US005877192A
`
`[19]
`United States Patent
`[11] Patent Number:
`5,877,192
`[45] Date of Patent: *Mar. 2, 1999
`Lindberg ct al.
`
`
`
`[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 Aktiebolag, Sodertalje, Sweden
`
`[*l
`
`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
`
`Related US. Application Data
`
`[63]
`
`Continuation—impart of Ser. No. 376,512, Jan. 23, 1995, Pat.
`No. 5,714,504, which is a continuation—in—part of Ser. No.
`256,174, Jun. 28, 1994, Pat. No. 5,693,818.
`
`[30]
`
`Foreign Application Priority Data
`
`May28, 1993
`Apr. 11, 1996
`
`[SE]
`[SE]
`
`Sweden .................................. 9301830
`Sweden .................................. 9601383
`
`........................... 514/338; 514/819; 514/927
`[52] US. Cl.
`[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—Kimberly Jordan
`Attorney, Agent, or Firm—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]sulfinyl]-1H-
`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
`
`DRL EXHIBIT 1007 PAGE 1
`
`DRL EXHIBIT 1007 PAGE 1
`
`

`

`US. Patent
`
`Mar. 2, 1999
`
`Sheet 1 0f3
`
`5,877,192
`
`:O__meprazole
`(—)enantiomer of
`omeprazole
`
`
`
`400
`
`TIme (mm)
`FIG.
`I
`
`+ O_—meprchole
`+(—)enantIomer of
`
`800
`
`Time(min)60
`FIG.2
`
`DRL EXHIBIT 1007 PAGE 2
`
`|500
`
`A
`<|
`3 IOOO
`
`
`
`
`
`O
`
`500
`
`O
`
`[2000
`
`
`
`8000'
`c»O O_O
`
`
`
`E 88
`
`Conc(nmol/L)
`
`DRL EXHIBIT 1007 PAGE 2
`
`

`

`US. Patent
`
`Mar. 2, 1999
`
`Sheet 2 0f3
`
`5,877,192
`
`Mean plasma concentration (day 7)
`
`AUG slow/AUC rapid
`
`(fl—omeprazole (—)—omeprazole
`
`(+)-omeprazole
`
`
`
`IO
`
`3
`
`30
`
`AUC=area under the plasma concentration vs. time curve
`
`'500
`
`|250
`IOOO
`
`750
`
`500
`
`250
`
`O
`
`
`
`rapid metabolisers
`+ (i)- omeprazole
`+ (—)-omeprazole
`+ (+ )-omeprazole
`
`
`
`O
`
`l
`
`2
`
`3
`
`4
`
`5
`
`6
`
`DRL EXHIBIT 1007 PAGE 3
`
`3\
`
`TED
`
`C 2
`
`O o
`
`DRL EXHIBIT 1007 PAGE 3
`
`

`

`US. Patent
`
`Mar. 2, 1999
`
`Sheet 3 0f3
`
`5,877,192
`
`Mean plasma concentration (day 7)
`
`AUG slow/AUC rapid
`
`(i)—omeprazole (-)-omeprazo|e (+)-omeprazo|e 3
`
`3O
`
`AUC=area under the plasma concentration vs. time curve
`
`[2000
`
`IOOOO --
`
`slow metabolisers
`—<>— (i)-0meprazole
`
`—o— (—) —omeprazole
`
`—o— (+)-omeprazole
`
`Conc(nmoI/L)
`
`DRL EXHIBIT 1007 PAGE 4
`
`DRL EXHIBIT 1007 PAGE 4
`
`

