Note: Descriptions are shown in the official language in which they were submitted.
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PHARMACEUTICAL FORMULATION FOR THE INTRAMUSCULAR ADMINISTRATION OF FULVESTRANT
The invention relates to a sustained release pharmaceutical formulation
adapted for
administration by injection containing the compound fulvestrant, 7a-[9-
(4,4,5,5,5-
pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17(3-diol, at
concentration of at
least 100mg/ml in solution in a ricinoleate vehicle which additionally
comprises at least one
alcohol and a non-aqueous ester solvent which is miscible in the ricinoleate
vehicle.
Oestrogen deprivation is fundamental to the treatment of many benign and
malignant
diseases of the breast and reproductive tract. In premenopausal women, this is
achieved by
l0 the ablation of ovarian function through surgical, radiotherapeutic, or
medical means, and, in
postmenopausal women, by the use of aromatase inhibitors.
An alternative approach to oestrogen withdrawal is to antagonise oestrogens
with
antioestrogens. These are drugs that bind to and compete for oestrogen
receptors (ER) present
in the nuclei of oestrogen-responsive tissue. Conventional nonsteroidal
antioestrogens, such
as tamoxifen, compete efficiently for ER binding but their effectiveness is
often limited by the
partial agonism they display, which results in an incomplete blockade of
oestrogen-mediated
activity (Fury and Jordan, Pharmacology & Therapeutics, 25:127-206, 1984; May
and
Westley, J Biol Chem 262:15894-15899, 1987).
The potential for nonsteroidal antioestrogens to display agonistic properties
prompted
2o the search for novel compounds that would bind ER with high affinity
without activating any
of the normal transcriptional hormone responses and consequent manifestations
of oestrogens.
Such molecules would be "pure" antioestrogens, clearly distinguished from
tamoxifen-like
ligands and capable of eliciting complete ablation of the trophic effects of
oestrogens. Such
compounds are referred to as Estrogen Receptor-Downregulators (E.R.D.). The
rationale for
the design and testing of novel, pure antioestrogens has been described in:
Bowler et al 1989,
Wakeling 1990a, 1990b, 1990c. Wakeling and Bowler 1987, 1988.
Steroidal analogues of oestradiol, with an alkylsulphinyl side chain in the 7a
position,
provided the first examples of compounds devoid of oestrogenic activity
(Bowler et al 1989).
One of these, 7a-[9-(4,4,5,5,5-pentafluoropentyl sulphinyl)nonyl]oestra-1,3,5-
(10)triene-
3,17(3-diol was selected for intensive study on the basis of its pure
oestrogen antagonist
activity and significantly increased antioestrogenic potency over other
available
antioestrogens. In vitro findings and early clinical experience with
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7a-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3-5(10)-triene-
3,17(3-diol have
promoted interest in the development of the drug as a therapeutic agent for
oestrogen-
dependent indications such as breast cancer and certain benign gynaecological
conditions.
7a-[9-(4,4,5,5,5-Pentafluoropentylsulphinyl)nonyl]oestra-1,3-5( 10)-triene-
3,17(3-diol,
or ICI 182,780, has been allocated the international non-proprietary name
fulvestrant, which is
used hereinafter. When referring to fulvestrant we include pharmaceutically-
acceptable salts
thereof and any possible solvates of either thereof.
Fulvestrant binds to ER with an affinity similar to that of oestradiol and
completely
blocks the growth stimulatory action of oestradiol on human breast cancer
cells in vitro; it is
l0 more potent and more effective than tamoxifen in this respect. Fulvestrant
blocks completely
the uterotrophic action of oestradiol in rats, mice and monkeys, and also
blocks the
uterotrophic activity of tamoxifen.
Because fulvestrant has none of the oestrogen-like stimulatory activity that
is
characteristic of clinically available antioestrogens such as tamoxifen or
toremifene, it may
offer improved therapeutic activity characterised by more rapid, complete, or
longer-lasting
tumour regression; a lower incidence or rate of development of resistance to
treatment; and a
reduction of tumour invasiveness.
In intact adult rats, fulvestrant achieves maximum regression of the uterus at
a dose
which does not adversely affect bone density or lead to increased
gonadotrophin secretion. If
also true in humans, these findings could be of extreme importance clinically.
Reduced bone
density limits the duration of oestrogen-ablative treatment for endometriosis.
Fulvestrant does
not block hypothalamic ER. Oestrogen ablation also causes or exacerbates hot
flushes and
other menopausal symptoms; fulvestrant will not cause such effects because it
does not cross
the blood-brain barrier.
European Patent Application No. 0 138 504 discloses that certain steroid
derivatives
are effective antioestrogenic agents. The disclosure includes information
relating to the
preparation of the steroid derivatives. In particular there is the disclosure
within Example 35
of the compound 7a-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-
1,3,5(10)-triene-3,17-diol, which compound is specifically named in Claim 4.
It is also
disclosed that the compounds of that invention may be provided for use in the
form of a
pharmaceutical composition comprising a steroid derivative of the invention
together with a
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pharmaceutically-acceptable diluent or carrier. It is stated therein that the
composition can be
in a form suitable for oral or parenteral administration.
Fulvestrant shows, along with other steroidal based compounds, certain
physical
properties which make formulation of these compounds difficult. Fulvestrant is
a particularly
lipophilic molecule, even when compared with other steroidal compounds, and
its aqueous
solubility is extremely low at around 10 ngml-' (this is an estimate from a
waterlsolvent
mixture solute since measurements this low could not be achieved in a water
only solute).
Currently there are a number of sustained release injectable steroidal
formulations
which have been commercialised. Commonly these formulations use oil as a
solvent and
wherein additional excipients may be present.
In US 5,183,814 Example 3 an oil based injection formulation of fulvestrant is
described which comprises SOmg of fulvestrant, 400mg of benzyl alcohol and
sufficient castor
oil to bring the solution to a volume of 1 ml. Manufacture at a commercial
scale of a
formulation as described in US 5,183,814 will be complicated by the high
alcohol
concentration. Therefore, there is a need to lower the alcohol concentration
in fulvestrant
formulations whilst preventing precipitation of fulvestrant from the
formulation.
The Table below shows the solubility of fulvestrant in a number of different
solvents.
SOLUBILITY OF FULVESTRANT
SOLVENT SOLUBILITY
(mgml-' at 25C)
Water 0.001
Arachis oil 0.45
Sesame oil 0.58
Castor oil 20
Miglyol 810 3.06
Miglyol 812 2.72
Ethyl oleate 1.25
Benzyl benzoate 6.15
Isopropyl myristate 0.80
Span 85 (surfactant) 3.79
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Ethanol >200
Benzyl Alcohol >200
As can be seen fulvestrant is significantly more soluble in castor oil than
any of the
other oils tested. The greater solvating ability of castor oil for steroidal
compounds is known
and is attributed to the high number of hydroxy groups of ricinoleic acid,
which is the major
constituent of the fatty acids within the triglycerides present in castor oil -
see (Rifflcin et.al. J.
Pharm. Sci., (1964), 53, 891).
