Note: Descriptions are shown in the official language in which they were submitted.
CA 02295016 1999-12-20
WO 99/08666 PCT/EP98/05194
1
PHARMACEUTICAL COMPOSITION
The present invention relates to certain pharmaceutical compositions
comprising 4-aza steroids andlor 6-aza steroids. In particular, the present
invention
relates to solutions comprising a steroid 5-alpha reductase inhibitor.
Pharmaceutically active compounds can be delivered in a variety of forms,
for example in a soft gelatin capsule. Methods for preparation of soft gelatin
capsules are well known. See, for example, J.P. Stanley, Sofit Gelatin
Capsules, Ch.
13 - Part Two in: The Theory and Practice of Industrial Pharmacy, eds. L.
Lachman
et. al., 3 rd Ed., pp. 398-412, 1986, and W.R. Ebert, Soft Elastic Gelatin
Capsules: A
Unique Dosage Form, Pharmaceutical Technology, Vol. 1, No. 5.
The choice of excipients is important in order to ensure good solubility and
good bioavailability of the pharmaceutically active compound. See For example,
A.
Matso, Excipienfs Commonly Used in Soft Gelatin Capsules: Their Analysis and
Usefulness, Novel Drug Formulation Systems and Delivery Devices International
Seminar, pp. 76-81,(1991). K. Hutchison, Encapsulation in Softgels for
Pharmaceutical Advantage, Spec. Pub. - R. Soc. Chem., Vol. 138, pp 86-97,
(1993),
M.S. Patel et. al., Advances in Softgel Formulation Technology, Manufacturing
Chemist, August 1989, and LR. Berry, Improving Bioavailability with Soft
Gelatin
Capsules, Drug & Cosmetic Industry, pp. 32, 102-108, (September, 1983).
Particular issues with respect to formulation of hydrophobic pharmaceutically
active
compounds has been described, for example in K. Hutchison, Formulation of
Softgels For Improved Oral Delivery of Hydrophobic Dnrgs, Spc. Pub. - R. Soc.
Chem., Vol. 161, pp 133-147 (1995).
Liquid filled hard gelatin capsules have also been utilized. See, for
example, D. Cade et. al., Liquid Filled and Sealed Hard Gelatin Capsules, Drug
Development and Industrial Pharmacy, 12{11-13): 2289-2300, (1986).
Aza steroids are an important class of pharmaceutically active compounds.
in particular there are 4-aza steroids and 6-aza steroids known to be
inhibitors of
CA 02295016 1999-12-20
WO 99/08666 PCT/EP98/05194
2
the enzyme testosterone 5-alpha-reductase (hereinafter "5AR inhibitors"). Such
compounds are thought to be useful in the treatment of benign prostatic
hyperplasia, prostate cancer and other diseases. See, for example, U.S. Pat.
Nos.
4,377,584 (Rasmusson et al.), 4,220,775 (Rasmusson et al.), 4,732,897
(Cainelli et
al.), 4,760,071 (Rasmusson), 4,845,104 (Carlin et al.), 4,859,681 (Rasmusson),
5,302,589 (Frye et al.), 5,438,061 (Bergman et al.), 5,543,406 (Andrews et
al.),
5,565,467 (Batchelor et al.), and WO 95/07926 (Batchelor et al.). One such 5AR
inhibitor, finasteride, is commercially available from Merck & Co., Inc. as
PROSCARTM. These pharmaceutically active compounds are not easy to dissolve.
These solubility challenges can affect bioavailability possibly resulting in
reduced or
unpredictable bioavailability.
A mixture of glyceride esters, commercially available from Abitec (P.O. Box
569, Columbus, Ohio) as Capmulr"" MCM, has been used for dissolving bile duct
stones. See, for example, "Cholesterol Stones Dissolved Harmlessly," Medical
World News, page 28 (1978), U. Leuschner and D. Landgraf, "Dissolution of
Biliary
Duct Stones with Mono-Octanoin," The Lancet, 2 p 8133 (1979), and J.L. Thistle
et
al., "Monooctanoin, a Dissolution Agent for Retained Cholesterol Bile Duct
Stones:
Physical Properties and Clinical Application," Gastroenterology 78, pp 1016-
1022
(1980).
Esters of glycerol and/or propylene glycol have been used in a variety of
formulations. See, for example, U.S. Pat. Nos. 4,316,917 (Antoshkiw et. al.)
and
4,343,823 (Todd et. al.).
