FIELD OF THE INVENTION
The present invention in general relates to the field of pharmaceutical formulations,
specifically to an injectable suspension comprising paliperidone ester (e.g., paliperidone
palmitate). In particular, the present invention relates to a process for preparing a stable
paliperidone ester injectable suspension ensuring effective redispersibility, unimodal particle
10 size distribution and resisting increase in particle size distribution (due to Ostwald ripening)
over stability.
BACKGROUND OF THE INVENTION
Paliperidone palmitate is a psychotropic agent belonging to the chemical class of
benzisoxazole derivatives with the chemical name (9RS)-3-[2-[4(6-Fluoro-1 ,2- benzisoxazol15 3-yl) piperidin-l -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4Hpyrido[1,2-a]pyrimadin-9-yl
hexadecanoate. The structural formula is as follows:
Paliperidone is currently offered in three different formulations for therapeutic use.
These include an oral extended-release formulation known as INVEGA® Extended Release
(ER) tablets, alternatively referred to as INVEGA®
20 prolonged-release (PR) tablets.
Additionally, there are three long-acting injectable (LAI) formulations available: paliperidone
palmitate one-month injection, marketed as INVEGA SUSTENNA®
or XEPLION®
,
paliperidone palmitate three-month injection, known as INVEGA TRINZA®
or TREVICTA®
and paliperidone palmitate six-month injection, known as INVEGA HAFYERA®
.
25 Paliperidone palmitate formulated as an aqueous nanosuspension is described in U.S.
Pat. Nos. 6,077,843, 6,555,544, and 6,577,545 each of which is incorporated herein by
reference.
3
5 However, injectable suspensions of paliperidone palmitate may exhibit poor solubility
or stability in solution. Further, achieving a stable suspension with desirable properties such as
particle size distribution and redispersibility remains a significant challenge.
Conventionally, wet grinding or bead milling has been utilized as a process for particle
size reduction and to obtain a desired particle size distribution in suspensions. However, these
10 processes can lead to particle agglomeration or Ostwald ripening, resulting in an increased
particle size distribution over time and reduced stability of the suspension.
Ostwald ripening is a phenomenon in which larger particles grow at the expense of
smaller particles due to differences in solubility, surface energy, or concentration gradients
within the suspension. This process can lead to the formation of larger aggregates or sediments,
15 negatively impacting the stability and efficacy of the suspension.
Hence, there is a need for an improved process to produce paliperidone ester injectable
suspension formulation that overcomes the limitations associated with particle size
distribution, redispersibility, and/or stability, specifically when employing wet grinding or
bead milling techniques.
20 Importantly, significant challenges in developing current market formulations and/or
US RLD formulations include ensuring the stability, efficacy, and/or bioequivalence of the
final product compared to the original RLD. Existing methods often encounter difficulties to
in achieving comparable physicochemical properties and therapeutic effects to those of the
RLD.
25 SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for preparing a stable
paliperidone ester injectable suspension formulation that exhibits improved redispersibility,
unimodal particle size distribution, and resistance to an increase in particle size distribution
due to Ostwald ripening. The process of the present invention allows to produce a stable
30 floccule of paliperidone palmitate injectable suspension.
In an aspect, the process comprises wet milling a premix slurry comprising
paliperidone ester to obtain a milled suspension; and subjecting the milled suspension to heat
treatment to produce a stable floccule of paliperidone palmitate injectable suspension.
4
5 In a further aspect, the premix slurry is obtained by a single-phase manufacturing
process or a two-phase manufacturing process.
In an aspect, the process comprises wet milling a premix slurry comprising
paliperidone ester to obtain a milled suspension; and subjecting the milled suspension to heat
treatment to produce a stable floccule of paliperidone palmitate injectable suspension; wherein
10 the premix slurry is obtained by a single-phase manufacturing process that combines all the
constituents of the slurry.
The paliperidone ester injectable suspension formulation prepared by the present
invention addresses one or more challenges known in the art. In one aspect, the formulation
demonstrates specifications comparable to those of the RLD, including stability, particle size
15 distribution, dispersibility, and/or pharmacokinetic profile.
In an aspect, the formulation obtained by the process of the present invention is stable
over the shelf life and shows comparable pharmacokinetic profile with RLD Invega Trinza®
in
pre-clinical dog pharmacokinetic model.
BRIEF DESCIRPTION OF THE DRAWING
20 Figure 1 illustrates a schematic representation of the manufacturing process flow chart
(Approach-II) of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
At the very outset of the detailed description, it may be understood that the ensuing
description only illustrates a particular form of this invention. However, such a particular form
25 is only exemplary embodiment, and without intending to imply any limitation on the scope of
this invention. Accordingly, the description is to be understood as an exemplary embodiment
and teaching of invention and not intended to be taken restrictively.
It is also to be understood that the terminology used herein is for the purpose of
describing particular embodiments only and is not intended to limit the present disclosure.
30 Where a range of values is provided, it is understood that each intervening value, to the
tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the
upper and lower limit of that range and any other stated or intervening value in that stated
range, is encompassed within the process. The upper and lower limits of these smaller ranges
5
5 may independently be included in the smaller ranges and are also encompassed within the
process, subject to any specifically excluded limit in the stated range. Where the stated range
includes one or both of the limits, ranges excluding either or both of those included limits are
also included in the process.
Certain ranges are presented herein with numerical values being preceded by the term
10 “about”. The term “about” is used herein to provide literal support for the exact number that it
precedes, as well as a number that is near to or approximately the number that the term
precedes. In determining whether a number is near to or approximately a specifically recited
number, the near or approximating unrecited number may be a number which, in the context
in which it is presented, provides the substantial equivalent of the specifically recited number.
15 In an embodiment, “about” can mean within one or more standard deviations, or within ± 30%,
25%, 20%, 15%, 10% or 5% of the stated value.
Unless defined otherwise, all technical and scientific terms used herein have the same
meaning as commonly understood by those of ordinary skill in the art to which the invention
belongs. Although any process and materials similar or equivalent to those described herein
20 can be used in the practice or testing of the present invention, preferred process and materials
are described. For the purposes of the present invention, the following terms are defined below.
The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at
least one) of the grammatical object of the article. By way of example, “an element” means
one element or more than one element.
25 The term 'at least one' refers to the requirement for the presence of a specified element,
component, or feature within an invention, while allowing for the possibility of additional
instances. For instance, in the phrase 'at least one pharmaceutically acceptable excipient,' it
indicates that the composition must contain at least one excipient meeting pharmaceutical
standards. This provision accommodates variations in the specific excipients used, ensuring
30 that the claimed invention encompasses compositions containing one or more such excipients.
As used herein, the term “comprises” or “comprising” is generally used in the sense to
include, that is to say permitting the presence of one or more features or components.
The term “excipient(s)” is used to describe an inert substance that is added to a
pharmaceutical composition to make it easier to administer the active ingredient. This can
35 include a range of substances, such as citric acid or its hydrate, sodium dihydrogen phosphate
6
5 monohydrate, disodium hydrogen phosphate anhydrous, sodium hydroxide, polysorbate 20 and
polyethylene glycol 4000.
The term “formulation” or “composition” refers to a stable pharmaceutical formulation
of paliperidone palmitate described herein with a pharmaceutically acceptable carrier and/or
excipient.
10 The term “pharmaceutically acceptable carrier” refers to a substance that is used as a
carrier, adjuvant, or diluent in the formulation of a drug, but does not cause significant irritation
to the body or interfere with the biological activity of the drug.
As used herein, the term "US RLD" refers to a "United States Reference Listed Drug."
A US RLD is an approved drug product that has been designated by the Food and Drug
15 Administration (FDA) as the standard to which new generic versions are compared to
demonstrate bioequivalence. In an embodiment, the “US RLD” referred to in the specification
refers to Invega Sustenna®, Invega Trinza®, or Invega Hafyera®.
As used herein, the term “bead mill” refers to a type of grinder or mill used to reduce
particle size by agitating beads within a chamber.
20 The term “subject” includes mammals (especially humans) and other animals, such as
domestic animals (e.g., household pets including cats and dogs) and non-domestic animals
(such as wildlife).
Each embodiment is provided by way of explanation of the invention and not by way
of limitation of the invention. In fact, it will be apparent to those skilled in the art that various
25 modifications and variations can be made to the compounds, and process described herein
without departing from the scope or spirit of the invention. For instance, features illustrated or
described as part of one embodiment can be applied to another embodiment to yield a still
further embodiment. Thus, it is intended that the present invention includes such modifications
and variations and their equivalents.
30 Other objects feature, and aspects of the present invention are disclosed in or are
obvious from, the following detailed description. It is to be understood by one of ordinary skill
in the art that the present discussion is a description of exemplary embodiments only and is not
to be construed as limiting the broader aspects of the present invention.
7
5 In an embodiment, the present invention provides a process for preparing a stable
paliperidone ester injectable suspension formulation, the process comprises:
- wet milling a premix slurry comprising paliperidone ester and at least one
pharmaceutically acceptable carrier or excipient to obtain a milled suspension; and
- subjecting the milled suspension to heat treatment to produce a stable floccule of
10 paliperidone palmitate injectable suspension.
In certain embodiments, the premix slurry is obtained by a single -phase manufacturing
process or a two -phase manufacturing process. Single-phase manufacturing process refers to
a process where all components or materials involved remain in a single homogeneous phase
throughout the manufacturing process. For instance, in an embodiment, in a single-phase
15 manufacturing process, the premix slurry is obtained by combining all the constituents of the
slurry at room temperature under stirring. Two-phase manufacturing process involves a process
where there are two distinct phases involved during manufacturing.
In certain embodiments, the premix comprises paliperidone ester, at least one surfactant
or a wetting agent, at least one suspending agent, and at least one anti-oxidant.
20 In certain embodiments, the premix comprises about 10% to about 40% of paliperidone
ester, about 0.1% to about 10% of at least one surfactant, about 1% to about 15% of at least
one suspending agent, and about 0.1% to about 3% of at least one anti-oxidant.
In certain embodiments, the premix further comprises at least one buffering agent, a pH
adjuster and at least one vehicle. In some instance, the premix further comprises two buffering
25 agents.
In certain embodiments, the premix comprises about 0.1% to about 1% of at least one
buffering agent, about 0.1% to about 1% of a pH adjuster and about 40% to about 80% of at
least one vehicle.
In certain embodiments, the premix comprises about 10% to about 40% of paliperidone
30 ester, about 0.1% to about 10% of at least one surfactant, about 1% to about 15% of at least
one suspending agent, about 0.1% to about 3% of at least one anti-oxidant, about 0.1% to about
1% of at least one buffering agent, about 0.1% to about 1% of a pH adjuster and about 40% to
about 80% of at least one vehicle.
In certain embodiments, paliperidone ester is paliperidone palmitate.
8
5 In certain embodiments, paliperidone ester is present in an amount from about 10% to
about 40%.
In certain embodiments, the surfactant or wetting agent is selected from a group
comprising polysorbate 20, polysorbate 80, lecithin, polyoxyethylene- and polyoxypropylene
ethers, sodium deoxycholate, sodium lauryl sulphate, sorbitan fatty acid esters and any
10 combination thereof. In some embodiments, the surfactant is polysorbate 20. In some instances,
surfactant or wetting agent having no peroxide. In some instances, surfactant or wetting agent
having low or no peroxide is used. In further instances, super refined grade surfactant or wetting
agent (super refined grade polysorbate 20) is used to formulate the suspension. In further
instances, super refined grade polysorbate 20 may provide advantages in maintaining stability
15 by exhibiting no color changes during long-term storage.
In some embodiments, the surfactant is present in an amount from about 0.1% to about
10%.
In certain embodiments, the surfactant or wetting agent comprises a peroxide value of
up to about 2 meqO2/Kg. In further embodiments, the surfactant or wetting agent has a peroxide
20 value of about 2 meqO2/Kg or lower, about 1.5 meqO2/Kg or lower, about 1 meqO2/Kg or
lower, or about 0.5 meqO2/Kg or lower. In some instances, the surfactant or wetting agent has
a peroxide value of about 0.43 meqO2/Kg or lower. In further instances, polysorbate such as
polysorbate-20 having a peroxide value of about 0.43 meqO2/Kg or lower may be used in the
invention.
25 In certain embodiments, the suspending agent is selected from a group comprising
methyl cellulose, sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose,
polyvinylpyrrolidone, alginates, chitosan, xanthan gum, dextrans, gelatin, polyethylene glycol,
polyoxyethylene ether, and polyoxypropylene ethers and any combination thereof. In some
embodiments, the suspending agent is polyethylene glycol 4000.
30 In certain embodiments, the suspending agent is present in an amount from about 1%
to about 15%.
In certain embodiments, the anti-oxidant is selected from a group comprising citric acid
or its hydrate, citric acid monohydrate, ascorbic acid, tartaric acid, tertiary butyl
hydroquinones, tocopherol, methionine, sodium metabisulfite, potassium metabisulfite,
35 benzoic acid, butylated hydroxyanisole, butylated hydroxytoluene, a gallate, a
9
5 hydroxybenzoate, EDTA, and any combination thereof. In some embodiments, the hydrate
forms of citric acid are either citric acid monohydrate or citric acid dihydrate, depending on
whether one or two molecules of water are associated with each molecule of citric acid.
In some embodiments, the anti-oxidant is citric acid monohydrate.
In some embodiments, the anti-oxidant is present in an amount from about 0.1% to
10 about 3%.
In certain embodiments, the buffering agent is selected from a group comprising
acetate, citrate, phosphate, glutamate and any combination thereof. In certain embodiments,
the paliperidone ester injectable suspension formulation comprises one buffering agent. In
further embodiments, the paliperidone ester injectable suspension formulation comprises two
15 buffering agents. In some embodiments, the buffering agent is phosphate. Examples, phosphate
buffer include, but are not limited to, sodium dihydrogen phosphate, sodium dihydrogen
phosphate hydrate (such as sodium dihydrogen phosphate monohydrate and the like), disodium
monohydrogen phosphate anhydrous, and the like. In some instances, the buffering agent is
sodium dihydrogen phosphate monohydrate. In some instances, the buffering agent is disodium
20 hydrogen phosphate anhydrous. In some instances, the buffering agent is sodium dihydrogen
phosphate monohydrate or disodium hydrogen phosphate anhydrous or combination thereof.
In certain embodiments, the buffering agent is present in an amount from about 0.1%
to about 1%.
In certain embodiments, the pH adjuster is a base. In some embodiments, the base is
25 selected from a group comprising an alkali metal salt of a hydroxide, an alkaline earth metal
salt of a hydroxide, alkali metal salt of a carbonate, an alkaline earth metal salt of a carbonate,
an alkali metal salt of a bicarbonate, an alkaline earth metal salt of a bicarbonate, an alkali
metal salt of a sesquicarbonate, an alkaline earth metal salt of a sesquicarbonate, an ammonium
salt of a carbonate, an ammonium salt of a bicarbonate, an ammonium salt of a sesquicarbonate,
30 and any combination thereof. In some embodiments, the base is sodium hydroxide.
In some embodiments, the pH adjuster is an alkali metal salt of a hydroxide. In some
embodiments, the pH adjuster is sodium hydroxide.
In certain embodiments, the pH adjuster is present in an amount from about 0.1% to
about 1%.
10
5 In certain embodiments, the vehicle is selected from a group comprising, water, saline,
and alcohol. In certain embodiments, alcohol is selected from ethanol or isopropyl alcohol. In
some embodiments, the vehicle is water.
In certain embodiments, the vehicle is present in an amount from about 40% to about
80%.
10 In certain embodiments, the premix slurry is obtained by the single-phase
manufacturing process comprising the step of dissolving at least one anti-oxidant, at least one
buffering agent, at least one base, at least one surfactant and at least one suspending agent into
water for injection at room temperature under stirring, and adding the paliperidone ester under
stirring/homogenization to produce a homogenous slurry of paliperidone ester particles. In
15 certain embodiments, the method comprises stirring the mixture at a speed of about 500 rpm
to about 10000 rpm to achieve optimal dispersion of components. In certain embodiments,
homogenization is performed using high shear forces at a rate sufficient to reduce particle size.
In some embodiments, the process comprises controlling agitation speed and duration to ensure
uniform distribution of constituents throughout the mixture.
20 In certain embodiments, in the single-phase manufacturing process, citric acid
monohydrate, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate
anhydrous, sodium hydroxide, polysorbate-20 and polyethylene glycol 4000 are dissolved in
water for injection at room temperature under stirring, and the paliperidone ester is added under
stirring/homogenization to produce a homogenous slurry of paliperidone ester particles. In
25 certain embodiments, the stirring is done for about 30 to 120 mins.
In certain embodiments, in the single-phase manufacturing process, citric acid
monohydrate, sodium dihydrogen phosphate monohydrate, sodium hydroxide, polysorbate-20
and polyethylene glycol 4000 are dissolved in water for injection at room temperature under
stirring, and the paliperidone ester is added under stirring/homogenization to produce a
30 homogenous slurry of paliperidone ester particles. In certain embodiments, the stirring is done
for about 30 to 120 mins.
In certain embodiments, the premix slurry is obtained by the two-phase manufacturing
process comprising surfactant phase and buffer phase.
