Note: Descriptions are shown in the official language in which they were submitted.
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PCT/TR2020/051001
A PHARMACEUTICAL FORM COMPRISING ACIDIC SUBSTANCE
Field of the Invention
The present invention relates to a pharmaceutical form comprises a core, an
acidic
substance having a pKa value of less than 6.65 and at least one binder wherein
the core is
coated with an acidic substance having a pKa value of less than 6.65 and at
least one
binder. The pharmaceutical form may use in a form of tablet or capsule as an
acidifying
agent.
Background of the Invention
Controlled release formulations of pharmaceutical agents are an extremely
large market in
the pharmaceutical and medical fields. It is well known to those skilled in
the art that
controlled release formulations which are effective in maintaining therapeutic
blood levels
over extended periods to time result in optimal therapy. They not only reduce
the frequency
of dosing for enhanced patient convenience and compliance, but they also
reduce the
severity and frequency of side effects, as they maintain substantially
constant blood levels
and avoid fluctuations associated with conventional immediate release
formulations
administered three to four times a day. The rate and extent of drug release
from most
controlled release systems are influenced by the pH of the dissolution medium
for drugs with
pH-dependent solubility.
.. Especially, organic acids can be used to control the solubility of drug by
changing the pH of
internal environment of the pharmaceutical dosage forms.
In this invention, an alternative way of using an acidic substance having a
pKa value of less
than 6.65 directly in the formulation has been found. An acidic substance
having a pKa value
of less than 6.65 pellets were prepared.
.. Nowadays, pellets are playing a dominating role in the world of
multiparticulate oral drug
delivery. Pellets are defined as spherical, free-flowing granules with a
narrow size
distribution, typically varying between 500 and 1500 mm for pharmaceutical
applications.
These pellets have many advantages over single-unit dosage forms like
controlled release.
Pellets can reduce the risk of side effect due to high drug concentration,
maximise drug
absorption, spherical shape exhibits a good flow property with narrow size
distribution.
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PCT/TR2020/051001
In this invention, the pharmaceutical form, the acidic substance having a pKa
value of less
than 6.65 pellet, was obtained. This may use in a form of tablet or capsule as
an acidifying
agent for controlled release formulations.
Thus, a pharmaceutical form has been developed that adjusts the pH of the
medium and
increases the stability of the formulation, helping to provide a good
dissolution profile.
Detailed Description of the Invention
The main objective of the invention is to provide a pharmaceutical form. When
this
pharmaceutical form is used in a formulation, it helps the formulation to
provide the desired
dissolution profile and provide the desired stability.
Another object of the present invention is to provide a pharmaceutical form
for controlled
release formulations that is effective and does not interact with other
excipients.
The term "core" will refer to a compact mass having a definite geometric shape
such as
tablets, granules, pellets, capsules.
The term 'acidic substance having a pKa value of less than 6.65 pellet' will
refer to a coated
core with acidic substance having a pKa value of less than 6.65 and at least
one excipient.
Also, it refers as pharmaceutical form in the present invention.
According to one embodiment of the present invention, a pharmaceutical form
comprises a
core, an acidic substance having a pKa value of less than 6.65 and at least
one binder
wherein the core is coated with an acidic substance having a pKa value of less
than 6.65 and
at least one binder. When the pharmaceutical form is used in the tablet or
capsule
formulation, the form is able to maintain a low pH and thus a sufficiently
high drug solubility.
By maintaining a low pH inside the pellets, a controlled drug release can be
achieved.
According to one embodiment of the present invention, the pharmaceutical form,
the acidic
substance having a pKa value of less than 6.65 pellets, may use in a form of
tablet or
capsule as an acidifying agent.
According to one embodiment of the present invention, the core is neutral
microcrystalline
cellulose pellet or sugar pellet.
According to one embodiment of the present invention, the sugar pellet is
sucrose or starch.
According to one embodiment of the present invention, an acidic substance
having a pKa
value of less than 6.65 is selected from the group comprising citric acid,
tartaric acid, malic
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acid, maleic acid, succinic acid, ascorbic acid, fumaric acid, adipic acid or
pharmaceutically
acceptable salts thereof or a mixture of thereof.
Citric acid is a weak organic acid that has the chemical formula C6H807. It
occurs naturally in
citrus fruits. In biochemistry, it is an intermediate in the citric acid
cycle, which occurs in the
metabolism of all aerobic organisms. Citric acid is used extensively for
various compositions,
pharmaceutical and otherwise. It is used widely as an acidifier, as a
flavoring and a chelating
agent.
According to one embodiment of the present invention, acidic substance having
a pKa value
of less than 6.65 is citric acid.
According to one embodiment of the present invention, preferably, the core is
neutral
microcrystalline cellulose pellet and the particle size of neutral
microcrystalline cellulose
pellet is between 0.3 mm and 0.7 mm. The neutral microcrystalline cellulose is
a suitable
core for the pharmaceutical form for having acceptable friability and high
resistance to
temperature.
According to one embodiment of the present invention, the amount of neutral
microcrystalline
cellulose pellets is between 10.0% and 40.0% by weight in the pharmaceutical
form.
According to one embodiment of the present invention, the amount of neutral
microcrystalline
cellulose pellets is between 15.0% and 37.0% or between 20.0% and 35.0% by
weight in the
pharmaceutical form.
According to one embodiment of the present invention, the amount of citric
acid is between
50.0% and 85.0% by weight in the pharmaceutical form.
According to one embodiment of the present invention, the amount of citric
acid is between
55.0% and 80.0% or between 65.0% and 75.0% by weight in the pharmaceutical
form.
According to one embodiment of the present invention, the core is free of
active agent.
Suitable binder is selected from the group comprising polyvinylpyrrolidone,
sodium
carboxymethyl cellulose, hydroxypropyl methylcellu lose, polyethylene glycol,
polyvinyl
alcohol, pregelatinized starch, glucose, natural gums, sucrose, sodium
alginate, gelatin,
carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers,
gelatin,
alginate, alginic acid, xanthan gum, hyaluronic acid, pectin, polysaccharides,
carbomer,
poloxamer, polyacrylamide, polyoxyethylene-alkyl ether, polydextrose,
polyethylene oxide or
mixtures thereof.
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According to one embodiment of the present invention, binder is
polyviylpyrrolidone.
According to one embodiment of the present invention, the amount of the binder
is between
0.5% and 10.0% by weight in the pharmaceutical form.
According to one embodiment of the present invention, the amount of the binder
is between
1.0% and 6.0% or between 1.0% and 4.0% by weight in the pharmaceutical form.
According to one embodiment of the present invention, the pharmaceutical form
further
comprises at least anti-adhesive agent which is selected from the group
comprising
magnesium stearate, calcium stearate, talc or mixtures thereof.
According to one embodiment of the present invention, the core is coated with
citric acid,
polyvinylpyrrolidone and talc.
According to one embodiment of the present invention, the particle size of
citric acid pellets is
between 0.8 mm and 1.4 mm.
According to one embodiment of the present invention, the acidic substance
having a pKa
value of less than 6.65 pellets may be prepared, using standard techniques and
manufacturing processes well known in the art, such as hot melt granulation,
hot melt
extrusion, fluidized bed granulation, extrusion/spheronization, spray drying
and solvent
evaporation.
According to one embodiment of the present invention, the acidic substance
having a pKa
value of less than 6.65 pellets are prepared with spraying by fluid bed
granulator. In this way,
it provides to obtain the desired homogeneous and stability form.
According to one embodiment of the present invention, the acidic substance
having a pKa
value of less than 6.65 pellets comprises;
- 10.0% ¨ 40.0% by weight of neutral microcrystalline cellulose pellet,
- 0.5%¨ 10.0% by weight of polyvinylpyrrolidone,
- 50.0% ¨ 85.0% by weight of acidic substance having a pKa value of less than
6.65,
- 1.0% ¨ 7.0% by weight of talc of the total the acidic substance having a
pKa value of
less than 6.65 pellets.
According to one embodiment of the present invention, the citric acid pellets
comprises;
- 10.0% ¨ 40.0% by weight of neutral microcrystalline cellulose pellet,
- 0.5%¨ 10.0% by weight of polyvinylpyrrolidone,
- 50.0% ¨ 85.0% by weight of citric acid,
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- 1.0% - 7.0% by weight of talc of the total the citric acid pellets.
According to one embodiment of the present invention, the process for the
preparation of
acidic substance having a pKa value of less than 6.65 pellets comprises steps
of:
- Adding acidic substance having a pKa value of less than 6.65,
polyvinylpyrrolidone
and talc in pure water and obtained a suspension,
- Spraying the suspension to neutral microcrystalline cellulose pellet for
coating at fluid
bed dryer,
- Obtained round acidic substance having a pKa value of less than 6.65
pellets.
According to one embodiment of the present invention, the process for the
preparation of
citric acid pellets comprises steps of:
- Adding citric acid, polyvinylpyrrolidone and talc in pure water and
obtained a
suspension,
- Spraying
the suspension to neutral microcrystalline cellulose pellet for coating at
fluid
bed dryer,
- Obtained round citric acid pellets.
According to one embodiment of the present invention, the said pharmaceutical
form
comprises citric acid to increasing the dissolution profile in weak acidic or
basic pH values.
The citric acid pellets led to a controlled release of an active agent
(solubility of its dependent
on the pH value), resulting from modulation of the microenvironmental pH
throughout the
dissolution period of 17 hours.
According to one embodiment of the present invention, an active agent may be
propiverine
or a pharmaceutically acceptable salt thereof or dabigatran or a
pharmaceutically acceptable
salt thereof.
Example 1: Citric acid pellets
Ingredients % by weight
Neutral microcrystalline cellulose pellet 10.0 ¨ 40.0
Polyvinylpyrrolidone 0.5 ¨ 10.0
Citric acid 50.0 ¨ 85.0
Talc 1.0 ¨ 7.0
TOTAL 100
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Example 2: Citric acid pellets
Ingredients % by weight
Neutral microcrystalline cellulose pellet 22.40
Polyvinylpyrrolidone 2.8
Citric acid 70.0
Talc 4.8
TOTAL 100
Process for example 1 or 2;
- Adding citric acid, polyvinylpyrrolidone and talc in pure water and
obtained a
suspension,
- Spraying the suspension to neutral microcrystalline cellulose pellet for
coating at fluid
bed dryer,
- Obtained round citric acid pellets.
Example 3: Using the above described citric acid pellets in a capsule
formulation
Ingredients % by weight
Citric acid pellets 45.0 ¨ 60.0
Propiverine hydrochloride 8.0 ¨ 20.0
Polyvinylpyrrolidone 1.0 ¨ 7.0
Citric acid 1.0 ¨ 5.0
Lactose monohydrate 1.0 ¨ 10.0
Talc 5.0 ¨ 15.0
Poly(methacrylic acid-co-methylmethacrylate)
1:2 (Eudragit S 100) 1.0 ¨ 7.0
Poly(methacrylic acid-co-methylmethacrylate)
1:1 (Eudragit L 100) 0.5 ¨ 5.0
Triethylcitrate 0.5 ¨ 5.0
Magnesium stearate 0.01 ¨ 1.0
Ethyl acrylate or methyl methacrylate or a low
content of methacrylic acid ester (Eudragit RS 1.0 ¨ 5.0
or Eudragit RL)
TOTAL 100
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Example 4: Using the above described citric acid pellets in a capsule
formulation
Ingredients % by weight
Citric acid pellets 55
Propiverine hydrochloride 14.7
Polyvinylpyrrolidone 3.8
Citric acid 2.0
Lactose monohydrate 4.0
Talc 10.0
Poly(methacrylic acid-co-methylmethacrylate)
1:2 (Eudragit S 100) 5.3
Poly(methacrylic acid-co-methylmethacrylate)
1.2
1:1 (Eudragit L 100)
Triethylcitrate 1.1
Magnesium stearate 0.1
Ethyl acrylate or methyl methacrylate or a low
content of methacrylic acid ester (Eudragit RS 2.8
or Eudragit RL)
TOTAL 100
Process for example 3 or 4;
First step;
a) Adding citric acid, polyvinylpyrrolidone, lactose monohydrate and talc in a
mixing
isopropyl alcohol-water and then, obtained a suspension,
b) Spraying the suspension to citric acid pellets for coating at fluid bed
dryer and
obtained rounded pellet 1,
Second step;
c) Adding poly(methacrylic acid-co-methylmethacrylate) 1:2 (Eudragit S 100),
poly
(methacrylic acid-co-methyl methacrylate) 1:1 (Eudragit L 100),
triethylcitrate and talc
in a mixing isopropyl alcohol-water and then, obtained a suspension,
d) Spraying the suspension to rounded pellet 1 for coating at fluid bed dryer
and obtained
rounded pellet 2,
Third step;
e) Adding propiverine hydrochloride, citric acid, polyvinylpyrrolidone, talc
and magnesium
stearate in a mixing isopropyl alcohol-water and then, obtained a suspension,
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f) Spraying the suspension to rounded pellet 2 for coating at fluid bed dryer
and obtained
rounded pellet 3,
Fourth step;
g) Adding ethyl acrylate or methyl methacrylate or a low content of
methacrylic acid ester
(Eudragit RS or Eudragit RL), poly(methacrylic acid-co-methylmethacrylate) 1:2
(Eudragit S 100), triethylcitrate and talc in a mixing isopropyl alcohol-water-
acetone
and then, obtained a suspension,
h) Spraying the suspension to granule 3 for coating at fluid bed dryer and
obtained
rounded pellet 4,
Fifth step;
i) Adding poly(methacrylic acid-co-methylmethacrylate) 1:2 (Eudragit S 100),
triethylcitrate and talc in a mixing isopropyl alcohol-water and then,
obtained a
suspension,
j) Spraying the suspension to rounded pellet 4 for coating at fluid bed dryer
and obtained
rounded pellet 5,
k) Curing the rounded pellet 5,
Sixth step;
I) Mixing the dried rounded pellet 5 and talc,
m) Filling the rounded pellets into capsule.
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