United States Patent [19]
`Phillips
`
`US005 84073 7A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,840,737
`Nov. 24, 1998
`
`[54] OMEPRAZOLE SOLUTION AND METHOD
`FOR USING SAME
`
`[75] Inventor: J e?'rey Owen Phillips, Columbia, Mo.
`
`[73] Assignee: The Curators of the University of
`Missouri, Columbia, Mo.
`
`[21] Appl. No.: 680,376
`[22]
`Filed:
`Jul. 15, 1996
`
`Related US. Application Data
`
`[60] Provisional application No. 60/009,608, Apr. 4, 1996.
`
`[51] Int. Cl.6 ................................................... .. A61K 31/44
`[52] US. Cl. ............................................................ .. 514/338
`[58] Field of Search ............................................. .. 514/338
`
`[56]
`
`References Cited
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`. Br J. Clin. Pharmacol., 29(5):557—63.
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`intravenous and oral doses of omepraZole. Eur J. Clin.
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`. .Ann.
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`Barie and Hariri (1992) Therapeutic use of omepraZole for
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`Bone (1991) Let’s agree on terminology: de?nition of
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`Borrero et al., (1986) Antacids vs sucralfate in preventing
`acute gastrointestinal tract bleeding in abdominal aortic
`surgery. Arch. Surg., 121:810—812.
`Brunton (1990) in The Pharmacologic Basis of T herapeu
`tics. Goodman AG, Rall TW, Nies AS, Taylor P (eds), NeW
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`Cantu and Korek (1991) Central nervous system reactions to
`histamine—2 receptor
`blockers. Ann Intern Med,
`114:1027—1034.
`Ciof? et al., (1994) Comparison of acid neutralizing and
`non—acid neutralizing stress ulcer prophylaxis in thermally
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`in critically ill patients. N. Engl. J. Med., 330:377—381.
`Cook et al., (1991) Stress ulcer prophylaxis in the critically
`ill: a meta—analysis Am. J. Med., 91:519—527.
`Cook et al., (1991) Nasocomial pneumonia and the role of
`gastric pH: a meta—analysis Chest, 100:7—13.
`CZaja et al., (1974) Acute gastroduodenal disease after
`thermal injury: an endoscopic evaluation of incidence and
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`Dobkin et al., (1990) Does pH paper accurately re?ect gastic
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`Driks et al., (1987) Nosocomial pneumonia in intubated
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`.
`. Crit. Care Med., 18:1092—1095.
`Fabian et al., (1993) Pneumonia and stress ulceration in
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`gastric acid secretion by blocking H+/K+—ATPase. Nature,
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`after H+/K+—ATPase blockade. Am. J. Physiol, 254 (3 pt 1);
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`
`(List continued on neXt page.)
`
`Primary Examiner—Jane Fan
`Attorney, Agent, or Firm—Kohn & Associates
`[57]
`ABSTRACT
`
`Apharmaceutical composition includes an aqueous solution/
`suspension of omepraZole or other substituted benZimida
`Zoles and derivatives thereof in a pharmaceutically accept
`able carrier comprising a bicarbonate salt of a Group IA
`metal. A method for treating and/or preventing gastrointes
`tinal conditions by administering to a patient a pharmaceu
`tical composition including an aqueous solution/suspension
`of omepraZole or other substituted benZimidaZoles and
`derivatives thereof in a pharmaceutically acceptable carrier
`including a bicarbonate salt of a Group IA metal Wherein the
`administering step consists of a single dosage form Without
`requiring further administering of the bicarbonate salt of the
`Group IA metal. Apharmaceutical composition for making
`a solution/suspension of omepraZole or other substituted
`benZimidaZoles and derivatives thereof includes omepraZole
`or other substituted benZimidaZoles and derivatives thereof
`and a bicarbonate salt of a Group IA metal in a form for
`convenient storage Whereby When the composition is dis
`solved in aqueous solution, the resulting solution is suitable
`for enteral administration.
`
`12 Claims, 1 Drawing Sheet
`
`Lupin Exh. 1016
`
`

`
`5,840,737
`Page 2
`
`OTHER PUBLICATIONS
`
`Gafter et a1., (1989) Thrombocytopenia associated With
`hypersensitivity to rantidine: possible cross—reactivity .
`.
`.
`Am. J. Gastroenterol, 64:560—562.
`Garner et a1., (1988) CDC de?nitions for nosocomial infec
`tions. Am. J. Infect. Control, 16:128—140.
`Heath et a1., (1988) Intragastic pH measurement using a
`novel disposable sensor. Intens. Care Med, 14:232—235.
`Kiilerich et a1., (1995) Effect of intravenous infusion of
`omepraZole and ranitidine on tWenty—four—hour intragastic
`pH .
`. .Digestion, 56:25—30.
`Laggner et a1., (1989) Prevention of upper gastrointestinal
`bleeding in long—term ventilated patients. Am. J. Med,
`86(supp1 6A):81—84.
`Landahl et a1., (1992) Pharmacokinetic study of omepraZole
`in elderly healthy volunteers. Clin. Pharmacokinet,
`Dec:23(6):469—76.
`Larson et a1., (1984) Gastric response to severe head injury.
`Am. J. Surg., 147:97—105.
`Marrone and Silen, (1984) Pathogenesis, diagnosis and
`treatment of acute gastric mucosa lesions. Clin. Gastroen
`terol, 13:635—650.
`Martin et a1., (1993) Continuous intravenous cimetidine
`decreases
`stress—re1ated
`upper
`gastrointestinal
`hemorrhage .
`.
`. Crit. Care Med, 21:19—39.
`Martin et a1., (1992) Stress ulcers and organ failure in
`intubated patients in surgical intensive care units. Ann.
`Surg., 215:332—337.
`Meiners et a1., (1982) Evaluation of various techniques to
`monitor intragastic pH. Arch. Surg., 117:288—291.
`Oh and Carroll (1994) Electrolyte and acid—base disorders.
`in The PharmacologicApproach to the Critically Ill Patient.
`(ChernoW B, ed) Williams & Wilkins, Baltimore, pp.
`966—967.
`Ostro et al. (1985) Control of gastric pH With cimetidine
`boluses versus primed infusions. Gastroeneterology,
`89:532—537.
`Peura and Johnson (1985) Cimetidine for prevention and
`treatment of gastroduodenal mucosal lesions in patients .
`.
`.
`Ann Intern Med, 103:173—177.
`Phillips and MetZler (1994) Simpli?ed omepraZole solution
`for the prophylaxis of stress—re1ated mucosal damage .
`.
`.
`Crit. Care Med, 22:A53.
`PickWorth et a1., (1993) Occurrence of nasocomial pneumo
`nia in mechanically ventilated trauma patients .
`.
`. Crit. Care
`Med, 12:1856—1862.
`Pilbrant et al. (1985) Development of an oral formulation of
`omepraZole. Gastroenterol Suppl, 108:113—20.
`Priebe and Skillman, (1981) Methods of prophylaxis in
`stress ulcer disease. World J. Surg., 5 :223—233.
`Regardh et a1., (1990) The pharmacokinetics of omepraZole
`in humans—a study of single intravenous and oral doses.
`Ther. Drug Monit., Mar: 12(2):163—72.
`
`Ryan et a1., (1993) Nasocomial pneumonia during stress
`ulcer prophylaxis With cimetidine and sucralfate. Arch.
`Surg., 128:1353—1357.
`Sax (1987) Clinically important adverse effects and drug
`interactions With H2—receptor antagonists: an update. Phar
`macotherapy, 7(6 pt 2): 110S—115S.
`Schepp (1993) Stress ulcer prophylaxis: still a valid option
`in the 1990? Digestion, 54:189—199.
`Schuman et a1., (1987) Prophylactic therapy for acute ulcer
`bleeding: a reappraisal. Ann Intern. Med, 106:562—567.
`Schuster (1993) Stress ulcer prophylaxis: in Whom? With
`What? Crit. Care Med, 21:4—6.
`Siepler (1986) Adosage alternative for H—2 receptor antago
`nists, continuous—infusion. Clin. T her., 8(Suppl A):24—33.
`Simms et a1., (1991) Role of gastric coloniZmation in the
`development of pneumonia in critically ill trauma
`patients .
`. .J. Trauma, 31:531—536.
`Skillman et a1., (1969) Respiratory failure, hypotension,
`sepsis and jaundice: a clinical syndrome associated With
`lethal .
`. .Am. J. Surg., 117:523—530.
