Note: Descriptions are shown in the official language in which they were submitted.
MODI.P0005
Oral Controlled Release Liquid Suspension Pharmaceutical
Formulation
Technical Field
The present invention relates to an improved
delivery system for the administration of drugs. In
particular it relates to drugs which are orally
administered.
Background
One of the major problems with the administration
of many drugs is the adverse reaction due to frequent
dosing. Attempts have been made in the past to control
the rate of release of the drug through the use of so-
called controlled release tablets. However, there often
is poor bioavailability of the drug due to incomplete
dissolution and/or disintegration of the tablets in the
gastrointestinal tract. In addition, in some instances,
for example in advanced stages of Parkinson's disease,
the patient finds it difficult to swallow tablets.
Furthermore, it often takes several hours for the tablet
to dissolve sufficiently for the patient to obtain
immediate relief from the drug. It is also known that
the pH in a patient's gastrointestinal tract sometimes
affects the rate of release of the drug from the tablet
and that the pH varies from time to time, thus making
treatment or control of the disease more difficult.
There is therefore a need to provide a drug delivery
system which gives faster initial availability of the
drug, improves the bioavailability of the drug, reduces
the adverse reactions and maintains a constant plasma
level of active ingredients for a prolonged time. The
present invention is intended to alleviate the
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aforementioned difficulties.
Disclosure of Invention
Accordingly the present invention provides a
controlled release oral formulation comprising a liquid
suspension of water, a stabilizer for the liquid
suspension, at least one pharmaceutically active
ingredient, and at least two water soluble biodegradable
polymers.
It will be recognized by those skilled in the art
that for many pharmaceutical compositions it is usual to
add at least one antioxidant to prevent degradation and
oxidation of the pharmaceutically active ingredients.
In one embodiment the polymers are selected from
the group consisting of polysucrose, copolymer of
sucrose and epichlorohydrin, hydroxymethyl cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl-ethyl cellulose, hydroxypropyl-methyl
cellulose, gelatine, starch, crosslinked starch,
polyethyleneimine, polyethylene glycol,
methoxypolyethylene glycol, ethoxypolyethylene glycol,
polyethylene oxide, cellulose acetate, polyvinyl
alcohol, sodium alginate, N,N-diethylaminoacetate, block
copolymers of polyoxyethylene and polyoxypropylene , a
mixture of hydroxyethyl cellulose and sodium
carboxymethyl cellulose, and combinations thereof.
In another embodiment the total concentration of
polymer is present in an amount of from 20 to 60 g for
every litre of water in the formulation. From a dosage
standpoint, this corresponds to 100 to 300 mg total
polymer for every 5 ml (teaspoon) water.
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2'~4~070
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In yet another embodiment the polymer is selected
from a combination of methoxypolyethylene glycol and
polyvinyl alcohol, a combination of polyethylene glycol
and polyvinyl alcohol, a combination of
methoxypolyethylene glycol and polysucrose, a
combination of methoxypolyethylene glycol and
polysucrose, a combination of starch and polysucrose,
methoxypolyethylene glycol and polysucrose, polyethylene
glycol and polysucrose, a combination of polyvinyl
alcohol and at least one of the celluloses, and a
combination of polyvinyl alcohol and polysucrose.
In a further embodiment, the formulation may
include an edible oil selected from the group consisting
of mineral oil, soyabean oil, coconut oil, vegetable oil
and sunflower oil and combinations thereof. The edible
oil may be present in an amount of from 2 to 10 g for
every litre of water in the formulation.
In yet another embodiment the stabilizer is
selected from the group consisting of oleic acid, cholic
acid, deoxycholic acid, pharmaceutically acceptable
salts thereof and combinations thereof.
In another embodiment the antioxidant is selected
from the group consisting of tocopherol, deteroxime
mesylate, methyl paraben and ascorbic acid.
In yet another embodiment the antioxidant is
present in an amount of 1 to 3 g for every litre of
water in the formulation.
In a further embodiment the stabilizer is present
in an amount of from 1 to 4 g for every litre of water
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in the formulation.
It will be understood by those skilled in the art
that colorants, flavouring agents and non-therapeutic
amounts of other compounds may be included in the
formulation.
The liquid suspension preferably has a viscosity
something akin to mineral oil or castor oil.
Although this disclosure exemplifies application of
the invention to anti-Parkinson's disease drugs in
particular, it is also applicable to other drugs, some
of which are indicated herein.
The invention also provides a controlled release
oral formulation comprising a liquid suspension of
water, an edible oil and a stabilizer for the liquid
suspension, at least one pharmaceutically active
ingredient selected from the group consisting of anti-
Parkinson drugs, dopamine agonists, anticholinergic
agents, anti-cholesterol agents, anti-arthritis agents,
anti-epileptic drugs, antidepressants, anti-ulcer drugs,
cardiovascular drugs, hypoglycemic agents and insulin,
and at least two water soluble biodegradable polymers,
wherein for every litre of water there is from 20 to
60 g of the polymers, and from 2 to 10 g of the edible
oil.
A preferred antioxidant to prevent degradation and
oxidation of certain pharmaceutically active ingredients
is tocopherol, e.g. vitamin E.
In one embodiment the active ingredient of the
anti-Parkinson drug is selected from carbidopa and
levodopa, benserazide and levodopa, bromocriptine,
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pergolide, ergot, seligine, and lisuride.
In a further embodiment the active ingredient is
carbidopa and levodopa in amounts of from 3 to 30 g
carbidopa and from 10 to 300 g levodopa per litre of
water.
In yet another embodiment the formulation contains
from 1 to 5 g antioxidant, preferably from 2 to 3 g
antioxidant per litre water. A preferred antioxidant is
tocopherol, e.g. vitamin E.
A preferred formulation comprises from 3 to 30 g
carbidopa, from 10 to 300 g levodopa, from 1 to 3 g of
an antioxidant selected from tocopherol, deteroxime
mesylate, methyl paraben and ascorbic acid, water, from
2 to 10 g of an edible oil selected from mineral oil,
vegetable oil, soyabean oil, coconut oil, and sunflower
oil, from 20 to 60 g total polymer, from 1 to 4 g of a
stabilizer selected from oleic acid, cholic acid,
deoxycholic acid, pharmaceutically acceptable salts
thereof and combinations thereof, from 2 to 3 g colorant
and from 2 to 3 g of a flavouring agent, said amounts
being expressed for every litre of water.
Examples of anti-cholesterol agents are lovastatin,
simvastatin, pravastatin, gemfibrosil and questran.
Examples of anti-arthritis agents are diclofenac
potassium, naproxen, catoprophen and indomethicine.
Examples of antidepressants are fluoxetin, sertraline
HC1, paroxetin and zopiclone. Examples of anti-ulcer H2
receptor antagonists are ranitidine and famotidine, and
other anti-ulcer drugs are omparazide, cesupride and
misoprostol. Examples of ACE inhibitor cardiovascular
6 - 2.~4 ~~ ~ p
drugs are analapril, lisinopril, captopril and
quinapril. Examples of cardiovascular calcium channel
blockers are diltiazem, verapamil, isosorbide
mononitrate, nifidipine and isradipe. Another
cardiovascular drug is coumarin. An example of a
hypoglycaemic agent is glizipide. Insulin is used for
the control of diabetes. As will be understood by those
skilled in the art, two or more pharmaceutically active
ingredients may be combined for specific effects. The
necessary amounts of active ingredient can be determined
by simple experimentation.
The invention also provides a controlled release
oral anti-epileptic drug formulation comprising a liquid
suspension of water, an edible oil and a stabilizer for
the liquid suspension, at least one pharmaceutically
active anti-epileptic ingredient, and at least two water
soluble biodegradable polymers, wherein for every litre
of water there is from 20 to 60 g of the polymers, and
from 2 to 10 g of the edible oil.
The present invention also provides a method for
making a controlled release oral formulation comprising
a liquid suspension of water, an edible oil and a
stabilizer for the liquid suspension, at least one
pharmaceutically active ingredient, and at least two
water soluble biodegradable polymers, wherein the
pharmaceutically active ingredient, the edible oil, the
stabilizer and the polymers are dissolved or dispersed
in water and vigorously mixed until a liquid suspension
is formed.
As indicated herein above, those skilled in the art
_ ~~~+~~~(~
recognize that for many pharmaceutical compositions it
is usual to add at least one antioxidant to prevent
degradation and oxidation of the pharmaceutically active
ingredients.
In one embodiment the polymer is selected from the
group consisting of polysucrose, a copolymer of sucrose
and epichlorohydrin, hydroxymethyl cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl-ethyl cellulose, hydroxypropyl-methyl
cellulose, gelatine, starch, crosslinked starch
polyethyleneimine, polyethylene glycol,
methoxypolyethylene glycol, ethoxypolyethylene glycol,
polyethylene oxide, cellulose acetate, polyvinyl
alcohol, sodium alginate, N,N-diethylaminoacetate, block
copolymers of polyoxyethylene and polyoxypropylene , a
mixture of hydroxyethyl cellulose and sodium
carboxymethyl cellulose, and combinations thereof.
In another embodiment the polymer is added in an
amount of from 20 to 60 g of total polymer for every
litre of water in the formulation.
In yet another embodiment the polymer is selected
from a combination of methoxypolyethylene glycol and
polyvinyl alcohol, a combination of methoxypolyethylene
glycol and polysucrose, a combination of polyvinyl
alcohol and at least one of the celluloses, a
combination of polysucrose and gelatine, and a
combination of polyvinyl alcohol and polysucrose.