`

`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 filed on Jan. 23, 1995 now US. Pat. No.
`5,714,504, which is a continuation-in-part of Ser. No.
`08/256,174 filed 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.
`
`FIEID OF THE INVENTION
`
`The present invention is related to the use of one of the
`single enantiomers of omeprazole, i.e. the (—)-enantiomer of
`5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-
`methyl]sulfinyl]—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.
`BACKGROUND OF THE INVENTION
`
`The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-
`2-pyridinyl)methyl]sulfinyl]-1H—benzimidazole, having the
`generic name omeprazole, and therapeutically acceptable
`salts thereof, are described in EP 5129. The specific 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. reflux 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 e.g.
`in
`patients on NSAID therapy,
`in patients with Non Ulcer
`Dyspepsia, in patients with symptomatic gastro-esophageal
`reflux disease (GERD), and in patients with gastrinomas.
`Omcprazolc may also be uscd in patients in intcnsivc carc
`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 configurations
`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 configuration, respectively. The
`conditions for the optical rotation measurement for each of
`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. Specific 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
`
`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 significant
`diiference 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, i.e. 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 efficiency in
`patients, could be of therapeutic benefit. 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 efficiency 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-
`prazolc and thc (—)-cnantiomcr of omcprazolc at stcady statc
`(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
`figure 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 defined
`
`Ln
`
`10
`
`15
`
`20
`
`25
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`DRL EXHIBIT 1007 PAGE 5
`
`DRL EXHIBIT 1007 PAGE 5
`
`

`

`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.
`CYP is a superfamily of enzymes. Each family consists of
`one or more subfamilies and each subfamily contains one or
`more specific 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 specifically, six dilIerent
`CYP isoforms within these families are of particular impor-
`tance. Each isoform demonstrates a certain substratc spcci-
`ficity. 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, i.e. 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
`
`Ln
`
`10
`
`15
`
`20
`
`25
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`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 benefit 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 defined by reference to the
`following experimental work describing in detail the study
`and results as well as the clinical relevance of the findings.
`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-
`
`DRL EXHIBIT 1007 PAGE 6
`
`DRL EXHIBIT 1007 PAGE 6
`
`

`

`5,877,192
`
`5
`prazole and omeprazole sodium salt were investigated. Nine
`healthy subjects, classified according to the urinary S/R
`mephenytoin ratio as five slow metabolisers and four rapid
`rnetabolisers of omeprazole, completed the study (Sanz E. J.
`et al, Clin Pharmacol 'lher 1989; 45:495—499).
`In slow metabolisers 60 mg doses of each compound were
`given once daily, while the rapid rnetabolisers were given
`once daily doses of 15 mg. The pharmacokinetics were
`studied in all subjects on days 1 and 7. The reason for using
`dilIerent doses was to optimise the conditions to explore the
`secondary aims of the study, to measure the effect on gastric
`acid secretion in rapid mctabolisers and to measure the
`potential effect on caffeine metabolism in slow rnetabolisers.
`Results and discussion:
`
`In rapid rnetabolisers 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 reflux 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 five 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 filled 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 filled in a hard gelatin capsule containing 20 mg
`raccmic omeprazole in thc non-salt form (Priloscc.).
`The intragastric pH was recorded over 24 hours on day
`five of each study period upon administering the fifth dose.
`The study was completed by 36 patients and the results
`therefrom were statistically evaluated. The effects of the
`
`Ln
`
`10
`
`15
`
`20
`
`25
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`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 elfect 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%
`confidence intervals for the true mean treatment effects,
`regarding percentage of time with EH > 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 significantly higher than that of
`racemic omeprazole at the 20 mg dose, and the 40 mg dose
`of (—)omeprazole produced a significantly 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 coefficient 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%
`confidence intervals for the true mean treatment effects,
`regarding AUC m_nol x h/L .
`
`Treatment
`
`Estimate
`
`Lower
`
`Iipper
`
`Omeprazole
`(7)0me
`(—)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.
`
`the steady-state AUC of (—)-
`It was observed that
`omeprazole in an average population was significantly
`higher (2-fold) than that of omeprazole racemate when each
`compound was given repeatedly in 20 mg daily doses.
`Therefore, the anti-secretory efiect, 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
`
`DRL EXHIBIT 1007 PAGE 7
`
`DRL EXHIBIT 1007 PAGE 7
`
`

