FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
5 &
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
10
MULTI-PARTICULATE PHARMACEUTICAL COMPOSITION OF
QUETIAPINE
15
SUN PHARMACEUTICAL INDUSTRIES LIMITED
20 A company incorporated under the laws of India having their office at SUN HOUSE, 201 B/1,
WESTERN EXPRESS HIGHWAY, GOREGOAN (E), MUMBAI-400063 MAHARASHTRA,
INDIA.
25 The following specification particularly describes the invention and the manner in which it is to
be performed:
2
CROSS REFERENCE
The present patent application is a national phase of PCT application number
PCT/IB2021/058588 dated September 21, 2021 which claims priority from Indian provisional
patent application no. 202021040886 dated September 21, 2020.
5
FIELD OF THE INVENTION
The present invention relates to an extended release multi-particulate composition
comprising a plurality of discrete units, each discrete unit comprising quetiapine or a
pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable
10 excipients, wherein said multi-particulate composition is sprinkled onto soft foods or edible
material or liquids for oral administration.
BACKGROUND OF THE INVENTION
Quetiapine is a psychotropic agent belonging to a chemical class, the dibenzothiazepine
derivatives. The chemical name of quetiapine is 2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-
15 piperazinyl)ethoxy]-ethanol. In general, it is present in various oral formulations like tablets
and capsules in its salt forms, preferably as the fumarate salt. The molecular formula for its
fumarate salt is C42H50N6O4S2.C4H4O4 and it has a molecular weight of 883.11. The structural
formulae of quetiapine and quetiapine fumarate are shown in below Formula I and II,
respectively:
20
Formula-I Formula-II
Quetiapine fumarate is a white to off-white crystalline powder which is moderately
soluble in water.
3
Quetiapine was initially approved by the FDA in 1997, it is a second-generation
atypical antipsychotic used in schizophrenia, major depression, and bipolar disorder.
Quetiapine demonstrates a high level of therapeutic efficacy and low risk of adverse effects
during long-term treatment. Quetiapine is used in the symptomatic treatment of schizophrenia,
5 in management of acute manic or mixed episodes in patients with bipolar I disorder, as a
monotherapy or combined with other drugs.
Various solid oral dosage forms of quetiapine are known. Quetiapine fumarate is
commercially available as an extended release tablet formulation and is marketed under the
brand name SEROQUEL XR®.
10 U.S. Patent No. 5,948,437 covers the marketed product and discloses a sustained release
quetiapine tablet formulation wherein the drug is compressed with a gelling agent to form the
tablet.
The commercially available extended release tablet of quetiapine fumarate is used for
treatment of schizophrenia, acute treatment of manic or mixed episodes associated with bipolar
15 disorder, in treatment of depressive episodes of bipolar disorders and as an adjunctive treatment
of major depressive disorder.
Solid oral dosage forms are not suitable for patients having difficulty swallowing or
with dysphagia as in case of geriatric and pediatric patients. Further, conventional solid oral
dosage forms like tablets and capsules are intended to be swallowed as whole. The available
20 marketed formulation of quetiapine should not be crushed or chewed, as drug release will be
compromised. The dosage and administration section of the SEROQUEL XR® prescribing
information states, “SEROQUEL XR® tablets should be swallowed whole and not split,
chewed or crushed.” It is also mandatory as per the SEROQUEL XR® label that the patient
should take the tablet without food or with light food. Therefore, there is poor compliance for
25 the marketed formulation in patients having dysphagia or with difficulty swallowing.
Dosing regimens for various antipsychotic solid oral dosage forms generally include
two or three tablets/capsules per day, however, such regimens were found to be associated with
problems such as lack of convenience, and more importantly lack of compliance, particularly in
patients with dysphagia and swallowing difficulty. Dysphagia plays a critical role in medication
30 management, since many older adults cannot swallow whole tablets and capsules because of
4
swallowing difficulty. Dysphagia can be caused by difficulties overriding the natural instinct to
chew solids/foodstuff before swallowing, or it may be a more complex disorder of swallowing
function affecting the ability to manage all food and fluid intake. The marketed formulation
SEROQUEL XR® (U.S. Patent No. 5,948,437) has not been very helpful in such patients.
5 Further, because the control of quetiapine plasma levels is critical during treatment, failures or
incidents, such as, the one that can be seen with patients having swallowing difficulty, leads to
instances of non-compliance or missed dosing, which can be detrimental to patient health and
safety.
Thus, there exists a need for a dosage form or composition of quetiapine which provides
10 a better compliance for the patients having dysphagia or difficulty swallowing or related
conditions like where s patient is hesitant or not willing to take medicine.
SUMMARY OF THE INVENTION
The present invention provides an extended release multi-particulate composition
comprising a plurality of discrete units, each discrete unit comprising quetiapine or a
15 pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable
excipients, whereby the composition can also be sprinkled onto soft foods or edible material or
liquids for oral administration.
In another aspect, the present invention provides a stable dosage form, wherein the
release profile of the quetiapine or its pharmaceutically acceptable salt is not affected by
20 sprinkling the multi-particulate composition according to the present invention onto soft foods
or edible material or liquids for oral administration. The integrity of the coating is not
influenced by longer exposure to soft foods or edible material or liquids. The dosage form may
be taken with or without food.
In some aspects, the multi-particulate composition can be administered through a
25 feeding tube in a long-term care setting to critically ill patients by dispersing in an aqueous
media before administration.
In one aspect, the present invention provides discrete units comprising quetiapine,
wherein the discrete units may be in the form of a pellet, granule, spheroid, particle, mini-tablet
or bead.
5
In another aspect, the multi-particulate sprinkle dosage form is substantially free of food
effect and devoid of problems associated with other known marketed formulations such as
delay in gastric emptying due to larger size of tablets or capsules and variability in
bioavailability.
5 In some aspects, the present invention provides an extended release multi-particulate
sprinkle dosage form comprising a plurality of discrete units, wherein each unit comprises a
drug core comprising quetiapine or a pharmaceutically acceptable salt thereof; at least two
coatings on the drug core wherein one of the at least two coatings comprises a pH sensitive
polymer; and wherein the release of the drug is controlled by a combination of the said at least
10 two coatings.
In one aspect, each of the discrete units according to the present invention comprises at
least two coatings on the drug core to control the release of the drug from the core; wherein at
least one coating comprises a pH sensitive polymer.
In another aspect, each of the discrete units according to the present invention
15 comprises at least two coatings on the drug core for controlling the release of the drug, wherein
one of the at least two coatings comprises a pH neutral polymer, and the other coating is a pH
sensitive polymer.
In yet another aspect, the core of the discrete units comprises an active ingredient
quetiapine or its pharmaceutically acceptable salt, and the coating is devoid of any active
20 ingredient.
In a further aspect according to the present invention, the core is devoid of a releasecontrolling polymer.
In one aspect, the extended release multi-particulate sprinkle dosage form according to
the present invention comprises a drug core of quetiapine or a pharmaceutically acceptable salt
25 thereof, coated with a pH neutral polymer coating and a pH sensitive polymer coating, wherein
the drug release from the dosage form is controlled by a combined effect of the pH neutral
polymer coating and the pH sensitive polymer coating.
6
DESCRIPTION OF THE INVENTION
As used herein, the word “a” or “plurality” before a noun represents one or more of the
particular noun.
For the terms “for example” and “such as,” and grammatical equivalences thereof, the
5 phrase “and without limitation” is understood to follow unless explicitly stated otherwise. As
used herein, the term “about” is meant to account for variations due to experimental error. All
measurements reported herein are understood to be modified by the term “about,” whether or
not the term is explicitly used, unless explicitly stated otherwise.
The term “dosage form” as used herein the description, can be used interchangeably
10 with the term ‘composition’ or ‘formulation’ or ‘pharmaceutical preparation’.
The term “coating” as used herein the description, can be used interchangeably with the
term ”coat” or ”layer” around the core.
Unless otherwise defined, all technical and scientific terms used herein have the same
meaning as commonly understood by one of ordinary skill in the art to which this invention
15 belongs. Methods and materials are described herein for use in the present invention; other,
suitable methods and materials known in the art can also be used. The materials, methods, and
examples are illustrative only and not intended to be limiting. All publications, patent
applications, patents, and other references mentioned herein are incorporated by reference in
their entirety. In case of conflict, the present specification, including definitions, will control.
20 The present inventors have developed a stable sprinkle dosage form of quetiapine in the
form of a multi-particulate dosage form comprising a plurality of discrete units. Such dosage
form is believed to be bioequivalent to the marketed SEROQUEL XR® formulation and can be
easily administered by sprinkling on the food. Further, such dosage form when administered as
a sprinkle over soft food or edible material or liquid for oral administration, it becomes easier
25 for patients to comply as well as get the maximum benefit out of therapy.
The present invention relates to an extended release multi-particulate composition
comprising a plurality of discrete units, each discrete unit comprising quetiapine or a
pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable
7
excipients, which is sprinkled onto soft foods or edible material or liquids for oral
administration.
In another embodiment, the present invention provides a stable dosage form, wherein
the release profile of the quetiapine or its pharmaceutically acceptable salt is not affected by
5 sprinkling the multi-particulate composition according to the present invention onto soft foods
or edible material or liquids for oral administration. The integrity of the coating is not
influenced by longer exposure to soft foods or edible material or liquids. The said dosage form
may be taken with or without food.
In a further embodiment, the multi-particulate composition can be administered through
10 a feeding tube in a long-term care setting to critically ill patients by dispersing in an aqueous
media before administration.
According to one embodiment of the present invention, the discrete units may be in the
form of a pellet, granule, spheroid, particle, mini-tablet or bead.
In another embodiment, the multi-particulate sprinkle dosage form according to the
15 present invention is bioequivalent to the marketed quetiapine formulation available under the
brand name SEROQUEL XR®. Further, the dosage form is substantially free of food effect and
devoid of problems associated with other known marketed formulations such as delay in gastric
emptying due to a larger size of tablets or capsules and variability in bioavailability.
In one embodiment, the present invention provides an extended release multi-particulate
20 sprinkle dosage form comprising a plurality of discrete units, wherein each unit comprises a
drug core comprising quetiapine or a pharmaceutically acceptable salt thereof; at least two
coatings on the drug core wherein one of the at least two coatings comprises a pH sensitive
polymer; and wherein the release of the drug is controlled by a combination of said at least two
coatings.
25 In another embodiment, the present invention provides an extended release multiparticulate sprinkle dosage form comprising a plurality of discrete units, wherein each unit
comprises a drug core comprising quetiapine or a pharmaceutically acceptable salt thereof; at
least two coatings on the drug core to control the release of the drug from the core; wherein at
least one coating comprises a pH sensitive polymer.
8
In yet another embodiment, the extended release multi-particulate sprinkle dosage form
according to the present invention comprises a plurality of discrete units, wherein each unit
comprises a drug core comprising quetiapine or a pharmaceutically acceptable salt thereof; at
least two coatings on drug core controlling the release of drug, wherein one of the at least two
5 coatings comprises a pH neutral polymer, and the other coating is a pH sensitive polymer.
In another embodiment, the discrete units according to present invention comprise a
core and at least two coatings. In another embodiment, the discrete units comprise a core and
more than one coating for modified release of the drug from the core.
In another embodiment, the core of the discrete units comprises an active ingredient
10 quetiapine or its pharmaceutically acceptable salt, and the coating is devoid of any active
ingredient.
In one aspect of the present invention, the coating may optionally comprise one or more
active ingredients.
In another embodiment of the present invention, the core is devoid of a release15 controlling polymer.
In one embodiment, the multi-particulate sprinkle composition of the invention may be
modulated to provide an extended drug release, controlled drug release, sustained drug release,
prolonged drug release, delayed drug release, modified drug release, immediate drug release or
a combination of immediate and extended drug release.
20 The term “granules”, “pellets” or “spheroids” as used herein can be used
interchangeably, and includes agglomeration from apparent solid powder particles to large
multi-particulates. The agglomeration may be achieved by either granulation, compaction,
extrusion, slugging, drug loading or the like. Such granules, pellets or spheroids have good
flow property and these may be spherical or oval in shape, and may have a density higher than
25 a powder. The granules or pellets or spheroids are coated, in particular, they can be preferably
coated with at least one functional coating, as described herein. The average diameter of coated
pellets or granules is about 500 μm to about 1800 μm, or about 600 μm to about 1500 μm. Also
included are granules as defined in USP <1151>, which is incorporated herein by reference.
9
The term “functional coating” in the context of this disclosure refers to one or more
controlled release layers, particularly an extended release layer that surrounds a drug core. The
term “extended release” as used herein can be used interchangeably with term "controlled
release", "modified release" or "sustained release" and refers to a means of releasing an active
5 agent from the dosage form thereof such that it is available to the site of absorption by the body
over a period of time.
The terms “non-functional coating” or “non-functional film coat” in the context of the
present disclosure refers to a coating that does not materially affect the release of quetiapine or
a pharmaceutically acceptable salt thereof from the formulation or dosage form. A non10 functional coating or non-functional film coat may still include some functions not related to
the dissolution of quetiapine, such as taste, color, or physical integrity.
The term “sprinkle” as used herein means that the multi-particulate pharmaceutical
composition is to be added onto food or any edible material, or liquid, such as water, juices etc.,
before administration. The pellets or granules or spheroids or particle of the multi-particulate
15 pharmaceutical composition may be packed in sachet or pouch or filled into capsules and may
be sprinkled onto soft food or edible material or into a liquid. Alternatively, multi-particulate
pharmaceutical composition may also be in the form of a dispersible dosage form which can be
dispersed in a liquid to yield a dispersion of the individual particles before drinking. The multiparticulate pharmaceutical composition of the present invention is configured so as to be
20 administered by initially opening a sachet or pouch or capsule filled with it and transferring it
to a vehicle, such as a soft food, for example, applesauce, pudding, custard, oatmeal and
yoghurt. Then, the vehicle into which the composition is sprinkled is swallowed immediately.
The multi-particulate pharmaceutical composition of the present disclosure may be swallowed
as a whole when in capsule, and can also be sprinkled onto the vehicle. Alternatively, geriatric
25 patients who have difficulty swallowing may add the composition of the present invention that
has been filled into sachet or pouch or capsule, into a liquid medium, such as water, to obtain a
suspension. The suspension may be then orally administered through, e.g., a nasogastric tube
into the stomach.
10
The term “mixture” as used herein means that the quetiapine or a pharmaceutically
acceptable salt thereof is mixed uniformly with excipients of various categories such as
stabilizers, alkalizing agents, buffering agents, disintegrants or diluents.
The term “stable” as used herein, refers to a physicochemical stability which means that
5 the extended/delayed release coat over the multi-particulate composition retain its structural
integrity and does not rupture in a significant way after exposure to acidic or any external
environment for the given time period as determined by the drug release and also includes
chemically stability which means the multi-particulate composition remains stable when stored:
- under the temperature and humidity conditions of 40ºC /75%RH for at least 6 months; or
10 - under the temperature and humidity conditions of 30°C/ 65%RH for at least 6 months; or
- under the temperature and humidity conditions of 25°C/ 60%RH for at least 6 months.
The term “pharmaceutically acceptable salt” as used herein means a salt which is,
within the scope of sound medical judgment, suitable for use in contact with the tissues of
humans and lower animals without undue toxicity, irritation, allergic response and the like,
15 commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and
magnesium salts, and the like. U.S. Patent No. 4,879,288 (hereafter ‘288) discloses a process
for the preparation of quetiapine or a pharmaceutically acceptable salt thereof which includes
hydrochloride, maleate, fumarate, citrate, phosphonate, methane sulphonate, and hemifumarate
20 salt. The disclosure of ‘288 also mentions that the compound of formula II (quetiapine) can
form a salt with physiologically acceptable organic and inorganic acids like hydrochloride,
maleate, fumarate, citrate, phosphonate, methane sulphonate, and hemifumarate salt. Only the
hydrochloride, maleate and hemifumarate salts of quetiapine have been prepared, the disclosure
of which is incorporated herein by reference.
25 The term “therapeutically effective amount” as used herein means that amount of
quetiapine or its pharmaceutically acceptable salt that when administered to a mammal for
treating a disease state, disorder or condition, is sufficient to effect such treatment. The
therapeutically effective amount will vary depending on the compound, the disease and its
severity and the age, weight, physical condition and responsiveness of the mammal or human to
30 be treated.
11
The term "bioequivalent" as used herein has its ordinary meaning as understood by
those skilled in the art and thus includes, without limitation, a drug or dosage form that, upon
administration to a suitable patient population, provides principle pharmacokinetic parameters,
e.g., AUC and Cmax that are in the range of 80% to 125% of those provided by a reference
5 standard. Also the terms “bioequivalent” or “bioequivalence”, as used herein are used
interchangeably and describes pharmaceutical equivalent products that display comparable
bioavailability when studied under similar experimental conditions. This term also used herein
is consistent with the definitions and concepts assigned to them under the U.S. Drug Price
Competition and Patent Term Restoration Act of 1984, including the conditions set forth in
10 §5500)(7)(B), and 21 CFR §320.24, which are incorporated herein by reference in their
entirety. Thus, the term “bioequivalent” as used herein, refers to the equivalent release of the
same drug substance from two or more drug products or formulations which lead to an
equivalent rate and extent of absorption from these products or formulations. In other words, if
a drug product contains a drug substance that is chemically identical and is delivered to the site
15 of action at the same rate and extent as another drug product, then it is equivalent. Methods to
define bioequivalence can be found in 21 CFR 320.24, and include (1) pharmacokinetic (PK)
studies, (2) pharmacodynamic (PD) studies, (3) comparative clinical trials, and (4) in-vitro
studies, which are incorporated herein by reference in their entireties. Of course, the choice of
study used, such as illustrated herein in the present specification, is based upon the site of
20 action of the drug and the ability of the study design to compare drug delivered to that site by
the two products.
By the term, “bioavailability”, it refers to the definition and concepts assigned to this
term under the Drug Price Competition and Patent Term Restoration Act of 1984, in particular
in §550(j)(8)(B) and is used herein consistent with such definition and concept, which is
25 incorporated herein by reference in its entirety.
According to the present invention, particle size of the coated multi-particulate discrete
units (pellets or granules or spheroids) may be such that D10 ranges from about 500 µm to
about 1100 µm; D50 ranges from about 950 µm to about 1250 µm and D90 ranges from about
1150 µm to about 1800 µm; Preferably D10 ranges from about 700 µm to about 1000 µm; D50
12
ranges from about 1050 µm to about 1150 µm and D90 ranges from about 1200 µm to about
1500 µm.
In one embodiment, the strength of the said quetiapine multi-particulate dosage form is
50 mg, 150 mg, 200 mg, 300 mg, or 400 mg. All doses strengths of the composition are
5 expressed as milligrams of quetiapine base, not as quetiapine fumarate salt.
In another embodiment, the multi-particulate dosage form according to the present
invention may be administered twice or thrice daily (BID or TID) depending upon the dose
requirement. In an aspect for instance, when the required dose is 800 mg, two 400 mg sachets
may be administered together; when the required dose is 400 mg, a single sachet may be
10 administered. In another aspect, the dosage form according to present invention can be
administered as a sprinkle dosage form over soft food or edible material or liquid for oral
administration, thereby a higher dose can be accommodated in a single administration without
any swallowing difficulty. In one embodiment, the multi-particulate dosage form according to
the present invention may be administered once daily.
15 In one embodiment, according to the present invention, the discrete unit of the multiparticulate composition comprises a drug core with one or more pharmaceutically acceptable
excipients, wherein the core is coated with at least one functional coating.
In another embodiment according to the present invention, the discrete unit of the multiparticulate composition comprises a drug core and optionally one or more non-functional
20 coatings.
In an embodiment of the present invention, the core containing the active ingredient
quetiapine or its pharmaceutically acceptable salt is coated by functional coating layers
comprising one extended release coating followed by one delayed release coating. In another
embodiment of the present invention, the core containing the active ingredient quetiapine or its
25 pharmaceutically acceptable salt is coated by functional coating layers comprising a delayed
release coating followed by an extended release coating. In another embodiment of the present
invention, the core containing the active ingredient quetiapine or its pharmaceutically
acceptable salt is coated by functional coating layers comprising an extended release coating, a
delayed release coating or combination thereof. In a related embodiment of the present
13
invention, the core containing the active ingredient quetiapine or its pharmaceutically
acceptable salt may also optionally be coated with a non-functional coating.
In a further embodiment, the present invention provides an extended release multiparticulate sprinkle dosage form comprising a plurality of discrete units, wherein each unit
5 comprises: a core comprising quetiapine or a pharmaceutically acceptable salt thereof, at least
one coating comprising a pH neutral polymer surrounding the core and at least one coating
comprising a pH sensitive polymer surrounding the core, wherein the drug release from the
multi-particulate dosage form is controlled by pH sensitive and pH neutral polymers in coatings
surrounding the core.
10 In yet another embodiment, the present invention provides an extended release multiparticulate sprinkle dosage form comprising a plurality of discrete units, wherein each unit
comprises a drug core comprising quetiapine or a pharmaceutically acceptable salt thereof; an
extended release coating and a delayed release coating surrounding the core.
In another embodiment, the present invention provides a controlled release sprinkle
15 composition comprising a plurality of particulates, wherein each particulate comprises: a core
comprising quetiapine, a pH neutral polymer layer surrounding the core and a pH sensitive
polymer layer surrounding the core, wherein the average particle size (D50) of coated
particulates is from 0.7 to 1.6 mm or average particle size of the coated particulate is less than
1.6 mm.
20 In an embodiment of the present invention, the multi-particulate dosage form has an
extended-release coating which comprises a pH neutral polymer in an amount of about 5% to
about 25% based on the weight of drug core.
In one embodiment of the present invention, the multi-particulate dosage form has an
extended release coating which comprises a pH neutral polymer in an amount of about 50% to
25 about 80% based on the weight of the enteric coating, preferably about 55% to about 75%
based on weight of the enteric coating.
In yet another embodiment of the present invention, the extended release coating
comprises about 12% to about 32% w/w of the drug core, preferably about 12% to 20% w/w.
14
In another embodiment of the present invention, the multi-particulate dosage form has a
delayed release coating which comprises a pH sensitive polymer in an amount of about 10% to
about 30% based on the weight of drug core.
In one embodiment of the present invention, the multi-particulate dosage form has a
5 delayed release coating which comprises a pH sensitive polymer in an amount of about 55% to
about 95% based on the weight of the delayed release coating, preferably about 60% to about
90% based on weight of the delayed release coating.
In a further embodiment of the present invention, the delayed release coating comprise
about 15% to about 45% w/w of the drug core, preferably about 15% to about 35% of the drug
10 core.
In one embodiment of the present invention, the active ingredient in the composition
comprises about 35% to about 70% w/w of a unit dosage form.
In yet another embodiment of the present invention, the active ingredient in the
composition comprises about 50% to about 70% w/w of the core.
15 In another embodiment, the present invention provides an extended release multiparticulate sprinkle dosage form comprising a plurality of discrete units, wherein each unit
comprises a drug core comprising quetiapine or a pharmaceutically acceptable salt thereof; an
extended release coating and a delayed release coating surrounding the core, wherein the drug
release from the multi-particulate dosage form is controlled with pH neutral and pH sensitive
20 polymers in the coatings respectively. In yet another embodiment, the present invention
provides an extended release multi-particulate sprinkle dosage form comprising a plurality of
discrete units, wherein each unit comprises a drug core comprising quetiapine or a
pharmaceutically acceptable salt thereof, at least two coatings on the drug core to control the
release of the drug from the core, wherein each coating comprises a pH sensitive polymer, a pH
25 neutral polymer or a combination thereof.
In one embodiment, the present invention provides an extended release multi-particulate
sprinkle dosage form comprising a plurality of discrete units, wherein each unit comprises a
drug core comprising quetiapine or a pharmaceutically acceptable salt thereof; an extended
release coating comprising a pH neutral polymer and a delayed release coating comprising a pH
15
sensitive polymer surrounding the core, wherein the drug release from the multi-particulate
dosage form is controlled with a combination of pH neutral and/or pH sensitive polymers in the
coatings.
In yet another embodiment, the present invention provides an extended release multi5 particulate sprinkle dosage form comprising a plurality of discrete units, wherein each unit
comprises a drug core comprising quetiapine or a pharmaceutically acceptable salt thereof; a
delayed release coating comprising a pH sensitive polymer and an extended release coating
comprising a pH neutral polymer surrounding the core, wherein the drug release from the
multi-particulate dosage form is controlled with a combination of pH sensitive and/or pH
10 neutral polymers in the coatings.
In a related embodiment, the present invention provides a multi-particulate dosage form
wherein the extended-release coating or the coating with pH neutral polymer comprises a
water-insoluble polymer.
In some embodiments, the extended release multi-particulate sprinkle dosage form
15 according to present invention comprises a plurality of discrete units, wherein each unit
comprises: a drug core comprising quetiapine or a pharmaceutically acceptable salt thereof; at
least two coatings on drug core for controlling the release of quetiapine from the drug core
wherein one of the at least two coatings comprises a pH sensitive polymer; and wherein said
dosage form when administered orally as a single dose has a mean Cmax under fasting
20 condition in the range of about 180 ng/mL to about 450 ng/mL and a mean Cmax under fed
condition in the range of about 250 ng/mL to about 650 ng/mL.
In some embodiments, the extended release multi-particulate sprinkle dosage form
according to present invention comprises a plurality of discrete units, wherein each unit
comprises: a drug core comprising quetiapine or a pharmaceutically acceptable salt thereof; at
25 least two coatings on drug core for controlling the release of quetiapine from the drug core
wherein one of the at least two coatings comprises a pH sensitive polymer; and wherein said
dosage form when administered orally as a single dose has a mean AUC0-inf under fasting
condition is in the range of 4000 hr.ng/mL to 4800 hr.ng/mL and a mean AUC0-inf under fed
condition in the range of about 4300 hr.ng/mL to 6300 hr.ng/mL.
16
In one embodiment, the extended release multi-particulate sprinkle dosage form
according to present invention comprises a plurality of discrete units, wherein each unit
comprises: a drug core comprising quetiapine or a pharmaceutically acceptable salt thereof; at
least two coatings on drug core for controlling the release of quetiapine from the drug core
5 wherein one of the at least two coatings comprises a pH sensitive polymer; and wherein the
said dosage form when administered orally as a single dose with high fat meals results in not
more than (NMT) a 35% change in Cmax or AUC when compared to a similar dosing under
fasting conditions.
In another embodiment, the present invention provides a pharmaceutical composition of
10 quetiapine or a pharmaceutically acceptable salt thereof, wherein said composition is believed
to be bioequivalent to an extended release multi-particulate sprinkle dosage form comprising a
plurality of discrete units, wherein each unit comprises: a drug core comprising quetiapine or a
pharmaceutically acceptable salt thereof; at least two coatings on drug core for controlling the
release of quetiapine from the drug core wherein one of the at least two coatings comprises a
15 pH sensitive polymer; and wherein the said dosage form when administered orally as a single
dose with high fat meals results in not more than (NMT) a 35% change in Cmax or AUC when
compared to a similar dosing under fasting conditions.
In a further embodiment, the multi-particulate dosage form according to the present
invention further comprises a pore former in the extended release coating, wherein the ratio of
20 extended release polymer and pore former in the coating is in a ratio of 70:30 to 99:1 or 75:25
to 97:3 or 80:20 to 95:5. Preferably, the ratio is 80:20 to 95:5. In another embodiment, the
multi-particulate dosage form according to the present invention further comprises a pore
former in the pH neutral coating, wherein the ratio of pH neutral polymer and pore former in
the coating is in a ratio of 70:30 to 99:1 or 75:25 to 97:3 or 80:20 to 95:5.Preferably the ratio is
25 80:20 to 95:5.
In an embodiment, the extended release multi-particulate sprinkle dosage form
comprises a plurality of discrete units, wherein each unit comprises: a drug core comprising
quetiapine or a pharmaceutically acceptable salt thereof; at least two coatings on drug core
wherein one of the at least two coatings comprises a pH sensitive polymer; and wherein the
30 release of the drug is controlled by a combination of said at least two coatings, wherein the
17
dosage form further comprises a pore former and the ratio of one of the two coatings and the
pore former is 80:20 to 95:5.
In one embodiment, the multi-particulate sprinkle dosage form according to the present
invention comprises coated particulates having a particle size in range of 0.5 mm – 1.6 mm, and
5 said sprinkle dosage form releases not more than 20% of quetiapine after two hours, when
measured in a United States Pharmacopeia (USP) type I dissolution apparatus, 200 rpm, at a
temperature of 37° C ± 0.5° C in 900 mL of pH 4.80 citrate buffer media.
In a further embodiment, the present invention provides a pharmaceutical composition
of quetiapine or a pharmaceutically acceptable salt thereof, wherein said composition is
10 believed to be bioequivalent to an extended release multi-particulate sprinkle dosage form
comprising a plurality of discrete units, wherein said multi-particulate sprinkle dosage form
comprises coated particulates having a particle size in range of 0.5 mm – 1.6 mm, and said
sprinkle dosage form releases not more than 20% of quetiapine after two hours when measured
in a United States Pharmacopeia (USP) type I dissolution apparatus, 200 rpm, at a temperature
15 of 37° C ± 0.5° C in 900 mL of pH 4.80 citrate buffer media.
In another embodiment of the present invention, the multi-particulate dosage form
releases about 30% to about 70% of quetiapine at eight hours, when measured in a United
States Pharmacopeia (USP) type I dissolution apparatus, 200 rpm, at a temperature of 37° C
±0.5° C in 1000 mL of pH 6.60 citrate buffer follow on media after 5th hour of pH 4.80 citrate
20 buffer media.
In one embodiment of the present invention, the multi-particulate dosage form releases
not more than 10% of quetiapine after 2 hours, when measured in a United States
Pharmacopeia (USP) type I dissolution apparatus, 200 rpm, at a temperature of 37° C ±0.5° C
in 1000 mL of pH 0.1 N HCl (40 mesh basket).
25 In another embodiment of the present invention, the multi-particulate dosage form
releases not more than 30% of quetiapine when measured in a United States Pharmacopeia
(USP) type I dissolution apparatus, 200 rpm, at a temperature of 37° C ±0.5° C in 1000 mL of
pH 6.60 phosphate buffer follow on media (after 2 hours dissolution in 0.1 NHCl) after 1st hour
of buffer stage (40 mesh basket).
18
In another embodiment of the present invention, the multi-particulate dosage form
releases about 40% to about 70% of quetiapine when measured in a United States
Pharmacopeia (USP) type I dissolution apparatus, 200 rpm, at a temperature of 37° C ±0.5° C
in 1000 mL of pH 6.60 phosphate buffer follow on media (after 2 hours dissolution in 0.1
NHCl) after 6th 5 hour of buffer stage (40 mesh basket).
In another embodiment of the present invention, the multi-particulate dosage form
releases about 40% to about 70% of quetiapine when measured in a United States
Pharmacopeia (USP) type I dissolution apparatus, 200 rpm, at a temperature of 37° C ±0.5° C
in 1000 mL of pH 6.60 phosphate buffer follow on media (after 2 hours dissolution in 0.1
NHCl) after 22nd 10 hour of buffer stage (40 mesh basket).
In one embodiment, the present invention provides a dosage form which is believed to
be bio-equivalent to an extended release multi-particulate sprinkle dosage form comprising a
plurality of discrete units, wherein each unit comprises: a drug core comprising quetiapine or a
pharmaceutically acceptable salt thereof; an extended release coating and a delayed release
15 coating surrounding the core, wherein the drug release from the multi-particulate dosage form
is controlled by pH sensitive and pH neutral polymers in the coatings, wherein the AUC and
Cmax is in the range 80-125%.
In another embodiment, the extended release multi-particulate sprinkle dosage form
according to the present invention comprises a plurality of discrete units, wherein each unit
20 comprises: a drug core comprising quetiapine or a pharmaceutically acceptable salt thereof; at
least two coatings on drug core wherein one of the at least two coatings comprises a pH
sensitive polymer; and wherein the release of the drug is controlled by a combination of the
said at least two coatings, wherein administration of the sprinkle dosage form under fasting
conditions provides AUC and Cmax values within the acceptable range of 80-125%.
25 In yet another embodiment, there is provided a pharmaceutical composition of
quetiapine or a pharmaceutically acceptable salt thereof, wherein said composition is believed
to be bioequivalent to an extended release multi-particulate sprinkle dosage form comprising a
plurality of discrete units, wherein each unit comprises: a drug core comprising quetiapine or a
pharmaceutically acceptable salt thereof; at least two coatings on the drug core wherein one of
30 the at least two coatings comprises a pH sensitive polymer; and wherein the release of the drug
19
is controlled by a combination of said at least two coatings, wherein administration of the
sprinkle dosage form under fasting conditions provides AUC and Cmax values within the
acceptable range of 80-125%.
In a further embodiment, the present invention provides an extended release multi5 particulate sprinkle dosage form comprising a plurality of discrete units, wherein each unit
comprises: a drug core comprising quetiapine or a pharmaceutically acceptable salt thereof; an
extended release coating and a delayed release coating surrounding the core, wherein the drug
release from the multi-particulate dosage form is controlled by pH sensitive and pH neutral
polymers in the coatings, and the core is devoid of any release controlling polymer.
10 In one embodiment of the present invention, the multi-particulate composition is
substantially free of an immediate release component.
In an embodiment of the present invention, the extended release coating comprises a
combination of a pH neutral and a pH sensitive polymer.
The term “pH neutral polymer(s)” as used herein includes, but is not limited to,
15 cellulose ethers such as ethyl cellulose; cellulose esters, polymethacrylic acid esters
copolymers, e.g., Eudragit® NE 30 D, and Eudragit® NE 40 D aminoalkyl methacrylate
copolymers, e.g., Eudragit® RL 100, Eudragit® RL PO, Eudragit® RS PO, and Eudragit® RS
100; polyvinyl acetate, copolymers of polyvinyl acetate and polyvinyl pyrrolidone, or a mixture
thereof. Preferably, the pH neutral polymer is ethyl cellulose.
20 The term “pH sensitive polymer(s)” as used herein includes, but is not limited to,
acrylic acid derivatives, e.g., methyl acrylate acrylic acid copolymer, methyl acrylate
methacrylic acid copolymer, butyl acrylate styrene acrylic acid copolymer, methacrylic acid
methyl methacrylate copolymer (e.g., Trade-names: Eudragit L 100 and Eudragit S, available
from Rohm Pharma), methacrylic acid ethyl acrylate copolymer, e.g., Eudragit L 100-55,
25 available from Rohm Pharma, methyl acrylate methacrylic acid octyl acrylate copolymer;
cellulose derivatives e.g. cellulose acetate phthalate, cellulose acetate succinate, cellulose
acetate maleate, cellulose acetate trimelliate, cellulose benzoate phthalate, cellulose propionate
phthalate, methylcellulose phthalate, carboxymethylethylcellulose, ethylhydroxyethylcellulose
phthalate, polyvinyl derivatives, e.g.. polyvinyl alcohol phthalate, polyvinylacetal phthalate,
20
polyvinyl butylate phthalate, polyvinylacetoacetal phthalate and maleic acid copolymers, or a
mixture thereof.
In one embodiment, the present invention provides a high drug load sprinkle dosage
form for nasogastric administration, wherein said dosage form comprises: quetiapine or its
5 pharmaceutically acceptable salt in a dose range of 200-400 mg twice or thrice daily; which can
be administered to psychiatric patients, or patients who are unconscious or are having
swallowing difficulty. In a related embodiment of this aspect, the multi-particulate composition
is sprinkled onto soft foods or edible material or liquids.
In yet another embodiment of the present invention, the multi-particulate composition is
10 sprinkled onto soft foods, for example, applesauce, yogurt, cottage cheese, peaches purees,
pears purees, lychee purees, apricots purees, grapes purees, strawberries purees, raspberries
purees, or bananas purees at the time of administration. In a further embodiment of the present
invention, the multi-particulate composition is sprinkled onto liquids, for example, cranberry
juice, grape fruit juice, orange juice, pineapple juice, mango juice, apple juice, vegetable juice,
15 tomatoes juice, water or milk at the time of administration. In a related embodiment of this
invention, the multi-particulate composition when sprinkled onto soft foods or edible material
or liquids are stable for at least about 15 minutes without affecting the stability of the extended
release coating.
In another embodiment, the composition according to present invention is a multi20 particulate dosage comprising a plurality of discrete units, where in each unit is separately
coated thereby in case of accidental rupture of two or three pellets or granules there won’t be
any significant dose dumping.
In a further embodiment, the multi-particulate composition according to present
invention also reduces the variability in bioavailability as the gastric emptying of the pellets or
25 granules are not significantly impacted due to the size of pellets less than 2 mm.
In yet another embodiment of the present invention, the multi-particulate composition
when sprinkled onto soft foods or edible material or liquids is stable to be administered
immediately with food. In another embodiment of this aspect, the multi-particulate composition
is suitable for administration to a patient via a feeding tube. In a further embodiment of this
30 aspect, the feeding tube is a nasogastric (NG) tube or a gastric (G) tube.
21
In one embodiment of the present invention, the multi-particulate composition when
dispersed in an aqueous media is stable when administered through a feeding tube after holding
for at least 10 minutes.
In another embodiment, the present invention provides an extended release multi5 particulate sprinkle dosage form comprising a plurality of discrete units, wherein the said multiparticulate sprinkle dosage form comprise coated discrete units having a particle size in range
of 0.5 mm – 1.6 mm, wherein the discrete units when exposed to water for 60 minutes in a
syringe, and then passed through a 12 French nasogastric tube into a dissolution medium of
0.1N HCl, releases not more than 0.5% of quetiapine N-oxide impurity or not more than 0.5%
10 of impurity C after 2 hours, when placed in 1000 mL of 0.1N HCl at 100 rpm in USP apparatus
I.
In one embodiment, the extended release multi-particulate sprinkle dosage form
according to present invention is stable for at least 6 months under storage conditions of
40⁰C/75%RH. In one embodiment according to present invention, the multi-particulate sprinkle
15 dosage has controlled level of impurities after storage period of at least 6 months, wherein the
dosage form contains not more than 0.5% of quetiapine N-oxide impurity (USP related
compound H), contains not more than 0.5% of impurity C (USP related compound G), any
unspecified degradation product not more than 0.5% and total impurities not more than 1% by
weight of quetiapine.
20 In some embodiments, the extended release multi-particulate sprinkle dosage form
according to present invention is stable for at least 6 months under storage conditions of
40⁰C/75%RH. In one embodiment according to present invention, the multi-particulate sprinkle
dosage has controlled level of impurities after a storage period of at least 6 months, wherein the
dosage form contains not more than 0.2% of quetiapine N-oxide impurity (USP related
25 compound H), contains not more than 0.2% of impurity C (USP related compound G), any
unspecified degradation product not more than 0.2% and total impurities not more than 0.6%
by weight of quetiapine.
In another embodiment, the present invention provides an extended release multiparticulate sprinkle dosage form comprising a plurality of discrete units, wherein the said multi30 particulate sprinkle dosage form comprise coated discrete units having a particle size in range
22
of 0.5 mm – 1.6 mm, wherein the discrete units when exposed to water for 60 minutes in a
syringe, and then passed through a 12 French nasogastric tube into a dissolution medium of
0.1N HCl, releases not more than 0.2% of quetiapine N-oxide impurity or not more than 0.2%
of impurity C after 2 hours, when placed in 1000 mL of 0.1N HCl at 100 rpm in USP apparatus
5 I.
In another embodiment according to present invention, the multi-particulate sprinkle
dosage form is stable for at least 6 months under storage condition of 40⁰C/75%RH, wherein
the water content of the dosage form is not more than 8.0%, preferably not more than 5.0, more
preferably not more than 3.5%, by weight of the composition.
10 In a preferred embodiment of the present invention, the multi-particulate composition
comprising coated discrete units may be filled into a pouch or a sachet.
In yet another embodiment of the present invention, the weight of pellets or granules or
spheroids filled in a sachet or a pouch may range from about 100 mg to about 200 mg for 50
mg strength of quetiapine; about 300 mg to about 600 mg for 150 mg; about 400 mg to about
15 800 mg for 200 mg strength of quetiapine; about 600 mg to about 1200 mg for 300 mg strength
and about 800 mg to about 1600 mg for 400 mg strength of quetiapine.
The multi-particulate composition of present invention may further comprise
pharmaceutically acceptable excipients, for example, binders, diluents, disintegrants, poreformers, lubricants/glidants, surfactants, sweeteners, anti-tacking agents, opacifiers, anti20 foaming agents, coloring agents, taste masking/flavoring agents, or a mixture thereof.
Examples of diluents that may be used in the present composition include, but are not
limited to, microcrystalline cellulose, lactose, sorbitol, calcium dihydrogen phosphate
dihydrate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, silicified
microcrystalline cellulose, mannitol, disaccharide sugars, starch, pregelatinized starch, or a
25 mixture thereof.
Examples of binders that may be used in the present composition include, but are not
limited to, corn starch, pregelatinized starch, microcrystalline cellulose, silicified
microcrystalline cellulose, methyl cellulose, hydroxypropyl cellulose (HPC-L),
23
methylcellulose, carboxymethyl cellulose sodium, guar gum, polyvinylpyrrolidone, or a
mixture thereof.
Examples of plasticizers that may be used in the present composition include, but are
not limited to, tributyl citrate, dibutyl sebacate, acetyl tributyl citrate, glyceryl monostearate,
5 diethyl phthalate, castor oil, acetylated monoglycerides, diacetylated monoglycerides, cetyl
alcohol, or a mixture thereof. The addition of plasticizer in the present invention helps in
maintaining integrity of coating layer(s) while achieving a desired rate of release of quetiapine
from multi-particulates.
Examples of lubricants and glidants that may be used in the present composition
10 include, but are not limited to, colloidal anhydrous silica, stearic acid, magnesium stearate,
glyceryl behenate, calcium stearate, sodium stearyl fumarate, stearic acid, talc, microcrystalline
wax, yellow beeswax, white beeswax, or a mixture thereof.
Examples of the disintegrants that may be used in the present composition include, but
are not limited to, crospovidone, sodium starch glycolate, sodium croscarmellose, guar gum,
15 carboxymethylcellulose, low viscosity hydroxypropylcellulose, potassium polacrilin, or a
mixture thereof.
Examples of surfactants that may be used in the present composition include, but are not
limited to, sorbitan monostearate, polyoxythylene sorbitan monostearate, e.g., Polysorbate 60
or Polysorbate 80, non-ethoxylated glyceryl monostearate, cetomacrogol, cetostearyl alcohol,
20 sodium stearoyl lactylate, lecithin, or a mixture thereof.
Examples of sweeteners that may be used in the present composition include, but are
not limited to, sucrose, sucralose, sorbitol, xylitol, dextrose, fructose, maltose, maltitol,
acesulfame potassium, aspartame, saccharin, saccharin sodium, glucose, cyclamate, sodium
cyclamate, or a mixture thereof.
25 Examples of opacifiers that may be used in the present composition include, but are not
limited to, titanium dioxide, silicon dioxide, talc, calcium carbonate, behenic acid, or a mixture
thereof.
Examples of anti-tacking agents that may be used in the present composition include,
but are not limited to, talc, colloidal silicon dioxide, or a mixture thereof.
24
Examples of anti-foaming agents that may be used in the present composition include,
but are not limited to, silicon based surfactants like polydimethylsiloxanes, e.g., simethicone;
vegetable oils; waxes; hydrophobic silica; polyethylene glycol, or a mixture thereof.
Suitable solvents are selected from water, methyl alcohol, ethyl alcohol, isopropyl
5 alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or a
mixture thereof.
The coloring agents and flavoring agents of the present invention may be selected from
any FDA approved suitable colors or flavors for oral use.
Coating may be carried out by using any conventional coating techniques known in the
10 art, such as, spray coating in a conventional coating pan, fluidized bed processor, or dry powder
coating, or a combination thereof.
The extended release multi-particulate composition of the present invention can be
prepared by various methods including fluidized bed granulation, wet granulation, solvent
evaporation, spray drying, or a combination thereof.
15 In yet another embodiment, the present invention provides a method for preparing a
multi-particulate composition of quetiapine.
In one embodiment, the present invention provides use of a combination of at least two
coatings for preparation of an extended release multi-particulate sprinkle dosage form of
quetiapine, wherein out of the at least two coatings on a drug core at least one coating
20 comprises a pH sensitive polymer; and wherein the release of the drug is controlled by a
combination of the at least two coatings.
In another embodiment, the present invention provides an extended release multiparticulate sprinkle dosage form prepared by a process comprising mixing quetiapine or its
pharmaceutically acceptable salt with suitable excipients and at least two coatings on a drug
25 core wherein one of the at least two coatings comprises a pH sensitive polymer; and wherein
the release of the drug is controlled by a combination of the at least two coatings.
In a further embodiment, the present invention provides a process of preparation of an
extended-release multi-particulate composition comprising a plurality of discrete units
25
comprising quetiapine or a pharmaceutical acceptable salt thereof, wherein the process
comprises:
i. mixing quetiapine or a pharmaceutical acceptable salt thereof with suitable
pharmaceutical acceptable excipients in a dry mix followed by granulation using a
5 suitable technique;
ii. extruding the resultant from step i) followed by spheronization;
iii. drying the resulting drug containing spheroids or granules or pellets from step ii);
iv. drying and sifting the resultant from step iii);
v. coating the drug containing core with a suitable pH neutral polymer;
10 vi. coating the core further with a suitable pH sensitive polymer; and
vii. lubricating the coated core followed by filling into a suitable sachet or pouch or
capsule.
In a further embodiment, the present invention provides a process of preparation of an
extended-release multi-particulate composition comprising a plurality of discrete units
15 comprising quetiapine or a pharmaceutical acceptable salt thereof, wherein the process
comprises:
i. mixing quetiapine or a pharmaceutical acceptable salt thereof with suitable
pharmaceutical acceptable excipients in a dry mix followed by granulation using a
suitable technique;
20 ii. extruding the resultant from step i) followed by spheronization;
iii. drying the resulting drug containing spheroids or granules or pellets from step ii);
iv. drying and sifting the resultant from step iii);
v. coating the drug containing core with a suitable pH sensitive polymer;
vi. coating the core further with a suitable pH neutral polymer; and
25 vii. lubricating the coated core followed by filling into a suitable sachet or pouch or
capsule.
In yet another related embodiment, the composition according to the present invention
26
may further comprise a suitable non-functional coating.
In one embodiment, the present invention provides a method of treating various
psychotic disorders. In an aspect, the present invention provides a method of treating
schizophrenia. In another aspect, there is provided a method of treatment of maniac or mixed
5 episodes associated with bipolar disorders. In a related aspect, the present invention also
provides a monotherapy or an adjunct therapy with other known therapies for the treatment of
manic or bipolar disorders. In a further aspect, the present invention provides an adjunctive
treatment of a major depressive disorder.
In a further embodiment, the present invention provides a method of treating
10 schizophrenia, major depression or bipolar disorder, said method comprising orally
administering to a human in need thereof, the multi-particulate pharmaceutical composition of
quetiapine according to the present invention.
In one embodiment, the present invention provides a use of an extended release multiparticulate composition comprising a plurality of discrete units of quetiapine or its
15 pharmaceutically acceptable salt according to the present invention for treatment of
schizophrenia, in management of acute manic or mixed episodes in patients with bipolar
disorder, as a monotherapy or in combination with other drugs.
In one embodiment, the stable multi-particulate pharmaceutical composition according
to the present invention is filled into a sachet or pouch or capsule with a controlled opening to
20 avoid spillage of the contents of such packing. This is particularly helpful for geriatric patients
or patients with poor locomotors control who have difficulty opening the sachet or pouch or
capsule to empty the contents onto soft food or edible material or liquid. Particularly, the
absence of fine powders in the multi-particulate pharmaceutical composition can avoid loss of
the composition which may result from blowing of the fine powder while being emptied from
25 the capsule or pouch onto the carrier solid or liquid food contents. Alternatively, the granules,
pellets or spheroids can be administered from a device which dispenses them directly onto the
soft food or edible material or liquid.
The following non-limiting examples illustrate the scope of the present disclosure
without any limitation thereto. It is to be understood that the disclosed embodiments are merely
30 exemplary of the invention, which can be embodied in various forms.
27
EXAMPLES:
Example 1: Various batches of quetiapine compositions were prepared with different
excipients to evaluate the impact of pH sensitive and pH neutral polymer:
Ingredients Example 1A Example 1B
Quetiapine Fumarate 230.270 230.270
Tri sodium citrate anhydrous 65.800 65.800
Avicel PH101 41.930 41.930
Pregelatinized starch
(Lycatab PGS) 20.000 20.000
Colloidal anhydrous silica
(Aerosil 200) 2.000 2.000
Core pellets 360.00 360.00
Opadry 18.000 18.000
Sub coated pellets wt. 378.00 378.00
Ethyl cellulose 20 cps 6.910 6.910
HPMC E5 8.446 8.446
Dibutyl sebacate 3.543 3.543
ER coated pellets 396.900 396.900
DR/ER coating DR ER
Eudragit L 100 55 (Enteric) 12.600 --
Ethyl cellulose -- 8.060
HPMC E5 3.150 8.060
Dibutyl sebacate 2.580 3.720
Talc 1.550 -
DR /ER coated pellets wt. 416.78 416.74
Talc 1.220 1.260
Total pellet weight 418.00 418.00
5 Table 1: Bio results of Example 1A and 1B:
Based on comparison
of Test / Reference
Fasting study results
Example 1A Example 1B
ln Cmax
(ng/mL)
ln AUC0-t
(ng.hr/mL)
ln AUC0-inf
(ng.hr/mL)
ln Cmax
(ng/mL)
ln AUC0-t
(ng.hr/mL)
ln AUC0-inf
(ng.hr/mL)
Based on
comparison
of T/R
Ratio (%)
(T/R) 118.63 91.84 94.45 160.13 77.79 85.90
90%
Confidence
96.84-
145.31
79.12-
106.60
81.36-
109.65
130.03-
197.20
66.75-
90.65
73.48-
100.42
28
Interval
Observation: From the Table 1 fasting study, it was found that the samples from Example 1B
showed risk of supra bioavailability with respect to Cmax as it did not have a pH sensitive
polymer. Cmax was on the higher side 160% (target 100% in ratio Test / Reference) when a pH
5 neutral polymer alone was used. When a combination of a pH sensitive and a pH neutral
polymer was used in the multi-particulate system, the Cmax was within the acceptable range of
80-125%.
Example 2:
10 Mixture of two different types of pellets: Pellet 1 – 70%w/w and Pellet 2 – 30%w/w, were
filled in a single sachet or pouch.
Composition of Pellet 1 (70% w/w)
Ingredients Quantity
Drug Core Pellets mg/unit dose
Quetiapine Fumarate eq. to quetiapine 200 mg 230.270
Microcrystalline cellulose (Avicel PH101) 75.730
Tri-Sodium Citrate dihydrate 50.000
Pregelatinized starch (Lycatab PGS) (Part A) 7.000
Pregelatinized starch (Lycatab PGS) (Part B) 15.000
Colloidal anhydrous silica 2.000
Purified water q.s.
Core pellet weight 380
DR Coating
Eudragit L30D 55 (solids polymer) 8.444
PEG 400 1.267
Talc 1.689
Purified water q.s.
DR coated weight 391.4
ER Coating
EC solids polymer (Aquacoat ARC I of II) 63.865
Guar gum (Aquacoat ARC II of II) 9.124
Dibutyl sebacate 15.966
29
Talc 8.895
Purified water q.s.
ER coated pellet wt. 489.25
Top Coat
Sodium Alginate CR8133 39.453
PEG 6000 5.793
Talc 52.604
Purified water q.s.
Total pellet weight per unit 587.1
Composition of Pellet 2 (30% w/w)
Ingredients Quantity
Drug Core Pellets mg/unit dose
Quetiapine Fumarate eq. to quetiapine 200 mg 230.270
Microcrystalline cellulose (Avicel PH101) 75.730
Tri-Sodium Citrate dihydrate 50.000
Pregelatinized starch (Lycatab PGS) (Part A) 7.000
Pregelatinized starch (Lycatab PGS) (Part B) 15.000
Colloidal anhydrous silica 2.000
Purified water q.s.
Core pellet weight 380
DR Coat
Hypromellose Acetate Succinate HF 95.00
Talc 19.00
Isopropyl alcohol q.s.
Purified water q.s.
DR coated pellet wt. 494.00
Top Coat
Sodium Alginate CR8133 39.84
PEG 6000 5.85
Talc 53.12
Total weight 592.80
Table 2: Bio results of Example 2 in fasting and food effect conditions:
ln Cmax
(ng/mL)
ln AUC0-t
(ng.h/mL)
ln AUC0-inf
(ng.h/mL)
30
Quetiapine: Fasting Equivalence
Ratio of Test &
Reference
(90% CI)
124.83 87.95 86.81
Quetiapine: Food Effect
Ratio of Test &
Reference
(90% CI)
110.79 108.05 107.97
Observation: From the Table 2 Bio-study it was found that the presence of food showed little
or no food effect.
5 Example 3: 200 mg equivalent of quetiapine formulation were prepared as per the composition
shown below:
S.
No Ingredients %w/w per Sachet
A B C D E F G H
Drug core
1
Quetiapine
fumarate 230.270 230.265 230.265 230.265 230.265 230.265 230.265 230.265
2
Microcrystalline
cellulose (PH101) 75.730 75.735 75.735 75.735 75.735 75.735 75.735 75.735
3
Tri Sodium
Citrate dihydrate 50.000 50.000 50.000 50.000 50.000 50.000 50.000 30.000
4
Pregelatinized
starch 22.000 22.000 22.000 22.000 22.000 22.000 22.000 22.000
6
Colloidal
anhydrous silica 2.000 2.000 2.000 2.000 2.000 2.000 2.000 2.000
7 Purified water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
ER Coating
8
Ethyl cellulose
dispersion (Solid) 62.005 39.683 43.084 39.683 49.603 62.004 49.603 39.683
9 Guar gum 8.858 5.669 2.241 5.669 7.086 8.858 7.086 5.669
10 Dibutyl sebacate 15.501 9.921 9.921 9.921 12.401 15.501 12.401 9.921
11 Talc 8.636 5.527 5.527 5.527 6.910 8.637 6.910 5.527
12 Purified water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
DR coating
13 Eudragit L30D 55
(solid) 70.370 65.304 65.304 70.528 54.044 39.970 67.556 65.304
14 Talc 14.074 13.061 13.061 8.816 8.107 5.996 10.133 13.061
15 PEG 400 10.556 9.795 9.795 8.816 10.809 7.994 13.511 9.795
31
16 Purified water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Top Coat
17 HPMC 6 CPS 19.136 -- -- -- -- -- -- --
18 Carbopol 971 P 1.222 -- -- -- -- -- -- --
19 Talc 8.144 -- -- -- -- -- -- --
20 Isopropyl alcohol q.s. -- -- -- -- -- -- --
21 Purified water q.s. -- -- -- -- -- -- --
Lubrication
22 Talc -- 5.290 5.290 5.290 5.290 5.290 5.290 5.290
Final Weight 598.502 534.250 534.250 534.250 534.250 534.250 552.672 514.250
Manufacturing process Example 3A:
1. Quetiapine, microcrystalline cellulose, part of pregelatinsed starch and colloidal silicon
dioxide were mixed in a dry mix followed by the addition of sodium citrate and remaining
5 part of pregelatinised starch in purified water;
2. The resulting mixture from step 1) was then granulated in a rapid mixture granulator;
3. The resulting mass from step 2) was extruded and spheronized to form particulates as
spheroids/pellets/granules which were subjected to drying and sifting;
4. A dispersion of ethyl cellulose was prepared, guar gum and dibutyl sebacate and purified
10 water added to it;
5. Then the step 3) sifted particulates were coated with the dispersion of step 4) to obtain
extended release coated cores.
6. A delayed release coat of Eudragit L 30 D 55, polyethylene glycol, talc and purified water
was coated onto the step 5) extended release coated cores.
15 7. HPMC and Carbopol were dissolved in isopropyl alcohol and water followed by coating the
delayed release coated particles of step 6) followed by lubrication with talc and filling into
sachet.
Manufacturing process Example 3(B-H):
32
1. Quetiapine, microcrystalline cellulose, part of pregelatinsed starch and colloidal silicon
dioxide were mixed in dry mix followed by addition of sodium citrate and remaining part of
pregelatinised starch in purified water;
2. The resulting mixture from step 1) was then granulated in a rapid mixture granulator;
5 3. The resulting mass from step 2) was extruded and spheronized to form spheroids/pellets
which were subjected to drying and sifting;
4. A dispersion of ethyl cellulose was prepared, guar gum and dibutyl sebacate and purified
water added to it;
5. Then the step 3) sifted spheroids/pellets were coated with the dispersion of step 4) to obtain
10 extended release coated cores.
6. A delayed release coat of Eudragit L 30 D 55, polyethylene glycol, talc and purified water
was coated onto the step 5) extended release coated cores.
7. The resulting delayed release coated core particles were then lubricated with talc and filled
into sachet.
15 Table 3: Bio results of Example 3B in fasting and food effect study conditions:
Ratio of Test and Reference ln Cmax
(ng/mL)
ln AUC0-t
(ng.hr/mL)
ln AUC0-inf
(ng.hr/mL)
Fasting Condition
Ratio (%) (T/R) 106.89 94.79 95.23
90% Confidence Interval 91.50 - 124.86 87.92 - 102.19 88.48 - 102.49
Intra-Subject CV (%) 27.07 12.92 12.63
Food Effect Study
Ratio (%) (T/R) 111.48 112.17 110.95
90% Confidence Interval 96.95 - 128.20 103.85- 121.15 102.89 - 119.65
Intra-Subject CV (%) 24.25 13.24 12.96
33
Observation: From Table 3, fasting data and the food effect data shows that food has no effect
on the drug release from the multi-particulate composition according to the present invention
and the Cmax was within the acceptable range of 80-125 %.
5 Example 4: 50 mg, 200 mg and 400 mg equivalent of quetiapine formulations were prepared as
per the compositions shown below:
S. No
Ingredients
%w/w per Sachet
50 mg Strength 200 mg Strength 400 mg Strength
A B C D E F G H I
Drug core
Quetiapine
fumarate
equivalent to
Quetiapine base
57.571 57.556 57.566 230.270 230.265 230.265 460.539 460.530 460.389
Microcrystalline
cellulose 17.491 19.592 18.934 78.132 75.735 81.242 148.91 151.47 153.35
Sodium Citrate
(tri sodium
citrate
dihydrate)
13.5 11.8 12.500 48.0 50.0 53.0 91.500 100 104
Pregelatinized
starch 6.3 4.8 5.500 24 22 18 48 44 39
Colloidal
Silicon dioxide 1 0.7 0.5 5 2 4 8 4 6
Purified water* q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Weight of Core 95.847 94.448 95.0 385.402 380.0 386.507 756.949 760.0 762.739
ER Coating
Ethyl cellulose
aq. dispersion
(Solid)#
10.227 10.836 9.921 38.643 39.683 41.503 85.554 79.366 74.756
Guar gum 1.65 1.81 1.417 5.137 5.669 4.328 12.160 11.338 15.312
Dibutyl
sebacate 2.92 3.17 2.48 8.789 9.921 7.786 17.435 19.842 16.811
Talc 1.41 1.16 1.382 5.231 5.527 3.245 9.853 11.054 12.348
Purified water* q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Weight of
extended release
pellets
112.054 111.424 110.2 443.202 440.8 443.369 881.951 881.6 881.966
DR coating
Methacrylic
acid copolymer 17.505 15.807 16.326 64.461 65.304 62.952 134.463 130.608 135.392
34
Dispersion
USNF
equivalent to
dry polymer^
Polyethylene
glycol 400 3.141 2.865 2.449 8.819 9.795 11.138 18.651 19.590 21.262
Talc 3.86 2.953 3.265 14.561 13.061 12.465 23.412 26.122 19.819
Purified water* q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Weight of
delayed release
pellets
136.56 133.049 145.676 531.043 528.96 529.924 1058.477 1057.92 1058.433
Lubrication
Talc 1.1 0.81 0.960 5.421 3.840 4.876 8.551 7.680 11.132
Weight of
lubricated
pellets
137.66 133.859 133.200 536.464 532.800 534.8 1067.028 1065.600 1069.565
* Evaporates during processing; # 30% of dispersion taken in solid form; ^ 30% of dispersion
taken as dry polymer; aq. Aqueous
Stability Data: The samples of Example 4 were kept for stability studies for 1, 3 and 6 months,
respectively. The stability analysis was done using an assay method for determining the content
5 of drug in the stored stability samples of Example 4. The stability analysis was also done by
performing dissolution studies at 0.1N HCl medial 1000ml for 2 hour, followed by pH 6.60
phosphate buffer media (1000ml); in USP-I with (40mesh basket) at 200 RPM. The details of
stability study results are provided in below Table 4 and Table 5:
Table 4: Stability study data of 50 mg and 200 mg strength samples:
Strength 50 mg 200 mg
Test
Stage->
Spec.
Initial 40⁰C/75%RH Initial 40⁰C/75%RH
1M 3M 6M 1M 3M 6M
Assay 90-110% 98.6 98.8 104.8 104.6 98.7 102.3 101.1 99.4
Dissolution
Acid stage - 2 hr NMT 10% 0 1 0 0 0 0 1 0
Buffer Stage - 1 hr NMT 30% 19 20 16 18 18 18 21 19
Buffer stage - 6 hr 40% - 70% 59 56 55 50 53 54 58 54
Buffer Stage - 22 hr NLT 80% 99 96 94 95 93 97 101 92
Related Substance
Quetiapine N Oxide
(USP Related
compound H)
NMT 0.2% 0.03 0.04 0.05 0.06 0.03 0.04 0.05 0.05
35
Impurity C
(USP Related
compound G)
NMT 0.2% BLQ BLQ 0.01 0.01 BLQ BLQ 0.01 0.01
Any individual
unspecified
degradation product
NMT 0.2% 0.01 0.04 0.01 0.01 BLQ 0.04 0.01 0.01
Total impurities NMT 0.6% 0.03 0.04 0.10 0.1 0.03 0.04 0.09 0.11
Water by KF NMT 8.0% 1.87 2.01 2.07 2.29 1.75 1.95 1.84 2.21
Note: BLQ – below limit of quantification; NMT – Not More Than; NLT – Not Less Than;
USP – United States Pharmacopoeia; HCl – Hydrochloric Acid;
Table 5: Stability study data of 400 mg strength samples:
Strength 400 mg
Test Stage->
Spec.
Initial 40⁰C/75%RH
1M 3M 6M
Assay 90-110% 101.1 98.9 98.6 98.1
Dissolution:
Acid stage - 2 hr NMT 10% 0 0 0 0
Buffer Stage - 1 hr NMT 30% 18 15 11 21
Buffer stage - 6 hr 40% - 70% 51 48 47 51
Buffer Stage - 22 hr NLT 80% 88 89 92 94
Related Substance:
Quetiapine N Oxide
(USP Related compound H) NMT 0.2% 0.03 0.04 0.05 0.06
Impurity C
(USP Related compound G) NMT 0.2% BLQ BLQ 0.01 0.004
Any individual unspecified
degradation product NMT 0.2% BLQ 0.04 0.01 0.02
Total impurities NMT 0.6% 0.03 0.08 0.12 0.14
Water by KF NMT 8.0% 1.85 1.79 1.74 2.99
5 Note: BLQ – below limit of quantification; NMT – Not More Than; NLT – Not Less Than;
USP – United States Pharmacopoeia; HCl – Hydrochloric Acid;
Since all five strengths (50mg, 150mg, 200mg, 300mg and 400mg) are dose proportional,
stability of data of intermediate strengths (150mg and 300mg) has not been generated.
Observation: From Table 4 and Table 5, stability data for assay and dissolution shows that:
10 - the assay of the drug was within the acceptable specification limits of 90.0% - 110.0%,
36
- the dissolution values of the stability batches were also within the acceptable limit of NMT
10% in acid stage and NLT 80% at end of Buffer stage, and
- the water content was also NMT 8.0%.
The samples of all the strengths used in the stability studies were found to be stable for at least
5 for 6 months.
Abbreviations:
DR: Delayed Release.
ER: Extended Release.
10 T/R Ratio: Test/Reference Ratio
Intra-subject CV: Intra-subject Coefficient of Variation
AUC: Area under the plasma concentration-time curve
Cmax: Maximum plasma concentration.
NLT: Not less than.
15 NMT: Not more than.
BLQ – below limit of quantification.
USP – United States Pharmacopoeia.
37
WE CLAIM:
1. An extended release multi-particulate sprinkle dosage form comprising a plurality of
discrete units, wherein each unit comprises:
a) a drug core comprising quetiapine or a pharmaceutically acceptable salt thereof;
5 b) at least two coatings on the drug core wherein one of the at least two coatings
comprises a pH sensitive polymer; and
wherein the release of the drug is controlled by a combination of said at least two
coatings.
2. The extended release multi-particulate sprinkle dosage form according to claim 1,
10 wherein out of the two coatings surrounding the core, at least one coating is an extended
release coating and the other coating is a delayed release coating.
3. The extended release multi-particulate sprinkle dosage form according to claim 2,
wherein the extended release coating comprises a pH neutral polymer in an amount of
about 50% to about 80% based on the weight of the enteric coating.
15 4. The extended release multi-particulate sprinkle dosage form according to claim 2,
wherein the delayed release coating comprises a pH sensitive polymer in an amount of
about 55% to about 95% based on the weight of the delayed-release coating
5. The extended release multi-particulate sprinkle dosage form according to claim 1,
wherein out of the two coatings surrounding the core, at least one coating comprises a
20 pH neutral polymer or a pH sensitive polymer.
6. The extended release multi-particulate sprinkle dosage form according to claim 1,
wherein the two coatings may optionally comprise a combination of a pH sensitive and
pH neutral polymer.
7. The extended release multi-particulate sprinkle dosage form according to any of the
25 preceding claims wherein the drug core is devoid of any release controlling polymer.
8. The extended release multi-particulate sprinkle dosage form according to claim 1,
wherein the coating may further comprise an optional non-function coating.
38
9. The extended release multi-particulate sprinkle dosage form according to claim 1,
wherein the dosage form is a sustained or controlled release dosage form.
10. The extended release multi-particulate sprinkle dosage form according to claim 1,
wherein the dosage form is a delayed or modified release dosage form.
5 11. The extended release multi-particulate sprinkle dosage form according to claim 1,
wherein said composition further comprises pharmaceutically acceptable excipients
selected from a diluent, a binder, a disintegrant, a pore-former, a lubricant, a glidant, a
surfactant, a sweetener, an anti-tacking agent, an opacifier, an anti-foaming agent, a
coloring agent, a flavoring agent, or a mixture thereof.
10 12. The extended release multi-particulate sprinkle dosage form according to claim 1,
wherein the drug release from the multiparticulate dosage form is controlled with a
combination of at least one pH neutral polymer in a pH neutral coating and at least one
pH sensitive polymer in a pH sensitive coating.
13. The extended release multi-particulate sprinkle dosage form according to any of the
15 preceding claims, wherein the dosage form is in the form of a sachet, pouch or capsule.
14. The extended release multi-particulate sprinkle dosage form according to any of the
preceding claims, wherein the discrete unit is a form selected from a pellet, a bead, a
particle, a granule or a mini-tablet.
15. The extended release multi-particulate sprinkle dosage form according to any of the
20 preceding claims, wherein the pH neutral polymer is a water-insoluble polymer.
16. The extended release multi-particulate sprinkle dosage form according to any of the
preceding claims, wherein the dosage form further comprises a pore former, wherein the
ratio of the pH neutral polymer and the pore former is 80:20 to 95:5.
17. The extended release multi-particulate sprinkle dosage form according to any of the
25 preceding claims, wherein the D50 of the discrete units is in a range of about 0.7 to 1.3
mm or particle size of the discrete units is less than about 1.6 mm.
18. The extended release multi-particulate sprinkle dosage form according to any of the
preceding claims, wherein said dosage form when administered orally as a single dose
39
with high fat meals results in not more than a 35% change in Cmax or AUC when
compared to a similar dosing under fasting condition.
19. The extended release multi-particulate sprinkle dosage form according to claim 1,
wherein the administration of the sprinkle dosage form under fasting conditions
5 provides a Cmax in range of about 180 ng/mL to about 450 ng/mL and/or a mean
AUC0-inf in the range of 4000 hr.ng/mL to 4800 hr.ng/mL.
20. The extended release multi-particulate sprinkle dosage form according to claim 1,
wherein the administration of the sprinkle dosage form under fed conditions provides a
Cmax in range of about 250 ng/mL to about 650 ng/mL and/or a mean AUC0-inf in the
10 range of 4300 hr.ng/mL to 6300 hr.ng/mL.
21. An extended release multi-particulate sprinkle dosage form comprising a plurality of
discrete units, wherein said multi-particulate sprinkle dosage form releases not more
than 30% of quetiapine when measured in a United States Pharmacopeia (USP) type I
dissolution apparatus, 200 rpm, at a temperature of 37° C ±0.5° C in 1000 mL of pH
6.60 phosphate buffer follow on media (after 2 hours dissolution in 0.1 NHCl) after 1st 15
hour of buffer stage.
22. An extended release multi-particulate sprinkle dosage form comprising a plurality of
discrete units, wherein said multi-particulate sprinkle dosage form releases about 40%
to about 70% of quetiapine when measured in a United States Pharmacopeia (USP) type
20 I dissolution apparatus, 200 rpm, at a temperature of 37° C ±0.5° C in 1000 mL of pH
6.60 phosphate buffer follow on media (after 2 hours dissolution in 0.1 NHCl) after 6th
hour of buffer stage.
23. An extended release multi-particulate sprinkle dosage form comprising a plurality of
discrete units, wherein said multi-particulate sprinkle dosage form comprise coated
25 discrete units having a particle size in the range of 0.5 mm – 1.6 mm, wherein the
discrete units when exposed to water for 60 minutes in a syringe, and then passed
through a 12 French nasogastric tube into a dissolution medium of 0.1N HCl, releases
not more than 0.5% of quetiapine N-oxide impurity after 2 hours, when placed in 1000
mL of 0.1N HCl at 100 rpm in USP apparatus I.
40
24. Use of a combination of at least two coatings for preparation of an extended release
multi-particulate sprinkle dosage form of quetiapine, wherein out of the at least two
coatings on a drug core at least one coating comprises a pH sensitive polymer; and
wherein the release of the drug is controlled by a combination of the at least two
5 coatings.
25. The extended release multi-particulate sprinkle dosage form according to any of the
preceding claims wherein, a higher amount of quetiapine in a dose range of 50-400 mg
can be administered as a sprinkle dosage form for nasogastric administration, wherein
the dosage form can be administered to a patient suffering from a psychiatric disorder
10 selected from schizophrenia, bipolar disorder, mania, depression where patients are
unconscious or having swallowing difficulty.
26. A method for treating a patient suffering from a psychotic disorders selected from
schizophrenia, bipolar disorder, mania, or depression, or as an adjunctive therapy with
an antidepressant, by administering a therapeutically effective amount of a multi15 particulate quetiapine sprinkle dosage form according to claim 1.
27. Use of a multi-particulate sprinkle dosage form according to any of the preceding
claims, for treatment of a psychotic disorder selected from schizophrenia, bipolar
disorder, mania, or depression, or as an adjunctive therapy with an antidepressant.
28. An extended release multi-particulate sprinkle dosage form prepared by a process
20 comprising: mixing quetiapine or its pharmaceutically acceptable salt with suitable
excipients and at least two coatings on a drug core wherein one of the at least two
coatings comprises a pH sensitive polymer; and wherein the release of the drug is
controlled by a combination of the at least two coatings.
29. The extended release multi-particulate sprinkle dosage form as claimed in claim 28,
25 wherein said process comprises the following steps:
i. mixing quetiapine or a pharmaceutical acceptable salt thereof with suitable
pharmaceutical acceptable excipients in a dry mix followed by granulation using a
suitable technique;
ii. extruding the resultant from step i above followed by spheronization;
41
iii. drying the resulting drug containing spheroids;
iv. sifting the resultant from step iii above;
v. coating the drug containing core with suitable coatings; and
vi. lubricating the coated core followed by filling into a suitable sachet or pouch or
5 capsule.
30. The extended release multi-particulate sprinkle dosage form as claimed in claim 28,
wherein the coating step v) comprises coating the drug containing core with a suitable
pH neutral polymer followed by coating the core further with a suitable pH sensitive
polymer.
31. The extended release multi-particulate sprinkle dosage form as claimed in claim 28,
wherein said excipient is selected from a diluent, a binder, a disintegrant, a pore-former,
a plasticizer, a lubricant, a glidant, a surfactant, a sweetener, an anti-tacking agent, an
opacifier, an anti-foaming agent, a coloring agent, a flavoring agent or a mixture
thereof.