Title: Cyclodextrin-drospirenone inclusion complexes
Abstract: Pharmaceutical compositions comprising low doses of sensitive complexes between an estrogen and a cyclodextrin are provided with improved stability. In specific embodiments the composition comprises a complex between ethinyl estradiol and β-cyclodextrin in a granulate preparation and in yet another embodiment the composition comprises a limited amount of polyvinylpyrrolidone since this excipient was found to degrade ethinyl estradiol. Furthermore, a method for improving the stability of an estrogen in a composition and for manufacturing such a stable composition is provided. Essentially, the granulate preparation are manufactured under careful control of the relative humidity.
Patent Number: 6,958,326 Issued on 10/25/2005 to Backensfeld, et al.
| Inventors:
|
Backensfeld; Thomas (Berlin, DE);
Heil; Wolfgang (Berlin, DE);
Lipp; Ralph (Berlin, DE)
|
| Assignee:
|
Schering AG (Berlin, DE)
|
| Appl. No.:
|
022845 |
| Filed:
|
December 20, 2001 |
Foreign Application Priority Data
| Current U.S. Class: |
514/58; 514/23; 514/25; 514/54; 514/60; 536/103; 536/123.1; 536/124 |
| Intern'l Class: |
A01N 043/04; A61K 031/71.5 |
| Field of Search: |
514/23,25,54,58,60
536/103,124,123.1
|
References Cited [Referenced By]
U.S. Patent Documents
| 4129564 | Dec., 1978 | Weichert et al.
| |
| 4154820 | May., 1979 | Simoons.
| |
| 4383992 | May., 1983 | Lipari.
| |
| 4596795 | Jun., 1986 | Pitha.
| |
| 4727064 | Feb., 1988 | Pitha.
| |
| 4877774 | Oct., 1989 | Pitha et al.
| |
| 5376641 | Dec., 1994 | Ammeraal.
| |
| 5798338 | Aug., 1998 | Backensfeld et al.
| |
| 5885978 | Mar., 1999 | Yamada et al.
| |
| 6228399 | May., 2001 | Parikh et al.
| |
| Foreign Patent Documents |
| 2016780 | Jul., 2000 | CA.
| |
| 0 349 091 | Jan., 1990 | EP.
| |
| 0 579 435 | Jan., 1994 | EP.
| |
| 0398460 | Jul., 1997 | EP.
| |
| 2515187 | Oct., 1982 | FR.
| |
| 2109381 | Jun., 1983 | GB.
| |
| WO 96/0227/7 | Feb., 1996 | WO.
| |
| WO 00/2157/0 | Oct., 1999 | WO.
| |
Other References
Krattenmacher Contraception (2000), vol. 62, pp. 29-38.
Hafrun Fridriksdottir, design andin vivo testing of 17B-estradiol-HPBCD sublingual
tablets, Die Pharmazie, Jan. 1996, pp. 39-42, No. 1, Eschborn, DE.
Thorsteinn Loftsson, The effect of water-soluble polymers on drug-cyclodextrin
complexation, International Journal of Pharmaceutics, 1994, vol. 110, pp. 169-177.
Rolf Krattenmacher, "Drospirenone: pharmacology and pharmacokinetics of a unique
progestogen," Contraception, vol. 2, No. 1, Jul. 2000, pp. 29-38.
P. Norman, "Drospirenone: Contraceptive, Hormone Replacement Therapy, Aldosterone
Antagonist, Progestogen: 1, 2-Dihydrospirorenone, SH-470, ZK-30595," Drugs of
the Future, vol. 25, No. 12, Dec. 2000, pp. 1247-1256.
K. Uekama et al., "Inclusion Complexations of Steroid Hormones With Cyclodextrins
in Water and in Solid Phase," International Journal of Pharmaceutics, 10
(1982), pp. 1-15.
K. Králová et al., "Interactions of β-cyclodextrin with steroid
compounds in aqueous solutions," Pharmazie, 1989, vol. 44, No. 9, pp. 623-625.
W.A.J.J. Hermens, "Delivery of hormones: some new concepts," Pharm. Weekbl.
Sci. Ed., 1992, vol. 14, No. 4 A, pp. 253-257.
K. Uekama, "Cyclodextrin Inclusion Compounds: Effects on Stability and Bio-Pharmaceutical
Properties," Topics in Pharmaceutical Sciences, Eds. D.D. Breimer and P.
Speiser, 1987, Elsevier Science Publishers (Biomedical Division), pp. 181-194.
K. Uekama et al., "Cyclodextrin Drug Carrier Systems," Chem. Rev., vol.
98, No. 5, Jul. 1, 1998, pp. 2045-2076.
Pitha et al., "Hydroxypropyl-β-cyclodextrin: preparation and characterization;
effects on solubility of drugs," International Journal of Pharmaceutics,
29(1), pp. 73-82 (1986).
|
Primary Examiner: Wilson; James O.
Assistant Examiner: Lewis; Patrick T.
Attorney, Agent or Firm: Millen, White, Zelano, Branigan, P.C.
Parent Case Text
This application claims priority to U.S. Provisional Application No. 60/256,484,
filed Dec. 20, 2000.
Claims
1. A composition comprising:
i) a granulated preparation comprising a complex between an estrogen and a cyclodextrin;
and
ii) optionally, one or more excipients,
the composition having a stability such that said estrogen is in an amount of
at least 90% w/w in relation to the initial content of said estrogen after storage
for 12 months at 40° C. and 75% relative humidity (RH); and
the composition being essentially free of polyvinylpyrrolidone.
2. The composition according to claim 1, wherein the estrogen is in an amount
from about 0.002% w/w to 2% w/w.
3. The composition according to claim 1, wherein the estrogen is in an amount
from about 0.004% w/w to 0.2% w/w.
4. The composition according to claim 1, wherein the estrogen is ethinyl estradiol
and the cyclodextrin is β-cyclodextrin, the ethinyl estradiol is in an amount
relative to the ethinyl-estradiol-β-cyclodextrin complex of from about 5%
w/w to 20% w/w.
