Title of Invention

"A SYNERGISTIC PHARMACEUTICAL COMPOSITION OF CELECOXIB WITH IMPROVED AQUEOUS SOLUBILITY"

Abstract The present invention relates to a pharmaceutical composition of a ternary mixture with enhanced aqueous solubility and a process for preparing the said composition comprising celecoxib, a polymeric stabilizer, pharmaceutically acceptable excipients and a non-surfactant solubility enhancer to provide improved solubility.
Full Text Field of the Invention
The present invention relates to a synergistic pharmaceutical composition of a ternary mixture with enhanced aqueous solubility containing celecoxib and other additives. The present invention also provides a a process for preparing the said pharmaceutical composition.
Background of the Invention
Celecoxib, chemically is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl] benzenesulfonamide, and is used for the prophylaxis and treatment of specific COX-2 mediated disorders. It has registered record sales 1.5 billion USD in year 1999 and the figure is expected to go beyond USD 3 billion by the end of year 2002.
Pharmacia Corporation, USA, holds the patent for this molecule and its various polymorphs and pseudo-polymorphs through a series of patents viz. US 5.466,823; WO 00/32189; WO 00/42021.
Poor aqueous solubility of a drug may be a limiting factor in the oral bioavailability of the dosage form. There is a need for improvement in aqueous solubility for rapid-onset of action of such drugs from immediate-release dosage forms, and achievement of predicted drug release profile from a controlled release (CR) or sustained release (SR) dosage from without compromising its oral bioavai lability.
A number of approaches like pH modification, co-solvents, complexation etc are available for improvement of aqueous solubility. A particularly useful approach for solid dosage forms is conversion of crystalline form to corresponding amorphous form. However, many times amorphous systems are not inherently stable to provide a meaningful product shelf life. Amorphous systems can be stabilized by inclusion of excipients, especially polymers like PVP, hydroxypropyl methyl cellulose (HPMC) etc.
Yoshioka et al. J. Pharm.Sci. 84(8). August 1995. 983 - 986 describe the stabilization of amorphous indornethacin.
Patent appliation WO 0141536 entitled "Solid-state form of celecoxib having enhanced bioavailability, provides a novel amorphous form of celecoxib. It provides lor amorphous