Our earlier application PCT/GBOI/00049, WO 01/51056, describes certain
fulvestrant
formulations at a most preferred concentration of 50mg/ml. This application
disclosed one
formulation with a solubility up to 102 mg/ml - see the last formulation in
Table 3 thereof
l0 with 15 % weight of ethanol per volume of formulation, 15 % weight of
benzyl alcohol per
volume of formulation, 15 % weight of benzyl benzoate per volume of
formulation in a
ricinoleate vehicle. However there is a need for further formulations of
fulvestrant that
contain high concentrations of fulvestrant to facilitate administration
thereof at higher doses
or less frequent intervals.
According to another aspect of the invention there is provided a
pharmaceutical
formulation adapted for intramuscular injection comprising 100 mg/ml or more
of fulvestrant,
10 % or more weight of a pharmaceutically acceptable alcohol per volume of
formulation
vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester
solvent per
volume of formulation vehicle and 5 % or more weight of ricinoleate excipient
per volume of
formulation vehicle provided the formulation vehicle comprises at least 5 %
weight of ethanol
per volume of formulation vehicle and provided that the following formulation
is excluded:
fulvestrant up to 102 mg/ml, 15 % weight of ethanol per volume of formulation
vehicle, 15
weight of benzyl alcohol per volume of formulation vehicle, 15 % weight of
benzyl benzoate
per volume of formulation vehicle and 30 % or more weight of ricinoleate
excipient per
volume of formulation vehicle.
A preferred pharmaceutical formulation adapted for intramuscular injection is
one
comprising 105 mg/ml or more of fulvestrant, 10 % or more weight of a
pharmaceutically
acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a
pharmaceutically acceptable non-aqueous ester solvent per volume of
formulation vehicle and
5 % or more weight of ricinoleate excipient per volume of formulation vehicle
provided the
formulation comprises at least 5 % weight of ethanol per volume of formulation
vehicle.
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A more preferred pharmaceutical formulation adapted for intramuscular
injection is
one comprising 110 mg/ml or more of fulvestrant, 10 % or more weight of a
pharmaceutically
acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a
pharmaceutically acceptable non-aqueous ester solvent per volume of
formulation vehicle and
5 % or more weight of ricinoleate excipient per volume of formulation vehicle
provided the
formulation vehicle comprises at least 5 % weight of ethanol per volume of
formulation
vehicle.
A more preferred pharmaceutical formulation adapted for intramuscular
injection is
one comprising 115 mg/ml or more of fulvestrant, 10 % or more weight of a
pharmaceutically
l0 acceptable alcohol per volume of formulation vehicle, 5 % or more weight of
a
pharmaceutically acceptable non-aqueous ester solvent per volume of
formulation vehicle and
5 % or more weight of ricinoleate excipient per volume of formulation vehicle
provided the
formulation vehicle comprises at least 5 % weight of ethanol per volume of
formulation
vehicle.
A more preferred pharmaceutical formulation adapted for intramuscular
injection is
one comprising 120 mg/ml or more of fulvestrant, 10 % or more weight of a
pharmaceutically
acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a
pharmaceutically acceptable non-aqueous ester solvent per volume of
formulation vehicle and
5 % or more weight of ricinoleate excipient per volume of formulation vehicle
provided the
formulation vehicle comprises at least S % weight of ethanol per volume of
formulation
vehicle.
A more preferred pharmaceutical formulation adapted for intramuscular
injection is
one comprising 130 mglml or more of fulvestrant, 15 % or more weight of a
pharmaceutically
acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a
pharmaceutically acceptable non-aqueous ester solvent per volume of
formulation vehicle and
S % or more weight of ricinoleate excipient per volume of formulation vehicle
provided the
formulation vehicle comprises at least 5 % weight of ethanol per volume of
formulation
vehicle.
A more preferred pharmaceutical formulation adapted for intramuscular
injection is
one comprising 140 mg/ml or more of fulvestrant, 15 % or more weight of a
pharmaceutically
acceptable alcohol per volume of formulation vehicle, 12.5 % or more weight of
a
pharmaceutically acceptable non-aqueous ester solvent per volume of
formulation vehicle and
5 % or more weight of ricinoleate excipient per volume of formulation vehicle
provided the
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formulation vehicle comprises at least 10 % weight of ethanol per volume of
formulation
vehicle.
A more preferred pharmaceutical formulation adapted for intramuscular
injection is
one comprising 150 mg/ml or more of fulvestrant, 15 % or more weight of a
pharmaceutically
acceptable alcohol per volume of formulation vehicle, 17.5 % or more weight of
a
pharmaceutically acceptable non-aqueous ester solvent per volume of
formulation vehicle and
5 % or more weight of ricinoleate excipient per volume of formulation vehicle
provided the
formulation vehicle comprises at least 10 % weight of ethanol per volume of
formulation
vehicle.
to Another aspect of the invention provides any of the formulations described
herein
stated as having any minimum ethanol content removed. For example, the
formulation
described in the paragraph immediately above becomes: a pharmaceutical
formulation adapted
for intramuscular injection is one comprising 150 mg/ml or more of
fulvestrant, 15 % or more
weight of a pharmaceutically acceptable alcohol per volume of formulation
vehicle, 17.5 % or
more weight of a pharmaceutically acceptable non-aqueous ester solvent per
volume of
formulation vehicle and 5 % or more weight of ricinoleate excipient per volume
of
formulation vehicle.
According to another aspect of the invention there is provided a
pharmaceutical
formulation having a solubility for fulvestrant of at least Y mg/ml adapted
for intramuscular
2o injection comprising;
100 mg/ml or more of fulvestrant;
5% (w/v) or more castor oil per volume of formulation vehicle;
and at least the following amounts (% weight/volume of formulation vehicle) of
ethanol
(ETOH), benzyl alcohol (BA), benzyl benzoate (BB) determined by the algorithm:
Y = -29.77 + 5.44 x ETON + 2.38 x BA + 1.57 x BB
wherein x is at least 100, ETON is at least 5, BA is at least 5 and BB is at
least 5.
A preferred pharmaceutical formulation is one wherein Y is selected from the
group
consisting of 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 170,
180, 190, and
200.
A more preferred pharmaceutical formulation is one wherein Y is selected from
the
group consisting of 120, 125, 130, 135, 140, 145, 150, 155, 160, 170, 180,
190, and 200.
A more preferred pharmaceutical formulation is one wherein Y is selected from
the
group consisting of 1 S0, 155, 160, 170, 180, 190 and 200.
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A more preferred pharmaceutical formulation is one wherein Y is selected from
150,
155, 160, 170, 180, 190 and 200 and the formulation comprises at least
150mg/ml of
fulvestrant.
A more preferred pharmaceutical formulation is one wherein Y is 200 and the
formulation comprises at least 200mg/ml of fulvestrant.
According to another aspect of the present invention there is provided a
pharmaceutical
formulation having a solubility for fulvestrant of at least 100 mg/ml adapted
for intramuscular
injection comprising;
100 mg/ml or more of fulvestrant;
l0 5% (w/v) or more castor oil per volume of formulation vehicle;
and at least the following amounts (% weight/volume of formulation vehicle) of
ethanol
(EtOH), benzyl alcohol (BA), benzyl benzoate (BB) determined by the algorithm:
100 = -29.77 + 5.44 x ETOH + 2.38 x BA + 1.57 x BB; and
provided that the following formulation is excluded: fulvestrant up to 102
mg/ml, 15
weight of ethanol per volume of formulation vehicle, 15 % weight of benzyl
alcohol per
volume of formulation vehicle, 15 % weight of benzyl benzoate per volume of
formulation
vehicle and 30 % or more weight of castor oil per volume of formulation
vehicle.