5. The composition according to claim 1, wherein the estrogen is ethinyl estradiol
and the cyclodextrin is β-cyclodextrin, the ethinyl estradiol is in an amount
relative to the ethinyl-estradiol-β-cyclodextrin complex of from about 8%
w/w to 15% w/w.
6. A method for improving the stability of an estrogen in a pharmaceutical composition
that comprises an estrogen and one or more excipients in a granulate preparation,
which method comprises:
i) forming a complex between said estrogen and a cyclodextrin; and
ii) granulating the complex to provide the granulate preparation;
provided that, the composition is prepared so that it is essentially free of
polyvinylpyrrolidone.
7. A process for manufacturing a granulate preparation comprising a complex between
an estrogen and a cyclodextrin, which comprises:
i) loading the complex, optionally one or more other therapeutically active agent(s),
and one or more excipients into a granulator;
ii) applying a liquid onto the loaded complex and the one or more excipients,
and
granulating and drying, so as to obtain granules having a relative humidity not
exceeding 60%, as determined at a temperature between 20° C. and 40°
C.
8. The process according to claim 7, wherein the complex and the optionally further
one or more therapeutically active agent(s) are provided as individual agent(s)
without being pre-mixed with excipients.
9. The process according to claim 7, wherein the relative humidity of the granulate
preparation does not exceed 55%, as determined at a temperature between 20°
C. and 40° C.
10. The process according to claim 7, wherein the relative humidity of the granulate
preparation does not exceed 45%, as determined at a temperature between 20°
C. and 40° C.
11. The process according to claim 7, wherein the relative humidity of the granulate
preparation does not exceed 40%, as determined at a temperature between 20°
C. and 40° C.
12. The composition according to claim 1, wherein the composition comprises one
or more excipient(s) which is/are selected from the group consisting of starch,
cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and maltodextrin.
13. The composition according to claim 1, wherein the estrogen is selected from
the group consisting of ethinyl estradiol, estradiol, estradiol sulfamates, estradiol
valerate, estradiol benzoate, estrone, estrone sulfate and mixtures thereof.
14. The composition according to claim 13, wherein the estrogen is ethinyl estradiol.
15. The composition according to claim 1, wherein the cyclodextrin is selected
from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin
and alkylated or acylated derivatives thereof.
16. The composition according to claim 1, wherein the cyclodextrin is β-cyclodextrin
or an alkylated or acylated derivative thereof.
17. The composition according to claim 1, wherein the estrogen is in an amount
relative to the cyclodextrin such that a molar ratio between the estrogen and the
cyclodextrin is from about 2:1 to 1:10.
18. The composition according to claim 1, further comprising one or more other
therapeutically active agent(s).
19. The composition according to claim 18, wherein the one or more other therapeutically
active agent(s) is a progestogen.
20. The composition according to claim 19, wherein the progestogen is selected
from the group consisting of drospirenone, levonorgestrel, norgestrel, gestodene,
dienogest, cyproterone acetate, norethisterone, norethisterone acetate, desorgestrel,
and 3-keto-desorgestrel.
21. The composition according to claim 20, wherein the progestogen is drospirenone.
22. The composition according to claim 21, wherein drospirenone is in micronized form.
23. The composition according to claim 22, wherein drospirenone is in an amount
from about 0.4% to 20% w/w.
24. The composition according to claim 1, wherein the complex is micronized.
25. The composition according to claim 1, further comprising an antioxidant.
26. The composition of claim 1, wherein the granulated preparation has a mean
particle size of at least about 100 μm.
27. The method according to claim 6, provided that the one or more excipient(s)
is/are selected from the group consisting of starch, cellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose and maltodextrin.
28. The process according to claim 7, provided that, when the granulated preparation
comprises polyvinylpyrrolidone, it is present in an amount of at most 2% w/w.
29. The method according to claim 7, provided that the one or more excipient(s)
is/are selected from the group consisting of starch, cellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose and maltodextrin.
30. The process according to claim 7, wherein the estrogen is selected from the
group consisting of ethinyl estradiol (EE), estradiol, estradiol sulfamates, estradiol
valerate, estradiol benzoate, estrone, estrone sulfate and mixtures thereof.
31. The process according to claim 30, wherein the estrogen is ethinyl estradiol.
32. The process of claim 7, wherein the granulating is by fluidized bed granulation.
Description
FIELD OF INVENTION
The present invention relates to pharmaceutical compositions and formulations
comprising a cyclodextrin-estrogen complex that confers very high chemical stability
to the estrogen. The invention allows for an improved physical stability of cyclodextrin-estrogen
complexes and of the chemical stability of estrogens such ethinyl estradiol upon storage.
BACKGROUND OF THE INVENTION
Degradation of estrogens, such as ethinyl estradiol, in conventional
pharmaceutical products is one of the most critical issues with regard to product
shelf life. Stabilization of the estrogen may be achieved by either product packaging
in hermetic containers or, more effectively, as in the present invention, by actual
stabilization of the pharmaceutical product.
Pharmaceutical products comprising naturally or synthetically derived
sex hormones often consist of low dosages of these active ingredients. Given the
small amounts of active ingredient required per single dosage, often ranging between
0.1 μg and 500 μg, it is problematic to manufacture unit dosage formulations
with reliably consistent amounts of active agent which do not fluctuate within
one batch or between batches. Thus, the requirements of content uniformity as set
forth by health authorities may not be met.
Moreover, degradation of these small amounts of active ingredient is a
further contributor to the fluctuations of the active ingredient in low dosage formulations.
In general, these low dose formulations comprising unstable active agents are
problematic in terms of their preparation, storage and use, and there is a need
for providing means for stabilization of such formulations.
Complexation of estrogens with cyclodextrins is widely used for improving
stability, solubility or bioavailability. For example, EP 0 349 091 discloses compositions
containing complexes between 17-β-estradiol and dimethyl-β-cyclodextrin
for improving nasal administration, Fridriksdottir et al (
Die Pharmazie,
vol. 51, 1996, pages 39-42) describes complexes between cyclodextrin and 17-β-estradiol
for improving the solubility in aqueous solution so as to improve sublinqual application.
