Note: Descriptions are shown in the official language in which they were submitted.
CA 02552925 2006-07-19
WO 2005/074890 PCT/EP2004/050057
TITLE OF THE INVENTION
SEMISOLID MATRIX PHARMACEUTICAL FORMULATIONS
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to pharmaceutical formulations with improved
stability
l0 comprising at least one oxidation-susceptible and poorly water-soluble drug
as active
ingredient and a water soluble derivative of vitamin E as antioxidant agent.
Discussion of the Back rg ound
Solid dispersions cover a wide range of systems comprising one or more active
ingredients in an inert pharmaceutical carrier or matrix in the solid or
semisolid state as
established by Chiou and Riegelman (Journal of Pharmaceutical Sciences 1971,
60(9);
1291-1302).
The authors report several solid dispersion manufacturing methods including
melting
method, solvent method and melting-solvent one.
Solid dispersions represent a useful pharmaceutical technique for increasing
and
modifying the dissolution kinetics of poorly soluble drugs to improve their
oral
bioavailability. Hydrophilic and highly soluble polymers have been widely
investigated as
inert carriers in solid dispersions for accelerating release profiles of
poorly water-soluble
drugs.
Always Chiou and Riegelman refer that water-soluble crystalline polymers of
high
molecular weight appear to be the preferred solid dispersion carriers for
sparingly water
soluble drugs, since the molecular weight of the most organic drug is usually
less than
1000. Low toxicity and lack of absorption from the gastrointestinal tract are
the
important advantages of these polymeric carriers.
Polyvinyl pyrrolidone (PVP) and polyethylene glycols (PEG) of high molecular
weight
are the most frequently investigated polymeric carriers, although thermal
decomposition
CA 02552925 2006-07-19
WO 2005/074890 PCT/EP2004/050057
2
of PVP makes not applicable the use of melting method and makes this polymer
less
attractive in formulation than PEGS.
Lheritier et al. (International Journal of Pharmaceutics 123, (1995) 273-279)
refer the
improved dissolution behavior of a new calcium family compound by means of
solid
dispersions containing PEG 6000.
It is well known to the man skilled in the art that the poor water solubility
of drugs could
affect their oral administration and absorption. When poor water solubility is
associated
with poor chemical stability properties due to oxidative reaction under
stressed
conditions (for example heat, moisture and light) the bioavailability of oral
formulations
l0 of the drug could further decrease.
This oxidative reaction happens in common oral dosage forms such as uncoated
tablets,
powders, fine granules, hard gelatin capsules; thus the content decreases and
visual
aspect alteration (for example color changes) can occur either during the
manufacturing
process and storage, that can be overcome through sugar coated film coated.
Non conventional oral dosage forms can overcome and increase the low water
solubility
of compounds thus impacting not only on the stability but also on the
dissolution
properties, the oral absorption and bioavailability of the active ingredient.
However, in case of oxidation-susceptible drugs a hydrophilic carrier based
solid
dispersion is not the preferred choice for the formulation skilled in the art;
especially high
molecular PEGS, according to their high solubilization properties, can undergo
autoxidation reactions during the storage catalyzing both its and the drug
degradation.
Traditional formulation skills and knowledge may suggest selection of
appropriate
stabilizing agents for overcoming oxidation degradations and improving
chemical
stability.
The most relevant selection criteria is miscibility of the stabilizing agent
with hydrophilic
carriers and good stability during the solid dispersion manufacturing process
that is
usually carried out by melting method at 50-70°C.
In some cases improved stability effects have been obtained adding stabilizing
agents that
can at the same time adversely affect the dissolution properties of the solid
dispersion
3o formulations.
CA 02552925 2006-07-19
WO 2005/074890 PCT/EP2004/050057
3
Conventional antioxidant agents such as ascorbic acid, butylated
hydroxyanisole (BHA),
butylated hydroxytoluene (BHT), propyl gallate (PG) and the like have been
shown to be
not compatible for PEGS based solid dispersions either due to physical
incompatibility
and chemical degradations.