The most preferred combinations are polysucrose and
cellulose, polysucrose and polyethylene glycol, and
polysucrose and gelatine.
8
In a further embodiment the edible oil is selected
from the group consisting of mineral oil, soyabean oil,
coconut oil, vegetable oil and sunflower oil and
combinations thereof.
The most preferred edible oil is coconut oil.
In yet another embodiment the edible oil is added in an
amount of from 2 to 10 g for every litre of water in the
formulation.
In yet another embodiment the stabilizer is
selected from the group consisting of oleic acid, cholic
acid, deoxycholic acid, pharmaceutically acceptable
salts thereof and combinations thereof.
In another embodiment the antioxidant is selected
from the group consisting of tocopherol, deteroxime
mesylate, methyl paraben and ascorbic acid.
In yet another embodiment the antioxidant is added
in an amount of 1 to 3 g for every litre water.
In a further embodiment the stabilizer is added in
an amount of from 1 to 4 g for every litre of water in
the formulation.
In another embodiment, vigorous mixing is
accomplished using a turbine mixer or ribbon blender.
The invention provides a method for making a
controlled release oral drug formulation comprising a
liquid suspension of water, an edible oil and a
stabilizer for the liquid suspension, at least one
pharmaceutically active ingredient selected from the
group consisting of anti-Parkinson drugs, dopamine
agonists, anticholinergic agents, anti-cholesterol
agents, anti-arthritis agents, anti-epileptic drugs,
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antidepressants, anti-ulcer drugs, cardiovascular drugs,
hypoglycemic agents and insulin, and at least two water
soluble biodegradable polymers, wherein there is added
from 20 to 60 g of the polymers, and from 2 to 10 g of
the edible oil for every litre of water, and wherein the
pharmaceutically active ingredient, the edible oil, the
stabilizer and the polymers are dissolved or dispersed
in water and vigorously mixed until a liquid suspension
is formed.
As indicated hereinabove, an antioxidant for the
pharmaceutically active ingredient is usually added.
In one embodiment the active ingredient of the
anti-Parkinson drug is selected from carbidopa and
levodopa, bromocriptine, pergolide, ergot, seligiline,
and lisuride.
In a further embodiment the active ingredient is
carbidopa and levodopa in amounts of from 3 to 30 g
carbidopa and from 10 to 300 g levodopa per litre of
water.
In yet another embodiment from 1 to 3 g
antioxidant is added to the formulation, e.g. from 2 to
3 g vitamin E per litre of water.
A preferred method for making an anti-Parkinson
controlled release formulation comprises adding from 3
to 30 g carbidopa, from 10 to 300 g levodopa, from 1 to
3 g of an antioxidant selected from tocopherol,
deteroxime mesylate, methyl paraben and ascorbic acid,
from 2 to 10 g of an edible oil selected from mineral
oil, vegetable oil, soyabean oil, coconut oil, and
sunflower oil, from 20 to 60 g total polymer, from 1 to
_ 10 _
4 g of a stabilizer selected from oleic acid, cholic
acid, deoxycholic acid, pharmaceutically acceptable
salts thereof and combinations thereof, from 2 to 3 g
colorant and from 2 to 3 g of a flavouring agent, to
water, said amounts being expressed for every litre
water, and vigorously mixing until a liquid suspension
is formed.
Examples of anti-cholesterol agents are lovastatin,
simvastatin, pravastatin, gemfibrosil and questran.
Examples of anti-arthritis agents are diclofenac
potassium, naproxen, catoprophen and indomethicine.
Examples of antidepressants are fluoxetin, sertraline
HC1, paroxetin and zopiclone. Examples of anti-ulcer H2
receptor antagonists are ranitidine and famotidine, and
other anti-ulcer drugs are omparazide, cesupride and
misoprostol. Examples of ACE inhibitor cardiovascular
drugs are enalapril, lisinopril, captopril and
quinapril. Examples of cardiovascular calcium channel
blockers are diltiazem, verapamil, isosorbide
mononitrate, nifidipine and isradipe. Another
cardiovascular drug is coumarin. An example of a
hypoglycaemic agent is glizipide. Insulin is used for
the control of diabetes.
The method of making the controlled release
formulation is easy to do. The concentrations of the
components of the formulation are adjusted until the
resulting suspension has a liquid consistency, so that
it is easily ingested and swallowed. A preferred
consistency is like mineral oil or castor oil. The
relative amounts of the components is found by easy
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experimentation. Mixing of the components may be
accomplished by vigorous stirring, vigorous shaking of
the vessel which contains the components, sonication,
use of high speed mixers or by other methods known to
those skilled in the art of making liquid suspensions.
In the selection of a suitable polymer combination,
it has been found that the amount of total polymer
should be less than about 60 g for every litre of water.
Preferably the amount of polyvinyl alcohol is less than
about 30 g. Polyvinyl alcohol has the advantage of
preventing the release of the drug over a long period of
time. This of course is a disadvantage for immediate
release of a drug. Accordingly it is desirable to
combine polyvinyl alcohol with one of the other, more
easily dissolved polymers such as polysucrose or one of
the celluloses. Preferred combinations are
methoxypolyethylene glycol and polyvinyl alcohol,
polysucrose and polyvinyl alcohol, polyvinyl alcohol and
cellulose, and methoxypolyethylene glycol and
polysucrose.
Advantages of the present formulation are that
adverse reactions are decreased, bioavailability is
increased, gastrointestinal side effects are decreased,
wearing-off is lessened, on-off dyskinesia and other
central nervous system (CNS) effects are greatly
improved, when compared to commercial controlled release
tablets. A further advantage of the formulation and
method over current commercial practices, e.g.
tabletting and regular capsules, is that the capital and
manufacturing costs are lower.
In the treatment of Parkinson's disease for
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example, with carbidopa and levodopa, the present
formulation will provide relief within about 30 minutes,
compared to about. 3 to 4 hours for commercially
available controlled release tablets. Additionally the
present formulation will maintain a relatively constant
level of active drug in the patient for a prolonged
period of time, for example 6 or more hours, thus
providing a longer lasting action and response to
treatment. Furthermore, fewer applications are needed
and high blood levels, which may cause dyskinesia, tend
to be avoided. Recommended daily doses will be 3 to 4
teaspoons (15 to 20 ml). That is, one teaspoon may be
taken every 6 to 7 hours.
For the treatment of Parkinson's disease a typical
formulation would comprise 200 mg levodopa, 50 mg
carbidopa, 200 mg of one or a combination of the water
soluble polymers, 20 mg coconut oil, 15 mg antioxidant
for the levodopa/carbidopa, 15 mg stabilizer, 10 mg
colorants and 15 mg flavouring agents and 5 m1 water.
To prepare the formulation these ingredients (in scaled-
up quantities) may be dissolved or dispersed in a
sterile brown glass container and vigorously stirred
until a uniform suspension is formed. The suspension so
formed would have a liquid consistency, suitable for
oral administration by spoon. Preferably the
consistency is about that of castor oil.
The invention is further illustrated by the
following non-limiting examples.
Example I
Two samples were prepared, each having 40 mg of L-
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dopa, 12 mg of carbidopa, 300 mg of polyethylene glycol
(PEG) and 300 mg of polysucrose (PS), mixed with 0.75 ml
distilled water, to form a suspension. The mixture was
gavaged orally to rats. Blood samples were taken from
the rats at either 30 minute or 60 minute intervals.
The blood samples were centrifuged to isolate the
plasma. The plasma was then analyzed for the L-dopa
concentration using FiPLC techniques.
It will be noted that the polymer concentration is
about 800 g/1. This is because the formulation is
intended to be given to rats, whose metabolism is far
faster than in human beings. Lower concentrations would
required for administration to humans.
A control sample was prepared from 40 mg L-dopa and
12 mg carbidopa mixed with 0.75 ml distilled water, i.e.
no polymer mixture was present. The sample was also
gavaged orally to a rat and blood samples taken and
analyzed similarly.
The results of the analyses are shown in Table I.
Table I
Time Control PEG/PS Suspension (mins.)
( ug/ml ) ( ~,g/ml )
2.0 3.0
25 60 3.5 4.1
120 6.4 4.4
180 4.2 5.8
240 2.8 5.6
300 2.5 5.2
30 360 2.2 4.8
420 1.9 4.8
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This table illustrates more controlled release of the L-
dopa when administered with the polymer suspension.
Example II
The experiment of Example I was repeated except the
suspension was made additionally with 15 mg ascorbic
acid as an antioxidant for the L-dopa and carbidopa.
After 7 weeks and the sample was gavaged to a rat.
Again, blood samples were taken and analyzed as in
Example I.
A control sample was prepared from a commercially
available tablet, crushed into powder. The sample
contained about 40 mg L-dopa and 12 mg carbidopa. No
polymer mixture was present. The sample was also
gavaged orally to a rat and blood samples taken and
analyzed similarly.
The results are shown in Table II.
Table II
Time PEG/PS Suspension Tablet Powder
(mins.) (ug/ml) (~,g/ml)
30 2,8 1.9
60 4.1 3,7
120 4.3 4.7
180 6.9 5.5
240 6.2 5.2
300 5.4 4.8
360 5.3 3.7
420 4.9 3.2
This table again illustrates extended, controlled
release of the L-dopa when administered with the polymer
suspension.
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