Improved solubility is also the focus of U.S. Pat. No. 4,596,795, which relates
to a complex between α-, β- and γ-cyclodextrins and derivatives
thereof with testosterone, progesterone, and estradiol. U.S. Pat. No. 4,383,992
discloses a water soluble inclusion compound formed by complexing a steroid compound,
such as an estrogen with beta-cyclodextrin.
Moreover, U.S. Pat. No. 5,798,338 discloses that the oxidative degradation
of 17-α-ethinyl estradiol is reduced upon forming clathrates (complexes)
between β-cyclodextrin and 17-α-ethinyl estradiol.
However, although complexation of estrogens with cyclodextrins may solve
critical issues with regards to solubility, bioavailability and stability, there
are still further problems to solve before complexes between active agents, such
as estrogens, and cyclodextrins are suitable for use in pharmaceutical products.
Namely, the complexes are prone to dissociation into the free estrogen and the
cyclodextrin, particularly upon contact with water. The lack of physical stability
of cyclodextrin-estrogen complexes results in significant amounts of free estrogen
present in compositions due to, for instance, exposure to aqueous media during
the manufacturing process, particularly during granulation. As a consequence, the
lifetime of the composition may be decreased due to degradation of free estrogen.
Moreover, the intended improved bioavailability sought by complexing estrogen
with cyclodextrin is not achieved due to the lack of physical stability of the
cyclodextrin-estrogen complex and the chemical instability of the free estrogen.
Various attempts have been made in order to stabilize compositions comprising
complexes between a cyclodextrin and an estrogen. For example, the composition
may be stabilized by stabilizing the complex itself. Thus, U.S. Pat. No. 4,727,064
attempts the stabilization of complexes upon using amorphous forms of the complex.
Alternatively, complexes may be stabilized and their solubility increased upon
adding polymers to the reaction medium upon complexation, as disclosed by Loftsson
et al. (
Int. J. Pharmaceutics, Vol. 110, 1994, pp169-177). EP 0579435 also
discloses complexes between estradiol and cyclodextrins wherein the addition of
polymers to the reaction medium increases the stability constant of the complex.
The compositions may also be stabilized upon avoiding a granulation step in the
manufacturing process of the composition, as disclosed in WO 00/21570.
There is a need in the art for processes for preparing physically stable complexes
of cyclodextrin and estrogen and for compositions, which improve the stability
of both the complex and the free estrogen. There is furthermore a need in the art
for granulate formulations which allow for physically stable cyclodextrin-estrogen complexes.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a stable and homogenous pharmaceutical
product comprising an estrogen, wherein the stability of the estrogen is significantly
improved over that of conventional products, which have complexed estrogens or
sensitive complexes between a cyclodextrin and an estrogen. Degradation of estrogens,
such as ethinyl estradiol, in conventional products, is one of the most critical
issues with regard to product shelf life.
It has surprisingly been found that products with improved stability of the estrogen
are achieved by means of complexing estrogen with cyclodextrins, the judicious
selection of excipients and/or proper adaptation of the manufacturing process.
Consequently, the shelf-life of an estrogen-containing product is improved.
Thus, an important aspect of the invention relates to formulations and compositions
comprising complexes between an estrogen and a cyclodextrin that are stable in
spite of being manufactured by granulation. That is to say that the invention relates
in a first aspect to a formulation comprising a complex between an estrogen and
a cyclodextrin, wherein the formulation is a granulate preparation, said granulation
preparation having a relative humidity of at most 60%, as determined at a temperature
between 20° C. and 40° C.
In a further aspect, the invention relates to compositions comprising i) a complex
between an estrogen and a cyclodextrin; and ii) one or more excipient(s), the composition
having a stability such that said estrogen is in amount of at least 85% w/w in
relation to the initial content of the estrogen after storage for 12 months at
40° C. and 75% relative humidity (RH). In a suitable embodiment thereof, the
composition comprises a granulate preparation comprising said complex. In a further
suitable embodiment, the composition is compressed directly into a tablet or equivalent
unit dosage forms. Upon further study of the specification and appended claims,
further aspects and advantages of this invention will become apparent to those
skilled in the art.
Thus, contrarily to previous findings, it is possible to obtain stable compositions
comprising an estrogen-cyclodextrin-complex in a granulate preparation.
Compositions of the present invention may be used as medicaments. Accordingly,
the use of a composition described infra for the preparation of a medicament for
female contraception, for hormone replacement therapy, or for treating acne or
PMDD (pre-menstrual dysfunction disorders), is a further aspect of the present invention.
In a broad sense, the present invention relates to a method of improving the
stability
of an estrogen in a pharmaceutical composition that comprises an estrogen-cyclodextrin
complex and one or more excipients in a granulate preparation, the method comprises
the steps of:
i) forming a complex between said estrogen and a cyclodextrin; and
ii) mixing under granulation conditions the said complex with the one or
more excipients such that the relative humidity of the final granulate does not
exceed 60%, as determined at a temperature between 20° C. and 40° C.
Finally, the invention relates to a process for manufacturing a composition
comprising a granulate preparation of a complex between an estrogen and a cyclodextrin,
wherein the processing of the granulate preparation comprises the steps of
i) loading the complex, one or more excipients and optionally one or more
therapeutically active agent(s) into a granulator;
ii) applying a liquid onto the loaded complex and the one or more excipients
under granulation conditions so as to obtain granules having a relative humidity
not exceeding 60%, as determined at a temperature between 20° C. and 40° C.
