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Patent US6780882 - Substituted benzimidazole dosage forms and method of using same - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsThere is provided a solid pharmaceutical composition having active ingredients that include at least one non-enteric coated proton pump inhibitor and at least one buffering agent. The proton pump inhibitor, for example, omeprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole, and...http://www.google.com/patents/US6780882?utm_source=gb-gplus-sharePatent US6780882 - Substituted benzimidazole dosage forms and method of using sameAdvanced Patent SearchPublication numberUS6780882 B2Publication typeGrantApplication numberUS 10/260,132Publication dateAug 24, 2004Filing dateSep 30, 2002Priority dateJan 4, 1996Fee statusPaidAlso published asCA2396159A1, CA2396159C, DE60123381D1, DE60123381T2, EP1246622A1, EP1246622A4, EP1246622B1, EP1430895A1, EP1927354A1, EP2305259A1, US6489346, US7399772, US20030118669, US20030144306, US20030215527, US20040058018, US20050042304, US20090022796, WO2001051050A1Publication number10260132, 260132, US 6780882 B2, US 6780882B2, US-B2-6780882, US6780882 B2, US6780882B2InventorsJeffrey O. PhillipsOriginal AssigneeThe Curators Of The University Of MissouriExport CitationBiBTeX, EndNote, RefManPatent Citations (102), Non-Patent Citations (189), Referenced by (17), Classifications (70), Legal Events (4) External Links: USPTO, USPTO Assignment, EspacenetSubstituted benzimidazole dosage forms and method of using sameUS 6780882 B2Abstract There is provided a solid pharmaceutical composition having active ingredients that include at least one non-enteric coated proton pump inhibitor and at least one buffering agent. The proton pump inhibitor, for example, omeprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole, and leminoprazole, or an enantiomer, isomer, derivative, free base, or salt thereof, is present in an amount of approximately 5 mg to approximately 300 mg; and the buffering agent is present in an amount of approximately 0.1 mEq to approximately 2.5 mEq per mg of proton pump inhibitor. The dosage form can be non-enteric coated and can be in the form of a suspension tablet, a chewable tablet, an effervescent powder, or an effervescent tablet. Also provided is a method for treating an acid-related gastrointestinal disorder in a subject in need thereof by administering to the subject a solid pharmaceutical composition of the present invention.
Patients with significant physiologic stress are at risk for stress-related gastric mucosal damage and subsequent upper gastrointestinal bleeding (Marrone and Silen, Pathogenesis, Diagnosis and Treatment of Acute Gastric Mucosa Lesions, Clin Gastroenterol 13: 635-650 (1984)). Risk factors that have been clearly associated with the development of stress-related mucosal damage are mechanical ventilation, coagulopathy, extensive burns, head injury, and organ transplant (Zinner et al., The Prevention of Gastrointestinal Tract Bleeding in Patients in an Intensive Care Unit, Surg. Gynecol. Obstet., 153: 214-220 (1981); Larson et al. , Gastric Response to Severe Head Injury, Am. J. Surg. 147: 97-105 (1984); Czaja et al., Acute Gastroduodenal Disease After Thermal Injury: An Endoscopic Evaluation of Incidence and Natural History, N Engl. J. Med, 291: 925-929 (1974); Skillman et al., Respiratory Failure, Hypotension, Sepsis and Jaundice: A Clinical Syndrome Associated with Lethal Hemorrhage From Acute Stress Ulceration, Am. J. Surg., 117: 523-530 (1969); and Cook et al., Risk Factors for Gastrointestinal Bleeding in Critically Ill Patients, N. Engl. J. Med., 330:377-381 (1994)). One or more of these factors are often found in critically ill, intensive care unit patients. A recent cohort study challenges other risk factors previously identified such as acid-base disorders, multiple trauma, significant hypertension, major surgery, multiple operative procedures, acute renal failure, sepsis, and coma (Cook et al., Risk Factors for Gastrointestinal Bleeding in Critically Ill Patients, N. Engl. J. Med., 330:377-381 (1994)). Regardless of the risk type, stress-related mucosal damage results in significant morbidity and mortality. Clinically significant bleeding occurs in at least twenty percent of patients with one or more risk factors who are left untreated (Martin et al., Continuous Intravenous Cimetidine Decreases Stress-related Upper Gastro-intestinal Hemorrhage Without Promoting Pneumonia, Crit. Care Med., 21: 19-30 (1993)). Of those who bleed, approximately ten percent require surgery (usually gastrectomy) with a reported mortality of thirty percent to fifty percent (Czaja et al., Acute Gastroduodenal Disease After Thermal Injury: An Endoscopic Evaluation of Incidence and Natural History, N Engl. J. Med, 291: 925-929 (1974); Peura and Johnson, Cimetidine for Prevention and Treatment of Gastroduodenal Mucosal Lesions in Patients in an Intensive Care Unit, Ann Intern Med., 103: 173-177 (1985)). Those who do not need surgery often require multiple transfusions and prolonged hospitalization. Prevention of stress-related upper gastrointestinal bleeding is an important clinical goal.
