Specification
AQUEOUS PHARMACEUTICAL FORMULATIONS OF ER SELECTIVE LIGANDS
FIELD OF THE INVENTION
The present invention relates to aqueous formulations of ER selective
ligands. In some embodiments, the formulations include an ER selective ligand, a
solubilizer/complexant component, and a pH adjusting component In some
preferred embodiments, the ER selective ligand is 2-(3-fluoro-4-hydroxyphenyl)-7-
vinyl-1,3-benzoxazol-5-ol or 3-(3-Fluoro-4-hydroxy-phenyl)-7-hydroxy-naphthalene-1-
carbonitrile.
BACKGROUND OF THE INVENTION
This invention relates to formulations for ER selective ligands, which are
useful as estrogenic agents.
The plelotropic effects of estrogens in mammalian tissues have been well
documented, and it is now appreciated that estrogens affect many organ systems
[Mendelsohn and Karas, New England Journal of Medicine 340: 1801-1811 (1999),
Epperson, et al., Psychosomatic Medicine 61: 676-697 (1999), Crandall, Journal of
Womens Health & Gender Based Medicine 8: 1155-1166 (1999), Monk and Brodaty,
Dementia & Geriatric Cognitive Disorders 11:1-10 (2000), Hum and Macrae, Journal
of Cerebral Blood Flow & Metabolism 20: 631-652 (2000), Calvin, Maturitas 34: 195-
210 (2000), Finking, et al., Zeitschrift fur Kardiologie 89: 442-453 (2000), Brincat,
Maturitas 35: 107-117 (2000), Al-Azzawi, Postgraduate Medical Journal 77: 292-304
(2001)]. Estrogens can exert effects on tissues in several ways, and the most well
characterized mechanism of action is their interaction with estrogen receptors leading
to alterations in gene transcription. Estrogen receptors are ligand-activated
transcription factors and belong to the nuclear hormone receptor superfamily. Other
members of this family include the progesterone, androgen, glucocorticoid and
mineralocorticoid receptors. Upon binding ligand, these receptors dimerize and can
activate gene transcription either by directly binding to specific sequences on DIMA
(known as response elements) or by interacting with other transcription factors (such
as AP1), which in turn bind directly to specific DNA sequences [Moggs and
Orphanrdes, EMBO Reports 2: 775-781 (2001), Hall, et al.. Journal of Biological
Chemistry 276: 36869-36872 (2001), McDonnell, Principles Of Molecular Regulation.
p351-361 (2000)]. A class of "coregulatory" proteins can also interact with the ligand-
bound receptor and further modulate its transcriptional activity [McKenna, et al.,
Endocrine Reviews 20: 321-344 (1999)]. It has also been shown that estrogen
receptors can suppress NF kB-mediated transcription in both a ligand-dependent and
independent manner [Quaedackers, et al., Endocrinology 142: 1156-1166 (2001),
Bhat, et al., Journal of Steroid Biochemistry & Molecular Biology 67: 233-240 (1998),
Pelzer, et al., Biochemical & Biophysical Research Communications 286: 1153-7
(2001)].
Estrogen receptors can also be activated by phosphorylation. This
phosphorylation is mediated by growth factors such as EGF and causes changes in
gene transcription in the absence of ligand [Moggs and Orphanides, EMBO Reports
2: 775-781 (2001), Hall, et al., Journal of Biological Chemistry 276: 36869-36872
(2001)].
A less well-characterized means by which estrogens can affect cells is
through a so-called membrane receptor. The existence of such a receptor is
controversial, but it has been well documented that estrogens can elicit very rapid
non-genomic responses from cells. The molecular entity responsible for transducing
these effects has not been definitively isolated, but there is evidence to suggest it is
at least related to the nuclear forms of the estrogen receptors (Levin, Journal of
Applied Physiology 91: 1860-1867 (2001). Levin, Trends in Endocrinology &
Metabolism 10: 374-377 (1999)].
Two estrogen receptors have been discovered to date. The first estrogen
receptor was cloned about 15 years ago and is now referred to as ER [Green, et al.,
Nature 320: 134-9 (1986)]. The second form of the estrogen receptor was found
comparatively recently and is called ER [Kuiper, et al., Proceedings of the National
Academy of Sciences of the United States of America 93: 5925-5930 (1996)]. Early
work on ER focused on defining its affinity for a variety of ligands and indeed, some
differences with ERa were seen. The tissue distribution of ER has been well
mapped in the rodent and it is not coincident with ERa. Tissues such as the mouse
and rat uterus express predominantly ERa, whereas the mouse and rat lung express
predominantly ERp [Couse, et al.. Endocrinology 138: 4613-4621 (1997), Kuiper, et
al., Endocrinology 138: 863-870 (1997)]. Even within the same organ, the
distribution of ERa and ER can be compartmentalized. For example, in the mouse
ovary, ERp is highly expressed in the granulosa cells and ER is restricted to the
thecal and stromal cells [Sar and Welsch, Endocrinology 140: 963-971 (1999),
Fitzpatrick, et al., Endocrinology 140: 2581-2591 (1999)]. However, there are
examples where the receptors are coexpressed and there is evidence from in vitro
studies that ERa and ER can form heterodimers [Cowley, et al., Journal of
Biological Chemistry 272: 19858-19862 (1997)].
A large number of compounds have been described that either mimic or block
the activity of 17-estradiol. Compounds having roughly the same biological effects
as 17-estradiol, the most potent endogenous estrogen, are referred to as "estrogen
receptor agonists". Those which, when given in combination with 17-estradiol,
block its effects are called "estrogen receptor antagonists". In reality there is a
continuum between estrogen receptor agonist and estrogen receptor antagonist
activity and indeed some compounds behave as estrogen receptor agonists in some
tissues and estrogen receptor antagonists in others. These compounds with mixed
activity are called selective estrogen receptor modulators (SERMS) and are
therapeutically useful agents (e.g. EVISTA) [McDonnell, Journal of the Society for
Gynecologic Investigation 7: S10-S15 (2000), Goldstein, et al.. Human Reproduction
Update 6: 212-224 (2000)]. The precise reason why the same compound can have
cell-specific effects has not been elucidated, but the differences in receptor
conformation and/or in the milieu of coreguiatory proteins have been suggested.
It has been known for some time that estrogen receptors adopt different
conformations when binding ligands. However, the consequence and subtlety of
these changes has been only recently revealed. The three dimensional structures of
ERa and ERP have been solved by co-crystallization with various ligands and clearly
show the repositioning of helix 12 in the presence of an estrogen receptor antagonist
which sterically hinders the protein sequences required for receptor-coregulatory
protein interaction [Pike, et al., Embo 18: 4608-4618 (1999), Shiau, et al., Cell 95:
927-937 (1998)]. In addition, the technique of phage display has been used to
identify peptides that interact with estrogen receptors in the presence of different
ligands [Paige, et al.. Proceedings of the National Academy of Sciences of the United
States of America 96: 3999-4004 (1999)]. For example, a peptide was identified that
distinguished between ERa bound to the full estrogen receptor agonists 17-estradiol
and diethylstilbesterol. A different peptide was shown to distinguish between
clomiphene bound to ER and ER. These data indicate that each ligand potentially
places the receptor in a unique and unpredictable conformation that is likely to have
distinct biological activities.
The preparation of exemplary ER selective ligands, including 2-(3-fluoro-4-
hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol (ERB-041), is described in U.S. Pat. No.
6,794,403, incorporated herein by reference in its entirety. Further ER selective
ligands include compounds set forth in U.S. Pat No. 6,794,403, U.S. Patent No.
6,914,074; and U.S. Patent Application Ser. No 60/637,144, filed December 17,
2004, each of which is incorporated herein by reference in its entirety.
As mentioned above, estrogens affect a panoply of biological processes. In
addition, where gender differences have been described (e.g. disease frequencies,
responses to challenge, etc), it is possible that the explanation involves the difference
in estrogen levels between males and females.
Given the importance of these compounds as pharmaceutical agents, it can
be seen that effective formulations for delivery of the compounds is of great import
This invention is directed to these, as well as other, important ends.
SUMMARY OF THE INVENTION
The present invention provides aqueous pharmaceutical compositions that
include an ER selective ligand. In some embodiments, the compositions include an
ER selective ligand, a solubilizer/complexant component, and, optionally, a pH
adjusting component.
In some embodiments, the ERp selective ligand is present in an amount of
from about 0.14 g/mL to about 40 mg/mL; the solubilizer/complexant component is
present in an amount of from about 0.00021% (w/v) to about 60% (w/v) of the
pharmaceutical composition; and the optional pH adjusting component, when
present, is present in a concentration of from about 8.75x10"7 N to about 1.0 N in the
pharmaceutical composition.
In some embodiments, the ER selective ligand is present in an amount of
from about 0.14 g/mL to about 10 mg/mL; the solubilizer/complexant component is
present in an amount of from about 0.00021% (w/v) to about 15% (w/v) of the
pharmaceutical composition; and the optional pH adjusting component, when
present, is present in a concentration of from about 8.75x10-7 N to about 0.0625 N in
the pharmaceutical composition.
In some embodiments, the ER selective ligand is present in an amount of
from about 1 mg/mL to about 40 mg/mL; and the solubilizer/complexant component
is present in an amount of from about 1% (w/v) to about 60% (w/v) of the
pharmaceutical composition. In some further embodiments, the ERP selective ligand
is present in an amount of from about 5 mg/mL to about 40 mg/mL; and the
solubilizer/complexant component is present in an amount of from about 5% (w/v) to
about 60% (w/v) of the pharmaceutical composition.
In some embodiments, the ER selective ligand is present in an amount of
from about 1 mg/mL to about 10 mg/mL; the solubilizer/complexant component is
present in an amount of from about 1% (w/v) to about 15% (w/v) of the
pharmaceutical composition; and the optional pH adjusting component, when
present, is present in a concentration of from about 8.75x10'7 N to about 0.0625 N in
the pharmaceutical composition. In some further embodiments, the ER selective
ligand is present in an amount of from about 5 mg/mL to about 10 mg/mL; the
solubilizer/complexant component is present in an amount of from about 5% (w/v) to
about 15% (w/v) of the pharmaceutical composition; and the optional pH adjusting
component, when present, is present in a concentration of from about 8.75x10"7 N to
about 0.0625 N in the pharmaceutical composition.
In some embodiments, the ER selective ligand is present in an amount of
from about 1 mg/mL to about 10 mg/mL; and the solubilizer/complexant component
is present in an amount of from about 1% (w/v) to about 15% (w/v) of the
pharmaceutical composition. In some further embodiments, the ER selective ligand
is present in an amount of from about 5 mg/mL to about 10 mg/mL; the
solubilizer/complexant component is present in an amount of from about 5% (w/v) to
about 15% (w/v) of the pharmaceutical composition.
In some embodiments, the solubilizer/complexant component is selected from
cyclodextrins and substituted cyclodextrins, preferably hydroxypropyl beta-
cyclodextrin and sulfobutyl ether beta-cyclodextrin, more preferably hydroxypropyl
beta-cyclodextrin. In some further embodiments, the pH adjusting component is
selected from the group consisting of group I and group II metal hydroxides, for
example NaOH and KOH, preferably NaOH.
The invention further provides methods for preparing pharmaceutical
compositions of the invention, products of the methods, and methods of using the
pharmaceutical compositions of the invention.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 depicts the water solubility of Compound 1 with increasing pH.
Figure 2 depicts the water solubility of the unionized form of Compound 1 with
increasing concentrations of hydroxypropyl-beta-cyclodextrin (HPBCD).
Figure 3 depicts the water solubility of the ionized form of Compound 1 at pH 9.0 and
10.3 with increasing concentrations of hydroxypropyl-beta-cyclodextrin (HPBCD).
Figure 4 depicts the effect of serial dilution on a 10 mg/mL (pH 9.2) and 30 mg/mL
(pH 10.5) solution of Compound 1 containing 15% hydroxypropyl-beta-cyclodextrin
(HPBCD) with Phosphate Buffered Saline as a blood model. The y-axis displays the
concentration of Compound 1, while the x-axis displays the pH of the solution. The
diamond and circle points represent the data points for the 10 mg/mL and the 30
mg/mL solutions of Compound 1, while the triangle points represent the water
solubility of Compound 1.
