Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~ 5~8
Abstract of the Disclosure
A liquid dosage form suitable ~or oral administration of
etoposide whicb is suf~iciently concentrated to be administrated
in capsule form an~ which provides improved absorption of the
5 drug rela~ive to prior oral formulations.
Field of t~e Invention
. .
The present invention refers to a drug bio effecting and
body treating composition having a glycosidic active ingredient
(Class 424, subclass 180~.
Descrip~ion of the Prior Art
Etoposide is a semi-synthetic product derived from
podophyllotoxin. The material is identified by the chemical name
4'-demethylepipodophyllotoxin-9-(4,6-O(R)-ethylidene-beta-D-gluc-
opyranoside). It is referred to in the literature as vP-16-213,
VePesidRt Ethylidene-Lignan P, and EPEG. It has been evaluated
for use in treatment of cancer under the auspicious of The
National Cancer Institute under the number NSC-131540. It ~as
recently been approved by the Federal ~ood and Drug
Administration for use in the treatment of refractory testicular
cancer and has been proposed for use in the treatment of small
cell lung cancer.
In investigations conducted under the auspicious of the
National Cancer Institute, the drug WAS supplied as a solution
for injection having the following composition: etopo~ide, 100
mg; citric acid, anhydrous 10 mg; benzyl alcohol~ 150 mg;
polysorbate 80, puriied, 400 mg; polyethylene glycol 300, 3.25
~; alcohol, absolute qs 5.12 9. Each ampule of the foregoing
composition consis~ed of 5 ml of olution which was diluted 20 to
2.
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~ 85~3
50 times with 0.9~ sodium chloride or 5~ dextrose for injection
before administration by slow intravenous infusion.
~hen the foregoing intravenous c~mposition w~s administered
by ingestion rather than injection, the 5 ml ampule was either
taken as a teaspoon dose ~orm or first diluted with water; it
was found that the bioavailability by the oral route was
approximately 90~ that by the intravenous route lM.D'Incalci et
al., Cancer Chemoterapy and Pharmacology (1982) 7:141-145). A
similar dose taken by capsule in which 100 mg of actIve
ingredient was contained in approximately 1.3 ml of encapsulated
solution in which the vehicle consisted of polyethylene glycol
400, slycerine, water, and citric acid yielded only about
one-balf the bioavailability of the intravenous sol~tion when
taken by ingestion (M.D'Incalci et al., loc. cit.). ~be present
invention addresses this problem of reduced bioavailabili~y of
the capsule dosage form, and provides a liguid formulation of
sufficiently high concentration for encapsulation which affords
- bioavailability upon ingestion equal to the intravenous solution.
SummarY of the Invention
The present invention takes advantage of our discovery that
taurocholic acid when included in a solution dosage composition
with etoposide results in markedly improved absorption of the
drug follPwing ingestion of the composition. It is belived that
this is due to the formation of a micellar solution of etoposide
on dilution thereof with the gastric contents.
In investigating this problem, we have found that the
capsule formulation referred to above when mixed with water in
the proportion of about 10 ml of water per 100 mg of etoposide
results in the immediate ~ormation of a heavy, milky white
precipitate. When as little as an equal weight ~f taurocholic
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acid relative to the etoposide is included in the liguid capsule
formulation, precipitate formation is delayed ~or over an hour on
mixing the îormulation with 10 ml of water. The ~ollowing
t~bulation illustrates this effect of taurocholic acid and other
bile acids.
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Surface tension measurements on the aqueous dilutions of ~he
bile acid formulations referred to in the foregoing table have
confirmed that, indeed, micellar s~luti~ns of etoposide are
produced. This is reflected in tb~ failure for a further
decrease in surface tension to occur as the concentration of
taurocholic acid in the solution is increased. ~hat
concentration where no further ~ecrease in surface tension occurs
is referred to as critical micellar concentration.