`

`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]sulfinyl]-1
`fl-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]sulfinyl]—1E-
`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.
`
`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]sulfinyl]—1fl-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
`
`5
`
`10
`
`15
`
`20
`
`25
`
`40
`
`45
`
`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
`
`50
`
`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.
`
`55
`
`DRL EXHIBIT 1007 PAGE 8
`
`DRL EXHIBIT 1007 PAGE 8
`
`

`

`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`CERTIFICATE OF CORRRECTION
`
`PATENT No.
`DATED
`
`: 5,377,192
`: March 2, 1999
`
`|NVENTOR(5)
`
`I Per Lindberg, et al.
`
`Page 1 of 4
`
`It is certified that error appears in the above-identified patent and that said Letters PaterIt is hereby
`corrected as shown below:
`
`On the title page insert the following under item [56]:
`
`U. S. PATENT DOCUMENTS
`
`
`
`
`INITIAL
`
`
`
`III II
`PATENT NUMBER
`DATE
`PATENTEE
`CLASS SUBCLASS IF APPROPRIATE
`
`flannnu- Brandstrom etal -
`
`[Illa-III- Makenoeta» I
`
`“In“ Brandstrom etal -
`null-III Lovgrenetal I
`IIIIIEIIE Lovgrenetal I
`
`
`
`
`DOCUMENT NUMBER
`DATE
`PATENT OFFICE
`CLASS suacuxss -“
`“HEB-fl 11/90 III-II
`
`
`
`fill-Ila“ 1114/87 “II-I
`
`
`PUBLICATION
`
`COUNTRY OR
`
`DRL EXHIBIT 1007 PAGE 9
`
`DRL EXHIBIT 1007 PAGE 9
`
`

`

`
`
`CERTIFICATE OF CORRRECTION
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`PATENTNO.
`DATED
`
`: 5,877,192
`: March 2, 1999
`
`INVENTOR(S)
`
`; Per Lindberg, et 31.
`
`Page 2 of A
`
`It is certified that error appears in the above-identified patent and that said Letters Patent is hereby
`corrected as shown below:
`
`FOREIGN PATENT DOCUMENTS
`
`-I_-_I-—DOCUMENT NUMBER
`CLASS SUBCLASS -_
`PATENTOFFICE
`DATE
`--flEfl-“ 1I25/96_-_-_
`—-flflfl“fl—m----
`_-fl-EHB--_m----
`—-flflu---fl—_--I_
`_-EI““B 12/23/92—----
`_-flflflfl-flfl 2/1/96 —----
`_-flllfl-flflfl__----
`_-B---flflfl_E_-_-_
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`DRL EXHIBIT 1007 PAGE 10
`
`DRL EXHIBIT 1007 PAGE 10
`
`

`

`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRRECTION
`
`PATENT NO.
`DATED
`INVENTOR(S)
`
`: 5,377,192
`1 March 2, 1999
`: Per Lindberg, et al.
`
`Page 3 0f 4
`
`It is certified that error appears in the above-identified 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.
`42(8) (1994) 1679-1681
`
`
`' Chem. Pharm. Bull.
`
`
`
`
`
`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
`e
`R search 13(4) (1996) 611-615
`
`
`M. Tanaka et al. "Direct determination of pantoprazole enantiomers..." Anal. Chem.
`
`
`
`-. 68 (1996) 1513-1516
`
`
`-. Erlandson et al. "Resolution ofthe enantiomers of omeprazole..." J. Chromatography
`
`
`
`
`(1990) 532: 305-319
`Chang et al. 1995 "lnterphenotype differences..." Brit. J. Clinical Pharmacology 39: 511-518
`
`
`
`
`
`
`
`
`
`
`DRL EXHIBIT 1007 PAGE 11
`
`DRL EXHIBIT 1007 PAGE 11
`
`

`

`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`CERTIFICATE OF CORRRECTION
`
`PATENTNO.
`DATED
`INVENT0R(S)
`
`: 5,877,192
`: March 2. 1999
`1 Per Lindberg, et al.
`
`Page 4 of 4
`
`it is certified that error appears in the above-identified patent and that said Letters Patent is h