US007838027B2

(12) Ulllted States Patent

Venkata Ramana Rao et a].
(54) PANTOPRAZOLE MULTIPARTICULATE
FORMULATIONS

(10) Patent N0.:

(45) Date of Patent:
5,888,535 A
5,945,124 A

US 7,838,027 B2
*Nov. 23, 2010

3/ 1999 Gray
8/1999 Sachs et al.

(75)

Inventors: Sripriya Venkata Ramana Rao, lselin, NJ (US) syed M- shah East Hanover N] Hanulnantharao Tatapudys Suffem, NY (US); Richard William Saunders, Palisades, NY (US); Mahdi Fawzi, MorristoWn, NJ (US); ArWinder

5,997,903 A

12/1999 D' tr' h tal.

6,013,281 A
A 6,077,541 A 6,093,734 A 6,096,340 A

1e 10 e 1/2000 Lundberg et al.

Sachs et al. 6/2000 Chen et a1~ 7/2000 Garst et a1. 8/2000 Chen et a1.

Nagi,T_11ie11S,NY(U$); Shailesh singh,

6,132,768 A

10/2000 Sachs et al.

?rdoma?bggs); sumonA'Hasm
Onroe ( )

6,132,771 A
6,136,344 A

10/2000 Depuietal.
10/2000 Depui et al.

(73) Assignee: Wyeth LLC, Madison, NJ (US)

(*) Notice: Subject to any disclaimer, the term of this

6,159,499 A
6,248,363 B1

12/2000 Seth
6/2001 Patel et a1.

6,274,173 B1

8/2001 Sachs et a1

llatselg llssixgelidelloosrg 221211151 under 35

' ' ' ( ) y ys'

6,277,412 B1
6,296,876 B1

8/2001 Otterbeck
10/2001 Odidi etal.

This patent is subject to a terminal disclaimer.

6,328,993 B1 6,346,269 B1 6,365,184 B1

12/2001 Linder et 31' 2/2002 Hsiao et al. 4/2002 Depui et al.

(21)
(22)

APP1~ N91
PCT Filed
'

10/5741210
sep 30 2004
'

6,379,705 B1
6,383,510 B1
6,391,342 B1

4/2002 Mendes et al.

5/2002 Linder et al.
5/2002 Henriksen etal.

(86)

PCT No.:

PCT/US2004/033058

371 (0)0), (2), (4) Date:

(87)

Aug. 29, 2006

(Continued)
FOREIGN PATENT DOCUMENTS
AU 2005204242 AZ 90005

PCT Pub. No.2 W02005/032513

PCT Pub. Date: Apr. 14, 2005

(65)

Prior Publication Data

US 2007/0042033 A1

Feb. 22, 2007

(Continued)
OTHER PUBLICATIONS I.C. Rodriguez, Sistemas de liberacin Bioadhesivos (Bioadhesive Release Systems, Bioadhesive delivery systems), Ars Pharmaceutica, 41(1):115-128, 2000.
_

Related US. Application Data (60) Provisional application No. 60/507,810, ?led on Oct. 1, 2003,
Int. Cl.

(51)

A61K 9/64
(52) (58)

(2006.01)

(Commued)
Primary ExamineriRoben Awax Assiszanz ExamineriBethany Barham

US. Cl. .................................................... .. 424/456 Field of Classi?cation Search ..................... .. None

See application ?le for complete search history.

(56) References Cited
U.S. PATENT DOCUMENTS
3,065,143 4,255,431 4,686,230 4,758,579 4,853,230 5,178,867 5,225,202 5,260,069 A A A A A A Christenson et a1. Junggren et a1. Rainer et a1. Kohl et a1. Lovgren et al. Guittard et a1. 7/1993 Hodges et al. 11/1993 Chen 11/1962 3/1981 8/1987 7/1988 8/1989 1/1993

(74) Angrney Age; 0r FirmiHowson & Howson LLP;

Maureen P. OBrien; Lisa A. Samuels

(57)

ABSTRACT

PantopraZole sodium multiparticulates are described Which avoid sticking to nasogastric and gastronomy tubes. The pan topraZole multiparticulates have a spheroid core of pantopra
Zole or an enantiomer thereof, or a salt thereof, a surfactant,

5,273,758
5,433,959 5,731,002

5,753,265

A A A A A A

and a disintegrant; a sub coat Which is comprised of hydrox

ypropyl methylcellulose (hypromellose) and Water, an enteric

coat on the sub-coat, and a ?nal seal coat over the enteric coat,

12/1993 Royce
7/1995 Makino et a1. 3/1998 Olovson et al.

Which is composed of hydroxypropyl methylcellulose

(hypromellose) and Water.

5/1998 Bergstrand et al.

7/1998 Conte et a1. 9/1998 Heeres et al.

5,780,057 A 5,811,426 A

24 Claims, No Drawings

US 7,838,027 B2
Page 2
US. PATENT DOCUMENTS
6,479,075 6,489,346 6,531,152 6,551,620 6,559,167 6,569,453 6,569,463 6,602,522 6,605,303 6,607,742 6,610,323 6,617,338 6,623,759 6,645,988 6,699,885 6,730,685 6,749,867 6,780,436 6,780,882 6953.808 7,041,313 7,544,370 B1 B1 B1 B2 B1 B2 B2 B1 B1 B2 B1 B2 B2 11/2002 12/2002 3/2003 4/2003 5/2003 5/2003 5/2003 8/2003 8/2003 8/2003 8/2003 9/2003 9/2003 Odidi et a1. Phillips Lerner et al. Otterbeck Garst et al. Linder et al. Patel et al. Chen et al. Karehill et al. Linder et al. Lundberg et al. Mali et a1. Heese et al.

EP EP Ep

Ep Ep Ep Ep Ep Ep GB W0 W0 W0 W0 W0

B2 B2 B1 B2 B1 B2 B2 B1 B2

11/2003 3/2004 5/2004 6/2004 8/2004 8/2004 10/2005 5/2006 6/2009

Phillips Phillips Brulls Robinson et al. Lopez-Cabrera Phillips Gray Dietrich et al. Venkata Ramana Rao
et al. ........................ .. 424/456

W0 W0 W0 W0 W0 W0 W0 W0 W0
W0

0 434 999 0 514 008 0 519 365 0 526 862 0 793 959 1 108 425 1 043 976 0 960 620 1652 514 2163347 W0 92/222821 WO 94/02140 W0 94/279gg WO 96/01623 WO 96/01624 WO 96/01625 WO 96/23500 WO 96/24338 WO 97/0202() WO 97/02021 W0 97/125g0 W0 97/25979 W0 97/217285 W0 97/218380
W0 gig/00115

A1 B1 A1 B1 A1 B1 B1 B1 A1 A
A1 A1 A1

7/ 1991 11/1992 12/1992

2/1993 9/1997 6/2005 12/2005 1/2006 5/2006 3/19g6 12/1992 2/1994 12/1994 1/1996 1/1996

A1 A1 A1 A1

A1 A1

1/1996 g/1996 8/1996 1/1997 1/1997 4/1997 7/1997 12/1997 12/1997

1/199g

7,550,153 B2

6/2009 Venkata Ramana Rao

et al. ........................ .. 424/456

W0
W0

WO 99/06027 A1
W0 99/1g93g A1

2/1999
4/1999

7,553,498 B2
2001/0053387 2002/0012676 2002/0039597 2002/0218293 2003/0118650 2004/0028737 2004/0146558 2004/0219211 2005/0003005 2005/0042277 2005/0042285 2005/0129761 2005/0220870 2005/0239844 2005/0245578 2005/0266075
2006/0057195

6/2009 Venkata Ramana Rao

et al. ........................ .. 424/456

W0
W0

WO 99/27917
W0 ()0/09092

6/1999
2/2000

A1 A1 A1

A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1 A1
A1

12/2001 1/2002 4/2002 9/2002 6/2003 2/2004 7/2004 11/2004 1/2005 2/2005 2/2005 6/2005 10/2005 10/2005

Hamied et al. Lundberg et al. Ukai et al. Rampal et al. Lizcano Garcia et a1. Deshpande et a1. Hirata et al. Criere et al. Shimizu et a1. Srinivas et al. Ukai et al. Rao et al. Hepburn et al. Lee et a1. 11/2005 Allegrini et al. 12/2005 Chebli
3/2006 Nonomura et al.

W0 W0 W0 W0 W0 W0 W0 W0 W0 W0 W0 W0 W0 W0

W0 ()1/2g559 W0 2004/0046g2 W0 2004/00471g WO 2004/035052 W0 2004/0669g2 W0 2004/0g0439 W0 2004/0g9333 W0 2004/09g573 W0 2004/09g577 W0 2004/09g577 W0 2004/09g594 WO 2005/004921 WO 2005001637 WO 2005/107721

A1 A2 A1 A1 A1 A1 A2 A1 A2 A3 A3 A1 A1 A2

4/2001 1/2004 1/2004 4/2004 g/2004 9/2004 10/2004 11/2004 11/2004 11/2004 11/2004 1/2005 2/2005 11/2005

OTHER PUBLICATIONS
_ _ _ _

2006/0165797 A1
2006/0189590 A1

7/2006 Plachetka
8/2006 K0111 et al.

Proton1x, PantopraZole Sodium, Product Literature, Rev1sed Apr.

2008' . . .

2006/0216346 A1
2006/0235053 A1

9/2006 Dietrich et a1
100006 Gebauer et a1

WyethTAyerst, Product Informat1on (rev1sed Jul. 10, 2003), Proton1x

Phys1c1ans Desk Reference, 2003, pp. 3461-3464. I I

2006/0240l00 A1 2006/0257467 A1
2006/0263426 A1

10/2006 Anstett 110006 Kostadinov et a1

110006 Dietrich et a1

M. Summers and M. Aulton, Chaper- 25 Granulat1on 1n Pharmaceutlcs: Sc1ence-of Dosage Form Des1gn by Aulton, M1chael
E., Second ed. (Churchlll L1v1ngston) p. 364, 365, 374, dated Oct.
2001.

FOREIGN PATENT DOCUMENTS

42 19 197 52 0 005 0 124 0 166 0 174 0 244 0 249 0 268 390 843 129 495 287 726 380 587 956 A1 A1 A1 A2 A1 A1 A2 B1 B2

Noti?cation for the Opinion of Examination dated Dec. 2, 2009, Four

pages in English language.

12/1992 7/1997 10/1979 11/1984 1/1986 3/1986 11/1987 12/1987 6/1988

Search Report dated Dec. 4, 2009. First Exam Report, Chilean Patent Application No. 2558-2004 in

English Language, Four pages.

Of?cial Action, Guatemala Patent Application No. PI-2004-0194 in

English Language.
Of?cial Communication and Response in EPO Patent Application No. 04 789 540.4, dated Feb. 12, 2008.

* cited by examiner

US 7,838,027 B2
1
PANTOPRAZOLE MULTIPARTICULATE FORMULATIONS CROSS-REFERENCE TO RELATED APPLICATIONS

2
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. This pantopraZole multiparticulate formulation of the
invention is less prone to adherence to the intestinal Walls,

This is a national stage application under 35 U.S.C. 371 of

PCT/U S04/ 033058, ?led Sep. 30, 2004, Which claims the bene?t under 35 U.S.C. 119(e) of the priority of US. Patent Application No. 60/507,810, ?led Oct. 1, 2003.
BACKGROUND OF THE INVENTION
PantopraZole, 5 - (di?uoromethoxy) -2 - [(3 ,4 -dimethoXy-2 -

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 dif?culty sWalloWing solid foods. This formulation also alloWs for drug delivery via nasogastric and gastrostomy tubes.
DETAILED DESCRIPTION OF THE INVENTION

pyridyl)methylsulphinyl]-1H-benZimidaZole, is a H+/K+-ad

enosine triphosphate (ATP) inhibitor (also knoWn 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

The present invention provides a multiparticulate formu lation of pantopraZole having a unique combination of excipi
20

generally lipophilic Weak bases With poor aqueous solubility

at loW pH. Many PPIs are unstable in loW pH solutions and

ents 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

undergo rapid acid-catalyZed degradation, and they are rela

tively stable at neutral or high pH.
The current commercial oral formulations of sodium pan
25

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 multi

topraZole are single unit coated tablets. See, e.g., US. Pat. No. 5,997,903, 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 stick
30

ing 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 pro

viding for reduced inter and intra subject variability, as com pared to single unit tablets (Intl. Journal of Pharmaceutics 140
35

particulates of the invention. In one aspect, the invention provides multiparticulate for mulations of pantopraZole having reduced release under gas tric 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 mul tiparticulate spheroids, Which is adaptable for use in a capsule or a foil packet, can be prepared by eXtrusion/spheroniZation

[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 technologiesi
40

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 pro

vides faster blood levels of the drug, in patients, and thereby

a faster onset of action. The smaller Tiag value of multipar
ticulate formulation as compared to that of a single mono
45

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.

lithic tablet based on the results from dog data indicates faster onset of action of multiparticulate formulation. The use of a multi particulate formulation facilitates do sing

SUMMARY OF THE INVENTION

50

to pediatric patients and patients Who have trouble sWalloW ing, 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

The invention provides a stable multiparticulate pantopra Zole 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
55

thereof, at least one surfactant, at least one distintegrant, and

about 1% to about 2% W/W Water; an enteric coat on the core,

prolonged duration of action (extended release), as compared

to the current marketed tablet.
60

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 1 mm in diameter.

I. Multiparticulates of the Invention Suitably, the multiparticles are in the range of about 0.1 to
2mm, or0.5 mmto 1.5 mm, or0.7mmto 1.25 mm, or0.8mm
to 1 mm. In one embodiment, the multiparticulates in a com

Advantageously, the multiparticulate formulations of the

invention are stable under room temperature storage condi tions for at least tWelve months. Based on the trend analysis using the tWelve month room temperature data and 6 month
65

position of the invention average about 1 mm in diameter. Typically, the multiparticles of the invention are no greater than about 1 mm in siZe in order to facilitate passage through

400 C./ 75% relative humidity (RH) data available to date, the

nasogastric tubes

US 7,838,027 B2
3
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

4
In one embodiment, the spheroid core contains, W/W based on the dry uncoated core, about 45% pantopraZole sodium

may be applied, e. g., comprising a coating of hydroxylpropyl methylcellulose (hypromellose). Also, over the enteric coat a ?nal seal coat may be applied, e.g., a coating of hydroxylpro

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:

pyl 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-(di?uoromethoxy)-2-[(3,4

dimethoxy-2-pyridyl)methylsulphinyl]-1 H-benZimidaZole
and enantiomers thereof and the term pantopraZole com

pound includes pantopraZole and enantiomers and salts and hydrates thereof. The active compound, pantopraZole is
described in European Patent 166 287, Which describes the

pantoprazole sodium sesquihydrate microcrystalline cellulose polysorbate 80 crospovidone hypromellose 2208

sodium carbonate

45.24% W/W 27.25% W/W

5% W/W 15% W/W 1% W/W
6.5% W/W

preparation thereof, and is available commercially under the

brand name PROTONIX. Examples of pharmaceutically

acceptable salts of pantopraZole include, e.g., sodium, mag

nesium, and calcium, among others; still others are described

In another embodiment, the spheroid core contains:

20

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

% W/W, based on

Amount/

total Weight

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.

Ingredients
Pantoprazole Sodium Sesquihydrate Microcrystalline Cellulose, NF/EP

Capsule
45.11 27.39
5.00
15.00
1.00 6.50

multiparticulate
21.911 13.304
2.429
7.286
0.486 3.157 q.s. to make Wet mass*
48.573

(Avicel PH 101)
Polysorbate 80, NP
Vegetable source
30 Crospovidone, NF

HoWever, particularly desirable are sodium lauryl sulfate, polysorbates, including, e.g., polysorbate 80, 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 sur

(Polyplasdone XL)

factant is present in a ratio of about 5:3 drug:surfactant (e.g.,

HPMC USP/EP (Methocel) K3 Sodium Carbonate, NP Puri?ed Water, USP/BP/EP

35

pantopraZole sodium sesquihydrate to sodium lauryl sulfate)

to about 10:1 drug:surfactant (e.g., pantopraZole sodium ses

Total

100.00 mg

quihydrate to polysorbate 80). Advantageously, the surfac

tants 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

Although moisture is removed from the core during the drying process Which is described beloW, the core preferably
40

retains about 1% to about 2% W/W Water. Without Wishing to

adjuster and, optionally a binder or another excipient such as

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 multi

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
45

particulate 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 modi?ed by one of skill in the art, a particularly suitable initial seal coat is

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 50:1 to about 40:1 by Weight drug: binder. 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.

composed of hydroxypropyl methylcellulose (hypromellose)

50

and Water. For example, a suitable initial seal coat can be

applied as a 7.5% W/W hypromellose solution. Typically, such

a seal coat is in the range of about 2% W/W to about 4% W/W of the uncoated core or about 1% W/W to about 2% W/W of the

coated multiparticulate.
55

In one embodiment, a multiparticulate With a subcoat con

The disintegrant may be selected from among other knoWn

tains:

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
60

% W/W, based
on total

among knoWn binders, including e.g., cellulose, and povi

done, among others. In one embodiment, the binder is
Ingredients
A. Sub Coat:

Amount/

Weight

Capsule
4.00 mg

multiparticulate
1.943

hydroxylpropyl methyl cellulose (hypromellose). Suitable

pH adjusters include, e.g., sodium carbonate, sodium bicar bonate, potassium carbonate, lithium carbonate, among oth
ers. Still other suitable components Will be readily apparent to
one of skill in the art.

Pantoprazole Sodium Pellets 65 (40 mg pantoprazole per 100 mg

100.00 mg

48.573

pellets)

US 7,838,027 B2
5
-continued
% w/w, based
on total

6
ratio of test/reference of 62 to 66 with a 90% con?dence interval of 56 to 74 for the ratio or an in-vitro dissolution pro?le as shown below:
weight
m

Amount/

Ingredients
Hydroxypropylmethyl cellulose 2910, USP, 6 cps Puri?ed water, USP/BP/EP

Capsule
4.00 mg

multiparticulate
% Drug Release
1.943

6 Months @
9.33 mg*
Media
104.00 mg 50.516 Acid 2 hrs
3 min
6 min 9 min

6 Months @
40 C./ 75% RH
0.6
0.85
1.83 16.45

*removed during processing

Total

Time

Initial
0.33
i
i i

25 C./ 60% RH
0.45
0.91
3.61 52.25

Target
NMT 10%
i
i i

(pH 1.0)
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 multipar ticulate. In one embodiment, the enteric coat is about 27.5 to
Followed by
Alkaline Buffer

(pH 6.8)

12 min 15 min 30 min

i 101.58 105.29

89.65 97.15 100.67

75.15 91.92 98.96

i i i

45 min
60 min

105.29
105.06

100.57
100.52

99.14
99.07

NLT 75%
i

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

20

In another embodiment, the resulting multiparticulate for

mulation of the invention achieves a mean AUC of 5451 to 5629 ng-h/ml and mean Cmax of 1865 to 1929 ng/ml or an
25

composed of a Eudragit L 30D-55 copolymer, talc, triethyl citrate, sodium hydroxide and water. More particularly, the enteric coating may contain about 30% w/w of multiparticu
late (applied as a 30 wt % dispersion) of Eudragit L 30D-55

in-vitro dissolution pro?le as shown below:

coating; about 15% W/ W talc, about 3% triethyl citrate; a pH

adjuster such as sodium hydroxide and water. Other suitable materials may be selected foruse in the enteric coat including,
30

% Drug Release*
Acid
Batch
Initial 6 Months @40 C./75% RH 12 Months @25 C./60% RH

Buffer min
15
101.77 95.44 96.11

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

2 hrs
0.08 0.73 0.30

30
107.44 101.12 101.92

45
107.38 101.21 102.20

follows:

35

*Speci?cations: Acid at 2 hrs - NMT 10.0%; Buffer at 45 min - NLT 75%

% w/w, based on

However, the invention is not limited to these exemplary

40

total weight

pro?les.
Without wishing to be bound by theory, it is believed that ?nal seal coat layer of hydroxypropyl methylcellulose pro
vides a physical barrier for reduced contact between the

Ingredients
Core + Subcoat

Amount/capsule
100.20 mg

multiparticulate
48.67

Eudragit L30D-55

208.00 mg

30.309

62.40 (solids)
Talc, USP, Altalc 500V Sodium Hydroxide, NF 1 N solution Triethyl Citrate, PG/NF 31.20 9.30 0.36 6.24 mg mg (solids) mg 15.155 0.175
45

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

3.031
99.186
50

Puri?ed Water, USP/BP/EP

183.38 mg*
204.20 mg

and absorption of the drug. In addition, the ?nal seal coat

*removed during processing

Total

layer of hydroxypropyl methylcellulose imparts anti-sticking

properties to the multiparticulates and thus the multiparticu
lates are not sticking to the pouch material and/ or nasogastric tube. The multiparticulates of the invention are useful for

In one embodiment, the enteric-coated multiparticulate is further coated with a ?nal seal coat. Suitably, this ?nal seal

coat is comprises hydroxypropyl methylcellulose, and about

0.1% w/w to 10% w/w ofthe 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 ?nal seal coat of hydroxypropyl methylcellulose in an amount of 0.5 to 1% w/w of the multi
55

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 pro

particulate 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 ?nal seal coat, in an amount
60

ducing the multiparticulate formulations of the invention. Typically, the uncoated pantopraZole compounds are pre pared 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, c. g., a Hobart mixer,

ofabout 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 formu

lation of the invention achieves a geometric mean AUC ratio of test/reference of 89 to 94 with a 90% con?dence interval of 84 to 100 for the ratio or achieving a geometric mean Cmax
65

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,

US 7,838,027 B2
7
With the rpm adjusted to the appropriate loW shear settings for

8
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.

the selected equipment. Optionally, hydroxypropyl methyl

cellulose or crospovidone may be substituted or additionally

included in this step. Additionally, a pH adjuster may be included in this step.

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

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 con ditions 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

(AUC) at least bioequivalent to Protonix 40 mg 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 suit

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

able 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 re?ux

disease (GERD), ulcers of the stomach and duodenum, and

optionally blended prior to storage.

The inventors have found that a signi?cant advantage is

Zollinger-Ellison Syndrome.
In another embodiment, the pantopraZole multiparticulates
20

provided to the stability of the compound When the multipar

ticulates of the invention are dried at loW temperature. Desir

are suspended in a physiologically compatible suspending

liquid.
In yet another embodiment, the pantopraZole multiparticu
lates are ?lled in capsules, caplets or the like for oral delivery. In still a further embodiment, the invention provides
25

ably, 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 400 C. for a period of 1 0 to 12 hours. When the drying conditions exceed this temperature and time period, impurities are ob served that contribute to instability. In one embodiment, drying of the core is performed in the range of35o C. to 400 C., or about 370 C. to 39 C. for about 8 to 72 hours. In another embodiment, the core is dryed at about 400 C. for 10 to 12 hours. Suitably,

method of treating a subject in need thereof by administering

an effective dose of the pantopraZole multiparticles of the invention.

The folloWing examples illustrate speci?c embodiments of

the invention and are not a limitation on the present invention.
30

Example 1

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
35

PantopraZole Sodium Multiparticulate Formulations

Using a NICA extruder/spheroniZer, during initial formu lation development, several prototypes of uncoated multipar
ticulates Were manufactured to obtain a target immediate
40

be applied to the uncoated multiparticulates. For example, an

initial seal coat composed of hydroxypropyl methylcellulose

and puri?ed Water can be applied on a ?uid 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

release pro?le similar to or faster than the pantopraZole sodium uncoated tablet, currently available as Protonix (20

mg and 40 mg) tablets. Levels of the disintegrant crospovi done 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.

above, is typically applied on a ?uid bed Wurster coater. In one embodiment, a ?nal seal coat is applied over the

45

A. Preparation of Uncoated PantopraZole Sodium Multi

enteric coat and, optionally, talc is utiliZed in the ?nal step prior to ?lling the multiparticulates into a suitable packaging unit. The multiparticulate of the invention may be in any suitable

particulates
More particularly, pantopraZole sodium sesquihydrate,

microcrystalline cellulose, hydroxypropyl methylcellulose

(hypromellose 2208), crospovidone and sodium carbonate
50

form including, e. g., granules, pellets, beads, minitabs,

sphelules, beadlets, microcapsules, millispheres, nonocap sules, microspheres, platelets, tablets, and capsules, depend
ing upon the desired route of delivery.

are dry blended in a Hobart mixer. Thereafter, polysorbate 80, NF (vegetable source) and puri?ed 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 400 C. and sifted, folloWed by transfer to a PK blender. The ?nal spheroids are stored in drums. One of the batches (an approximately 200 gm batch) With

III. Formulations, Kits and Methods of Delivery In another embodiment, the present invention provides

55

products containing the pantopraZole multiparticulates of the

invention.

15% disintegrant crospovidone and With 1% hydroxypropyl

methylcellulose (Hypromellose 2208) Was selected as a pro
60

Suitably, the multiparticulate compositions of the inven

tion 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

totype With similar release pro?le. The sieve cut of the uncoated spheroids from this batch Was betWeen 500-1000 microns.

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

B. Prototype Lab Batch (Batch A)

Approximately 100 grams of these uncoated spheroids
65

Were coated in a 3" Wurster Fluid Bed coater With Eudragit

L30D-55 and hypromellose to result in Enteric coated multi

period of time, e.g., 3 days to 3 Weeks, one Week to 3 months,

particulates.

US 7,838,027 B2
10
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 coat ing chamber instead of being a part of the suspension. This 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

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

prepared. The multiparticulates Were hand ?lled into siZe #2 HPMC capsules at a ?ll Weight of 206 mg. The capsules Were tested in vitro in 0.1 N HCl 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.

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 multiparticu

lates enhances stability of the multiparticulates. Additionally,

more enteric polymer loading may be bene?cial to control the release in acid media as the process is scaled up.

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 that these multiparticulates released drug at a much

faster rate than the current Protonix tablet in pH 6 .8 phosphate buffer as desired. The ?nal seal coat comprises hydroxypro

20

Example 3

pyl methylcellulose (hypromellose) and Water. This batch

Was packaged as spheroids in clear glass vials and placed on stability at accelerated conditions (30 C./ 65% relative

Preparation of PantopraZole Multiparticulates

Scale-Up Batch
25

humidity (RH) and 40 C./75% RH). The stability Was moni

tored 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 mul

tiparticulates ?lled into capsules at each stability time point

met all dissolution and stability criteria Dissolution Was tested by ?lling the stored spheroids into
30

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

capsule shells, and dissolving in 0.1 N HCl (target release at 2 hours: not more than (NMT) 10%), 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.

of the dry polymer, Eudragit L30D-55 used Was 22.16% W/W.

This batch Was ?lled into siZe #3 HPMC capsules at a ?ll Weight of 156 mg. The release in 0.1 N HCl at 2 hours Was
35

greater than the desired 10%. Based on this, taking 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

TABLE I
Stability of multiparticulates in clear glass vials.
Test
Dissolution

40

resulting in Wet multiparticulates. The multiparticulates Were

tray dried at 40 C. for 10 to 12 hours to the desired % LOD of3.4% to 4.3%. The batch Was screened and only 16 kg of uncoated multiparticulates Were used for coating to ensure

Percentage Released avg

45

Strength
(HPLC)
Unit
Initial Ambient Room Temp 300 C./60% RH

Secondary
dissolution in
phosphate buffer
91.6% 88.5% 94.1% 83.4% NA 82.2% 86.11 NA 89.4%
50

uniformity and completeness of coating in the GPCG-ma

chine. The sieved uncoated multiparticulates Were coated With an initial hydroxypropyl methycellulose seal coat, fol loWed by an Eudragit L30D-55 enteric coat, folloWed by a hydroxypropyl methycellulose ?nal coat to result in 33 kg of coated multiparticulates. This batch Was ?lled into siZe #2 HPMC capsules at a ?ll Weight of 206 mg.
The release in 0.1 N HCl at 2 hours Was less than the 10%
55

Time
1 7 1 2 3 1 2 3 month month month month month month month month

% Label 0.1 N HCl

100.0% 97.2% 108.5% 99.3% 98.3% 104.4% 95.4% 97.3% 102.7% 0.9% 0.8% 0.8% 0.5% NA 0.7% 0.7% NA 0.7%

40 C./75% RH

limit and in pH 6.8 phosphate buffer, it Was greater than the

80% limit at 45 minutes. The batch met in vitro release char acteristics. The one month stability date shoWed that the

1One capsule - 78% released.

60

multiparticulates Were stable at 40 C./75% RH for one month. Currently, this batch is stable up to one year at room

Example 2

Coated PantopraZole Sodium Multiparticulate Formulations (Batch B)

65

Based upon the lab batch A, a further scale-up batch of

1400 g Was manufactured using a 7" Wurster ?uid bed coater.

temperature and up to 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 ?lled capsule had a faster in vitro release (dissolution) as compared to the Protonix 40 mg tablet in pH

6.8 phosphate buffer.

US 7,838,027 B2
11
TABLE II
Stability of PantopraZole Sodium Spheroid-?lled Capsules 40 mg
Test

12

Appearance
and Description #2 Opaque white capsules
(cap and

Strength (HPLC)

Water (KF)

Purity Speci?cation
Largest Single Known
or Total

Dissolution

Dissolution in

Dissolution in

body) containing
white to off-white colored
spheroids
Initial Initial Conforms

90.0110.0% Label Claim (LC)

Unknown Impurity
For Information 20.5 (RRT)

Known and Unknown

Impurities 22.0 Unit
%
BRL

0.1N HCl NMT 10% in

2 hrs. Conforms to USP <724>

Phosphate Buffer NLT 75% in

45 min. Conforms to USP <724>

%
100.3

%
5 .1

%
BRL

%
0 0

%
105 107

(Spheroids only)
25 C./60% RH
1 No 99.5 101.4 101.2 101.3 5.2 4.6 4.5 4.5 0.17 0.17 0.23 0.17 0.24 1 0 0 0 0 103 101 100 100 1 12

Month
2

Change
No

(1.39)
0.15

Month
3

Change
No

(1.3 8)l7
0.17

Month
6

Change
No

(1.39)
0.18

Month
6

Change

(1.3 8)l7

Month

(Spheroids only)
9 Months No 99.2 5.1 0.21 0.33 0 101

Change
9 Months

(1.40%
0 108

(Spheroids only)
12 Months No 99.1 5.1 0.08 0.23 0 102

Change
12 Months

(0.14)
0 104

(Spheroids only)
BRL = Below Reporting Limit (0.05%).
NMT = Not more than.

NLT = Not less than. RRT = Relative retention time.

Initial and revalidation dissolution results are provided for Pantoprazole Sodium Spheroids, 40 mg/206 mg, which is the ingoing batch of spheroids used for

manufacture ofPantoprazole Sodium Spheroid-?lled Capsules, 40 mg.

bCorresponds to the impurity at RRT = 1.39.

50

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

eters and relative bioavailability of pantopraZole is illustrated

in the Table III below.

As illustrated, the non-optimized lab batch of sodium pan

55

topraZole multiparticulate formulation dosed in dogs shows

smaller lag time than the current marketed tablet. In the fol lowing table, AUC refers to the area under a curve plotting

marketed tablet. This provides earlier absorption and thereby

a faster onset of action. The 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 gas trointestinal (GI) disorders.
PantopraZole sodium formulations have been evaluated in

60

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. Tiag refers to the time following administration before effective amounts of the drug are observed in the circulation;

t1)2 (hr) provides the half-life for drug elimination. Relative

65

bioavailability compares the absorption of a product from the

gut in comparison with a dose given intravenously (assumed

Beagle Dogs (n:5). The mean (SD) pharmacokinetic param

100%).

US 7,838,027 B2
13
A. Study Design
TABLE III

14
The study consists of two sets of samples. The ?rst set

The mean (SD) pharmacokinetic parameters and

relative bioavailability of pantopraZole

20 mg 40 mg Multiparticulate

contained drug and excipient. The second set contained drug, excipient and approximately 2 ul water. The reason for the
water along with the drug and the excipient is to see whether additional water present causes any incompatibility.
10 The excipients were mixed with the drug in the ratio indi cated in the following table. The excipients and the drug were

Market Tablet
Batch A

Capsule
Batch A with enteric coat

Parameter

PantopraZole Na PantopraZole Na

AUC (ugghr/mL) Cmax (ug/mL) Tmax (hr)

16.3 (2.46) 11.7 (3.55) 1.70 (0.84)

17.3 (2.33) 7.10 (1.76) 1.20 (0.27) 0.25 (0.18) 0.77 (0.21)
AUC: 106%! Cmax: 61%!7

tlag (hr) tl/z (hr) Relative Bioavailability

1.10 (0.91) 0.62 (0.17)

weighed into a glass vial. Then the vials were vortexed for 15 seconds. Similarly, a second set of samples was prepared. 15 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 ?rst and second set of vials were capped and placed in stability chambers. The conditions tested were 40/75% RH and 51
20 C. for 3 weeks.

AUC and Cmax are normalized to a 40 mg dose

bRelative to Market Product Tablet

25

B. Results

The dog data of the sodium pantopraZole multi particulate

formulation gives a similar AUC as the current marketed

The results of this drug-excipient compatibility study are

presented as % recovery in the Table IV below. The selection criteria for the compatibility or incompatibility are based on the % recovery between 90-110%.

tablet. Without wishing to be bound by theory, it is believed that the faster release and similar AUC of the multi particu lates is achieved by lowering the level of the disintegrating

TABLE IV
Drug: Excipient Comnatibilitv Results
% Recovery
Drug + Excipient
Ratio of 40 C./75% RH 51 C.

Drug + Excipient + Water

40 C./75% RH 51 C.

Excipient
Control (Drug alone)

Drug:Excipient
i

3 weeks
94.67

3 weeks
100.53

3 weeks
94.60

3 weeks
96.64

Hypromellose 2208, USP, 3 cps Sodium Lauryl Sulfate

10:1
5:3
10:1 10:1

99.209
99.947
100.080 98.301

93.248
98.763
98.908 90.961

93.811
95.466
97.201 99.908

97.421
95.088
105.716 81.405

(SLS)
Crospovidone, NF Polysorbate-80, NF

BP/EP (vegetable

source)

From the results shown in the table, the following conclu agent crospovidone (as compared to the level in the tablet) and incorporating the functional excipient polysorbate 80 in 55 sions can be drawn. Hypermellose 2208, SLS, crospovidone the core of the spheroids. and polysorbate-80 are compatible with pantopraZole sodium

Example 5

sequihydrate at 40 C./75% RH for 3 weeks. Hypromellose 2208, SLS and crospovidone are compatible with pantopra
Zole sodium sequihydrate at 40 C./75% RH and 51 C. with
60 and without additional water for 3 weeks.

PantopraZole Sodium Sesquihydrate: Excipient

Formulations

In this study degradation compounds were not studied.

This study was performed to determine the compatibility

However, the pediatric clinical formulation, [pantopraZole sodium sesquihydrate 45.24% w/w; microcrystalline cellu
6.5% w/w; puri?ed water q.s.], was studied under accelerated

of pantopraZole sodium sesquihydrate with hypromellose 65 lose 27.25% w/w; polysorbate 80 5% w/w; crospovidone 15% w/w; hypromellose 2208 1% w/w; sodium carbonate 2208, sodium lauryl sulfate (SLS), crospovidone, and

polysorbate-80.

US 7,838,027 B2
15
conditions of 400 C./75% RH and is stable up to 6 months, providing a 2 year room temperature shelf life.

16
TABLE VI
Human PK study Results

The components of the pediatric formulation are provided in the following Table V.

A. Spheroids sprinkled in applesauce:

PK parameter

Test/Reference GM ratio
90

90% CI for ratio*

84-96

Formulation:
Ingredients
Core:

Multiparticulates
AUC

Amount/Capsule

% W/W

AUCT
Cmax

89
62

84-95
56-70

Pantoprazole Sodium Sesquihydrate Microcrystalline Cellulose, NF/EP

45 .11 27.39
5.00
15.00
1.00 6.50

21.911 13.304
2.429
7.286
0.486 3.157 q.s. to make
Wet mass*

B. Spheroids in suspension:
PK parameter
AUC

(Avicel PH 101)
Polysorbate 80, NF
Vegetable source

Test/Reference GM ratio
94

90% CI for ratio

88-100

Crospovidone, NF

(Polyplasdone XL)
HPMC USP/EP (Methocel) K3 Sodium Carbonate, NF Puri?ed Water, USP/BP/EP
20

AUCT
Cmax

94
66

88-100
60-74

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

Total Enteric Coat:

100.00 mg 100.20 mg

48.573 48.67

Eudragit L30D-55

208.00 mg

30.309
25

62.40 (solids)
Talc, USP, Altalc 500V Sodium Hydroxide, NF 1 N solution 31.20 mg 9.30 mg 15.155 0.175

0.36 (solids)
Triethyl Citrate, PG/NF Puri?ed Water, USP/BP/EP 6.24 mg 183 .3 8 mg* 3.031 *removed

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 Cmax is loWer than the tablet. HoWever, the period of time folloWing administration that pantopraZole remained in the circulation is similar for the
3 formulations.

during processing
Total Final Seal Coat: 204.20 mg 1.54 mg 99.186 0.748

All documents identi?ed herein are incorporated by refer

30

ence. One of skill in the art Will recogniZe that minor modi ?cations to the conditions and techniques described in the speci?c embodiments described herein can be varied Without

Hydroxypropyl Methylcellulose,
USP 2910, 6 cps Puri?ed Water, USP/BP/EP

1.54 mg
18.99 mg*

0.748
*removed
35

departing from the present invention. Such minor modi?ca

tion and variants are Within the scope of the invention as

during processing
Total 205.74 mg 99.934

de?ned by the folloWing claims.

The invention claimed is:

1. PantopraZole multiparticulates having reduced release

Talc, USP, Altalc 500V
Total

0.14 mg
205.88 mg

0.068
40

under gastric conditions and fast release at neutral pH, Wherein each of said multiparticulates comprises: a spheroid
core comprising about 20% W/W to about 45% W/W of a pantopraZole salt or a hydrate thereof, as the sole active com

100.002

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

45

ponent in the multiparticulate and about 25% to about 30% W/W microcrystalline cellulose, about 4% to about 6% W/W polysorbate 80, about 14% to about 16% W/W crospovidone, about 0.5 to about 2% W/W hydroxypropyl methylcellulose, about 5% to about 8% W/W sodium carbonate, and about 1 to about 2% W/W Water; an initial seal coat comprising hydroxypropylmethyl cel
lulose on the spheroid core; and
an enteric coat on the initial seal coat,

50

Wherein said multiparticulates have an average diameter of

about 0.7 mm to about 1.25 mm.
55

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 pharma cokinetic (PK) parameters, AUC (area under the concentra
tion curve), AUCT is the area under the concentration time curve, and Cmax, maximum concentration. The second col umn provides the test/reference geometric mean (GM) ratio. The third column provides the con?dence interval for the GM ratio. [The FDA considers a test product to be bioequivalent to a reference product if the 90% con?dence interval (CI) of the geometric mean ratio of AUC and Cmax betWeen the test and reference fall Within 80-125%]. -The con?dence interval is

2. The multiparticulates according to claim 1, Wherein the pantopraZole salt is selected from pantopraZole sodium and

pantopraZole magnesium.
3. The multiparticulates according to claim 1, Wherein the hydrate is a sesquihydrate. 4. The multiparticulates according to claim 1, Wherein the

60

pantopraZole salt or hydrate thereof is present in an amount of about 45% W/W.

5. The multiparticulates according to claim 1, Wherein said

multiparticulates have an average diameter of about 1 mm.
65

6. The multiparticulates according to claim 1, Wherein said enteric coat comprises about 48% W/W of the particulate. 7. The multiparticulates according to claim 1, further com
prising a ?nal seal coat on the enteric coat.

calculated using WinNonlin softWare.

US 7,838,027 B2
17
8. The multiparticulates according to claim 7, wherein the
?nal seal coat comprises about 0.1 to 10 Wt % of the multi

18
16. The product according to claim 14, Wherein said plu
rality of multiparticulates are in an aqueous suspension.

particulates.
9. The multiparticulates according to claim 7, Wherein the

17. The product according to claim 14, Wherein said plu

rality of multiparticulates are in a capsule. 18. A method of producing a multiparticulate formulation

?nal seal coat comprises hydroxypropyl methylcellulose

(hypromellose).
10. The multiparticulates according to claim 1, Wherein
said initial seal coat is in the range of about 2 to about 4% W/W of the Weight of the uncoated core.

of pantopraZole having reduced release under gastric condi

tions and fast release at neutral pH, said method comprising:
producing a spheroid core comprising a pantopraZole salt or a hydrate thereof in an amount of about 40% W/W free, as the

11. The multiparticulates according to claim 1, Wherein the enteric coating comprises about 30% W/W of methacrylic acid and methyacrylate copolymer, about 15% W/W talc, about 3% triethyl citrate and a pH adjuster; said amounts being by

Weight of the multiparticulates. 12. PantopraZole multiparticulates having reduced release

under gastric conditions and fast release at neutral pH, Wherein each of said multiparticulates comprises: a spheroid
core comprising a pantopraZole salt or a hydrate thereof in an

sole active component in the multiparticulate and about 25% to about 30% W/W microcrystalline cellulose, about 4% to about 6% W/W polysorbate 80, about 14% to about 16% W/W crospovidone, about 0.5 to about 2% W/W hydroxypropyl methylcellulose, about 5% to about 8% W/W sodium carbon ate, and about 1 to about 2% W/W Water, via extrusion and spheroniZation; applying an initial seal coat comprising

hydroxypropyl methyl cellulose to the spheroid core; apply

ing an enteric coating to the initial seal coated spheroid core,
20

amount of about 40% W/W free pantopraZole, as the sole

active component in the multiparticulate and about 25% to about 30% W/W microcrystalline cellulose, about 4% to about 6% W/W polysorbate 80, about 14% to about 16% W/W crospovidone, about 0.5 to about 2% W/W hydroxypropyl methylcellulose, about 5% to about 8% W/W sodium carbon
ate, and about 1 to about 2% W/W Water; an initial seal coat

said enteric coating comprising a copolymer of methacrylic acid and methacrylates; and optionally applying a ?nal seal
coat to the enteric-coated spheroid core, said ?nal seal coat

being about 1 Wt % of the multiparticulate; Wherein the mul

tiparticulates have an average diameter of about 0.7 mm to
about 1.25 mm.
25

comprising hydroxypropylmethyl cellulose on the spheroid

core; and an enteric coat on the initial seal coat, Wherein said multiparticulates have an average diameter of about 0.7 mm
to about 1.25 mm.

19. The method according to claim 18, Wherein the spher oid core is prepared by mixing the ingredients in a loW shear
mixer at loW shear conditions at a range of about 25 rpm to 35 rpm.

20. The method according to claim 19, Wherein the loW

30

13. A product comprising a plurality of pantopraZole mul

tiparticulates, each comprising a spheroid core comprising a pantoprazole salt or a hydrate thereof in an amount of about 40% W/W free pantopraZole, as the sole active component in the multiparticulate and about 25% to about 30% W/W micro

shear conditions are 32 rpm.

21. The method according to claim 18, Wherein the spher

oid cores are dried at a loW temperature not exceeding about 400 C. for a period of 8 to 72 hours to a percent (%) loss-on
35

crystalline cellulose, about 4% to about 6% W/W polysorbate

80, about 14% to about 16% W/W crospovidone, about 0.5 to about 2% W/W hydroxypropyl methylcellulose, about 5% to about 8% W/W sodium carbonate, and about 1 to about 2% W/W Water; an initial seal coat comprising hydroxypropylm
ethyl cellulose on the spheroid core; and an enteric coat on the initial seat coat, Wherein said multiparticulates have an aver age diameter of about 0.7 mm to about 1.25 mm.

drying (LOD) of 3.4% to 4.3%. 22. The method according to claim 18, 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 multiparticulates. 23. The method according to claim 18, Wherein the enteric coating is sprayed as a suspension onto the spheroid core. 24. A method of treating ulcers of the stomach and duode num, gastroesophageal re?ux disease (GERD), or Zollinger

40

14. The product according to claim 13, comprising about

10 mg to about 100 mg pantopraZole, based upon the Weight of free pantopraZole base. 15. The product according to claim 14, comprising about 40 mg pantopraZole, based upon the Weight of free pantopra
Zole base.
45

Ellison Syndrome in a mammalian subject, comprising the step of administering to the subject a plurality of pantopraZole multiparticulates according to claim 1 comprising about 10 mg to about 100 mg pantopraZole, based upon the Weight of free pantopraZole base.
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