According to another aspect of the invention there is provided a
pharmaceutical
formulation comprising fulvestrant at a concentration of at least 100 mg/ml in
which the
2o formulation is adapted for intra-muscular injection into a human and which
is capable after
injection of attaining a therapeutically significant blood plasma fulvestrant
concentration in a
human for at least 2 months and provided that the following formulation is
excluded:
fulvestrant up to 102 mg/ml, 15 % weight of ethanol per volume of formulation
vehicle, 15
weight of benzyl alcohol per volume of formulation vehicle, 15 % weight of
benzyl benzoate
per volume of formulation vehicle and 30 % or more weight of ricinoleate
excipient per
volume of formulation vehicle.
According to another aspect of the invention there is provided a
pharmaceutical
formulation comprising fulvestrant in which the formulation is adapted for
intra-muscular
injection into a human and which is capable after injection of attaining a
therapeutically
3o significant blood plasma fulvestrant concentration in a human for at least
2 months.
According to another aspect of the invention there is provided a
pharmaceutical
formulation comprising fulvestrant at a concentration of at least 100 mg/ml in
which the
formulation is adapted for intra-muscular injection into a human and which is
capable after
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injection of attaining a therapeutically significant blood plasma fulvestrant
concentration in a
human for at least 2 months.
According to another aspect of the invention there is provided a
pharmaceutical
formulation comprising fulvestrant at a concentration of at least 150 mg/ml in
which the
formulation is adapted for intra-muscular injection into a human and which is
capable after
injection of attaining a therapeutically significant blood plasma fulvestrant
concentration in a
human for at least 2 months.
According to another aspect of the invention there is provided a
pharmaceutical
formulation comprising fulvestrant at a concentration of at least 200 mg/ml in
which the
l0 formulation is adapted for intra-muscular injection into a human and which
is capable after
injection of attaining a therapeutically significant blood plasma fulvestrant
concentration in a
human for at least 2 months.
According to another aspect of the invention there is provided a
pharmaceutical
formulation comprising fulvestrant at a concentration of at least 300 mg/ml in
which the
formulation is adapted for intra-muscular injection into a human and which is
capable after
injection of attaining a therapeutically significant blood plasma fulvestrant
concentration in a
human for at least 2 months.
According to one aspect of the invention there is provided any one of the
following
pharmaceutical formulations comprising about:
zo i)
10% weight per volume of ethanol
20% weight per volume of benzyl alcohol
15% weight per volume of benzyl benzoate
500-SSSmg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil;
ii)
10% weight per volume of ethanol
20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
500-700mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil;
iii)
10% weight per volume of ethanol
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20% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
500-750mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil;
iv)
20% weight per volume of ethanol
20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
500-1175mg of fulvestrant for each Sml of finished formulation
1 o and the remaining amount as castor oil;
v)
15% weight per volume of ethanol
10% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
500-810 mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil;
vi)
15% weight per volume of ethanol
20% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
500 mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil;
vii)
15% weight per volume of ethanol
20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
500-630mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil;
viii)
3o 10% weight per volume of ethanol
20% weight per volume of benzyl alcohol
SO% weight per volume of benzyl benzoate
750mg of fulvestrant for each Sml of finished formulation
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and the remaining amount as castor oil;
ix)
20% weight per volume of ethanol
20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5m1 of finished formulation
and the remaining amount as castor oil;
x)
15% weight per volume of ethanol
l0 10% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
750mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil;
xi)
9% weight per volume of ethanol
19% weight per volume of benzyl alcohol
47% weight per volume of benzyl benzoate
700mg of fulvestrant for each 5m1 of finished formulation
and the remaining amount as castor oil;
xii)
14% weight per volume of ethanol
19% weight per volume of benzyl alcohol
48% weight per volume of benzyl benzoate
700mg of fulvestrant for each 5m1 of finished formulation
and the remaining amount as castor oil;
xiii)
15% weight per volume of ethanol
20% weight per volume of benzyl alcohol
45% weight per volume of benzyl benzoate
750mg of fulvestrant for each 5m1 of finished formulation
and the remaining amount as castor oil;
xiv)
9% weight per volume of ethanol
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19% weight per volume of benzyl alcohol
47% weight per volume of benzyl benzoate
750mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil;
xv)
19% weight per volume of ethanol
19% weight per volume of benzyl alcohol
28% weight per volume of benzyl benzoate
750mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil;
xvi)
14% weight per volume of ethanol
9% weight per volume of benzyl alcohol
47% weight per volume of benzyl benzoate
750mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil;
xvii)
14% weight per volume of ethanol
19% weight per volume of benzyl alcohol
47% weight per volume of benzyl benzoate
750mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil;
xviii)
10% weight per volume of ethanol
20% weight per volume of benzyl alcohol
45% weight per volume of benzyl benzoate
750mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil;
xix)
15% weight per volume of ethanol
10% weight per volume of benzyl alcohol
45% weight per volume of benzyl benzoate
750mg of fulvestrant for each Sml of finished formulation
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and the remaining amount as castor oil;
xx)
20% weight per volume of ethanol
20% weight per volume of benzyl alcohol
25% weight per volume of benzyl benzoate
750mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil;
xxi)
10% weight per volume of ethanol
1o 30% weight per volume of benzyl alcohol
25% weight per volume of benzyl benzoate
750mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil;
xxii)
10% weight per volume of ethanol
25% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
750mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil;
XXlll)
10% weight per volume of ethanol
30% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
750mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil;
xxiv)
15% weight per volume of ethanol
25% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
750mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil;
xxv)
1 S% weight per volume of ethanol
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2s% weight per volume of benzyl alcohol
25% weight per volume of benzyl benzoate
750mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil; and
s xxvi)
15% weight per volume of ethanol
20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
750mg of fulvestrant for each sml of finished formulation
l0 and the remaining amount as castor oil.
The term "comprising about" in this context means that the numerical value
assigned
to each component of the formulation may be varied independently to
accommodate
manufacturing specifications encountered by a skilled person when making up
the
formulations. Typically this means plus or minus S%, more preferably plus or
minus 4%,
is more preferably plus or minus 3%, more preferably plus or minus 2%, more
preferably plus or
minus 1 %. In a preferred embodiment, more variation in drug level is allowed
compared with
other components. For example:
Drug (+/- %) Other components (+/-
%)
s 4,3,2or1
4 3,2or1
3 2 or 1
2 1
2o The individual formulations described herein may comprise further
excipients
commonly used in the formulation field including, for example, an antioxidant
preservative, a
colorant or a surfactant.
According to another aspect of the invention there is provided any one of the
following
pharmaceutical formulations:
Zs i)
10% weight per volume of ethanol
20% weight per volume of benzyl alcohol
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15% weight per volume of benzyl benzoate
500-SSSmg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil
ii)
10% weight per volume of ethanol
20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
500-700mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil
iii)
10% weight per volume of ethanol
20% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
500-750mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil
iv)
20% weight per volume of ethanol
20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
500-1175mg of fulvestrant for each 5m1 of finished formulation
and the remaining amount as castor oil
v)
15% weight per volume of ethanol
10% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
500-810 mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil
vi)
15% weight per volume of ethanol
20% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
500 mg of fulvestrant for each 5m1 of finished formulation
and the remaining amount as castor oil
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vii)
15% weight per volume of ethanol
20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
500-630mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil
viii)
10% weight per volume of ethanol
20% weight per volume of benzyl alcohol
l0 50% weight per volume of benzyl benzoate
750mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil
ix)
20% weight per volume of ethanol
20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
750mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil
x)
15% weight per volume of ethanol
10% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
750mg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil.
A preferred pharmaceutical formulation described herein is one wherein the
pharmaceutically-acceptable alcohol is a mixture of ethanol and benzyl
alcohol.
A preferred pharmaceutical formulation described herein is one wherein the
pharmaceutically-acceptable non-aqueous ester solvent is selected from benzyl
benzoate, ethyl
oleate, isopropyl myristate, isopropyl palmitate or a mixture of any thereof.
A preferred pharmaceutical formulation described herein is one wherein the
pharmaceutically-acceptable non-aqueous ester solvent is benzyl benzoate.
A preferred pharmaceutical formulation described herein is one wherein the
ricinoleate
excipient is castor oil.
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According to one aspect of the present invention there is provided a
pharmaceutical
formulation adapted for intramuscular injection comprising 100 mg/ml or more
of fulvestrant,
% or more weight of a pharmaceutically acceptable alcohol per volume of
pharmaceutical
formulation, 5 % or more weight of a pharmaceutically acceptable non-aqueous
ester solvent
5 per volume of pharmaceutical formulation and S % or more weight of
ricinoleate excipient per
volume of pharmaceutical formulation provided:
a) the pharmaceutical formulation comprises at least 5 % weight of ethanol per
volume
of pharmaceutical formulation;
b) if the pharmaceutically acceptable alcohol is less than or equal to 13%,
then the
l0 pharmaceutical formulation must comprise at least 50 % non-aqueous ester
solvent; and
c) if the pharmaceutically acceptable alcohol is greater than 20 % but less
than or equal to
25 %, then the pharmaceutical formulation must comprise at least 30 % non-
aqueous ester
solvent;
and also provided that the following pharmaceutical formulation is excluded:
fulvestrant up to
102 mg/ml, 15 % weight of ethanol per volume of formulation vehicle, 15 %
weight of benzyl
alcohol per volume of formulation vehicle, 15 % weight of benzyl benzoate per
volume of
formulation vehicle and 30 % or more weight of ricinoleate excipient per
volume of
formulation vehicle.
A preferred pharmaceutical formulation adapted for intramuscular injection is
one
2o comprising 100 mg/ml or more of fulvestrant, 20 % or more weight of a
pharmaceutically
acceptable alcohol per volume of pharmaceutical formulation, 5 % or more
weight of a
pharmaceutically acceptable non-aqueous ester solvent per volume of
pharmaceutical
formulation and 5 % or more weight of ricinoleate excipient per volume of
pharmaceutical
formulation provided:
a) the pharmaceutical formulation comprises at least 10 % weight of ethanol
per volume
of pharmaceutical formulation;
b) if the pharmaceutically acceptable alcohol is 20%, then the pharmaceutical
formulation must comprise at least 22.5 % non-aqueous ester solvent; and
c) if the pharmaceutically acceptable alcohol is greater than 20 % but less
than or equal to
25 %, then the pharmaceutical formulation must comprise at least 15 % non-
aqueous ester
solvent;
and also provided that the following pharmaceutical formulation is excluded:
fulvestrant up to
102 mg/ml, 15 % weight of ethanol per volume of formulation vehicle, 15 %
weight of benzyl
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alcohol per volume of formulation vehicle, 15 % weight of benzyl benzoate per
volume of
formulation vehicle and 30 % or more weight of ricinoleate excipient per
volume of
formulation vehicle.
A more preferred pharmaceutical formulation adapted for intramuscular
injection is
one comprising 1 SO mg/ml or more of fulvestrant, 25 % or more weight of a
pharmaceutically
acceptable alcohol per volume of pharmaceutical formulation, 30 % or more
weight of a
pharmaceutically acceptable non-aqueous ester solvent per volume of
pharmaceutical
formulation and 5 % or more weight of ricinoleate excipient per volume of
pharmaceutical
formulation provided:
1o a) the pharmaceutical formulation comprises at least 10 % weight of ethanol
per volume
of pharmaceutical formulation;
b) if the pharmaceutically acceptable alcohol is less than 30 %, then the
pharmaceutical
formulation must comprise at least 35 % non-aqueous ester solvent.
A particularly preferred pharmaceutical formulation is one which comprises 15%
w/v
or less of ethanol and in which the solubility of fulvestrant is at least
155mg/ml.
According to another aspect of the invention there is provided a unit dose of
a
pharmaceutical formulation as described herein wherein the total volume of the
formulation is
6m1 or less.
According to another aspect of the invention there is provided a
pharmaceutical
formulation adapted for intramuscular injection, as defined in any preceding
claim for use in
medical therapy.
According to another aspect of the invention there is provided use of
fulvestrant in the
preparation of a pharmaceutical formulation, as defined herein for the
treatment of a benign or
malignant disease of the breast or reproductive tract.
According to another aspect of the invention there is provided use of
fulvestrant in the
preparation of a pharmaceutical formulation, as defined in any preceding claim
for the
treatment of a benign or malignant disease of the breast or reproductive tract
in a human with
dosage intervals of at least 8 weeks.
According to another aspect of the invention there is provided a sterile
syringe or vial
3o comprising a pharmaceutical formulation as defined in any preceding claim.
The term "pharmaceutical formulation" as used herein means the combination of
drug
plus formulation vehicle. The terms "finished formulation" and "finished
pharmaceutical
formulation" mean the same as "pharmaceutical formulation".
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The term "formulation vehicle" as used herein means the combination of all
excipients
used in the pharmaceutical formulation (and therefore excludes drug per se).
The distinction between pharmaceutical formulation and formulation vehicle is
important for the following reason. For example, if the concentration (y %
w/v) of an
excipient "A" is measured by its concentration in formulation vehicle and then
drug is added,
the addition of drug will result in a concentration of excipient A that is
lower than
concentration y in the finished pharmaceutical formulation. To convert a
concentration
expressed in terms of "formulation vehicle" into a concentration of "finished
pharmaceutical
formulation" it is necessary to use a displacement value.
1 o The "displacement value" is defined as the number of parts by weight of
compound
that displaces one part by weight of the formulation vehicle. The displacement
value allows
determination of the amount of formulation vehicle displaced by the compound.