Briefly, in one aspect, the present invention discloses a novel solution
comprising a therapeutically effective amount of a pharmaceutically active aza
steroid, and a fatty acid ester of glycerol or propylene glycol. The fatty
acids are
preferably carboxylic acids containing from 6 to 12 carbon atoms. Preferably,
the
ester is a monoester.
CA 02295016 1999-12-20
WO 99/08666 PC'T/EP98/05194
3
In another aspect, the present invention discloses a pharmaceutical
composition comprising the solution of this invention. The composition of this
invention is particularly suitable for use as a fill formulation for gelatin
capsules.
In another aspect, the present invention discloses a gelatin capsule filled
with the composition of the present invention.
The composition of this invention has improved bioavailability over standard
tablets or suspensions .
Some of the steroids useful in this invention are potent teratogens.
Converting the steroid from a free powder to a solution early in the
manufacturing
process provides a safer process. There is less risk in working with the
solution
than with the free solid.
Also, some of these steroids are prone to oxidation. Gelatin capsule
formulations can be much more resistant to oxidation due to the low oxygen
permeation of typical gelatin shells. See, for example, F.S. Hom et al., Soft
Gelatin
capsules II: Oxygen Permeability Study of Capsule Shells, J. Pharm. Sci., Vol.
64
(No. 5), pp 851-887 (1975).
The esters useful in this invention preferably are derived from Carboxylic
acids containing from 6 to 12 carbon atoms. Particularly preferred are those
esters
derived from caprylic acid (8 carbon atoms). While mono, di, and tri-esters
are all
useful in this invention, monoesters are preferred. In addition, the ester may
be
part of a mixture comprising differing carbon atom content in the esters
and/or
comprising a mixture of monoglycerides, diglycerides, and triglycerides.
Commercially available esters are often such mixtures. For example Capmul TM
MCM and PG-8 (both available from Abitec Corporation, Janesville, Wisconsin)
are
such mixtures. The composition of CapmuITM MCM is a mixture of fatty acid
esters
of glycerol and is approximately 95% monoester, 1 % glycerin, 2% free fatty
acid,
and less than 0.5% water and is derived from approximately 85% caprylic acid
and
15% capric acid (all percentages are weight percents). PG-8 is a mixture of
fatty
CA 02295016 1999-12-20
WO 99/08666 PCT/EP98/05194
4
acid esters of propylene glycol and is approximately 96% monoester, .05%
diester,
1.3% free propylene glycol, and is derived from caprylic acid.
The aza steroids useful in this invention can be any pharmaceutically active
aza steroid or pharmaceutically acceptable solvate thereof. Preferred classes
of aza
steroids are the 4-azasteroid class and the 6-azasteroid class of 5AR
inhibitors. For
example, any of the 5AR inhibitors disclosed in the above cited patents.
Particularly
preferred aza steroids are the 4-aza steroids. Particularly preferred 4-aza
steroids
include finasteride, 17-beta-N-(2,5,-bis(trifluoromethyl)}-phenylcarbamoyl-4.-
aza-5-
alpha-androst-1-en-3-one which is the steroid that is disclosed in U.S. Pat.
No.
5,565,467 (Batchelor et al.), and 17-beta-N-1-(3,4-methylenedioxy-phenyl)-
cyclohexylcarbamoyl-4-aza-5-alpha-androst-1-en-3-one and 17-beta-N-(1-(p-
chlorophenyl))cyclopentylcarbamoyl-4-aza-5-alpha-androst-1-en-3-one which are
both disclosed in WO 95/07926 (Batchelor et al.). These steroids can be
prepared
by welt-known methods, for example as described in the above cited patents.
The aza steroid is preferably present in the range of from 0.0025 to 2.5% by
weight of the solution of this invention, more preferably from 0.025 to 1.5 %
by
weight of the solution of this invention.
It may also be useful to include an anti-oxidant in the composition. Suitable
anti-oxidants include butytated hydroxytoluene (BHT), butylated hydroxyanisole
(BHA), and ascorbic acid. A particularly preferred anti-oxidant is butylated
hydroxytoluene. Antioxidants may be used alone or in combination. The
antioxidant
or mixture of antioxidants is preferably from 0.001 to 0.5% by weight of the
composition of this invention.
The pharmaceutical composition of the present invention is particularly
useful as a fill formulations for gelatin capsules, most preferably for soft
gelatin
capsules.
