Note: Descriptions are shown in the official language in which they were submitted.
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967-125 PD-4088-01-RXN
G7.Y~I9ROZIL FOR~ TION~
The present invention relates to improved for~ula-
tions of gemfikrozil.
Bac~around
Gemfibrozll, or 5~(2,5-dimethylphenoxy)-2,2-di-
methylpentanoic ac~d, is a widely used antihyperlipo-
proteinemic agent. Physically the chemical is a crys-
talline material which melts in the range of 61- to
63-c (hexane) and exhibits a boiling point of 158-
1590.O2C. The suDstance is nonhygroscopic and gener-
ally compatible with common pharmaceutical excipientsbut has ve~y pcor solubility in water. This is partic-
ularly true in a highly acidic medium (such as is
encountered in the stomach) since its apparent pKa is
4.7.
The typical daily dose is high, generally about
1200 mg, probably because of the poor water solubility.
This dosage generally ig administered using for example
two capsules of 300 mg or a single compressed tablet of
600 mg, administration in each case being b.i.d.
The present invention pertains to improvements in
gemfibrozil formulations which improve the compound's
dissolution profile and thus increase the drug's blood
levels upon oral administration.
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U.S. Patent No. 4,716,033 discloses a medicament
adsorbate such as magnesium aluminum silicate having a
medicament, including inter alia gemfibrozil, and sur-
factant adsor~ed thereon.
U.S. Patent No. 4,753,800 discloses a medicament
adsorbate having a medicament, including inter alia
gemfibrozil, dispersed in an edible wax adsorbed
thereon.
U.S. Patent No. 4,814,354 discloses pharmaceutical
compositions of an anion exchange resin lipid regula-
tor, such as cholestyramine or cholestipol, and gemfi-
brozil.
U.S. Patent No. 4,778,676 discloses a chewable
confection delivery system of coated cholestyramine and
lS a confectionery matrix
U.S. Patent No. 4,816,264 discloses an oral deliv-
ery syste~ having a core portion of drug and a cellu-
losic gelling polymer and a semipermeable membrane
around the core.
U.S. ~atent No. 4,865,850 discloses a method of
expelling fat from the gastrointestinal tract by admin-
istering non-biodegradable collagen particles having
fat receptors, including inter alia gemfibrozil, on
their surface.
EP-A 295,637 A2 discloses pharmaceutical co~posi-
tions in which a lipid regulating component, including
inter alia gemfibrozil, is combined with inhibitor of
acylCoA:cholesterol acyltransferase.
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E2-~ 261, 693 ~l discloses a lipid regulating com-
pcnent, including inter alia gemfibrozil, which has
been pretreated to render it stable until such time as
it reaches the proximal section of the intestines.
PCT WO 88/05296 discloses pharmaceutical composi-
ticns in ~hich a lipid regulating component, including
inter alia gemfibrozil, is combined with inhibitor of
3-hydro~f-3-methylgluta~yl coenzyme A reductase.
Commercially available gemfibrozil capsules con-
tain a small amount of sodium lauryl sulfate, typically
less than 0.2~. Compressed tablets of gemfibrozil
which are comme~~ially available contain somewhat more
but again less than 1%; e.~., 0.7%.
Detailed Descri~tion
lS The present invention is based on the discovery
when gemfibrozil is admixed with from 1 to 4~, by
weight of gemfibrozil, of a pharmaceutically acceptable
surfactant having a hydrophilic-lipophylic balance
value ("HLB") of from about 10 to about 50, significant
improvements in the rate of dissolution in both acid
and alkaline media are observed.
Suitable pharmaceutically acceptable surfactants~
having an HLB value of from about 10 to about 50
include polysorbates, pluronics, alkali metal salts
of fatty alcohol sulfates, such as sodium lauryl
sulfate, salts of fatty acids such as sodium oleate and
triethanolamine oleate, and the like. The following
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list exemplifies trpical surfactants and their HLB
values:
Surf ctant HLB
Pluronic F68 29.0
Sodium oleate 18.0
~een 20 16.7
~een 40 15.6
~een 80 15.0
~een 60 14.8
~een 21 13.3
Triethanolamine oleate 12.0
~een 85 11.0
~een 65 10.5
~een 81 10.0
A preferred ratio utilizes from 1% to about 2~
of the surfactant. In addition, the pharmaceutically
acceptable sur~actant preferably has an HLB value of
from about 15 to about 40.
Generally the indicated amount of surfactant is
dissolved with the amount of water ultimately required
for granulation of the gemfibrozil. The gemfibrozil,
together with any other excipients to be granulated
such as silicon dioxide, hydroxypropyl cellulose
starch, and the like is then granulated in this aqueous
solution. After granulation and drying, any other dry
ingredients, as for example microcrystalline starch,
lubricants such as calcium stearate, additional sili-
con dioxide, and the like, are added and blended and
the mixture then compressed into tablets.
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The following is a t~pical formulation:
Gemfibrezil ........................... 600.00
Silicon Dioxide......................... 12.00
Hydro~ypro~yl cPllulose ................ 16.00
Preselatinized starch 1551............. 141.00
The foregoing components, including the active
ingredient and the granulation additives, are milled
through a ~0 screen and blended with 141.00 g of
pregelatinized starch 1551. This mixture then is gran-
ulated with a solution of the selected surfactant
(indicated below) in 100 mL of purified water USP. The
granulation is dried, combined with an additional 10.00
g of silicon dioxide, remilled through a Fitzmill No.
2A RH screen and t~en blended with 64.80 g of granular
microcrystalline cellulose and 10.00 g of calcium
stearate.
Aliquots of 860 mq are punched on 0.745" x 0.360"
elliptical punches at a hardness of 12 to 16 kp and
about 0.300" gauge.
Tablets prepared in the foregoing manner were
tested to evaluate their rate of dissolution in various~
media: O.lN hydrochloric acid, 0.05M phosphate buffer
at two pH values (5.5 and 7.4), and 0.2 phosphate
buffer at pH 7.4. the results are as follows:
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(1) o.l~ Hydrochloric Acid
Polysorbate 80
Time Amount of Surfactant
~minutes) 0.0% O.S% 1.0% 2.0
% Dissolved
0.3 0.9 1.4 1.7
0.5 1.0 1.8 2.2
0.8 1.3 2.2 2.5
1.2 1.5 2.3 2.6
1.5 1.7 2.4 2.7
1.7 1.9 2.5 2.7
1.9 2.0 2.5 2.7
Sodium Lauryl Sulfate
Time Amount of Surfactant
(minutes) 0.0% 0.5% 1.0% 2.0
% Dissolved
0.3 1.0 0.8 1.5
- 10 0.5 1.1 1.1 1.9
0.8 1.6 1.7 2.2
1.2 2.0 2.0 2.2
1.5 2.1 2.2 2.3
1.7 2.2 2.3 2.3
1.9 2.4 2.3 2.3
(2) 0.05M Phosphate Buffer (pH 5.5)
Polysorbate 80
TimeAmount of Sur~actant
(minutes) o.o% 0.5% 1.0% 2.0
% Dissolved
0.13 0.6 3.9 8.0
0.7 0.7 6.5 10.5
1.9 3.6 9.4 11.7
3.2 5.310.6 11.9
4.4 6.811.2 12.1
5.5 . 8.011.3 12.1
6.4 8.911.5 12.1
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Sodium Lauryl Sulfate
Time A~ount of Surfactant
5(minutes) 0.0~ 0.5% 1.0~ 2.0
~ Dissolved
0.1 1.8 1.4 5.4
0.7 2.1 2.8 7.6
1.9 3.4 5.1 9.7
3.2 4.6 7.0 10.6
4.4 5.8 8.3 11.0
5.5 6.8 9.3 11.2
6.4 7.7 9.9 11.3
(3) 0.05~ Phosphate Buffer (pH 7.4
Polysor~ate 80
Time A~ount of Surfactant
(minutes) 0.0~ 0.5% 1.0% 2.0
% Dissolved
12.223.9 57.5 82.3
23.844.0 78.9 95.0
43.369.0 94.6 99.5
58.583.7 98.4 100.0
69.192.5 99.4 100.0
77.097.7 100.0 100.0
82.9100.6100.0 100.0
Sodium Lauryl Sulfate
Time~ount of Surfactant
(minutes) o.o~ 0.5% 1.0~ 2.0
% Dissolved
12.2 22.127.8 68.2
23.8 42.451.9 86.5
43.3 69.080.1 100.0
5~.s 83.592.6 100.0
69.1 91.197.4 100.0
77.0 95.1100.0 100.0
82.9 97.2100.0 100.0
(4) 0.2M Phosphate Buffer (pH 7.4)
Polysorbate 80
20 Time~ount of Surfactant
(minutes) 0.0~ 0.5% 1.0% 2.0%
~ Dissolved
17.921.6 62.1 87.7
33.042.0 84.8 96.2
56.868.7 97.3 100.0
73.184.4 99.6 100.0
83.792.9 100.0 100.0
90.897.6 100.0 100.0
95.4100.0 100.0 100.0
Sodium Lauryl Sulfate
Time Amount of Surfactant
(minutes) 0.0% 0.5% 1.0% 2.0%
% Dissolved
17.930.5 46.3 82.0
33.056.4 74.4 91.5
56.885.0 94.5 100.0
73.195.0 98.7 100.0
83.798.4 99.7 100.0
90.899.7 100.0 100.0
95.4100.0 100.0 100.0
As can be seen from the above, the ~ncorporation
of the surfactant significantly increases the rate of
dissolution in otherwise identical formulations over a
wide range of pH values.
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