Note: Descriptions are shown in the official language in which they were submitted.
CA 02425688 2003-04-11
WO 02/38577 PCT/USO1/32055
EXTENDED RELEASE ERYTHROMYCIN DERIVATIVES
The invention relates to a pharmaceutical composition of erythromycin
derivatives
with an extended release profile.
Erythromycin, as well as derivatives thereof, have been used as an
antibacterial agent,
and are generally provided as an immediate release composition.
U.S. Patent 6,010,718 discloses a pharmaceutical composition having extended
release characteristics wherein erythromycin or a derivative thereof is
employed in a
pharmaceutical composition wherein the pharmaceutically acceptable carrier for
the
erythromycin or derivative thereof is a polymer, with such polymer generally
being in an
amount from about 5% to about 50% by weight of the composition.
In accordance with an aspect the present invention, there is provided a
pharmaceutical
composition for extended release of an erythromycin derivative wherein such
erythromycin
derivative is combined with a non-polymer hydrophobic material. Such material
provides for
extended release of the erythromycin derivative and is preferably at least one
of a clay, a long
chain hydrocarbon, a long chain alcohol, a long chain ester or a long chain
acid.
CA 02425688 2003-04-11
WO 02/38577 PCT/USO1/32055
More particularly, the extended release characteristics for the erythromycin
derivative
are provided by coating the erythromycin derivative with a clay, a long chain
hydrocarbon, a
long chain alcohol, a long chain ester, or a long chain acid.
A long chain hydrocarbon is a hydrocarbon that contains at least 12 carbon
atoms, and
in general, such a hydrocarbon contains from about 12 to 22 carbon atoms. The
hydrocarbon
may be branched or unbranched, or may be saturated or unsaturated, and; when
unsaturated,
may contain one or more double bonds.
A long chain carboxylic acid and/or long chain carboxylic acid ester and/or a
long
chain alcohol also preferably contains at least 12 carbon atoms, and more
preferably, contains
from 12 to 22 carbon atoms. In general, such hydrocarbons are aliphatic
hydrocarbons, and
may be saturated or unsaturated and may be branched or unbranched. If
unsaturated, the
hydrocarbon portion may contain one or more double bonds. In addition, such
long chain
alcohols, esters and acids may contain three carbon rings or hydroxyl groups.
Thus, for example, a long chain alcohol is represented by an aliphatic
hydrocarbon
alcohol that preferably contains at least 12 carbon atoms, and may contain one
or more
hydroxyl groups.
As representative examples of long chain carboxylic acids, there may be
mentioned:
n-dodecanoic acid, a-tetradecanoic acid, a-hexadecanoic acid, caproic acid,
caprylic acid,
capric acid, lauric acid, myristic acid, palmitic acid, stearic acid,
arachidic acid, behenic acid,
montanic acid and melissic acid. Also useful are unsaturated monoolefinic
straight chain
monocarboxylic acids. Examples of these are oleic acid, gadoleic acid and
erucic acid. Also
useful are unsaturated (polyolefinic) straight chain monocarboxyilic acid.
Examples of these
are linoleic acid, ricinoleic acid, linolenic acid, arachidonic acid and
behenolic acid. Useful
branched acids include, for example, diacetyl tartaric acid.
As representative examples of long chain carboxylic acid esters, there may be
mentioned: glyceryl monostearates; glyceryl monopalmitates; mixtures of
glyceryl
monostearate and glyceryl monopalmitate (Myvaplex 600. Eastman Fine Chemical
Company); glyceryl monolinoleate; glyceryl monooleate; mixtures of glyceryl
monopalmitate, glyceryl monostearate, glyceryl monooleate and glyceryl
monolinoleate
2
CA 02425688 2003-04-11
WO 02/38577 PCT/USO1/32055
(Myverol 18-92, Eastman Fine Chemical Company); glyceryl monolinolenate;
glyceryl
monogadoleate; mixtures of glyceryl monopalmitate, glyceryl monostearate,
glyceryl
monooleate, glyceryl monolinoleate, glyceryl monolinolenate and glyceryl
monogadoleate
(Myverol 18-99, Eastman Fine Chemical Company); acetylated glycerides such as
distilled
acetylated monoglycerides (Myvacet S-07, 7-07 and 9-45, Eastman Fine Chemical
Company); mixtures of propylene glycol monoesters, distilled monoglycerides,
sodium
stearoyl lactylate and silicon dioxide (Myvatex TL, Eastman Fine Chemical
Company);
mixtures of propylene glycol monoesters, distilled monoglycerides, sodium
stearoyl lactylate
and silicon dioxide (Myvatex TL, Eastman Fine Chemical Company) d-alpha
tocopherol
polyethylene glycol 1000 succinate (Vitamin E TPGS, Eastman Chemical Company);
mixtures of mono- and di-glyceride esters such as Atmul (Humko Chemical
Division of
Witco Chemical); calcium stearoyl lactylate; ethoxylated mono- and di-
glycerides; lactated
mono- and di-glycerides; lactylate carboxylic acid ester of glycerol and
propylene glycol;
lactylic esters of long chain carboxylic acids; polyglycerol esters of long
chain carboxylic
acids, propylene glycol mono- and di-esters of long chain carboxylic acids;
sodium stearoyl
lactylate; sorbitan monostearate; sorbitan monooleate; other sorbitan esters
of long chain
carboxylic acids; stearyl heptanoate; cetyl esters of waxes; stearyl
octanoate; Clo-C3o
cholesterol/lavosterol esters; and sucrose long chain carboxylic acid esters.
As representative examples of clays, there may be mentioned: Kaolin,
Bentonite,
magnesium aluminum silicate, magnesium trisilicate, talc, or calcium silicate.
The erythromycin derivative is coated with a material as hereinabove described
to
provide for sustained release of the erythromycin derivative.
The extended released material, as hereinabove described, is generally
employed in an
amount of from about 1 % to about 60%, by weight of the composition, and
preferably from
about 5% to about 50% of the composition.
The composition may further include pharmaceutically acceptable excipients
and/or
fillers and extenders such as lactose, starches, dicalcium phosphate, calcium
sulfate, calcium
carbonate, glucose, sucrose, mannitol and silicic acid, lubricants such as
talc, calcium
stearate, magnesium stearate, etc.
3
CA 02425688 2003-04-11
WO 02/38577 PCT/USO1/32055
In accordance with the present invention, unlike U.S. Patent 6,010,718,
extended
release properties are achieved without using a polymer to provide such
properties.
Although extended release properties are achieved in accordance with the
invention
by using the extended release agents as hereinabove described, whereby it is
not necessary to
add a polymer to the composition, it is possible to include a polymer in the
composition for
other purposes.
In general, if a polymer is present in the composition, such polymer is
present in an
amount of less than 5% by weight, generally in an amount less than 2% by
weight, and more
preferably in an amount less than 1% by weight. In most cases, the composition
is free of a
polymer in that a polymer is not required to achieve extended release
properties.
The composition is preferably used as an oral dosage form; for example, in the
form
of a tablet or capsule.
The oral dosage form of the present invention which provides for extended
release of
an erythromycin derivative may also be employed in a liquid oral dosage form,
which may
include an emulsion, a micro-emulsion, a suspension, syrup, etc.
In general, the pharmaceutical composition of the present invention includes
an
erythromycin derivative in an amount from about 45% to about 60% by weight,
and
preferably contains about 50% by weight of the erythromycin derivative. The
erythromycin
derivative is preferably 6-0-methoxy erythromycin A, known as Clarithromycin.
The composition of the invention is administered to a host in an amount
effective to
treat a bacterial infection. A daily dose of the composition of the invention
is preferably
delivered in a single dose and can range from about 500 mg to 1000 mg per day,
with the
pharmaceutical generally being administered for periods of from 5 to 14 days.
It has been found that it is possible to provide an extended release
pharmaceutical
composition of an erythromycin derivative, without use of a polymer to provide
for extended
release, and that such a pharmaceutical composition has properties similar to
those of the
extended release composition of U.S. 6,010,718.
4
CA 02425688 2003-04-11
WO 02/38577 PCT/USO1/32055
Tn particular, a pharmaceutical composition in accordance with the invention,
(similarly to the pharmaceutical composition of U.S. Patent 6,010,718) can
induce a
statistically significantly lower mean fluctuation index in the plasma than
ari immediate
release composition while maintaining a similar bio-availability, or providing
for increased
bio-availability.
The invention will be further described with respect to the following
examples;
however, the scope of the invention is not to be limited thereby. Unless
otherwise specified,
all parts and percentages are by weight.
Ingredient Conc.
Example 1: Clarithromycin 50
Lactose 19
Glyceryl monostearate 30
Magnesium Stearate 1.0
Method A: Melt the glyceryl monostearate and add the clarithromycin. Let cool
and then
mill through a screen. Blend the mixture with the lactose in a tumble blender
for about 20
minutes. Add magnesium stearate and blend for 5 minutes. Compress the blend
using a
rotary tablet press.
Method B: Granulate lactose, glyceryl monostearate and clarithromycin together
using a
high shear granulator. Stop granulating when the gylceryl monosterate has
completely
melted. Screen the granulate. Blend the granulate and magnesium stearate for 5
minutes in a
tumble blender. Compress the blend using a rotary tablet press.
Example 2: Clarithromycin 50
Lactose 19
ATMUL 84S 30
Magnesium Stearate 1
Method A: Melt the ATMUL 84S and add the clarithromycin. Let cool and then
mill
through a screen. Blend the mixture with the lactose in a tumble blender for
about 20
S
CA 02425688 2003-04-11
WO 02/38577 PCT/USO1/32055
minutes. Add magnesium stearate and blend for 5 minutes. Compress the blend
using a
rotary tablet press.
Example 3: Clarithromycin 50
Lactose 35
Cetyl alcohol 10
Stearic Acid 5
Method A: Granulate lactose, cetyl alcohol and clarithromycin together using a
high shear
granulator. Stop granulating when the cetyl alcohol has completely melted.
Screen the
granulate. Blend the granulate and magnesium stearate for 5 minutes in a
tumble blender.
Compress the blend using a rotary tablet press.
Method B: Dissolve the cetyl alcohol in ethanol (95%). Granulate the
clarithromycin and
lactose with the cetyl alcohol solution. Screen the granulate and then dry.
Blend the dried
granulate and stearic acid in a tumble blend for 5 minutes. Compress the blend
using a rotary
tablet press.
Example 4: Clarithromycin 50
Lactose 34
Kaolin 15
Magnesium Stearate 1
Example 5: Clarithromycin 50
Lactose 30
Starch 3
Kaolin 16
Magnesium Stearate 1
Example 6: Clarithromycin 50
Lactose 25
Starch 3
Cetyl alcohol 17
Stearic Acid 5
6
CA 02425688 2003-04-11
WO 02/38577 PCT/USO1/32055
Example 7: Clarithromycin 50
Sucrose 25
Starch 3
Cetyl alcohol 17
Stearic Acid 5
Example 8: Clarithromycin 50
Dextrose 34
Kaolin 15
Magnesium Stearate 1
The compositions of Examples 4-8 are formulated in a manner similar to the
previous
examples.
Numerous modifications and variations of the present invention are possible in
light
of the above teachings and, therefore, Within the scope of the pending claims,
the invention
may be practiced otherwise then as particularly described.
7
