COMPLEXES OF CELECOXIB AND ITS SALTS AND DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract

Disclosed herein are stable complexes with controlled particle size, increased apparent solubility and increased dissolution rate comprising as active compound Celecoxib, its salts, or derivatives thereof, which is useful in the treatment of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, acute pain especially in cancer related acute pain, primary dysmenorrhea. More specifically, the complexes possess instantaneous redispersibility, increased apparent solubility and permeability that provide faster onset of action for acute pain relief and lower GI related side effects. Further disclosed are methods of formulating and manufacturing the complexes described herein, pharmaceutical compositions, and uses and methods of treatment.

Claims

1. A stable complex comprising as active compound chosen from Celecoxib, its salts or derivatives thereof; and at least one complexation agent chosen from polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol, hydroxypropylcellulose, poloxamers (copolymers of ethylene oxide and propylene oxide blocks), vinylpyrrolidone/vinyl acetate copolymer, poly(2-ethyl-2-oxazoline), polyvinylpyrrolidone, poly(maleic acid/methyl vinyl ether), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyoxyl 15 hydroxystearate, ethylene oxide/propylene oxide tetra functional block copolymer, and d-alpha tocopheryl polyethylene glycol 1000 succinate; said complexes characterized in that it possesses at least one of the following properties: a. are instantaneously redispersable in physiological relevant media b. are stable in solid form and in colloid solution and/or dispersion; c. have an apparent solubility in water of at least 1 mg/mL; d. have a PAMPA permeability of at least 0.5×10.sup.−6 cm/s when dispersed in FaSSIF or FeSSIF biorelevant media, which does not decrease in time at least for 1 month; and e. have a PAMPA permeability of at least 0.4×10.sup.−6 cm/s when dispersed in simulated saliva at pH=6.8.

2. The complex as recited in claim 1, wherein said complexation agent is chosen from polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol, hydroxypropylcellulose, poloxamers (copolymers of ethylene oxide and propylene oxide blocks), vinylpyrrolidone/vinyl acetate copolymer, polyethylene glycol, poly(2-ethyl-2-oxazoline), polyvinylpyrrolidone, poly(maleic acid/methyl vinyl ether), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyoxyl 15 hydroxystearate, ethylene oxide/propylene oxide tetra functional block copolymer, and d-alpha tocopheryl polyethylene glycol 1000 succinate.

3. The complex as recited in claim 1, wherein said complexation agent is chosen from a copolymer of vinylpyrrolidone and vinyl acetate, polyvinylpyrrolidone, and a poloxamer.

4. The complex as recited in claim 1, wherein complexation agent is polyvinylpyrrolidone.

5. The complex as recited in claim 1, wherein complexation agent is a copolymer of vinylpyrrolidone and vinyl acetate.

6. The complex as recited in claim 1, wherein complexation agent is a poloxamer.

7. The complex as recited in claim 1, wherein said complex further comprises at least one pharmaceutically acceptable excipient selected from the group of sodium lauryl sulfate and lactose.

8. The complex as recited in claim 7, wherein said pharmaceutically acceptable excipient is sodium lauryl sulfate.

9. The complex as recited in claim 1, wherein said complex has a controlled particle size in the range between 10 nm and 500 nm.

10. The complex as recited in claim 9, wherein said particle size is between 10 nm and 200 nm.

11. The complex as recited in claim 1, wherein said complex further comprises one or more additional active agents.

12. The complex as recited in claim 9, wherein said additional active agent is chosen from agents useful for the treatment of any type of cancer.

13. The complex as recited in claim 1, wherein said complex is shows earlier t.sub.max and time to onset of action when compared to the current oral formulation.

14. The complex as recited in claim 1, wherein said complex possesses at least two of the properties described in a)-e).

15. The complex as recited in claim 1, wherein said complex possesses at least three of the properties described in a)-e).

16. The complex as recited in claim 1, wherein said complex shows X-ray amorphous character in the solid form.

17. The complex as recited in claim 1, wherein said complex has an increased dissolution rate compared to Celebrex®.

18. A stable complex comprising an active compound selected from the group of Celecoxib, its salt, or derivatives thereof; at least one complexation agent chosen from polyvinylcaprolactam-polyvinyl acetate-polyethylene-glycol graft copolymers; poloxamers; polyvinylpyrrolidone; copolymers of vinylpyrrolidone and vinyl-acetate; and poly(maleic acid-co-methyl-vinyl-ether); and at least one pharmaceutically acceptable excipient chosen from sodium lauryl sulfate and lactose; wherein said complex obtained via a mixing process.

