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(12) Patent Application Publication (10) Pub. No.: US 2008/0103169 A1 Phillips (43) Pub US 20080 1031 69A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0103169 A1 Phillips (43) Pub. Date: May 1, 2008 (54) COMPOSITIONS COMPRISING ACID filed on Jan. 29, 2007. Provisional application No. LABLE PROTON PUMPINHIBITING 60/863,179, filed on Oct. 27, 2006. AGENTS, AT LEAST ONE OTHER PHARMACEUTICALLY ACTIVE AGENT AND Publication Classification METHODS OF USING SAME (51) Int. C. (75) Inventor: Jeffrey O. Phillips, Ashland, MO (US) A6II 3L/4375 (2006.01) A6II 3/4439 (2006.01) Correspondence Address: A6IP I/00 (2006.01) MLAYER BROWN LLP A6IP I/02 (2006.01) P.O. BOX2828 A6IP I/04 (2006.01) CHICAGO, IL 60690 (US) A6IP II/06 (2006.01) B67D 5/30 (2006.01) (73) Assignee: The Curators of the University of Mis (52) U.S. Cl. .............................. 514/303; 222/14: 514/338 souri, Columbia, MO (21) Appl. No.: 11/925,414 (57) ABSTRACT (22) Filed: Oct. 26, 2007 The present disclosure relates to pharmaceutical composi tions comprising combinations of proton pump inhibitors, Related U.S. Application Data their salt forms or related compounds and at least one other pharmaceutically active agent. Methods of using such com (60) Provisional application No. 60/950,459, filed on Jul. positions, including methods of and an apparatus for admin 18, 2007. Provisional application No. 60/887,095, istering Such compounds, are also provided , eggs, s 359. G-17 5. G-7 ELISA 2.5 25 gaol, pgton, 1. I 20 g.g. s : "e s 5pginL 10 gig 5. 5 go . s 2. s 25 SO ? time (minutes) 9eg 40mg and nanna sana as a on range at effective inhibitory 9. eatgg 40mg and eragg at effective inhibitory gang. NaHCO2Omeq Patent Application Publication May 1, 2008 Sheet 1 of 21 US 2008/O103.169 A1 Figure 1 ***ysrig Patent Application Publication May 1, 2008 Sheet 2 of 21 US 2008/O103.169 A1 Figure 2 L?u??sæ9eu||esag------~---------*-------- 3?ILLSAQU00UUnJøSNIELSWE) \_/,\, Patent Application Publication May 1, 2008 Sheet 3 of 21 US 2008/O103.169 A1 Figure 3 - First Day Data uue8O?ud08:6uJolj?uu|| Patent Application Publication May 1, 2008 Sheet 4 of 21 US 2008/O103.169 A1 Figure 4 - First Day Data |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||| uudOLO?uJe8uuou?Bu?L Patent Application Publication May 1, 2008 Sheet 5 of 21 US 2008/O103.169 A1 Figure 5 Dual chambered example shown with optional 2 into 1 mixing attachment removable (to affix plungers to actuate as one) Patent Application Publication May 1, 2008 Sheet 6 of 21 US 2008/O103.169 A1 Figure 6 Dual chambered apparatus connected to an optional syringe for oral administration Patent Application Publication May 1, 2008 Sheet 7 of 21 US 2008/010.3169 A1 Figure 7 Example of another type of multi-chambered apparatus Patent Application Publication May 1, 2008 Sheet 8 of 21 US 2008/O103.169 A1 Figure 8 Dispenserhead of multi-chambered device Patent Application Publication May 1, 2008 Sheet 9 of 21 US 2008/O103.169 A1 Figure 9 Optional attachment Figure 10 Dual chambered apparatus connected to optional syringe for oral administration Patent Application Publication May 1, 2008 Sheet 10 of 21 US 2008/O103.169 A1 Figure 11 120 mg omeprazole +200mg cimetidine + 1680 mg sodium bicarbonate ts s o t esc t eozeldeutoufino ul t s s s spoZedouloufS is Patent Application Publication May 1, 2008 Sheet 11 of 21 US 2008/O103.169 A1 Figure 12 Omeprazole half-life as 0.9 he Patent Application Publication May 1, 2008 Sheet 12 of 21 US 2008/O103.169 A1 Figure 13 s O f O onapaola ngskg big strick-AgeingEffieldine of carbagh.pretreatment rats. The rats were givenesiuratin on the potency doseif oneprazole of inetidine to (10g Dr Eartha (35. ESOnin effe Sybcutaeus injectior coineprazole at the indicated dose, heriterrificed h after dosing arid the gastrit mucos rrosories were analyzed for H-K-ATPase activity. The data represent swerage values of three deterThatlans. Experi?ental errors abserved with several experiments werless than 2.s.l. Patent Application Publication May 1, 2008 Sheet 13 of 21 US 2008/0103169 A1 Figure 14 Effect of Intravenous Omeprazole (5 umol/kg) on the Acid Response to 4 Hours of Stinulation. With Pentagastrin (8 g/kg - hy Acid output mEq.f4 h) Control 5,6 it 3.3 Omeprazole 3O.7 3. Oneprazole + cinetidine 55.9 + 2.7 Oneprazole + somatostatin 56.2t 8.5 Stimulation with pentagastrin was performed 18 h after the administration of omeprazole. Oneprazole was given either alone or during an infusion of somatostatin (4 g/kg. b) or after intra venais injection of cimetidine (8 mg/kg). p < 0.01; p < 0.05 as compared to omeprazole alone. The raean acid outputs observed during the omeprazole + cinetidine and omeprazole + somato statin experiments were not statistically different from those observed during control experinents. Patent Application Publication May 1, 2008 Sheet 14 of 21 US 2008/O103.169 A1 Figure 15 PENTAGASFRNugg hour CortFol Oreprazole M+Cimetidine omeprazole 4 Storatostar 5. Oriprazole 2. minutes Effect of intravenous administration of oneprazole (5 panol/kg) on gastric acid response to pentagastria in gastric fistula dogs, Stimulation with pentagastrin was performed 18 h after administration of omeprazole. Omeprazole was given either alone, or during an infu sion of somatostatin (4 g/kg. h), or after intravenous administration of cimetidine (8 mg/kg). Mean of eight tests on 4 dogs, Patent Application Publication May 1, 2008 Sheet 15 of 21 US 2008/O103.169 A1 Figure 16 500 -O- Time (Min.) vs Conc. (mcg/L) 400 5 us 5 3OO ( ) 200 OO O 5O OO 150 2OO Time (Min) Patent Application Publication May 1, 2008 Sheet 16 of 21 US 2008/O103.169 A1 Figure 17:20:1 L-carnosine + 20:1 sodium bicarbonate 0.8 g L-carnosine + 0.8 g. sodium bicarbonate + 40 mg omeprazole 8 7 6 5 4 3 2 1 O O 10 2O 30 40 50 60 Time Patent Application Publication May 1, 2008 Sheet 17 of 21 US 2008/O103.169 A1 Figure 18:20:1 L-carnosine + 20:1 sodium bicarbonate 0.8 g L-carnosine + 0.8 g. sodium bicarbonate + 40 mg omeprazole 1 Time Patent Application Publication May 1, 2008 Sheet 18 of 21 US 2008/010.3169 A1 Figure 19:40:1 1.6 g sodium bicarbonate + 40 mg omeprazole 8 7 6 5 4 3 2 1 O O 10 20 3O 40 50 SO Time Patent Application Publication May 1, 2008 Sheet 19 of 21 US 2008/O103.169 A1 Figure 20:40:1 1.6 g sodium bicarbonate + 40 mg omeprazole 122 83838 O 3 O Time Patent Application Publication May 1, 2008 Sheet 20 of 21 US 2008/O103.169 A1 Figure 21:20:1 aluminum glycinate +20:1 sodium bicarbonate 0.8 g aluminum glycinate + 0.8 g. sodium bicarbonate + 40 mg omeprazole Time Patent Application Publication May 1, 2008 Sheet 21 of 21 US 2008/O103.169 A1 Figure 22:20:1 aluminum glycinate +20:1 sodium bicarbonate 0.8 g aluminum glycinate + 0.8 g. sodium bicarbonate + 40 mg omeprazole 22838 13 Time US 2008/O 1031 69 A1 May 1, 2008 COMPOSITIONS COMPRISING ACID LABLE 0005. It is believed that the neutral PPIs reach parietal cells PROTON PUMP INHIBITINGAGENTS, AT LEAST from the blood and diffuse into the secretory canaliculi where ONE OTHER PHARMACEUTICALLY ACTIVE they become protonated and thereby trapped. The protonated AGENT AND METHODS OF USING SAME agent is then believed to rearrange to form a Sulfenic acid and a Sulfenamide. The Sulfenamide, in turn, is thought to interact RELATED APPLICATIONS covalently with sulfhydryl groups at critical sites in the extra cellular (luminal) domain of the membrane-spanning H'. 0001. This application claims priority to U.S. Provisional K"-ATPase. See e.g. Hardman et al., Goodman & Gilman's Application Ser. No. 60/950,549, filed on Jul.18, 2007; U.S. The Pharmacological Basis of Therapeutics, p. 907, 9" ed. Provisional Application Ser. No. 60/887,095, filed on Jan. 29, (1996). 2007; U.S. Provisional Application Ser. No. 60/863,179, filed on Oct. 27, 2006; PCT/US2007/060723 filed Jan. 18, 2007, 0006 Unfortunately, commercially available substituted which claims priority to U.S. Provisional Application Ser. benzimidazole compounds are unstable at neutral or acidic No. 60/760,256, filed on Jan. 19, 2006, now abandoned; pH and undergo decomposition in gastrointestinal fluid upon PCT/US2006/040756 filed Oct. 18, 2006, which claims pri oral administration, thereby resulting in loss of therapeutic ority to U.S. Provisional Application Ser. No. 60/728,125, activity. To overcome this acid instability, such compounds filed on Oct. 19, 2005, now abandoned; PCT/US2006/015939 are typically formulated for oral delivery as enteric coated filed Apr. 25, 2006, which claims priority to U.S. Provisional Solid dosage forms, for example enteric coated tablets, which Application Ser. No. 60/675,122, filed on Apr. 26, 2005, now coating protects the drug from contact with acidic stomach abandoned; PCT/US2006/015982 filed Apr. 25, 2006, which secretions. An undesirable consequence of such enteric coat claims priority to U.S. Provisional Application Ser. No. ing is that therapeutic onset time is significantly delayed by 60/675,133, filed on Apr. 26, 2005, now abandoned; and comparison with non-enteric coated dosage forms. Such pro PCT/US2006/015983 filed Apr. 25, 2006, which claims pri longed time to therapeutic onset is particularly undesirable ority to U.S. Provisional Application Ser. No. 60/675,260, for patients in need of rapid relief from one or more of the filed on Apr.
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