Granted Patent
B2
US 12,465,593 · App. 18/484,337 · Granted Nov 11, 2025
Pharmaceutical composition
Inventors:
Nicola Frances Bateman (Macclesfield, GB); Paul Richard Gellert (Macclesfield, GB); Kathryn Jane Hill (Macclesfield, GB)
View Patent ↗
Loading inventors, assignments & file history…
Abstract
The invention concerns pharmaceutical compositions containing a hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide and solvates, crystalline forms and amorphous forms thereof, to the use of said compositions as a medicament; and to processes for the preparation of said compositions.
Claims (14)
1 . A process for stabilizing a hydrogen sulphate salt of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)amide against dissociation into its free base form, the process comprising:
dispersing a hydrogen sulphate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide into a carrier matrix consisting of Vitamin E TPGS, in order to obtain a homogenous mixture of finely divided particles that are dispersed throughout the carrier matrix, wherein the homogenous mixture is semi-solid or solid at ambient temperature and consists of:
(i) about 15 to about 25 parts of a hydrogen sulphate salt of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)amide; and
(ii) about 75 to about 85 parts of Vitamin E TPGS;
wherein both parts are by weight and the sum of the parts (i)+(ii)=100.
2 . The process of claim 1 , further comprising filling the homogenous mixture into a capsule.
3 . The process of claim 1 , wherein the homogenous mixture consists of:
(i) about 18 to about 22 parts of a hydrogen sulphate salt of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)amide; and
(ii) about 78 to about 82 parts of Vitamin E TPGS;
wherein both parts are by weight and the sum of the parts (i)+(ii)=100.
4 . The process of claim 3 , wherein the homogenous mixture consists of:
(i) about 19 to about 21 parts of a hydrogen sulphate salt of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)amide; and
(ii) about 79 to about 81 parts of Vitamin E TPGS;
wherein both parts are by weight and the sum of the parts (i)+(ii)=100.
Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Nov 13, 2025
From: ASTRAZENECA AB
To: ALEXION PHARMA INTERNATIONAL OPERATIONS LIMITED
Reel/Frame 072888/0633 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Dec 3, 2024
From: BATEMAN, NICOLA FRANCES; GELLERT, PAUL RICHARD; HILL, KATHRYN JANE
To: ASTRAZENECA AB; ARRAY BIOPHARMA, INC.
Reel/Frame 069473/0115 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jun 6, 2024
From: BATEMAN, NICOLA FRANCES; GELLERT, PAUL RICHARD; HILL, KATHRYN JANE
To: ASTRAZENECA AB
Reel/Frame 067647/0913 →
Continuity (10)
Provisional Application
61040372
· Mar 28, 2008
References Cited (114)
US 5891469A
· Anselem
· 1999
[cited by applicant]
US 5891845A
· Myers
· 1999
[cited by applicant]
US 5968987A
· Charman et al.
· 1999
[cited by applicant]
US 6022852A
· Klokkers et al.
· 2000
[cited by applicant]
US 6723339B2
· Meinzer et al.
· 2004
[cited by applicant]
US 9561178B2
· Graham et al.
· 2017
[cited by applicant]
US 20030104048A1
· Patel et al.
· 2003
[cited by applicant]
US 20030236236A1
· Chen et al.
· 2003
[cited by applicant]
US 20040127551A1
· Zhang et al.
· 2004
[cited by applicant]
US 20050096296A1
· Fikstad et al.
· 2005
[cited by applicant]
US 20060003002A1
· Fikstad et al.
· 2006
[cited by applicant]
US 20060052432A1
· Remenar et al.
· 2006
[cited by applicant]
US 20070134319A1
· Zannou et al.
· 2007
[cited by applicant]
US 20070190129A1
· Ahmed
· 2007
[cited by examiner]
US 20090246274A1
· Bateman et al.
· 2009
[cited by applicant]
US 20120114750A1
· Bateman et al.
· 2012
[cited by applicant]
US 20130195971A1
· Bateman et al.
· 2013
[cited by applicant]
US 20160030574A1
· Bateman et al.
· 2016
[cited by applicant]
US 20170056375A1
· Bateman et al.
· 2017
[cited by applicant]
US 20190030004A1
· Bateman et al.
· 2019
[cited by applicant]
US 20200179344A1
· Bateman et al.
· 2020
[cited by applicant]
WO WO1995027492A1
· 1995
[cited by applicant]
WO WO1996036316A1
· 1996
[cited by applicant]
WO WO1997003654A2
· 1997
[cited by applicant]
WO WO1997035587A1
· 1997
[cited by applicant]
WO WO2000076482A1
· 2000
[cited by applicant]
WO WO2003077914A1
· 2003
[cited by applicant]
WO WO2004105694A2
· 2004
[cited by applicant]
WO WO2005074890A1
· 2005
[cited by applicant]
WO WO2006138431A2
· 2006
[cited by applicant]
WO WO2007076245A2
· 2007
[cited by examiner]
WO WO2009117151A2
· 2009
[cited by applicant]
Hector Guzman, et al, Combined Use of Crystalline Salt Forms and Precipitation Inhibitors to Improve Oral Absorption of Celecoxib from Solid Oral Formulations, 96 J Pharma. Sci. 2686 (Year: 2007).
[cited by examiner]
Katrijn Bogman, et al., The Role of Surfactants in the Reversal of Active Transport Mediated by Multidrug Resistance Proteins, 92 J Pharma. Sci. 1250 (Year: 2003).
[cited by examiner]
Agarwal, R; Annual Meeting May 30, 2008-Jun. 3, 2008 XP-002534888.
[cited by applicant]
Bogman, K., et al., “The role of surfactants in the reversal of active transport mediated by multidrug resistance proteins,” J Pharm Sci 92(6):1250-1251, John Wiley & Sons Inc., United States (Jun. 2003).
[cited by applicant]
Eastman, “Vitamin E TPGS,” Eastman Brochure, Eastman Chemical Co., Kingsport, Tenn. (Nov. 2002).
[cited by applicant]
Guzman, H.R., et al., “Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations,” J Pharm Sci 96(10):2686-2702, John Wiley & Sons Inc., Uni…
[cited by applicant]
Ping, L., et al., “Developing Early Formulations: Practice and Perspective,” International Journal of Pharmaceutics, May 2007, www.elsevier.com/locate/ijpharm; 341 (2007) pp. 1-19.
[cited by applicant]
Rowe et al., “Handbook of Pharmaceutical Excipients,” Fifth Edition Pharmaceutical Press; 2005.
[cited by applicant]
Khoo; S.M., et al., “The formulation of Halofantrine as either non-solubilizing PEG 6000 or solubilizing lipid based solid dispersions: physical stability and absolute bioavailability assessment,” Int J Pharm 205(1-2):6…
[cited by applicant]
U.S. Appl. No. 12/411,865 Office Action dated Oct. 5, 2010.
[cited by applicant]
U.S. Appl. No. 12/411,865 Office Action dated Apr. 26, 2011.
[cited by applicant]
U.S. Appl. No. 13/293,368 Office Action dated Jul. 24, 2012.
[cited by applicant]
U.S. Appl. No. 13/747,853 Office Action dated Jan. 22, 2014.
[cited by applicant]
U.S. Appl. No. 13/747,853 Office Action dated Sep. 15, 2018.
[cited by applicant]
U.S. Appl. No. 14/884,343 Office Action dated May 12, 2016.
[cited by applicant]
U.S. Appl. No. 15/348,053 Office Action dated Jan. 8, 2018.
[cited by applicant]
International Search Report for PCT/GB2009/050293 mailed Jul. 15, 2009.
[cited by applicant]
Cole, “Liquid filled and sealed hard gelatin capsules,” Gattefosse' Bulletin (1999).
[cited by applicant]
Communication for EP 09726304 dated Jun. 1, 2011.
[cited by applicant]
Decision to grant patent for EP 09726304 dated Dec. 28, 2011.
[cited by applicant]
U.S. Appl. No. 16/023,102 Office Action dated Apr. 10, 2019.
[cited by applicant]
U.S. Appl. No. 16/597,237 Office Action dated Nov. 10, 2020.
[cited by applicant]
U.S. Appl. No. 17/313,312 Office Action dated Nov. 22, 2022.
[cited by applicant]
Alsenz, J., and Kansy, M., “High throughput solubility measurement in drug discovery and development,” Adv Drug Deliv Rev 59(7):546-567, Elsevier, Netherlands (Jul. 2007).
[cited by applicant]
Augustijns, P., and Brewster M., “Supersaturating Drug Delivery Systems: Fast is Not Necessarily Good Enough”, Journal of Pharmaceutical Sciences 101(1):7-9, John Wiley & Sons Inc., United States (Jan. 2012).
[cited by applicant]
Bai et al., “Use of Nonactive Pharmaceutical Excipients in Oral Drug Formulations: Biopharmaceutical Classification System Considerations”, Taylor & Francis Group, LLC:181-195 (2006).
[cited by applicant]
Barakat, N.S., “Capsules: An Approach to Improve Dissolution and Stability of Etodolac Formulation”, Drug Dev Ind Pharm 32(7):865-876, Informa Healthcare, United States (Aug. 2006).
[cited by applicant]
Barzegar-Jalali, M., et al., “Kinetic Analysis of Drug Release From Nanoparticles”, J Pharm Pharmaceut. Sci 11(1):167-177, John Wiley & Sons Inc., United States (2008).
[cited by applicant]
Beig, A., et al., “Concomitant solubility-permeability increase: Vitamin E TPGS vs. amorphous solid dispersion as oral delivery systems for etoposide”, Eur J Pharm Biopharm 121:91-103, Elsevier, Netherlands (Dec. 2017).
[cited by applicant]
Brewster, M.E., et al., “Supersaturating drug delivery systems: effect of hydrophilic cyclodextrins and other excipients on the formation and stabilization of supersaturated drug solutions”, Pharmazie 63(3):217-220, Gov…
[cited by applicant]
Chen, J., et al., “Preparation, Characterization and In Vitro Evaluation of Solid Dispersions Containing Docetaxel,” Drug Dev Ind Pharm 34(6):588-594, Informa Healthcare, United States (Jun. 2008).
[cited by applicant]
Crowley, M.M., et al., “Stability of polyethylene oxide in matrix tablets prepared by hot-melt extrusion,” Biomaterials 23(21):4241-4248, Elsevier BV, United Kingdom (Nov. 2002).
[cited by applicant]
Crowley, Michael McDonald, “Physicochemical and Mechanical Characterization of Hot-Melt Extruded Dosage Forms”, Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin, 24 pages…
[cited by applicant]
Festo, Damian Rwihura, “Development and Evaluation of Solid Dispersions of the Antiviral Thiocarboxanilide Uc-781 (Acta Biomedica Lovaniensia, 246)”, Leuven Univ. Pr. Belgium, 146 pages (2001).
[cited by applicant]
Galop, M., “Study of Pharmaceutical Solid Dispersions by Microthermal Analysis,” Pharm Res 22(2): 293-302, Springer New York, United States (Feb. 2005).
[cited by applicant]
Ghosh, I., and Michniak-Kohn, B., “A comparative study of Vitamin E TPGS/HPMC supersaturated system and other solubilizer/polymer combinations to enhance the permeability of a poorly soluble drug through the skin,” Drug…
[cited by applicant]
Guo, Y., et al., “The applications of Vitamin E TPGS in drug delivery,” Eur J Pharm Sci 49(2):175-186, Elsevier, Netherlands (May 2013).
[cited by applicant]
Hauss, D.J., “Oral lipid-based formulations,” Adv Drug Deliv Rev 59(7):667-676, Elsevier, Netherlands (Jul. 2007).
[cited by applicant]
Jagdishchandra, Jani Kaushalkumar, “Formulation and Evaluation of solid dispersions of Aceclofenac”, Dissertation Submitted to the Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore, 24 pages (2006).
[cited by applicant]
Jannin, V., et al., “Approaches for the development of solid and semi-solid lipid-based formulations,” Adv Drug Deliv Rev 60(6):734-746, Elsevier, Netherlands (Mar. 2008).
[cited by applicant]
Jannin, V., “The Application of Gattefossé Products: A 2005-2006 Literature Review”, Bulletin Technique Gattefosse 99, 5 pages (2006).
[cited by applicant]
Kang, E., et al., “Paclitaxel distribution in poly(ethylene glycol)/poly(lactide-co-glycolic acid) blends and its release visualized by coherent anti-Stokes Raman scattering microscopy,” J Control Release 122(3):261-268…
[cited by applicant]
Karnachi , A.A., et al., “Comparative Evaluation of the Severity of Gastric Ulceration by Solid Dispersions and Coprecipitates of Indomethacin,” J Drug Target 4(5):297-301, Informa Healthcare, United Kingdom (1997).
[cited by applicant]
Kim, M.S., et al., “Enhancement of Wettability and Dissolution Properties of Cilostazol Using the Supercritical Antisolvent Process: Effect of Various Additives,” Chem Pharm Bull 58(2):230-233, Pharmaceutical Society of…
[cited by applicant]
Kogan, A., et al., “Viability and permeability across Caco-2 cells of CBZ solubilized in fully dilutable microemulsions,” Colloids Surf B Biointerfaces 66(1):1-12, Elsevier, Netherlands (Oct. 2008).
[cited by applicant]
Late, S., “Enhancement of Carbamzepine Solubility Using Selected Water Soluble Polymers and a Solid Dispersion Technique”, Open Access Mater's Theses, Paper 261, pp. 1-131 (2004).
[cited by applicant]
Li, J., and Chiappetta, D., “An investigation of the thermodynamic miscibility between VeTPGS and polymers,” Int J Pharm 350(1-2):212-219, Elsevier, Netherlands (Feb. 2008).
[cited by applicant]
Li, P., and Zhao, L., “Developing early formulations: Practice and perspective,” Int J Pharm 341(1-2):1-19, Elsevier, Netherlands (Aug. 2007).
[cited by applicant]
Ly, Jade C.Y., “Characterization and Evaluation of Hydrophilic Tocopherol Derivatives as Solubilizing and Emulsion-Stabilizing Agents”, Dissertation submitted to the faculty of the College of Pharmacy and Allied Health …
[cited by applicant]
Porter, C.J.H., et al., “Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs,” Nat Rev Drug Discov 6(3):231-248, Nature Publishing Group, United Kingdomd (Mar. 2007).
[cited by applicant]
Pouton, C., and Porter, C.J.H., “Formulation of lipid-based delivery systems for oral administration: Materials, methods and strategies,” Adv Drug Deliv Rev 60(6):625-637, Elsevier, Netherlands (Mar. 2008).
[cited by applicant]
Prajapati et al., “Conventional And Alternative Pharmaceutical Methods to Improve Oral Bioavailability of Lipophilic Drugs”, Asian Journal of Pharmaceutics, 1(1): 1-8 (2007).
[cited by applicant]
Rajebahadur, M., et al., “Mechanistic Study of Solubility Enhancement of Nifedipine Using Vitamin E TPGS or Solutol HS-15,” Drug Deliv 13(3):201-206, Informa Healthcare, United Kingdom (May-Jun. 2006).
[cited by applicant]
Repka, M.A., et al., “Pharmaceutical Applications of Hot-Melt Extrusion: Part II”, Drug Dev Ind Pharm 33(10):1043-1057, Informa Healthcare, United States (Oct. 2007).
[cited by applicant]
Sant, V.P., et al., “Enhancement of oral bioavailability of poorly water-soluble drugs by poly(ethylene glycol)-block-poly(alkyl acrylate-co-methacrylic acid) self-assemblies,” J Control Release 104(2):289-300, Elsevier…
[cited by applicant]
Schamp, K., et al., “Development of an in vitro/in vivo correlation for lipid formulations of EMD 50733, a poorly soluble, lipophilic drug substance,” Eur J Pharm Biopharm 62(3):227-234, Elsevier, Netherlands (Apr. 2006…
[cited by applicant]
Serajuddin, A.T.M., “Solid Dispersion of Poorly Water-Soluble Drugs: Early Promises, Subsequent Problems, and Recent Breakthroughs,” J Pharm Sci 88(10): 1058-1066, John Wiley & Sons Inc., United States (Oct. 1999).
[cited by applicant]
Sethia, S., and Squillante, E., “In Vitro-In Vivo Evaluation of Supercritical Processed Solid Dispersions: Permeability and Viability Assessment in Caco-2 Cells,” J Pharm Sci 93(12): 2985-2993, John Wiley & Sons Inc., U…
[cited by applicant]
Sethia, S., and Squillante, E., “Solid dispersion of carbamazepine in PVP K30 by conventional solvent evaporation and supercritical methods,” Int J Pharm 272(1-2):1-10, Elsevier, Netherlands (Mar. 2004).
[cited by applicant]
Sethia, S., and Squillante, E., “Solid Dispersions: Revival with Greater Possibilities and Applications in Oral Drug Delivery,” Crit Rev Ther Drug Carrier Syst 20(2&3):215-247, Begell House Inc., United States (2003).
[cited by applicant]
Sethia, S., “In Vitro-In Vivo Evaluation of Carbamazepine Solid Dispersions Formulated by Supercritical and Conventional Solvent Evaporation Method”, College of Pharmacy and Allied Health Professions at St. John's Unive…
[cited by applicant]
Shah, P., et al., “Role of Caco-2 Cell Monolayers in Prediction of Intestinal Drug Absorption,” Biotechnol Prog 22(1):186-198, Wiley-Blackwell, United States (Jan.-Feb. 2006).
[cited by applicant]
Shanbhag, A., et al., “Method for screening of solid dispersion formulations of low-solubility compounds-Miniaturization and automation of solvent casting and dissolution testing,” Int J Pharm 351(1-2):209-218, Elsevier…
[cited by applicant]
Shokrl et al., “Improvement of the dissolution rate of indomethacin by a cogrinding technique using polyethylene glycols of various molecular weights,” J Drug Del Sci Tech 16(3):203-209, Editions de Sante, France (2006).
[cited by applicant]
Sihn et al., “The studies of interaction between methamphetamine and melanin pigment in hair,” College of Pharmacy, Sookmyuyng Women's University, Seoul, Korea, 2 pages (2001).
[cited by applicant]
Six, K., et al., “Clinical study of solid dispersions of itraconazole prepared by hot-stage extrusion,” Eur J Pharm Sci 24(2-3):179-186, Elsevier, Netherlands (Feb. 2005).
[cited by applicant]
Strickley, Robert G., “Currently Marketed Oral Lipid-Based Dosage Forms: Drug Products and Excipients”, Formulation and Process Development, Gilead Sciences, Inc., Foster City, California, U.S.A., 32 pages (2007).
[cited by applicant]
Strickley, R.G., “Solubilizing Excipients in Oral and Injectable Formulations,” Pharm Res 21(2):201-230, Springer New York, United States (Feb. 2004).
[cited by applicant]
Tanaka, Y., et al., “Nanoparticulation of probucol, a poorly water-soluble drug, using a novel wet-milling process to improve in vitro dissolution and in vivo oral absorption,” Drug Dev Ind Pharm 38(8):1015-1023, Inform…
[cited by applicant]
Van Speybroeck, M., et al., “Enhanced absorption of the poorly soluble drug fenofibrate by tuning its release rate from ordered mesoporous silica,” Eur J Pharm Sci 41(5):623-630, Elsevier, Netherlands (Dec. 2010).
[cited by applicant]
Vandecruys, R., et al., “Use of a screening method to determine excipients which optimize the extent and stability of supersaturated drug solutions and application of this system to solid formulation design,” Int J Phar…
[cited by applicant]
Werle, M., “Natural and Synthetic Polymers as Inhibitors of Drug Efflux Pumps,” Pharm Res 25(3):500-511, Springer New York, United States (Mar. 2008).
[cited by applicant]
Young, Christopher Ryan, “Properties of Spherical Pellets Produced by a Hot-Melt Extrusion and Spheronization Process,” Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin, …
[cited by applicant]
Zhai, G., et al., “A Liposomal Delivery Vehicle for the Anticancer Agent Gossypol,” Anticancer Res 28(5A):2801-2806, International Institute of Anticancer Research, Greece (Sep.-Oct. 2008).
[cited by applicant]
Zhang, J., et al., “Analysis of the Literature and Patents on Solid Dispersions from 1980 to 2015,” Molecules 23(7):1697, Multidisciplinary Digital Publishing Institute, Switzerland (Jul. 2018).
[cited by applicant]
Zhang, W., et al., “Impact of Surfactant and Surfactant-Polymer Interaction on Desupersaturation of Clotrimazole,” J Pharm Sci 108(10):3262-3271, John Wiley & Sons Inc., United States (2019).
[cited by applicant]
Zhou, Y., “Cyclosporine A: Solubilization, Solid Dispersion and Solid-State Transformation.” A Thesis Submitted to the Faculty of Purdue University, 154 pages (2000).
[cited by applicant]