DETAILED DESCRIPTION OF THE INVENTION
The term "complex" is intended to mean a complex between an estrogen and a cyclodextrin,
wherein a molecule of said estrogen is at least partially inserted into the cavity
of one cyclodextrin molecule. Furthermore, the molecule of an estrogen may at least
partially be inserted into the cavity of more cyclodextrin molecules, and two moieties
of a single estrogen molecule may each be inserted into one cyclodextrin molecule
to give 2:1 ratio between cyclodextrin and estrogen. Thus, the complex may be termed
as an inclusion complex (clathrate) between an estrogen and a cyclodextrin. Similarly,
the complex may comprise more than one molecule of estrogen at least partially
inserted into one or more cyclodextrin molecules, wherein for example 2 estrogen
molecules are at least partially inserted into a single cyclodextrin molecule,
to give a 1:2 ratio between cyclodextrin and estrogen. Complexes wherein one estrogen
molecule is complexed with one or more cyclodextrin molecules are certainly anticipated
such as 1 estrogen molecule complexed with 2 cyclodextrin molecules or 3 cyclodextrin
molecules. Typically, the ethinyl estradiol-β-cyclodextrin complex as prepared
by the present invention is preferably a complex between one molecule of ethinyl
estradiol and two molecules of β-Cyclodextrin.
The term "ethinyl estradiol-β-Cyclodextrin complex" or "EE-β-CD"
is intended to mean a complex, of any ratio, between ethinyl estradiol and β-cyclodextrin.
The term "granulate preparation" relates to a preparation of a powder, wherein
the particle size of the powder is either increased upon processing with a liquid
or by compression. The liquid may be of any kind of aqueous or organic solvents,
or mixtures thereof, optionally further comprising a binder such as a starch. Thus,
a "granulate preparation" relates in a broad sense to granules, pellets and compressed
powder or any particle formed by granulation, pelletation or compression of powder
such that a mean particle size of at least about 100 μm are formed.
The term "cyclodextrin" is intended to mean a cyclodextrin or a derivative thereof
as well as mixtures of various cyclodextrins, mixtures of various derivatives of
cyclodextrins and mixtures of various cyclodextrins and their derivatives. The
cyclodextrin is further defined according to the invention.
The present inventors have developed products, wherein a remarkable improvement
of the stability of an estrogen has been achieved by combined means. One such means
is by the protection of the estrogen by forming a cyclodextrin complex. Another
such means is by the judicious adaptation of the granulation process such that
e.g. the dissociation of the complex into free estrogen and cyclodextrin is restricted
during the manufacturing of the granulate preparation. The present inventors have
provided data indicating that a complex between ethinyl estradiol and β-cyclodextrin
is poorly stable when exposed to water. Actually, in the event where the complex
is dissolved in water, about 50% of the complex are dissociated into free ethinyl
estradiol and cyclodextrin within 3 minutes (see Example 6 herein). Thus, without
being limited to a particular theory, the stability of the products is, at least
in part, improved by limiting the dissociation of the complex into free estrogen
during the manufacturing process, thereby limiting the content of free estrogen
in the final product.
Therefore, in a first aspect the invention relates to a formulation comprising
a complex between an estrogen and a cyclodextrin, wherein the formulation is a
granulate preparation, said granulation preparation having a relative humidity
of at most 60%, as determined at a temperature between 20° C. and 40°
C. Preferably, the relative humidity is at most 55%, preferably of at most 45%,
most preferably of at most 40%, as determined at a temperature between 20°
C. and 40° C.
As stated, the present invention has lead to stable products comprising sensitive
complexes between an estrogen and a cyclodextrin. Thus, in a second aspect, the
invention relates to a composition comprising:
i) a complex between an estrogen and a cyclodextrin; and
ii) one or more excipient(s), the composition having a stability such that
said estrogen is in an amount of at least 85% w/w in relation to the initial content
of the estrogen after storage for 12 months at 40° C. and 75% relative humidity
(RH). The initial content of estrogen should be understood as the weighed quantity
of estrogen included in the composition upon manufacturing the final formulation.
In one embodiment hereof, the composition is in a form of a tablet manufactured
by direct compression of the composition. Preferably the composition comprises
a restricted amount of polyvinylpyrrolidone as disclosed further herein.
In yet another embodiment, the complex between an estrogen and a cyclodextrin
is formulated into the granulate preparation as defined herein.
In preferred embodiments, the composition has a stability such that said estrogen
is in an amount of at least 90% w/w, more preferably of at least 95% w/w, most
preferably of at least 97% w/w such as of at least 98% in relation to the initial
content of the estrogen after storage for 12 months at 40° C. and 75% relative
humidity (RH).
One further means for improving the stability of an estrogen in such formulations
and compositions comprises the judicious selection of excipients such that the
content of excipients capable of inducing degradation of ethinyl estradiol are
minimised or excluded from the formulations. One such critical excipient is polyvinylpyrrolidone,
which is typically used as a binding agent for fluid bed granulation. As disclosed
herein, the ethinyl estradiol is sensitive to polyvinylpyrrolidone and significant
quantities of ethinyl estradiol is degraded in formulations and compositions, nonetheless
the ethinyl estradiol is protected in the form of a clathrate. For example, compositions
comprising polyvinylpyrrolidone and prepared as disclosed in Example 3 of U.S.
Pat. No. 5,798,338, by fluid bed granulation have a poor stability with respect
to ethinyl estradiol. The present inventors has found that in such a composition
the content of ethinyl estradiol is decreased by 25% in relation to the initial
content of the ethinyl estradiol after storage for 12 months at 40° C. and
75% relative humidity (See table 1.4, Example 1, Table A). Therefore, one aspect
of the invention relates to compositions/formulations low in the content of compounds
with relatively high oxidising potential such as an oxidising potential greater
than or similar to polyvinylpyrrolidone. For example, the compositions/formulations
of the present invention preferably have less polyvinylpyrrolidone than the compositions
of Example 3 of U.S. Pat. No. 5,798,338. More preferably, suitable embodiments
of the invention relate to compositions/formulations comprising at most 2% w/w
of polyvinylpyrrolidone, preferably at most 1% w/w, more preferably at most 0.5%
w/w, most preferably at most 0.2% w/w of polyvinylpyrrolidone. Moreover, particular
interesting embodiments relate to compositions/formulations essentially free of polyvinylpyrrolidone.
Individually, or acting in concert, the above mentioned means have
resulted in compositions, wherein the estrogen is more stable than in conventional
compositions comprising polyvinylpyrrolidone that are manufactured by direct compression
or by an improper fluid bed granulation process. The thus provided stable compositions
is characterised by having a content of said estrogen of at least 90% w/w in relation
to the initial content of said estrogen after storage for 3 months at 40°
C. and 75% relative humidity (RH). Preferably, the content of said estrogen is
least 92% w/w, more preferably at least 94% w/w, even more preferably at least
96% w/w and most preferably at least 98% w/w in relation to the initial content
of estrogen after storage for 3 months at 40° C. and 75% relative humidity (RH).
Likewise, the compositions are also stable at higher temperatures, e.g.
at 60° C. and 75% relative humidity, wherein the stability is such that a
content of estrogen, as determined after 3 months storage at 60° C. and 75%
relative humidity (RH), is 85% w/w in relation to the initial content of said estrogen,
preferably at least 90% w/w, more preferably at least 92% w/w, even more preferably
at least 94% w/w, most preferably at least 96% w/w in relation to the initial content
of said estrogen.
Importantly, the compositions according to the invention are more stable
at ambient conditions in comparison to conventional compositions. Thus, the compositions
as disclosed herein have improved stability upon storage for 12 months at 25°
C. and 60% relative humidity (RH), such that said estrogen is in an amount of at
least 95% w/w in relation to the initial content of said estrogen. Preferably,
the content of estrogen is at least 96% w/w, more preferably at least 97% w/w,
most preferably at least 98% w/w in relation to the initial content of estrogen
after storage for 12 months at 25° C. and 60% relative humidity (RH).
As the person skilled in the art will appreciate, the estrogen may be selected
from the group consisting of ethinyl estradiol (EE), estradiol, estradiol sulfamates,
estradiol valerate, estradiol benzoate, estrone, estriol, estriol succinate and
conjugated estrogens, including conjugated equine estrogens such as estrone sulfate,
17β-estradiol sulfate, 17α-estradiol sulfate, equilin sulfate, 17β-dihydroequilin
sulfate, 17α-dihydroequilin sulfate, equilenin sulfate, 17β-dihydroequilenin
sulfate and 17β-dihydroequilenin sulfate or mixtures thereof. Particular
interesting estrogens are selected from the group consisting of ethinyl estradiol
(EE), estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, and
estrone sulfate or mixtures thereof, notably ethinyl estradiol (EE), estradiol
valerate, estradiol benzoate and estradiol sulfamates. Most preferred is ethinyl
estradiol (EE).
In the preferred embodiment wherein the estrogen is ethinyl estradiol (EE), some
of the degradation products are well known. Thus, unstable compositions, e.g. those
comprising a sensitive complex between an ethinyl estradiol and a cyclodextrin
that are manufactured by said conventional granulation methods, comprises degradation
products of ethinyl estradiol, in particular following storage for a period of
time. Moreover, since more ethinyl estradiol is degraded in said conventional compositions
than in those developed by the present inventors (see Example 2, table 1.3), the
conventional compositions may comprise higher quantities of these degradation products.
Accordingly, the stability according to one embodiment of the present
invention is such that a molar sum product of known degradation products of ethinyl
estradiol is at most 0.8% in relation to the initial content of ethinyl estradiol.
Thus, wherein the estrogen is ethinyl estradiol, the molar sum product of 6-α-hydroxy-ethinyl
estradiol, 6-β-hydroxy-ethinyl estradiol, 6-keto-ethinyl estradiol, Δ6,7-ethinyl
estradiol and Δ-9,11-ethinyl estradiol totals at the most 0.8% in relation
to the initial molar content of ethinyl estradiol as determined after storage for
12 months at 25° C. and 60% relative humidity (RH). Preferably, the molar
sum product totals at the most 0.7% and more preferably at the most 0.6% at these
storage conditions.
Furthermore, the stability is such that a molar sum product 6-α-hydroxy-ethinyl
estradiol, 6-β-hydroxy-ethinyl estradiol, 6-keto-ethinyl estradiol, Δ6,7-ethinyl
estradiol and Δ-9,11-ethinyl estradiol, totals at the most 3% in relation
to the initial molar content of ethinyl estradiol as determined after storage for
12 months at 40° C. and 75% relative humidity (RH). Preferably, the molar
sum product totals at most 2% and more preferably at the most 0.6% at those storage conditions.
As stated, an object of the present invention is to provide a pharmaceutical
composition/pharmaceutical
formulation comprising a complex between an estrogen and cyclodextrin, wherein
the stability of said estrogen is significantly improved over that of conventional
compositions/formulations. Thus, for further improving the stability or ensuring
the stability of embodiments according to the invention, the composition/formulations
further comprises an antioxidant. The antioxidant may either be included in the
granulate preparation or added to the composition as a further excipient.
The cyclodextrin may be selected from α-cyclodextrin, β-cyclodextrin,
γ-cyclodextrin and derivatives thereof. The cyclodextrin may be modified
such that some or all of the primary or secondary hydroxyls of the macrocycle,
or both, may be alkylated or acylated. Methods of modifying these alcohols are
well known to the person skilled in the art and many are commercially available.
Thus, some or all of the hydroxyls of cyclodextrin may modified cyclodextrins have
be substituted with an O—R group or an O—C(O)—R, wherein R is
an optionally substituted C
1-6 alkyl, an optionally substituted C
2-6
alkenyl, an optionally substituted C
2-6 alkynyl, an optionally
substituted aryl or heteroaryl group. Thus, R may be methyl, ethyl, propyl, butyl,
pentyl, or hexyl group. Consequently, O—C(O)—R may be an acetate. Furthermore,
with the commonly employed 2-hydroxyethyl group, or 2-hydroxypropyl group R may
be used to derivatize cyclodextrin. Moreover, the cyclodextrin alcohols may be
per-benzylated, per-benzoylated, or benzylated or benzoylated on just one face
of the macrocycle, or wherein only 1, 2, 3, 4, 5, or 6 hydroxyls are benzylated
or benzoylated. Naturally, the cyclodextrin alcohols may be per-alkylated or per-acylated
such as per-methylated or per-acetylated, or alkylated or acylated, such as methylated
or acetylated, on just one face of the macrocycle, or wherein only 1, 2, 3, 4,
5, or 6 hydroxyls are alkylated or acylated, such as methylated or acetylated.
The estrogen-cyclodextrin complex may be obtained by methods known to the person
skilled in the art (e.g. U.S. Pat. No. 5,798,338).
The ethinyl estradiol-β-cyclodextrin complex may also be obtained by co-precipitation
as follows: Ethinyl estradiol is dissolved in ethanol; β-cyclodextrin is
dissolved at 45° C. in water; the ethinyl estradiol solution is added to the
beta-cyclodextrin solution; the obtained suspension is stirred for some hours at
20 to 25° C. and afterwards at 2° C.; the crystallisation product is
isolated and dried.
Alternatively, the ethinyl estradiol-β-cyclodextrin complex
may be obtained as follows: Ethinyl estradiol is dissolved in acetone; β-cyclodextrin
is dissolved at 45° C. in water; the ethinyl estradiol solution is added to
the β-cyclodextrin solution; the obtained suspension is stirred for some
hours at temperatures below 25° C.; afterwards, the crystallisation product
is isolated and dried.
Preferably, the complex between a cyclodextrin and an estrogen may have
a given lipophilicity (hydrophobicity). Thus, suitable embodiments according to
the invention relates to those, wherein the complex has a n-octanol/water partition
coefficient of the complex at pH 7 ranging from about 2 to 5, preferably from about
3 to 4. Further interesting embodiments comprises the complex in crystalline form.
Thus, in a limited aspect, the invention relates to crystalline complexes between
an estrogen and a cyclodextrin. The term "crystalline" relates to various modifications
of the physical structure of a compound, wherein a part of the compound can be
in amorphous form. Crystalline compounds may be characterised by being hydrated
and containment of crystal water. Finally, the complexes may be defined by the
examples provided herein such as those hydrated complexes disclosed in Example
12. Moreover, the crystalline complex may contain parts of free ethinyl estradiol
and free cyclodextrin.
Preferably, the complex comprises of β-cyclodextrin or a derivative
thereof, most preferably β-cyclodextrin. Thus, in a particularly preferred
embodiment of the invention, which is a combination of preferred embodiments, the
estrogen is ethinyl estradiol and the cyclodextrin is β-cyclodextrin.
In an alternative embodiment of the invention, the composition further comprises
one or more therapeutically active agent. Thus, in this embodiment, the composition
further comprises a progestogen. The progestogen may be selected from the group
consisting of drospirenone, levonorgestrel, norgestrel, gestodene, dienogest, cyproterone
acetate, norethisterone, norethisterone acetate, desorgestrel, 3-keto-desorgestrel.
However, the preferred progestogen is drospirenone.
In the preferred embodiment wherein the therapeutically active substance is drospirenone,
said drospirenone may optionally be micronized. In the preferred embodiment where
the therapeutically active substance is drospirenone, all or substantially all
of said drospirenone may be present as a complex with cyclodextrin. As the person
skilled in the art will appreciate, the dissociation of the drospirenone cyclodextrin
complex may result in a mixture of cyclodextrin-complexed drospirenone and uncomplexed
(free) drospirenone. As was the case for uncomplexed drospirenone, the complexed
drospirenone may also be micronized.
Thus, a preferred embodiment of the invention relates to a composition/formulation
wherein the estrogen is ethinyl estradiol and the one or more therapeutically active
agent(s) is drospirenone. A further interesting embodiment in connection hereto
is where both the estrogen-cyclodextrin complex and the drospirenone are micronized.
As stated, the compositions and formulations comprises low doses of active agent,
such that typical embodiments according to the invention comprises estrogen in
an amount corresponding to a therapeutically equivalent amount of ethinyl estradiol
of from about 0.002% w/w to 2% w/w.
In yet other typical embodiments, the composition/formulations comprises the
estrogen,
ethinyl estradiol, in an amount from about 0.002% w/w to 2% w/w. Preferably, the
amount is from about 0.004% w/w to 0.2% w/w, more preferably from about 0.008%
w/w to 0.1% w/w, most preferably from about 0.02% w/w to 0.05% w/w.
When taking the amount of the cyclodextrin into account such as in preferred
embodiments wherein the estrogen is ethinyl estradiol and the cyclodextrin is β-cyclodextrin,
the ethinyl estradiol is in an amount relative to the ethinyl-estradiol-β-cyclodextrin
complex of from about 5% w/w to 20% w/w, preferably from about 8% w/w to 15% w/w,
most preferably from about 9% w/w to 13% w/w.
Furthermore, according to the invention, the ratio between the estrogen
and the cyclodextrin may be adjusted. Therefore, in suitable embodiments, the estrogen
is in an amount relative to the cyclodextrin such that a molar ratio between the
estrogen and the cyclodextrin is from about 2:1 to 1:10, preferably from about
1:1 to 1:5, most preferably from about 1:1 to 1:3, such as 1:1 and 1:2.
In embodiments wherein the composition further comprises a therapeutically active
compound and that said compound is drospirenone, the drospirenone is in an amount
from about 0.4% to 20% w/w, preferably from about 0.8% w/w to 10% w/w, more preferably
from about 1.5% w/w to 5% w/w.
A further object of the invention is to provide a composition or a formulation
as described herein further formulated as a unit dosage form, preferably such as
a tablet, capsule or sachets.
A typical embodiment of the invention relates to a composition or a formulation
in form of granules, pellets or dry compressed blends that may be filled into hard
gelatine capsules or sachets, or compressed into tablet cores. In that event, the
composition or formulation comprises (% wt/wt):
- i) Active agent: complex between ethinyl estradiol and β-cyclodextrins;
- ii) 0-95% w/w of filling agents such as lactose, starch, cellulose and/or others;
- iii) 0-15% w/w of binding agents such as starch, cellulose, hydroxypropylcellulose
hydroxypropylmethylcellulose, maltodextrine and/or others;
- iv) 0-5% w/w of glidants such as colloidal silicon dioxide and/or others;
- v) 0-15% w/w of disintegrating agents such as starch, carmellose-calcium,
crosscarmellose-sodium, carboxymethylstarch sodium and/or others;
- vi) 0-5% w/w of stabilizers/antioxidants such as tocopherole acetate,
propyl gallate, ascorbic acid, ascorbic palmitate and/or others; and
- vii) 0-5% w/w of lubricants such as magnesium stearate and/or others.
In the embodiment wherein the composition/formulation further comprises a therapeutically
active compound, such as a progestogen, preferably drospirenone, a typical formulation
may further comprise 0.1-15% w/w of drospirenone.
A particular interesting embodiment relates to a unit dosage form comprising:
| |
|
| |
Drospirenone (micronized) |
3.00 mg |
| |
Ethinyl estradiol as β-cyclodextrin |
0.02 mg* |
| |
clathrate (micronized) |
| |
Lactose |
48.18 mg** |
| |
Corn starch |
28.00 mg |
| |
Magnesium stearate |
0.8 mg |
| |
Water |
(processing aid) |
| |
|
| |
*0.02 is the concentration of ethinyl estradiol (not taken β-cyclodextrin
into consideration). The amount of ethinyl estradiol in the β-cyclodextrin
clathrate is 9.5 to 12.5%. |
| |
**the amount of lactose is to be adjusted to the amount of β-cyclodextrin. |
A further aspect of the invention relates to a method for improving the stability
of an estrogen in a pharmaceutical composition that comprises an estrogen and one
or more excipients in a granulate preparation, the method comprises the steps of:
i) forming an complex between said estrogen and a cyclodextrin; and
ii) mixing under granulation conditions the said complex with the one or
more excipients such that the relative humidity of the final granulate does not
exceed 60%, as determined at a temperature between 20° C. and 40° C.
As described herein, this method of stabilizing results in compositions that
are
more stable than reported for conventional compositions. The important features
leading to the improved stability relates, at least in part, to the granulation
process and to the proper choice of excipients. Thus, the method of improving the
stability relates to the proper adjusting of the relative humidity of the granulate
preparation. Most importantly, the relative humidity may not exceed 60% relative
humidity, as determined at a temperature between 20° C. and 40° C. Preferably,
the relative humidity does not exceed 55%, more preferably does not exceed 45%,
most preferably does not exceed 40%, as determined at a temperature between 20°
C. and 40° C.
In a further related aspect hereof, the invention relates to a method for improving
the stability of an estrogen in a pharmaceutical composition that comprises an
estrogen and one or more excipients, the method comprises the steps of:
i) forming an complex between said estrogen and a cyclodextrin; and
ii) adding excipients in an amount so as to minimise the overall amount
of excipients which have an oxidising potential greater than or similar to polyvinylpyrrolidone.
The aim is to restrict or minimise the amount of excipients, which have oxidising
potentials greater than or similar to polyvinylpyrrolidone.
Thus, the method of stabilizing also relates to limiting the content of excipients
with an oxidising potential greater than or similar to polyvinylpyrrolidone, including
limiting the content of polyvinylpyrrolidone in the compositions/formulations.
Thus, interesting embodiments of the invention relate to those wherein the one
or more excipient(s) comprises polyvinylpyrrolidone in an amount of at most 2%
w/w. Preferably, the amount is at most 1% w/w, more preferably at most 0.5% w/w,
most preferably at most 0.2% w/w. In a very preferred embodiment, the method of
improving stability relates to excluding polyvinylpyrrolidone from the pharmaceutical
composition. Thus, a method of stabilizing an estrogen in a pharmaceutical composition
relates to a composition/formulation essentially free of polyvinylpyrrolidone.
A still further object of the invention is to provide a process for preparing
compositions
and formulations that are stable and homogenous and as described supra. Suitable
process conditions comprise the steps of preparing a granulation liquid, individually
loading the active agents and the one or more excipient(s) into equipment suitable
for granulation, granulating and drying. In a preferred embodiment hereof, the
thus obtained granules have a relative humidity of at most 60%.
Thus, the invention relates to a process for manufacturing a granulate preparation
comprising a complex between an estrogen and a cyclodextrin, wherein the processing
of the granulate preparation comprises the steps of:
i) loading the complex and one or more excipients into a granulator;
ii) applying a liquid onto the loaded complex and the one or more excipients
under granulation conditions so as to obtain granules having a relative humidity
not exceeding 60%, as determined at a temperature between 20° C. and 40° C.
The process has lead to novel compositions comprising less degraded estrogen
and less degradation products in comparison to those compositions manufactured
by conventional processes such as those granulation techniques using polyvinylpyrrolidone
and/or techniques wherein the relative humidity are not properly adjusted.
Thus, in preferred embodiments according to the invention, the granulation
conditions are even more restricted such as the relative humidity of the granulate
preparation does not exceed 55%, preferably does not exceed 45%, most preferably
does not exceed 40%, as determined at a temperature between 20° C. and 40°
C. Furthermore, the amount of polyvinylpyrrolidone is restricted.
As stated, the formulation comprises low doses of the active agents, in particularly
of the ethinyl-estradiol-cyclodextrin complex. Consequently, it is critical to
achieve homogenous formulations and to meet the requirements of content uniformity.
Thus, an important issue to consider, when manufacturing compositions/formulations
containing low doses of the active ingredient, is the homogeneity of the granulate
preparation. Common practice applies to the use of pre-mixes of the active ingredient
with an excipient, e.g. lactose when manufacturing low-dosages formulations. The
pre-mix is normally made in a separate blending step. However, the present inventors
have developed a process for manufacturing low-dosage formulations without using
a step of pre-mixing the active agent with a suitable excipient.
Thus, an interesting embodiment of the invention relates to a method as described
supra wherein the complex and the optionally further one or more therapeutically
active agent(s) are provided as individual agent(s) without being pre-mixed with
excipients. In a further embodiment related hereto, one or more therapeutically
active agent(s), such as drospirenone, is further added to the granulator.
As stated, the properly adapted process of the invention has lead to the manufacturing
of homogenous batches of the granulate preparation. In the event where the process
further lead to unit dosage forms, such as a tablet, content uniformity is achieved.
Thus, in very suitable embodiments of the invention, batches of final granulate
and/or final unit dosage forms comply with the content uniformity so as to be within
the range of 85% and 115%, preferably within the range of 90% and 110%, more preferably
within 95% and 105%. The content uniformity is determined by taking 10 random samples
of the granulate preparation or by randomly taken 10 tablets from a batch of tablets,
determining the quantitative content of estrogen in each sample or tablet, and
finally calculating the coefficient of variation based on the individual quantities
of estrogen.
The low doses referred to in this context relate to compositions/formulations
comprising the complex in an amount of from about 0.005% w/w to 20% w/w, preferably
from about 0.01% w/w to 2% w/w, more preferably from about 0.05% w/w to 1% w/w,
even more preferably from about 0.1% w/w to 0.7% w/w, most preferably from about
0.15% w/w to 0.5% w/w.
The granulation may be provided by any equipment that will provide a stable and
homogenous granulate according to the invention. That is to say any equipment suitable
for obtaining granules having a relative humidity of at most 60% at temperatures
from 20° C. to 40° C. However, in a preferred embodiment, the granulation
conditions are provided by fluidised bed granulation.
A further object of the invention is related to the use of compositions described
herein and in the Examples in the preparation of a medicament for female contraception,
for hormone replacement therapy, or for treating acne or PMDD (pre-menstrual dysfunction disorder).
The use of a compound of the present invention for hormone replacement therapy
relates to treating menopausal, pre-menopausal, and/or post-menopausal symptoms
in a female. The medicament is suitably formulated according to general knowledge
for a person skilled in the pharmaceutical art typically for oral administration.
In a preferred embodiment, the medicament is suitable for inhibiting ovulation
in a female. 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 ethinyl estradiol.
As stated, the use of compositions for the preparation of a medicament for oral
administration, preferably comprises the use of compositions comprising a complex
between ethinyl estradiol and β-cyclodextrin and further comprising a therapeutically
active agent. Most preferably, the agent is drospirenone. In a combination of preferred
embodiments, the dose of ethinyl estradiol is from 0.015 mg to 0.04 mg, in particular
from about 0.015 mg to 0.03 mg, and the dose of drospirenone is from about 2.5
mg to 3.5 mg, in particular about 3 mg for a daily dosage unit. More particularly,
the compositions of the invention comprise an amount of drospirenone corresponding
to a daily dosage of from about 3.0 to 3.5 mg and ethinyl estradiol in an amount
corresponding to from about 0.015 to 0.03 mg.
The medicament for use in inhibiting ovulation may be an 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 an interesting embodiment of the present invention relating to the use of a
medicament for inhibiting ovulation, the medicament is administered 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 ethinyl estradiol
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.
In a further suitable embodiment, each of the daily dosage units comprising a
combination of drospirenone and ethinyl estradiol are to be administered for 21,
22, 23 or 24 consecutive days, and each of the daily dosage units containing no
active agent may be administered for 7, 6, 5 or 4 consecutive days, as appropriate.
Furthermore, the daily dosage units comprising the combination of drospirenone
and ethinyl estradiol may be administered for 28 consecutive days or 30 or 31 consecutive
days. Suitably, the use of said medicament 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 ethinyl estradiol
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 ethinyl estradiol
alone in an amount of from about 0.01 mg to about 0.05 mg.
In this alternative method, the daily dosage units comprising the combination
of drospirenone and ethinyl estradiol may suitably be administered for 21, 22,
23 or 24 consecutive days, and wherein the daily dosage units comprising ethinyl
estradiol 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 ethinyl estradiol 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 ethinyl estradiol
for 21 consecutive days and subsequently administration of the daily dosage units
comprising ethinyl estradiol alone for 7 consecutive days.
The entire disclosures of all applications, patents and publications, cited herein,
and of U.S. Provisional Application Ser. No. 60/256,484, filed Dec. 20, 2000, and
of EP Application No. 00610135.6, filed Dec. 20, 2000, are hereby incorporated
by reference.
The present invention is further defined by the Examples.
BRIEF DESCRIPTION OF THE EXAMPLES
Example 1 discloses a pharmaceutical product according to some embodiments
of the present invention along with pharmaceutical products known to the person
skilled in the art. Table 1.3 illustrates the performance in terms of stability
in comparison to known formulations after a fixed period of time under controlled
environmental conditions. The data shows that direct compression of the powder
blend results in good stability of ethinyl estradiol when provided in the form
of a cyclodextrin complex (Product D). The product E was prepared to be polyvinylpyrrolidone-free
according to the present invention. This product also shows good stability of the
ethinyl estradiol in spite of being manufactured by granulation. However, in the
case where the product includes polyvinylpyrrolidone and is manufactured according
to Example 3 in U.S. Pat. No. 5,798,338 (Tablet A), the product is poorly stable.
Example 2 illustrates the stability of EE in Formulations D and E in comparison
to other formulations in terms of the breakdown products isolated from samples
upon storage after a fixed period of time under controlled environmental conditions.
Example 3 discloses the contents of one embodiment of the present invention,
wherein the composition further comprises drospirenone.
Example 4 describes the morphology or some physical characteristics of a
typical dosage form of a formulation according to the present invention.
Example 5 discloses a typical process for the preparation of a tablet.
Example 6 describes the method in which certain physical properties, namely
the rate constant of the dissociation constant of the complex between EE and CD,
was studied. The half-life of the 1:1 complex was determined to be 155.8 s and
the dissociation constant was determined to be 4.45×10
-3 s
-1.
Example 7 describes the method in which the equilibrium stability constant
(formation constant) of the complex between EE and CD was studied. The stability
constant of the 1:1 complex was found to be 9.5×10
-4 M
-1.
The solubility of complexed ethinyl estradiol was found to improve in comparison
to the free steroid.
Example 8 describes the method in which the equilibrium stability constant
(formation constant) of the complex between EE and CD in acidic medium was studied.
The stability constant of the 1:1 and 1:2 complex in acidic medium is disclosed.
The solubility