Surprisingly a stability improvement has been obtained by adding a low amount
of a
water soluble vitamin E derivative, in particular vitamin E polyethylene
glycol succinate
(Vitamin E TPGS) in the solid dispersion composition.
Vitamin E TPGS (Eastman) is a water miscible d-~tocopheryl derivate obtained
by
esterification of the acid group of crystalline d-e~tocopheryl acid succinate
by
polyethylene glycol (see U.S.Phannacopeia 25 - National Formulary 20); having
a dual
nature of lipophilicity and hydrophilicity, similar to a surface active agent.
Vitamin E TPGS is already known as a pharmaceutical antioxidant active
ingredient for
treatment human diseases. For example, US 6,069,167 discloses the use of this
water-
soluble derivative of Vitamin E to treat cholestatic liver disease, and US
5,972,993
discloses the use of tocopherol derivatives such as vitamin E TPGS for the
treatment of
skin disorders.
However, its use in pharmaceutical applications as excipients is as
emulsifier, solubilizer,
and absorption enhancer. WO 96/36316, US 5,891,845 and WO 00/76482 may be
cited
as examples.
2o WO 00/03753 discloses the use of Vitamin E TPGS as a component of
microdisperse
drug delivery system for enhancing the bioavailability of therapeutics agents;
in this case
Vitamin E TPGS acts as a semisolid carrier in mixture with polyglycolyzed
glycerides to
produce a solid, semi-solid or liquid dosage form.
WO 01/37834 describes a stable oral pharmaceutical dosage form containing an
acid
benzimidazole compound mixed with pharmaceutical acceptable excipients
including
vegetable and/or animals oils, and/or synthetic triglycerides. The preferred
stabilizing
agent is Vitamin E TPGS added for improving chemical stability of labile acids
active
ingredient but in this case the stabilization effect is not linked to
oxidation but to liability
to acid of said molecules.
3o We have found that unexpected improvements in chemical stability of
oxidation-
susceptible and poorly water-soluble drugs formulated in a hydrophilic carrier
based solid
CA 02552925 2006-07-19
WO 2005/074890 PCT/EP2004/050057
dispersion can be obtained by adding low amount of vitamin E TPGS as
antioxidant
agent.
CA 02552925 2006-07-19
WO 2005/074890 PCT/EP2004/050057
DETAILED DESCRIPTION OF THE INVENTION
Object of the present invention is a stable pharmaceutical solid or semisolid
dispersion
comprising at least one oxidation-susceptible and poorly water-soluble drug as
active
ingredient, a hydrophilic carrier, a water-soluble vitamin E derivative as
antioxidant
5 agent and optionally other excipients_
Another object of the invention is a method of inhibiting oxidative
degradation of
pharmaceutical formulations containing at least one oxidation-susceptible and
poorly
water-soluble drug as active ingredient which method comprises adding to the
formulation a low amount of a water soluble vitamin E derivative as
antioxidant.
l0 A further object of the invention is a simple, quick and cheap
manufacturing process for
preparing a stable solid or semisolid dispersion for oral administration of an
oxidation-
susceptible and poorly water-soluble drug which process comprises mixing the
oxidation-susceptible and poorly water-soluble drug, the hydrophilic carrier
and the
water soluble vitamin E derivative, and melting the resultant mixture.
Although a broad number of oxidation-susceptible and poorly water-soluble
drugs could
benefit from the improved stability provided by the present invention, active
ingredients
incorporating at least one amine, ahdheyde or hydroxy functional group or
having at least
a double or triple bond in their chemical structure and having an intrinsic
solubility in
water of less than about 500 ~g/mL, especially less of about 200 ~g/mL are
preferred.
Specific examples of active ingredients wlich can be used in the present
invention are
posaconazole, tocoretinate, nitrendipine, tiagabine, hydrocortisone/cortisol,
tacrolimus,
testosterone, metachazepam, morphine, metamethasone vaherate, captopril,
nicotine,
dronabinol, fonnestane, atamestane and exemestane.
Exemestane is the most preferred oxidation-susceptible and poorly water-
soluble drug
according to the present invention.
In fact, exemestane is an irreversible aromatase inactivator that works on the
aromatase
enzyme inhibiting the conversion of androgens to estrogens. This compound has
low
water solubility, about 70 ~g/mL, that could affect the oral administration
and absorption
of this active drug. Besides exemestane exhibits poor chemical stability
properties due to
oxidative reaction under stressed conditions.
CA 02552925 2006-07-19
WO 2005/074890 PCT/EP2004/050057
6
The drug can be dispersed in the pharmaceutical solid dispersion in the range
of from
about 25% to 1% and more preferably from 15% to 2%.
The pharmaceutical composition of this invention further comprises a
hydrophilic carrier,
a water soluble vitamin E derivative as antioxidant and optionaly further
excipients.
Hydrophilic polymers are added as inert carrier of the solid dispersion to
improve the
dissolution release profile and the solubilization of the active drug from the
pharmaceutical dosage form.
Examples of hydrophilic carriers are high molecular weight polyethylene
glycols such as
PEG 1000, 2000, 3000, 4000, 6000, 8000 and 20,000.
l0 Hydrophilic carriers can be in an amount from 20% to 95% w/w and preferably
from
90% to 70% w/w.
The antioxidant agent is water soluble vitamin E derivative, preferably d-
alpha-
tocopherol polyethylene glycol ester, and more preferably d-alpha-tocopherol
polyethylene glycol 1000 succinate, also known as vitamin E TPGS.
The water-soluble vitamin E derivative is used in the range from 1% to 0.01%
w/w of
the pharnzaceutical composition, and preferably from 0.5% to
0.02°!° w/w.
Other suitable excipients which can be optionally added to the pharmaceutical
composition of the invention are surface active agents for improving the
dissolution of
the active drug from the solid dispersion filled in capsules.
They may comprise polysorbates (for example Tween 80) and/or pluronics in the
range
from 20% to 0.5 % w/w and preferably from 5 % to 1 % w/w of the pharmaceutical
composition.
The preferred manufacturing process is mixing the oxidation-susceptible and
poorly
water-soluble drug, the hydrophilic carrier and the water soluble vitamin E
derivative,
then optionally adding one or more other pharmaceutical components and melting
the
final mixture at temperatures between 50°C and 70°C.
The melt solid dispersions are mixed from several hours up to 48 hours. Final
dosage
forms are hard gelatin capsules (HGC), soft gelatin capsules (SGC) or
hydroxypropylmethyl cellulose capsules (HPMC) prepared by direct filling of
the molten
excipients with the active drug.
CA 02552925 2006-07-19
WO 2005/074890 PCT/EP2004/050057
7
With the aim of better illustrating the present invention, without limiting to
it, the
following examples are now given.
Example 1
Solid dispersion of exemestane in PEG 4000.
5 mL of PEG 4000 were melted at 70°C and 750 mg of exemestane were
dispersed
under magnetic stirrer. After 4, 24 and 48 hours at 60°C, "4" size hard
gelatin capsules
were manually filled with 0.160 mL of molted dispersion and correlates assay
is
performed by means HPLC method.
The accepted limit content of the known degradation exemestane compounds is
the
l0 following:
Related substance "A": less than 1
Related substance "B": less than 0.5°!°
The results on the said composition are the following:
Area % After After After 48h
4h 24h
Related substance 0.62 0.57 1.03
"A"
Related substance 0.86 0.95 1.26
"B"
Example 2
A solid dispersion having the following composition:
PEG 4000 88.5 % (w/w)
exemestane 11 °S° (w/w)
propyl gallate 0.5 % (w/w)
was prepared by the melting method described in Example 1.
After 48 hours sensitive change in solid dispersion color, from white to
brown, were
observed due a chemical instability of propyl gallate at high temperatures.
Example 3
Solid dispersions having the following composition:
PEG 4000 87.3 % (w/w)
exemestane 12.7% (w/w)
CA 02552925 2006-07-19
WO 2005/074890 PCT/EP2004/050057
8
were prepared by the melting method described in Example 1, adding
respectively 0.2%
w/w, 0.02% wlw of butylated hydroxyanisole (BHT) or butylated hydroxytoluene
(BHT).
After 4, 24 and 48 hours at 60°C, "4" size hard gelatin capsules were
manually filled with
0.160 mL of molted dispersion and correlates assay is performed by means HPLC
method.
The results of all compositions are the following:
Area % After After After 48h
4h 24h
Related substance 0 0 0
"A"
Related substance 0 0 0
"B"
Nevertheless after 48 hours dramatic decrease of dissolution profiles were
observed in
comparison to pharmaceutical composition described in Example 1 probably due
to
l0 physical incompatibility between PEG and these phenol derivatives (see
Figure 1 and 2).
Example 4
A solid dispersion having the following composition:
PEG 4000 87.3 % (w/w)
exemestane 12.5% (w/w)
Vitamin E TPGS 0.2 % (w/w)
was prepared by the melting method described in Example 1.
After 4, 24 and 48 hours at 60°C, "4" size hard gelatin capsules were
manually filled with
0.160 mL of molted dispersion and correlates assay is performed by means HPLC
method.
The results on the said composition are the following:
Area % After After After 48h
4h ~~ 24h
Related substance 0 0 0
"A"
Related substance 0 0 0
"B"
No solid dispersion color changes were observed among the manufacturing
process.
CA 02552925 2006-07-19
WO 2005/074890 PCT/EP2004/050057
9
Example 5
A solid dispersion having the following composition:
PEG 4000 87.48 % (w/w)
exemestane 12.5% (w/w)
Vitamin E TPGS 0. 02 % (w/w)
was prepared by the melting method described in Example 1.
After 4, 24 and 48 hours at 60°C, "4" size hard gelatin capsules were
manually filled with
0.160 mL of molted dispersion and correlates assay is performed by means HPLC
method.
to The results on the said composition are the following:
Area Jo After After After 48h
4h 24h
Related substance 0 0 0
"A"
Related substance 0 0 0
"B"
No solid dispersion color changes were observed among the manufacturing
process.
Example 6
A solid dispersion having the following composition:
is PEG 4000 86.8 % (w/w)
Exemestane 10 % (w/w)
Vitamin E TPGS 0.2 % (w/w)
Tween 80 3 % (w/w)
was prepared by the melting method described in Example 1.
20 After 48 hours at 60°C, "2" size hard gelatin capsules were manually
filled with 0.247
mL of molted dispersion.
These capsules were stored at 55°C, 25°C/60% HR and
40°C/75% HR according to the
following stability protocol:
CA 02552925 2006-07-19
WO 2005/074890 PCT/EP2004/050057
Conditions Timepoints
TO 15 days 1 month3 months6 months
55C A A A
40C-75!HR A A A A
25C-60%HR A A A
A- Assay and correlates
The results are the following:
lmat3mat 3mat 6mat 6mat
15 1 40C 40C 25C 40C 25C
days m ! / / / /
at at
T 0 55C 55C 75% 5% 60% 75% GO%
RH RH RH RH RH
Assay AssayAssayAssayAssay AssayAssayAssay
Assay 102.64%102.64%104.87%103.16%100.79%103.14%101.41%101.15%
Related
substance
nAn 0% 0! 0% 0% 0% 0% 0% 0%
Related
substance
"B" o% o% o% o% o% o% o% o%