The
displacement value is used to calculate the actual composition of the finished
formulation in
terms of proportions of excipients. The density of the compound affects the
amount of
formulation vehicle required to make the pharmaceutical formulation to the
correct
concentration. One part by weight of the compound with a density equal to the
formulation
vehicle will displace an equivalent volume of the formulation vehicle. A
compound with
twice the density of the formulation vehicle will displace half the volume. It
is therefore
necessary to make allowance for the compound in terms of the particular
formulation vehicle,
using the displacement value.
For the avoidance of any doubt when using the term % weight per volume of
formulation for the constituents of the formulation we mean that within a unit
volume of the
formulation a certain percentage of the constituent by weight will be present,
for example a
1 % weight per volume formulation will contain within a 1 OOmI volume of
formulation 1 g of
the constituent. By way of further illustration
of x by weight per volume of weight of x in 1 ml of formulation
formulation
30% 300mg
20% 200mg
10% IOOmg
5% SOmg
1 % 1 Omg
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Where whole numbers are used for % weight per volume of formulation, these
refer to
rounded numbers where appropriate. For example, 4.6% would be rounded to 5%.
It is appreciated that in the formulation an excess of formulation may be
included to
allow the attendant physician or care giver to be able to deliver the required
dose. Therefore,
when a 5m1 dose is required it would be appreciated that an excess of up to
0.25m1, preferably
up to 0.15m1 will also be present in the formulation. Typically the
formulation will be
presented in a vial or a prefilled syringe, preferably a prefilled syringe,
containing a unit
dosage of the formulation as described herein, these being further features of
the invention.
The pharmaceutically-acceptable alcohol may consist of one alcohol or a
mixture of
to two or more alcohols, preferably a mixture of two alcohols. Preferred
pharmaceutically-
acceptable alcohols for parenteral administration are ethanol, benzyl alcohol
or a mixture of
both ethanol and benzyl alcohol.
The pharmaceutically-acceptable non-aqueous ester solvent may consist of one
or a
mixture of two or more pharmaceutically-acceptable non-aqueous ester solvents,
preferably
just one. A preferred pharmaceutically-acceptable non-aqueous ester solvent
for parenteral
administration is selected from benzyl benzoate, ethyl oleate, isopropyl
myristate,isopropyl
palmitate or a mixture of any thereof.
It will be understood by the skilled person that the pharmaceutically-
acceptable
alcohol will be of a quality such that it will meet pharmacopoeia) standards
(such as are
2o described in the US, British, European and Japanese pharmacopoeias) and as
such will contain
some water and possibly other organic solvents, for example ethanol in the US
Pharmacopeia
contains not less than 94.9% by volume and not more than 96.0% by volume of
ethanol when
measured at 15.56°C. Dehydrated alcohol in the US Pharmacopeia contains
not less than
99.5% ethanol by volume when measured at 15.56°C.
It will be understood by the skilled person that the pharmaceutically-
acceptable non-
aqueous ester solvent will be of a quality that it will meet pharmacopoeia)
standards (such as
described in the US, British, European and Japanese pharmacopoeias).
Preferred combinations of pharmaceutically-acceptable alcohol and
pharmaceutically-
acceptable non-aqueous ester solvent in the formulation are set out below:
3o By the use of the term ricinoleate excipient we mean an oil which has as a
proportion
(at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% w/v) of its
composition as
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triglycerides of ricinoleic acid. The ricinoleate vehicle may be a synthetic
oil or conveniently
is castor oil, ideally of pharmacopoeia) standards, as described above.
We have surprisingly found that the above formulations of the invention
provide, after
intra-muscular injection, satisfactory release of fulvestrant over an extended
period of time.
We have found that despite the rapid elimination of the additional
solubilising
excipients, i.e. the alcohol and pharmaceutically-acceptable non-aqueous ester
solvent, from
the formulation vehicle and the site of injection after injection of the
formulation, extended
release at therapeutically significant levels of fulvestrant over an extended
period can still
achieved by the formulation of the invention.
l0 By use of the term "extended release" we mean at least 4 weeks, at least 5
weeks, and,
preferably at least 8 weeks of continuous release of fulvestrant is achieved.
In a preferred
feature extended release is achieved for at least 8 weeks or 2 months, more
preferably for at
least 12 weeks or 3 months.
It will be understood that the attendant physician may wish to administer the
15 intramuscular injection as a divided dose, i.e. a Sml formulation is
sequentially administered
in two separate injections of 2.5m), this is a further feature of the
invention
Simply solubilising fulvestrant in an oil based liquid formulation is not
predictive of a
good release profile.
Preferably Sml of the intramuscular injection is administered.
2o Additional excipients commonly used in the formulation field including, for
example,
an antioxidant preservative, a colorant or a surfactant may be used. A
preferred optional
excipient is a surfactant, more preferably an antioxidant.
As described above fulvestrant is useful in the treatment of oestrogen-
dependent
indications such as breast cancer and gynaecological conditions, such as
endometriosis.
25 In addition to fulvestrant another similar type of molecule is currently
under clinical
investigation. SH-646 ( 11 (3-fluoro- 7a-( 14,14,15,15,15-pentafluoro-6-
methyl-10-thia-6-azapentadecyl)estra-1,3,5(10)-triene-3,17~i-diol) is also
putatively a
compound with the same mode of action as fulvestrant and has a very similar
chemical
structure. It is believed that the compound will also share with fulvestrant
similar physical
30 properties and therefore the current invention will also have application
with this compound.
Further features of the invention are those as described above but in which SH-
646 is
substituted for fulvestrant.
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References
1. Bowler J, Lilley TJ, Pittam JD, Wakeling AE. Novel steroidal pure
antioestrogens.
Steroids, 54: 71-100, 1989.
2. Wakeling AE. Novel pure antioestrogens: mode of action and therapeutic
prospects.
American New York Academy Science 1990a; 595: 348-56.
3. Wakeling AE. Steroidal pure antioestrogens. In Lippman M, Dickson R,
editors. Regulatory
mechanisms in breast cancer. Boston: Kluwer Academic, 1990b: 239-57.
4. Wakeling AE. Therapeutic potential of pure antioestrogens in the treatment
of breast
cancer. Journal Steroid Biochemistry 1990c; 37: 771-5.
l0 5. Wakeling AE, Bowler J. Steroidal pure antioestrogens. Journal
Endocrinology 1987; 112:
R7-10.
6. Wakeling AE, Bowler J. Biology and mode of action of pure antioestrogens.
Journal
Steroid Biochemistry 1988; 3: 141-7.
The invention will now be illustrated by the following non-limiting Examples
in
which:
Figure 1 shows plasma profiles obtained following IM injection (data
normalised for
rabbit weight, based on 3.2 kg rabbit) in which the y-axis is conc (ng/ml) and
the x-axis is
time (days);
Figure 2 shows comparison of plasma profiles in which:
Figure 2A shows plasma profiles from group A in which the y-axis is conc
(ng/ml) and
the x-axis is time (days); and
Figure 2B shows plasma profiles from group B in which the y-axis is conc
(ng/ml) and
the x-axis is time (days);
Figure 3 shows plasma profiles from formulations 1, 5 and Control (normalised
for
rabbit weight, based on 3.2 kg rabbit in which the y-axis is conc (ng/ml) and
the x-axis
is time (days);
Figure 4 shows muscle residue data from 3 month PK study in which the y-axis
is
fulvestrant remaining per injection site and the x-axis is formulation number.
Each bar
represents one injection site (2 sites per animal).
Figure 5 shows predicted versus actual solubility
Figure 6 shows a confidence interval for predicted solubility
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Figure 7 shows plasma profiles obtained following IM injection (data
normalised for
rabbit weight, based on 3.2 kg rabbit) in which the y-axis is conc (ng/ml) and
the x-
axis is time (days);
Abbreviations
IM intramuscular
PK pharmacokinetic
AUC area under curve
SD standard deviation
Reference Example 1
Measurement of Solubility of Fulvestrant in Formulations
1. Materials and Apparatus
Balance
2 mL glass vials with screw caps
Magnetic stirrer bars
Temperature control reaction block with magnetic stirring facility
Positive displacement pipette (PDP) 20 - 25 ~L with appropriate microsyringe
tips
Polycarbonate ultracentrifuge tubes
Ultracentrifuge
Pipette 0.5 - 200 ~L PDP with appropriate microsyringe tips
Pipette 200 ~L - 1 mL with appropriate plastic tips
2 mL amber Snap Top glass HPLC vials
1 mm Snap Caps for HPLC vials
HPLC kit with diode array detector
Methanol (MeOH) HPLC Grade
Acetonitrile (ACN) Far UV HPLC Grade
Ultrapure de-ionised water
25 cm HS ODS 5~ 4.6 mm i.d. HPLC column
Vortex mixer
Ultrasonic bath
20 - 200 ~L pipette with appropriate plastic tips
Aluminium weigh pans 5 mL glass volumetric flasks
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2. Experimental procedure
2.1 1 ml formulation vehicles were made up in triplicate by adding the
appropriate volumes of
alcohols and benzyl benzoate, and then adding castor oil by weight
2.2 Fulvestrant was then added to excess, until no more drug was seen to
visibly dissolve.
The weight of fulvestrant added was noted.
2.3 A magnetic stirrer bar was placed in each vial.
2.4 All the samples were overlaid with nitrogen and the vials were capped
placed in
the reaction block and stirred at a speed of 1000 at a temperature of
4°C
2.5 Using the PDP 20 - 200 ~L pipettor, 200 ~L aliquots were removed from each
vial
after 6 days and transferred to ultracentrifuge tubes. These tubes were
centrifuged at a speed of 80,000 r.p.m. for 30 minutes at 25°C.
2.6 HPLC eluent was prepared by adding 1400 mL methanol, 450 mL water and 150
mL
acetonitrile to a 2 litre plastic-coated solvent bottle.
2.7 990 ~L HPLC eluent was added to 60 amber glass HPLC vials using a 1mL
Pipette.
2.8 3 x 10 PL of supernatant were removed from each ultracentrifuge tube using
the Pipette
PDP 0.5-25 ~L pipette and added to the vials containing eluent.
2.9 The samples were diluted again 1 in 10. 1001 sample was added to 9001 HPLC
eluent
2.10 The amber vials were capped, vortex mixed for 10 seconds, sonicated for
10 minutes and
then placed in the HPLC autosampler tray.
3. Calibration preparation
3.1 Approximately 10 mg fulvestrant was accurately weighed into an aluminium
weigh pan on
the microbalance and placed in a S mL glass volumetric flask The actual weight
was
recorded.
3.2 Approximately 4.5 mL HPLC eluent was added to the flask using a plastic
pasteur pipette.
The flask was then sonicated for 5 minutes prior to making accurately to
volume (to give a
spiking solution of approximately 2 mg.mL-')
3.3 0 - 250 ~L spiking solution was added to 2 mL amber HPLC vials using the
appropriate
Pipette and the volume made to 1 mL with HPLC eluent using a 1 mL Pipette
as shown in the table below:
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Volume Spiking Volume HPLC Theoretical
Solution eluent fulvestrant
(pL) (pL) Concentration
(Ng~mL-~)
0 1000 0
995 10
25 975 SO
SO 950 100
100 900 200
150 850 300
200 800 400
250 750 500
3.4 The HPLC vials were capped, vortexed for 10 seconds and placed on the HPLC
autosampler tray.
5 3.5 A calibration was prepared (as per 3.1 - 3.4) for both batches of ICI
182780.
4. HPLC Conditions
Eluent : 70% MeOH / 22.5% Water / 7.5% ACN
Column : 25 cm 5~ Hypersil ODS 4.6 mm i.d. with guard column
Detection wavelength : 280 nm
Flow rate : 1.2 mL.mim'
Temperature : Ambient
Injection volume : 50 ~L
Retention time : 12 minutes approximately
Example 1
Pharmaceutical Formulations
Fulvestrant is mixed with ethanol and benzyl alcohol, stirring until
completely
dissolved. Benzyl benzoate is added and the solution is made to final weight
with castor oil
and stirred, (for convenience weight is used rather than volume by using the
weight to volume
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ratio). The bulk solution is overlaid with nitrogen. The solution is
sterilised by filtration using
one or two filters of 0.2wm porosity. The sterile filtrate is kept under a
nitrogen overlay as it
is filled under aseptic conditions into washed and depyrogenised, sterile
primary containers,
for example vials or pre-filled syringes. An overage is included in the
primary pack to
facilitate removal of the dose volume. The primary packs are overlaid with
sterile nitrogen,
before aseptically sealing. The process flow diagram below depicts the
manufacturing
process.
Quantities of each component of the formulation is chosen according to the
required
formulation specification, examples are described above. For example
quantities are added of
each component to prepare the following formulations:
a)
10% weight per volume of ethanol
20% weight per volume of benzyl alcohol
15% weight per volume of benzyl benzoate
SOOmg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil
b)
10% weight per volume of ethanol
20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
SOOmg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil
c)
10% weight per volume of ethanol
20% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
SOOmg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil
d)
20% weight per volume of ethanol
20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
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SOOmg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil
e)
15% weight per volume of ethanol
10% weight per volume of benzyl alcohol
50% weight per volume of benzyl benzoate
SOOmg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil
15% weight per volume of ethanol
20% weight per volume of benzyl alcohol
30% weight per volume of benzyl benzoate
SOOmg of fulvestrant for each Sml of finished formulation
and the remaining amount as castor oil
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FLOW DIAGRAM OF MANUFACTURING
Ingredients/Components Process
Fulvestrant STAGE I: DISSOLUTION
OF
Alcohol -' ~ ACTIVE AGENT
Benzyl Alcohol
Benzyl Benwate STAGE 2: MIX
~
STAGE 3; MAKE TO
Castor Oil WEIGHT
STAGE 4: STERILE FILTRATION
(0.2wm)
INTO BULK RECEIVING
VESSEL
STAGE 5: STERILE (0.2~m)
IN-LINE FILTRATION
STAG~6: ASEPTIC FILLING
AND STOPPERING
STAG~7: VISUAL
INSPECTION
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Example 2
Stability studies to 4 months for selection of stable 100mg/ml Pharmaceutical
formulations
ormulation Fulvestrant96% Benzyl Benzyl Castor Observations
No. EtOH Alcohol Benzoate oil visual
(mg/ml % w/v % w/v % w/v % w/v 4 months
Sam 1e 1 100 5 10 15 to 100%Preci
itated
Sam 1e 2 100 5 10 30 to 100%Preci
hated
Sam 1e 3 100 7.5 10 15 to 100%Preci
itated
Sam 1e 4 100 7.5 10 30 to 100%Preci
itated
Sam 1e S 100 10 10 15 to 100%Preci
itated
Sam 1e 6 100 10 10 17.5 to 100%Preci
itated
Sam 1e 7 100 10 10 20 to 100%Preci
hated
Sam 1e 8 100 10 10 22.5 to 100%Solution
Sam 1e 9 100 10 10 25 to 100%Solution
Sam 1e 10 100 10 10 27.5 to 100%Solution
Sam 1e 11 100 10 10 30 to 100%Solution
Sam 1e 12 100 10 10 40 to 100%Solution
Sam 1e 13 100 10 10 50 to 100%Solution
Sam 1e 14 100 10 15 15 to 100%Solution
Sam 1e 15 100 10 15 30 to 100%Solution
Sam 1e 16 100 10 15 40 to 100%Solution
Sam 1e 17 100 10 1 S 50 to 100%Solution
Sam 1e 18 100 10 20 15 to 100%Solution
Sam 1e 19 100 10 20 30 to 100%Solution
Sam 1e 20 100 10 20 40 to 100%Solution
Sam 1e 21 100 10 20 50 to 100%Solution
Sam 1e 22 100 15 10 15 to 100%Solution
Sam 1e 23 100 15 10 30 to 100%Solution
Sam 1e 24 100 15 10 40 to 100%Solution
Sam 1e 25 100 15 10 50 to 100%Solution
Sam 1e 26 100 20 5 15 to 100%Solution
Sam 1e 27 100 20 5 30 to 100%Solution
Sam 1e 28 100 20 10 15 to 100%Solution
Sam 1e 29 100 20 10 30 to 100%Solution
Sam 1e 30 100 20 10 40 to 100%Solution
Sam 1e 31 100 20 10 50 to 100%Solution
Sam 1e 32 100 15 15 15 to 100%Solution
Sam 1e 33 100 15 15 30 to 100%Solution
Sam 1e 34 100 15 15 40 to 100%Solution
Sam 1e 35 100 15 15 50 to 100%Solution
Sam 1e 36 100 15 20 15 to 100%Solution
Sam 1e 37 100 15 20 30 to 100%Solution
Sam 1e 38 100 15 20 50 to 100%Solution
Sam 1e 39 100 20 20 15 to 100%Solution
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Sam 1e 40 100 20 20 30 to 100%Solution
Control 52.16 10 10 15 60 Solution
Sample
The Control Sample refers to the following Pharmaceutical formulation:
fulvestrant 50mg/ml,
ethanol 10% w/v, benzylalcohol 10% w/v, benzyl benzoate 15% w/v and made to
volume
with castor oil.
Example 3
Pharmaceutical formulations selected for in vivo deposition and in vitro
precipitation
studies
The pharmaceutical formulations below were selected from Example 2 for further
study.
ormulationFulvestrant95% ETON Benzyl AlcoholBenzyl BenzoateCastor oil
% W/V %W/V %W/V %W/V % W/V
Sample 10 10 10 30 to 100%
1
Sample 10 10 10 50 to 100%
2
Sample 10 10 20 15 to 100%
3
Sample 10 10 20 30 to 100%
4
Sample 10 10 20 SO to 100%
5
Sample 10 20 5 15 to 100%
6
Sample 10 20 5 30 to 100%
7
Sample 10 20 20 15 to 100%
8
Sample 10 20 20 30 to 100%
9
Sample 10 15 10 15 to 100%
Sample 10 15 10 30 to 100%
11
Sample 10 15 10 50 to 100%
12
Sample 10 15 20 15 to 100%
13
Sample 10 15 20 50 to 100%
14
Sample 10 15 20 30 to 100%
Sample 5 10 10 15 to 100%
16
A matrix of 7 pharmaceutical formulations (samples 3, 4, 5, 9, 12, 14 and 16 -
see Example 3
below) was identified for further evaluation from in vitro precipitation and
deposition studies.
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Sample 16 was a control. The precipitation experiment involved visual
inspection of each
sample under conditions where evaporation of alcohols led to precipitation of
drug.
Example 4
In vivo Studies
Pharmaceutical
formulations
identified
for
further
in vivo
evaluation
Excipients (% w/v)
No. Fulvestrant Ethanol Benzyl Benzyl Castor
(%w/v_)
96% alcohol benzoate oil
F1 10 10 20 15 45
F2 10 10 20 30 30
F3 10 10 20 50 10
F4 10 20 20 30 20
FS 10 15 10 50 15
F6 10 15 20 50 5
F7 10 15 20 30 25
Control 5 10 10 15 60
(a) An in vivo pharmacokinetic (PK) study on these 7 pharmaceutical
formulations was
performed over 3 months duration; results are shown in Figures 1, 2 and 3.
Analysis of PK results
Plasma levels were more variable than Control over the first 30 days;
variability was
similar to control thereafter. After 2 months, drug levels were equivalent to
Control at 1
month indicating a prolonged period of action over Control. This release
profile was
surprising because, compared with Control which does not precipitate drug
locally, local
precipitation at the site of injection of the tested formulations was expected
to impair their
release profile.
Some differences in profiles were noted over the first 30 days such that they
were
divided into 2 groups (with Formulation F7 showing intermediate behaviour).
Group A, rapid release early time points (50% Benzyl benzoate and low castor
oil <- 15%) -
see figure 2A
Group B, lower release, flatter profile (< 30% Benzyl benzoate and higher
castor oil >- 20%) -
see figure 2B
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(b) Histopathology
Local tolerance was assessed to 1M injection of the 7 pharmaceutical
formulations and
Control. Lesions were observed over a 51 day period. All pharmaceutical
formulations
caused tissue reactions greater than Control.
(c) Plasma levels for 100mg dose at critical time points (ng/ml)
Form Dose Time point
(days)
(m~ 28 56 84
1 100 8.7 4.6 3.5
2 100 8.0 3.6 2.6
3 100 9.4 3.5 2.0
4 100 7.7 5.0 3.4
5 100 9.1 4.5 2.6
6 100 9.9 3.3 1.9
7 100 9.9 5.5 3.2
Control 50 3.3 1.7
Summary
Duration for 100mg dose = min 2 months.
Duration for 150mg dose = min 3 months.
(d) Measurement of Fulvestrant solubility in 7 pharmaceutical formulations
after 6 days
Formulation Solubility (mg/ml)
6days
F1 111
F2 140
F3 175
F4 235
F5 162
F6 212
F7 126
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Example 5
Model for Fulvestrant Solubility
Formulation Measured
vehicles
for Fulvestrant
- solubility
FulvestrantPredicted
Formulation96% Benzyl AlcoholBenzyl te CastorSolubilitysolubility
Benzoa oil
ETOH
No. % w/v % w/v % w/v % w/v (mg/ml) (mg/ml)
Sample 5 5 0 to 100% 27 9.4
1
Sample 5 5 15 to 100% 36 32.8
2
Sample 10 5 0 to 100% 46 48.5
3
Sample 10 5 15 to 100% 54 36.6
4
Sample 10 10 0 to 100% 45 60.1
Sample 10 10 15 to 100% 65 72
6
Sample 15 15 0 to 100% 76 87.6
7
Sample 15 15 15 to 100% 102 111.1
8
Sample 11 22 17 to 100% 111 109.8
9
Sample 11 22 33 to 100l0140 166.1
Sample 11 22 56 to 100% 175 135.8
11
Sample 22 22 33 to 100% 235 174.4
12
Sample 17 11 56 to 100% 162 170.6
13
Sample 17 22 56 to 100% 212 200.9
14
Sample 17 22 33 to 100% 126 196.3
5
A linear regression model was fitted to solubility data from 15 samples using
as independent
variables the % ethanol, benzyl alcohol and benzyl benzoate levels in the
formulations. The
following model was obtained which had an R-Squared value of 93.2%:
SOLUBILITY = -29.77 + 5.44 x ETON + 2.38 x BA + 1.57 x BB
10 Benzyl alcohol = BA, benzyl benzoate = BB, Ethanol = ETOH.
Solubility measured as mg/ml
See Figures S and 6 based on the following data
measured lower predicted upper
C.L. C.L.
27 0 9.4 31.1
36 10 32.8 55.7
45 31.6 48.5 65.4
46 17.1 36.6 56.1
54 40.9 60.1 79.2
65 59 72 85
76 64.7 87.6 110.6
102 95.6 111.1 126.7
111 85.4 109.8 134.1
126 149 166.1 183.1
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140 114.2 135.8 157.5
162 142.5 174.4 206.3
175 143.4 170.6 197.9
212 179.6 200.9 222.2
235 168.7 196.3 224
The table below shows predicted solubilities for a matrix of pharmaceutical
formulations
tested for stability. A good correlation was obtained with visual
observations.
Formulation of Fulvestrant - stability
Predicted
FormulationFulvestrant95% Benzyl Benzyl te Castor solubility
Alcohol Benzoa oil
Observations
ETOH
No. (mg/ml) % % w/v % w/v % w/v 4 months(mg/ml)
w/v
Sample 100 5 10 15 60 Precipitated53.1
1
Sample 100 5 10 30 45 Precipitated79.2
2
Sample 100 7.5 10 15 57.5 Precipitated68.2
3
Sample 100 7.S 10 30 42.5 Precipitated94.3
4
Sample 100 10 10 IS SS Precipitated83.3
S
Sample 100 IO IO I7.5 52.5 Precipitated87.6
6
Sample 100 10 10 20 SO Precipitated92.0
7
Sample 100 10 10 22.5 47.5 Solution96.4
8
Sample 100 10 10 25 4S Solution100.7
9
Sample 100 10 10 27.5 42.5 Solution105.1
Sample 100 10 IO 30 40 Solution109.5
11
Sample 100 10 10 40 30 Solution126.9
12
Sample 100 10 10 SO 20 Solution144.3
13
Sample 100 10 15 1S 50 Solution96.5
14
Sample 100 10 15 30 3S Solution122.7
Sample 100 10 IS 40 2S Solution140.1
16
Sample 100 10 1 S 50 1 S Solution157.6
17
Sample 100 10 20 1 S 4S Solution109.7
18
Sample 100 10 20 30 30 Solution135.9
19
Sample 100 10 20 40 20 Solution153.3
Sample 100 10 20 50 I 0 Solution170.8
21
Sample 100 15 10 IS 50 Solution113.5
22
Sample 100 15 10 30 35 Solution139.7
23
Sample 100 15 10 40 25 Solution157.
24 i
Sample 100 15 10 50 15 Solution174.6
Sample 100 20 5 15 50 Solution130.5
26
Sample 100 20 5 30 35 Solution156.7
27
Sample 100 20 10 15 45 Solution143.7
28
Sample 100 20 10 30 30 Solution169.9
29
Sample 100 20 10 40 20 Solution187.3
Sample 100 20 10 SO 10 Solution204.8
31
Sample 100 15 15 15 4S Solution126.7
32
Sample 100 1S 15 30 30 Solution152.9
33
Sample 100 15 15 40 20 Solution170.3
34
Sample 100 1 15 50 10 Solution187.8
S
Sample 100 15 20 15 40 Solution140.0
36
Sample 100 15 20 30 2S Solution166.1
37
Sample 100 15 20 50 5 Solution201.0
38
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Sample 39 100 20 20 15 35 Solution 170.2
Sample 40 100 20 20 30 20 Solution 196.3
Control Sample 52.16 10 10 15 60 Solution 72.0
[Faslodex]
The Tables below show predicted formulations for various solubilities of
fulvestrant; where
an "X" means in solution. Note that the Tables include some impractical
formulations where
the sum of components becomes greater than 100%. The principal purpose is to
illustrate the
wide combinations of ethanol/ benzyl alcohol / benzyl benzoate taught by the
invention to
achieve different solubilities of fulvestrant.
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X X xXXX XXX XX XX X Xx X XXX XX X XX XX XXX XXX
X X X X X X X X
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X X X X X X X
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x X X X x X X
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Example 6
In-vivo Pharmacokinetic study using compositions at 140mg/ml of fulvestrant
Formulations F3 and F6 as described in Example 4 were modified to contain an
increased level of fulvestrant to 140mg/ml. The modified formulations were
named F8 and
F9 as described below.
Formulation Composition
The compositions of the formulations dosed in the PK study are shown in the
table
below.
FormulationFulvestrantEthanol Benzyl Benzyl Castor
96% Oil
No. (%w/v) (%w/v) alcohol Benzoate (%w/v)
(%w/v) (%w/v)
F8 14 9 19 47 To 100%
F9 14 14 19 48 To 100%
PK Profile
The results are set out in Figure 7. The composition of the Control is the
same as
described in Example 4. Compositions F8 and F9 gave similar profiles with
improved
performance in terms of extended release of higher levels fulvestrant compared
with Control.
Example 7
Compositions at 150mg/ml fulvestrant
Compositions analogous or similar to F3, F4, FS and F6 (see Example 4) but
comprising 1 SOmg/ml of fulvestrant are prepared as follows.
FormulationFulvestrantEthanol Benzyl Benzyl Castor
No. (%w/v) 96% alcohol Benzoate Oil
(%w/v) (%w/v) (%w/v) (%w/v)
F10 15 10 20 50 To 100%
F11 15 20 20 30 To 100%
F12 15 15 10 SO To 100%
F 13 15 1 S 20 45 To 100%
F 14 15 9 19 47 To 100%
F 15 15 19 19 28 To 100%
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F 16 15 14 9 47 To 100%
F 17 15 14 19 47 To 100%
F 18 15 10 20 45 To 100%
F 19 15 15 10 45 To 100%
F20 15 20 20 25 To 100%
F21 15 10 30 25 To 100%
F22 1 S 10 25 30 To 100%
F23 15 10 30 30 To 100%
F24 1 S 15 25 30 To 100%
F25 15 15 25 25 To 100%
F26 1 S 15 20 30 To 100%