In addition to general supportive care, the use of drugs to prevent stress-related mucosal damage and related complications is considered by many to be the standard of care (AMA Drug Evaluations). However, general consensus is lacking about which drugs to use in this setting (Martin et al., Continuous Intravenous Cimetidine Decreases Stress-related Upper Gastrointestinal Hemorrhage Without Promoting Pneumonia, Crit. Care Med., 21: 19-30 (1993); Gafter et al., Thrombocytopenia Associated With Hypersensitivity to Ranitidine: Possible Cross-reactivity with Cimetidine, Am. J. Gastroenterol, 84: 560-562 (1989); Martin et al., Stress Ulcers and Organ Failure in Intubated Patients in Surgical Intensive Care Units, Ann Surg., 215: 332-337 (1992)). In two recent meta-analyses (Cook et al., Stress Ulcer Prophylaxis in the Critically Ill: A Meta-analysis, Am. J. Med., 91: 519-527 (1991); Tryba, Stress Ulcer Prophylaxis�Quo Vadis? Intens. Care Med. 20: 311-313 (1994)) antacids, sucralfate, and H2-antagonists were all found to be superior to placebo and similar to one another in preventing upper gastrointestinal bleeding. Yet, prophylactic agents are withdrawn in fifteen to twenty percent of patients in which they are employed because of failure to prevent bleeding or control pH (Ostro et al., Control of Gastric pH With Cimetidine Boluses Versus Primed Infusions, Gastroenterology, 89: 532-537 (1985); Siepler, A Dosage Alternative for H-2 Receptor Antagonists, Continuous-Infusion, Clin. Ther., 8(Suppl A): 24-33 (1986); Ballesteros et al., Bolus or Intravenous Infusion of Ranitidine: Effects on Gastric pH and Acid Secretion: A Comparison of Relative Cost and Efficacy, Ann. Intern. Med., 112:334-339 (1990)), or because of adverse effects (Gafter et al., Thrombocytopenia Associated With Hypersensitivity to Ranitidine: Possible Cross-reactivity With Cimetidine, Am. J. Gastroenterol, 84: 560-562 (1989); Sax, Clinically Important Adverse Effects and Drug Interactions With H2-Receptor Antagonists: An Update, Pharmacotherapy 7 (6 pt 2): 110S-115S (1987); Vial et al., Side Effects of Ranitidine, Drug Saf, 6:94-117(1991); Cantu and Korek, Central Nervous System Reactions to Histamine-2 Receptor Blockers, Ann. Intern Med., 114: 1027-1034 (1991); and Spychal and Wickham, Thrombocytopenia Associated With Ranitidine, Br. Med. J., 291: 1687 (1985)). In addition, the characteristics of an ideal agent for the prophylaxis of stress gastritis were analyzed by Smythe and Zarowitz, Changing Perspectives of Stress Gastritis Prophylaxis, Ann Pharmacother, 28: 1073-1084 (1994) who concluded that none of the agents currently in use fulfill their criteria.
Another controversy surrounding stress ulcer prophylaxis is which drug to use. In addition to the various H2-antagonists, antacids and sucralfate are other treatment options for the prophylaxis of stress-related mucosal damage. An ideal drug in this setting should possess the following characteristics: prevent stress ulcers and their complications, be devoid of toxicity, lack drug interactions, be selective, have minimal associated costs (such as personnel time and materials), and be easy to administer (Smythe and Zarowitz, Changing Perspectives of Stress Gastritis orophylaxis, Ann Pharmacother, 28: 1073-1084 (1994)). Some have suggested that sucralfate is possibly the ideal agent for stress ulcer prophylaxis (Smythe and Zarowitz, Changing Perspectives of Stress Gastritis Prophylaxis, Ann Pharmacother, 28 : 1073-1084 (1994)). Randomized, controlled studies support the use of sucralfate (Borrero et al., Antacids vs. Sucralfate in Preventing Acute Gastrointestinal Tract Bleeding in Abdominal Aortic Aurgery, Arch. Surg., 121: 810-812 (1986); Tryba, Risk of Acute Stress Bleeding and Nosocomial Pneumonia in Ventilated Intensive Care Patients. Sucralfate vs. Antacids, Am. J. Med., 87(3B): 117-124 (1987); Cioffi et al., Comparison of Acid Neutralizing and Non-acid Neutralizing Stress Ulcer Prophylaxis in Thermally Injured Patients. J. Trauma, 36: 541-547 (1994); and Driks et al., Nosocomial Pneumonia in Intubated Patients Given Sucralfate as Compared With Antacids or Histamine Type 2 Blockers, N. Engl. J. Med., 317: 1376-1382 1987)), but data on critical care patients with head injury, trauma, or burns are limited. In addition, a recent study comparing sucralfate and cimetidine plus antacids for stress ulcer prophylaxis reported clinically significant bleeding in three of forty-eight (6%) sucralfate-treated patients, one of whom required a gastrectomy (Cioffi et al., Comparison of Acid Neutralizing and Non-acid Neutralizing Stress Ulcer Prophylaxis in Thermally Injured Patients, J. Trauma, 36: 541-547 (1994)) In the study performed by Driks and coworkers that compared sucralfate to conventional therapy (H2-antagonists, antacids, or H2-antagonists plus antacids), the only patient whose death was attributed to stress-related upper gastrointestinal bleeding was in the sucralfate arm (Driks et al., Nosocomial Pneumonia in Intubated Patients Given Sucralfate as Compared With Antacids or Histamine Type 2 Blockers, N. Engl. J. Med., 317: 1376-1382(1987)).
H2-antagonists fulfill many of the criteria for an ideal stress ulcer prophylaxis drug. Yet, clinically significant bleeds can occur during H2-antagonist prophylaxis (Martin et al., Continuous Intravenous Cimetidine Decreases Stress-related Upper Gastrointestinal Hemorrhage Without Promoting Pneumonia, Crit. Care Med., 21: 19-39 (1993); Cook et al., Stress Ulcer Prophylaxis in the Critically Ill: A Meta-analysis, Am. J. Med., 91: 519-527 (1991); Schuman et al., Prophylactic Therapy for Acute Ulcer Bleeding: A Reappraisal, Ann Intern. Med, 106: 562-567 (1987)). Adverse events are not uncommon in the critical care population (Gafter et al., Thrombocytopenia Associated With Hypersensitivity to Ranitidine: Possible Cross-Reactivity With Cimetidine, Am. J. Gastroenterol, 64: 560-562 (1989); Sax, Clinically Important Adverse Effects and Drug Interactions With H2-receptor Antagonists: An Update, Pharmacotherapy 7(6 pt 2): 110S-115S (1987); Vial et al., Side Effects of Ranitidine, Drug Saf., 6:94-117(1991); Cantu and Korek, Central Nervous System Reactions to Histamine-2 Receptor Blockers, Ann. Intern Med., 114: 1027-1034 (1991); Spychal and Wickham, Thrombocytopenia Associated With Ranitidine, Br. Med. J., 291: 1687 (1985)).
One reason proposed for the therapeutic H2-antagonist failures is lack of pH control throughout the treatment period (Ostro et al., Control of Gastric pH With Cimetidine Boluses Versus Primed Infusions, Gastroenterology, 89: 532-537 (1985)). Although the precise pathophysiologic mechanisms involved in stress ulceration are not clearly established, the high concentration of hydrogen ions in the mucosa (Fiddian-Green et al., 1987) or gastric fluid in contact with mucosal cells appears to be an important factor. A gastric pH>3.5 has been associated with a lower incidence of stress-related mucosal damage and bleeding (Larson et al., Gastric Response to Severe Head Injury, Am. J. Surg. 147: 97-105 (1984); Skillman et al., Respiratory Failure, Hypotension, Sepsis and Jaundice: A Clinical Syndrome Associated With Lethal Hemorrhage From Acute Stress Ulceration, Am. J. Surg., 117: 523-530 (1969); Skillman et al., The Gastric Mucosal Barrier: Clinical and Experimental Studies in Critically Ill and Normal Man and in the Rabbit, Ann Surg., 172: 564-584 (1970); and Priebe and Skillman, Methods of Prophylaxis in Stress Ulcer Disease, World J. Surg., 5: 223-233 (1981)). Several studies have shown that H2-antagonists, even in maximal doses, do not reliably or continuously increase intragastric pH above commonly targeted levels (3.5 to 4.5). This is true especially when used in fixed-dose bolus regimens (Ostro et al., Control of Gastric pH With Cimetidine Boluses Versus Primed Infusions, Gastroenterology, 89: 532-537 (1985); Siepler, A Dosage Alternative for H-2 Receptor Antagonists, Continuous-infusion, Clin. Ther., 8 (Suppl A): 24-33 (1986); Ballesteros et al., Bolus or Intravenous Infusion of Ranitidine: Effects on Gastric pH and Acid Secretion: A Comparison of Relative Cost and Efficacy, Ann. Intern. Med., 112:334-339 (1990)). In addition, gastric pH levels tend to trend downward with time when using a continuous-infusion of H2-antagonists, which may be the result of tachyphylaxis (Ostro et al., Control of Gastric pH With Cimetidine Boluses Versus Primed Infusions, Gastroenterology, 89: 532-537 (1985); Wilder-Smith and Merki, Tolerance During Dosing With H 2-receptor Antagonists. An Overview, Scand. J. Gastroenterol 27 (suppl. 193): 14-19 (1992)).
Omeprazole (Prilosec�), lansoprazole (Prevacid�) and other PPIs reduce gastric acid production by inhibiting H+,K+-ATPase of the parietal cell�the final common pathway for gastric acid secretion (Fellenius et al., Substituted Benzimidazoles Inhibit Gastric Acid Secretion by Blocking H + ,K +-ATPase, Nature, 290: 159-161 (1981); Wallmark et al, The Relationship Between Gastric Acid Secretion and Gastric H + ,K +-ATPase Activity, J. Biol.Chem., 260: 13681-13684 (1985); Fryklund et al., Function and Structure of Parietal Cells After H + ,K +-ATPase Blockade, Am. J. Physiol., 254 (3 pt 1); G399-407 (1988)).
PPIs contain a sulfinyl group in a bridge between substituted benzimidazole and pyridine rings, as illustrated below. At neutral pH, omeprazole, lansoprazole and other PPIs are chemically stable, lipid-soluble, weak bases that are devoid of inhibitory activity. These neutral weak bases reach parietal cells from the blood and diffuse into the secretory canaliculi, where the drugs become protonated and thereby trapped. The protonated agent rearranges to form a sulfenic acid and a sulfenamide. The sulfenamide interacts covalently with sulfhydryl groups at critical sites in the extracellular (luminal) domain of the membrane-spanning H+,K+-ATPase (Hardman et al., Goodman & Gilman's The Pharmacological Basis of Therapeutics, p. 907 (9th ed. 1996)). Omeprazole and lansoprazole, therefore, are prodrugs that must be activated to be effective. The specificity of the effects of PPIs is also dependent upon: (a) the selective distribution of H+,K+-ATPase; (b) the requirement for acidic conditions to catalyze generation of the reactive inhibitor; and (c) the trapping of the protonated drug and the cationic sulfenamide within the acidic canaliculi and adjacent to the target enzyme. (Hardman et al., 1996)).
The absence of an intravenous or oral liquid dosage S form in the United States has limited the testing and use of omeprazole, lansoprazole and rabeprazole in the critical care patient population. Barie et al., Therapeutic Use of Omeprazole for Refractory Stress-induced Gastric Mucosal Hemorrhage, Crit. Care Med., 20: 899-901 (1992) have described the use of omeprazole enteric-coated pellets administered through a nasogastric tube to control gastrointestinal hemorrhage in a critical care patient with multi-organ failure. However, such pellets are not ideal as they can aggregate and occlude such tubes, and they are not suitable for patients who cannot swallow the pellets. Am J. Health-Syst Pharm 56:2327-30 (1999).
Several buffered omeprazole oral solutions/suspensions have been disclosed. For example, Pilbrant et al., Development of an Oral Formulation of Omeprazole, Scan. J. Gastroent. 20(Suppl. 108): 113-120 (1985) teaches the use of micronized omeprazole suspended in water, methylcellulose and sodium bicarbonate in a concentration of approximately 1.2 mg omeprazole/ml suspension.
Nakagawa, et al., Lansoprazole: Phase I Study of lansoprazole (AG-1749) Anti-ulcer Agent, J. Clin. Therapeutics & Med.(1991) teaches the oral administration of 30 mg of lansoprazole suspended in 100 ml of sodium bicarbonate (0.3 mg/ml), which was administered to patients through a nasogastric tube.
Sixth, because the buffered omeprazole solutions of the prior art require prolonged administration of sodium bicarbonate, it makes it difficult for patients to comply with the regimens of the prior art. For example, Pilbrant et al. disclose an oral omeprazole administration protocol calling for the administration to a subject who has been fasting for at least ten hours, a solution of 8 mmoles of sodium bicarbonate in 50 ml of water. Five minutes later, the subject ingests a suspension of 60 mg of omeprazole in 50 ml of water that also contains 8 mmoles of sodium bicarbonate. This is rinsed down with another 50 ml of 8 mmoles sodium bicarbonate solution Ten minutes after the ingestion of the omeprazole dose, the subject ingests 50 ml of bicarbonate solution (8 mmoles). This is repeated at twenty minutes and thirty minutes post omeprazole dosing to yield a total of 48 mmoles of sodium bicarbonate and 300 ml of water in total which are ingested by the subject for a single omeprazole dose. Not only does this regimen require the ingestion of excessive amounts of bicarbonate and water, which is likely to be dangerous to some patients, it is unlikely that even healthy patients would comply with this regimen.
FIG. 5 is a graph illustrating the environmental pH values after administration of the proton pump inhibiting agent/buffer formulation.
FIG. 6 is a graph illustrating the environmental pH values after administration of the proton pump inhibiting agent/buffer formulation.
The liquid oral pharmaceutical composition of the present invention is prepared by mixing omeprazole (Prilosec� AstraZeneca) or other proton pump inhibitor or derivatives thereof with a solution including at least one buffering agent (with or without a parietal cell activator, as discussed below). Preferably, omeprazole or other proton pump inhibitors, which can be obtained from a capsule or tablet or obtained from the solution for parenteral administration, is mixed with a sodium bicarbonate solution to achieve a desired final omeprazole (or other PPI) concentration. As an example, the concentration of omeprazole in the solution can range from approximately 0.4 mg/ml to approximately 10.0 mg/ml. The preferred concentration for the omeprazole in the solution ranges from approximately 1.0 mg/ml to approximately 4.0 mg/ml, with 2.0 mg/ml being the standard concentration. For lansoprazole (Prevacid� TAP Pharmaceuticals, Inc.) the concentration can range from about 0.3 mg/ml to 10 mg/ml with the preferred concentration being about 3 mg/ml.
Such parietal cell activators are administered in an amount sufficient to produce the desired stimulatory effect without causing untoward side effects to patients. For example, chocolate, as raw cocoa, is administered in an amount of about 5 mg to 2.5 9 per 20 mg dose of omeprazole (or equivalent pharmacologic dose of other PPI). The dose of activator administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response (i.e., enhanced effect of PPI) over a reasonable time frame. The dose will be determined by the strength of the particular compositions employed and the condition of the person, as well as the body weight of the person to be treated. The size of the dose also will be determined by the existence, nature, and extent of any adverse side effects that might accompany the administration of a particular composition.
Chocolate (raw cocoa)
to 2.5 g
to 25 mEq
to 1.5 Gm
Peppermint oil - (powdered form)
to 1 Gm
Spearmint oil - (powdered form)
to 240 ml
EXAMPLE I A. Fast Disintegrating Suspension Tablets of Omeprazole.
(or lansoprazole or pantoprazole or other PPI in an
equipotent amount)
(or lansoprazole or pantoprazole or other PPI
in an equipotent amount)
E. Powder for Reconstitution for Oral Use (or per ng tube).
EXAMPLE II Standard Tablet of PPI and Buffering Agent.
The effervescent powder and tablets can alternatively be formulated by employing the above mixture but adding an additional 200 mg of sodium bicarbonate USP to create a resulting solution with a higher pH Further, instead of the excess 200 mg of sodium bicarbonate, 100 mg of calcium glycerophosphate or 100 mg of calcium lactate can be employed. Combinations of the same can also added.
EXAMPLE V Parietal Cell Activator �Choco-Base�� Formulations and Efficacy.
Applicant performed a retrospective evaluation of children with GERD referred to the University of Missouri-Columbia from 1995 to 1998 who received treatment with the experimental omeprazole or lansoprazole Choco-Base� suspension formulated in accordance with Formulation 1 stated below. Data were included on all patients with follow up information sufficient to draw conclusions about pre/post treatment (usually >6 months). There were 25 patients who met the criteria for this evaluation. Age range was several weeks to greater than 5 years. Most patients had a history of numerous unsuccessful attempts at ameliorating the effects of GERD. Medication histories indicated many trials of various drugs.
Of the 24 remaining patients, 18 were males and 6 were females. Ages at implementation of PPI therapy ranged from 2 weeks of age to 9 years old. Median age at start of therapy was 26.5 months [mean of 37 mo.] Early on, reflux was usually documented by endoscopy and confirmed by pH probe. Eventually, pH probe was dropped and endoscopy was the sole method for documenting reflux, usually at the time of another surgery (most often T-tubes or adenoidectomy). Seven patients had pH probe confirmation of GERD, whereas 18 had endoscopic confirmation of reflux including all eight who had pH probing done. Reflux was diagnosed on endoscopy most commonly by cobblestoning of the tracheal wall, with laryngeal and pharyngeal cobblestoning as findings in a few patients. Six patients had neither pH nor endoscopic documentation of GERD, but were tried on PPI therapy based on symptomatology alone.
Most patients had been treated in the past with medical therapy in the form of antibiotics, steroids, asthma medications and other diagnosis-appropriate therapies. In addition, nine of the patients had been on reflux therapy in the past, most commonly in the form of conservative therapy such as head of bed elevation 30�, avoidance of evening snacks, avoidance of caffeinated beverages as well as cisapride and ranitidine
The proton pump inhibitor suspension used in this group of patients was Choco-Base suspension of either lansoprazole or omeprazole. The dosing was very uniform, with patients receiving doses of either 10 or 20 mg of omeprazole and 23 mg of lansoprazole. Initially, in April of 1996 when therapy was first instituted 10 mg of omeprazole was used. There were 3 patients in this early phase who were treated initially with 10 mg po qd of omeprazole. All three subsequently were increased to either 20 mg po qd of omeprazole or 23 mg po qd of lansoprazole. All remaining patients were given either the 20 mg omeprazole or the 23 mg lansoprazole treatment qd, except in one case, where 30 mg of lansoprazole was used. Patients were instructed to take their doses once per day, preferably at night in most cases. Suspensions were all filled through the University of Missouri Pharmacy at Green Meadows. This allowed for tracking of usage through refill data
Patients were categorized based on review of clinic notes and chart review into general categories: (1) improved; (2) unchanged; (3) failed; and (4) inconclusive. Of 24 patients with sufficient data for follow up, 18 showed improvement in symptomatology upon commencement of PPI therapy [72%]. The seven who did not respond were analyzed and grouped. Three showed no change in symptomatology and clinical findings while on therapy, one complained of worsening symptoms while on therapy, one patient had therapy as prophylaxis for surgery, and two stopped therapy just after its commencement. Setting aside the cases in which therapy was stopped before conclusions could be drawn and the case in which PPI therapy was for purely prophylactic reasons, leaves (17/21) 81% of patients that responded to Choco-Base suspension. This means that 19% (4/21) of patients received no apparent benefit from PPI therapy. Of all these patients, only 4% complained of worsening symptoms and the side effects were 4% (1/21) and were mild bloody stool that completely resolved upon cessation of therapy.
The standard of therapy for the treatment of GERD in the pediatric population has become a progression from conservative therapy to a combination of a pro-kinetic agent and H-2 blocker therapy. Nonetheless, many patients fail this treatment protocol and become surgical candidates. In adults, PPI therapy is effective in 90% of those treated for gastroesophageal reflux disease. As a medical alternative to the H-2 blockers, the proton pump inhibitors have not been studied extensively in the pediatric population. Part of the reason for this lack of data may be related to the absence of a suitable dosage formulation for this very young population, primarily under 2 years of age, that does not swallow capsules or tablets. It would be desirable to have a true liquid formulation (solution or suspension) with good palatability such as is used for oral antibiotics, decongestants, antihistamines, H-2 blockers, cisapride, metoclopramide, etc. The use of lansoprazole granules (removed from the gelatin capule) and sprinkled on applesauce has been approved by the Food and Drug Administration as an alternative method of drug administration in adults but not in children. Published data are lacking on the efficacy of the lansoprazole sprinkle method in children. Omeprazole has been studied for bioequivalence as a sprinkle in adults and appears to produce comparable serum concentrations when compared to the standard capsule. Again no data are available on the omeprazole sprinkle in children. An additional disadvantage of omeprazole is its taste which is quinine-like. Even when suspended in juice, applesauce or the like, the bitter nature of the medicine is easily tasted even if one granule is chewed. For this reason applicant eventually progressed to use lansoprazole in Choco-Base. Pantoprazole and rabeprazole are available as enteric-coated tablets only. Currently, none of the proton pump inhibitors available in the United States are approved for pediatric use. There is some controversy as to what the appropriate dosage should be in this group of patients. A recent review by Israel D., et al. suggests that effective PPI dosages should be higher than that originally reported, i.e., from 0.7 mg/kg to 2 or 3 mg/kg omeprazole. Since toxicity with the PPI's is not seen even at >50 mg/kg, there appears little risk associated with the higher dosages. Based on observations at the University of Missouri consistent with the findings of this review, applicant established a simple fixed dosage regimen of 10 ml Choco-Base suspension daily. This 10 ml dose provided 20 mg omeprazole and 23 mg lansoprazole.
Add Part B to Part A to create a total volume of approximately
130 ml with an omeprazole concentration of about 1.5 mg/ml.
Mix the constituents of Part B together thoroughly and then
add to Part A. This results in a total volume of approximately
This formulation is reconstituted at the time of use by a
pharmacist. Part B is mixed first and is then uniformly
mixed with the components of Part A. A final volume of
about 130 ml is created having an omeprazole concentration
FIG. 4 illustrates the lansoprazole/cocoa combination resulted in higher pHs at hours 19-56 than lansoprazole alone at hours 4-18. Therefore, the combination of the lansoprazole with chocolate enhanced the pharmacologic activity of the lansoprazole. The results establish that the sodium bicarbonate as well as chocolate flavoring and calcium were all able to stimulate the activation of the proton pumps, perhaps due to the release of gastrin. Proton pump inhibitors work by functionally inhibiting the proton pump and effectively block activated proton pumps (primarily those inserted into the secretory canalicular membrane). By further administering the proton pump inhibitor with one of these activators or enhancers, there is a synchronization of activation of the proton pump with the absorption and subsequent parietal cell concentrations of the proton pump inhibitor. As illustrated in FIG. 4, this combination produced a much longer pharmacologic effect than when the proton pump inhibitor was administered alone.
1.3┌check of fg pH
1.3┌check of gf pH
Study Population: All adult (>18 years old) patients admitted to the surgical intensive care and burn unit at the University of Missouri Hospital with an intact stomach, a nasogastric tube in place, and an anticipated intensive care unit stay of at least forty-eight hours were considered for inclusion in the study. To be included patients also had to have a gastric pH of <4, had to be mechanically ventilated and have one of the following additional risk factors for a minimum of twenty-four hours after initiation of omeprazole suspension: head injury with altered level of consciousness, extensive burns (>20% Body Surface Area) acute renal failure, acid-base disorder, multiple trauma, coagulopathy, multiple operative procedures, Coma, hypotension for longer than one hour or sepsis (see Table 2). Sepsis was defined as the presence of invasive pathogenic organisms or their toxins in blood or tissues resulting in a systematic response that included two or more of the following: temperature greater than 38� C. or less than 36� C., heart rate greater than 90 beats/minute, respiratory rate greater than 20 breaths/minute (or pO2 less than 75 mm Hg), and white blood cell count greater than 12,000 or less than 4,000 cells/mm3 or more than 10 percent bands (Bone, Let's Agree on Terminology: Definitions of Sepsis, Crit. Care Med. , 19: 27 (1991)). Patients in whom H2-antagonist therapy had failed or who experienced an adverse event while receiving H2-antagonist therapy were also included.
Risk factors present in patients in this study (n = 75) TABLE 3
3 minutes ($40/br)
Note: Does not include the cost of failure and/or adverse effect. Acquisition, preparation and delivery costs of traditional agents. TABLE 4
The average length of treatment was 9 days. Cost of care was calculated from these days.
40 mg load � 2 5.66/dose)
Product acqusition cost
2/75 patient require 40 mg simplified omeparzole solution per day (days 2-9)
TOTAL 43 113.43
Simplified Omeprazole Solution cost per day
Pharmacoeconomic evaluation of omeprazole cost of care TABLE 5
Stability of Simplified Omeprazole Solution at room temperature (25� C.). Values are the mean of three samples. EXAMPLE X Bacteriostatic and Fungistatic Effects of Omeprazole Solution
(a) 20 mg of a liquid formulation of approximately 20 mg omeprazole in 4.8 mEq sodium bicarbonate qs to 10 ml with water;
(b) 20 mg of a liquid formulation of approximately 2 mg omeprazole per 1 ml of 8.4% sodium bicarbonate;
(c) Prilosec� (omeprazole) 20 mg capsule;
(d) capsule prepared by inserting the contents of an omeprazole 20 mg capsule into a #4 empty gelatin capsule (Lilly) uniformly dispersed in 240 mg of sodium bicarbonate powder USP to form an inner capsule. The inner capsule is then inserted into a #00 empty gelatin capsule (Lilly) together with a homogeneous mixture of 600 mg sodium bicarbonate USP and 110 mg pregelatinized starch NF.
Blood samples will be centrifuged within 2 hours of collection and the plasma will then be separated and frozen at −10� C. (or lower) until assayed. Pharmacokinetic variables will include: time to peak concentration, mean peak concentration, AUC (0-t) and (0-infinity). Analysis of variance will be used to detect statistical difference. Bioavailability will be assessed by the 90% confidence interval of the two one-sided tests on the natural logarithm of AUC.
Omeprazole and internal standard (H168/24) will be used. Omeprazole and internal standard will be measured by modification of the procedure described by Amantea and Narang. (Amantea M A, Narang P K. Improved Procedure for Quantification of Omeprazole and Metabolites Using Reversed-Phased High Performance Liquid Chromotography. J. Chromatography 426; 216-222. 1988). Briefly, 20 μl of omeprazole 2 mg/ml NaHCO3 or Choco-Base� omeprazole suspension and 100 μl of the internal standard are vortexed with 150 μl of carbonate buffer (pH=9.8), 5 ml of dichloroethane, 5 ml of hexane, and 980 μl of sterile water. After the sample is centrifuged, the organic layer is extracted and dried over a nitrogen stream. Each pellet is reconstituted with 150 μl of mobile phase (40% methanol, 52% 0.025 phosphate buffer, 8% acetonitrile, pH=7.4). Of the reconstituted sample, 75 μl is injected onto a C18 5 U column equilibrated with the same mobile phase at 1.1 ml/min. Under these conditions, omeprazole is eluted at approximately 5 minutes, and the internal standard at approximately 7.5 minutes. The standard curve is linear over the concentration range 0-3 mg/ml (in previous work with SOS), and the between-day coefficient of variation has been <8% at all concentrations. The typical mean R2 for the standard curve has been 0.98 in prior work with SOS (omeprazole 2 mg/ml NaHCO3 8.4%).
(a) 40 mg IV over 15 to 30 minutes in combination with a 20 ml oral dose of sodium bicarbonate 8.4%; and
(b) 40 mg IV over 15 to 30 minutes in combination with a 20 ml oral dose of water.
The subjects will receive a single dose of (a) or (b) above, and will be crossed-over to (a) and (b) in random fashion. Serum concentrations of pantoprazole versus time after administration data will be collected, as well as gastric pH control as measured with an indwelling pH probe.
A solution was prepared by mixing 8.4% sodium bicarbonate with omeprazole to produce a final concentration of 2 mg/ml to determine the stability of omeprazole solution after 12 months. The resultant preparation was stored in clear glass at room temperature, refrigerated and frozen. Samples were drawn after thorough agitation from the stored preparations at the prescribed times. The samples were then stored at 70� C. Frozen samples remained frozen until they were analyzed. When the collection process was completed, the samples were shipped to a laboratory overnight on dry ice for analysis. Samples were agitated for 30 seconds and sample aliquots were analyzed by HPLC in triplicate according to well known methods. Omeprazole and the internal standard were measured by a modification of the procedure described by Amantea and Narang. Amantea M A, Narang P K, Improved Procedure For Quantitation Of Omeprazole And Metabolites Using Reverse-Phased High-Performance Liquid Chromatography, J. Chromatography, 426: 216-222 (1988). Twenty (20) μl of the omeprazole 2 mg/ml NaHCO3 solution and 100 μl of the internal standard solution were vortexed with 150 μl of carbonate buffer (pH=9.8), 5 ml dichloroethane, 5 ml hexane, and 980 μl of sterile water. The sample was centrifuged and the organic layer was extracted and dried over a nitrogen stream. Each pellet was reconstituted with 150 μl of mobile phase (40% methanol, 52% 0.025 phosphate buffer, 8% acetonitrile, pH=7.4). Of the reconstituted sample, 75 μl were injected onto a C185u column equilibrated with the same mobile phase at 1.1 ml/min. Omeprazole was eluted at −5 min, and the internal standard at −7.5 min. The standard curve was linear over the concentrated range 0-3 mg/ml, and between-day coefficient of variation was <8% at all concentrations. Mean R2 for the standard curve was 0.980.
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II.", Chem Pharm Bull (Tokyo), vol. 40, No. 3, pp. 675-682 (Mar. 1992).188Yasuda, et al., "Antacids Have No Influence on the Pharmacokinetics of Rabeprazole, A New Proton Pump Inhibitor, In Healthy Volunteers", International Journal of Clinical Pharmacology and Therapeutics, vol. 37, No. 5, pp. 249-253 (1999).189Zinner, et al., "The Prevention of Upper Gastro-Intestinal Tract Bleeding in Patients in an Intensive Care Unit", Surgery, Gynecology and Obstetrics, vol. 153, pp. 214-220 (Aug. 1981).Referenced byCiting PatentFiling datePublication dateApplicantTitleUS7271146Oct 14, 2003Sep 18, 2007Vecta Ltd.Methods for treatment of Helicobacter pylori-associated disordersUS7399772 *Aug 15, 2003Jul 15, 2008Curators Of The University Of MissouriSubstituted benzimidazole dosage forms and method of using sameUS7544370Sep 30, 2004Jun 9, 2009WyethPantoprazole multiparticulate formulationsUS7550153Mar 30, 2007Jun 23, 2009WyethPantoprazole multiparticulate formulationsUS7553498Mar 30, 2007Jun 30, 2009WyethPantoprazole multiparticulate formulationsUS7598273Oct 4, 2006Oct 6, 2009Auspex Pharmaceuticals, IncInhibitors of the gastric H+, K+-ATPase with enhanced therapeutic propertiesUS7803817Jul 27, 2005Sep 28, 2010Vecta, Ltd.Composition and methods for inhibiting gastric acid secretionUS7838027Sep 30, 2004Nov 23, 2010Wyeth LlcPantoprazole multiparticulate formulationsUS7981908May 14, 2008Jul 19, 2011Vecta, Ltd.Compositions and methods for inhibiting gastric acid secretionUS8206741May 16, 2005Jun 26, 2012Pozen Inc.Pharmaceutical compositions for the coordinated delivery of NSAIDsUS8216610Nov 27, 2006Jul 10, 2012Imaginot Pty Ltd.Oral paracetamol formulationsUS8247440 *Feb 19, 2009Aug 21, 2012Curators Of The University Of MissouriComposition comprising omeprazole, lansoprazole and at least one buffering agentUS8557285Aug 23, 2011Oct 15, 2013Pozen Inc.Pharmaceutical compositions for the coordinated delivery of NSAIDsUS20130115294 *Oct 11, 2012May 9, 2013Cts Chemical Industries Ltd.Stable liquid oily ready-to-use formulations, preparation thereof and use thereofEP2649989A1Apr 13, 2012Oct 16, 2013King Saud UniversityMethod for preparing a solid dispersion, solid dispersion obtained thereby and use thereofWO2005065726A1 *Dec 23, 2004Jul 21, 2005Akhilesh Ashok DixitPharmaceutical compositionWO2009012393A1 *Jul 17, 2008Jan 22, 2009Univ MissouriPharmaceutical composition comprising a proton pump inhibitor and protein component* Cited by examinerClassifications U.S. Classification514/338, 424/717International ClassificationA61P1/04, A61K9/16, A61K45/00, A61K36/534, A61K33/10, A61K9/14, A61K9/08, A61K31/522, A61K36/74, A61K9/48, A61K36/185, A61K36/18, A61K33/06, A61K47/46, A61K31/198, A61K36/53, A61K36/82, A61K36/00, A61K33/00, A61K31/4439, A61K9/28, A61K9/24, A61K47/02, A61K45/06, A61K31/00, A61K9/20, A61K9/00, A61K9/46, C07D401/12Cooperative ClassificationA61K31/4439, A61K9/2009, A61K9/0056, A61K9/2054, A61K36/534, A61K9/0007, A61K45/06, A61K36/74, A61K33/00, A61K47/02, A61K9/209, A61K9/2013, A61K9/1611, A61K9/0095, A61K36/82, A61K9/2813, A61K9/2086, A61K31/00, A61K36/185, A61K9/4808European ClassificationA61K33/00, A61K36/185, A61K9/16H2, A61K36/82, A61K36/534, A61K36/74, A61K9/00Z6, A61K31/00, A61K45/06, A61K9/00L6, A61K9/20H6F2, A61K9/20H2, A61K9/20H4, A61K9/00M18B, A61K9/28H2, A61K47/02, A61K9/20K4B, A61K31/4439, A61K9/20K4Legal EventsDateCodeEventDescriptionJan 25, 2012FPAYFee paymentYear of fee payment: 8Mar 3, 2008REMIMaintenance fee reminder mailedFeb 25, 2008FPAYFee paymentYear of fee payment: 4Mar 12, 2003ASAssignmentOwner name: CURATORS OF THE UNIVERSITY OF MISSOURI, MARYLANDFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PHILLIPS, JEFFREY O.;REEL/FRAME:013836/0806Effective date: 20030217Owner name: CURATORS OF THE UNIVERSITY OF MISSOURI 615 LOCUSTFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PHILLIPS, JEFFREY O. /AR;REEL/FRAME:013836/0806RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services©2012 Google