celecoxib per se, celecoxib drug substance that comprises amorphous celecoxib, so as to provide enhanced dissolution. The invention also provides celecoxib - crystallization inhibitor composites using crystallization inhibitors like PVP, HPMC, HPMC phthalate, ethylcelluslose, hydroxyethyicellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, dextran acacia, starches, cyclodextrins, block co-polymers of ethylene oxide and propylene oxide, PVA and PEG. Povidone (PVP) and HPMC are the preferred polymers for the invention. A process for preparation of the amorphous celecoxib drug substance and celecoxib-crystallization inhibitor composite is also provided. The process consists either of quench cooling the melt or dissolving in solvent followed by evaporation of the same. This patent also describes amorphous celecoxib or celecoxib crystallization inhibitor composite, and its process of preparing a formulation using pharmaceutically acceptable excipients to obtain a suitable pharmaceutical composition.
US Patent Nos. 6,387,901; 6,376,519; 6,342,521; 6,329,397; 6,214,870; 6,197,810; 6,156,798; 6,114,361 and 6,110,964 describes different New Chemical entities as meglumine salt and it's use in combination therapy with celecoxib. However, celecoxib is not incorporated along with the meglumine salt of new chemical entity to obtain pharmaceutical composition.
The aqueous solubility of drug from stabilized amorphous system can be further improved by inclusion of excipients additional to the one used for stabilizing the amorphous form. This gives advantages in terms of increased aqueous solubility, thus improving functioning of immediate release and controlled release formulations.
Celecoxib has poor aqueous solubility and consequently its absorption from the gastrointestinal tract is limited. Improvement in its aqueous solubility will increase its oral bioavailability and will also help in rapid-onset of action, which provides significant benefits in terms of faster relief from pain.
Objects of the Invention
Mam object of the invention is to provide a pharmaceutical composition selected Irorn celecoxib with an improved aqueous solubility.
Another object of the invention is to obtain amorphous celecoxib from crystalline
celecoxib.
Yet another object of the invention is to stabilize amorphous celecoxib obtained by using
a polymer.
Still another object of the present invention is to provide a pharmaceutical composition
having enhanced bioavailability.
Yet another object of the invention is to provide use of less dosage of celecoxib
pharmaceutical composition for the treatment.
Yet another object of the invention is to provide solid dosage forms including binders,
disintegrants, diluents, lubricants, glidants, anti-adherants, surface active agents, coating
polymers, flavors and colors.
Still yet another object of the invention is to provide a sustained release or controlled
release formulation for celecoxib.
Still yet another object of the invention is to minimize the side effects caused by the drug
celecoxib.
Further object of the invention is to provide a stable pharmaceutical composition of
celecoxib amorphous.
Summary of the Invention
In accordance, the present invention provides a synergistic pharmaceutical composition of a ternary mixture containing ceiecoxib, a polymer, non-surfactant solubility ebhancer and a pharmaceutically acceptable excipient and an efficient and economical process for the preparation of the said pharmaceutical composition.STATEMENT OF INVENTION:
Accordingly, the invention relates to a synergistic pharmaceutical composition of a ternary mixture with enhanced aqueous solubility, the said composition comprising:
a) Celecoxib in the range of 30 to 80 % by weight substantially in amorphous form;
b) a polymer such as herein described in the range of 5-50% by weight;
c) a non surfactant solubility enhancer in the range of 5-25% by weight, wherein the non-surfactant solubility enhancer in an amino sugar; and
d) one or more pharmaceutically acceptable excipient
One embodiment of the invention provides a composition, wherein the polymer used is selected from PVP, HPMC, HPC or HPMCP, ethyl cellulose, sodium CMC and preferably PVP.
Another embodiment, the polymer used is in the range of 5-50 %, preferably in the range of 10-40 % and more preferably 15-25 %.
Another embodiment of the invention, the celecoxib used is in the range of 30 to 80 % by weight, preferably in the range of 50 to 70 % by weight.
Still another embodiment, the nonsurfactant solubility enhancer used is an amino sugar, which is selected from N-methyl-D-glucamine (meglumine) in the range of 5-25 %, preferably in the range of 5-20 % and more preferably 5-15 %.
Still another embodiment, the celecoxib exists atleast in detectable amount in amorphous form and preferably more than 90 % in the amorphous form.
Yet another embodiment, the pharmaceutically acceptable excipients are selected from the group consisting of starch, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, acacia, tragacanth, disintegrants selected from starch, croscarmellose sodium, crospovidone, sodium starch glycollate, diluents selected from microcrystalline cellulose, dicalcium phosphate, starch, lactose, mannitol, xylitol, calcium sulphate, lubricants selected from stearic acid, magnesium stearate, hydrogenated vegetable oil, glidants selected from colloidal silicon dioxide, anti-adherents like talc, surface active agents such as sodium lauryl sulphate, cremophor RH 40, polysorbate 80, coating polymers selected from hydroxy propyl methyl cellulose, hydroxy propyl cellulose, flavors and coloring agents.
Yet another embodiment, the non-surfactant solubility enhancer, enhances ihe aqueous solubitility of celecoxib by at least 1-50 times.
Yet another embodiment the polymer used stabilizes the celecoxib amorphous formed.
Yet another embodiment, the dosage can be provided in the form of immediate release, sustained release, modified release or controlled release, which can be a tablet, capsule or any other acceptable solid dosage form.
One more embodiment of the present invention provides a process for the preparation of pharmaceutical composition, the said process comprising steps of:
a) dissolving celecoxib, a polymer and an non-surfactant solubility enhancer
in an organic solvent,
b) evaporating the organic solvent of step (a) solution at a temperature range
of 50 to 60°C to obtain a residue,
c) heating the residue of step (b) to a temperature range of 150 ° to 180 ° C
to obtain a melt for thorough mixing,
d) cooling immediately the molten mass of step (c) by dipping in a liquid
nitrogen or dry ice-acetone mixture to obtain a ternary mixture containing
celecoxib, and
e) formulating the ternary mixture of step (d) containing celocoxib with one
or more pharmaceutically acceptable excipients to obtain the required
pharmaceutical composition.
Another embodiment of the invention provides a process, wherein the celecoxib exists atleast in detectable amount in amorphous form and preferably more than 90 % in the amorphous form.
Another embodiment, the nonsurfactant solubility enhancer used is an amino sugar selected from N-methyl-D-glucamine (meglumine).
In another embodiment, the organic solvent used is selected from a group consisting of. methanol, ethanol, isopropanol, dichloromethane, water or mixture thereof.
In another embodiment, the polymer used is selected from a group consisting of PVP (polyvinylpyrolidine), (hydroxypropylmethyl cellulose) HPMC. HPC (hydroxypropyl cellulose) or HPMCP. EC (Ethyl cellulose), sodium CMC (sodium curboxy methyl cellulose) and preferably PVP.
Still another embodiment, the evaporation is carried out by either spray drying, lyophili/aiion or distillation under reduced pressure.
Still another embodiment, the heating is done at a temperature range of 150° -180° and preferably in the range of 170 ° - 180 °C.
Still another embodiment, the pharmaceutically acceptable excipients are selected from group consisting of are selected from starch, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, acacia, tragacanth), disintegrants (starch, croscarmellose sodium, crospovidone, sodium starch glycollate), diluents (microcrystalline cellulose, dicalcium phosphate, starch, lactose, mannitol, xylitol, calcium sulphate), lubricants (stearic acid, magnesium stearate, hydrogenated vegetable oil), glidants (colloidal silicon dioxide), anti-adherents (talc), surface active agents (sodium lauryl sulphate, cremophor RH 40, polysorbate 80), coating polymers (hydroxy propyl methyl cellulose, hydroxy propyl cellulose), flavors and colors
The solubility of poorly aqueous soluble drugs like celecoxib can be improved by converting their crystalline form to amorphous state. Amorphous state is characterized by absence of long-range order in the molecular arrangement in the solid state. Although there may be regions showing short-range order (micro-crystallites / nano-crystallites), such an order over long range is missing. Such systems give diffused peaks in the X-ray diffractogram.
The aqueous solubility of the drug candidate can be further improved by addition of judiciously chosen excipient to the 'drug-stabilizer' system. This improvement may be provided due to specific interactions between the drug and the excipient.
Another important aspect to be considered during development of such systems is that the percentage of the excipients used as stabilizer and solubilizer should be kept to a minimum to maintain flexibility in the formulation approaches.
The composition of the present invention is a synergistic mixture exhibiting unexpected /surprising property. In this composition, celecoxib is present in the range of 30 to 805 by weight, the polymer is in the range of 10 to 40% by wt. non-surfactant solubility
enhancer in the range of 5 to 25 % by wt and/remaining/one or more pharmaceutically
acceptable additives/excipient.
The percentage values indicated in the synergistic composition are expressed in weight percentage basis unless otherwise specified.
In the present invention exemplified by celecoxib amorphous system, the solubility of drug was significantly improved by addition of meglumine (N-methyl-oD-glucamine) to celecoxib-PVP mixture. As is reported earlier (WO 0141536), polymers like PVP, HPMC, HPMCP, ethyl cellulose (EC), Sodium CMC, etc. are able to stabilize the amorphous form of celecoxib and provide improved solubility of celecoxib.
The maximum solubility achieved with celecoxib-PVP binary system is about 20 meg/ml which is achieved when the system consists of 20% PVP. Any increase in PVP beyond 20% concentration does not provide any further improvement in solubility (Refer Table 1 for solubility data). PVP concentration of 20% and above is also able to retard the conversion of amorphous celecoxib to crystalline form.
Table 2 provides the solubility of celecoxib achieved from a celecoxib-meglumine binary mixture. Peak solubility values of about 15 meg/ml are achieved using 25 and 50 % of meglumine.
Surprisingly, it was found that the peak solubility values achieved with a 'celecoxib-PVP-meglumine' ternary mixture is higher as compared to the values achieved with corresponding binary systems of 'celecoxib-PVP' and 'celecoxib-meglumine'. As is shown in Table 3 a composition consisting of celecoxib:PVP:meglumine 70:10:20 gives a peak solubility of 47 meg/ml as compared to solubility of 14.83 and 16.59 meg/ml obtained with celecoxib:PVP 90:10 and celecoxib:meglumine 80:20 binary systems, respectively.
The composition of the ternary mixture of this embodiment can consist 5-60% of PVP
and 5-30% of meglumine, preferably 10-40% of PVP and 5-20% of meglumine, and still
more preferably 15-25% of PVP and 5-15% of meglumine. Celecoxib in such a system
exists at least in detectable amount in amorphous form and preferably more than 90%
celecoxib present is in the amorphous form.
The system of the present embodiment on exposure to 40'C / 75'/f RH, in an open dish tor a period of 14 days, maintains celecoxib in amorphous state. The transformation of
amorphous celecoxib to crystalline form was no more than 50%, preferably no more than 25% and still more preferably no more than 10% of the initial amorphous content.
It is sometimes difficult to achieve the desired release kinetics from the SR/CR dosage form prepared using poorly aqueous soluble drug. In such cases, the ternary system of the present embodiment can help in achieving the desired release kinetics from the formulation. Illustrative non-limiting example of excipients in such cases would be rate-controlling polymers (cellulosic polymers like hydroxy propyl methyl cellulose, hydroxy propyl cellulose, ethyl cellulose, carrageenan, xanthan gum), diluents, polymers, binders, and coating polymers, etc.
The present invention is illustrated with the following examples, which should not be construed to limit the scope of the invention:
EXAMPLES
Example I: To dichloromethane (25 ml), added celecoxib (7 gms), PVP (2 gm) and meglumtne (1 gm) and dissolved. Heated the mixture to a temperature aroumd 50 to 60 ° C to evaporate completely the solvent and continued heating till a molten mass is obtained. Cooled the molten mass immediately in a cooling bath containing liquid nitrogen or dry ice acetone to get the required Celecoxib ternary mixture.
Example II: To dichloromethane (18 ml), added celecoxib (5 gms), PVP (3 gm) and meglumine (2 gm) and dissolved. Heated the mixture to a temperature aroumd 50 to 60 ° C to evaporate completely the solvent and continued heating till a molten mass is obtained. Cooled the molten mass immediately in a cooling bath containing liquid nitrogen or dry ice acetone to get the required Celecoxib ternary mixture
Example III: To dichloromethane (18 ml), added celecoxib (5 gms). PVP (4 gm) and meglumine (1 gm) and dissolved. Heated the mixture to a temperature aroumd 50 to 60 ° C lo evaporate completely the solvent and continued heating till a molten mass is
obtained. Cooled the molten mass immediately in a cooling bath containing liquid nitrogen or dry ice acetone to get the required Celecoxib ternary mixture
Removal of solvents in Examples I to III can also be performed by employing spray drying, freeze drying or any other suitable method.
Examples IV to VI: A celecoxib ternary mixture can be prepared using the procedure of examples I to III mentioned earlier without using the solvent
Example VII: SOLUBILITY DATA
Table 1
Solubility data for Celecoxib-PVP binary systems

(Table Removed)
Crystalline celecoxib has solubility of 3.36 + 0.16 mcg/ml and amorphous celecoxib has a solubility of 4.66 ± 0.62 mcg/ml.
Table 2
Solubility data of Celecoxib-Meglumine binary systems

(Table Removed)
Table 3
Solubility data for Celecoxib-PVP-Meglumine ternary systems

(Table Removed)
* Percent improvement over solubility of crystalline celecoxib ** Percent improvement over solubility of celecoxib-PVP binary mixture containing identical percentage of PVP *** Stored at 40 C / 75 % RH
The main advantages of the invention are:
1. The present invention provides a pharmaceutical composition containing celeccoxib
with enhanced aqueous solubility.
2. The present invention provides enhanced bio-availability of celecoxib.
3. The present invention also provides the possibility of minimizing the side effects
caused by the drug.
4. The present invention provides the use of less quantity of drug in the treatment of
disease.
5. The present invention provides a pharmaceutical composition with improved release
kinetic in sustained or controlled release dosage forms.








I






WE CLAIM:
1. A synergistic pharmaceutical composition of a ternary mixture with enhanced
aqueous solubility, the said composition comprising:
a) Celecoxib in the range of 30 to 80 % by weight substantially in amorphous form;
b) a polymer such as herein described in the range of 5-50% by weight;
c) a non surfactant solubility enhancer in the range of 5-25% by weight, wherein the non-surfactant solubility enhancer in an amino sugar; and
d) one or more pharmaceutically acceptable excipient

2. A composition as claimed in claim 1, wherein the polymer used is selected from polyvinyl pyrrolidone (PVP), hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose (HPC) or hydroxy propyl methyl cellulose phthalate (HPMCP), ethyl cellulose, sodium carboxy methyl cellulose (CMC) and preferably polyvinyl pyrrolidone (PVP).
3. A composition as claimed in claim 1, wherein preferably the polymer is in the range of 10-40% by weight and more preferably 15-25 % by weight.
4. A composition as claimed in claim 1, wherein preferably the celecoxib is in the range of 50 to 70% by weight.
5. A composition of claim 1, wherein the amino sugar used is N-methyl-D-glucamine (meglumine).
6. A composition as claimed in claim 5, wherein preferably the meglumine is in the range of 5-20% and more preferably 5-15%.
7. A composition as claimed in claim 1, wherein preferably more than 90% celecoxib exists in amorphous form.
8. A composition as claimed in claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of starch, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, acacia, tragacanth. disintegrants selected from starch, croscarmellose sodium, crospovidone sodium starch glycollate, diluents selected from microcrystalline cellulose, dicalcium phosphate, starch, lactose, mannitol, xylitol, calcium sulphate, lubricants selected from stearic acid, magnesium stearate, hydrogenated vegetable oil, glidants selected from colloidal silicon dioxide, anti-adherents like talc, surface active agents such as sodium lauryl sulphate,
cremophor RH 40, polysorbate 80, coating polymers selected from hydroxy propyl methyl cellulose, hydroxy propyl cellulose, flavors and coloring agents.
9. A process for the preparation of a synergistic pharmaceutical composition of claim 1,
the said process comprising the steps of:
a) dissolving celecoxib, a polymer such as herein described and an non-
surfactant solubility enhancer such as herein described in an organic solvent
such as herein described,
b) evaporating the organic solvent of step (a) solution at a temperature range of
50 to 60°C to obtain a residue,
c) heating the residue of step (b) to a temperature range of 150° to 181°C to obtain a melt for thorough mixing,
d) cooling immediately the molten mass of step (c) by dipping in a liquid nitrogen or dry ice-acetone mixture to obtain a ternary mixture containing celecoxib, and
e) formulating the ternary mixture of step (d) containing celocoxib with one or
more pharmaceutically acceptable excipients to obtain the required
pharmaceutical composition.
10. A process as claimed in claim 9, wherein in step (a), the organic solvent used is
selected from a group consisting of methanol, ethanol, isopropanol, dichloromethane,
water or mixture thereof.
11. A synergistic pharmaceutical composition of a ternary mixture containing celecoxib,
with enhanced aqueous solubility as herein described with reference to examples.
12. A process for preparation of a synergistic pharmaceutical composition of a ternary
mixture containing celecoxib with enhanced aqueous solubility as herein described
with reference to examples.

Documents:

685-del-2002-abstract.pdf

685-del-2002-Claims-(06-12-2010).pdf

685-del-2002-claims.pdf

685-del-2002-Correspondence-Others-(06-12-2010)-.pdf

685-del-2002-Correspondence-Others-(06-12-2010).pdf

685-del-2002-correspondence-others.pdf

685-del-2002-Description (Complete)-(06-12-2010).pdf

685-del-2002-description (complete).pdf

685-del-2002-form-1.pdf

685-del-2002-form-18.pdf

685-del-2002-form-2.pdf

685-del-2002-form-26.pdf

685-del-2002-form-3.pdf

685-del-2002-form-5.pdf

685-del-2002-GPA-(06-12-2010).pdf

685-DELN-2002-Abstract-(10-03-2010).pdf

685-DELN-2002-Claims-(10-03-2010).pdf

685-DELN-2002-Correspondence-Others-(10-03-2010).pdf

685-DELN-2002-Description (Complete)-(10-03-2010).pdf

685-DELN-2002-Form-1-(10-03-2010).pdf

685-DELN-2002-Form-2-(10-03-2010).pdf


Patent Number 248660
Indian Patent Application Number 685/DEL/2002
PG Journal Number 31/2011
Publication Date 05-Aug-2011
Grant Date 02-Aug-2011
Date of Filing 26-Jun-2002
Name of Patentee NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER)
Applicant Address SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB -160 062, INDIA
Inventors:
# Inventor's Name Inventor's Address
1 PIYUSH GUPTA NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER),SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB -160 062, INDIA
2 ARVIND KUMAR BANSAL NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER),SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB -160 062, INDIA
3 VASU KUMAR KAKUMANU NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER),SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB -160 062, INDIA
PCT International Classification Number C07D233/54
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA