Note: Descriptions are shown in the official language in which they were submitted.
CA 02380312 2002-O1-31
WO 01/10446 - PCT/EP00/07678
1
FORMULATIONS FOR PARENTERAL USE OF ESTRAMUSTINE PHOSPHATE
AND ALBUMIN
The present invention relates to pharmaceutical
formulations of estramustine phosphate for parenteral use
and, more particularly, to formulations of estramustine
phosphate for parenteral use further comprising human
albumin.
Estramustine phosphate (The Merck Index, XII Ed., No. 3749,
1996) is an estradiol-173-phosphate derivative widely known
in the art as antitumor agent, currently used in the
treatment of advanced adenocarcinoma of the prostate.
The drug is usually administered orally, preferably at a
dose of 10-15 mg/kg/day. Intravenous administration,
however, is also adopted in some particular cases.
For example, initial intravenous administration of
estramustine phosphate, followed by oral administration,
has been reported at dosages paralleling the oral
administration for the drug, i.e. 300-600 mg daily given
intravenously and usually repetitively over for several
consecutive days (see, for a reference, British Journal of
Urology, 1977, 49, 73-79; J. Uro1.108:303-306, 1972; Eur.
Clin. Pharmacol. 26(1), 113-119, 1984; Eur. Urol. 1990, 17,
216-218).
Estramustine phosphate as well as other well-known
cytotoxic compounds used in antitumor therapy are known to
cause, or potentially cause, vascular damages at the site
of injection when parenterally, in particular
intravenously, administered.
As an example, studies in patients treated with
estramustine phosphate administered as a slow intravenous
injection or as a bolus, at 300 mg/day, revealed
CA 02380312 2002-O1-31
WO 01/10446 PCT/EP00/07678
2
thrombophlebitis and local irritations at the peripheral
intravenous injection sites.
These drawbacks are considered major limitations for the
intravenous administration of estramustine phosphate, thus
requiring, in many patients, the establishment of central
line administration or, in some cases, even discontinuation
of the treatment.
With the aim of minimising the unwanted effects associated
with the intravenous administration of cytotoxic agents, a
few means are reported in the art.
Among them is the use of cyclodextrins in the preparation
of formulations for parenteral administration of cytotoxic
known to cause ulcerative lesions. See, for a reference, US
patent No. 5,804,568 in the name of Supergen Inc.
Also known in the art are formulations for the intravenous
administration of estramustine phosphate containing human
albumin, reported to be characterised by fewer local side-
effects upon injection of the active (see, for a reference,
H. Schutz et al.; Krankenhauspharmazie, II year, issue No.
3, 1988).
In this respect, we found formulations for parenteral use
comprising estramustine phosphate together with human
albumin which, unexpectedly, resulted to achieve optimal
protection from side-effects even at lower concentrations
of human albumin, with respect to the active, compared to
the albumin concentration of the prior art formulations.
It is therefore the object of the present invention a
formulation for parenteral use comprising estramustine
phosphate in admixture with human albumin, wherein the
weight ratio between estramustine phosphate and human
albumin is from about 1:5 to about 1:0.3, respectively.
Once administered intravenously to patients, the
formulations object of the present invention do not provoke
CA 02380312 2002-O1-31
WO 01/10446 PCT/EP00/07678
3
ulcerative damages, nor thrombophlebitis, at the site of
injection.
In the present invention, unless otherwise specified, with
the term formulation comprising estramustine phosphate, as
the active ingredient, we intend any formulation comprising
estramustine phosphate either in the acid form or as a
pharmaceutically acceptable salt for parenteral
administration such as, for instance, a salt with a basic
amino acid or with N-methyl glucamine, otherwise referred
to as meglumine.
Preferably, estramustine phosphate is in the form of its
meglumine salt.
According to a preferred embodiment of the invention, the
above formulations are advantageously used for intravenous
use.
As such, these formulations can be administered to patients
either as a slow injection, e.g. over about 30 minutes to
about 3 hours, or as a bolus injection, also referred to as
IV (intravenous) push.
Preferably, the formulations object of the present
invention comprise estramustine phosphate in admixture with
human albumin wherein the weight ratio between estramustine
phosphate and human albumin is from about 1:4 to about
1:0.4, respectively.
Even more preferably, the said weight ratio between
estramustine phosphate and human albumin is from about 1:1
to about 1:0.5, respectively.
In addition, in view of the low amount of required albumin,
the formulations of the invention provide a very
advantageous method for delivering estramustine phosphate
intravenously, even when high doses of the active are
needed.
It is therefore a further object of the invention a
formulation for parenteral use comprising estramustine
CA 02380312 2002-O1-31
WO 01/10446 PCT/EP00/07678
4
phosphate, as a single infusion dosage of the active
exceeding 1300 mg, in admixture with human albumin, wherein
the weight ratio between estramustine phosphate and human
albumin is from about 1:5 to about 1:0.3, respectively.
According to another preferred embodiment of the invention,
it is further provided a formulation for parenteral use
comprising estramustine phosphate, as a single infusion
dosage of the active exceeding 950 mg/mz, in admixture with
human albumin, wherein the weight ratio between
estramustine phosphate and human albumin is from about 1:5
to about 1:0.3, respectively.
The formulations object of the present invention allow the
administration of the active either as a single agent or,
alternatively, in combination with known anticancer
treatments such as radiation therapy or chemotherapy
regimen in combination with cytostatic or cytotoxic agents,
antibiotic-type agents, alkylating agents, antimetabolite
agents, hormonal agents, e.g. aromatase inhibitors,
immunological agents, interferon-type agents,
cyclooxygenase inhibitors (e. g. COX-2 inhibitors),
metallomatrixprotease inhibitors, telomerase inhibitors,
tyrosine kinase inhibitors, anti-growth factor receptor
agents, anti-HER agents, anti-EGFR agents, anti-
angiogenesis agents, farnesyl transferase inhibitors, ras-
raf signal transduction pathway inhibitors, cell cycle
inhibitors, other cdks inhibitors, tubulin binding agents,
topoisomerase I inhibitors, topoisomerase II inhibitors,
and the like.
As an example, the above formulations can be administered
in combination with one or more chemotherapeutic agents,
optionally within liposomal formulations thereof.
Examples of chemotherapeutic agents are, for instance,
taxane, taxane derivatives, CPT-11, camptothecin and
derivatives thereof, anthracycline glycosides, e.g.
doxorubicin, idarubicin or epirubicin, etoposide,
CA 02380312 2002-O1-31
WO 01/10446 PCT/EP00/07678
navelbine, vinblastine, carboplatin, cisplatin and the
like, optionally within liposomal formulations thereof.
In addition, the above formulations can be also
administered in combination with protein kinase inhibitors
5 such as, for instance, the indolinone derivatives disclosed
by Sugen in the international patent applications WO
96/40116 and WO 99/61422, which are herewith incorporated
by reference.
In this respect, the formulations object of the invention
can be preferably administered in combination with 3-[4-(2
carboxyethyl-3,5-dimethylpyrrol-2-yl)methylidenyl]-2
indolinone and 3[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-
indolinone, better known as Sugen SU 6668 and SU 5416,
respectively.
The formulations of the invention may be administered
sequentially with known anticancer agents when a
combination formulation is inappropriate.
Therefore, it is a further object of the present invention
a product containing a formulation for parenteral use of
estramustine phosphate in admixture with human albumin,
wherein the weight ratio between estramustine phosphate and
human albumin is from about 1:5 to about 1:0.3, and one or
more chemotherapeutic agents, as a combined preparation for
simultaneous, separate or sequential use in anticancer
therapy.
Toxicology
To study the local irritant effects of estramustine
phosphate after repeated intravenous administrations to
rats, in comparison to a formulation of estramustine
phosphate according to the present invention, the active
was dissolved in different vehicles such as water solution
for injection and water solution for injection further
containing different amounts of human albumin.
CA 02380312 2002-O1-31
WO 01/10446 PCT/EP00/07678
6
In particular, the following solutions of estramustine
phosphate:human albumin in a weight ratio of 1:3.3 and of
1:0.8, were prepared and tested.
Male Sprague-Dawley rats were used because of their
acceptance as a predictor of toxic change in man. The rats
were 6 weeks old at the start of the study.
Estramustine phosphate, in the form of meglumine salt, was
administered to groups of rats as a repeated intravenous
injection during 3 days. Rats were then sacrificed: a half
of the rats at the fourth day and a half at the fifth day.
The dose level of estramustine phosphate, in all the
different tested solutions, was of 150 mg/kg/day.
Clinical observations were recorded daily. Thrombophlebitic
side effects resulted in a dark bluish/blackish coloration
of the tail during the treatment period.
A score system based on tail coloration and its extension
was used to evaluate the different tested formulations.
The score system considered estramustine phosphate water
solution as the positive control (i.e. marked toxicity).
Water for injection was administered to the control group
as negative control (i.e. no toxicity signs).
Histological evaluation was carried out on the tail of the
rats treated with the composition of the invention.
Estramustine phosphate in a water solution induced, at the
used dose, local irritant effects at the injection site
after the first administration and marked toxicity signs at
the end of the experiment.
Albumin containing formulations, according to the present
invention, showed no toxicity signs even when albumin was
present at very low concentrations. Histological evaluation
of the tail of the rats treated with the formulations
containing albumin did not reveal any damage when compared
to the tails of the control group.
It was thus concluded that estramustine phosphate in a
water solution containing human albumin, according to the
present invention, induced markedly less local irritant
effects when compared with a water solution of the same.
CA 02380312 2002-O1-31
WO 01/10446 PCT/EP00/07678
'7
One particularly preferred schedule for administering the
formulation of estramustine phosphate according to the
invention is a single infusion given once weekly to a
maximal dose of 4000 mg or 3500 mg/m2.
Another preferred schedule is the administration of a
single drug infusion once every two to four weeks.
One schedule may be preferred over another in consideration
of schedules with other optional concomitant therapy. These
schedules may repeat in serial or as repetitive fashion.
The formulations of the present invention are useful in
antitumor therapy, particularly in the treatment of
prostate cancer, breast cancer, melanoma, lung cancer,
pancreatic cancer, colorectal cancer, ovarian cancer and
cancers of the brain.
The formulations object of the present invention are
prepared according to conventional techniques adopted in
the preparation of pharmaceutical forms for parenteral use.
Typically, a proper amount of estramustine phosphate,
either as a dry powder or into a lyophilised form, is
dissolved in a pharmaceutically acceptable solution for
parenteral use and then admixed with a proper amount of
human albumin, either as a dry powder or as a commercially
available solution, e.g. human albumin 250, 200 or 50,
optionally properly diluted.
As an example, a proper amount of estramustine phosphate in
the form of a suitable salt such as, for instance, N-methyl
glucamine salt, is dissolved in a suitable amount of
sterile water or aqueous dextrose solution, e.g. 5%
dextrose in water for intravenous administration, and then
admixed with a proper amount of powdered human albumin.
The above admixture is then stirred, sterilised, and
subsequently lyophilised according to conventional
techniques.
CA 02380312 2002-O1-31
WO 01/10446 PCT/EP00/07678
8
The freeze-dried formulation is prepared and stored in
vials for injection; the addition of a proper amount of
sterile water or of a physiological solution for parenteral
use enables the preparation of the final formulation to be
injected.
Alternatively, a proper amount of estramustine phosphate,
for instance as N-methyl-glucamine salt and under
lyophilized form, is added to a proper amount of water or
of a physiological solution for parenteral use already
containing human albumin.
In such a way, the preparation of the final formulation to
be injected is prepared just before its use, by
reconstituting the lyophilized form containing the active
principle, for instance estramustine phosphate N-methyl-
glucamine salt, in the presence of a physiological solution
for parenteral use containing a proper amount of human
albumin.
It is therefore a further object of the invention a product
comprising estramustine phosphate or salts thereof, under
lyophilized form, and a physiological solution for
parenteral use containing human albumin.
The above methods are also suitable for preparing high
dosages estramustine phosphate formulations whilst
maintaining the desired weight ratio between the
components.
The unit strength of the formulation to be injected
depended on the concentration of the active in the solution
itself and, of course, on the filling volume of the vials
used to prepare the final formulation.
Additionally, the formulations of the present invention may
optionally contain pharmaceutically acceptable excipients
for parenteral administration such as, for instance,
bulking agents, e.g. lactose or mannitol, pH buffering
agents, anti-oxidant agents, preservative agents, tonicity
adjusters and the like.
CA 02380312 2002-O1-31
WO 01/10446 PCT/EP00/07678
9
The following examples are herewith intended to better
illustrate the present invention without representing any
limitation to it.
Example 1
Preparation of estramustine phosphate: albumin=1:3.3 weight
ratio
Estramustine phosphate (300 mg) were weighed in a beaker
and dispersed by means of magnetic stirring in 5 ml of
water. N-methyl-glucamine (120.8 mg) was then added under
stirring to the watery dispersion of the active and, after
a few minutes, a clear solution was obtained. 4 ml of a
commercially available solution of human albumin at 250
concentration were added whilst maintaining the solution
under stirring.
The obtained solution was then brought to the final volume
of 10 ml with water so as to reach a final concentration of
30 mg/ml of estramustine phosphate and 100 mg/ml of human
albumin (1:3.3 weight ratio respectively).
A solution prepared as previously described, properly
sterilized by filtration, was tested for its local vein
tolerability in rats.
Example 2
The formulation described in Example 1 was also prepared by
dissolving the commercially available Estracyt° freeze-
dried formulation containing 300 mg/vial of the active. The
reconstitution of the formulation was made by using 10 ml
of a 100 mg/ml human albumin solution so as to obtain a
final concentration of 30 mg/ml of estramustine phosphate
and 100 mg/ml of human albumin (1:3.3 weight ratio
respectively).
The albumin solution could be prepared either by dissolving
in water a proper amount of human albumin as a dry powder
or by properly diluting a commercially available human
albumin solution.
CA 02380312 2002-O1-31
WO 01/10446 PCT/EP00/07678
i0
Example 3
Preparation of estramustine phosphate: albumin=1:0.8 weight
ratio
300 mg of estramustine phosphate were weighed in a beaker
and dispersed by means of magnetic stirring in 5 ml of
water. 120.8 mg of N-methyl-glucamine were then added under
stirring to the watery dispersion of the active and, after
a few minutes, a clear solution was obtained. 1 ml of a
commercially available solution of human albumin at 250
concentration was added whilst maintaining the solution
under stirring.
The obtained solution was then brought to the final volume
of 10 ml with water so as to reach a final concentration of
30 mg/ml of estramustine phosphate and 25 mg/ml of human
albumin (1:0.8 weight ratio respectively).
A solution prepared as previously described, properly
sterilized by filtration, was tested for its local vein
tolerability in rats.
Example 4
The formulation described in Example 3 was also prepared by
dissolving the commercially available Estracyt~ freeze-
dried formulation containing 300 mg/vial of the active. The
reconstitution of the formulation was made by using 10 ml
of a 25 mg/ml human albumin solution so as to obtain a
final concentration of 30 mg/ml of estramustine phosphate
and 25 mg/ml of human albumin (1:0.8 weight ratio
respectively).
The albumin solution could be prepared either by dissolving
in water a proper amount of human albumin as a dry powder
or by properly diluting a commercially available human
albumin solution.