DETAILED DESCRIPTION
The present invention provides aqueous pharmaceutical compositions that
include an ERp selective ligand. in some embodiments, the compositions include an
ER selective ligand, a sotubitizer/complexant component, and, optionally, a pH
adjusting component. The pharmaceutical compositions of the invention are useful
for the administration of ER selective (igands, preferably via injection, preferably via
intravenous injection.
Generally, the ER selective ligand is present in an amount of from about
0.14 g/mL to about 40 mg/mL of the pharmaceutical composition; or from about 1
mg/mL to about 40 mg/mL of the pharmaceutical compositioh; from about 5 mg/mL
to about 40 mg/mL of the pharmaceutical composition; from about 0.14 g/mL to
about 10 mg/mL of the pharmaceutical composition; from about 1 mg/mL to about 10
mg/mL of the pharmaceutical composition; or from about 5 mg/mL to about 10
mg/mL of the pharmaceutical composition. In some embodiments, the ER selective
figand has the Formula I:
wherein:
R1 is hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, trifluoroalkyl of
1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms,
trifluoroalkoxy of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, sulfoxoalkyl of 1-6
carbon atoms, sulfonoalkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, a 5 or 6-
membered heterocyclic ring having 1 to 4 heteroatoms selected from O, N or S, -
NO2, -NR5R6, -N(R5)COR6, -CN, -CHFCN. -CF2CN, alkynyl of 2-7 carbon atoms, or
alkenyl of 2-7 carbon atoms; wherein the alkyl or alkenyl moieties are optionally
substituted with hydroxyl, -CN, halogen, trifluoroalkyl, trifluoroalkoxy, -COR5, -CO2R5,
-NO2, CONR5R6, NR5R6 or N(R6)COR6;
Rzand R2a are each, independently, hydrogen, hydroxyl, halogen, alkyl of 1-6
carbon atoms, alkoxy of 1-4 carbon atoms, alkenyl of 2-7 carbon atoms, or alkynyl of
2-7 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon
atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl. -
CN, halogen, trifluoroalkyl, trifluoroalkoxy, -CORs. -CO2RS, -NO2. C0NR5R6, NR5R6 or
N(R6)COR6;
R3, R3a. and R4 are each, independently, hydrogen, alkyl of 1-6 carbon atoms,
alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen, alkoxy of 1-4
carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon
atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl, -
CN, halogen, trifluoroalkyl, trifluoroalkoxy, -COR5. -CO2R5, -NO2 CONR5R6, NR5R6 or
N(R5)COR6;
R5. Re are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl of
6-10 carbon atoms;
XisO,S,or NR7;and
R7 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, -COR5,
-CO2R5 or -SO2R5;
or a pharmaceutically acceptable salt thereof. In some such embodiments,
the ER0 selective ligand has the Formula II:
wherein:
R1 is alkenyi of 2-7 carbon atoms; wherein the alkenyl moiety is optionally
substituted with hydroxyl, -CN, halogen, trifluoroalkyl. trifluoroalkoxy, -COR5, -CO2R5.
-NO2, CONRSR6. NR5R8 or NC(R5)COR6
R2and R2aare each, independently, hydrogen, hydroxyl, halogen, alkyl of 1-6
carbon atoms, alkoxy of 1-4 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyt of 2-
7 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon
atoms; wherein the alkyi, alkenyl, or alkynyl moieties are optionally substituted with
hydroxyl, -CN, halogen, trifluoroalkyl, trifluoroalkoxy, -CORS, -CO2R5, -NO2t
CONR5R6, NR5R6 or N(R5)COR6;
R3, and R3a are each, independently, hydrogen, alkyl of 1-6 carbon atoms,
alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen, alkoxy of 1-4
carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon
atoms; wherein the alkyl, alkenyl, or alkynyl moieties are optionally substituted with
hydroxyl, -CN, halogen, trifluoroalkyl, trifluoroalkoxy, -CORS, -CO2RS. -NO2,
CONR5R6, NR5R6 or N(R5)COR6;
R5, R6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl of
6-10 carbon atoms;
X is O, S, or NR7; and
R7 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, -COR5,
-CO2R5 or -SO2R5;
or a pharmaceutically acceptable salt thereof. In some embodiments where
the ERp selective ligand has the Formula II, X is O, and R1 is alkenyl of 2-3 carbon
atoms, which is optionally substituted with hydroxyl, -CN, halogen, trifluoroalkyl,
trifluoroalkoxy, -COR5, -C02R5, -NO2, CONR5Re, NRsRe or N(R3)COR6. In some
preferred embodiments, the ER selective ligand is 2-(3-fluoro-4-hydroxyphenyl)-7-
vinyl-1,3-benzoxazol-5-ol (ERB-041) which has the Formula:
or a pharmaceutically acceptable salt thereof. ERB-041, and compounds of
Formulas I and II, can be prepared by the procedures described in U.S. Patent No.
6,794,403, which is incorporated herein by reference in its entirety.
In some further embodiments, the ER selective ligand has the Formula III:
wherein:
R11, R12. R``13, and R``14 are each, independently, selected from hydrogen,
hydroxyl, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen;
R15, R16. R17, R18, R19, and R20 are each, independently, hydrogen, alkyl of 1-6
carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen,
alkoxy of 1-6 carbon atoms, -CN, -CHO, phenyl, or a 5 or 6-membered heterocyclic
ring having 1 to 4 heteroatoms selected from O, N or S; wherein the alkyl or alkenyl
moieties of R15, R16, R17, R16, R19, or R20 may be optionally substituted with hydroxyl,
CN, halogen, trifluoroalkyl, trifluoroalkoxy, NO2, or phenyl; wherein the phenyl moiety
of R15, R16, R17, R15. R19. or R20 may be optionally mono-, di-, or tri-substituted with
alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen, hydroxyl, alkoxy of
1-6 carbon atoms, CN, -NO2, amino, alkylamino of 1-6 carbon atoms, dialkylamino of
1-6 carbon atoms per alkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of
1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon
atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl; and
wherein at least one of R11, R12, R``13, R``14, R17, R16. R19 or R20 is hydroxyl, or a
pharmaceutically acceptable salt thereof. In some such embodiments. The ER
selective ligand has the Formula IV:
wherein.