`Skillman et a1., (1970) The gastric mucosal barrier: clinical
`and experimental studies in critically ill and normal man .
`.
`.
`Ann Surg., 172:564—584.
`Smythe and ZaroWitZ (1994) Changing perspectives of
`stress
`gastritis
`prophylaxis. Ann Pharmacother,
`28:1073—1084.
`Spychal and Wickham (1985) Thrombocytopenia associated
`With ranitidine. Br. Med. J., 291:1687.
`Tryba (1994) Stress ulcer prophylaxis—quo vadis? Intens.
`Care Med, 20:311—313.
`Tryba (1987) Risk of acute stress bleeding and nosocmial
`pneumonia in ventilated intensive care patients. Sucralfate
`vs. antacids. Am. J. Med, 87(3B):117—124.
`Vial et a1., (1991) Side effects of ranitidine. Drug Saf.,
`6:94—117.
`Wallmark et a1., (1985) The relationship betWeen gastric
`acid secretion and gastric H+/K+—ATPase activity. J. Biol.
`Chem., 260:13681—13684.
`Wilder—Smith and Merki (1992) Tolerance during dosing
`With H2 receptor antagonists. An overvieW. Scand. J. Gas
`troenterol. , 27(suppl 193): 14—19.
`Zinner et a1., (1981) The prevention of gastro—intestinal tract
`bleeding in patients in an intensive care unit. Surg. Gynecol.
`Obstet, 153:214—220.
`Gray et al. (1985) In?uence of insulin antibodies on phar
`macokinetics and bioavailability of recombinant human .
`.
`.
`British Medical Journal, 290:1687—1690.
`Lind et a1., (1986) Inhibition of basal and betaZole— and
`sham—feeding—induced acid secretion by omepraZole in
`man. Scand. J. Gastroenterol, 21:1004—1010.
`NakagaWa et a1., (1991) LansopraZole: Phase I Study of
`LansopraZole (AG—1749) antiulcer agent Abstract in
`english; text in Japanese.
`
`

`
`U.S. Patent
`
`Nov. 24, 1998
`
`5,840,737
`
`8
`'7
`E 6
`2 5
`c:
`a 4
`<C
`U 3
`
`2
`
`1
`
`9~
`8-
`7_
`
`5_
`
`4_
`3_
`
`2...
`
`1 —‘
`
`I
`pre-SOS
`
`I
`2 hr {3
`1st DOSE
`
`|
`DAILY, PRE
`DOSE (Y)
`llgi
`
`I
`THE LOWEST
`GASTRIC pH
`
`NO PRIOR SRMD
`PROPHYLAXIS
`n:65
`
`I-I—2 ASSOCIATED
`CLINICAL FAILURES
`n:8
`
`H-Z ASSOCIATED
`ADVERSE EFFECTS
`{1:4
`
`77 PATIENTS RECEIVED
`OMEPRAZOLE
`
`2 PATIENTS WERE
`INEVALUABLE
`
`75 PATIENTS
`WERE EVALUABLE
`OVERALL PATIENT ENROLLMENT SCHEME
`
`1|:
`‘l-
`
`>
`
`n
`T
`
`n:
`
`GASTRIC pH
`pre SOS
`3‘5i1.9
`
`,
`
`pH 4 hr
`MEAN pH
`post SOS
`post SOS
`7.I1LI.1
`6.8i0‘6
`Fig-3
`
`LOWEST pH
`post SOS
`5.6i1.3
`
`I
`
`

`
`1
`OMEPRAZOLE SOLUTION AND METHOD
`FOR USING SAME
`
`This application is a continuation-in-part of US. Prov.
`App. Ser. No. 60/009,608 ?led on Jan. 4, 1996.
`
`TECHNICAL FIELD
`
`The present invention relates to a pharmaceutical prepa
`ration containing a substituted benZimidaZole. More
`particularly, the present invention relates to a substituted
`benZimidaZole solution/suspension suitable for oral admin
`istration.
`
`BACKGROUND OF THE INVENTION
`
`OmepraZole is a substituted benZimidaZole, 5-methoxy
`2-[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sul?nyl]
`1H-benZimidaZole, that inhibits gastric acid secretion. Ome
`praZole belongs to a class of antisecretory compounds, the
`substituted benZimidaZoles, that do not exhibit anti
`cholinergic or H2 histamine antagonist properties. Drugs of
`this class suppress gastric acid secretion by the speci?c
`inhibition of the H"/K+ ATPase enZyme system at the
`secretory surface of the gastric parietal cell.
`Typically, omepraZole in the form of a delayed-release
`capsule, is prescribed for short-term treatment of active
`duodenal ulcers, gastric ulcers, gastroesophageal re?ux dis
`ease (GERD), severe erosive esophagitis, poorly responsive
`systematic GERD, and pathological hypersecretory condi
`tions such as Zollinger Ellison syndrome. These conditions
`are caused by an imbalance betWeen acid and pepsin
`production, called aggressive factors, and mucous,
`bicarbonate, and prostaglandin production, called defensive
`factors.
`These above-listed conditions commonly arise in healthy
`or critically ill patients and may be accompanied by signi?
`cant upper gastrointestinal bleeding. H2 antagonists,
`antacids, and sucralfate are commonly administered to mini
`miZe the pain and the complications related to these condi
`tions. These drugs have certain disadvantages associated
`With their use. Some of these drugs are not completely
`effective in the treatment of the aforementioned conditions
`and/or produce adverse side effects, such as mental
`confusion, constipation, diarrhea, thrombocytopenia,
`(loWered platelet count) and/or are relatively costly modes
`of therapy as they require the use of automated infusion
`pumps for continuous intravenous delivery.
`Patients With signi?cant physiologic stress are at risk for
`stress-related gastric mucosal damage and subsequent upper
`gastrointestinal bleeding (Marrone and Silen, 1984). Risk
`factors that have been clearly associated With the develop
`ment of stress-related mucosal damage are mechanical
`ventilation, coagulopathy, extensive burns, head injury, and
`organ transplant (Zinner et al., 1981; Larson et al., 1984;
`CZaja et al., 1974; Skillman et al., 1969; and Cook et al.,
`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 identi?ed such
`as acid-base disorders, multiple trauma, signi?cant
`hypertension, major surgery, multiple operative procedures,
`acute renal failure, sepsis, and coma (Cook et al., 1994).
`Regardless of the risk type, stress-related mucosal damage
`results in signi?cant morbidity and mortality. Clinically
`signi?cant bleeding occurs in at least tWenty percent of
`patients With one or more risk factors Who are left untreated
`(Martin et al., 1993). Of those Who bleed, approximately ten
`percent require surgery (usually gastrectomy) With a
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
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`65
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`5,840,737
`
`2
`reported mortality of thirty percent to ?fty percent (CZaja et
`al., 1974; Peura and Johnson, 1985). Those Who do not need
`surgery often require multiple transfusions and prolonged
`hospitaliZation. Prevention of stress-related upper gas
`trointestinal bleeding is an important clinical goal.
`In addition to general supportive care, the use of drugs to
`prevent stress-related mucosal damage 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., 1993; Gafter et al., 1989;
`Martin et al., 1992). In tWo recent meta-analyses (Cook et
`al., 1991; Tryba, 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 ?fteen
`to tWenty percent of patients in Which they are employed
`because of failure to prevent bleeding, or control pH (Ostro
`et al., 1985; Siepler, 1986; Ballesteros et al., 1990), or
`because of adverse effects (Gafter et al., 1989; Sax, 1987;
`Vial et al., 1991; Cantu and Korek, 1991; Spychal and
`Wickham, 1985). In addition, the characteristics of an ideal
`agent for the prophylaxis of stress gastritis and concluded
`that none of the agents currently in use ful?ll their criteria
`(Smythe and ZaroWitZ, 1994).
`OmepraZole reduces gastric acid production by irrevers
`ibly inhibiting the H+/K+ ATPase of the parietal cell—the
`?nal common pathWay for gastric acid secretion (Fellenius
`et al., 1981; Wallmark et al., 1985; Frylund et al., 1988).
`Because this drug maintains gastric pH control throughout
`the dosing interval and has a very good safety pro?le, it is
`a logical choice for stress ulcer prophylaxis. The absence of
`an intravenous or oral liquid dosage form in the United
`States, hoWever, has limited the testing and use of omepra
`Zole in the critical care patient population. Subsequently,
`Barie et al (Barie and Hariri, 1992) 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.
`Stress ulcer prophylaxis has become routine therapy in
`intensive care units in most hospitals (Fabian et al, 1993.;
`Cook et al., 1991). Controversy remains regarding pharma
`cologic intervention to prevent stress-related bleeding in
`critical care patients. It has been suggested that the incidence
`and risk of gastrointestinal bleeding has decreased in the last
`ten years and drug therapy may no longer be needed (Cook
`et al., 1994; Tryba, 1994; Schepp, 1993). This reasoning is
`not supported by a recent placebo-controlled study. Martin
`et al. conducted a prospective, randomiZed, double-blind,
`placebo-controlled comparison of continuous-infusion
`cimetidine and placebo for the prophylaxis of stress-related
`mucosal damage (Marten et al., 1993). The study Was
`terminated early because of excessive bleeding-related mor
`tality in the placebo group. It appears that the natural course
`of stress-related mucosal damage in a patient at risk Who
`receives no prophylaxis remains signi?cant. In the placebo
`group, thirty-three percent of patients developed clinically
`signi?cant bleeding, nine percent required transfusion, and
`six percent died due to bleeding-related complications. In
`comparison, fourteen percent of cimetidine-treated patients
`developed clinically signi?cant bleeding, six percent
`required transfusions, and 1.5% died due to bleeding-related
`complication; the difference in bleeding rates betWeen treat
`ment groups Was statistically signi?cant. This study clearly
`demonstrated that continuous-infusion cimetidine reduced
`morbidity in critical care patients. Although, these data Were
`used to support the approval of continuous-infusion cime
`tidine by the Food and Drug Administration for stress ulcer
`
`

`
`3
`prophylaxis, H2-antagonists fall short of being the optimal
`pharmacotherapeutic agents for preventing of stress-related
`mucosal bleeding.
`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 dam
`age. An ideal drug in this setting should possess the folloW
`ing characteristics: prevent stress ulcers and their
`complications, be devoid of toxicity, lack drug interactions,
`be selective, have minimal associated costs (such as person
`nel time and materials), and be easy to administer (Smythe
`and ZaroWitZ, 1994).
`Some have suggested that sucralfate is possibly the ideal
`agent for stress ulcer prophylaxis (Smythe and ZaroWitZ,
`1994). Randomized, controlled studies support the use of
`sucralfate (Borrero et al., 1986; Tryba, 1987; Ciof? et al.,
`1994; Driks et al., 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 ant
`acids for stress ulcer prophylaxis reported clinically signi?
`cant bleeding in three of forty-eight (6%) sucralfate-treated
`patients, one of Whom required a gastrectomy (Ciof? et al.,
`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., 1987).
`H2-antagonists ful?ll many of the criteria for an ideal
`stress ulcer prophylaxis drug. Yet, clinically signi?cant
`bleeds can occur during H2-antagonist prophylaxis (Martin
`et al., 1993; Cook et al., 1991; Schuman et al., 1987) and
`adverse events are not uncommon in the critical care popu
`lation (Gafter et al., 1989; Sax, 1987, Vial et al., 1991; Cantu
`and Korek, 1991; Spychal and Wickham, 1985). One reason
`proposed for the therapeutic H2-antagonist failures is lack of
`pH control throughout the treatment period (Ostro et al.,
`1985). Although the precise pathophysiologic mechanism(s)
`involved in stress ulceration are not clearly established, the
`high concentration of hydrogen ions in the mucosa (Fiddian
`Green et al., 1987) or gastric ?uid 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., 1984; Skillman
`et al., 1969; Skillman et al., 1970; Priebe and Skillman,
`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 ?xed-dose bolus regi
`mens (Ostro, 1985; Siepler, 1986; Ballesteros et al., 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., 1985 ;
`Wilder-Smith and Merki, 1992).
`Because stress ulcer prophylaxis is frequently employed
`in the intensive care unit, it is essential from both a clinical
`and economic standpoint to optimiZe the pharmacotherapeu
`tic approach. In an attempt to identify optimal therapy, cost
`of care becomes an issue. All treatment costs should be
`considered, including the costs of treatment failures and
`drug-related adverse events. While the actual number of
`failures resulting in mortality is loW, morbidity (e.g., bleed
`ing that requires blood transfusion) can be high, even though
`its association With the failure of a speci?c drug is often
`unrecogniZed.
`OmepraZole represents an advantageous alternative to the
`use of H2 antagonists, antacids, and sucralfate as a treatment
`
`10
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`15
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`20
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`25
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`30
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`35
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`40
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`5,840,737
`
`4
`for complications related to stress-related mucosal damage.
`HoWever, in its current form (capsules containing an enteric
`coated granule formulation of omepraZole), omepraZole can
`be dif?cult or impossible to administer to patients Who are
`unable (critically ill patients, children, elderly, patients suf
`fering from dysphagia) or patients Who are either unWilling
`or unable to sWalloW tablets or capsules. Therefore, it Would
`be desirable to formulate an omepraZole solution Which can
`be enterally delivered to a patient thereby providing the
`bene?ts of omepraZole Without the draWbacks of the current
`capsule dose form.
`OmepraZole has been formulated in many different
`embodiments such as in a mixture of polyethylene glycols
`formed a mixture of adeps solidus and sodium lauryl sulfate
`in a soluble, basic amino acid to yield a formulation
`designed for administration in the rectum as shoWn in US.
`Pat. No. 5,219,870 to Kim. US. Pat No. 5,395,323 to
`Berglund (’323) discloses a device for mixing a pharma
`ceutical from a solid supply into a parenterally acceptable
`liquid form for parenteral administration to a patient. The
`’323 patent teaches the use of an omepraZole tablet Which is
`placed in the device and dissolved by normal saline, and
`infused into the patient. This device and method of infusing
`omepraZole does not provide the omepraZole solution as an
`enteral product nor is this omepraZole solution directly
`administered to the diseased or affected areas, namely the
`stomach and upper gastrointestinal tract, nor does this ome
`praZole formulation provide the immediate anti-acid effect
`of the present formulation.
`US. Pat. No. 4,786,505 to Lovgren et al., discloses a
`pharmaceutical preparation containing omepraZole together
`With an alkaline reacting compound or an alkaline salt of
`omepraZole optionally together With an alkaline compound
`as a core material in a tablet formulation. The use of the
`alkaline material, Which can be chosen from such substances
`as the sodium salt of carbonic acid, are used to form a
`“micro-pH” around each omepraZole particle to protect the
`omepraZole Which is highly sensitive to acid pH. The
`poWder mixture is then formulated to small beads, pellets,
`tablets and may be loaded into capsules by conventional
`pharmaceutical procedures.
`This formulation of omepraZole does not provide an
`omepraZole dose form Which can be enterally administered
`to a patient Who may be unable and/or unWilling to sWalloW
`capsules or pellets nor does it teach a convenient form Which
`can be used to make an omepraZole solution.
`Several buffered omepraZole solutions have been dis
`closed. Andersson et al., 1993; Landahl et al., 1992; Ander
`sson et al., 1990; Regardh et al., 1990; Andersson et al.,
`1990; Pilbrant et al., 1985.
`All of the buffered omepraZole solutions described in
`these references Were administered orally and Were given to
`healthy subjects Who Were able to ingest the oral dose. In all
`of these studies, omepraZole Was suspended in a solution
`including sodium bicarbonate, as a pH buffer, in order to
`protect the acid sensitive omepraZole during administration.
`In all of these studies, repeated administration of sodium
`bicarbonate both prior to, during, and folloWing omepraZole
`administration Were required in order to prevent acid deg
`radation of the omepraZole given via the oral route of
`administration. As a result, the ingestion of the large
`amounts of sodium bicarbonate and large volumes of Water
`Were required. In the above-cited studies, as much as 48
`mmoles of sodium bicarbonate in 300 ml of Water must be
`ingested for a single dose of omepraZole to be orally
`administered.
`
`

`
`5,840,737
`
`5
`Initial reports of increased frequency of pneumonia in
`patients receiving stress ulcer prophylaxis With agents that
`raise gastric pH has in?uenced the pharmacotherapeutic
`approach to management of critical care patients. HoWever,
`several recent studies (Simms et al., 1991; PickWorth et al.,
`1993; Ryan et al., 1993; Fabian et al., 1993), a meta-analysis
`(Cook et al., 1991), and a closer examination of the studies
`that initiated the elevated pH-associated pneumonia hypoth
`eses (Schepp, 1993) cast doubt on a causal relationship. The
`relationship betWeen pneumonia and antacid therapy is
`much stronger than for H2-antagonists. The shared effect of
`antacids and H2-antagonists on gastric pH seems an irre
`sistible common cause explanation for nosocomial pneumo
`nia observed during stress ulcer prophylaxis. HoWever, there
`are important differences betWeen these agents that are not
`often emphasiZed (Laggner et al., 1989). When antacids are
`exclusively used to control pH in the prophylaxis of stress
`related upper gastrointestinal bleeding, large volumes are
`needed. Volume, With or Without subsequent re?ux, may be
`the underlying mechanism(s) promoting the development of
`pneumonia in susceptible patient populations rather than the
`increased gastric pH. The rate of pneumonia in our study
`(12%) Was not unexpected in this critical care population
`and compares With sucralfate, Which does not signi?cantly
`raise gastric pH (PickWorth et al., 1993; Ryan et al., 1993).
`The buffered omepraZole solutions of the above cited
`prior art require large amounts of sodium bicarbonate to be
`given by repeated administration. This is necessary to pre
`vent acid degradation of the omepraZole. The administration
`of large amounts of sodium bicarbonate can produce at least
`four signi?cant adverse effects Which can dramatically
`reduce the efficacy of the omepraZole in patients and reduce
`the overall health of the patients. In the above-cited studies,
`basically healthy volunteers rather than sick patients Were
`given only one or tWo dosages of omepraZole utiliZing
`pre-dosing and post-dosing With large volumes of sodium
`bicarbonate. This dosing protocol Would not be suitable for
`sick or critically ill patients Who must receive multiple doses
`of omepraZole.
`Since bicarbonate is usually neutraliZed in the stomach or
`is absorbed, such that belching results, patients With gas
`troesophageal re?ux may exacerbate or Worsen their gas
`troesophageal re?ux disease as the belching can cause
`upWard movement of stomach acid (Brunton, 1990).
`Patients With conditions, such as hypertension or heart
`failure, are standardly advised to avoid the intake of exces
`sive sodium as this can cause aggravation or exacerbation of
`their hypertensive conditions (Brunton, 1990).
`Additionally, patients With numerous conditions Which
`typically accompany critical illness should avoid the intake
`of excessive sodium bicarbonate as it can cause metabolic
`alkalosis Which can result in a serious Worsening of the
`patient’s condition. Furthermore, excessive antacid intake
`(such as sodium bicarbonate) can result in drug interactions
`Which produce serious adverse effects. For example, by
`altering gastric and urinary pH, antacids can alter rates of
`drug dissolution and absorption, bioavailability, and renal
`elimination (Brunton, 1990).
`Since buffered omepraZole solution requires prolonged
`administration of the antacid, sodium bicarbonate, it makes
`it dif?cult for patients to comply With the above recommen
`dation.
`In addition to the disadvantages associated With excessive
`intake of sodium bicarbonate, the above-cited prior art
`teaches a relatively complex regimen for the oral adminis
`tration of omepraZole. For example, in the Pilbrant et al.
`
`10
`
`15
`
`25
`
`35
`
`45
`
`55
`
`65
`
`6
`(1985) reference, the oral omepraZole administration proto
`col calls for administering 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 Which 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, it is unlikely
`that a healthy patient Would comply With this regimen for
`each dose of omepraZole over the course of a prescribed
`omepraZole protocol. It is unlikely or even improbable that
`a critically ill patient Would be able to comply With this
`regimen.
`Even in healthy patients, the complexity of the drug
`regimen leads to the conclusion that patients Would be
`unlikely to comply With this regimen thereby leading to a
`lack of bene?cial outcome for the patient. It is Well docu
`mented that patients Who are required to folloW complex
`schedules for drug administration are non-compliant and,
`thus, the ef?cacy of the buffered omepraZole solutions of the
`prior art Would be expected to be reduced due to non
`compliance. Compliance has been found to be markedly
`reduced When patients are required to deviate from a sched
`ule of one or tWo (usually morning and night) doses of a
`medication per day. The use of the prior art buffered ome
`praZole solutions Which require administration protocols
`With numerous steps, different drugs (sodium bicarbonate+
`omepraZole+PEG400 versus sodium bicarbonate alone), and
`speci?c time allotments betWeen each stage of the total
`omepraZole regimen in order to achieve ef?c