The phenomenon of micellar solubilization of poorly water-
soluble drugs mediated by bile acids, including taurocholic acid,
has been previously reportsd with respect to griseofulvin,
hexesterol, glutethimide (Bates et al., Journal of Pharmaceutical
Sciences, 55, 191-199~, reserpine, Malone et al., ibid. 55,
972-974 (1966), fatty acids, and cholesterol (Westergaard et al.,
Journal of Clinical Investigation, 58, 97-108 (1976)~;
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~3~35~
DETAILED DESCRIPTION OF THE INVENTION
~ he present invention involves a pharmaceutical solution of
etoposide which has the unique property of providing a stable
apparent solution of the drug upon dilution thereof with from 1
~ to 10D volumes ~f water. The solution is stable and fre~ ~
precipitate for a period of at least two hours sufficient to
permit administration to and absorption by the mamm~lian organism.
It has been found that the bioavailability of etoposide following
Of al administration of the present dosage form is substantially
equivalent to that achieved by intravenous administ~ation of a
solution of a drug. It is believed that ingestion of the present
dosage form and resulting dilution thereof by the stomach contents
results in the formation of a micellar solution of etoposide in
the stomach which is readily absorbed by the ~astrointestinal
,15 tract. ~pplicants aO not wish to be bound, however, ~y any
theoretical explanation of the mechanism by which the superior
oral bioavailability of the present formulation is achieved.
Polyethylene glycol having a molecular weight of from 200 to
400 has been chosen as the vehicle for the present composition.
Polyethylene glycol has the necessary solvent capability for
etoposide and exhibits acceptable viscosity and dispersibility in
water to meet the requirements of the present invention. Poly-
ethylene glycol having molecular weight of from 200 to 300 is
preferred because i~ is less viscous than polyethylene glycol
400. The lower viscosity facilitates manufacturing manipu-
lations, and increases the dispersibility of the composition on
mixing with water or gastric contents. Other ingredients of the
composition serve to improve dispersibility and to facilitate
micelle formation on mixing thereof with water, or to improve
compatibility of the solution with the oapsule shell when the
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material is encapsulated in a soft gelatin c~psule according to a
preferred embodiment of the invention.
From 5 to 9 parts by weight of polyethylene glycol 300 per
par~ by weight of etoposide is preferably employed. Within this
range the rate of solution of the etoposide is sufficient ~or
manufacturing convenience, a sufficiently fluid mixtu~e is
obtained for convenient handling,.and the solution is sufficiently
concen~rated so tha~ a unit dosage form may be contained in a
sufficiently small volume of solution to permit encapsulation
within a soft gelatin capsule. More dilute solutions may, of
course, be prepared for dropper or teaspoon dosage use. Such is
also contemplated by the present invention.
The etoposide is preferably micronized prior to formulation
into the present composition, but this is prima~ily a convenience
1~ and not a necessity since a true solution of etoposi~e in the
polyethylene glycol is formed. Ordinarily when etoposide is
dissolved in a water soluble organic solvent, and the resulting
solution mixed with water, the etopocide precipitates because of
its very low water solubility. ~ccording to the present invention,
taurocholic acid is included in the composition and the presence
of this ingredient results, presumably, in the formation of a
micellar solution when the composition is mixed with water.
Other bile acids will similarly promote the formation o
apparent micellar ~olutions on mixing of the polyethylene glycol
solution with water, but they are unsuited for use in the present
compositions since the so-produced micellar solutions are unstable
or do not form at acid pH. Sodium deoxycholate or sodium cholate
form micellar solutions with etoposide, but the micellar solutions
have pH values of pH 10.9 and pH 11.0 respectively. ~pon ~cidifi-
cation, the etoposide precipitates from such solutions. Such arenot therefor suitable for ingestion due to ~he acidic nature of
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~Z38~8
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the gastric contents. Furthermore, for encapsulation within a
soft gelatin capsule shell an acidic pH is preferred because the
gelatin shell is disrupted by fill-solutions having pH values i~
excess of pH 8. O. It has been found by empirical experimentation
that preferably bout 3.5 parts by wei~ht of taurocholic acid per
part by weight o etoposide are desirable to provide a stable
micellar solution on dilution of the composition with water.
Smaller amounts such as 2.0 parts-by weight, and larger amounts
of taurocholic acid may be employed. No useful purpose is served
by using more than about 10 parts by weight of taurocholic acid
per part by weight of etoposide.