Experimental
CA 02295016 1999-12-20
WO 99/08666 PCT/EP98/05194
In the following experiments, a pharmaceutically active 4-aza steroid was
utilized
in various solubility studies. The pharmaceutically active steroid utilized
was 17-
beta-N-(2,5,-bis(trifluoromethyl))phenylcarbamoyl-4-aza-5-alpha-androst-1-ene-
3-
one. This steroid is described in the '467 patent and can be prepared by known
5 methods including the methods described in the '467 patent.
The solubility of the steroid was determined by suspending an excess
amount of the steroid in about 1 mL of various aqueous and organic media. The
resulting suspension was tumbled in a Vankel~ rotating water bath maintained
at
25°C and protected from light. At the end of an equilibration time,
usually between 1
and 12 days, excess solid was removed by filtercentrifugation through 0.22N
filters.
The resulting supernatant was then assayed for steroid concentration against
an
external standard. The concentration of steroid in the supernatant was
determined
by HPLC analyses using a Hewlett Packard 1090 Series II/M with a DOS Chem
Station. The HPLC conditions are summarized below in Tabie 1. The results of
the
solubility in various aqueous media is summarized in Table 2, and in various
organic
media is summarized in Table 3. Table 4 summarizes the solubility in various
compositions containing a complexing agent (2-hydroxypropyl-beta-
cyclodextrin).
Table 5 summarizes the solubility in various oils and in CapmuITM MCM. Table 6
summarizes the results of the solubility in mixtures of CapmuITM MCM and
polyethylene glycol having an average molecular weight of 400 (PEG 400). In
the
following Tables and experiments, Mili QT"" plus water is a reverse osmosis
water,
CMC is carboxy methyl cellulose, THF is tetrahydrofuran, DMSO is
dimthylsulfoxide,
PG is propylene glycol, LabrafilTM is a mixture of unsaturated polyglycolyzed
gylcerides obtained by partial alcoholysis of corn oil or apricot kernel oil,
consisting
of glycerides and polyethylene glycol esters, SDS is sodium dodecyl sulfate,
"model
duodenum bile salts" is a mixture of sodium glycocholate, sodium
glycochenodesoxycholate, sodium glycodesoxycholate, sodium taurochotate,
sodium taurochenodesoxycholate, sodium taurodesoxycholate, sodium chloride,
lecithin, and phosphate buffer, Tween 80 is polyoxyethylene(20)sorbitan
CA 02295016 1999-12-20
WO 99/08666 PCT/EP98/05194
6
monooleate, the polyethylene glycol 400 was purchased form Union Carbide,
MolescusolT"" is 2-hydroxypropyl-beta-cyclodextrin, and Intralipid is a
mixture of soy
bean oil, phospholipids, glycerin USP, and water for injection. Unless stated
otherwise, all % are by weight, for example, "v/v" means % by volume.
Table 9. HPLC Conditions
Column 250 x 4.6 mm Zorbax Rx C 18
Mobile Phase A. 0.1 % v/v TFA
B. 0.05% v/v TFA in Acetonitrile
Percent Composition 40%B-95%B in 20 minutes (10 min
hold)
Flow rate 1.0 mL/minute
Detection wavelength 210/240
Oven Temperature 35C
CA 02295016 1999-12-20
WO 99/08666 PCT/EP98/05194
Table 2. Solubility in Aqueous Media
Medium ~ Concentration (mg/mL)
Milli Q~ plus water < 0.0039
O.1N HCl < 0.0039
0.5% CMC < 0.0039
1 % Labrafil~ highly degraded
0.02% SDS < 0.0039
0.01% docusate sodium < 0.0039
0.1% Tween 80 < 0.0039
0.1 % Tween 80/0.02% < 0.0039
SDS
Model duodenum bile 0.0386
salts
Table 3. Solubility in Organic Media
Medium Concentration (mg/mL)
Propylene glycol 6.21
Polyethylene glycol 3.27
400
PEG 400, 0.1 % Tween 3.91
80
Propylene carbonate 6.24
Ethyl acetate 14.49
225.44
Acetonitrile 7.44
Acetone 46.97
DMSO 130.40
Benzyl Alcohol >34
Ethanol 45.59
70% aqueous ethanol 2.73
Isopropanol 29.98
CA 02295016 1999-12-20
WO 99/08666 PCT/EP98/05194
Table 4. Solubility in 2-Hydroxypropyl-~i-cyclodextrin Solutions
Medium Concentration (mg/mL)
10% Molecusol~ 0.03
20% Molecusol~ 0.12
40% Molecusol~ 0.79
40% Molecusol~, 25% PEG400,0.08
5%PG
40% Molecusol~, 50% aqueous0.56
PEG 400
Table 5. Solubility in Various Oil Base Systems
Medium Concentration (mg/mL)
Sesame oil 0.52
Safflower oil 0.39
Soybean oil 0.44
Cottonseed oil 0.53
Corn oil 0.56
Castor oil 2.01
Olive oil 0.44
Peanut oil 0.46
Mineral oil 0.007
1 % Span 20, cotton seed0.62
oil
10% benzyl alcohol, cottonseed2.77
oil
Intralipid~ 20% 0.009
Capmul"'' MCM 28.24
CA 02295016 1999-12-20
WO 99/08666 PCT/EP98/05194
9
Table 6. Solubility in mixtures of CapmulT"~ MCM and PEG
CapmulTM MCM (%) in PEG400Concentration (mg/mL)
6.95
25 10.01
50 14.11
100 28.24
The solubility data show that these types of steroids are very difficult to
dissolve. The data also show that solubility in CapmuITM MCM is significantly
higher
5 than in the other systems which were tested.
CapmuITM MCM was then used to prepare fill formulations suitable for use
in gelatin capsules. For manufacture of 0.01, 0.05, 0.5, 2.5, 5.0, and 10.0 mg
soft-
gelatin capsules, Capmuf~'' MCM was heated to approximately 26-28°C.
Then
butylated Hydroxytoluene NF is added and the mixture is stirred until
dissolved.
10 Then the steroid was added and mixed, and the temperature of the mixture
was
maintained and monitored to ensure that it did not exceed 40°C, until
dissolved. The
solution was deaerated prior to encapsulation.
The gelatin was prepared by blending gelatin NF, glycerin USP, sorbitol
special and purified water USP. The resulting mixture was heated in a
pressurized
reactor to melt the gelatin. The gelatin was then maintained in the molten
state until
used for encapsulation.
Encapsulation was performed using a rotary die process. The heated
gelatin was fed to .an encapsulation machine where it entered two spreader
boxes
which cast the gelatin on a cooling drum, thus forming two gelatin ribbons.
Each
gelatin ribbon was lubricated with Fractionated Coconut Oil on the internal
side and
Fractionated Coconut Oil with 0.1 % Lecithin NF on the external side. The
Fractionated Coconut Oil prevents the gelatin from sticking to equipment and
the
Lecithin NF prevents the capsules from sticking together after manufacture,
prior to
drying. The ribbons were then conveyed to the encapsulation roller. Die
cavities to
CA 02295016 1999-12-20
WO 99/08666 PCT/EP98/05194
form the capsules are located on the circumference of the fwo adjacent
rollers,
which rotate and pull the gelatin ribbons between them. The fill solution was
injected, by a metered positive-displacement pump, between the gelatin ribbons
forcing them to expand and fill the die cavities. As the capsules were filled,
they
5 were simultaneously shaped, sealed and cut from the gelatin ribbon by the
encapsulation rollers. The capsules were then conveyed to the rotating basket
dryer.
The capsules were dried by tumbling in a rotating basket dryer to remove
sufficient moisture to allow handling. They were then transferred onto trays
and
10 allowed to dry until the moisture level of the fill solution was not more
than 2% (w/w).
Drying time is the time required to reach the 2% moisture level.
Six batches were prepared containing 0.01, 0.05, 0.5, 2.5, 5.0, or 10.0 mg
of steroid, 0.035 mg of butylated hydroxytoluene NF, and sufficient CapmuITM
MCM
to make a total fill composition of 350 mg, except the 10 mg capsule was made
with
a total fill of 500 mg.
These compositions were evaluated for relative bioavailability using
standard methods. Volunteers were randomized to receive drug in either a soft
gelatin capsule of the present invention or in a conventional tablet. Plasma
samples
were collected and pharmaco kinetic parameters (AUC, Cmax, TmaX) were compared
between the treatment groups. The relative bioavailabilityr from the soft
gelatin
capsule of this invention was 80% to 90% compared to 10% to 20% for the same
amount of steroid in a tablet.
The application of which this description and claims forms part may be used
as a basis for priority in respect of any subsequent application. The claims
of such
subsequent application may be directed to any novel feature or combination of
features described herein and may include, by way of example and without
limitation, one or more of the following claims.
