WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 7 =
`
`(11) International Publication Number:
`
`WO 00/26185
`
`C07D
`
`A2
`
`_
`_
`_
`(43) International Publication Date:
`
`11 May 2000 (I 1.05.00)
`
`(21) International Application Number:
`
`PCT/US99/25592
`
`(22) International Filing Date:
`
`29 October 1999 (29.l0.99)
`
`(30) Priority Data;
`09/183,422
`
`30 October 1998 (30.l0.98)
`
`US
`
`(71) Applicant: THE CURATORS OF THE UNIVERSITY OF
`MISSOURI
`[US/US]; 509 Lewis Hall, Columbia, MO
`65211 (US).
`
`(72) Inventor: PHILLIPS, Jeffrey, 0.; 4919 Millbrook Boulevard,
`Columbia, MO 65203 (US).
`
`(74) Agents: MAHONEY, Joseph, A. et al.; Sonnenschein Nath
`& Rosenthal, 8000 Sears Tower, 233 S. Wacker Drive,
`Chicago, IL 60606£404 (US).
`
`(81) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG,
`BR, BY, CA, CH, CN, CU, CZ, DE, DK, DM, EE, ES, Fl,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD,
`SE, SG, SI, SK, SL, TJ, TM, TR, TI‘, TZ, UA, UG, UZ,
`VN, YU, ZA, ZW, ARIPO patent (GH, GM, KE, LS, MW,
`SD, SL, SZ, TZ, UG, ZW), Eurasian patent (AM, AZ, BY,
`KG, KZ, MD, RU, TJ, TM), European patent (AT, BE, CH,
`CY, DE, DK, ES, FI, FR, GB, GR, IE, IT. LU» MC. NL.
`PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN,
`GW, ML, MR, NE, SN, TD, TG).
`
`Published
`Without international search report and to be republished
`upon receipt of that report.
`
`(54) Title: OMEPRAZOLE SOLUTION AND METHOD OF USING SAME
`
`©"‘l\3£0-hChO:\I®©
`
`GASTRIC pH
`prc SOS
`3.5i:l.9
`
`pH 4 in ma pit
`post 303
`post SOS
`7.lil.1
`6.8i0.6
`
`’ mi/ssr ,;i;
`post SOS
`5611.3
`
`(57) Abstract
`
`A method of treating gastric acid disorders by administering to a patient a pharmaceutical composition including a proton pump
`inhibitor in a pharmaceutically acceptable carrier including a bicarbonate salt of a Group IA metal where the administering step consists of
`a single dosage form without requiring further administering of the bicarbonate salt of the Group IA metal. A pharmaceutical composition
`includes a dry formulation of a proton pump inhibitor in a pharmaceutically acceptable carrier including a bicarbonate salt of a Group IA
`metal. A pharmaceutical composition for making a dry formulation of a proton pump inhibitor which includes a proton pump inhibitor and
`a bicarbonate salt of a Group IA metal in a form for convenient storage, whereby when the composition is in a dry formulation which is
`suitable for enteral administration.
`
`Lupin Exh. 1015
`
`

`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cote d’Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`SZ
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`US
`UZ
`VN
`YU
`ZW
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`

`
`W0 00/26185
`
`PCT/US99/25592
`
`OMEPRAZOLE SOLUTION AND METHOD OF USING SAME
`
`This application is a continuation—in—part of United
`
`States Serial Number 08/680,376 filed on January 4, 1996.
`
`TECHNICAL FIELD
`
`5
`
`The present
`
`invention relates
`
`to a pharmaceutical
`
`preparation. containing a substituted benzimidazole, more
`
`specifically known as proton pump inhibitor(s)
`
`(ppi). More
`
`particularly,
`
`the
`
`present
`
`invention
`
`relates
`
`to
`
`a
`
`substituted benzimidazole solution/suspension suitable for
`
`10
`
`oral administration.
`
`BACKGROUND OF THE INVENTION
`
`Omeprazole is a substituted benzimidazole,
`
`5—methoxy—
`
`2—[
`
`(4—methoxy—3,5—dimethyl—2—pyridinyl) methyl] sulfinyl]~
`
`lH—benzimidazole,
`
`that
`
`inhibits gastric acid secretion.
`
`15 Omeprazole belongs to a class of antisecretory compounds,
`
`the proton pump
`
`inhibitor
`
`that
`
`do not
`
`exhibit
`
`anti-
`
`cholinergic or H2 histamine antagonist properties.
`
`Drugs
`
`of
`
`this class
`
`suppress gastric acid secretion by
`
`the
`
`specific
`
`inhibition of
`
`the HUG? ATPase
`
`enzyme
`
`system
`
`20
`
`(proton pump)
`
`at
`
`the secretory surface of
`
`the gastric
`
`parietal cell.
`
`Typically, omeprazole and lansoprazole or other proton
`
`pump inhibitors in the form of a delayed—release capsule,
`
`is prescribed for short—term treatment of active duodenal
`
`25
`
`ulcers, gastric ulcers,
`
`gastroesophageal
`
`reflux disease
`
`(GERD),
`
`severe
`
`erosive
`
`esophagitis,
`
`poorly
`
`responsive
`
`systematic GERD, and pathological hypersecretory conditions
`
`such as Zollinger Ellison syndrome.
`
`These conditions are
`
`

`
`WO 00/26185
`
`PCT/US99/25592
`
`_
`
`2
`
`_
`
`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
`
`significant
`
`upper gastrointestinal
`
`bleeding.
`
`H2
`
`antagonists,
`
`antacids,
`
`and
`
`sucralfate
`
`are
`
`commonly
`
`administered.
`
`to Ininimize the pain and the complications
`
`related.
`
`to these conditions.
`
`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 significant 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 development 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
`
`10
`
`15
`
`20
`
`25
`
`

`
`W0 00/26185
`
`PCT/US99/25592
`
`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., 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.,
`
`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.,
`
`1974; Peura. and Johnson,
`
`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
`
`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
`
`}g—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.,
`
`10
`
`15
`
`20
`
`25
`
`

`
`WO 00/26185
`
`PCT/US99/25592
`
`_ 4
`
`_
`
`1985; Siepler, 1986; Ballesteros et al., 1990), or because
`
`of adverse effects (Gafter et al., 1989; Sax,
`
`l987;
`
`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 fulfill their criteria
`
`(Smythe and Zarowitz, 1994).
`
`10
`
`15
`
`20
`
`Omeprazole and lansoprazole and the other proton pump
`
`inhibitors reduce gastric acid production by irreversibly
`
`inhibiting the H+/K+ ATPase of
`
`the parietal cell
`
`—
`
`the
`
`final 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 profile,
`
`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
`
`omeprazole
`
`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
`
`25
`
`intensive care units
`
`in most hospitals
`
`(Fabian et al,
`
`1993.; Cook et al., 1991).
`
`Controversy remains regarding
`
`pharmacologic
`
`intervention
`
`to
`
`prevent
`
`stress—related
`
`bleeding in critical care patients.
`
`It has been suggested
`
`

`
`WO 00/26185
`
`PCT/US99/25592
`
`_ 5
`
`_
`
`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 mortality 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
`
`significant.
`
`In
`
`the
`
`placebo group,
`
`thirty—three percent of patients developed
`
`clinically significant bleeding,
`
`nine percent
`
`required
`
`transfusion,
`
`and six percent died due to bleeding—related
`
`complications.
`
`In
`
`comparison,
`
`fourteen
`
`percent
`
`of
`
`cimetidine—treated
`
`patients
`
`developed
`
`clinically
`
`significant bleeding,
`
`six percent
`
`required transfusions,
`
`and.
`
`1.5% died. due
`
`to bleeding—related complication;
`
`the
`
`difference in bleeding rates between treatment groups was
`
`statistically significant. 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 cimetidine by
`
`the
`
`Food
`
`and Drug Administration
`
`for
`
`stress
`
`ulcer
`
`prophylaxis, }g—antagonists fall short of being the optimal
`
`pharmacotherapeutic agents for preventing of stress—related
`
`mucosal bleeding.
`
`10
`
`15
`
`20
`
`25
`
`

`
`WO 00/26185
`
`PCT/US99/25592
`
`_ 6 _
`
`Another
`
`controversy
`
`surrounding
`
`stress
`
`ulcer
`
`prophylaxis
`
`is which drug to use.
`
`In addition.
`
`to the
`
`various }g—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 Ininimal associated
`
`costs (such as personnel
`
`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;
`
`Cioffi 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 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., 1994).
`
`In
`
`the study performed by Driks and coworkers
`
`that compared
`
`sucralfate
`
`to
`
`conventional
`
`therapy
`
`Gg—antagonists,
`
`antacids,
`
`or
`
`}g—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).
`
`10
`
`15
`
`20
`
`25
`
`

`
`WO 00/26185
`
`PCT/US99/25592
`
`_'7_
`
`H2—antagonists fulfill many" of
`
`the criteria for
`
`an
`
`ideal
`
`stress ulcer prophylaxis drug.
`
`Yet,
`
`clinically
`
`significant
`
`bleeds
`
`can
`
`occur
`
`during
`
`}g—antagonist
`
`prophylaxis
`
`(Martin et al.,
`
`1993; Cook et al.,
`
`1991;
`
`Schuman et al., 1987)
`
`and adverse events are not uncommon
`
`in the critical care population (Gafter et al., 1989; Sax,
`
`1987, Vial et al., 1991; Cantu and Korek, 1991; Spychal and
`
`Wickham, 1985).
`
`One
`
`reason proposed for the therapeutic
`
`}g—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. ,
`
`l987) 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., 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 fixed—dose bolus regimens
`
`(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
`
`Ig—antagonists,
`
`which. may be
`
`the
`
`result of
`
`tachyphylaxis
`
`(Ostro et al., 1985; Wilder—Smith
`
`and Merki, 1992).
`
`10
`
`15
`
`20
`
`25
`
`

`
`W0 00/26185
`
`PCT/US99/25592
`
`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
`
`pharmacotherapeutic 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.,
`
`bleeding that
`
`requires blood
`
`transfusion) can be high, even though its association with
`
`the failure of a specific drug is often unrecognized.
`
`Proton pump inhibitors such as omeprazole represent an
`
`advantageous alternative to the use of
`
`H2 antagonists,
`
`antacids,
`
`and sucralfate as a treatment
`
`for complications
`
`related to stress—related mucosal
`
`damage.
`
`However,
`
`in
`
`their current
`
`form (capsules containing an enteric—coated
`
`granule formulation of proton pump inhibitor), proton pump
`
`inhibitors can be difficult or impossible to administer to
`
`patients who are unable (critically ill patients, children,
`
`elderly, patients suffering from dysphagia) or patients who
`
`are
`
`either unwilling or
`
`unable
`
`to
`
`swallow tablets or
`
`capsules.
`
`Therefore,
`
`it would be desirable to formulate a
`
`proton pump inhibitor solution or suspension which can be
`
`enterally delivered.
`
`to a patient
`
`thereby providing the
`
`benefits of the proton pump inhibitor without the drawbacks
`
`of the current capsule dose form.
`
`Omeprazole,
`
`the first proton pump inhibitor introduced
`
`into use, has been formulated in many different embodiments
`
`10
`
`15
`
`20
`
`25
`
`

`
`WO 00/26185
`
`PCT/US99/25592
`
`-9-
`
`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 United States
`
`Patent No. 5,219,870 to Kim.
`
`United States Patent No. 5,395,323 to Berglund ('323)
`
`discloses a device for mixing a pharmaceutical
`
`from a solid
`
`supply into a parenterally acceptable
`
`liquid form for
`
`parenteral administration.tx3 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
`
`omeprazole
`
`formulation provide
`
`the
`
`immediate
`
`anti—acid
`
`effect of the present formulation.
`
`United States Patent 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
`
`10
`
`15
`
`20
`
`formulation.
`
`The use of
`
`the alkaline material, which can
`
`25
`
`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
`
`

`
`WO 00/26185
`
`PCTHJS99/25592
`
`_ 10 _
`
`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 or other proton
`
`pump inhibitor solution or suspension.
`
`10
`
`Several
`
`buffered
`
`omeprazole
`
`solutions
`
`have
`
`been
`
`disclosed. Andersson et al., 1993; Landahl et al., 1992;
`
`Andersson et al., 1990; Regardh et al., 1990; Andersson et
`
`al., 1990; Pilbrant et al., 1985.
`
`All of the buffered omeprazole solutions described in
`
`15
`
`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
`
`20
`
`administration.
`
`In all of
`
`these studies,
`
`repeated administration of
`
`sodiunl bicarbonate both prior
`
`to, during,
`
`and following
`
`omeprazole administration were required in order to prevent
`
`acid degradation of the omeprazole given via the oral route
`
`25
`
`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
`
`

`
`WO 00/26185
`
`PCT/US99/25592
`
`-11-
`
`mmoles of
`
`sodium bicarbonate in 300 ml of water must be
`
`ingested.
`
`for
`
`a
`
`single dose of omeprazole
`
`to be orally
`
`administered.
`
`Initial reports of increased frequency of pneumonia in
`
`patients receiving stress ulcer prophylaxis with. agents
`
`that
`
`raise
`
`gastric
`
`pH
`
`has
`
`influenced
`
`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 hypotheses
`
`(Schepp, 1993)
`
`cast doubt
`
`on.
`
`a causal
`
`relationship.
`
`The
`
`relationship
`
`between pneumonia and antacid therapy is much stronger than
`
`for }g—antagonists.
`
`The shared effect of antacids and H2-
`
`antagonists
`
`on gastric pH seems
`
`an irresistible common
`
`cause explanation for nosocomial pneumonia 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
`
`reflux, may be the underlying nechanism(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,
`
`10
`
`15
`
`20
`
`25
`
`

`
`WO 00/26185
`
`PCT/US99/25592
`
`-12-
`
`which does not significantly raise gastric pH (Pickworth et
`
`al .v, 1993; Ryan et al., 1993).
`
`The buffered omeprazole solutions of
`
`the above cited
`
`prior art require large amounts of sodium bicarbonate to be
`
`given kn!
`
`repeated administration.
`
`This
`
`is necessary to
`
`prevent
`
`acid.
`
`degradation.
`
`of
`
`the
`
`omeprazole.
`
`The
`
`administration of
`
`large amounts of
`
`sodium bicarbonate can
`
`produce at least four significant adverse effects which can
`
`dramatically reduce
`
`the efficacy of
`
`the omeprazole
`
`patients and reduce the overall health of the patients.
`
`in
`
`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
`
`sodiun1 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. gastroesophageal
`
`reflux may exacerbate or
`
`worsen
`
`their
`
`gastroesophageal
`
`reflux 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
`
`excessive
`
`sodium as
`
`this
`
`can cause
`
`aggravation or
`
`exacerbation of
`
`their hypertensive conditions
`
`(Brunton,
`
`1990).
`
`10
`
`15
`
`20
`
`25
`
`

`
`WO 00/26185
`
`PCT/US99/25592
`
`_
`
`_
`
`Additionally, patients with numerous conditions which
`
`typically accompany critical
`
`illness
`
`should avoid the
`
`intake of excessive sodiuw1 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
`
`sodiunx 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 difficult
`
`for patients
`
`to comply with
`
`the
`
`above
`
`recommendation.
`
`In addition to the disadvantages
`
`associated with
`
`excessive intake of
`
`sodiunt bicarbonate,
`
`the above—cited
`
`prior art teaches a relatively complex regimen for the oral
`
`administration of omeprazole.
`
`For example,
`
`in the Pilbrant
`
`et al.
`
`(1985)
`
`reference,
`
`the oral omeprazole administration
`
`protocol 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
`
`LII
`
`10
`
`15
`
`20
`
`25
`
`

`
`W0 00/26135
`
`PCT/US99/25592
`
`_l4_
`
`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 gmescribed
`
`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 beneficial outcome for the patient.
`
`It
`
`is well
`
`documented that patients who are required to follow complex
`
`schedules
`
`for drug administration. are non-compliant and,
`
`thus,
`
`the efficacy 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
`
`schedule of one or two (usually morning and night) doses of
`
`a medication per day.
`
`The use of
`
`the prior art buffered
`
`omeprazole solutions which require administration protocols
`
`with numerous steps, different drugs
`
`(sodium bicarbonate +
`
`omeprazole + PEG4OO versus sodium bicarbonate alone),
`
`and
`
`specific time allotments between each stage of
`
`the total
`
`omeprazole regimen in order to achieve efficacious results
`
`10
`
`15
`
`20
`
`25
`
`

`
`WO 00/26185
`
`PCT/US99/25592
`
`-15..
`
`is clearly in contrast with both current drug compliance
`
`theories and human nature.
`
`The prior art
`
`(Pilbrant et al., 1985)
`
`teaches that the
`
`buffered
`
`omeprazole
`
`suspension
`
`can
`
`be
`
`stored
`
`at
`
`refrigerator temperatures for a week and deep frozen for a
`
`year while still maintaining 99% of their initial potency.
`
`It would be desirable to have an omeprazole or other proton
`
`pump inhibitor solution or suspension which could be stored
`
`at
`
`room temperature or
`
`i11 a refrigerator for periods of
`
`10
`
`time which exceed those of
`
`the prior art while still
`
`maintaining 99% of
`
`the initial potency. Additionally,
`
`it
`
`would be advantageous to have a form of the omeprazole and
`
`bicarbonate which.
`
`can. be utilized.
`
`to instantly‘ make
`
`the
`
`omeprazole
`
`solution/suspension of
`
`the present
`
`invention
`
`which
`
`is
`
`supplied in a
`
`solid form which
`
`imparts
`
`the
`
`advantages of
`
`improved shelf—life at
`
`room temperature,
`
`lower cost
`
`to produce,
`
`less expensive shipping costs,
`
`and
`
`which is less expensive to store.
`
`The present
`
`invention provides a solution/suspension
`
`of proton pump inhibitors such as omeprazole,
`
`lansoprazole
`
`or other proton pump inhibitor (pantoprazole,
`
`rabeprazole,
`
`dontoprazole, habeprozole, perprazole or other proton pump
`
`inhibitor) which
`
`is
`
`suitable
`
`for
`
`administration which
`
`includes all of the aforementioned advantages.
`
`It would,
`
`therefore, be desirable to have an proton
`
`pump inhibitor formulation which provides a cost effective
`
`means
`
`for the treatment of
`
`the aforementioned conditions
`
`15
`
`20
`
`25
`
`

`
`WO 00/26185
`
`PCT/US99/25592
`
`_l6_
`
`without
`
`the
`
`adverse
`
`’effect
`
`profile
`
`of
`
`H2
`
`receptor
`
`antagonist, antacids, and sucralfate. Further, it would be
`
`desirable to have a proton pump inhibitor formulation which
`
`is convenient
`
`to prepare and administer to patients unable
`
`to ingest capsules, which is rapidly absorbed,
`
`can be
`
`orally cn: enterally delivered as
`
`ea
`
`liquid form cm: solid
`
`form which becomes
`
`a
`
`liquid in the stomach or upper GI
`
`tract
`
`(the desired treatment
`
`regimen.).
`
`It
`
`is desirable
`
`that the liquid formulation not clog indwelling tubes, such
`
`as nasogastric tubes or other similar tubes, and which acts
`
`as an antacid immediately upon delivery.
`
`Furthermore,
`
`it
`
`would be desirable to have a pharmaceutical composition
`
`which
`
`is highly efficacious
`
`for
`
`the
`
`treatment
`
`of
`
`the
`
`aforementioned conditions.
`
`SUMMARY OF THE INVENTION AND ADVANTAGES
`
`In. accordance with.
`
`the present
`
`invention,
`
`there is
`
`provided a method of
`
`treating gastric acid disorders by
`
`administering to a patient
`
`a pharmaceutical
`
`composition
`
`including a proton. pump
`
`inhibitor
`
`in a pharmaceutically
`
`acceptable carrier including a bicarbonate salt of a Group
`
`IA metal where the administering step consists of a single
`
`dosage form without requiring further administering of the
`
`bicarbonate salt of the Group IA metal.
`
`The
`
`present
`
`invention
`
`further
`
`provides
`
`a
`
`pharmaceutical composition includes a dry formulation of a
`
`proton pump
`
`inhibitor
`
`in.
`
`a pharmaceutically acceptable
`
`carrier including a bicarbonate salt of a Group IA metal.
`
`10
`
`15
`
`20
`
`25
`
`

`
`WO 00/26185
`
`PCT/US99/25592
`
`-17..
`
`The
`
`present
`
`invention
`
`further
`
`provides
`
`a
`
`phannaceutical composition for making a dry formulation of
`
`a proton pump
`
`inhibitor
`
`which
`
`includes
`
`a proton pump
`
`inhibitor and a bicarbonate salt of a Group IA metal
`
`in a
`
`form for convenient storage, whereby the composition is in
`
`a
`
`dry
`
`formulation which
`
`is
`
`suitable
`
`for
`
`enteral
`
`administration.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Other advantages of
`
`the present
`
`invention. will
`
`be
`
`readily appreciated as the same becomes better understood
`
`by"
`
`reference to the following detailed. description. when
`
`considered in connection with the
`
`accompanying drawing
`
`wherein:
`
`Figure
`
`l
`
`is
`
`a
`
`graph
`
`showing
`
`the
`
`effect
`
`of
`
`the
`
`omeprazole solution/suspension of
`
`the present
`
`invention on
`
`gastric pH in patients at risk for upper gastrointestinal
`
`bleeding from stress—related mucosal damage;
`
`Figure
`
`2
`
`is
`
`a
`
`flow chart
`
`illustrating a patient
`
`enrollment scheme;
`
`Figure 3
`
`is a bar graph illustrating gastric pH both
`
`pre—
`
`and
`
`post—administration
`
`of
`
`omeprazole
`
`solution/suspension according to the present
`
`invention; and
`
`10
`
`15
`
`20
`
`Figure 4 is a graph illustrating the stomach pH values
`
`of both. chocolate plus
`
`lansoprazole in. powder
`
`form and
`
`25
`
`lansoprazole alone.
`
`

`
`WO 00/26185
`
`PCT/US99/25592
`
`_ 18 _
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`A. pharmaceutical
`
`composition which can include
`
`an
`
`aqueous solution/suspension, or dry formulation, of proton
`
`pump inhibitors,
`
`such as omeprazole or other substituted
`
`benzimidazoles which. are proton. pump
`
`inhibitors such as
`
`lansoprazole,
`
`pantoprazole,
`
`rabeprazole,
`
`dontroprazole,
`
`perprazole,
`
`habeprazole,
`
`and derivatives
`
`thereof
`
`in a
`
`pharmaceutically acceptable carrier including a bicarbonate
`
`salt of a Group IA metal is disclosed.
`
`For the purposes of
`
`description,
`
`the
`
`composition includes dry formulations,
`
`solutions and/or
`
`suspensions of
`
`the omeprazole or other
`
`proton pump inhibitors.
`
`Hereinafter,
`
`the use of
`
`the term
`
`“solution”
`
`includes
`
`solutions and/or
`
`suspensions of
`
`the
`
`substituted benzimidazoles.
`
`The
`
`pharmaceutical
`
`composition
`
`of
`
`the
`
`present
`
`invention is prepared by mixing omeprazole
`
`(Merck & Co.
`
`Inc., West Point,
`
`PA) or other proton pump inhibitors or
`
`derivatives thereof with a solution including a bicarbonate
`
`salt of a Group IA metal.
`
`Preferably, omeprazole or other
`
`proton pump
`
`inhibitor‘ powder or granules, which can be
`
`obtained
`
`from a
`
`capsule,
`
`are mixed with
`
`a
`
`sodium
`
`bicarbonate solution to achieve a desired final omeprazole
`
`concentration.
`
`As
`
`an
`
`example,
`
`the
`
`concentration of
`
`omeprazole
`
`in
`
`the
`
`solution/suspension can
`
`range
`
`from
`
`approximately 0.5 mg/ml
`
`to approximately 6.0 mg/ml.
`
`The
`
`preferred
`
`concentration
`
`for
`
`the
`
`omeprazole
`
`in
`
`the
`
`solution/suspension ranges from approximately 1.0 mg/ml
`
`to
`
`10
`
`15
`
`20
`
`25
`
`

`
`WO 00/26185
`
`PCT