In certain embodiments, in the surfactant phase, at least one surfactant is dissolved in
35 water for injection at room temperature followed by the dispersing the paliperidone ester API
11
5 under stirring/homogenization to produce the homogenous slurry of paliperidone ester
particles. In certain embodiments, the stirring is done for about 2000 to 5000 rpm for about 30
to 120 mins.
In some embodiments, in the surfactant phase, polysorbate-20 is dissolved in water for
injection at room temperature followed by the dispersing the paliperidone palmitate API under
10 stirring/homogenization to produce the homogenous slurry of paliperidone palmitate particles.
In certain embodiments, the stirring is done for about 2000 to 5000 rpm for about 30 to 120
mins.
In certain embodiments, in the buffer phase, at least one anti-oxidant, at least one
buffering agent, at least one base, and at least one suspending agent are dissolved in water for
15 injection at room temperature under stirring. In certain embodiments, the stirring is done for
about 500 to 2000 rpm for about 15 to 60 mins.
In some embodiments, in the buffer phase, citric acid monohydrate, sodium dihydrogen
phosphate monohydrate, sodium hydroxide and polyethylene glycol 4000 are dissolved in
water for injection at room temperature under stirring. In certain embodiments, the stirring is
20 done for about 500 to 2000 rpm for about 15 to 60 mins.
In certain embodiments, in the two-phase manufacturing process, the surfactant phase
is subjected to wet grinding using beads through bead mill and adding the buffer phase into it
to produce the final suspension.
In certain embodiments, the milling is done using milling media comprising beads.
25 In certain embodiments, the beads are in size of about 0.3 mm to about 6.0 mm.
In certain embodiments, the milling step lasts from about 1 minute to about 300
minutes.
In certain embodiments, the milled suspension is subjected to heat treatment under
stirring at about 40°C to about 115°C. In some embodiments, the milled suspension is subjected
30 to heat treatment under stirring at about 40°C, about 45°C, about 50°C, about 55°C about
60°C, about 65°C about 70°C, about 75°C about 80°C, about 85°C about 90°C, about 95°C
about 100°C, about 105°C, about 100°C, or about 115°C. In some instance, the milled
suspension is subjected to heat treatment under stirring at about 50°C or 60°C.
12
5 In certain embodiments, the milled suspension is subjected to heat treatment under
stirring for about 0.5h to about 6h. In some embodiments, the milled suspension is subjected
to heat treatment under stirring for about 0.5 hour, about 1 hour, about 2 hours, about 3 hours,
about 4 hours, about 5 hours, or about 6 hours. In some embodiments, the milled suspension is
subjected to heat treatment under stirring for about 3 hours.
10 In an embodiment, the present invention provides, a paliperidone ester injectable
suspension formulation obtained by the process of the present invention.
In some embodiments, the paliperidone ester injectable suspension formulation is
stable.
In an embodiment, the present invention provides a process for preparing a stable
15 paliperidone ester injectable suspension formulation, the process comprises:
• wet milling a premix slurry comprising paliperidone ester and at least one
pharmaceutically acceptable carrier or excipient to obtain a milled suspension;
• subjecting the milled suspension to heat treatment to produce a stable floccule of
paliperidone palmitate injectable suspension;
20 wherein the premix slurry is obtained by a single-phase manufacturing process that
combines all the constituents of the slurry, or by a two-phase manufacturing process.
In certain embodiments, the premix comprises paliperidone ester, and at least one
pharmaceutically acceptable carrier or excipient.
In certain embodiments, the premix comprises paliperidone ester, at least one
25 surfactant, and a pharmaceutically acceptable excipient.
In certain embodiments, the premix comprises paliperidone ester, at least one surfactant
or wetting agent, at least one suspending agent, at least one anti-oxidant, at least one buffering
agent, a pH adjuster, and at least one vehicle. The paliperidone ester, surfactant or wetting
agent, suspending agent, anti-oxidant, buffering agent, pH adjuster and vehicle are as defined
30 in the preceding embodiments.
In certain embodiments, the distribution of polysorbate-20 over storage have a
satisfactory redispersibility behaviour.
13
5 In certain embodiments, the premix comprises paliperidone palmitate, polysorbate 20,
citric acid monohydrate, disodium hydrogen phosphate anhydrous, polyethylene glycol 4000,
sodium dihydrogen phosphate monohydrate, sodium hydroxide, and water for injection.
In certain embodiments, the premix comprises paliperidone palmitate, polysorbate 20,
citric acid monohydrate, polyethylene glycol 4000, sodium dihydrogen phosphate
10 monohydrate, sodium hydroxide, and water for injection.
In certain embodiments, the paliperidone palmitate injectable suspension comprises
paliperidone palmitate, polysorbate 20, citric acid monohydrate, disodium hydrogen phosphate
anhydrous, polyethylene glycol 4000, sodium dihydrogen phosphate monohydrate, sodium
hydroxide, and water. In some embodiments, the paliperidone palmitate injectable suspension
15 comprises about 10% to about 40% of paliperidone palmitate, about 0.1% to about 10%
polysorbate 20, about 0.1% to about 3% citric acid monohydrate, about 1% to about 15%
polyethylene glycol 4000, about 0.1% to about 1% sodium dihydrogen phosphate
monohydrate, about 0.1% to about 1% disodium hydrogen phosphate anhydrous, about 0.1%
to about 1% sodium hydroxide, and about 40% to about 80% water.
20 In some embodiments, the paliperidone palmitate injectable suspension comprises
about 10% to about 40% of paliperidone palmitate, about 0.1% to about 10% polysorbate 20,
about 0.1% to about 3% citric acid monohydrate, about 1% to about 15% polyethylene glycol
4000, about 0.1% to about 1% sodium dihydrogen phosphate monohydrate, about 0.1% to
about 1% sodium hydroxide, and about 40% to about 80% water.
25 In certain embodiments, the paliperidone palmitate injectable suspension comprises
paliperidone palmitate, polysorbate 20, citric acid monohydrate, disodium hydrogen phosphate
anhydrous, polyethylene glycol 4000, sodium dihydrogen phosphate monohydrate, sodium
hydroxide, and water. In some embodiments, the paliperidone palmitate injectable suspension
comprises about 10% to about 40% of paliperidone palmitate, about 0.1% to about 10%
30 polysorbate 20, about 0.1% to about 3% citric acid monohydrate, about 1% to about 15%
polyethylene glycol 4000, about 0.1% to about 1% sodium dihydrogen phosphate
monohydrate, about 0.1% to about 1% sodium hydroxide, and about 40% to about 80% water.
In an embodiment, the present invention provides a process for preparing a stable
paliperidone ester injectable suspension formulation; wherein the process comprises:
14
5 • wet milling a premix slurry comprising paliperidone ester, at least one surfactant,
at least one suspending agent, at least one anti-oxidant, at least one buffering agent,
a pH adjuster and at least one vehicle to obtain a milled suspension; and
• subjecting the milled suspension to heat treatment to produce a stable floccule of
paliperidone palmitate injectable suspension;
10 wherein the premix slurry is obtained by a single-phase manufacturing process that
combines all the constituents of the slurry, or by a two-phase manufacturing process.
In an embodiment, the present invention provides a process for preparing a stable
paliperidone ester injectable suspension formulation; wherein the process comprises:
• wet milling a premix slurry comprising paliperidone ester, at least one surfactant,
15 at least one suspending agent, at least one anti-oxidant, at least one buffering agent,
a pH adjuster and at least one vehicle to obtain a milled suspension; and
• subjecting the milled suspension to heat treatment to produce a stable floccule of
paliperidone palmitate injectable suspension;
wherein the premix slurry is obtained by a single-phase manufacturing process that
20 combines all the constituents of the slurry.
In another embodiment, the present invention provides a process for preparing a stable
paliperidone palmitate injectable suspension formulation; wherein the process comprises:
• wet milling a premix slurry prepared by a single-phase manufacturing process
comprising the step of adding citric acid monohydrate, sodium dihydrogen
25 phosphate monohydrate, sodium hydroxide, polysorbate-20 and polyethylene
glycol 4000 into water for injection at room temperature under stirring and adding
the paliperidone palmitate under stirring/homogenization to produce a homogenous
slurry of paliperidone palmitate particles to obtain a milled suspension; and
• subjecting the milled suspension to heat treatment to produce a stable floccule of
30 paliperidone palmitate injectable suspension.
In another embodiment, the present invention provides a process for preparing a stable
paliperidone palmitate injectable suspension formulation; wherein the process comprises:
15
5 • wet milling a premix slurry prepared by a single-phase manufacturing process
comprising the step of adding citric acid monohydrate, sodium dihydrogen
phosphate monohydrate, sodium hydroxide, polysorbate-20 and polyethylene
glycol 4000 into water for injection at room temperature under stirring and adding
the paliperidone palmitate under stirring/homogenization to produce a homogenous
10 slurry of paliperidone palmitate particles to obtain a milled suspension; and
• subjecting the milled suspension to heat treatment at a temperature of 40°C or more
to produce a stable floccule of paliperidone palmitate injectable suspension.
In another embodiment, the present invention provides a process for preparing a stable
paliperidone palmitate injectable suspension formulation; wherein the process comprises:
15 • wet milling a premix slurry prepared by a single-phase manufacturing process
comprising the step of adding citric acid monohydrate, sodium dihydrogen
phosphate monohydrate, sodium hydroxide, polysorbate-20 and polyethylene
glycol 4000 into water for injection at room temperature under stirring and adding
the paliperidone palmitate under stirring/homogenization to produce a homogenous
20 slurry of paliperidone palmitate particles to obtain a milled suspension; and
• subjecting the milled suspension to heat treatment at a temperature of 50°C or 60°C
to produce a stable floccule of paliperidone palmitate injectable suspension.
In an embodiment, the present invention provides a process for preparing a stable
paliperidone ester injectable suspension formulation; wherein the process comprises:
25 • wet milling a premix slurry comprising paliperidone ester, at least one surfactant,
at least one suspending agent, at least one anti-oxidant, at least one buffering agent,
a pH adjuster and at least one vehicle to obtain a milled suspension; and
• subjecting the milled suspension to heat treatment to produce a stable floccule of
paliperidone palmitate injectable suspension;
30 wherein the premix slurry is obtained by a two-phase manufacturing process.
In another embodiment, the present invention provides a process for preparing a stable
paliperidone palmitate injectable suspension formulation; wherein the process comprises:
• wet milling a premix slurry prepared by the two-phase manufacturing process
comprising surfactant phase and buffer phase; wherein, in the surfactant phase,
16
5 polysorbate-20 is dissolved in water for injection at room temperature followed by
dispersing the paliperidone palmitate API under stirring/homogenization to produce
the homogenous slurry of paliperidone palmitate particles, and in the buffer phase,
citric acid monohydrate, sodium dihydrogen phosphate monohydrate, sodium
hydroxide and polyethylene glycol 4000 are dissolved in water for injection at room
10 temperature under stirring to obtain a milled suspension; and
• subjecting the milled suspension to heat treatment to produce a stable floccule of
paliperidone palmitate injectable suspension.
In another embodiment, the present invention provides a process for preparing a stable
15 paliperidone palmitate injectable suspension formulation; wherein the process comprises:
• wet milling a premix slurry prepared by the two-phase manufacturing process
comprising surfactant phase and buffer phase; wherein, in the surfactant phase,
polysorbate-20 is dissolved in water for injection at room temperature followed by
dispersing the paliperidone palmitate API under stirring/homogenization to produce
20 the homogenous slurry of paliperidone palmitate particles, and in the buffer phase,
citric acid monohydrate, sodium dihydrogen phosphate monohydrate, sodium
hydroxide and polyethylene glycol 4000 are dissolved in water for injection at room
temperature under stirring to obtain a milled suspension; and
• subjecting the milled suspension to heat treatment at a temperature of 40°C or more
25 to produce a stable floccule of paliperidone palmitate injectable suspension.
In another embodiment, the present invention provides a process for preparing a stable
paliperidone palmitate injectable suspension formulation; wherein the process comprises:
• wet milling a premix slurry prepared by the two-phase manufacturing process
comprising surfactant phase and buffer phase; wherein, in the surfactant phase,
30 polysorbate-20 is dissolved in water for injection at room temperature followed by
dispersing the paliperidone palmitate API under stirring/homogenization to produce
the homogenous slurry of paliperidone palmitate particles, and in the buffer phase,
citric acid monohydrate, sodium dihydrogen phosphate monohydrate, sodium
hydroxide and polyethylene glycol 4000 are dissolved in water for injection at room
35 temperature under stirring to obtain a milled suspension; and
17
5 • subjecting the milled suspension to heat treatment at a temperature of 50°C or 60°C
to produce a stable floccule of paliperidone palmitate injectable suspension.
In certain embodiments, the present invention provides a process for preparing a stable
floccule of paliperidone ester injectable suspension formulation comprising about 10% to about
40% of paliperidone ester, about 0.1% to about 10% of at least one surfactant, about 1% to
10 about 15% of at least one suspending agent, about 0.1% to about 3% of at least one anti-oxidant,
about 0.1% to about 1% of at least one buffering agent, about 0.1% to about 1% of a pH adjuster
and of at least one vehicle about 40% to about 80%; wherein the process comprises:
• wet milling a premix slurry comprising paliperidone ester, at least one surfactant,
at least one suspending agent, at least one anti-oxidant, at least one buffering agent,
15 a pH adjuster and at least one vehicle to obtain a milled suspension; and
• subjecting the milled suspension to heat treatment to produce a stable floccule of
paliperidone palmitate injectable suspension;
wherein the premix slurry is obtained by a single-phase manufacturing process that
combines all the constituents of the slurry.
20 In certain embodiments, the present invention provides a process for preparing a stable
floccule of paliperidone ester injectable suspension formulation comprising about 10% to about
40% of paliperidone ester, about 0.1% to about 10% of at least one surfactant, about 1% to
about 15% of at least one suspending agent, about 0.1% to about 3% of at least one anti-oxidant,
about 0.1% to about 1% of at least one buffering agent, about 0.1% to about 1% of a pH adjuster
25 and of at least one vehicle about 40% to about 80%; wherein the process comprises:
- wet milling a premix slurry comprising paliperidone ester, at least one surfactant, at
least one suspending agent, at least one anti-oxidant, two buffering agent, a pH adjuster
and at least one vehicle to obtain a milled suspension; and
- subjecting the milled suspension to heat treatment to produce a stable floccule of
30 paliperidone palmitate injectable suspension;
wherein the premix slurry is obtained either by a single-phase manufacturing process
that combines all the constituents of the slurry, or by a two-phase manufacturing process.
Premix Slurry:
18
5 In an embodiment, the premix slurry is obtained by a single-phase manufacturing
process that combines all the constituents of the slurry, or by a two-phase manufacturing
process. The single-phase manufacturing process mMeans all the constituents of the premix
slurry are mixed in a single step.
In certain embodiments, two-phase manufacturing process comprises preparing a
10 paliperidone ester API slurry in the first phase, which undergoes a wet milling process to
achieve the target particle size. Once the target particle size is achieved, a second aqueous
phase is mixed with the first phase to yield the final product. For instance, in certain
embodiments, the premix slurry is obtained by a two-phase manufacturing process comprising
a surfactant phase and a buffer phase.
15 In certain embodiments, in the surfactant phase, at least one surfactant is dissolved in
water for injection at room temperature followed by the dispersing the paliperidone ester API
under stirring/homogenization to produce the homogenous slurry of paliperidone ester
particles. In certain embodiments, the stirring is done for about 30 to 120 mins. In some
embodiments, in the surfactant phase, polysorbate-20 is dissolved in water for injection at room
20 temperature followed by the dispersing the paliperidone palmitate API under
stirring/homogenization to produce the homogenous slurry of paliperidone palmitate particles.
In certain embodiments, the stirring is done for about 30 to 120 mins.
In certain embodiments, in the buffer phase, at least one anti-oxidant, at least one
buffering agent, at least one base, and at least one suspending agent are dissolved in water for
25 injection at room temperature under stirring. In certain embodiments, the stirring is done for
about 15 to 60 mins. In some embodiments, in the buffer phase, citric acid monohydrate,
sodium dihydrogen phosphate monohydrate, sodium hydroxide and polyethylene glycol 4000
are dissolved in water for injection at room temperature under stirring. In certain embodiments,
the stirring is done for about 15 to 60 mins.
30 In certain embodiments, in the two-phase manufacturing process, the surfactant phase
is subjected to wet grinding using beads in a bead mill, followed by the addition of the buffer
phase to produce the final suspension.
In certain embodiments, the premix slurry comprises paliperidone ester, and at least
one pharmaceutically acceptable carrier or excipient. In certain embodiments, the premix slurry
35 comprises paliperidone ester, at least one surfactant, at least one suspending agent, at least one
19
5 anti-oxidant, at least one buffering agent, a pH adjuster and at least one vehicle. The
paliperidone ester, at least one surfactant, at least one suspending agent, at least one antioxidant, at least one buffering agent, a pH adjuster and at least one vehicle are same as defined
above.
In certain embodiments, in the single-phase manufacturing process, citric acid
10 monohydrate, sodium dihydrogen phosphate monohydrate, sodium hydroxide, polysorbate-20
and polyethylene glycol 4000 are dissolved in water for injection at room temperature under
stirring. The paliperidone ester is added under stirring/homogenization to produce homogenous
slurry of paliperidone ester particles. In certain embodiments, in the single-phase
manufacturing process, citric acid monohydrate, sodium dihydrogen phosphate monohydrate,
15 disodium hydrogen phosphate anhydrous, sodium hydroxide, polysorbate-20 and polyethylene
glycol 4000 are dissolved in water for injection at room temperature under stirring. The
paliperidone ester is added under stirring/homogenization to produce homogenous slurry of
paliperidone ester particles.
Wet Milling:
20 In an embodiment, the process comprises wet milling the premix slurry to form a milled
suspension. The milling process utilizes milling media, which comprises beads. Examples of
suitable beads include, but are not limited to, zirconium, polystyrene, stainless steel, zirconium
silicate, zirconium oxide, glass, ceramic material, copper, silicon carbide, porcelain, quartz,
aluminum oxide and the like. In certain embodiments, the milling media comprises zirconium
25 beads and/or polymeric polystyrene beads. The size of the beads can vary depending on the
desired particle distribution, ranging from about 0.3 mm to 6.0 mm.
In certain embodiments, the milling process is employed to reduce the size of the
paliperidone ester to achieve the desired particle size distribution. The particle size distribution
is carefully controlled to ensure satisfactory dosage content uniformity, dissolution profiles,
30 and/or a controlled release profile. The particle size distribution may range from about 0.2 µm
to about 200 µm. In certain embodiments, the milling process is employed to reduce the size
of the paliperidone ester to achieve the desired particle size distribution. The particle size
distribution is carefully controlled to ensure satisfactory dosage content uniformity, dissolution
profiles, and/or a controlled release profile. The particle size distribution may range from about
35 0.5 µm to about 200 µm.
20
5 The time required for the milling step may vary depending on the components of the
suspension and the total amount of suspension prepared. In certain embodiments, the milling
step may last from about 1 minute to about 300 minutes. In some embodiments, the milling
step may last for about 1 minute, about 10 minutes, about 20 minutes, about 30 minutes, about
40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90
10 minutes, about 100 minutes, about 110 minutes, about 120 minutes, 130 minutes, about 140
minutes, about 150 minutes, about 160 minutes, about 170 minutes, about 180 minutes, about
190 minutes, about 200 minutes, about 210 minutes, about 220 minutes, 230 minutes, about
240 minutes, about 250 minutes, about 260 minutes, about 270 minutes, about 280 minutes,
about 290 minutes, or about 300 minutes.
15 The temperature at which the milling step is conducted may vary depending on the
specific active pharmaceutical ingredient (API) being processed. In certain embodiments, the
milling step may take place at a temperature ranging from about 40°C to about 115 °C. In
certain embodiments, the milling step may take place at a temperature ranging from about 40°C
to about 70 °C. In some embodiments, the milling step may occur at room temperature or
20 about 20-30°C.
The tip speed during the milling step may vary based on factors such as the mill used,
media milling size, and the desired final particle size distribution. In certain embodiments, the
milling speed may range from about 1 m/s to about 30 m/s. In some embodiments, the milling
speed is predetermined to ensure effective particle size reduction and achieve desired results.
25 Heat treatment of the milled suspension:
In certain embodiments, subjecting the milled suspension to heat treatment to produce
a stable floccule of paliperidone palmitate injectable suspension.
Increase in particle size is a common phenomenon observed over stability in case of
suspension formulations. The increase in particle size is due to the dissolution of fine drug
30 particles and their deposition over the large particles. The dissolution of the fine particles is
majorly due to heat imparted to the suspending particle by the storage temperature. Increase in
particle size is an undesirable phenomenon as it impacts syringe ability, redispersibility and
most importantly it deviates intended drug release pattern which is governed through particle
size distribution.
21
5 In one embodiment, moderate heat treatment of the milled suspension is incorporated
into the manufacturing process to facilitate the acceleration of particle size increase. By
introducing the heat treatment, the number of fines is reduced, leading to improved product
quality. Additionally, this approach helps limit excessive particle size increase over time,
ensuring stability is maintained. The effect of different combinations of heat and time was
10 investigated in relation to particle size increase during the heat treatment and its impact on
stability.
In certain embodiments, the milled suspension is subjected to heat treatment under
stirring at about 40°C or more. In some embodiments, the milled suspension is subjected to
heat treatment under stirring at more than about 50°C. In some embodiments, the milled
15 suspension is subjected to heat treatment under stirring at more than about 50°C but not beyond
the melting point of the paliperidone ester. In some instances, the milled suspension is
subjected to heat treatment at about 40°C to about 115°C for about 0.5h to about 6h.
In some embodiments, the milled suspension is subjected to heat treatment under
stirring at about 50 °C or about 60 °C for about 3h.
20 In certain embodiments, the milling step may take place at a temperature ranging from
about 40°C to about 70 °C.
In certain embodiments, the milling step may take place at a temperature ranging from
50°C± 5°C or about 60°C ± 5°C.
In certain embodiments, the milling step may take place at a temperature of 45°C, 55°C,
25 or 65°C.
In certain embodiments, the process disclosed in the present invention produces a stable
suspension with unimodal particle distribution that is easy to redisperse and avoids increase in
particles size on stability.
The stability of paliperidone palmitate injectable suspension is studied and narrowed
30 down to low peroxide value of polysorbate-20, distribution of polysorbate-20 over paliperidone
palmitate particles and aqueous phase and avoiding Ostwald ripening on course of stability.
The optimized formulation is stable over the shelf life and shows comparable
pharmacokinetic profile with reference-listed drug Invega Trinza®
in pre-clinical dog
pharmacokinetic model.
22
5 In one embodiment the present invention provides a single-phase manufacturing
process wherein, citric acid monohydrate, sodium dihydrogen phosphate monohydrate, sodium
hydroxide, polysorbate 20 and polyethylene glycol 4000 dissolved in water followed by API
(paliperidone palmitate) dispersion by stirring/ homogenization to form premix slurry. The
premix slurry subjected to wet grinding using bead milling to yield target particle size
10 distribution PSD. The milled suspension is subjected to heating for specified temperature and
time. Post-mill suspension is filled into pre-filled syringes.
In one embodiment the present invention provides a single-phase manufacturing
process wherein, citric acid monohydrate, sodium dihydrogen phosphate monohydrate,
disodium hydrogen phosphate anhydrous, sodium hydroxide, polysorbate 20 and polyethylene
15 glycol 4000 dissolved in water followed by API (paliperidone palmitate) dispersion by stirring/
homogenization to form premix slurry. The premix slurry subjected to wet grinding using bead
milling to yield target particle size distribution PSD. The milled suspension is subjected to
heating for specified temperature and time. Post-mill suspension is filled into pre-filled
syringes.
20 In another embodiment, the present invention provides that all the excipients dissolved
in water followed by paliperidone palmitate API dispersion and wet milling to get the desired
particle size distribution (PSD). The milled suspension subjected heating for specified
temperature and time.
In one embodiment the present invention provides that the heating temperatures is in
25 the range of about 50°C and 60°C and heating time is in the range of about 3hrs and about 6hrs.
In an embodiment, the present invention provides a process for preparing a stable
paliperidone ester injectable suspension formulation; wherein the process comprises: wet
milling a premix slurry comprising paliperidone ester, at least one surfactant, at least one
suspending agent, at least one anti-oxidant, at least one buffering agent, a pH adjuster and at
30 least one vehicle to obtain a milled suspension; and subjecting the milled suspension to heat
treatment at a temperature of about 50ºC or more to produce a stable floccule of paliperidone
palmitate injectable suspension; wherein the premix slurry is obtained by a single-phase
manufacturing process that combines all the constituents of the slurry. In certain embodiments
of this process, the stable paliperidone ester injectable suspension formulation is one or more
35 of the formulations shown in Table below, which correspond to formulations of RLD:
23
Ingredients Formulation A
(INVEGA
SUSTENNA)
Formulation B
(INVEGA TRINZA)
Formulation C
(INVEGA
HAFYERA)
Paliperidone palmitate 156mg/ml
117mg/0.75ml
234mg/1.5ml
39mg/0.25ml
78mg/0.5ml
273mg/0.875ml
410mg/1.315ml
(311.79mg/ml)
546mg/1.75ml
819mg/2.625ml
(312mg/ml)
1,092 mg/3.5 mL
1,560 mg/5 mL
Polysorbate 20 12 mg/mL 10 mg/mL 10 mg/mL
Polyethylene glycol 4000 30 mg/mL 75mg/mL 75mg/mL
Citric acid monohydrate 5 mg/mL 7.5 mg/mL 7.5 mg/mL
Disodium hydrogen
phosphate anhydrous
5mg/mL Nil Nil
Sodium dihydrogen
phosphate. H2O
2.5mg/mL 6 mg/mL 6 mg/mL
Sodium hydroxide 2.84mg/mL 5.4 mg/mL 5.4 mg/mL
Water for injection. q.s. q.s. q.s.
5
In yet another embodiment, the present invention provides a composition of
paliperidone palmitate injectable suspension comprising a paliperidone palmitate in an amount
of 156 mg/ml; a polysorbate 20 in an amount of 12 mg/ml; a polyethylene glycol 4000 in an
amount of 30 mg/ml; a citric acid monohydrate in an amount of 5 mg/ml; disodium hydrogen
10 phosphate anhydrous in an amount of 5 mg/ml; a sodium dihydrogen phosphate monohydrate
in an amount of 2.5 mg/ml; a sodium hydroxide in an amount of 2.84 mg/ml; and q.s.water for
injection vehicle.
In another embodiment, the present invention provides a composition of paliperidone
palmitate injectable suspension comprising a paliperidone palmitate in an amount of 312
15 mg/ml; a polysorbate 20 in an amount of 10 mg/ml; a polyethylene glycol 4000 in an amount
of 75 mg/ml; a citric acid monohydrate in an amount of 7.5 mg/ml; a sodium dihydrogen
phosphate monohydrate in an amount of 6 mg/ml; a sodium hydroxide in an amount of 5.4
mg/ml; and q.s. water for injection vehicle.
24
5 In another embodiment, the present invention provides a composition of paliperidone
palmitate injectable suspension comprising a paliperidone palmitate in an amount of 1,092
mg/ml or 1560 mg/ml; a polysorbate 20 in an amount of 10 mg/ml; a polyethylene glycol 4000
in an amount of 75 mg/ml; a citric acid monohydrate in an amount of 7.5 mg/ml; a sodium
dihydrogen phosphate monohydrate in an amount of 6 mg/ml; a sodium hydroxide in an
10 amount of 5.4 mg/ml; and q.s. water for injection vehicle.
The present invention provides a satisfactory redispersibility behaviour to a
paliperidone palmitate injectable suspension and provides advantages of heating on the stability
of suspension.
EXAMPLES
15 Although the content of the present invention is further specifically explained using
Examples, the present invention is not limited to the following Examples as long as the gist of
the present invention is not exceeded. Values of various manufacturing conditions and
evaluation results in the following Examples mean preferable values of an upper limit or a
lower limit in the embodiments of the present invention, and a preferable range may be a range
20 defined by a combination of the above-described upper limit or the above-described lower limit
and the values of the following Examples or a combination of the values of Examples.
Example 1: Two-Phase Manufacturing Process (without heat treatment)
Ingredient Qty. (mg)
Paliperidone Palmitate 312
Polysorbate 20 10
Polyethylene glycol 4000 75
Citric acid monohydrate 7.5
Sodium dihydrogen phosphate
monohydrate
6
Sodium hydroxide 5.4
Water for injection q.s. to 1 mL
25
5
Manufacturing Procedure:
Phase-1 (Surfactant phase):
1. The required quantity of water for injection (WFI) is taken in a manufacturing vessel and
purge with nitrogen gas at room temperature.
10 2. The dispensed quantity of polysorbate-20 is added to the solution of step-1 at room
temperature followed by the dispersion of paliperidone palmitate API under
homogenization at 5000 rpm for about 120 minutes to produce a homogenous slurry of
paliperidone palmitate particles. This phase is called surfactant phase.
3. The surfactant phase is subjected to wet grinding using polymeric polystyrene beads
15 through Netzsch bead mill. The bead milling process produced the desired particle size
distribution.
Phase-2 (Buffer phase):
1. A dispensed quantity of citric acid monohydrate, sodium dihydrogen phosphate
monohydrate, sodium hydroxide and polyethylene glycol 4000 added to water for
20 injection under continuous stirring to get a clear solution at room temperature. This phase
is called buffer phase.
2. The phase-2 i.e., buffer phase is added to the phase-1 i.e., milled suspension under stirring
to produce a final suspension. The suspension is homogenized at 2500 rpm for 30
minutes.
25 3. The final suspension is filled into pre-filled syringes.
Example 2: Single-Phase Manufacturing Process (with and without treatment)
Ingredient Qty. (mg)
Paliperidone Palmitate 312
Polysorbate 20 10
Polyethylene glycol 4000 75
26
Citric acid monohydrate 7.5
Sodium dihydrogen phosphate
monohydrate
6
Sodium hydroxide 5.4
Water for injection q.s. to 1 mL
5
Brief Manufacturing Procedure:
1. The required quantity of WFI is taken in a manufacturing vessel and purged with nitrogen
gas at room temperature.
2. The dispensed quantity of excipients one after the other is added into the manufacturing
10 vessel under continuous stirring to get a clear solution at room temperature.
3. The dispensed quantity of Paliperidone Palmitate is added gradually to solution of step2 under continuous stirring/homogenization at 500 rpm for 120 minutes to form a
homogenous premix at room temperature.
4. Premix phase is subjected to wet grinding using polymeric polystyrene beads through
15 Netzsch bead mill. The bead milling process produced the desired particle size
distribution.
5. Once the desired particle size distribution is achieved, the bulk suspension is collected
from mill.
6. Without heating: The milled bulk suspension is subjected to stirring/homogenization at
20 room temperature for 3 hours.
7. With heating: The milled bulk suspension is subjected to heating at 60°C for 3 hours
under stirring.
8. Final suspension is filled into pre-filled syringes.
25 1. Selection of polysorbate grade:
The quality of polysorbate plays a pivotal role in the stabilization of paliperidone
palmitate injectable suspension. Polysorbate acts as a wetting agent for crystalline solid particle
and in combination with flocculating agents make a floccule of solid particles that has ability
to redisperse completely on application of force.
27
5 The peroxide value, acid value and inorganic residue present in the polysorbate affect
the physical stability such as redispersibility and color of suspension by degrading the
polysorbate present in the suspension formulation. High pure grade of polysorbate have
comparatively more content of free fatty acids and inorganic impurities than super refined
grades. Super refined grade is manufactured by an additional final step of flash
10 chromatography, which involves removal of primary and secondary oxidative impurities.
Table 1: Physical observation of paliperidone palmitate injectable suspension
manufactured with high pure and super refined polysorbate grade:
Polysorbate Grade Description
Super refined White to off white
suspension
High pure Yellow colored suspension
The paliperidone palmitate injectable suspension manufactured with high pure
15 polysorbate showed color change and issue in redispersibility on storage. Therefore, super
refined grade selected to formulate the suspension.
Polysorbate can undergo oxidative degradation on storage and exposure to air that can
affect the physical stability of suspension. The suspension formulation manufactured with
polysorbate with different peroxide value.
20 Table 2: Peroxide value of polysorbate-20:
Polysorbate grade
Peroxide value
(meqO2/kg)
Storage Condition
Super refined 0.43 Stored under nitrogen headspace
High pure 2.32 Stored under air headspace
The high peroxide value indicates the oxidation on storage.
28
5 Table 3: Physical observation of paliperidone palmitate injectable suspension
manufactured with different peroxide content of polysorbate:
Paliperidone palmitate
injectable suspension
manufactured with
Peroxide value
(meqO2/kg)
Description
Super refined 0.43 White to off white suspension
High pure 2.32 Yellow colored suspension
The paliperidone palmitate injectable formulation manufactured with high peroxide
content showed color change on stability. Additionally, the formulation with high peroxide
10 content did not redisperse completely by shaking. Therefore, it is critical to ensure the quality
of polysorbate for preparing paliperidone palmitate injectable suspension.
Example 3: Impact of polysorbate-20 distribution on redispersibility of suspension:
Paliperidone palmitate injectable suspension contains an excipient polysorbate-20 as a
wetting agent at concentration of 10 mg/mL. The distribution of polysorbate-20 between solid
15 particles and supernatant is a key attribute for redispersibility over stability. An optimum level
of polysorbate on sediment, i.e., adsorbed onto the crystalline particles, and within the
supernatant of the suspension, is required to maintain better flocculation in the suspension. This
better flocculation results from the synergistic interaction among polysorbate 20, crystalline
API particles and PEG-4000. Enhanced flocculation imparts better redispersibility attribute to
20 the suspension over stability.
Example 4: Comparative Analysis with Reference Listed Drug (RLD): Polysorbate-20
Distribution and Redispersibility Behavior of Paliperidone Palmitate Injectable
Suspension.
25
Table 4: Polysorbate-20 distribution and redispersibility behaviour of paliperidone
palmitate injectable suspension:
29
Samples
US RLD
(Invega
Trinza)
Approach-II (Example No.2)
(Without Heat treatment)
Stability Condition
Initial
25°C/ 40%RH 40°C/ NMT 25%RH
Time NA 81 days 170 days 81 days 170 days
Polysor
bate-20
distrib
ution
Supernat
ant (%)
54 41 12 15 10 13
Sediment
(%)
46 59 88 85 90 87
Description
White to
off white
suspensio
n
White
to off
white
suspen
sion
White to
off white
suspension
White to off
white
suspension
White to
off white
suspensio
n
White to
off white
suspension
with paste
like
consistency
No. of shakings to
redisperse the
sample
2-4 2-4 3-5 12-14 12-16
Not redispersed
5
The distribution of polysorbate-20 on paliperidone palmitate particles and supernatant was
estimated. It has been observed that the initial polysorbate-20 distribution is comparable to the
reference product. Whereas on the stability, it shifts to the paliperidone palmitate particles, and
it has reached near to 90% on particles.
10 All the samples were studied for redispersibility behaviour where total number of shakes to
redisperse the paliperidone palmitate suspension was recorded. The samples where the
polysorbate-20 distribution was more towards the paliperidone palmitate particles, showed a
greater number of shakes to redisperse the sample.
The sample stored at 40°C/ 25% RH for 170 days did not redisperse completely. Therefore, it
15 is important to maintain the polysorbate-20 distribution over storage to have satisfactory
redispersibility behaviour.
30
5 The sample is not heat-treated formulation therefore number of shakes increase with respect to
time and temperature exposure. As the time passes, hard sediment forms that is difficult to
redisperse.
The 40°C/ 25% RH exposure at 6 months (180 days) is equivalent to 24 months (720 days) at
25°C/ 40%RH.
10
2. Selection of manufacturing process and grinding media:
The manufacturing process was selected to obtain a stable paliperidone palmitate
injectable suspension formulation. The target particle size distribution of paliperidone
palmitate injectable suspension was obtained by the wet milling process through Netzsch
15 DV15-300 bead mill. The agitator tip speed, flow rate and grinding media such as zirconium
beads and polymeric polystyrene beads are optimized to produce a stable suspension.
• Approach-I (Two-phase manufacturing process)
The two-phase manufacturing process involved the preparation of API slurry in one
phase that was subjected to wet milling process to achieve the target particle size. Once the
20 target particle size was achieved, the second aqueous phase was mixed with the first phase
to yield the final product.
Phase-1 (Surfactant phase): The polysorbate-20 was dissolved in water for injection at
room temperature followed by the dispersing the paliperidone palmitate API under stirring/
homogenization to produce the homogenous slurry of paliperidone palmitate particles. This
25 phase was called the surfactant phase.
The surfactant phase was subjected to wet grinding using zirconium beads or polymeric
polystyrene beads through Netzsch DV15-300 bead mill. The bead milling process produced
the desired particle size distribution.
Phase-2 (Buffer phase): The citric acid monohydrate, sodium dihydrogen phosphate
30 monohydrate, sodium hydroxide and polyethylene glycol 4000 were dissolved in the water
for injection at room temperature under stirring. This phase is called buffer phase.
The phase-2 i.e. buffer phase is added to the phase-1 i.e. milled suspension under stirring to
produce the final suspension. Final suspension was filled into pre-filled syringes.
35 • Approach-II (Single-phase manufacturing process)
In single-phase manufacturing process, the citric acid monohydrate, sodium
dihydrogen phosphate monohydrate, sodium hydroxide, polysorbate-20 and polyethylene
31
5 glycol 4000 are dissolved in water for injection at room temperature under stirring. The
paliperidone palmitate API was added under stirring/ homogenization to produce the
homogenous slurry of paliperidone palmitate particles.
The paliperidone palmitate slurry was subjected to the wet grinding using zirconium
beads or polymeric polystyrene beads through Netzsch DV15-300 bead mill. The bead milling
10 process produced the desired particle size distribution. Post-mill, suspension was filled into
pre-filled syringes.
The paliperidone palmitate injectable suspension was manufactured with approach-I and
approach-II using both zirconium beads and polymeric polystyrene beads by wet milling
process.
15 Accelerated redispersibility model was developed to mirror the long-term redispersibility
behaviour. The samples were kept at 60°C in a hot air oven for 96 hr, and the number of
shakings required to re-disperse the sample was recorded.
Table 5: Redispersibility behaviour of paliperidone palmitate injectable suspension by
20 accelerated redispersibility model:
Manufacturing
Process
Approach-I Approach-II
Grinding
Media
Zirconium,
1.0 mm
Polymeric
Polystyrene,
0.7 mm
Zirconium,
0.5mm
Polymeric
Polystyrene,
0.7 mm
No. of shakings
to redisperse
the sample
28 30-32 6-8 6-8
A significant difference was observed in the redispersibility behaviour between samples
prepared using approach-I and approach-II. The paliperidone palmitate injectable suspension
32
5 samples manufactured with approach-II exhibited a lower number of shakes required for
redispersion.
Example 5: Impact of heat treatment of final suspension:
A moderate heat treatment of milled suspension was introduced to accelerate the
particle size increase as a part of manufacturing process to reduce number of fines, and thereby
10 limiting increase in particle size over stability. Different heating temperature and time were
studied with respect to increase in particle size during the heat treatment process and on
stability.
Table 6: Effect of heat treatment on particle size distribution paliperidone palmitate
injectable suspension
Manufacturing Process Approach-II (Example 2)
Grinding Media Polymeric Polystyrene, 0.7 mm
Post Mill Temperature
Room
Temperature
50 °C 60 °C
Time 3hr 3hr 6hr 3hr 6hr
PSD (µm)
D10 2.30 2.36 2.37 2.77 3.50
D50 6.49 6.47 6.63 7.44 8.75
D90 15.94 15.67 15.73 16.67 18.16
Polysorbate20
distribution
Supernatant
(%) 49 52 51 51 48
Sediment
(%)
51 48 49 49 52
15
The paliperidone palmitate injectable suspension samples were manufactured with
approach-II and heat stirred at 50°C and 60°C for 3hr and 6hr. It was hypothesized that the
particle size will slightly increase after heat treatment as an effect of reducing number of fines.
33
5 There was little or no change in the particle size distribution following 50°C heat
treatment for 3hr and 6hr duration. Whereas heating at 60°C resulted in increase in particle size
thus reducing the number of fines. The polysorbate-20 distribution was also estimated. There
was no significant difference in the polysorbate-20 distribution following the heat treatment.
The paliperidone palmitate injectable suspension were prepared by approach-II
10 followed by room temperature stirring and heat stirring at 60°C.
Samples subjected to heat treatment, as well as those stirred at room temperature, were
subjected to long-term and accelerated stability conditions to assess their particle size
distribution.
Example 6: Comparative Particle Size Distribution of Paliperidone Palmitate Injectable
15 Suspension with and without Heat Treatment Compared to RLD.
Table 7: Particle size distribution of paliperidone palmitate injectable suspension with
and without heat treatment:
34
Parameters Reference Product
(Invega Trinza)
Test Formulation (Example No.2)
Manufacturing
Process Not available Approach-II
Grinding
Media
Not available Polymeric Polystyrene, 0.7 mm
Stability
Condition
Initial 40°C / NMT
25%RH
Initial
25°C/
40%RH
40°C /
NMT
25%RH Initial
25°C/
40%RH
40°C/
NMT
25%RH
Time
90 days 180
days
81 days 81 days
Post Mill
Temperature
NA
Room Temperature 60 °C
Time NA 3 hr 3 hr
PSD (µm)
D10 2.48 2.55 2.80 2.35 2.61 2.91 2.60 2.83 2.88
D50 6.65 6.87 7.00 6.45 7.12 7.67 6.84 7.71 7.60
D90 17.27 18.06 18.50 15.84 16.82 17.45 16.33 17.41 16.96
5 The heat stirred samples did not undergo significant change in particle size under long
term and accelerated stability conditions, whereas room temperature stirred samples showed
an increase in particle size.
Further, the polysorbate-20 distribution was estimated, and the number of shakes
required to redisperse the samples was recorded on long term and accelerated stability
10 conditions.
Example 7: Comparative Polysorbate-20 Distribution and Redispersibility Behavior of
Paliperidone Palmitate Injectable Suspension on Stability Compared to RLD.
35
5 Table 8: Polysorbate-20 distribution and redispersibility behaviour of paliperidone
palmitate injectable suspension on stability:
Parameters
Reference
Product
(INVEGA
TRINZA)
Test Formulation (Example
No.2)
Manufacturing Process Not available Approach-II
Grinding Media Not available Polymeric Polystyrene, 0.7 mm
Stability Condition
Initial
40°C/
NMT
25%RH Initial
25°C/
40%RH
40°C/
NMT
25%RH
Time 81 days
81
days
170
days
81
days
170
days
Polysorbate20
distribution
Supernatant
(%)
54 47
51 46 39 48 51
Sediment
(%)
46 53
49 54 61 52 49
No. of shakings to
redisperse the sample
2-4 6 to 10
2-4 2-4 2-4 8 4-6
There was little or no change observed in the polysorbate-20 distribution over the
10 stability. As a secondary quality attribute, satisfactory redispersibility behaviour was observed
for heat-processed samples.
While preferred embodiments and example have been shown and described, it is to be
understood that various further modifications and additional configurations will be apparent to
those skilled in the art. It is intended that the specific embodiments herein disclosed are
15 illustrative of the preferred and best modes for practicing the invention and should not be
interpreted as limitations on the scope of the invention.
36
5 WE CLAIM:
1. A process for preparing a stable paliperidone ester injectable suspension formulation
comprising paliperidone ester and at least one pharmaceutically acceptable carrier, the
process comprises:
- wet milling a premix slurry comprising paliperidone ester and at least one
10 pharmaceutically acceptable carrier or excipient to obtain a milled suspension; and
- subjecting the milled suspension to heat treatment to produce a stable floccule of
paliperidone palmitate injectable suspension.
2. The process as claimed in claim 1, wherein the premix slurry is obtained by a single-phase
15 or two-phase manufacturing process.
3. The process as claimed in claim 1, wherein, the premix comprises paliperidone ester, at
least one surfactant or wetting agent, at least one suspending agent, and at least one
antioxidant.
20
4. The process as claimed in claim 3, wherein, the premix comprises about 10% to about 40%
of paliperidone ester, about 0.1% to about 10% of at least one surfactant, about 1% to about
15% of at least one suspending agent, and about 0.1% to about 3% of at least one antioxidant.
25
5. The process as claimed in claim 1, wherein, the premix further comprises a buffering agent,
a pH adjuster and at least one vehicle.
6. The process as claimed in claim 5, wherein, the premix comprises about 0.1% to about 1%
30 of a buffering agent, about 0.1% to about 1% of a pH adjuster and about 40% to about 80%
of at least one vehicle.
7. The process as claimed in any one of the claims 1 to 6, wherein, the premix comprises about
10% to about 40% of paliperidone ester, about 0.1% to about 10% of at least one surfactant,
35 about 1% to about 15% of at least one suspending agent, about 0.1% to about 3% of at least
one anti-oxidant, about 0.1% to about 1% of a buffering agent, about 0.1% to about 1% of
a pH adjuster and about 40% to about 80% of at least one vehicle.
37
5
8. The process as claimed in any one of the claims 1 to 7, wherein the paliperidone ester is
paliperidone palmitate.
9. The process as claimed in any one of the claims 3 to 8, wherein the surfactant or wetting
10 agent is selected from a group comprising polysorbate 20, polysorbate 80, lecithin,
polyoxyethylene- and polyoxypropylene ethers, sodium deoxycholate, sodium lauryl
sulphate, sorbitan fatty acid esters and any combination thereof.
10. The process as claimed in any one of the claims 3 to 9, wherein the surfactant or wetting
15 agent comprises a peroxide value of up to about 2 meqO2/Kg.
11. The process as claimed in any one of the claims 3 to 10, wherein the suspending agent is
selected from a group comprising methyl cellulose, sodium carboxymethyl cellulose and
hydroxypropyl methyl cellulose, polyvinylpyrrolidone, alginates, chitosan, xanthan gum,
20 dextrans, gelatin, polyethylene glycol, polyoxyethylene ether, and polyoxypropylene ethers
and any combination thereof.
12. The process as claimed in any one of the claims 3 to 11, wherein the suspending agent is
polyethylene glycol 4000.
25
13. The process as claimed in any one of the claims 3 to 12, wherein the anti-oxidant is selected
from a group comprising citric acid or its hydrate, ascorbic acid, tartaric acid, tertiary butyl
hydroquinones, tocopherol, methionine, sodium metabisulfite, potassium metabisulfite,
benzoic acid, butylated hydroxyanisole, butylated hydroxytoluene, a gallate, a
30 hydroxybenzoate, EDTA, and any combination thereof.
14. The process as claimed in any one of the claims 5 to 7, wherein, the buffering agent is
selected from a group comprising acetate, citrate, phosphate, glutamate and any
combination thereof.
35
15. The process as claimed in claim 14, wherein, the buffering agent is phosphate
componentselected from a group comprising sodium dihydrogen phosphate
monohydrate,disodium hydrogen phosphate anhydrous, and a combination thereof.
38
5
16. The process as claimed in any one of the claims 5 to 7, wherein, the pH adjuster is a base
selected from a group comprising an alkali metal salt of a hydroxide, an alkaline earth metal
salt of a hydroxide, alkali metal salt of a carbonate, an alkaline earth metal salt of a
carbonate, an alkali metal salt of a bicarbonate, an alkaline earth metal salt of a bicarbonate,
10 an alkali metal salt of a sesquicarbonate, an alkaline earth metal salt of a sesquicarbonate,
an ammonium salt of a carbonate, an ammonium salt of a bicarbonate, an ammonium salt
of a sesquicarbonate, and any combination thereof.
17. The process as claimed in any one of the claims 5 to 7, wherein the vehicle is selected from
15 a group comprising water, saline, and alcohol.
18. The process as claimed in claim 2, wherein, the premix slurry is obtained by the singlephase manufacturing process comprising the step of dissolving at least one anti-oxidant, at
least one buffering agent, at least one base, at least one surfactant and at least one
20 suspending agent into water for injection at room temperature under stirring, and adding
the paliperidone ester under stirring/homogenization to produce a homogenous slurry of
paliperidone ester particles.
25 19. The process as claimed in claim 18, wherein, the premix slurry is obtained by the singlephase manufacturing process comprising the step of dissolving citric acid monohydrate,
sodium dihydrogen phosphate monohydrate, sodium hydroxide, polysorbate-20 and
polyethylene glycol 4000 are into water for injection at room temperature under stirring
and adding the paliperidone palmitate under stirring/homogenization to produce a
30 homogenous slurry of paliperidone palmitate particles.
20. The process as claimed in claim 2, wherein, the premix slurry is obtained by the two-phase
manufacturing process comprising surfactant phase and buffer phase; wherein, in the
surfactant phase, at least one surfactant is dissolved in water for injection at room
35 temperature followed by the dispersing the paliperidone ester API under
stirring/homogenization to produce a homogenous slurry of paliperidone ester particles;
and in the buffer phase, at least one anti-oxidant, at least one buffering agent, at least one
39
5 base, and at least one suspending agent are dissolved in water for injection at room
temperature under stirring.
21. The process as claimed in claim 20, wherein, in the surfactant phase, polysorbate-20 is
dissolved in water for injection at room temperature followed by dispersing the
10 paliperidone palmitate API under stirring/homogenization to produce the homogenous
slurry of paliperidone palmitate particles, and in the buffer phase, citric acid monohydrate,
sodium dihydrogen phosphate monohydrate, sodium hydroxide and polyethylene glycol
4000 are dissolved in water for injection at room temperature under stirring.
15 22. The process as claimed in claim 20, wherein, in the two-phase manufacturing process, the
surfactant phase is subjected to wet grinding using beads in a bead mill and adding the
buffer phase into it to produce a final suspension.
23. The process as claimed in claim 1, wherein the stable paliperidone ester injectable
20 suspension formulation comprises paliperidone palmitate as paliperidone ester in an
amount of about 312 mg; polysorbate 20 as a surfactant in an amount of 10 mg;
polyethylene glycol 4000 as a suspending agent in an amount of about 75 mg; citric acid
monohydrate as an anti-oxidant in an amount of about 7.5 mg; sodium dihydrogen
phosphate monohydrate as a buffering agent in an amount of about 6 mg; a sodium
25 hydroxide as a pH adjuster in an amount of about 5.4 mg; and water as a vehicle for
injection in an amount of q.s. to 1 mL.
24. The process as claimed in claim 1, wherein the milling is done using milling media
comprising beads.
30
25. The process as claimed in claim 24, wherein the beads are in size of about 0.3 mm to 6.0
mm.
26. The process as claimed in claim 1, wherein the milling step lasts for about 1 to 300 minutes.
35
27. The process as claimed in claim 1, wherein the milled suspension is subjected to heat
treatment under stirring at about 40°C or more.
40
5 28. The process as claimed in claim 27, wherein the milled suspension is subjected to the heat
treatment at about 50°C± 5°C or about 60°C ± 5°C.
29. A stable paliperidone ester injectable suspension formulation obtained by the process as
claimed in any one of the claims 1 to 28