the case may be. In a further embodiment of the
present preparation, the number of daily dosage units comprising
the combination of drospirenone and ethinylestradiol is 28, or a
multiple of 28 such as 2-4, in particular 2 or 3, times 28.
[0032] In an alternative embodiment, the invention relates to a
contraceptive preparation consisting of a number of separately
packaged and individually removable daily dosage units placed in a
packaging unit and intended for oral administration for a period of
at least 28 consecutive days, wherein at least 21 of said daily
dosage units comprises a combination of drospirenone in an amount
of from about 2 mg to about 4 mg and ethinylestradiol in an amount
from about 0.01 to about 0.05 mg, and wherein 7 or less of said
daily dosage units contain ethinylestradiol alone in an amount from
about 0.01 to about 0.05 mg.
[0033] By including an appropriate number of dosage units
comprising ethinylestradiol alone, high contraceptive reliability,
low follicular development and satisfactory cycle control with
little or no intermenstrual bleeding may be obtained.
[0034] In this case, too, the preparation may be one in which the
amounts of either active agent remains constant for the entire at
least 21-day period (i.e. a two-phase preparation), or the amounts
of either or both active agents may be varied over the at least
21-day period to generate a multiple-phase preparation, e.g., a
three- or four-phase preparation, substantially as disclosed in,
e.g., EP 148 724. In case of multiple-phase preparation, it may be
possible to include a natural estrogen such as estradiol, e.g. in
an amount of from about 0.5 mg to about 4 mg per day, instead of
ethinylestradiol.
[0035] In suitable embodiments of the present preparation, the
number of daily dosage units comprising the combination of
drospirenone and ethinylestradiol may be 21, 22, 23 or 24, and the
number of daily dosage units containing ethinylestradiol alone may
then be 7, 6, 5 or 4, as the case may be.
[0036] In one embodiment of the present method of inhibiting
ovulation, the method comprises administering, to said mammal, on
each day of at least 21 consecutive days, a daily dosage unit
comprising a combination of drospirenone in an amount of from about
2 mg to about 4 mg and ethinylestradiol in an amount from about
0.01 to about 0.05 mg, followed by administering, on each day of 7
or less consecutive days, a daily dosage unit containing no active
agent, or alternatively, administering no dosage units for 7 days
or less.
[0037] In suitable embodiments of this method, the daily dosage
units comprising the combination of drospirenone and
ethinylestradiol may be administered for 21, 22, 23 or 24
consecutive days, and the daily dosage units containing no active
agent may then be administered for 7, 6, 5 or 4 consecutive days;
as appropriate. Furthermore, the daily dosage units comprising the
combination of drospirenone and ethinylestradiol may be
administered for 28 consecutive days. In a variant of this
embodiment, the daily dosage units comprising the combination of
drospirenone and ethinylestradiol are administered for 2-4,
preferably 2 or 3, times 28 consecutive days, followed by
administration of the daily dosage units comprising the combination
of drospirenone and ethinylestradiol for 21, 22, 23 or 24
consecutive days and subsequently administration of the daily
dosage units containing no active agent, or administration of no
daily dosage units, for 7, 6, 5, or 4 consecutive days.
[0038] Alternatively, the present method comprises administering,
on each day of at least 21 consecutive days, a daily dosage unit
comprising a combination of drospirenone,in an amount of from about
2 mg to about 4 mg and ethinylestradiol in an amount from about 10
0.01 to about 0.05 mg, followed by administering, on each day of 7
or less consecutive days, a daily dosage unit containing
ethinylestradiol alone in an amount of from about 0.01 mg to about
0.05 mg.
[0039] In this alternative method, the daily dosage units
comprising the combination of drospirenone and ethinylestradiol may
suitably be administered for 21, 22, 23 or 24 consecutive days, and
wherein the daily dosage units comprising ethinylestradiol alone
may then be administered for 7, 6, 5 or 4 consecutive days, as
appropriate. In a further embodiment of the method, the daily
dosage units comprising the combination of drospirenone and
ethinylestradiol are administered for 2-4, preferably 2 or 3, times
28 consecutive days, followed by administration of the daily dosage
units comprising the combination of drospirenone and
ethinylestradiol for 21 consecutive days and subsequently
administration of the daily dosage units comprising
ethinylestradiol alone for 7 consecutive days.
[0040] For use according to the invention, the pharmaceutical
preparation may suitably be in the form of a number of separately
packaged and individually removable daily dosage units placed in a
packaging unit and intended for oral administration for a period of
at least 21 consecutive days, wherein each of said daily dosage
units each comprises a combination of drospirenone in an amount of
from about 2 mg to about 4 mg and ethinylestradiol in an amount
from about 0.01 to about 0.05 mg.
[0041] As indicated above, the preparation may further comprise 7
or less daily dosage units containing no active agent (or may
contain 7 or less empty "places", e.g. in the form of empty
blisters in a blister pack, marking the days on which no daily
dosage units are administered).
[0042] Alternatively, the pharmaceutical preparation may be in the
form of a number of separately packaged and individually removable
daily dosage units placed in a packaging unit and intended for oral
administration for a period of at least 28 consecutive days,
wherein at least 21 of said daily dosage units each comprises a
combination-of drospirenone in an amount of from about 2 mg to
about 4 mg and ethinylestradiol in an amount of from about 0.01 to
about 0.05 mg, said packaging unit further comprising 7 or less
daily dosage units comprising ethinylestradiol alone in an amount
of from about 0.01 mg to about 0.05 mg.
[0043] The composition of the invention may be formulated in any
manner known in the pharmaceutical art. In, particular; as
indicated above, the composition may be formulated by a method
comprising providing drospirenone and, if desired, ethinylestradiol
in micronized form in said unit dosage form, or sprayed from a
solution onto particles of an inert carrier in admixture with one
or more pharmaceutically acceptable excipients that promote
dissolution of the drospirenone and ethinylestradiol so as to
promote rapid dissolution of drospirenone and preferably
ethinylestradiol on oral administration. Examples of suitable
excipients include fillers, e.g. sugars such as lactose, glucose or
sucrose, sugar alcohols such as mannitol, sorbitol or xylitol,
starch such as wheat, corn or potato starch, modified starch or
sodium starch glycolate, lubricants such as talc, magnesium
stearate, calcium stearate, colloidal silica or stearic acid, and
binders such as polyvinylpyrrolidone, cellulose derivatives,
carboxymethyl cellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, methyl cellulose or gelatin, for
making oral dosage forms such as tablets, pills or capsules.
[0044] Tablets may Conveniently be coated with a suitable
film-forming agent, e.g. hydroxypropylmethyl
cellulose,hydroxypropyl cellulose or ethyl cellulose, to which a
suitable excipient may optionally be added, e.g. a softener-such as
glycerol, propylene glycol, diethylphthalate or glycerol
triacetate, filler such as sucrose, sorbitol, xylitol, glucose or
lactose, a colorant such as titanium hydroxide, etc.
[0045] The present composition may also be formulated in liquid
form, e.g. as a solution, suspension or emulsion, together with
conventional diluents or excipients in a manner known per se in the
pharmaceutical art.
[0046] A packaging unit comprising the daily dosage units described
above may be prepared in a manner analogous to that of making other
oral contraceptives. This may for instance be a conventional
blister pack or any other form known for this purpose, for instance
a pack comprising the appropriate number of dosage units (in this
case at least 21, or for particular applications, 28 or a multiple
of 28) in a sealed blister pack with a cardboard, paperboard, foil
or plastic backing and enclosed in a suitable cover. Each blister
container may conveniently be numbered or otherwise marked, e.g.
starting with the first of the at least 21 dosage units that
contain the combination of drospirenone and ethinylestradiol,
optionally followed by 7 or less empty blisters or by the 7 or less
dosage units that contain no active agent or that only contain
ethinylestradiol (although the numbering may also start with the
first of the 7 or less dosage units that only contain
ethinylestradiol).
[0047] It is also envisaged that the present composition may be in
the form of a parenteral formulation such as a subcutaneous implant
or transdermal formulation. For making implants, the active agents
may suitably be formulated together with one or more polymers that
are gradually eroded or degraded when in use, e.g. silicone
polymers, ethylene yinylacetate, polyethylene or polypropylene.
[0048] Where transdermal formulations are concerned, they may be
prepared in the form of matrices or membranes or as fluid or
viscous formulations in oil or hydrogels. For transdermal patches,
an adhesive which is compatible with the skin should be included,
such as polyacrylate, a silicone adhesive or polyisobutylene, as
well as a foil made of, e.g. polyethylene, polypropylene, ethylene
vinylacetate, polyvinylchloride, polyvinylidene chloride or
polyester, and a removable protective, foil made from, e.g.,
polyester or paper coated with silicone or a fluoropolymer. For the
preparation of transdermal solutions or gels, water or organic
solvents or mixtures thereof may be .sup.-used. Transdermal gels
may furthermore contain one Or more suitable gelling agents or
thickeners such as silicone, tragacanth, starch or starch
derivatives, cellulose or cellulose derivatives or polyacrylic
acids or derivatives thereof. Transdermal formulations may also
suitably contain one or more substances that enhance absorption
though the skin, such as bile salts or derivatives thereof and/or
phospholipids. Suitable transdermal formulations may, for instance,
be made in a manner analogous to that described in WO 94/04157 for
3-ketodesogestrel. Alternatively, transdermal formulations may be
prepared according to a method disclosed in, e.g., B W Barry,
"Dermatological Formulations, Percutaneous Absorption", Marcel
Dekker Inc., New York--Basel, 1983, or Y W Chien, "Transdermal
Controlled Systemic Medications", Marcel Dekker Inc., New
York--Basel, 1987.
[0049] The present invention is further described in the following
examples which are not in any way intended to limit the scope of
the invention as claimed.
[0050] Experimental
EXAMPLE 1
[0051] Preparation of Tablets Containing Drospirenone and
Ethinylestradiol
[0052] Tablet Cores of the Following Composition
TABLE-US-00001 micronized drospirenone 3.00 mg micronized
ethinylestradiol 0.03 mg lactose monohydrate 48.17 mg corn starch
14.40 mg modified starch 9.60 mg polyvinylpyrrolidone 25,000 4.00
mg magnesium stearate 0.80 mg
were prepared by charging a fluidized bed granulator with 31.68 kg
corn starch, 21.12 kg modified starch, 6.60 micronized
drospirenone, 0.066 kg micronized ethinylestradiol and 105.974 kg
lactose monohydrate and activating the fluidized bed. An aqueous
solution of 8.80 kg polyvinylpyrrolidone 25,000 in 46.20 kg
purified water was sprayed continuously onto the fluidized bed
while drying by heating the air stream of the fluidized bed. At the
end of the process 1.76 kg magnesium stearate was sucked into the
granulator and mixed with the granules by maintaining the fluidized
bed. The resulting granulate was pressed into tablet cores by
compression using a rotary tablet press.
[0053] 2.22464 kg of hydroxypropylmethylcellulose and 0.44528
macrogol 6000 were dissolved in 14.67 kg purified water. 0.44528 kg
talc, 1.22430 kg titanium dioxide and 0.06050 kg ferric oxide
pigment were suspended in 10.26 kg purified water with stirring and
homogenized. The solution and suspension were combined and used to
coat the tablet cores by continuous application of the coating
suspension in a coater.
EXAMPLE 2
[0054] Dissolution of Drospirenone from Tablets
[0055] The rate of dissolution of drospirenone from the tablets
prepared in Example 1 was determined by the USP XXIII Paddle Method
using a USP Dissolution Test Apparatus 2 including 6 covered glass
vessels and 6 paddles. Tablets were placed in 900 ml water at a
temperature of 37.degree. C. (.+-.0.5.degree. C.) and stirred at 50
rpm.
[0056] The results appear from FIGS. 1, 2 and 4. From FIG. 1, it
appears that the batch numbered V8 containing macrocrystalline
drospirenone (but otherwise identical to the tablets prepared in
Example 1) exhibited an extremely slow dissolution rate of
drospirenone, whereas all batches containing micronized
drospirenone exhibited a dissolution rate of more than 70% within
30 minutes.
[0057] FIG. 2 and FIG. 4 shows the results of dissolution of
drospirenone from tablet cores and film-coated tablets,
respectively. In both cases more than 70% of the active agent is
dissolved within 30 minutes. Thus, the film coating did not
significantly influence the rate of dissolution.
EXAMPLE 3
[0058] Dissolution Rate of Ethinylestradiol from Tablets In
Vitro
[0059] The rate of dissolution of ethinylestradiol from tablets
prepared as described in Example 1 was determined according to the
USP Paddle Method as described in Example 2 for drospirenone. The
results appear from FIGS. 3 and 5 showing the dissolution rates
from tablet cores and film-coated tablets, respectively. In both
cases, more than 70% of the active agent was dissolved within 30
minutes. Thus, the film coating did not significantly influence the
rate of dissolution.
EXAMPLE 4
[0060] Bioavailability of Drospirenone and Ethinylestradiol from
Tablets Containing 3 mg of Drospirenone and 0.03 mg
Ethinylestradiol
[0061] 42.healthy women between 18 and 35 years of age were
included in an open-label crossover study after their informed
consent had been obtained. The aim of the study was to investigate
the relative bioavailability of drospirenone and ethinylestradiol
from a tablet formulation containing 3 mg drospirenone and 0.03 mg
ethinylestradiol with reference to an oral suspension containing 6
mg of drospirenone and 0.06 mg ethinylestradiol per vial.
[0062] The bioavailability was determined using serum
concentrations of each active agent as parameters. Compared to the
oral suspension, the relative bioavailability of drospirenone and
ethinylestradiol from the tablets is 107% and 117%, respectively.
It was therefore concluded that both drospirenone and
ethinylestradiol are completely released from the tablets in
vivo.
[0063] The absolute bioavailability of drospirenone was determined
in two studies to be 76%.+-.13% after oral administration of 2 mg
drospirenone to 8 young healthy women and 20 85%.+-.24% after oral
administration of a microcrystalline suspension containing 3.13 mg
drospirenone to 6 postmenopausal women.
[0064] The oral bioavaliability of ethinylestradiol was determined
in several studies, and mean values of from 36% to 59% were
reported in the literature, indicating a first-pass effect.
EXAMPLE 5
[0065] Contraceptive Efficacy of Formulations Containing
Drospirenone and Ethinylestradiol
[0066] An open-label, randomized trial with 52 female volunteers
aged 20-35 years whose informed consent had been obtained included
1 pre-treatment cycle, 3 treatment cycles with two different tablet
containing 2-mg and 3 mg drospirenone, respectively, but otherwise
corresponding to the tablets prepared in Example 1, and a follow-up
phase. A wash-out phase of 1 month preceded the treatment.
[0067] At defined time points, selected central and peripheral
parameters were investigated: LH, FSH, 17.beta.-estradiol,
progesterone, cervical score, "spinnbarkeit", fern phenomenon.
Ovarian function was checked by ultrasound. In addition, SHBG, CBG,
prolactine, total testosterone, androstenedione, DHEA-S and
selected metabolic parameters (serum glucose, triglycerides,
cholesterol, HDL, LDL) were examined. Blood pressure, heart rate,
body weight and cycle control were documented.
[0068] The results of the study showed that both LH and FSH were
clearly suppressed with both trial preparations. Accordingly, the
secretion of estradiol and progesterone were greatly reduced over
all three treatment cycles with the exception of 3 volunteers
receiving the 2 mg drospirenone preparation. This result was, in
principle, confirmed by the accompanying ultrasound examinations.
Follicular ripening occurred in several cases with both trial
preparations. Although three ovulations were diagnosed with the
preparation containing 2 mg drospirenone (one of which was
described as "equivocal" and the other as a "tablet-taking error"),
no differences were demonstrable statistically (p>0.05) between
the two trial preparations as regards the hormones LH, FSH,
estradiol and progesterone, and the parameter "ovulation during the
treatment cycles". In keeping with the hormones, cervical function
was greatly limited and the "spinnbarkeit" and crystallisability of
the cervical mucus was greatly reduced with both trial
preparations. Prolactin increased minimally and SHBG and CBG
distinctly with both preparations. Triglycerides and HDL levels
increased with both trial preparations, while LDL levels decreased.
Total cholesterol was largely unchanged in both treatment groups.
Oral glucose tolerance remained virtually unchanged-or was slightly
decreased. Testosterone, androstenedione and DHEA-S decreased
minimally.
[0069] The subjective and objective tolerance was good with both
treatments. This was also the case for cycle control with the
exception of the first Cycle with 2 mg drospirenone. Blood
pressure, heart rate and body weight remained constant in the
majority of cases or showed a slight tendency to decrease.
[0070] After three months' treatment, it was concluded:
[0071] The two trial preparations were equally good as regards the
subjective and objective tolerance.
[0072] No negative metabolic effects were observed with either
preparation. HDL was influenced positively in the sense of an
increase.
[0073] The results confirmed the results of earlier studies that
the 2 mg drospirenone preparation was in the threshold region of
ovulation inhibition, whereas the 3 mg drospirenone preparation had
a demonstrable ovulation-inhibiting effect in all cases
examined.
[0074] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0075] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, utilize the
present invention to its fullest extent. The preceding preferred
specific embodiments are, therefore, to be construed as merely
illustrative, and not limitative of the remainder of the disclosure
in any way whatsoever.
[0076] The entire disclosure of all applications, patents and
publications, cited above and below, and of corresponding U.S.
application Ser. No. 09/386,274, are hereby incorporated by
reference.
[0077] From the foregoing description, one skilled in the art can
easily ascertain essential characteristics of this invention, and
without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *