(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization

International Bureau
(10) International Publication Number
(43) International Publication Date
10 September 2010 (10.09.2010) WO 2010/101485 A2

(51) International Patent Classification: Not classified (81) Designated States (unless otherwise indicated, for every
kind of national protection available): AE, AG, AL, AM,
(21) International Application Number: AQ A AU AZ βA ββ B β βR βw βγ βz
PC 1/PL20 10/0000 18 CA C( CR DE DK D]y D(
(22) International Filing Date: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
3 March 2010 (03.03.2010) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
(25) Filing Language: English ME MG MI MN y ς MZ NA NG NI
(26) Publication Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
(30) Priority Data: TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
P.387415 6 March 2009 (06.03.2009) PL
(84) Designated States (unless otherwise indicated, for every
(71) Applicant (for all designated States except US): ZAK- kind of regional protection available): ARIPO (BW, GH,
LADY FARMACEUTYCZNE POLPHARMA SA GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
[PL/PL]; ul. Pelplinska 19, 83-200 Starogard Gdanski ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
(PL)- TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
i Λ
(17 piitnrs- n E S ' FI> F R ' G B ' G R ' H R ' 1
' ' IS ' L T ' LU ' LV '
) iTn
nven t ors, na MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM,
D f l [PL/
(75) Inventors/Applicants (for US OnIy) LUNIO Rafal rM / ' ' - - '
PL]; Ul Porebskiego 35/1 8 -18 Gdansk (PL). MAZ- M L MR, NE, SN, TD, TG).
GALSKI Jaroslaw [PL/PL]; ul. Jowisza 2A/3, 83-010
Straszyn (PL). Published:
(74) Agent: MATYKA, Malgorzata; Zaklady Farmaceuty- — without international search report and to be republished
czne POLPHARMA SA, ul. Pelplinska 19, 83-200 upon receipt of that report (Rule 48. 2(g))
Starogard Gdanski (PL).

(54) Title: A PHARMACEUTICAL COMPOSITION CONTAINING CELECOXIB AND A PROCESS OF THE MANUF AC-
TURE THEREOF
(57) Abstract: The subject matter of the invention is a pharmaceutical composition containing celecoxib as the active substance
and a pharmaceutically acceptable carrier. The pharmaceutical composition contains a cross-linked polymer. The subject matter of
the invention also includes the process of manufacturing of the pharmaceutical composition.
 A pharmaceutical composition containing celecoxib and a process of the
manufacture thereof

The subject matter of the invention is a pharmaceutical composition containing

celecoxib and a process of the manufacture thereof.

Celecoxib is a known compound with the following formula:

Celecoxib selectively inhibits cyclooxygenase-2; therefore, it is used mainly in the

treatment of inflammation and other inflammation-related disorders, such as
treatment of rheumatoid arthritis.

Celexocib belongs to Group II of medicines according to the Biopharmaceutical

Classification System (BCS) which means that it is sparingly soluble in water, but
it penetrates biological barriers easily. The bioavailability of medicines from this
group is limited by their low solubility.

Active substances with low solubility used in pharmacy may contribute to

difficulties during the formulation of pharmaceutical compositions. In the case of
such substances, solubility-enhancing excipients are used for the formulation of
pharmaceutical compositions, such as surfactants.
Pharmaceutical compositions which contain celecoxib as the active substance are
described in a number of patent applications.
In the publication of international patent application WO 95/15316 (PL 180717 B)
pharmaceutical compositions are disclosed which contain celecoxib as the active
substance in a dose between 0. 1 and 2000 mg, which, if present in the oral dosage
form, can be admixed with pharmaceutically acceptable excipients, such as
lactose, saccharose, starch powder and other typically used excipients.

In the publication of international patent application WO 02/15884 (PL 195955

B), in turn, several pharmaceutical compositions are disclosed which contain
celecoxib intended for the administration via various routes (e.g. orally in the
form of tablets, hard or soft gelatine capsules, etc.). Typical excipients employed
in pharmacy can be used in the compositions in the form of tablets and capsules,
such as lactose, saccharose, starch powder and other typically used excipients.

Based on patent specification EP 1049467 B (PL 200957 B), in which the

composition of CELEBREX ® is disclosed, it is known that a surfactant (sodium
lauryl sulphate or polysorbate 80) is used in the formulation of the pharmaceutical
composition. It is also disclosed that the preparation of the granulate for the
formulation of the pharmaceutical composition is performed in two stages: At the
first stage, crystalline celecoxib is milled until a mean particle size (D90) of below
25 µm is achieved; subsequently, the other ingredients of the composition are
added and a wet granulation process is carried out.
Such a process of preparing of the pharmaceutical composition is fairly time-
consuming and not quite efficient. The wet granulation process is a complex and
multi-stage one; therefore, it may affect the final quality of the finished product.
Furthermore, in order to ensure appropriate solubility and wettability of celecoxib,
a surfactant in used in a range of 0.4% to even 10% by weight of the composition.
The use of high concentration of the surfactant, such as sodium lauryl sulphate,
which is irritating to mucous membranes of the gastro-intestinal tract, among
other things, may lead to adverse effects experienced by patients.
It is known from literature that the use of the wet granulation process during
granulate preparation for the formulation of pharmaceutical compositions
containing celecoxib ensures that homogenous granulate with a very high
compaction rate is obtained. However, it is necessary to use surfactants in order to
achieve required wettability and solubility of celecoxib (based on X . Hea, M.R.
Barone, PJ. Marsac, D.C. Sperry; Development of a rapidly dispersing tablet of a
poorly wettable compound-formulation DOE and mechanistic study of effect of
formulation excipients on wetting of celecoxib, Int. J. Pharm. 353 (2008) 176-
186].
Furthermore, it is disclosed in the international publication of patent publication
WO 02/15884 (EP 1309315 B) that due to the physicochemical properties of
celecoxib, such as electrostatic properties, viscosity, low bulk volume as well as
low compaction potential and weak flow properties, celecoxib crystals tend to
separate from the other excipients during the mixing process and to form
agglomerates.
Therefore, an oral composition for the formulation was suggested, with immediate
release (so-called ODT, orodispersible tablet, which quickly disintegrates in the
oral cavity) in which cellulose derivatives, starch and polyhydroxy alcohols, such
as mannitol, sorbitol, etc., are used.
Furthermore in the international publication of patent application WO 02/15884
(EP 1309315 B) it is also disclosed that the preparation of granulate for the
formulation of the pharmaceutical composition does not require wet granulation;
however, when the mixture of the active substance with excipients is in a liquid or
semi-solid (paste) form, tablets form in the vacuum drying or freeze-drying
process. The average concentration of celecoxib in the granulate manufactured
using this process is approximately 20-50%.
Such a process of preparing of the oral pharmaceutical composition for the
immediate release formulation containing celecoxib as the active substance is very
difficult in terms of technology and expensive. Furthermore, the low
concentration of celecoxib in the granulate prepared according to the process
 -A-

disclosed in the publication in question prevents the granulate from being used for
the preparation of a composition in the form of capsules with a size acceptable by
patients.

It is known that celecoxib is a very adhesive substance, it forms agglomerates

easily and its crystals have a shape of needles; therefore, the use of typical
processes of granulate preparation for the formulation of a pharmaceutical
composition in the form of a capsule will not lead to the elimination of the
unfavourable physical parameters of celecoxib.
In addition, the active substance (celecoxib) contributes to the high percentage of
total capsule weight. This restricts the possibility of using large amounts of
excipients, because granulate volume is the parameter which determines capsule
size and, in consequence, the convenience of use by patients.

It turned out unexpectedly during the formulation of the pharmaceutical

composition containing celecoxib that the preparation of the granulate for the
formulation of a pharmaceutical composition in the dry granulation process and
use of a cross-linked polymer ensure the preparation of a pharmaceutical
composition with desired release profile parameters.
Furthermore, also unexpectedly, the use of the dry granulation process during
granulate preparation for the formulation of the pharmaceutical composition
proved to contribute to obtaining granulate with much reduced bulk volume;
therefore, smaller capsules can be used, which increases the convenience of its use
by patients.

The objective of the invention has been to develop a new pharmaceutical

composition containing celecoxib and to develop a new process of manufacturing
of a pharmaceutical composition containing celecoxib.
The pharmaceutical composition containing celecoxib as the active substance
according to the invention is characterised in that it contains a cross-linked
polymer as the pharmaceutically acceptable carrier.
Crospovidone is preferably used as the pharmaceutically acceptable carrier in the
pharmaceutical composition according to the invention.
Micronised crospovidone is preferably used as the pharmaceutically acceptable
carrier in the pharmaceutical composition according to the invention.
A mixture of crospovidone and polyethylene glycol (PEG) can be used as the
pharmaceutically acceptable carrier in the pharmaceutical composition according
to the invention.
The pharmaceutical composition according to the invention is characterised in that
its quantitative composition is proportional. This means that respective doses of
the formulation are prepared from the same granulate.

The process of manufacturing of the pharmaceutical composition containing

celecoxib according to the invention is characterised in that it consists of the
following stages:
a. the active substance (celecoxib) is subjected to granulation with at least
one pharmaceutically acceptable carrier,
b. the resulting pellets are standardised,
c. the standardised granulate is mixed with the excipient,
d. capsules are manufactured from the granulate.

The granulation process is preferably carried out in dry conditions using the
compaction process.
The compaction process consists in the compaction using high pressure forces of
the active substance or a mixture thereof with an appropriate excipient.

The process of preparing of the pharmaceutical composition according to the

invention preferably occurs during the celecoxib compaction process with one of
the following carrier systems: crospovidone, crospovidone and PEG.
The excipient used as a glidant is preferably magnesium stearate.

Owing to the use of the compaction process of granulate preparation for the
manufacture of the pharmaceutical composition containing celecoxib, the bulk
volume of the granulate is largely reduced, its flow properties improve and the
dusting effect and losses due to the adhesion of the active substance to
manufacturing equipment are eliminated.
Furthermore, the dry granulation process involves three stages only, while wet
granulation consists of at least six stages. Therefore, the use of the dry granulation
process ensures better process control and, in consequence, higher quality of the
finished product.
Owing to the use of compaction technology for celecoxib combined with at least
one cross-linked polymer as the carrier, the size of celecoxib particles can be
efficiently reduced and granulate with high integration of the active substance
with the carrier can be obtained.
The resulting granulate is characterised by high celecoxib concentration. As
a result, a smaller capsule size for large doses of the finished formulation can be
used and, in consequence, the convenience of use of the medicine by patients is
enhanced.
The embodiments of the subject matter of the invention are shown in the Figure
and:
Fig. 1 shows the diagram of the manufacture of an exemplary composition
containing celecoxib in the form of capsules whose quantitative and qualitative
composition corresponds to that of Example 1.

Fig. 2 shows the diagram of the manufacture of an exemplary composition

containing celecoxib in the form of capsules whose quantitative and qualitative
composition corresponds to that of Example 2.
Fig. 3 shows the release profile of the celecoxib active substance for the
composition of Example 1 and Example 2 in the form of hard gelatine capsules
compared with the release profile for the reference medicine.
Fig. 4 shows the diagram of the manufacture of an exemplary composition
containing celecoxib in the form of capsules whose quantitative and qualitative
composition corresponds to that of Example 4.
Fig. 5 shows the release profile of the celecoxib active substance for the
composition of Example 1 and Example 4 in the form of hard gelatine capsules
compared with the release profile for the reference medicine.

The invention is illustrated by the following examples which in no way restrict its
scope.

Example 1.

Powder for compaction in the amount of 3.0 kg, which contained in its
composition substances specified in the table below, was prepared in a bin mixer
with a bin volume of 20 1, by Zanchetta. The dry granulation process was carried
out using an Alexanderwerk WP 150 Pharma compactor. A pressure force of 12
kN/cm 2 and a sieve with a mesh size of 0.8 mm were used to mill the resulting
strips. A proportional composition of the granulate was used.

An example of the composition is shown in the table below.

Substance name Mg / tabl. Percentage (%)
Celecoxib 200.0 66.7
Crospovidone 98.5 32.8
Magnesium stearate 1.5 0.5

The flow chart of the manufacture of the composition is shown in Fig. 1.

 1 Celecoxib
2 Crospovidone mixing

1 Celecoxib compaction
2 Crospovidone

1 Celecoxib milling
2 Crospovidone

3 Magnesium stearate 1 Celecoxib

2 Crospovidone mixing

1 Celecoxib
2 Crospovidone capsule
3 Magnesium stearate manufacturing

Fig. 1. Diagram of the manufacture of an exemplary composition containing

celecoxib in the form of capsules.

Example 2.

Powder for compaction in the amount of 3.0 kg, which contained in its
composition substances specified in the table below, was prepared in a bin mixer
with a bin volume of 20 1, by Zanchetta. The dry granulation process was carried
out using an Alexanderwerk WP 150 Pharma compactor. A pressure force of 12
kN/cm2 and a sieve with a mesh size of 0.8 mm were used to mill the resulting
strips. A proportional composition of the granulate was used.

Substance name Mg / tabl. Percentage (%)

Celecoxib 200.0 66.9
Crospovidone 48.25 16.1
PEG 6000 49.25 16.5
Magnesium stearate 1.5 0.5
The flow chart of the manufacture of the composition is shown in Fig. 2.

1 Celecoxib mixing
2

1 Celecoxib compaction
2 Crospovidone
3 PEG 6000

1 Celecoxib milling
2 Crospovidone
3 PEG 6000

mixing

capsule
manufacturing

Fig. 2. Diagram of the manufacture of an exemplary composition containing

celecoxib in the form of capsules.

Example 3.

This is a comparative example which illustrates the release profile for exemplary
compositions according to the invention containing celecoxib in a 200 mg dose in
the form of hard gelatine capsules and the brand-name product, Celebrex® 200
mg, Pfizer, commercially available in the form of hard gelatine capsules.
The same analytical procedure was used for all the products, selected based on the
Food and Drug Administration (FDA) methodology.
It includes the evaluation of active substance release from the dosage form using
an USP II paddle apparatus, that is, an apparatus equivalent to apparatus II
according to Ph. Eur., with a speed of 50 rpm in 0. 1 M HCl solution with 2%
sodium lauryl sulphate.

The results are presented below:

10 20 30 40 50 60 70
czas [min]

[legend:]
% release
time [min]
Celebrex® 200 mg, lot no. 610256534
Composition of Example 1
Composition of Example 2

Fig. 3. The release profile of the celecoxib active substance from the composition
of Example 1 and Example 2 in the form of hard gelatine capsules compared with
the release profile for the reference medicine (0. 1 M HCl with 2% sodium lauryl
sulphate).

Example 4.

This is a comparative example which illustrates the release profile for exemplary
compositions according to the invention containing celecoxib in a 200 mg dose in
the form of hard gelatine capsules whose quantitative and qualitative composition
is shown in the table below, with two distinct granulation techniques used: dry
granulation and wet granulation.
Dry granulation was carried out as described in Example 1; the flow chart of the
preparation of the composition is shown in Fig. 1. Wet granulation, in turn, was
carried out as described below.

Powder for granulation in the amount of 1.5 kg, which contained in its
composition substances specified in the tables below, was prepared in a Zanchetta
bin mixer. The wet granulation process was carried out using a Glatt VG5 WP
150 Pharma high-speed granulator. The granulate was wetted with water in the
amount of 50% of powder weight during the process. The wet granulate was dried
and homogenised using sieves with 0.8 mm mesh size.

Substance name Mg / tabl. Percentage (%)

Celecoxib 200.0 66J
Crospovidone 98.5 32.8
Magnesium stearate 1.5 0.5

The same analytical procedure was used for all the products, selected based on the
FDA methodology.
It includes the evaluation of active substance release from the dosage form using
an USP II paddle apparatus, that is, an apparatus equivalent to apparatus II
according to Ph. Eur., with a speed of 50 rpm in 0.1 M HCl solution with 2%
sodium lauryl sulphate.
The flow chart of the manufacture of the composition is shown in Fig. 5.

mixing

wetting

granulation

drying

1 Celecoxib milling
2 Crospovidone

mixing

capsule
manufacturing
— - Fig. 5. Diagram of the manufacture of an exemplary composition containing

celecoxib in the form of capsules (Example 4)

C 10 20 30 40 50 60 70
cias[ml π]

[legend:]
% release
time [min]
Celebrex® 200 mg, lot no. 610256534
Composition of Example 1
Composition of Example 4

Fig. 4. The release profile of the active substance from Celecoxib 200 mg hard
gelatine capsules in which two distinct granulation processes were used (0.1 M
HCl with 2% sodium lauryl sulphate).
Patent claims

1. A pharmaceutical composition containing celecoxib as the active

substance and a pharmaceutically acceptable carrier, characterised in that
it contains a cross-linked polymer as the pharmaceutically acceptable
carrier.
2. A pharmaceutical composition according to Claim 1, characterised in that
the pharmaceutically acceptable carrier contains crospovidone.
3. A pharmaceutical composition according to Claim 2, characterised in that
the pharmaceutically acceptable carrier contains micronised crospovidone.
4. A pharmaceutical composition according to Claim 1, characterised in that
the pharmaceutically acceptable carrier is crospovidone and PEG.
5. A pharmaceutical composition according to Claim 1, characterised in that
its quantitative composition is proportional.
6. A process of manufacturing of the pharmaceutical composition containing
celecoxib as the active substance, characterised in that it consists of the
following stages:
a. the active substance (celecoxib) is subjected to granulation with at
least one pharmaceutically acceptable carrier,
b. the resulting pellets are standardised,
c. the standardised granulate is mixed with the excipient,
d. capsules are manufactured from the granulate.
7. A process according to Claim 6, characterised in that the granulation
process is carried out in dry conditions.
8. A process according to Claim 7, characterised in that dry granulation
constitutes compaction.
9. A process according to Claim 6, characterised in that the resulting pellets
are standardised by milling.
10. A process according to Claim 6, characterised in that a glidant, preferably
magnesium stearate, is an excipient.