R11 and R12 are each, independently, selected from hydrogen, hydroxyl, alkyl
of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, and alkynyl of 2-7 carbon atoms,
alkoxy of 1-6 carbon atoms, or halogen;
R15, RI6. R17. R18, and R19 are each, independently, hydrogen, alkyl of 1-6
carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen,
alkoxy of 1-6 carbon atoms, -CN, -CHO, trifluoromethyl, phenylalkyl of 7-12 carbon
atoms, phenyl, or a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms
selected from O, N or S; wherein the alkyl or alkenyl moieties of R15, R16, R17, R18. or
R19 may be optionally substituted with hydroxyl, -CN, halogen, trifluoroalkyl,
trifluoroalkoxy, -NO2, or phenyl; wherein the phenyl moiety of R15, R16, R17, R18. or R19
may be optionally mono-, di-, or tri-substituted with alkyl of 1-6 carbon atoms, alkenyl
of 2-7 carbon atoms, halogen, hydroxyl, alkoxy of 1-6 carbon atoms, -CNr - NO2,
amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl
group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms,
alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, alkylcarbonyl
of 2-7 carbon atoms, or benzoyl; and
wherein at least one of R15 or R19 is not hydrogen, or a pharmaceutically
acceptable salt thereof. In some such embodiments, the ERP selective ligand has
the Formula V:
R11 and R12 are each, independently, selected from hydrogen, hydroxyl, alkyl
of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, and alkynyl of 2-7 carbon atoms,
alkoxy of 1-6 carbon atoms, or halogen;
R15. R16. R17, R18, and R19 are each, independently, hydrogen, alkyl of 1-6
carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen,
alkoxy of 1-6 carbon atoms, -CN, -CHO, trifluoromethyl, phenylalkyl of 7-12 carbon
atoms, phenyl, or a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms
selected from O, N or S; wherein the alkyl or alkenyl moieties of R15, R16. R17 R``14, or
R19 may be optionally substituted with hydroxyl, CN, halogen, trifluoroalkyl,
trifluoroalkoxy, NO2, or phenyl; wherein the phenyl moiety of R15. R16. R17. R18 or R9
may be optionally mono-, di-, or tri-substituted with alkyl of 1-6 carbon atoms, alkenyl
of 2-7 carbon atoms, halogen, hydroxyl, alkoxy of 1-6 carbon atoms, CN, -NO2,
amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl
group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms,
alkylsutfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, alkylcarbonyl
of 2-7 carbon atoms, or benzoyl; and
wherein at least one of R15 or R19 is not hydrogen, or a pharmaceutically
acceptable salt thereof. In some such embodiments, the 5 or 6-membered
heterocyclic ring having 1 to 4 heteroatoms selected from O, N or S is furan,
thiophene or pyridine, and R15, R16, R17, R18. and R19 are each, independently,
hydrogen, halogen, -CN, or alkynyl of 2-7 carbon atoms. In some such
embodiments, R16, R17, and R18 are hydrogen. In some embodiments, the ERp
selective ligand is the compound 3-(3-Fluoro-4-hydroxy-phenyl)-7-hydroxy-
naphthalene-1-carbonitrile (Compound 1), which has the Formula:
or a pharmaceutically acceptable salt thereof. Compound 1, and compounds of
Formulas III, IV and V, can be prepared by the procedures described in U.S. Patent
No. 6,914,074, which is incorporated herein by reference in its entirety.
The aqueous pharmaceutical compositions of the invention include a
solubilizer/complexant component, to aid in solubilizing the ERp selective ligand. For
example, Compound 1, described above, is insoluble in water, and although an
acidic compound, is poorly soluble even at the pH maxima considered safe for IV
administration (i.e., about pH 10; see Figure 1 for the solubility profile of Compound
1). Accordingly, present compositions include, a solubilizer/complexant component to
aid in solubilization. Generally, the solubilizer/complexant component consists of
one or more solubilizing and/or complexing agents known to be useful in the
preparation of pharmaceutical formulations. In some embodiments, the
solubilizer/complexant component consists of a single solubilizing and/or complexing
agent In some embodiments, the solubilizer/complexant component includes, but is
not limited to, cosolvents such as glycerine, ethanol, propylene glycol, sorbitol and
polyethylene glycol, and surfactants such as the polyoxyethylene sorbitan fatty acid
esters (e.g., polysorbate 80), polyoxyethylene castor oil derivatives (e.g., cremophor
EL, cremophor RH40), vitamin E TPGS (d-alpha-tocopheryl polyethylene glycol),
solutol (polyethylene glycol esters of hydroxystearate), polyoxyethylene-
polyoxypropyiene copolymers, polyoxyethylene fatty alcohol ethers, polyethoxylated
fatty acid esters, polyoxyethylene-glycerol fatty esters, polyglycolized glycerides,
polyethoxylated cholesterols, polyethoxylated sterols, and polyethoxylated vegetable
oils. In some embodiments, the solubilizer/complexant component includes, but is
not limited to, cosolvents such as glycerine, ethanol, propylene glycol, and
polyethylene glycol, and surfactants such as the polyoxyethylene sorbitan fatty acid
esters, polyoxyethylene castor oil derivatives, vitamin E TPGS, and solutol. In some
embodiments, the solubilizer/complexant component is one or more cyclic
oligosaccharides which can be substituted (e.g. with one or more C1-8 alkyl groups,
hydroxyl-C1-8-alkyl groups, or sulfo(C14-alkyl)ether (MOSO2-(C1-4-alkyO)-O-) groups
(wherein M is a metal salt such as sodium) or unsubstituted. Examples of some
preferred solubilizing and/or complexing agents include cyclodextrins (including
alpha, beta and gamma cyclodextrins) and substituted cyclodextrins, for example
hydroxypropyl beta-cyclodextrin and sulfobutyl ether beta-cyclodextrin, with
hydroxypropyl beta-cyclodextrin being preferred. Generally, the
solubilizer/complexant component is present in an amount of from about 0.00021%
(w/v) to about 60% (w/v) of the pharmaceutical composition; from about 1% (w/v) to
about 60% (w/v) of the pharmaceutical composition; from about 5% (w/v) to about
60% (w/v) of the pharmaceutical composition; from about 0.00021% (w/v) to about
15% (w/v) of the pharmaceutical composition; from about 1% (w/v) to about 15%
(w/v) of the pharmaceutical composition; or from about 5% (w/v) to about 15% (w/v)
of the pharmaceutical composition.ln some embodiments, the solubilizer/complexant
component does not comprise an anionic or non-ionic surfactant or wetting agent In
some embodiments, the solubilizer/complexant component does not comprise one or
more poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol,
cetomacrogol emulsifying wax, sorbitan esters, or sodium dodecylsulfate; or
subembodiments thereof.
As used herein, the term "fatty acid" refers to an aliphatic acid that is
saturated or unsaturated. In some embodiments, the fatty acid in a mixture of
different fatty acids. In some embodiments, the fatty acid has between about eight
to about thirty carbons on average. In some embodiments, the fatty acid has about
eight to about twenty-four carbons on average. In some embodiments, the fatty acid
has about twelve to about eighteen carbons on average. Suitable fatty acids include,
but are not limited to, stearic acid, lauric acid, myristic acid, erucic acid, palmitic acid,
palmitoleic acid, capric acid, caprylic acid, oleic acid, linoleic acid, linolenic acid,
hydroxystearic acid, 12-hydroxystearic acid, cetostearic acid, isostearic acid,
sesquioleic acid, sesqui-9-octadecanoic acid, sesquiisooctadecanoic acid, benhenic
acid, isobehenic acid, and arachidonic acid, or mixtures thereof. Other suitable fatty
alcohols include, but are not limited, the Hystrene® series (available from Humko).
As used herein, the term "fatty alcohol" refers to an aliphatic alcohol that is
saturated or unsaturated. In some embodiments, the fatty alcohol in a mixture of
different fatty alcohols. In some embodiments, the fatty alcohol has between about
eight to about thirty carbons on average. In some embodiments, the fatty alcohol
has about eight to about twenty-four carbons on average. In some embodiments,
the fatty alcohol has about twelve to about eighteen carbons on average. Suitable
fatty alcohols include, but are not limited to, stearyl alcohol, lauryl alcohol, palmityl
alcohol, palmitolyl acid, cetyl alcohol, capryl alcohol, caprylyl alcohol, oleyl alcohol,
Knolenyl alcohol, arachidonic alcohol, behenyl alcohol, isobehenyl alcohol, selachyl
alcohol, chimyl alcohol, and linoleyl alcohol, or mixtures thereof.
As used herein, the term "fatty ester" refers to an ester compound formed
between a fatty acid and an organic compound containing a hydroxyl group.
As used herein, the term "polyethylene glycol" refers to a polymer containing
ethylene glycol monomer units of formula -O-CH2-CH2-. Suitable polyethylene
glycols may have a free hydroxy group at each end of the polymer molecule, or may
have one hydroxy group etherified with a lower alkyl, e.g., a methyl group. Also
suitable are derivatives of polyethylene glycols having esterifiable carboxy groups.
Polyethylene glycols useful in the present invention can be polymers of any chain
length or molecular weight, and can include branching. In some embodiments, the
average molecular weight of the polyethylene grycol is from about 200 to about 9000.
In some embodiments, the average molecular weight of the polyethylene glycoi is
from about 200 to about 5000. In some embodiments, the average molecular weight
of the polyethylene glycol is from about 200 to about 900. In some embodiments,
the average molecular weight of the polyethylene glycol is about 400. Suitable
polyethylene glycols include, but are not limited to polyethylene glycol-200.
polyethylene glycol-300, polyethylene glycol-400, polyethylene glycol-600, and .
polyethylene glycol-900. The number following the dash in the name refers to the
average molecular weight of the polymer. In some embodiments, the polyethylene
giycol is polyethylene glycol-400. Suitable polyethylene glycols include, but are not
limited to the Carbowax™ and Carbowax™ Sentry series (available from Dow), the
Lipoxol™ series (available from Brenntag), the Lutrol™ series (available from BASF),
and the Pluriol™ series (available from BASF).
As used herein, the term "polyethoxylated fatty acid ester" refers to a
monoester or diester, or mixture thereof, derived from the ethoxylation of a fatty acid.
The polyethoyxylated fatty acid ester can contain free fatty acids and polyethylene
giycol as well. Fatty acids useful for forming the polyethoxylated fatty acid esters
include, but are not limited to, those described herein. Suitable polyethoxylated fatty
acid esters include, but are not limited to, Emulphor™ VT-679 (stearic acid 8.3 mole
ethoxylate, available from Stepan Products), the Alkasurf™ CO series (available from
Alkaril), macrogol 15 hydroxystearate, Solutol™ HS15 (available from BASF), and
the polyoxyethylene stearates listed in R. C. Rowe and P. J. Shesky, Handbook of
pharmaceutical excipients, (2006), 5th ed., which is incorporated herein by reference
in its entirety.
As used herein, the term "polyethoxyfated cholesterol" refers to a compound,
or mixture thereof, formed from the ethoxylation of cholesterol.
As used herein, the term "polyglycolized glycerides", employed alone or in
combination with other terms, refers to the products formed from the esterification of
polyethylene giycol, glycerol, and fatty acids; the transesterification of glycerides and
polyethylene giycol; or the ethoxylation of a glyceride of a fatty acid. As used herein,
the term "polyglycolized glycerides" can, alternatively or additionally, refer to mixtures
of monoglycerides, diglycerides, and/or triglycerides with monoesters and/or diesters
of polyethylene giycol. Polyglycolized glycerides can be derived from the fatty acids,
glycerides of fatty acids, and polyethylene glycols described herein. The fatty ester
side-chains on the glycerides, monoesters, or diesters can be of any chain length
and can be saturated or unsaturated. The polyglycolized glycerides can contain
other materials as contaminants or side-products, such as, but not limited to,
polyethylene giycol, glycerol, and fatty acids.
As used herein, the term "polyethoxylated vegetable oil" refers to a
compound, or mixture of compounds, formed from ethoxylation of vegetable oil,
wherein at least one chain of polyethylene glycol is covalently bound to the the
vegetable oil. In some embodiments, the fatty acids has between about twelve
carbons to about eighteen carbons. Suitable polyethoxylated vegetable oils, include
but are not limited to, Cremaphor™ EL or RH series (available from BASF),
Emulphor™ EL-719 (available from Stepan products), and Emulphor™ EL-620P
(available from GAF).
As used herein, the term "polyoxyethylene castor oil derivative", refers to a
compound formed from the ethoxylation of castor oil, wherein at least one chain of
polyethylene glycol is covalently bound to the castor oil. The castor oil may be
hydrogenated or unhydrogenated. Synonyms for polyethoxylated castor oil include,
but are not. limited to polyoxyl castor oil, hydrogenated polyoxyl castor oil,
mcrogolglyceroli ricinoleas, macrogolglyceroli hydroxystearas, polyoxyl 35 castor oil,
and polyoxyl 40 hydrogenated castor oil. Suitable polyethoxylated castor oils
include, but are not limited to, the Nikkol™ HCO series (available from Nikko
Chemicals Co. Ltd.), Emulphor™ EL-719 (castor oil 40 mole-ethoxylate, available
from Stepan Products), the Cremophore™ series (available from BASF), and the
Emulgin® RO and HRE series (available from Cognis PharmaLine). Other suitable
polyoxyethylene castor oil derivatives include those listed in R. C. Rowe and P. J.
Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed., which is
incorporated herein by reference in its entirety.
As used herein, the term "polyethoxylated sterol" refers to a compound, or
mixture of compounds, derived from the ethoxylation of a sterol molecule. Suitable
polyethoyxlated sterols include, but are not limited to, PEG-24 cholesterol ether,
Solulan™ C-24 (available from Amerchol); PEG-30 cholestanol, Nikkol™ DHC
(available from Nikko); Phytosterol, GENEROL™ series (available from Henkel);
PEG-25 phyto sterol, Nikkol™ BPSH-25 (available from Nikko); PEG-5 soya sterol,
Nikkol™ BPS-5 (available from Nikko); PEG-10 soya sterol, Nikkol™ BPS-10
(available from Nikko); PEG-20 soya sterol, Nikkol™ BPS-20 (available from Nikko);
and PEG-30 soya sterol, Nikkol™ BPS-30 (available from Nikko). As used herein,
the term "PEG" refers to polyethylene glycol.
As used herein, the term "polyoxyethylene-glycerol fatty ester" refers to
ethoxylated fatty acid ester of glycerine, or mixture thereof. Suitable
polyoxyethylene-glycerol fatty esters include, but are not limited to, PEG-20 glyceryl
laurate, Tagat™ L (Goldschmidt); PEG-30 glyceryi iaurate, Tagat™ L2
(Goldschmidt); PEG-15 glyceryl laurate, Glycerox™ L series (Croda); PEG-40
glyceryl laurate, Glycerox™ L series (Croda); PEG-20 glyceryl stearate, Capmul™
EMG (ABITEC), Aldo MS-20 KFG (Lonza); PEG-20 glyceryl oleate, Tagat™ 0
(Goldschmidt); PEG-30 glyceryl oleate, Tagat™ 02 (Goldschmidt).
As used herein, the term "polyoxyethylene fatty alcohol ether" refers to an
monoether or diether, or mixtures thereof, formed between polyethylene glycol and a
fatty alcohol. Fatty alcohols that are useful for deriving polyoxyethylene fatty alcohol
ethers include, but are not limited to, those defined herein. In some embodiments,
the polyoxyethylene fatty alcohol ether comprises ethoxylated stearyl alcohols, cetyl
alcohols, and cetylstearyl alcohols (cetearyl alcohols). Suitable polyoxyethylene fatty
alcohol ethers include, but are not limited to, the Brij™ series of surfactants (available
from Uniqema), the Cremophor™ A series (available from BASF), the Emulgen™
series (available from Kao Corp.), the Ethosperse™ (available from Lonza), the
Ethylan™ series (available from Brenntag), the Plurafac™ series (available from
BASF), the Ritoleth™ and RHox™ series (available from Rita Corp.), the Volpo™
series (available from Croda), and the Texafor™ series. Blends of polyoxyethylene
fatty alcohol ethers with other materials are also useful in the invention. Other
suitable polyoxyethylene fatty alcohol ethers include those listed in R. C. Rowe and
P. J. Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed., which is
incorDorated herein by reference in its entirety.
As used herein, the term "polyoxyethylene-polyoxypropylene copolymer"
refers to a copolymer that has both oxyethylene monomer units and oxypropylene
monomer units. Suitable polyoxyethylene-polyoxypropylene copolymers for use in
the invention can be of any chain length or molecular weight, and can include
branching. The chain ends may have a free hydroxyl groups or may have one or
more hydroxyl groups etherified with a lower alkyl or carboxy group. The
polyoxyethylene-polyoxypropylene copolymers can also include other monomers
which were coporymerized and which form part of the backbone. For example,
butyiene oxide can be copolymerized with ethylene oxide and propylene oxide to
form polyoxyethylene-polyoxypropylene copolymers useful in the present invention.
In some embodiments, the polyoxyethylene-polyoxypropylene copolymer is a block
copolymer, wherein one block is polyoxyethylene and the other block is
polyoxypropylene. Suitable polyoxyethylene-polyoxypropylene copolymers include,
but are not limited to, the Pluronic® series of surfactants (available from BASF), and
which consist of the group of surfactants designated by the CTFA name of
Poloxamer 108, 124, 188, 217, 237, 238, 288, 338, 407, 101, 105, 122J 123, 124,
181, 182, 183, 184, 212, 231, 282, 331, 401, 402,185, 215, 234, 235, 284, 333, 334,
335, and 403.
Suitable sorbitols include, but are not limited to, Neosorb (available from
Roquette), Partech™ SI (available from Merck), Liponic™ 70-NC and 76-NC
(available from Lipo Chemical), and Sorbogem™ (available from SPI polyots).
In some embodiments, the pharmaceutical compositions of the invention
include a pH adjusting component, that is used to adjust the pH of the composition to
a desired value. In some preferred embodiments, the pharmaceutical compositions
of the invention are provided at basic pH, for example from about 9 to about 9.3. In
some embodiments, the pH adjusting component, when present, is present in a
concentration of from about 8.75x10'7 N to about 1.0 N; or about 8.75x10"7 N to
about 0.0625 N in the pharmaceutical composition. The concentration of pH
adjusting component is based on the amount added to the composition and,
therefore, includes any portion which later reacts with another component of the
composition through acid-base reactions. Accordingly, in some embodiments, such
as those wherein the ERB selective ligand is ERB-041 or Compound 1 shown above,
the pH adjusting component includes or consists of a base, for example a group I or
group II metal hydroxide, for example NaOH and KOH; metal carbonates and
bicarbonates, for example, sodium carbonate, potassium carbonate, sodium
bicarbonate, or potassium bicarbonate; or an amine base. In some embodiments,
the pH adjusting component includes or consists of NaOH or KOH. In some
preferred embodiments, the pH adjusting component includes or consists of NaOH.
The pH adjusting component can be added as a solid or as a concentrated solution.
In some embodiments, the pH component is a base, for example NaOH, added as
an aqueous solution.
In some embodiments, the pharmaceutical compositions have greater
chemical stability as compared with compositions of the ERp selective ligands
without any solubillzer/complexant component. In some embodiments, the
pharmaceutical composition has a potency of the ERp selective ligand greater than
or equal to about 99% at two months at 4 °C. In some embodiments, the
pharmaceutical composition has a potency of the ERp selective ligand greater than
or equal to about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%,
about 99.6%, about 99.7%, about 99.8%, or about 99.9% at 4 °C. As used herein,
potency refers to the percent of the initial API concentration.
In some embodiments, the pharmaceutical compositions have less tendency
to precipitate as compared with compositions of the ERp selective ligands without
any solubilizer/complexant component. In some embodiments, the pharmaceutical
compositions have less tendency to induce phlebitis when administered as
compared with compositions of the ER selective ligands without any
solubilizer/complexant component.
In some embodiments, less than or equal to about 0.1% of the ER selective
ligand precipitates in two minutes after a 1000-fold dilution of said pharmaceutical
. composition with phosphate buffered saline. In some embodiments, less than or
equal to about 0.01% of the ERp selective ligand precipitates in two minutes after a
1000-fold dilution of said pharmaceutical composition with phosphate buffered saline.
In some embodiments, less than or equal to about 1% or 0.001% of the ERP
selective ligand precipitates in two minutes after a 1000-fold dilution of said
pharmaceutical composition with phosphate buffered saline In some embodiments,
less than or equal to about 1%, about 0.1%, about 0.01%, or about 0.001% of the
ERp selective ligand precipitates in two minutes after a 100-fold dilution of said
pharmaceutical composition with phosphate buffered saline. In some embodiments,
no visible precipitate of said ERP selective ligand is observed in two minutes after a
1000-fold dilution of said pharmaceutical composition with phosphate buffered saline.
The invention further provides methods for preparing pharmaceutical
compositions of the invention, in some embodiments, the methods include R17, RIB. or R19
may be optionally mono-, di-, or tri-substituted with alkyl of 1-6 carbon atoms, alkenyl
of 2-7 carbon atoms, halogen, hydroxyl, alkoxy of 1-6 carbon atoms, -CN, - NO2,
amino, alkylamino of 1-6 carbon atoms, dialkylamfno of 1-6 carbon atoms per alkyl
group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms,
alkylsulfbnyl of 1-6 carbon atoms, alkoxycarbonyi of 2-7 carbon atoms, alkylcarbonyl
of 2-7 carbon atoms, or benzoyl; and
wherein at least one of R15 or R19 is not hydrogen, or a pharmaceutically
acceptable salt thereof.
25. The pharmaceutical composition of claim 24, wherein the ERp
selective liqand has the Formula V:
wherein:
R11 and R12 are each, independently, selected from hydrogen, hydroxyl, alkyl
of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, and alkynyl of 2-7 carbon atoms,
alkoxy of 1-6 carbon atoms, or halogen;
R15. R16. R17. R18. and R19 are each, independently, hydrogen, alkyl of 1-6
carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen,
alkoxy of 1-6 carbon atoms, -CN, -CHO, trifluoromethyl, phenylalkyl of 7-12 carbon
atoms, phenyl, or a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms
selected from O, N or S; wherein the alkyt or alkenyl moieties of R15, R16, R17. R18. or
R19 may be optionally substituted with hydroxyl, CN, halogen, trifluoroalkyl,
trifluoroalkoxy, NO2, or phenyl; wherein the phenyl moiety of R15, R16, R17> R18 or Rg
may be optionally mono-, di-, or tri-substituted with alkyl of 1-6 carbon atoms, alkenyl
of 2-7 carbon atoms, halogen, hydroxyl, alkoxy of 1-6 carbon atoms, CN, -NO2,
amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl
group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms,
alkylsulfonyi of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, alkylcarbonyl
of 2-7 carbon atoms, or benzoyl; and
wherein at least one of R15 or R19 is not hydrogen, or a pharmaceutically
acceptable salt thereof.
26. The pharmaceutical composition of claim 25, wherein the 5 or 6-
membered heterocyclic ring having 1 to 4 heteroatoms selected from O, N or S is
furan, thiophene or pyridine, and R15. R16, R17. R18, and R19 are each, independently,
hydrogen, halogen, -CN, or alkynyl of 2-7 carbon atoms.
27. The pharmaceutical composition of claim 25 or claim 26, wherein R16,
R17, and R18 are hydrogen.
28. The pharmaceutical composition of claim 14, wherein the ERp"
selective ligand has the Formula IV:
wnerein.