19. The complex as recited in claim 17, wherein said complexation agent is chosen from a copolymer of vinylpyrrolidone and vinyl acetate, polyvinylpyrrolidone, and a poloxamer.

20. The complex as recited in claim 17, wherein said complex is obtained via a continuous flow mixing process.

21. A complex according to claim 1 comprising a complexation agent chosen from a copolymer of vinylpyrrolidone and vinyl acetate, polyvinylpyrrolidone, and a poloxamer; and a pharmaceutically acceptable excipient chosen from sodium lauryl sulfate and lactose; in a total amount ranging from about 1.0 weight % to about 95.0 weight % based on the total weight of the complex.

22. The complex as recited in claim 20 wherein said complexation agent chosen from a copolymer of vinylpyrrolidone and vinyl acetate, polyvinylpyrrolidone, and a poloxamer; and pharmaceutically acceptable excipient chosen from sodium lauryl sulfate and lactose; comprise 50 weight % to about 95 weight % of the total weight of the complex.

23. A process for the preparation of the complex according to claim 17, comprising the steps of mixing a solution comprising Celecoxib, its salt, or derivatives thereof, and at least one complexation agent chosen from polyvinylcaprolactam-polyvinyl acetate-polyethylene-glycol graft copolymers; poloxamers; polyvinylpyrrolidone; copolymers of vinylpyrrolidone and vinyl-acetate; and poly(maleic acid-co-methyl-vinyl-ether); d-alpha tocopheryl polyethylene glycol 1000 succinate in a pharmaceutically acceptable solvent with an aqueous solution containing at least one pharmaceutically accepted excipient chosen from sodium lauryl sulfate and lactose.

24. The process as recited in claim 22, wherein said process is performed in a continuous flow instrument.

25. The process as recited in claim 23, wherein said continuous flow instrument is a microfluidic flow instrument.

26. The process as recited in claim 22, wherein said pharmaceutically acceptable solvent is chosen from methanol, ethanol, 2-propanol, 1-propanol, acetone, acetonitrile, dimethyl-sulfoxide, tetrahydrofuran, and methyl-ethyl-ketone, or combinations thereof.

27. The process as recited in claim 25 wherein said pharmaceutically acceptable solvent is chosen from methanol, 1-propanol, and 2-propanol.

28. The process as recited in claim 22, wherein the solvent and the aqueous solution are miscible with each other.

29. The process as recited in claim 22, wherein the aqueous solution comprises 0.1 to 99.9% weight of the final solution.

30. A pharmaceutical composition comprising the complex according to claim 1 together with pharmaceutically acceptable carrier.

31. A pharmaceutical composition comprising the complex according to claim 1 wherein said composition is suitable for oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ocular, otic, local, buccal, nasal, or topical administration.

32. The pharmaceutical composition comprising the complex according to claim 30, wherein said composition is suitable for oral administration.

33. The pharmaceutical composition comprising the complex according to claim 31, wherein said composition comprises liquid dispersible granules.

34. The pharmaceutical composition comprising the complex according to claim 32, wherein said granules are suitable for the preparation of a sachet or buccal powder dosage forms.

35. A method of treatment of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, acute pain especially in cancer related acute pain, primary dysmenorrhea comprising administration of a therapeutically effective amount of the complex according to claim 1.

36. A method for reducing t.sub.max and time to onset of action when compared to the current oral formulation, said method comprising oral administration of a pharmaceutical composition according to claim 34.

37. A stable complex comprising a) 10-40% by weight of Celecoxib, its salt, or derivatives thereof; b) 35-70% by weight of a polyvinylpyrrolidone; and c) 5-50% by weight of sodium lauryl sulfate wherein said complex has a controlled particle size in the range between 10 nm and 500 nm; and wherein said complex is not obtained via a milling process, high pressure homogenization process, encapsulation process or solid dispersion processes.

38. A stable complex comprising a) 5-30% by weight of Celecoxib, its salt, or derivatives thereof; b) 40-80% by weight of a copolymer of vinylpyrrolidone and vinyl acetate; and c) 1-30% by weight of sodium lauryl sulfate wherein said complex has a controlled particle size in the range between 10 nm and 500 nm; and wherein said complex is not obtained via a milling process, high pressure homogenization process, encapsulation process or solid dispersion processes.

39. Further disclosed herein is a stable complex comprising a) 5-30% by weight of Celecoxib, its salt, or derivatives thereof; b) 30-65% by weight of a poloxamer; and c) 15-60% by weight of lactose wherein said complex has a controlled particle size in the range between 10 nm and 500 nm; and wherein said complex is not obtained via a milling process, high pressure homogenization process, encapsulation process or solid dispersion processes.

40. The complex as recited in claim 37, wherein said particle size is between 50 nm and 200 nm.

41. The complex as recited in claim 38, wherein said particle size is between 50 nm and 200 nm.

42. The complex as recited in claim 39, wherein said particle size is between 50 nm and 200 nm.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0144] The accompanying figures, which are incorporated and form part of the specification, merely illustrate certain non-limiting embodiments. They are meant to serve to explain specific modes to those skilled in the art.

[0145] FIG. 1. shows the redispersibility of complex Celecoxib formulations in ultrapurified water.

[0146] FIG. 2. shows the redispersibility of complex Celecoxib formulations in simulated saliva.

[0147] FIG. 3. shows the PAMPA permeability of selected complex Celecoxib formulations.

[0148] FIG. 4. shows the composition optimization of complex Celecoxib formulation containing polyvinylpyrrolidone and sodium lauryl sulfate.

[0149] FIG. 5. shows the manufacturing process intensification and process parameter optimization.

[0150] FIG. 6. shows the optimization of the ratio of Solution 1 and Solution 2.

[0151] FIG. 7. shows the optimization of the production rate.

[0152] FIG. 8. shows the dissolution of Celecoxib from different solid forms.

[0153] FIG. 9. shows the PAMPA permeability of complex Celecoxib formulations in simulated saliva (pH=6.8).

[0154] FIG. 10. shows the PAMPA permeabilities of complex Celecoxib formulations containing polyvinylpyrrolidone and sodium lauryl sulfate.

[0155] FIG. 11. shows the PAMPA permeabilities of complex Celecoxib formulations containing copolymer of vinylpyrrolidone and vinyl acetate and sodium lauryl sulfate.

[0156] FIG. 12. shows the PAMPA permeabilities of complex Celecoxib formulations containing polyvinylpyrrolidone and sodium lauryl sulfate.

[0157] FIG. 13. shows the PAMPA permeabilities of complex Celecoxib formulations containing copolymer of vinylpyrrolidone and vinyl acetate and sodium lauryl sulfate.

[0158] FIG. 14. shows the PXRD diffractograms of complex Celecoxib formulations containing copolymer of vinylpyrrolidone and vinyl acetate and sodium lauryl sulfate at different time points.

[0159] FIG. 15A. shows the SEM images of Complex Celecoxib formulation containing polyvinylpyrrolidone and sodium lauryl sulfate;

[0160] FIG. 15B. shows the SEM images of Complex Celecoxib formulation containing copolymer of vinylpyrrolidone and vinyl acetate and sodium lauryl sulfate;

[0161] FIG. 15C. shows the SEM images of Complex Celecoxib formulation containing poloxamer and lactose.

[0162] FIG. 16A. shows the Raman spectra of unformulated crystalline Celecoxib;

[0163] FIG. 16B. shows the Raman spectra of Complex Celecoxib formulation containing polyvinylpyrrolidone and sodium lauryl sulfate;

[0164] FIG. 16C. shows the Raman spectra of Placebo sample containing polyvinylpyrrolidone and sodium lauryl sulfate;

[0165] FIG. 16D. shows the Raman spectra of Polyvinylpyrrolidone;

[0166] FIG. 16E. shows the Raman spectra of Sodium lauryl sulfate.

[0167] FIG. 17A. shows the Raman spectra of unformulated crystalline Celecoxib;

[0168] FIG. 17B. shows the Raman spectra of Complex Celecoxib formulation containing polyvinylpyrrolidone and sodium lauryl sulfate;

[0169] FIG. 17C. shows the Raman spectra of Complex Celecoxib formulation containing copolymer of vinylpyrrolidone and vinyl acetate and sodium-lauryl-sulfate;

[0170] FIG. 17D. shows the Raman spectra of Complex Celecoxib formulation containing poloxamer and lactose.

[0171] FIG. 18A. shows the ATR spectra of unformulated crystalline Celecoxib;

[0172] FIG. 18B. shows the ATR spectra of Complex Celecoxib formulation containing polyvinylpyrrolidone and sodium lauryl sulfate;

[0173] FIG. 18C. shows the ATR spectra of Placebo sample containing polyvinylpyrrolidone and sodium lauryl sulfate;

[0174] FIG. 18D. shows the ATR spectra of Polyvinylpyrrolidone;

[0175] FIG. 18E. shows the ATR spectra of Sodium-lauryl-sulfate.

[0176] FIG. 19A. shows the Powder XRD diffractograms of Complex Celecoxib formulation containing polyvinylpyrrolidone and sodium lauryl sulfate;

[0177] FIG. 19B. shows the Powder XRD diffractograms of Complex Celecoxib formulation containing copolymer of vinylpyrrolidone and vinyl acetate and sodium lauryl sulfate;

[0178] FIG. 19C. shows the Powder XRD diffractograms of Complex Celecoxib formulation containing poloxamer and lactose.

[0179] FIG. 15. shows the PK parameters of complex Celecoxib formulations in Beagle dogs.

[0180] FIG. 16. shows the PK parameters of complex Celecoxib formulations in Beagle dogs in fasted and fed condition.

[0181] FIG. 17. shows the PK parameters of complex Celecoxib formulations in healthy volunteers in fasted and fed condition.

EXAMPLES

[0182] Specific non-limiting embodiments will further be demonstrated by the following examples.

Selection of Complex Celecoxib Formulations with Improved Material Properties

[0183] Several complexation agents and pharmaceutically acceptable excipients and their combinations were tested in order to select the formulae having instantaneous redispersibility as shown in FIG. 1 and FIG. 2.

[0184] Examples that displayed an acceptable level of redispersibility was selected for further analysis.

[0185] PAMPA permeability of the selected formulations was measured in order to select the complex Celecoxib formulation having the best in-vitro performance (FIG. 3). PAMPA permeability measurements were performed as described by M. Kansi et al. (Journal of medicinal chemistry, 41, (1998) pp 1007) with modifications based on S. Bendels et al (Pharmaceutical research, 23 (2006) pp 2525). Permeability was measured in a 96-well plate assay across an artificial membrane composed of dodecane with 20% soy lecithin supported by a PVDF membrane (Millipore, USA). The receiver compartment was phosphate buffered saline (pH 7.0) supplemented with 1% sodium dodecyl sulfate. The assay was performed at room temperature; incubation time was 4 hours in ultrapurified water or 10-20 and 30 minutes in simulates saliva, respectively. The concentration in the receiver compartment was determined by UV-VIS spectrophotometry (Thermo Scientific Genesys S10).

[0186] Polyvinylpyrrolidone and sodium lauryl sulfate were selected as the complexation agent and pharmaceutically acceptable excipient, respectively, to form complex Celecoxib formulation having improved material characteristics.

[0187] Copolymer of vinylpyrrolidone and vinyl acetate and sodium lauryl sulfate were selected as the complexation agent and pharmaceutically acceptable excipient, respectively, to form complex Celecoxib formulation having improved material characteristics.

[0188] Poloxamer F127 and lactose were selected as the complexation agent and pharmaceutically acceptable excipient, respectively, to form complex Celecoxib formulation having improved material characteristics.

Composition Optimization and Manufacturing of Complex Celecoxib Formulations

[0189] The ratio of the selected complexation agents and pharmaceutically acceptable excipients was optimized. Solid complexes of Celecoxib were prepared by using different ratios of complexation agents and pharmaceutically acceptable excipients.

[0190] A solution mixture of Celecoxib complex formulation was prepared by continuous flow mixing in a flow instrument. 100 mL Solution 1 was prepared by dissolving 200 mg Celecoxib and 400 mg polyvinylpyrrolidone (PVP 40) in 100 mL methanol. The prepared Solution 1 was passed into the instrument with 1.25-2 mL/min flow rate. Meanwhile, Solution 2 containing 30-50 mg sodium lauryl sulfate in 100 mL water was passed into the instrument with 5-10 mL/min flow rate, where Celecoxib formed complex Celecoxib formulation. The solution mixture of the complex Celecoxib formulation is continuously produced at atmospheric pressure and ambient temperature. The produced solution mixture was frozen on dry-ice and then it was lyophilized using a freeze drier equipped with −110° C. ice condenser, with a vacuum pump.

[0191] The appearance of produced solution mixture and stability of the redispersed complex Celecoxib formulation were monitored. Based on the physical appearance and stability of the reconstituted solid complex Celecoxib formulation, the best composition was selected for analytical investigations (FIG. 4).

[0192] In order to make the production process industrially feasible, process intensification was performed by increasing the concentrations of the starting solutions. A solution mixture of complex Celecoxib formulation was prepared by mixing process. Methanolic Solution 1 containing 1.25-10 mg/mL Celecoxib and 2.5-20 mg/mL polyvinylpyrrolidone (PVP 40) was mixed with aqueous Solution 2 containing 0.2812-18 mg/mL sodium lauryl sulfate in different ratios in order to optimize the production condition. The solution mixture of the complex Celecoxib was produced at atmospheric pressure and ambient temperature. The produced solution mixture was frozen on dry-ice and then it was lyophilized using a freeze drier equipped with −110° C. ice condenser, with a vacuum pump.

[0193] Different concentrations and solvent ratios were tested to determine the optimal manufacturing condition. The stability of the produced solvent mixture was used to determine the optimal parameter of the production. FIG. 5 summarizes the results.

[0194] Based on the results, 10 mg/mL Celecoxib, 20 mg/mL polyvinylpyrrolidone and 18 mg/mL sodium lauryl sulfate were chosen for starting concentrations. The ratio of the solutions was found to be optimal at 2:1 ratio.

[0195] Solution mixture of complex Celecoxib formulation comprising polyvinylpyrrolidone and sodium lauryl sulfate and prepared by optimal parameter sets was spray-dried (Yamato DL-410/GAS410) in order to obtain solid powder. The spray-drying process was optimized. The optimal production parameters were found to be T.sub.inlet=95° C., Drying airflow=0.8 m.sup.3/min, Solution feed rate=18 mL/min, atomization pressure=1 bar, T.sub.out=63-64° C. The spray-dried formulation was granulated and used for iv-vivo dog PK studies. A solution mixture of complex Celecoxib formulation was prepared by mixing process. 2-propanolic Solution 1 containing 5 mg/mL Celecoxib and 20 mg/mL copolymer of vinylpyrrolidone and vinyl acetate (Kollidon VA64) was mixed with aqueous Solution 2 containing 1.25 mg/mL sodium lauryl sulfate. The solution mixture of the complex Celecoxib was produced at atmospheric pressure and ambient temperature. The ratio of the solutions was 1:4 (2-Propanol:Water). The produced solution mixture was frozen on dry-ice and then it was lyophilized using a freeze drier equipped with −110° C. ice condenser, with a vacuum pump.

[0196] Different flow rates and concentrations were tested in order to determine the optimal manufacturing condition. The appearance and stability of the produced solvent mixture was used to determine the optimal parameter of the production. FIG. 6 and FIG. 7 summarizes the results.

[0197] Based on the results, 10 mg/mL Celecoxib, 40 mg/mL copolymer of vinylpyrrolidone and vinyl acetate and 20 mg/mL sodium lauryl sulfate were chosen as starting concentration. The ratio of Solution 1 and Solution 2 was found to be optimal at 2:1 ratio at 40 mL/min and 20 mL/min flow rate ratio.

[0198] The solution mixture of complex Celecoxib formulation prepared by the optimal parameter sets was spray-dried (Yamato DL-410/GAS410). The spray-drying process was optimized. Optimal production parameters were found to be T.sub.inlet=95° C., Drying airflow=0.8 m.sup.3/min, Solution feed rate=18 mL/min, atomization pressure=1 bar, T.sub.out=63-64° C. The spray-dried formulation was granulated and used for iv-vivo dog PK studies.

[0199] The solution mixture of complex Celecoxib formulation comprising copolymer of vinylpyrrolidone and vinyl acetate and sodium lauryl sulfate prepared by optimal parameter sets was spray-dried (Procept 4M-8Trix) in order to obtain solid powder. Production process was performed under cGMP condition to support the Phase I human clinical study. Optimal production parameters were found to be T.sub.inlet=135° C., drying airflow=0.3 m.sup.3/min, solution feed rate=3-4 g/min, atomization pressure=1-3 bar, atomization flow=19 L/min T.sub.out=70-72° C. and the diameter of the nozzle was 0.8 mm. The spray-dried formulation was granulated and used for Phase 1 human clinical study. A solution mixture of complex Celecoxib formulation was prepared by mixing process. 1-propanolic Solution 1 containing 2 mg/mL Celecoxib and 6 mg/mL Poloxamer 407 (Lutrol F127) was mixed with aqueous Solution 2 containing 1 mg/mL lactose. The solution mixture of the complex Celecoxib was produced at atmospheric pressure and ambient temperature. The ratio of the solutions was 1:4 (1-Propanol:Water). The produced solution mixture was frozen on dry-ice and then it was lyophilized using a freeze drier equipped with −110° C. ice condenser, with a vacuum pump.

Pharmaceutical Development

[0200] Liquid dispersible granules comprising said complex Celecoxib formulations may be obtained by wet or dry processes.

[0201] Liquid dispersible granules comprising said complex Celecoxib formulations were obtained by dry process. Compacts with uniform dimensions and mass were prepared of the solid complex Celecoxib formulations. The compacts were broken up by physical impact in order to form granulates within appropriate mesh size. After that granulates were mixed with pharmaceutically acceptable excipients.

[0202] Liquid dispersible granules comprising said complex Celecoxib formulations were obtained by dry process. The solid Celecoxib formulations were mixed with pharmaceutically acceptable excipients. After that compacts with uniform dimensions and mass were prepared of the powder mixtures comprising said complex formulations of Celecoxib. The compacts were broken up by physical impact in order to form granulates within appropriate mesh size.

[0203] Liquid dispersible granules for buccal and oral administrations were prepared by compacting 40 mg solid complex Celecoxib formulation comprising polyvinylpirrolidone and sodium lauryl sulfate using 0.5 ton load. The height of the compact was found to be optimal between 0.8-1.0 mm. The compacts were broken up by physical impact to form granulates. The particle size of the granulates was controlled by sieving with appropriate mesh size to achieve 160-800 micrometers particle size.

[0204] Liquid dispersible granules for oral administration were prepared by compacting 500 mg solid complex Celecoxib formulation comprising copolymer of vinylpirrolidone and vinyl acetate and sodium lauryl sulfate using 3 ton load. The height of the compact was found to be optimal between 4-6 mm. The compacts were broken up by physical impact to form granulates. The particle size of the granulates was controlled by sieving with appropriate mesh size to achieve 160-800 micrometers particle size.

[0205] Liquid dispersible granules for oral administration were prepared from the spry-dried powder by compacting 1900 mg solid complex Celecoxib formulation comprising copolymer of vinylpirrolidone and vinyl acetate and sodium lauryl sulfate using a flat faced tooling with 22 mm diameter and pressed with 3 ton load. The height of the compact was found to be optimal between 4.5-5.5 mm. The compacts were broken up by physical impact to form granulates. The particle size of the granulates was controlled by sieving with appropriate mesh size to achieve 150-850 micrometers particle size.

[0206] Liquid dispersible granules comprising said complex Celecoxib formulations were obtained by wet process. The pharmaceutically acceptable excipients were moisturized by water or aqueous binder solution. The solid complex Celecoxib formulations were mixed with the preliminary moisturized excipients to form granulates. After the drying step the particle size of the granulates was controlled by physical impact.

[0207] Liquid dispersible granules comprising said complex Celecoxib formulations were obtained by wet process. The pharmaceutically acceptable excipients were moisturized by the solvents mixtures comprising the complex Celecoxib formulations to form granulates. After the drying step the particle size of the granulates was controlled by physical impact.

Improved Apparent Solubility of Complex Celecoxib Formulation

[0208] The apparent solubility of said complex Celecoxib formulations were measured by UV-VIS spectroscopy at room temperature. The solid complex Celecoxib formulations were dispersed in ultrapurified in 1-50 mg/mL Celecoxib equivalent concentration range. The resulting solutions were filtered by 100 nm disposable syringe filter. The Celecoxib content in the filtrate was measured by UV-Vis spectrophotometry and the apparent solubility was calculated. The filtrate may contain Celecoxib complex particles which could not be filtrated out using 100 nm pore size filter.

[0209] The apparent solubility of said complex Celecoxib formulation comprising polyvinylpyrrolidone and sodium lauryl sulfate was 1.009; 10.334; 25.148 and 40.362 mg/mL, when 1; 10; 25 and 50 mg/mL Celecoxib equivalent formulations were dispersed in ultrapurified water, respectively.

[0210] The apparent solubility of said complex Celecoxib formulation comprising copolymer of vinylpyrrolidone and vinylacetate and sodium lauryl sulfate formulation was 1.015; 9.605; 22.358 and 34.142 mg/mL, when 1; 10; 25 and 50 mg/mL Celecoxib equivalent formulations were dispersed in ultrapurified water, respectively.

[0211] Solubility of complex Celecoxib formulae was 1 mg/mL.

Improved Dissolution Profile of Complex Celecoxib Formulation

[0212] Comparative dissolution tests were performed by dispersing the complex Celecoxib formulations, the physical mixtures of Celecoxib, complexation agents and excipients, unformulated crystalline Celecoxib and Celebrex (commercial formulation) in purified water at 1 mg/mL concentrations. The dissolved amount was measured with UV-VIS spectrophotometry after filtration with 0.1 μm pore size filter at different time points. Dissolution of Celecoxib from the complex formulation was instantaneous, within 10 min more than 90% of the Celecoxib dissolved from the complex Celecoxib formulations. The dissolution of Celecoxib from the physical mixture and Celebrex® was incomplete and slow.

Comparative In-Vitro PAMPA Assays

[0213] PAMPA permeabilities of complex Celecoxib formulations were above 0.5×10.sup.−6 cm/s in simulated saliva condition, while it was 0.3×10−6 cm/s for the unformulated compound, see FIG. 9.

[0214] PAMPA permeabilities of complex Celecoxib formulations containing polyvinylpyrrolidone and sodium lauryl sulfate in water, FaSSIF and FeSSIF media were above 2.3×10.sup.−6 cm/s, 1.9×10.sup.−6 cm/s and 1.7×10.sup.−6 cm/s, respectively (FIG. 10). PAMPA permeabilities of complex Celecoxib formulations containing copolymer of vinylpyrrolidone and vinyl acetate and sodium lauryl sulfate in water, FaSSIF and FeSSIF media were above 2.1×10.sup.−6 cm/s, 1.5×10.sup.−6 cm/s and 2.6×10.sup.−6 cm/s, respectively (FIG. 11).

Stability of the Solid Form

[0215] PAMPA permeabilities of the solid complex Celecoxib formulations containing polyvinylpyrrolidone and sodium lauryl sulfate were used to monitor the physical stability of the formulation. PAMPA permeability was measured after storage at different conditions. 1 month storage at RT or 40° C. and 75% relative humidity showed no significant decrease in the measured PAMPA permeability under any of the conditions tested (FIG. 12).

[0216] PAMPA permeabilities of the solid complex Celecoxib formulations containing copolymer of vinylpyrrolidone and vinylacetate and sodium lauryl sulfate were used to monitor the stability of the formulation. PAMPA permeability was measured after storage at different conditions. 6-month storage at RT or 40° C. and 75% relative humidity showed no significant decrease in the measured PAMPA permeability under any of the conditions tested (FIG. 13).

[0217] XRD diffractograms of the solid complex Celecoxib formulations containing copolymer of vinylpyrrolidone and vinylacetate and sodium lauryl sulfate were used to monitor the stability of the formulation. pXRD was measured after storage at different conditions. 6-month storage at RT or 40° C. and 75% relative humidity showed no crystallization under any of the conditions tested (FIG. 14).

Structural Analysis

[0218] Morphology of complex Celecoxib was investigated using FEI Quanta 3D scanning electron microscope. Complex Celecoxib formulations comprise spherical particles in the size range of less than 200 nm (Figure Error! Reference source not found.).

[0219] Structural analysis was performed by using Bruker Vertex 70 FT-IR spectrometer with Bruker Platinum diamond ATR unit. Continuous flow mixing of Celecoxib in the presence of selected complexation agents and pharmaceutically acceptable excipients, resulted in a stable complex of Celecoxib.

[0220] In an embodiment said complex containing polyvinylpyrrolidone and sodium lauryl sulfate or its pharmaceutical compositions characterized by the Raman spectrum shown in FIG. 16 and AIR spectrum shown in FIG. 18.

[0221] In an embodiment said complex containing copolymer of vinylpyrrolidone and vinyl acetate and sodium lauryl sulfate or its pharmaceutical composition is characterized by the Raman spectrum shown in FIG. 17 and ATR spectrum shown in FIG. 18.

[0222] In an embodiment said complex containing poloxamer and lactose or its pharmaceutical composition is characterized by the Raman spectrum shown in FIG. 17 and ATR spectrum shown I in FIG. 18.

[0223] The structures of the complex Celecoxib formulations were investigated by powder X-ray diffraction (XRD) analysis (Philips PW1050/1870 RTG powder-diffractometer). The measurements showed that the Celecoxib in the complex formulations was XRD amorphous (See FIG. 19). Characteristic reflections on the diffractograms of complex Celecoxib formulation at 43 and 44 2Theta could be attributed to sample holder.

In-Vivo Pharmacokinetics

In-Vivo PK Test in Large Animals

[0224] A beagle dog study using the granulated complex formulation containing polyvinylpyrrolidone and sodium lauryl sulfate at a dose of 5 mg/kg was performed in the fasted and in the fed state following a high fat meal. The granulated complex formulation containing polyvinylpyrrolidone and sodium lauryl sulfate was administered under the tongue of the animals as the granule or orally as reconstituted dispersion, respectively. The absorption of the Celecoxib was fast with t.sub.max values at 1-2 hours with 65% of C.sub.max reached within 0.5 hours, when the granulated complex formulation containing polyvinylpyrrolidone and sodium lauryl sulfate formulation was administered under the tongue of the animals (FIG. 20). The absorption of the Celecoxib was fast with t.sub.max value at 0.5 hours with 70% of C.sub.max reached within 0.25 hours when the granulated complex formulation containing polyvinylpyrrolidone and sodium-lauryl-sulfate formulation was administered orally (FIG. 20).

[0225] A beagle dog study using the granulated complex formulation containing copolymer of vinylpyrrolidone and vinyl acetate and sodium lauryl sulfate at a dose of 5 mg/kg was performed in fasted and the fed state following a high fat meal. The granulated complex formulation containing copolymer of vinylpyrrolidone and vinyl acetate and sodium lauryl sulfate was administered orally as reconstituted dispersion. The absorption of Celecoxib was fast with t.sub.max values at 0.75-1 hours with 90% of C.sub.max reached within 0.5 hours, when the granulated complex formulation containing copolymer of vinylpyrrolidone and vinyl acetate and sodium lauryl sulfate formulation was administered orally both in the fasted state of following a high-fat meal (FIG. 16).

Phase I Clinical Trial

[0226] A Human phase I clinical study was performed using the copolymer of vinylpyrrolidone and vinylacetate and sodium lauryl sulfate. The granulated complex formulation containing copolymer of vinylpyrrolidone and vinylacetate and sodium lauryl sulfate was administered orally as reconstituted dispersion. The clinical methodology was a single center, open-label, non-randomized, single dose, fixed sequence crossover study in 12 healthy male subjects. Each subject received 200 mg Celecoxib formulation in the fasted state or following a high-fat meal breakfast. The absorption of the Celecoxib was fast with t.sub.max values at 0.75 and 2 hours in the fasted state and following a high-fat breakfast, respectively. Regardless of feeding conditions the effective plasma concentration (250 ng/ml) was achieved within 12 minutes following administration when the granulated complex formulation containing copolymer of vinylpyrrolidone and vinyl acetate and sodium lauryl sulfate formulation was administered orally (FIG. 17).

[0227] From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt it to various usages and conditions.