This application is divided out of the Indian Patent Application no.: 733/KOLNP/2006
BACKGROUND OF THE INVENTION
Pantoprazole, 5-(difluoromethoxy)-2-[(3,4-dimethoxy-2- s
pyridyl)methylsulphinyrj-lH-benzimidazole, is a H+/K+-adenosine diphosphate
(ATP) inhibitor (also Icnown as acid pump or proton pump inhibitor (PPI), is an
enzyme present in the gastric parietal cells. It is believed that these drugs are
metabolized in the parietal cells to active sulfenamide metabolites that inactivate the
sulfhydryl group of the proton pump, thus reducing the hydrogen ion secretion. PPIs
are generally lipophilic weak bases with poor aqueous solubility at low pH. Many
PPIs are unstable in low pH solutions and undergo rapid acid-catalyzed degradation,
and they are relatively stable at neutral or high pH.
The current commercial oral formulations of sodium pantoprazole are single
unit coated tablets. See, e.g., US Patent 5997903, which describes oral forms of
pantoprazole that consist of a core, an intermediate layer and an outer layer. The
current coating has a tendency to cause undesirable sticking of the tablet to the
gastrointestinal tract.
Multiparticulate formulations, because of their nature of dispersing in the
gastrointestinal tract, show a reduced food effect and variability in gastric emptying
times, thereby providing for reduced inter and intra subject variability, as compared to
single unit tablets (Intl. Journal of Pharmaceutics 140 [1996] 229-235).
Several unsuccessful attempts have been made in the past to develop a
multiparticulate formulation of pantoprazole. However, these attempts yielded
multiparticulates that were not bioequivalent to tablets, only 70% relative
bioavailability was found. Another attempt using different technologies- non-pareil
seed coating and extrusion/spheronization, resulted in a product that did not provide
the appropriate release in acid conditions. In addition, these attempts yielded product
that was unstable, as observed by discoloration, when stored at room temperature.

SUMMARY OF THE INVENTION
The invention provides a stable multiparticulate pantoprazole formulation that
provides reduced inter and intra subject variability.
In one embodiment, the pantoprazole multiparticulates of the invention is
composed of a spheroid core comprising pantoprazole or an enantiomer thereof, or a
salt or hydrate thereof, at least one surfactant, at least one distintegrant, and about 1 %
to about 2% w/w water; an enteric coat on the core, said enteric coat comprising a
copolymer of methacrylic acid and methacrylates in the range of about 15 to about 45
% w/w of the spheroid core; wherein said multiparticulates have an average size of
about 1mm in diameter.
Advantageously, the multiparticulate formulations of the invention are stable
under room temperature storage conditions for at least twelve months. Based on the
trend analysis using the twelve month room temperature data and 6 month 40 °C/75%
relative humidity (RH) data available to date, the multiparticulates of the invention
should have a shelf life of over 2 years. Typically, a multiparticulate formulation of
the invention is considered stable if it retains 90% to 110% of its potency during shelf
life storage.
Tins pantoprazole multiparticulate formulation of the invention is less prone to
adherence to the intestinal walls, nasogastric and gastromy tubes, and pouch material
thereby giving predictable delivery of the drug product to the site of drug release. It
also provides for an early onset of action for relief of gastro-intestinal pain and has a
prolonged duration of action. This formulation allows dosing to pediatric patients and
patients who have difficulty swallowing solid foods. This formulation also allows for
ding delivery via nasogastric and gastrostomy tubes.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a multiparticulate formulation of pantoprazole
having a unique combination of excipients and a surfactant (e.g., polysorbate 80) that
are compatible with pantoprazole sodium in the presence of an alkaline pH
environment. Further, the invention provides a process that utilizes low shear during
granulation and low temperature during drying for preparation of the multiparticulate.

This process contributes to the stability of the core of the multiparticulates of the
invention.
In one aspect, the invention provides multiparticulate formulations of
pantoprazole havingsreduced release under gastric conditions and fast release at
neutral pH, i.e., in the lower gastrointestinal tract.
The multi particulate formulation of sodium pantoprazole of the invention
provides an enhanced system for the delivery of pantoprazole to patients. The current
marketed formulation is a single monolithic tablet. The present formulation of
multiparticulate spheroids, which is adaptable for use in a capsule or a foil packet, can
be prepared by extrusion/spheronization plus coating technology.
The composition of the multiparticle of the invention, and the enteric coat,
e.g., Eudragit, allows for reduced release at low pH (~1) and fast release at a neutral
pH (~7). This provides faster blood levels of the drag, in patients, and thereby a faster
onset of action. The smaller T|ag value of multiparticulate formulation as compared to
that of a single monolithic tablet based on the results from dog data indicates faster
onset of action of multiparticulate formulation.
The use of a multi particulate formulation facilitates dosing to pediatric
patients and patients who have trouble swallowing, by dispersing the spheroids in a
suspending liquid or sprinkling/dispersing in a low pH liquid like applesauce, prior to
administration. The suspending liquid could be made prior to administration by
mixing a blend of powder material with water. The smaller size of the multi
particulates, in a capsule or pouch or any other container, also allows dosing through
nasogastric or gastrostomy tube.
This formulation allows for a faster relief of GI pain, and prolonged duration
of action (extended release), as compared to the current marketed tablet.
I. Multiparticulates of the Invention
Suitably, the multiparticles are in the range of about 0.1 to 2 mm, or 0.5 mm to
1.5 mm, or 0.7 mm to 1.25 mm, or 0.8 mm to 1 mm. In one embodiment, the
multiparticulates in a composition of the invention average about 1 mm in diameter.

Typically, the multiparticles of the invention are no greater than about 1mm in size in
order to facilitate passage through nasogastric tubes
The multiparticulates of the invention are composed, at a minimum, of a
spheroid core with an enteric coat over the core. In between the core and enteric coat
an initial seal coat may be applied, e.g., comprising a coating of hydroxylpropyl
metrrylcellulose (hypromellose). Also, over the enteric coat a final seal coat may be
applied, e.g., a coating of hydroxylpropyl methyl cellulose (hypromellose). The
spheroid core is composed of, at a minimum, a pantoprazole or a salt thereof, and a
surfactant.
As used herein unless the context requires otherwise, the term 'pantoprazole'
refers to 5-(difluoromethoxy)-2-[(3,4-dimethoxy-2-pyidyI)methylsulphinyl]-lH-
benzimidazole and enantiomers thereof and the term 'pantoprazole compound'
includes pantoprazole and enantiomers and salts and hydrates thereof. The active
compound, pantoprazole is described in European Patent 166 287, which describes
the preparation thereof, and is available commercially under the brand name
PROTONIX ®. Examples of pharmaceutically acceptable salts of pantoprazole
include, e.g., sodium, magnesium, and calcium, among others; still others are
described in the European Patent 166 286, which is incorporated by reference herein.
The selection of a suitable salt is not a limitation of the invention. In one
embodiment, the salt is sodium. Typically, the pantoprazole compound is present in
the range of from about 5 to 50 % w/w, more preferably about 20 to 45 % w/w, of the
total multiparticulate.
Suitable surfactants are known to those of skill in the art. However,
particularly desirable are sodium lauryl sulfate, polysorbates, including, e.g.,
polysorbate SO, and mixtures of these components. Typically, the surfactant is
present in the core in an amount of about 2 to about 7 % w/w, and desirably, about 5%
w/w of the core. In another embodiment, the surfactant is present in a ratio of about
5:3 drug: surfactant (e.g., pantoprazole sodium sesquihydrate to sodium lauryl sulfate)
to about 10:1 drug: surfactant (e.g., pantoprazole sodium sesquihydrate to polysorbate
80). Advantageously, the surfactants in the multiparticulate formulation have been
found to enhance the wettability and, thus, the speed and extent of release and

absorption of the sodium pantoprazole, from the multi particulate formulation of the
invention.
The spheroid core can further contain a disintegrant, a pH adjuster and,
optionally a binder or another excipient such as hydroxypropyl methylcellulose (e.g.,
hypromellose 2208). Suitably, the total amount of disintegrant(s) present in the core is
an amount of about 15 % w/w to about 80 % w/w, or about 20% w/w to about 70 %
w/w, or about 25% w/w to about 45% w/w, or about 30% w/w to about 42 % w/w.
In one embodiment, the total amount of drug to binder is represented by a ratio of
from about 5 0:1 to about 40:1 by weight drugrbinder. The total amount of a pH
adjuster in the formulation can range from about 0.1% w/w to about 10% w/w of the
multiparticulate, or about 1% w/w to about 8% w/w, or about 3% w/w to about 7%
w/w. However, these percentages can be adjusted as needed or desired by one of skill
in the art.
The disintegrant may be selected from among other known disintegrants,
including, e.g., cellulose, and crospovidone, among others. In one embodiment, the
disintegrant is selected from among microcrystalline cellulose and crospovidone, and
mixtures thereof. The binder may be selected from among known binders, including
e.g., cellulose, and povidone, among others. In one embodiment, the binder is
hydroxylpropyl methyl cellulose (hypromellose). Suitable pH adjusters include, e.g.,
sodium carbonate, sodium bicarbonate, potassium carbonate, lithium carbonate,
among others. Still other suitable components will be readily apparent to one of skill
in the art.
In one embodiment, the spheroid core contains, w/w based on the dry
uncoated core, about 45% pantoprazole sodium sesquihydrate (about 40% free
pantoprazole) , about 25 to 30%, and preferably about 27% microcrystalline cellulose,
about 4 to 6%, and preferably about 5% polysorbate 80, about 14 to 16%, and
preferably about 15% crospovidone, about 0.5 to 2 %, and preferably about 1%
hypromellose 2208, about 5 to 8%, and preferably about 6.5% sodium carbonate. In
one embodiment, the spheroid core contains:


Although moisture is removed from the core during the drying process which
is described below, the core preferably retains about 1% to about 2% w/w water.
Without wishing to be bound by theory, the inventors believe that this water content
contributes the stability of this multiparticulate as compared to the failed prior art
attempts at forming a multiparticulate pantoprazole.
Optionally, an initial seal coat (or subcoat) can be applied directly to the core
prior to coating with the enteric coat. Although the components of this seal coat can
be modified by one of skill in the art, a particularly suitable initial seal coat is
composed of hydroxypropyl methylcellulose (hypromellose) and water. For example,
a suitable initial seal coat can be applied as a 7.5% w/w hypromellose solution.


The enteric coat is applied over the initial seal coat, if present, or directly to
the uncoated spheroid core. Suitably, the enteric coat is applied such that it coats the
core in an amount of about 15 to 45 % w/w, or about 20 % w/w to about 30% w/w, or
about 25% w/w to 30% w/w of the multiparticulate. In one embodiment, the enteric
coat is about 27.5 to 32.5 % w/w of the multiparticulate. Suitably, the enteric coat
contains a product which is a copolymer of methacrylic acid and methacrylates, such
as the commercially available Eudragit L 30D-55. In one embodiment, the enteric
coat is composed of a Eudragit L30D-55 copolymer, talc, triethyl citrate, sodium
hydroxide and water. More particularly, the enteric coating may contain about 30%
w/w of multiparticulate ( applied as a 30 wt% dispersion) of Eudragit L 30D-55
coating; about 15% w/w talc, about 3% triethyl citrate; apH adjuster such as sodium
hydroxide and water. Other suitable materials may be selected for use in the enteric
coat including, e.g., hydroxypropyl methylcellulose phthalate, cellulose acetate
phthalate and the like.
In one embodiment, a multiparticulate of the invention is provided with a
subcoat over the core and an enteric coat as follows:


In one embodiment, the enteric-coated multiparticulate is further coated with a
final seal coat. Suitably, this final seal coat is comprises hydroxypropyl
methylcellulose, and about 0.1% w/wto 10 % w/w of the coated multiparticle, 0.1%
w/w to about 5% w/w, or about 0.2% w/w to about 4% w/w.
In one embodiment, a final seal coat of hydroxypropyl methylcellulose in an
amount of 0.5 to 1 % w/w of the multiparticulate in water (which is removed during
processing) is applied over the enteric coat. Following this, a coating of talc can
optionally be applied over the final seal coat, in an amount of about 0.05 w/w to about
1 % w/w, and preferably 0.1 % w/w to 0.5 % w/w.
In one embodiment, the resulting multiparticulate formulation of the invention
achieves a geometric mean AUC ratio of test/reference of 89 to 94 with a 90%
confidence interval of 84 to 100 for the ratio or achieving a geometric mean Cmax
ratio of test/reference of 62 to 66 with a 90% confidence interval of 56 to 74 for the
ratio or an in-vitro dissolution profile as shown below:


Specifications: Acid at 2hrs- NMT 10.0%; Buffer at 45 min- NLT 75%
However, the invention is not limited to these exemplary profiles.
Without wishing to be bound by theory, it is believed that final seal coat layer
of liydroxypropyl methylcellulose provides a physical barrier for reduced contact
between the mucoadhesive Eudragit layer and the upper GI tract, and thereby allows

the reliable transit of the multiparticulates to the proper pH environment in the GI
tract for effective release and absorption of the drug. In addition, the final seal coat
layer of hydroxypropyl methylcellulose imparts anti-sticking properties to the
multiparticulates and-thus the multiparticulates are not sticking to the pouch material
and/or nasogastric tube. The multiparticulates of the invention are useful for
administration via the nasogastric tube and via food vehicles, particularly acidic food
vehicles.
II. Method of Producing Multiparticulate Formulations of Invention
In another aspect, the invention provides a method of producing the
multiparticulate formulations of the invention.
Typically, the uncoated pantoprazole compounds are prepared are follows.
The dry components, including, at least the pantoprazole compound and the binder are
dry blended in a suitable mixer under low shear conditions. Suitable low shear
conditions can be readily achieved using, e.g., a Hobart mixer, at a range of about 25
rpm to 35 rprn, and most desirably, 32 rpm. However, one of skill in the art will be
able to achieve comparable low shear- conditions using different equipment, with the
rpm adjusted to the appropriate low shear settings for the selected equipment.
Optionally, hydroxypropyl methylcellulose or crospovidone may be substituted or
additionally included in this step. Additionally, a pH adjuster may be included in this
step.
Subsequently, the liquid components, e.g., the surfactant and water, are mixed
in to afford a granulated product by mixing under low shear conditions. Suitable low
shear conditions can be readily achieved using, e.g., a Hobart mixer, at a range of
about 25 rpm to 35 rpm, and most desirably, 32 rpm. However, one of skill in the art
will be able to achieve comparable low shear conditions using different equipment,
with the rpm adjusted to the appropriate low shear settings for the selected equipment.
The granulation is then extruded and spheronized through a suitable device (e.g., a
NICA extruder/spheronizer) and the resulting spheroids are dried, sifted, and
optionally blended prior to storage.

The inventors have found that a significant advantage is provided to the
stability of the compound when the multiparticulates of the invention are dried at low
temperature. Desirably, the spheroid cores of the pantoprazole multiparticulates of
the invention are dried to a percent (%) loss-on-drying (LOD) of 3.4% to 4.3%. As
used herein, low temperature drying refers to a temperature not exceeding about 40°C
for a period of 10 to 12 hours. When the dtying conditions exceed this temperature
and time period, impurities are observed that contribute to instability. In one
embodiment, drying of the core is performed in the range of 35°C to 40°C, or about
37 °C to 39 °C for about 8 to 72 hours. In another embodiment, the core is dryed at
about 40°C for 10 to 12 hours. Suitably, when coating layers are applied as described,
the drying temperature for the various coating layers is also in this range.
Optionally, an initial seal coat of a hydrophilic polymer can be applied to the
uncoated multiparticulates. For example, an initial seal coat composed of
hydroxypropyl methylcellulose and purified water can be applied on a fluid bed
coater, e.g., by spraying.
The enteric coat can be applied directly to the uncoated spheroid core, i.e., the
uncoated multiparticulate, or may be applied over an initial seal coat. The enteric coat
as described above, is typically applied on a fluid bed wurster coater.
In one embodiment, a final seal coat is applied over the enteric coat and,
optionally, talc is utilized in the final step prior to filling the multiparticulates into a
suitable packaging unit.
The multiparticulate of the invention may be in any suitable form including,
e.g., granules, pellets, beads, minitabs, spherules, beadlets, microcapsules,
millispheres, nonocapsules, microspheres, platelets, tablets, and capsules, depending
upon the desired route of delivery.
III. Formulations, Kits and Methods of delivery
In another embodiment, the present invention provides products containing the
pantoprazole multiparticulates of the invention.
Suitably, the multiparticulate compositions of the invention are formulated
such that a patient receives a suitable amount of the pantoprazole, e.g., 5 mg to 200

mg, about 10 mg to about 100 mg, or about 40 mg (measured based upon free
pantoprazole). Preferably, the formulations are such that a suitable dose is delivered
in a single dosage unit. These doses may be administered daily for a suitable period
of time, e.g., 4 weeks to 8 weeks, but can be delivered for a shorter period of time,
e.g., 3 days to 3 weeks, one week to 3 months, or over a longer period, e.g., over 6
months, or longer. These compositions can be delivered alone or in combination with
an antacid or other suitable composition.
In one embodiment, the invention provides a method of treating humans by
administering an effective dose of the pantoprazole multiparticulates such that an area
under curve (AUC) at least bioequivalent to Protonix® 40mg tablet and Cmax as listed
in Table VI are achieved.
In one embodiment, the pantoprazole multiparticulates are packaged for use
by the patient or his caregiver. For example, the multiparticulates can be packaged in
a foil or other suitable package and is suitable for mixing into a food product (e.g.,
applesauce and other acidic food vehicles) or into a drink for consumption by the
patient.
The pantoprazole multiparticulate formulations of the invention are useful for
treatment of gastroesophageal reflux disease (GERD), ulcers of the stomach and
duodenum, and Zollinger-Ellison Syndrome.
In another embodiment, the pantoprazole multiparticulates are suspended in a
physiologically compatible suspending liquid.
In yet another embodiment, the pantoprazole multiparticulates are filled in
capsules, caplets or the like for oral delivery.
In still a further embodiment, the invention provides method of treating a
subject in need thereof by administering an effective dose of the pantoprazole
rnultiparticles of the invention.
The following examples illustrate specific embodiments of the invention and
are not a limitation on the present invention.

Example 1 -PANTOPRAZOLE SODIUM MULTIPARTICULATE
FORMULATIONS
Using a NICA extruder/spheronizer, during initial formulation development,
several prototypes of uncoated multiparticulates were manufactured to obtain a target
immediate release profile similar to or faster than the pantoprazole sodium uncoated
tablet, currently available as Protonix (20 mg and 40 mg) tablets. Levels of the
disintegrant crospovidone from 5 to 28.5% and the binder hydroxypropyl methyl
cellulose from 0.5 to 1% were evaluated during preparation of uncoated
multiparticulates over four batches.
A. Preparation of Uncoated Pantoprazole Sodium Multiparticulates
More particularly, pantoprazole sodium sesquihydrate,
microcrystalline cellulose, hydroxypropyl methylcellulose (hypromellose 2208),
crospovidone and sodium carbonate are dry blended in a Hobart mixer. Thereafter,
polysorbate 80, NF (vegetable source) and purified water, USP, are added to the
Hobart mixer. The resulting granulated produce is extruded and spheronized in a
NICA® extruder/spheronizer and the spheroids are tray dried at a temperature not
beyond 40°C and sifted, followed by transfer to a PK blender. The final spheroids are
stored in drums.
One of the batches (an approximately 200 gm batch) with 15%
disintegrant crospovidone and with 1% hydroxypropyl methylcellulose
(Hypromellose 2208)-was selected as a prototype with similar release profile. The
sieve cut of the uncoated spheroids from this batch was between 500 - 1000 microns.
B. Prototype Lab Batch (Batch A)
Approximately 100 grams of these uncoated spheroids were coated in a
3" Wurster Fluid Bed coater with Eudragit L30D-55 and hypromellose to result in
Enteric coated multiparticulates.
During coating for this batch, the level of hydroxypropyl methyl
cellulose (HPMC) initial seal coat was 4% of the weight of the uncoated
multiparticulates. The % w/w of the dry polymer Eudragit L30D-55 used was
22.16%. In the coating batch, talc was introduced as dry powder in the coating
chamber instead of being a part of the suspension. Tins was due to the small nozzle

size (0.5 mm) used for coating the 100 g batch, which could potentially be clogged.
The percent of talc and triethyl citrate used for the lab batch was less as compared to
the clinical batches which were subsequently prepared. The multiparticulates were
hand filled into size #2 HPMC capsules at a fill weight of 206 mg. The capsules were
tested in vitro in 0.1 N HC1 and pH 6.8 phosphate buffer. Less than 1% was released
in acid media in 2 hours and greater than 80% was released in basic media in 45
minutes as desired.
These capsules were tested in dogs. The Cmax and AUC were
compared against the current marketed Protonix 20 mg tablet (and values were
extrapolated to the 40 mg strength). It was seen mat these multiparticulates released
drug at a much faster rate than the current Protonix tablet in pH 6.8 phosphate buffer
as desired. The final seal coat comprises hydroxypropyl methylcellulose
(hypromeilose) and water. This batch was packaged as spheroids in clear glass vials
and placed on stability at accelerated conditions (30 °C/65% relative humidity (RH)
and 40 °C/75% RH). The stability was monitored for 3 months. The potency and
dissolution results are presented in Table I. The multiparticulates were stable over the
three month period and a 40 mg equivalent dose of multiparticulates filled into
capsules at each stability time point met all dissolution and stability criteria
Dissolution was tested by filling the stored spheroids into capsule
shells, and dissolving in 0.1 N HC1 (target release at 2 hours: not more than (NMT)
lO/'o), followed by dissolution in pH 6.8 phosphate buffer (target release at 45 min:
not less than (NLT) 75%. The acceptance criteria further required a strength of 90 to
110% of the label claim.


Example 2 - COATED PANTOPRAZOLE SODIUM MULTIPARTICULATE
FORMULATIONS (BATCH B)
Based upon the lab batch A, a further scale-up batch of 1400 g was
manufactured using a 7" wurster fluid bed coater. During coating for this batch, the
level of hydroxypropyl methyl cellulose initial seal coat was 2% of the weight of the
uncoated multiparticulates as compared to 4% for the coated Batch A. The % w/w of
the dry polymer, Eudragit L30D-55 used was 22.16% w/w. Also, the talc was added
directly to the coating suspension as a larger nozzle size (1 mm) was used.
Initial release of coated multiparticulates in 0.1 N acid was high (9.0%) and
very close to the limit of 10%. This Batch (B) did not meet the stability and
dissolution criteria when tested at accelerated conditions (30 °C/60% relative
humidity (RH) and 40 °C/75% RH). Trial from this batch indicated that an initial seal
coat of greater than 2% of uncoated multiparticulates enhances stability of the
multiparticulates. Additionally, more enteric polymer loading may be beneficial to
control the release in acid media as the process is scaled up.

Example 3 - PREPARATION OF PANTOPRAZOLE MULTIPARTICULATES
SCALE-UP BATCH
A. Technical Batch
Using a NICA extruder/spheronizer, a 36 kg technical batch of
uncoated multiparticulates was prepared and 20 kg of this batch were enteric coated in
a Glatt GPCG-15 machine to result in a 32 kg batch of coated multiparticulates. The
% w/w of the dry polymer, Eudragit L30D-55 used was 22.16% w/w. This batch was
filled into size #3 HPMC capsules at a fill weight of 156 mg. The release in 0.1 N
HC1 at 2 hours was greater than the desired 10%. Based on this, talcing into account
scale-up effects, minor adjustments were made to the formula and process for clinical
batch.
B. Clinical Batch
Two 12 kg sub batches of a wet granulated mass were extruded and
spheronized on a NICA extruder/spheronizer resulting in wet multiparticulates. The
multiparticulates were tray dried at 40 °C for 10 to 12 hours to the desired % LOD of
3.4% to 4.3%. The batch was screened and only 16 kg of uncoated multiparticulates
were used for coating to ensure uniformity and completeness of coating in the GPCG-
15 machine. The sieved uncoated multiparticulates were coated with an initial
hydroxypropyl methycellulose seal coat, followed by an Eudragit L30D-55 enteric
coat, followed by a hydroxypropyl methycellulose final coat to result in 33 kg of
coated multiparticulates. Tins batch was filled into size #2 HPMC capsules at a fill
weight of 206 mg.
The release bO.lN HC1 at 2 hours was less than the 10% limit and in
pH 6.8 phosphate buffer, it was greater than the 80% limit at 45 minutes. The batch
met in vitro release characteristics. The one month stability date showed that the
multiparticulates were stable at 40 °C/75% RH for one month. Currently, this batch is
stable up to one year at room temperature and upto 6 months at 40 deg.C/ 75% RH.
Stability study at room temperature condition beyond one year is ongoing. The one
year room temperature stability results of this batch are shown in the following Table
II.

The spheroid filled capsule had a faster in vitro release (dissolution) as
compared to the Protonix 40 mg tablet in pH 6.8 phosphate buffer.



Example 4 - Evaluation of Batch A Formulation in Beagle Dogs
The in-vitro release data of the sodium pantoprazole multi particulate
formulation shows a faster release than the current marketed tablet. This provides
earlier absorption and thereby a faster onset of action. Tire dog data clearly shows
earlier drug levels of sodium pantoprazole from multiparticulates as compared to the
single monolithic tablets. Earlier onset of action provides faster relief from gastric
pain and other gastrointestinal (GI) disorders.
Pantoprazole sodium formulations have been evaluated in Beagle Dogs (n=5).
The mean (SD) pharmacokinetic parameters and relative bioavailability of
pantoprazole is illustrated in the Table III below.

As illustrated, the non-optimized lab batch of sodium pantoprazole
multiparticulate formulation dosed in dogs shows smaller lag time than the current
marketed tablet. In the following table, AUC refers to the area under a curve plotting
mean concentration against protocol time. Cmax refers to the maximum observed
concentration value in the blood sample after administration. Tmax refers to the time
point when C max occurs. Tag refers to the time following administration before
effective amounts of the drug are observed in the circulation; t/2 (hr) provides the
half-life for drug elimination. Relative bioavailability compares the absorption of a
product from the gut in comparison with a dose given intravenously (assumed 100%).

The dog data of the sodium pantoprazole multi particulate formulation gives a
similar AUC as the current marketed tablet. Without wishing to be bound by theory, it
is believed that the faster release and similar AUC of the multi particulates is achieved
by lowering the level of the disintegrating agent crospovidone (as compared to the

level in the tablet) and incorporating the functional excipient polysorbate 80 in the
core of the spheroids.
EXAMPLE 5- PANTOPRAZOLE SODIUM SESQUIHYDRATE :EXCIPIENT
FORMULATIONS
This study was perfonned to determine the compatibility of pantoprazole
sodium sesquihydrate with hypromellose 2208, sodium lauryl sulfate (SLS),
crospovidone, and polysorbate-80.
A. Study Design
The study consists of two sets of samples. The first set contained drug
and excipient. The second set contained drug, excipient and approximately 2 \x\ water.
The reason for the water along with the drug and the excipient is to see whether
additional water present causes any incompatibility.
The excipients were mixed with the drug in the ratio indicated in the
following table. The excipients and the drug were weighed into a glass vial. Then the
vials were vortexed for 15 seconds. Similarly, a second set of samples was prepared.
Approximately 2 ul (the smallest amount of water that can be added with the pipette
in the lab) was added to these vials. Then the vials were vortexed for 5 seconds.
Finally, the first and second set of vials were capped and placed in stability chambers.
The conditions tested were 40775%RH and 51°C for 3 weeks.
B. Results
The results of this drug-excipient compatibility study are presented as
% recovery in the Table IV below. The selection criteria for the compatibility or in-
compatibility are based on the % recovery between 90-110%.


From the results shown in the table, the following conclusions can be drawn.
Hypermellose 2208, SLS, crospovidone and polysorbate-80 are compatible with
pantoprazole sodium sequihydrate at 40°C/75%RH for 3 weeks. Hypromellose 2208,
SLS and crospovidone are compatible with pantoprazole sodium sequihydrate at
40°C/75%RH and 51°C with and without additional water for 3 weeks.
In this study degradation compounds were not studied. However, the pediatric
clinical formulation, [pantoprazole sodium sesquihydrate 45.24% w/w;
microcrystalline cellulose 27.25% w/w; polysorbate 80 5 % w/w; crospovidone 15 %
w/w; hypromellose 2208 1% w/w; sodium carbonate 6.5% w/w; purified water q.s.],
was studied under accelerated conditions of 40°C/75%RH and is stable up to 6
months, providing a 2 year room temperature shelf life.
The components of the pediatric formulation are provided in the following
Table V.

EXAMPLE 6 - Evaluation of Pantoprazole Sodium Formulation in Human
Adult Subjects
In this study, 40 mg pantoprazole sodium, formulated as described,
clinical pediatric formulation, was administered to healthy human adults (n=24) by
sprinkling in applesauce, in tablet form, or as an aqueous suspension prepared using
an inactive powder blend and water (8 in each group).
In the following Table VI, column 1 provides the pharmacokinetic (PK)
parameters, AUC (area under the concentration curve), AUCT is the area under the
concentration time curve, and Cmax, maximum concentration. Tire second column
provides the test/reference geometric mean (GM) ratio. The third column provides the
confidence interval for the GM ratio. [The FDA considers a test product to be
bioequivalent to a reference producL if the 90% confidence interval (CI) of the
geometric mean ratio of AUC and Cmax between the test and reference fall within 80-
125%]. -The confidence interval is calculated using WinNonlin software.



The lag time in the absorption of the tablet was higher compared to the
sprinkle and suspension formulations. The entire drug in the tablet is released over a
small time interval and therefore a higher Cmax is obtained. With the spheroid
formulations, drug from each spheroid is released over a longer time interval and
therefore the Cmaxis lower than the tablet. However, the period of time following
administration that pantoprazole remained in the circulation is similar for the 3
formulations.
All documents identified herein are incorporated by reference. One of skill in
the art will recognize that minor modifications to the conditions and techniques
described in the specific embodiments described herein can be varied without
departing from the present invention. Such minor modification and variants are
within the scope of the invention as defined by the following claims.

WE CLAIM:
1. Pantoprazole multiparticulates having reduced release under gastric
conditions and fast release at neutral pH, wherein each of said multiparticulates
comprises:
a spheroid core comprising pantoprazole or an enantiomer thereof, or a salt
or hydrate thereof and at least one surfactant present in a ratio from 10:1 to 5:3
pantoprazole:surfactant (w/w) and/or from 2% to 7% (w/w) of surfactant to core;
an initial seal coat on the spheroid core;
and
an enteric coat on the initial seal coat,
wherein said coated multiparticulates have a diameter in the range from 0.7
to 1.25 mm.
2. Pantoprazole multiparticulates according to claim 1, wherein said
spheroid core comprises pantoprazole or an enantiomer thereof, or a salt or hydrate
thereof present in an amount of about 40 mg of pantoprazole per 100 mg uncoated
multiparticulate, wherein the amount of pantoprazole is measured in the free base
form.
3. Pantoprazole multiparticulates according to claim 1, in which the
pantoprazole or an enantiomer thereof, or a salt or hydrate thereof is a pantoprazole
sodium.
4. Pantoprazole multiparticulates according to any of claims 1 to 3,
wherein
the multiparticulates comprise pantoprazole sodium sesquihydrate and are
administrable in the form of a suspension comprising 40 mg of pantoprazole,
wherein following administration of the suspension to humans the
pantoprazole is characterised by a geometric mean AUC ratio of 88% to 100% (40
mg multiparticulate to 40 mg commercial pantoprazole tablet) and a geometric

mean Cmax ratio of 60% to 74% (40 mg multiparticulate to 40 mg commercial
pantoprazole tablet).
5. Pantoprazole multiparticulates according to any of claims 1 to 3,
wherein
the multiparticulates comprise pantoprazole sodium sesquihydrate and are
administrable in an amount of 40 mg pantoprazole in applesauce,
wherein following administration of the 40 mg of pantoprazole
multiparticulates sprinkled in applesauce to humans the pantoprazole is
characterised by a geometric mean AUC ratio of 84% to 96% (40 mg
multiparticulate to 40 mg commercial pantoprazole tablet) and a geometric mean
Cmax ratio of 56% to 70% (40 mg multiparticulate to 40 mg commercial
pantoprazole tablet).
6. Pantoprazole multiparticulates according to any one of claims 1 to 5,
wherein the surfactant comprises sodium lauryl sulfate or a polysorbate. or a
combination thereof.
7. Pantoprazole multiparticulates according to claim 6 wherein the
surfactant is polysorbate 80.
8. Pantoprazole multiparticulates according to any one of claims 1 to 7
wherein the core further comprises a disintegrant comprising from 25% to 45%
(w/w) of the core.
9. Pantoprazole multiparticulates according to claim 8, wherein said
disintegrant is selected from the group consisting of microcrystalline cellulose,
crospovidone, and mixtures thereof.
10. Pantoprazole multiparticulates according to any one of claims 1 to 9
wherein the core further comprises a binder.

11. Pantoprazole multiparticulates according to claim 10 wherein said
binder is present in the amount of 50:1 to 40:1 (w/w) of pantoprazole to binder.
12. Pantoprazole multiparticulates according to claim 10 or claim 11,
wherein said binder is hydroxypropylmethyl cellulose.
13. Pantoprazole multiparticulates according to any of claims 1 to 12
wherein the multiparticulates have an average diameter of about 1 mm.
14. Pantoprazole multiparticulates according to any of claims 1 to 13
wherein the core further comprises a pH adjuster.
15. Pantoprazole multiparticulates according to claim 14 wherein said
pH adjuster is present in from 3% to 7% (w/w) of the multiparticulate..
16. Pantoprazole multiparticulates according to claim 14 or claim 15
wherein said pH adjuster is selected from sodium carbonate, sodium bicarbonate,
potassium carbonate and lithium carbonate,
17. Pantoprazole multiparticulates according to any of claims 1 to 16,
wherein said core further comprises from 1% to 2% water.
18. Pantoprazole multiparticulates according to any of claims 1 to 17,
wherein said pantoprazole is present as a pantoprazole sodium sesquihydrate.
19. Pantoprazole multiparticulates according to any of claims 1 to 18,
wherein said enteric coat comprises a copolymer of methacrylic acid and
methacrylates in the range of 15% to 45% (w/w) of the core.

20. Pantoprazole multiparticulates according to any one of claims 1 to
19, further comprising a final seal coat on the enteric coat.
21. Pantoprazole multiparticulates according to claim 20, wherein the
final seal coat comprises 0.1 to 10 wt% of the multiparticulates.
22. Pantoprazole multiparticulates according to claim 20 or claim 21,
wherein the final seal coat comprises hydroxypropyl methylcellulose
(hypromellose).
23. Pantoprazole multiparticulates according to any one of claims 1 to
22 wherein said initial seal coat is in the range of 2 to 4 % w/vv of the weight of the
uncoated core.
24. Pantoprazole multiparticulates according to any of claims 1 to 23,
wherein the initial seal coat comprises hypromellose.
25. Pantoprazole multiparticulates according to any one of claims 1 to
24, wherein the pantoprazole or an enantiomer thereof, or a salt or hydrate thereof,
is present in the range of from 5 to 50% w/w, of the spheroid core.
26. Pantoprazole multiparticulates according to claim 25, wherein the
core comprises microcrystalline cellulose in an amount of 25 to 30% w/w of the
spheroid core.
27. Pantoprazole multiparticulates according to claim 25 or claim 26,
wherein the core comprises crospovidone in an amount of 14 to 16% w/w of the
spheroid core.
28. Pantoprazole multiparticulates according to any of claims 1 to 27,
wherein the spheroid core consists essentially of:


29. Pantoprazole multiparticulates according to 28, wherein the enteric
coat comprises 15 to 45% w/w of the multiparticulate.
30. The pantoprazole multiparticulates according to claim 28 or claim
29, wherein the enteric coating comprises about 30% w/w of Eudragit L 30 D-55
coating, about 15% w/w talc, about 3% triethyl citrate and a pH adjuster; said
amounts being by weight of the multiparticulate.
31. Pantoprazole multiparticulates according to any one of claims 1 to
30, wherein said microparticulates comprise 40 mg of pantoprazole in the form of
the sodium salt in a capsule wherein following administration to a dog, said
multiparticulate provides a lag time ratio of (0.25)/(1.10) = 0.23 compared to a 20
mg commercially available pantoprazole tablet.
32. Pantoprazole multiparticulates according to any one of claims 1 to
31, wherein said multiparticulate composition provides a mean AUC of 5451 to
5629 ng.h/mL and mean Cmax of 1865 to 1929 ng/mL.
33. Pantoprazole multiparticulates according to any one of claims 1 to
32 for use in treating gastroesophageal reflux disease (GERD), ulcers of the
stomach or duodenum, or Zollinger-Ellison Syndrome in a human.

34. A pantoprazole formulation for use in dosing to pediatric patients,
said formulation comprising a suspension comprising the pantoprazole
multiparticulates of any one of Claims 1 to 33 and a physiologically compatible
suspending liquid.
35. A capsule comprising the pantoprazole multiparticulates of any one
of Claims 1 to 34.
36. A foil packet comprising the pantoprazole multiparticulates of any
one of Claims 1 to 35.
37. A method of producing a multiparticulate formulation of
pantoprazole, said method comprising the steps of:
producing a spheroid core comprising pantoprazole or an enantiomer
thereof, or a salt or hydrate thereof and a surfactant or a combination of surfactants
present in a ratio from a 10:1 to 5:3 pantoprazole:surfactant (w/w) and/or a from
2% to 7% (w/w) of surfactant to core, via extrusion and spheronization;
applying an initial seal coat to the spheroid core,
applying an enteric coating over the initial seal coat; and
optionally applying a final seal coat to the enteric-coated spheroid
core,
wherein said multiparticulates have a diameter in the range from 0.7
to 1.25 mm.
38. The method according to claim 37, wherein the spheroid core is
prepared by mixing the ingredients in a low shear mixer at low shear conditions at a
range of 25 rpm to 35 rpm.
39. The method according to claim 38, wherein the low shear conditions
are 32 rpm.

31
40. The method of claims 37 to 39, wherein the spheroid cores are dried
at a low temperature not exceeding about 40°C for a period of 8 to 72 hours to a
percent (%) loss-on-drying (LOD) of 3.4% to 4.3%.
41. The method of claims 37 to 40 wherein said initial seal coat is 2 to
4% w/w of the uncoated multiparticulate.
42. The method of claims 37 to 40 wherein said final seal coat is about
1% w/w of the multiparticulate.
43. The method according to claim 37, further comprising the step of
applying a layer of talc in an amount of 0.05% w/w to 0.1% w/w of the
multiparticulate.
44. The method according to claim 37, wherein the enteric coating is
sprayed as a suspension onto the spheroid core.

Pantoprazole sodium multiparticulates are described which avoid sticking to nasogastric and gastronomy tubes. The pantoprazole multiparticulates have a spheroid core of pantoprazole or an enantiomer thereof, or a salt thereof , a surfactant, and a disintegrant; a sub coat which is comprised of hydroxypropyl
methylcellulose (hypromellose) and water, an enteric coat on the sub-coat, and a final seal coat over the enteric coat, which is composed of hydroxypropyl methylcellulose (hypromellose) and water.