R11 and R12 are each, independently, selected from hydrogen, hydroxyl, alkyl
of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, and alkynyl of 2-7 carbon atoms,
alkoxy of 1-6 carbon atoms, or halogen;
R15, R16. R17. R18. and R19 are each, independently, hydrogen, alky) of 1-6
carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen,
alkoxy of 1-6 carbon atoms, -CN, -CHO, trifluoromethyl, phenylalkyl of 7-12 carbon
-atoms, phenyl, or a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms
selected from O, N or S; wherein the alkyl or alkenyl moieties of R1S, R16, R17. R18, or
R19 may be optionally substituted with hydroxyl, -CN, halogen, trifluoroalkyl,
trffluoroalkoxy, -NO2, or phenyl; wherein the phenyl moiety of R15, Ri6. R17, Rie, or R19
may be optionally mono-, di-, or tri-substituted with alkyl of 1-6 carbon atoms, alkenyl
of 2-7 carbon atoms, halogen, hydroxyl, alkoxy of 1-6 carbon atoms, -CN, - NO2,
amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl
group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms,
alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, alkylcarbonyl
of 2-7 carbon atoms, or benzoyl; and
wherein at least one of R15 or R19 is not hydrogen, or a pharmaceutically
acceptable salt thereof.
29. The pharmaceutical composition of any one of claims 1 to 18, wherein
the ER selective ligand is a compound having the Formula:
or a pharmaceutically acceptable salt thereof.
31. The pharmaceutical composition of any one of claims 1 to 30, wherein
the solubilizer/complexant component is selected from cyclodextrins and substituted
cyclodextrins.
32. The pharmaceutical composition of any one of claims 1 to 30, wherein
the solubilizer/complexant component is selected from the group consisting of
hydroxypropyl beta-cyclodextrin and sutfobutyt ether beta-cyclodextrin.
33. The pharmaceutical composition of claim 32, wherein the
solubilizer/complexant component comprises hydroxypropyl beta-cyclodextrin.
34. The pharmaceutical composition of any one of claims 1 to 33, wherein
the pH adjusting component is selected from the group consisting of group I and
group II metal hydroxides.
35. The pharmaceutical composition of any one of claims 1 to 30,
wherein:
the solubilizer/complexant component is selected from the group consisting of
hydroxypropyl beta-cyclodextrin and sulfobutyl ether beta-cyclodextrin; and
the pH adjusting component is selected from the group consisting of group I
and group II metal hydroxides.
36. The pharmaceutical composition of claim 34 or claim 35, wherein the
pH adjusting component is selected from the group consisting of NaOH and KOH.
37. The pharmaceutical composition of any one of claims 1 to 30,
wherein the solubilizer/complexant component is hydroxypropyl beta-cyclodextrin;
and
the pH adjusting component comprises NaOH.
38. The pharmaceutical composition of claim 1, wherein:
the solubilizer/complexant component is selected from the group consisting of
hydroxypropyl beta-cyclodextrin and surfobutyl ether beta-cyclodextrin; and
the ERp selective
or a pharmaceutically acceptable salt thereof.
39 The pharmaceutical composition of claim 38, wherein the
solubilizer/complexant component comprises hydroxypropyl beta-cyclodextrin.
40. The pharmaceutical composition of claim 38 or claim 39, wherein the
pH adjusting component is selected from the group consisting of group I and group II
metal hydroxides.
41. The pharmaceutical composition of claim 38 or claim 39, wherein the
pH adjusting component is selected from the group consisting of NaOH and KOH.
- 42. The pharmaceutical composition of claim 38 or claim 39, wherein the
pH adjusting component comprises NaOH.
43. The pharmaceutical composition of any one of claims 38 to 42,
wherein:
said ERp selective ligand is present in an amount of from about 5 mg/mL to
about 10 mg/mL; and
said solubilizer/complexaht component is present in an amount of from about
5% (w/v) to about 15% (w/v) of the pharmaceutical composition.
44. The pharmaceutical composition of any one of claims 38 to 42,
wherein:
said ERp selective ligand is present in an amount of about 10 mg/mL; and
said solubilizer/complexant component is present in an amount of about 15%
(w/v) of the pharmaceutical composition.
45. The pharmaceutical composition of any one of claims 1 to 44 having a
potency of the ERp selective iigand in said pharmaceutical composition greater than
or equal to about 99% at two months at 4 °C.
46. The pharmaceutical composition of any one of claims 1 to 45, wherein
less than or equal to about 0.01% of the ERp selective ligand precipitates in two
minutes after a 1000-fold dilution of said pharmaceutical composition with phosphate
buffered saline.
47. The pharmaceutical composition of any one of claims 1 to 45, wherein
less than or equal to about 0.1% of the ERp selective ligand precipitates in two
minutes after a 1000-fold dilution of said pharmaceutical composition with phosphate
buffered saline.
48. A method for preparing a pharmaceutical composition of any one of
claims 1 to 47, the method comprising:
(i) providing a container comprising said ERp selective ligand;
(ii) adding said solubiiizer/complexant component to said container to
form a first mixture;
(Hi) adding sterile water to said container to form a second mixture;
(iv) adding said pH adjustment component to said second mixture to form
a third mixture;
(v) dissolving the components of said third mixture to form a solution; and
(vi) filtering said solution.
49. A product of the process of claim 48.
50. A method for treating a subject suffering from arthritis or
endometriosis, the method comprising administering to said subject a therapeutically
effective amount of a pharmaceutical composition of any one of claims 1 to 47 and
45.
51. The method of claim 50, wherein said solubilizer/comptexant
component is present in an amount sufficient to reduce the incidence of phlebitis as
compared to administration of a therapeutically effective amount of a pharmaceutical
composition of any one of claims 1 to 43 which does not comprise said
solubilizer/complexant component.
52. A kit comprising a composition of any one of claims 1 to 47 and 49,
and container therefor.
The present invention relates to aqueous formulations of ERβ selective ligands. In some embodiments, the formulations include an ERβ selective ligand, a solubilizer/complexant component, and a pH adjusting component. The invention further provides preparations of the formulations, and uses thereof.