Ulllted States Patent [19]
`Lindberg et al.
`
`US005877192A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,877,192
`*Mar. 2, 1999
`
`[54] METHOD FOR THE TREATMENT OF
`GASTRIC ACID-RELATED DISEASES AND
`PRODUCTION OF MEDICATION USING (-)
`ENANTIOMER OF OMEPRAZOLE
`
`[75] Inventors: Per Lindberg, Molndal; Lars Weidolf,
`Vastra Frolunda, both of Sweden
`
`[73] Assignee: Astra Aktlebolag, SodertaIJe, Sweden
`[ * ]
`Notice:
`The term of this patent shall not extend
`beyond the expiration date of Pat. No.
`5,714,504.
`
`[21] AppL NO‘: 833,962
`
`[22]
`
`Filed:
`
`Apr. 11, 1997
`
`[63]
`
`Related U-S- APPIiCZItiOII Data
`_
`_
`_
`C°nt1nuat1°n'1n'PaT_t°f_SeT~ NO- _376,§12,_Jan- 23, 1995, Pat
`No. 5,714,504, which is a continuation-m-part of Ser. No.
`256,174, Jun. 28, 1994, Pat. NO. 5,693,818.
`FOI‘EigIl APPIiCHtiOII PI‘iOI‘itY Data
`[30]
`9301830
`Ma 28 1993 [SE]
`Sweden
`Api]. 11’ 1996 [SE]
`Sweden 2:111:33:11:11:: 9601383
`
`[52] US. Cl. ......................... .. 514/338; 514/819; 514/927
`[58] Field of Search ................................... .. 514/338, 819,
`514/927
`
`[56]
`
`References Cited
`
`U'S' PATENT DOCUMENTS
`
`5,714,504
`2/1998 Linberg et al. ....................... .. 514/338
`Primary Examiner
`.mberly Jordan
`Attorney’ Agent’ Or F ir m—White & Case LLP
`[57]
`ABSTRACT
`
`A method for treatment of gastric acid related diseases by
`inhibition of gastric acid secretion comprising administering
`to a mammal in need of treatment a therapeutically effective
`amount of the (—)-enantiomer of 5-methoXy-2-[[(4
`methoXy-3,5-dimethyl-2-pyridinyl)methyl]sul?nyl]-1E
`benZimidaZole or a pharmaceutically acceptable salt thereof,
`so as to effect decreased interindividual variation in plasma
`levels upon administration. The use of the (—)-enantiomer of
`omeprazole to receive increased average plasma levels
`.
`.
`.
`(AUC) upon administration of the same doses of the (—)
`enantiomer of omepraZole compared to those of racemic
`omepraZole is also claimed, as Well as an improved anti
`Secretory effect and a better Clinical effect
`
`[51] Int. Cl.6 ................................................... .. A61K 31/44
`
`23 Claims, 3 Drawing Sheets
`
`Lupin Exh. 1008
`
`

`
`U.S. Patent
`
`Mar. 2, 1999
`
`Sheet 1 of3
`
`5,877,192
`
`I500 -
`
`O O O 5
`O O O
`
`_ _ O
`
`3%5588
`
`l2000
`3 I0000
`8000
`6000
`4000
`2000
`
`\ BESoeoQ
`
`m
`m MD.
`D. Om
`f 0
`W mm 0
`Z .wm 4
`
`+ + 3
`
`O I_\ O
`
`HP. 0
`
`O m
`
`O
`
`O O 2
`Time (min)
`FIG. I
`
`+ Ornepruzole
`+ (-) encmtiomer of
`omeprclzole
`
`600
`
`800
`
`200
`
`400
`T|me(m|n)
`FIG. 2
`
`

`
`U.S. Patent
`
`Mar. 2, 1999
`
`Sheet 2 of3
`
`5,877,192
`
`Mean plasma concentration (day 7)
`
`AUG slow/AUC rapid
`(?-omeprozole (—)-omeprozole (+)-omeprozole
`IO
`3
`3O
`AUC=oreo under the plasma concentration vs. time curve
`
`‘500 F
`
`rapid metobolisers
`
`+ (i ) - omeprozole
`+(—)-omeprozole
`+ (+)-omeprozole
`
`2 I250 r
`E: ‘000 _
`C
`
`‘C’
`O
`u
`
`750 —
`
`500
`
`250 -
`
`O
`O
`
`l
`
`2
`
`5
`
`6
`
`4
`
`3
`Time (h)
`FIG.3A
`
`

`
`U.S. Patent
`
`Mar. 2, 1999
`
`Sheet 3 of3
`
`5,877,192
`
`Mean plasma concentration (day 7)
`
`AUG slow/AUC rapid
`(i)-omeprazole (—)—omeprazole (+)—omeprazole
`IO
`3
`3O
`AUC=area under the plasma concentration vs. time curve
`
`‘2000 r
`
`slow metabolisers
`—o- (i)-omeprazole
`
`—0— (-)-orneprazole
`—o- (+)-omeprazole
`
`4000
`
`O0
`O
`
`2
`
`4
`
`6
`
`8
`
`-
`IO
`
`l2
`
`IOOOO --
`
`8000
`
`6000:
`
`Conc(nmol/L) 2000
`
`

`
`5,877,192
`
`1
`METHOD FOR THE TREATMENT OF
`GASTRIC ACID-RELATED DISEASES AND
`PRODUCTION OF MEDICATION USING (-)
`ENANTIOMER OF OMEPRAZOLE
`
`This application is a continuation-in-part of Ser. No.
`08/376,512 ?led on Jan. 23, 1995 now US. Pat. No.
`5,714,504, Which is a continuation-in-part of Ser. No.
`08/256,174 ?led Jun. 28, 1994, now US. Pat. No. 5,693,818.
`The description of the salt forms of the single enanti
`omers of omepraZole and the process of making the same is
`herein incorporated by reference to copending Ser. No.
`08/376,512.
`
`FIELD OF THE INVENTION
`
`The present invention is related to the use of one of the
`single enantiomers of omepraZole, ie the (—)-enantiomer of
`5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)
`methyl]sul?nyl]-1H-benZimidaZole or a pharmaceutically
`acceptable salt thereof, in the treatment of gastric acid
`related diseases. The expression single enantiomer refers to
`the fact that the (—)-enantiomer is substantially free from its
`(+)-enantiomeric contaminant.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`BACKGROUND OF THE INVENTION
`The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl
`2-pyridinyl)methyl]sul?nyl]-1H-benZimidaZole, having the
`generic name omepraZole, and therapeutically acceptable
`salts thereof, are described in EP 5129. The speci?c alkaline
`salts of omepraZole are described in EP 124 495. Omepra
`Zole is effective as a gastric acid secretion inhibitor, and is
`useful as an antiulcer agent. In a more general sense,
`omepraZole may be used for prevention and treatment of
`gastric-acid related diseases in mammals and especially in
`man, including e.g. re?ux esophagitis, gastritis, duodenitis,
`gastric ulcer and duodenal ulcer. Furthermore, omepraZole
`may be used for treatment of other gastrointestinal disorders
`Where gastric acid inhibitory effect is desirable eg in
`patients on NSAID therapy, in patients With Non Ulcer
`Dyspepsia, in patients With symptomatic gastro-esophageal
`re?ux disease (GERD), and in patients With gastrinomas.
`OmepraZole may also be used in patients in intensive care
`situations, in patients With acute upper gastrointestinal
`bleeding, pre-and postoperatively to prevent aspiration of
`gastric acid and to prevent and treat stress ulceration.
`Further, omepraZole may be useful in the treatment of
`psoriasis as Well as in the treatment of Helicobacter infec
`tions and diseases related to these.
`OmepraZole is a sulfoxide and a chiral compound,
`Wherein the sulfur atom being the stereogenic center. Thus,
`omepraZole is a racemic mixture of its tWo single
`enantiomers, the (+)-enantiomer of omepraZole and the
`(—)-enantiomer of omepraZole. The absolute con?gurations
`of the enantiomers of omepraZole have been determined by
`an X-ray study of an N-alkylated derivative of the (+)
`enantiomer in neutral form. The (+)-enantiomer of the
`neutral form and the (—)-enantiomer of the neutral form Were
`found to have the R and S con?guration, respectively. The
`conditions for the optical rotation measurement for each of
`60
`the compounds mentioned above are described in WO
`94/27988.
`Different salts of the single enantiomers of omepraZole
`are also described in WO 94/27988. Speci?c processes for
`the preparation of the single enantiomers of substituted
`benZimidaZoles are described in WO 96/02535. An oral
`pharmaceutical dosage form of omepraZole or one of its
`
`45
`
`50
`
`55
`
`65
`
`2
`single enantiomers is described in WO 96/01623. Other oral
`dosage forms for the (—)-enantiomer of omepraZole can be
`found in EP 247 983.
`There are feW studies on the single enantiomers of ome
`praZole. One previous in vitro study on inhibition of acid
`secretion in isolated gastric glands shoWed no signi?cant
`difference in effect betWeen the tWo single enantiomers of
`omepraZole and the racemic mixture, see Erlandsson P. et al,
`Journal of Chromatography 1990; 532: 305—319. It has also
`been shoWn that, When omepraZole Was administered intra
`venously to one subject, the plasma levels of the tWo
`enantiomers Were similar, see Cairns A. M. et al, Journal of
`Chromatography B, 1995; 666: 323—328.
`More than 135 million prescriptions by doctors indicate
`that omepraZole is an effective and safe drug.
`NotWithstanding, omepraZole exhibits polymorphic
`metabolism, ie a feW individuals (3% among the Caucasian
`populations and 15—20% among Orientals) metabolise ome
`praZole sloWly (sloW metabolisers) compared to the rest of
`the population (rapid metabolisers). SloW metabolisers of
`omepraZole Will obtain higher than the average plasma
`concentrations of the drug. Since the inhibition of gastric
`acid secretion is correlated to the area under the plasma
`concentration versus time curve (AUC), a more pronounced
`effect from omepraZole is expected in these sloW metabolis
`ing individuals. A less interindividual variation, i.e. espe
`cially sloW versus rapid metabolisers, and on the average
`higher plasma levels, giving higher dose ef?ciency in
`patients, could be of therapeutic bene?t. Thus, one of the
`enantiomers of omepraZole, referred to as the (—)
`enantiomer of omepraZole, or a pharmaceutically acceptable
`salt thereof, is hereby claimed to be an improved alternative
`to omepraZole in the treatment of gastric acid related dis
`eases resulting in higher dose ef?ciency and in less interin
`dividual variation in plasma levels (AUC), both betWeen
`rapid and sloW metabolisers and Within the group of rapid
`metabolisers.
`
`SUMMARY OF THE INVENTION
`The use of the (—)-enantiomer of omepraZole, or a phar
`maceutically acceptable salt thereof, in the treatment of
`gastric acid related diseases as a mean to decrease interin
`dividual variation in plasma levels compared to omepraZole
`is claimed. The use of the (—)-enantiomer of omepraZole to
`receive increased average plasma levels (AUC) of the sub
`stance compared to those of racemic omepraZole and
`thereby a higher dose efficiency is also claimed.
`
`DETAILED DESCRIPTION OF THE DRAWINGS
`FIG. 1 shoWs the mean plasma levels of racemic ome
`praZole and the (—)-enantiomer of omepraZole at steady state
`(Day 7) in rapid metabolisers folloWing administration of 15
`mg doses of each substance.
`FIG. 2 shoWs the mean plasma levels of racemic ome
`praZole and the (—)-enantiomer of omepraZole at steady state
`(Day 7) in sloW metabolisers folloWing administration of 60
`mg doses of each substance.
`FIGS. 3a and 3b shoW the mean plasma levels of racemic
`omepraZole, the single (—)-enantiomer of omepraZole and
`the single (+)-enantiomer of omepraZole at steady state in
`rapid and sloW metabolisers folloWing administration of 15
`mg and 60 mg doses of each substance, respectively. The
`?gure sheet also comprises the ratios betWeen the mean
`AUCs at steady state of sloW and rapid metabolisers.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`OmepraZole is metabolised mainly in the liver by the
`cytochrome P450 system (CYP). Metabolism can be de?ned
`
`

`
`5,877,192
`
`3
`as the property of the body to transform lipophilic com
`pounds into hydrophilic derivatives, Which more easily can
`be excreted from the body. The metabolism can generally be
`divided into phase I and phase II reactions. During a phase
`I reaction, polar groups are formed via oxidation,
`hydroxylation, or hydrolysis. These reactions are mainly
`associated With the CYP enZymes. Phase II reactions are
`conjugation reactions, in Which even further hydrophilic
`moities are attached to the drug or to its metabolites.
`CY P is a superfamily of enZymes. Each family consists of
`one or more subfamilies and each subfamily contains one or
`more speci?c CYP isoforms. Apart from metabolising drugs,
`the CYP isoforms also have the property to metabolise
`endogenous compounds, such as steroids, fatty acids, and
`prostaglandins.
`With respect to drug metabolism in man, three families,
`CYP1, CYP2, and CYP3 or, more speci?cally, six different
`CYP isoforms Within these families are of particular impor
`tance. Each isoform demonstrates a certain substrate speci
`?city. The expression of these enZymes is under genetic
`control, Which is one of the reasons for the interindividual
`variation in rate and extent of metabolism demonstrated for
`most drugs. Moreover, at least tWo of the CYP isoforms,
`CYP2C19 and CYP2D6, are polymorphically expressed.
`Thus, a feW individuals among the population, ie the sloW
`metabolisers, lack or express a mutated form of the relevant
`CYP isoform, and consequently metabolise substrates for
`this isoform sloWly. Metabolism still occurs in these sloW
`metabolisers, although at a loWer rate, because it is sWitched
`to other CYP isoforms Which are less important for the
`metabolism of the substrate in the rest of the population.
`OmepraZole is knoWn to be a substrate for the polymor
`phically expressed CYP2C19. In vitro studies in human liver
`microsomes have surprisingly indicated that the (—)
`enantiomer of omepraZole is less metabolised by CYP2C19
`than omepraZole. In agreement With this, it has also been
`found, according to the present invention, that administra
`tion of the (—)-enantiomer of omepraZole or an acceptable
`therapeutical salt thereof results in a less pronounced dif
`ference in plasma levels betWeen sloW and rapid metabo
`lisers.
`Some studies have been published indicating that sloW
`metabolisers, With higher than average plasma concentra
`tions of omepraZole, are more prone to develop hypergas
`trinemia (Chang M. et al. Br J Clin Pharmacol 995; 39:
`511—518, Caraco Y. et al. Clin Pharmacol Ther 1996; 59, 2:
`216) as Well as to slightly induce the levels of CYP1A2
`(Rost KL et al. Clin Pharmacol Ther 1992; 52: 170—180,
`Rost KL et al. Clin Pharmacol Ther 1994; 55: 402—411), a
`CYP isoform distinct from CYP2C19. Some authors have
`therefore suggested that there might be a need for dosage
`adjustment in these individuals. The use of the (—)
`enantiomer of omepraZole Would decrease the potential for
`CYP1A2 induction in sloW metabolisers as a result of the
`loWer plasma levels (AUC) of this compound obtained in
`these individuals. Since the gastrin levels obtained simply
`are a result of a natural feedback mechanism determined by
`the degree of inhibition of gastric acid secretion, the use of
`the (—)-enantiomer of omepraZole may also potentially result
`in a less pronounced increase in gastrin in sloW metabolisers.
`The clinical study reported beloW supports the claimed
`invention and discusses the results more in detail.
`The (—)-enantiomer of omepraZole is effective as a gastric
`acid secretion inhibitor, and is useful as an antiulcer agent.
`In a more general sense, the (—)-enantiomer of omepraZole
`can be used for prevention and treatment of the same
`
`10
`
`15
`
`25
`
`35
`
`45
`
`55
`
`4
`gastric-acid related diseases in mammals and especially in
`man as omepraZole, see above.
`Any suitable route of administration may be employed for
`providing the patient With an effective dosage of the (—)
`enantiomer of omepraZole. For example, oral, parenteral,
`subcutaneous, intramuscular, rectal, transdermal and the like
`may be employed. Dosage forms include capsules, tablets,
`dispersions, suspensions, solutions and the like.
`The pharmaceutical compositions of the present invention
`comprise the (—)-enantiomer of omepraZole as active
`ingredient, or a pharmaceutically acceptable salt thereof, and
`may also contain a pharmaceutically acceptable carrier and
`optionally other therapeutic ingredients. The term “pharma
`ceutically acceptable salt” refers to both acid and alkaline
`pharmaceutically acceptable non-toxic salts. Compositions
`comprising other therapeutic ingredients are especially of
`interest in the treatment of Helicobacter infections.
`The compositions include compositions suitable for oral,
`rectal or parenteral such as subcutaneous, intramuscular, and
`intravenous administration. The most preferred route of the
`present invention is the oral route. The compositions may be
`conveniently presented in unit dosage forms, and prepared
`by any methods Well knoWn in the art of pharmacy.
`The most suitable route of administration as Well as the
`magnitude of a therapeutic dose of the (—)-enantiomer of
`omepraZole or a pharmaceutically acceptable salt thereof in
`any given case Will depend on the nature and severity of the
`disease to be treated. The dose, and dose frequency, may also
`vary according to the age, body Weight, and response of the
`individual patient. Special requirements may be needed for
`patients having Zollinger-Ellison syndrome, such as a need
`for higher doses than the average patient. Children and
`patients With liver diseases generally Will bene?t from doses
`that are someWhat loWer than the average. Thus, in some
`conditions it may be necessary to use doses outside the
`ranges stated beloW. Such higher and loWer doses of the
`(—)-enantiomer of omepraZole are Within the scope of the
`present invention.
`In general, a suitable oral dosage form may cover a dose
`range from 5 mg to 80 mg total daily dose, administered in
`one single dose or equally divided doses. A preferred dose
`range is from 20 mg to 60 mg total daily dose. For a
`parenteral dosage form the same dose ranges may apply.
`The (—)-enantiomer of omepraZole may be combined as
`the active component in intimate admixture With a pharma
`ceutical carrier according to conventional techniques, such
`as the oral formulations described in W0 96/ 01623 and EP
`247 983, the disclosures of Which are hereby incorporated in
`a Whole by reference.
`Different routes of preparation of the (—)-enantiomer of
`omepraZole and pharmaceutically acceptable salts thereof
`are described in W0 94/ 27988 and W0 96/ 02535, the
`disclosures of Which are hereby incorporated in a Whole by
`reference.
`The invention is further de?ned by reference to the
`folloWing experimental Work describing in detail the study
`and results as Well as the clinical relevance of the ?ndings.
`
`EXPERIMENTAL STUDY
`
`Methods:
`In an open, randomised, three Way cross-over designed
`study, consisting of three treatment periods, each With a
`duration of 7 days and each separated by a Washout period
`of tWo Weeks, the sodium salt of the (—)-enantiomer of
`omepraZole, the sodium salt of the (+)-enantiomer of ome
`
`65
`
`

`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`5
`praZole and omepraZole sodium salt Were investigated. Nine
`healthy subjects, classi?ed according to the urinary S/R
`mephenytoin ratio as ?ve sloW metabolisers and four rapid
`metabolisers of omepraZole, completed the study (SanZ E. J.
`et al, Clin Pharmacol Ther 1989; 45:495—499).
`In sloW metabolisers 60 mg doses of each compound Were
`given once daily, While the rapid metabolisers Were given
`once daily doses of 15 mg. The pharmacokinetics Were
`studied in all subjects on days 1 and 7. The reason for using
`different doses Was to optimise the conditions to explore the
`secondary aims of the study, to measure the effect on gastric
`acid secretion in rapid metabolisers and to measure the
`potential effect on caffeine metabolism in sloW metabolisers.
`Results and discussion:
`In rapid metabolisers the mean AUC at steady state (Day
`7) of the (—)-enantiomer of omepraZole Was almost 90%
`higher than that of omepraZole. (FIG. 1). This resulted in a
`more pronounced gastric acid antisecretory effect for the
`(—)-enantiomer of omepraZole compared to that of omepra
`Zole. The inhibition of pentagastrin stimulated gastric acid
`secretion Was 62% for omepraZole and 79% for the (—)
`enantiomer of omepraZole folloWing administration of 15
`mg doses of each substance.
`In sloW metabolisers the mean AUC at steady state (Day
`7) of the (—)-enantiomer of omepraZole Was about 30%
`loWer than that of omepraZole. (FIG. 2). Thus, after correc
`tion for different dose levels, the resulting difference in AUC
`betWeen sloW and rapid metabolisers Was almost 10-fold for
`omepraZole and only 3-fold for the (—)-enantiomer of ome
`praZole. With the (+)-enantiomer of omepraZole, on the
`other hand, the difference in AUC Was much greater,
`approximately 30-fold (FIG. 3).
`In conclusion, the interindividual variation in plasma
`levels upon administration of the (—)-enantiomer of ome
`praZole Will be less than for omepraZole and more patients
`Will get optimal plasma concentrations With respect to
`gastric acid antisecretory effect and potentially also a better
`clinical effect folloWing administration of the same doses.
`Another study Was conducted in 38 patients With symp
`tomatic gastroesophageal re?ux disease in Which the effects
`on 24 hour intragastric acidity by oral treatment With 20 mg
`omepraZole racemate (capsules) and the magnesium salt of
`(—)-omepraZole (corresponding to 20 mg or 40 mg of the
`neutral compound) Were compared. In addition, the plasma
`concentrations of (—)-omepraZole and omepraZole racemate
`Were determined on the last treatment day (day 5).
`The study Was conducted as a double-blind, randomiZed,
`three-Way cross-over trial consisting of three study periods,
`each With ?ve days of daily oral administration of formu
`lations containing the magnesium salt of (—)-omepraZole or
`omepraZole racemate separated by a Wash-out period of at
`least tWo Weeks. The 38 patients (22 females) ranged in age
`from 29—58 years. 32 of the patients Were Helicobacter
`pylori negative.
`Enteric coated pellets comprising the magnesium salt of
`(—)-omepraZole Were ?lled in hard gelatin capsules calcu
`lated to correspond to either 20 mg or 40 mg of neutral
`(—)-omepraZole compound.
`These formulations Were compared With an identical
`treatment except for using enteric coated pellets comprising
`omepraZole ?lled in a hard gelatin capsule containing 20 mg
`racemic omepraZole in the non-salt form (Prilosec®).
`The intragastric pH Was recorded over 24 hours on day
`?ve of each study period upon administering the ?fth dose.
`The study Was completed by 36 patients and the results
`therefrom Were statistically evaluated. The effects of the
`
`50
`
`55
`
`60
`
`65
`
`5,877,192
`
`6
`treatments on intragastric pH are summariZed in Table 1 and
`the AUC values are shoWn in Table 2.
`As shoWn in Table 1 the percentage of time (of the
`24-hour period assessed) With pH above 4 (a direct measure
`of inhibitory effect on gastric acid secretion) Was 44% for 20
`mg omepraZole racemate and 53% for 20 mg (—)
`omepraZole (p<0.0001), Which means that patients treated
`With (—)-omepraZole Will have 2.2 hours longer time With
`pH above 4 than those treated With omepraZole racemate in
`corresponding doses.
`
`TABLE 1
`
`Least square estimates and 95%
`con?dence intervals for the true mean treatment effects,
`regarding percentage of time With pH > 4 during 24 hours.
`
`Treatment
`
`Estimate
`
`LoWer
`
`Upper
`
`Omeprazole
`(—)ome
`(—)ome
`
`20 mg
`20 mg
`40 mg
`
`43.7
`53.0
`69.8
`
`36.7
`46.0
`62.8
`
`50.7
`60.0
`76.8
`
`The data of Table 2 shoWn beloW demonstrate that the
`AUC of (—)omepraZole is signi?cantly higher than that of
`racemic omepraZole at the 20 mg dose, and the 40 mg dose
`of (—)omepraZole produced a signi?cantly higher AUC than
`the 20 mg dose of (—)-omepraZole (p<0.0001).
`The interindividual variation in AUC and thus the inhibi
`tory effect is less pronounced folloWing administration of
`(—)-omepraZole than folloWing administration of omepra
`Zole racemate. This Was judged by the coef?cient of varia
`tion for the mean AUC Which Was 59% for 20 mg of the
`magnesium salt of (—)-omepraZole and 88% for 20 mg of
`omepraZole racemate (p<0.0001).
`
`TABLE 2
`
`Least square estimates and 95%
`con?dence intervals for the true mean treatment effects,
`regarding AUC (umol x h/L).
`
`Treatment
`
`Estimate
`
`LoWer
`
`Upper
`
`Omeprazole
`(—)ome
`(—)ome
`
`20 mg
`20 mg
`40 mg
`
`2.3
`4.2
`12.6
`
`1.8
`3.3
`9.9
`
`3.0
`5.4
`16.2
`
`As a consequence of the less pronounced difference in
`AUC betWeen sloW and rapid metaboliZers, the interindi
`vidual variation in AUC of (—)-omepraZole is less than that
`of omepraZole. Furthermore, available data indicate that the
`interindividual variation in AUC of (—)omepraZole Within
`the group of rapid metaboliZers also is less than that
`observed for omepraZole racemate. These characteristics
`taken together may potentially result in a larger fraction of
`patients attaining plasma concentrations Which Would be
`optimal With respect to the desired gastric acid anti-secretory
`effect in the clinical situation.
`It Was observed that the steady-state AUC of (—)
`omepraZole in an average population Was signi?cantly
`higher (2-fold) than that of omepraZole racemate When each
`compound Was given repeatedly in 20 mg daily doses.
`Therefore, the anti-secretory effect, Which is directly corre
`lated to the AUC irrespective of compound, Was higher for
`(—)-omepraZole than for omepraZole racemate folloWing
`administration of identical doses. This is expected to give a
`clinical advantage for (—)-omepraZole, since the number of
`patients healed from the acid-related disease is expected to
`be higher, and healing is also expected to be achieved Within
`
`

`
`5,877,192
`
`7
`a shorter time frame. It might also be expected that a more
`rapid symptom relief Will be obtained.
`The clinical studies outlined above demonstrate that the
`alkali metal salts of (—)-omepraZole have unexpected phar
`macokinetic advantages over the omepraZole racemate, such
`as less interindividual variation in plasma levels (AUC) both
`betWeen rapid and sloW metaboliZers and Within the group
`of rapid metaboliZers. The alkali metal salts of (—)
`omepraZole provide for a larger fraction of patients With
`optimal plasma concentrations With respect to desired anti
`secretory effect. Higher average AUC results in a more
`pronounced inhibitory effect on gastric-acid secretion and is
`eXpected to result in a better overall clinical effect. Thus, the
`alkaline salts of (—)-omepraZole can provide an improved,
`alternative pharmaceutical formulation and method for the
`treatment of gastric acid-related diseases.
`What is claimed is:
`1. A method for treatment of gastric acid related diseases
`by inhibition of gastric acid secretion comprising adminis
`tering to a mammal in need of treatment a therapeutically
`effective amount of a proton pump inhibitor consisting
`essentially of the (—)-enantiomer of 5-methoXy-2-[[(4
`methoXy-3,5-dimethyl-2-pyridinyl)methyl]sul?nyl]-1
`H-benZimidaZole or a pharmaceutically acceptable salt
`thereof, so as to effect decreased interindividual variation in
`plasma levels (AUC) during treatment of gastric acid related
`diseases.
`2. A method for treatment of gastric acid related diseases
`by inhibition of gastric acid secretion comprising adminis
`tering to a mammal in need of treatment a therapeutically
`effective amount of a proton pump inhibitor consisting
`essentially of the (—)-enantiomer of 5-methoXy-2-[[(4
`methoXy-3,5-dimethyl-2-pyridinyl)methyl]sul?nyl]-1H
`benZimidaZole or a pharmaceutically acceptable salt thereof,
`so as to effect an increased average plasma levels (AUC) per
`dosage unit.
`3. The method according to claim 1 or 2 so as to effect a
`less pronounced increase in gastrin levels in sloW metabo
`lisers during treatment of gastric acid related diseases.
`4. The method according to claim 1 or 2 so as to effect a
`decreased CYP1A induction in sloW metabolisers during
`treatment of gastric acid related diseases.
`5. The method according to claim 1 or 2 so as to elicit an
`improved antisecretory effect during the treatment of gastric
`acid related diseases.
`6. The method according to claim 1 or 2 so as to elicit an
`improved clinical effect comprising accelerated rate of heal
`ing and accelerated rate of symptom relief during the
`treatment of gastric related diseases.
`7. The method according to claim 1 or 2, Wherein the
`(—)-enantiomer of omepraZole or a pharmaceutically accept
`able salt thereof, is administered orally in the form of a tablet
`or a capsule.
`8. The method according to claim 1 or 2, Wherein the
`(—)-enantiomer of omepraZole or a pharmaceutically accept
`able salt thereof, is administered parenterally.
`
`15
`
`25
`
`35
`
`45
`
`55
`
`8
`9. The method according to claim 1 or 2, Wherein the
`(—)-enantiomer of omepraZole or a pharmaceutically accept
`able salt thereof, is administered by intravenous infusion.
`10. The method according to claim 1 or 2, Wherein the
`amount administered is about 5—80 mg total daily dose.
`11. The method according to claim 1 or 2, Wherein the
`amount administered is about 20—60 mg total daily dose.
`12. A method for the production of a medicament for
`treating gastric acid related diseases, Which comprises: com
`bining a therapeutically effective amount of a proton pump
`inhibitor consisting essentially of the (—)-enantiomer of
`5-methoXy-2-[[(4-methoXy-3,5dimethyl-2-pyridinyl)
`methyl]sul?nyl]-l?-benzimidazole or a pharmaceutically
`acceptable salt thereof, With a pharmaceutically acceptable
`carrier.
`13. The method according to claim 12, Wherein the
`medicament causes a decreased interindividual variation in
`plasma levels (AUC) per unit dosage during the treatment of
`gastric acid related diseases.
`14. The method according to claim 12, Wherein the
`medicament causes an increased average plasma level
`(AUC) per unit dosage during the treatment of gastric acid
`related diseases.
`15. The method according to claim 12, Wherein the
`medicament causes a less pronounced increase in gastrin
`levels in sloW metabolisers during treatment of gastric acid
`related diseases.
`16. The method according to claim 12, Wherein the
`medicament causes a decreased CYP1A induction in sloW
`metabolisers during treatment of gastric acid related dis
`eases.
`17. The method according to claim 12, Wherein the
`medicament causes an improved antisecretory effect during
`the treatment of gastric acid related diseases.
`18. The method according to claim 12, Wherein the
`medicament causes an improved clinical effect comprising
`accelerated rate of healing and accelerated rate of symptom
`relief during the treatment of gastric related diseases.
`19. The method according to claim 12, Wherein the
`medicament produced for oral administration is in the form
`of a tablet or capsule.
`20. The method according to claim 12, Wherein the
`medicament is administered parentally, by intravenous infu
`sion.
`21. The method according to any of claims 12—20,
`Wherein the medicament is administered in the amount of
`about 5 mg to 80 mg total daily dose.
`22. The method according to any of claims 12—20,
`Wherein the medicament is administered in the amount of
`about 20 mg to 60 mg total daily dose.
`23. The method according to claim 1 or 2 Wherein the
`(—)-enantiomer of the proton pump inhibitor is essentially
`devoid of its (+)-enantiomeric contaminant.
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRRECTION
`
`PATENTNO. ; 5,877,192
`DATED
`I March 2, 1999
`|NVENTOR($) I Per Lindberg, et al.
`
`Page 1 of 4
`
`It is certi?ed that error appears in the above-identi?ed patent and that said Letters PaterIt is hereby
`corrected as shown below:
`
`On the title page insert the following under item [56]:
`
`EXAMINER
`INITIAL
`
`PATENT NUMBER
`
`U. S. PATENT DOCUMENTS
`ISSUE
`DATE
`
`PATENTEE
`
`FILING DATE
`CLASS SUBCLASS IF APPROPRIATE
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`4
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`5
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`4
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`6 3
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`6 4
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`0
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`7
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`4
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`3
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`5
`
`8
`
`3
`
`9
`
`4 8 5
`
`3 2
`
`4
`
`7
`
`8 6 5
`
`9
`
`2
`
`7
`
`3
`
`0
`
`9
`
`1
`
`4
`
`0
`
`5
`
`1/13/96
`
`Brandstrom et al
`
`9/3/91
`
`Makino et al
`
`4/19/88
`
`Brandstrom et al
`
`8/1/89
`
`Lovgren et a1
`
`11/22/88
`
`Lovgren et al
`
`FOREIGN PATENT DOCUMENTS
`PUBLICATION
`COUNTRY 0R
`DATE
`PATENT OFFICE
`
`DOCUMENT NUMBER
`
`TRANSLATION
`CLASS SUBCLASS YES
`
`4
`
`0
`
`0
`
`3
`
`5 4
`
`1
`
`2 4 4
`
`5
`
`9
`
`5
`
`5
`
`11/90
`
`1/14/87
`
`DE
`
`EP
`
`

`
`UN1TED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRRECTION
`
`PATENTNO. : 5,877,192
`DATED
`: March 2, 1999
`INVENTOR($) ; Per Lindberg, et al.
`
`Page 2 of 4
`
`It is certified that error appears in the above-identi?ed patent and that said Letters Patent is hereby
`corrected as shown below:
`
`FOREIGN PATENT DOCUMENTS
`
`9
`0
`0
`9
`9
`9
`9
`6
`
`N-hOINUIUJ/OOI
`
`DOCUMENT NUMBER
`0
`1
`6
`
`WMQQQ¢~NN
`
`uoocnawwcow
`
`PUBLICATION
`
`COUNTRY 0R
`
`TRANSLATION
`
`PATENT OFFICE
`WiPO
`EP
`EP
`
`DATE
`1/25/96
`4/29/81
`5/2/90
`1/19/95
`12/23/92
`2/1/96
`12/8/94
`4/16/87
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRRECTION
`
`PATENTNO. : 5,877,192
`DATED
`: March 2, 1999
`INVENTOR(S) : Per Lindberg, et: al.
`
`Page 3 of A
`
`it is certi?ed that error appears in the above-identi?ed patent and that said Letters Patent is hereby
`corrected as shown below:
`
`OTHER DOCUMENTS
`Cairns, et al. "Enantioselective HPLC determination..." Journal of Chromatography
`8,666 (1995) 323-328
`Yamada et al. "Synthesis and isomerization of optical active." Chem. Pharm. Bull.
`42(8) (1994) 1679-1681
`K. Miwa et al. "Jpn. Pharmacol. Ther. "Proton pump inhibitor in rats, mice and dogs"
`18 (1990) 165-187 (transL)
`H. Katsuki et al. "Determination of R(+)- and S(-)-Lansoprazole" Pharmaceutical
`Research 13(4) (1996) 611-615
`M. Tanaka et al. ‘Direct determination of pantoprazole enantiomers..." Anal. Chem.
`68 (1996) 1513-1516
`Erlandson et al. "Resolution of the enantiomers of omeprazole..." J. Chromatography
`(1990) 532: 305-319
`Chang et al. 1995 "lnterphenotype differences..." Brit. J. Clinical Pharmacology 39: 511-518
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CER