A water soluble acid is included in the composition to
assure th~t an acidic pH value is obtained upon dilution ~o form
the micellar solution. For purposes of pharmaceutical elegance
and ease of handling in a manufacturing operation, we prefer t~
use a solid water-soluble organic carboxylic acid, but other
acids may be employed. We prefer maleic, tartaric, citric,
gluconic, or ascorbic acids which are water-soluble, non-toxic
and convenient to handle in a pharmaceutical manufacturing
operation. Most preferred is citric acid which we have found to
be appropriate when used in from 0.1 to 0.5 parts by weight per
part by weight of etoposide. The most preferred proportion is
0.2 parts by weight of citric acid per part by weight of etoposide.
Ethanol se~ves the important purpose in the composition o~
promoting rapid dispersion on mixing with water and facilitates
formation of the micellar solution. Other water-soluble polar
organic solvents such as methanol, propanol, acetone, etc. which
are also effective are not suitable for ingestio~ and, accordingly,
ethanol has been selected ~or this purpose. At least 5~ by
weight of the composition of ethanol is necessary for this
purpose, but higher amounts up to 20~ by weight may be used,
particularly for purposes of a dropper or teaspoon dosage form.
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~Z38~78
For encapsulation within a soft gelatin capsule, a maximum of 10
by weight ~f etbanol in the composi~ion may be used~ Solutions
having higher concentrations of ethanol than 10~ by weight may
cause dehydration of the gelatin capsule wall and hence may not
be suitable for encapsulation with this type of a capsule.
Finally, for use of the present composition in a unit dose
form contained within a soft gelatin capsule it is desirable to
include up to about one part by weight of water per part by
weight of etoposide to improve the compatibility of the composition
with the soft gelatin capsule shell. ~he hydrophilic nature of
polyethyleneglycol, ethanol, citric acid, and taurocholic acid
causes the composition to abstract the water from the capsule
shell and may cause it rupture on prolonged storage. Sufficient
water is therefore included in the composition, preferably one
part by weight of water per part by weight of etoposide, to
render the composition compatible with the capsule shelI and
prevent dehydration thereof. It is desirable to select an amount
of water which will confer stability for a storage period of two
years at room temperature when the capsules are stored in a
: closed container
The preferr~d embodiments of the present invention are
stabie, liguid compositions in the form of true solutions having
the following composition:
, 10
..... .... . . ~
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Ingred~ent Parts by Weight
i
polyethanol glycol 3D0 5 to 9
etoposide
citric acid 0.1 to 0.5
taurocholio acid 2.0 to 10
ethanol 5 to 204 by weight of
total solution weight
The most preferred embodiment of the ~resent invention is
the following composition:
Ingredient ~ 3_~Y~ 8
polyethylene glycol 300 6.8
. esoposide, micronized 1.0
citric acid 0.2
ethanol 1.0
taurocholic acid 3.5
water 1.0
The following example constitutes a description of the
pr~ferred composition of the present invention.
Example
The ~ollowing ingredient~ were weighed:
Etoposide 25.09
Citric Acid, Anhydrous, USP5;0g
Polyethyle~e glycol 300170.09
Alcohol, USP 25.09
Taurocholic Acid . 87.5g
Purified Water, USP 25~09
.,.,-~ , 11
...... . . . .. ~
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~he taurocholic acid i. added p~rtionwise to the polyethylene
glyrol 300 wi~h s~irring to form a suspension. The water is then
added followed by the alcohol and citric acid. A solution forms
which is warmed to 65~C, ~llowed to cool to 35C, and filtered
(Millipore AP 25 29325). An atmosphere of nitrogen is main~ained
over the solution during those steps. The filtrate is kept at
30-3SC, and the etoposide is then dissolved therein. The
solution is then assayed (found 71.3 mg/g of e'coposide) and
filled into soft gelatin capsules at 100 mg etoposide per
capsule.
The foregoing capsule-fill solution has the following
characteristics, and stability.
5YIo_o_-~LL __ 6
1~ Color Dark Brown
2. pH 4.6
3. Viscosity Satisfactory
. Dispersibility Easily dispersible
5. Shell Compatibility~ Physical Compatible
6. Precipitation formation
time on dilution with ~2 to ~3 hours
1:1, 1:5, 1:10 and 1:100
* A trademark
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STABILITY
Storage TemperatureStorage I'ime4 Remaining
tDays)
4 C ( Control ) 8 100
70~C 5 102
70C 8 102
56C 8 102
37~ 8 105
25C 8 99
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