`omeprazole
`PfLBRANT A and CEDERBERG C
`Departments of Pharmaceutics and Medicine,
`AB Hassle, Molndal, Sweden.
`
`113
`
`Pilbrant A, Cederberg C. Development of an oral formulation of omeprazole.
`Scand J Gastroenterol 1985;20(suppl108): 113-120.
`
`Omeprazole has a low water solubility and is chemically labile in an acid environment. In
`the formulation of an oral dosage form of omeprazole the possibilities of dissolution rate
`limited absorption and preabsorption degr;~dation must be kept in mind. A water suspen(cid:173)
`sion of omeprawle was tested in a pilot bioavailabllhy study. The suspension was
`given to six hca1tby, fasting volunteers on ~wo occasions -together with sodium bicar(cid:173)
`bonate solution and together with the same volume of water. When the suspension was
`given with water the bioavailability was reduced by about SO o/o owing to preabsorption
`degradation. In another bioavailablllty study the slowest of three granule formulations
`with differing in vitro dissolution rates showed a reduced extent of absorption.
`A controlled·release pellet fonnulation (enteric-coated) was formulated and tested in a
`series of bioavailability studies. A single dose given with food resulted in a delayed
`absorption and possibly lower bioavailability than under fasting conditions. When the
`granules were given on an empty stomach before the morning meal the lenl!lh of time
`between dosage and meal was of no importance. Concomitant admiQistration of a liquid
`antacid had no influence on the bioavailab!lity of omeprazole.
`Key-words: Bioavailability; controlled release; dosage form; enteric coating; omeprazole;
`stability
`Ake Pi/brant, Form. L1c., Dept of Pharmaceutics, AB Hl/ss/e,
`S-431 83 Molnd«l. Swe4en
`
`Introduction
`is a substituted b~nz
`Omeprazole (Figure 1)
`imidazole which selectively inhibits the proton
`pump in the gastric muCDsa (1, 2). Omeprazole is
`very slightly soluble in water, but is very soluble in
`alkaline solutions as the negatively charged ion. It is
`an ampholyte with pK3 ~4 (pyrldinium) and 8.8
`(benzimidazole).
`
`Omeprazole degrades very rapidly in water solu-
`1ions at low pH-values. Figure 2 shows a plot of the
`logarithm of the observed rate constant for
`degradation as a function of pH. In each experi(cid:173)
`ment,
`the
`initial, pseudo-first-order
`rate of
`degradation was calculated from the amount of un(cid:173)
`changed omcprazole in buffer solutions (3). The
`rate of degradation proceeds with a half-life of less
`
`than 10 minutes at pH-values below 4. At pH 6.5 the
`half-life of degradation is 18 hours; at pH J1 about
`300 days.
`Pre formulation studies have shown that moisture,
`solvents and acidic substances have a deleterious ef.
`feet on the stability of omeprazole and should be
`avoided in pharmaceutical formulations.
`
`-·-···- ------'
`Figure 1. Omepr~zole, H 168/68, 5-methoxy-2-[[(4-
`methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl) -IH(cid:173)
`benzimld:izole-
`
`
`
`114
`
`log kobs
`•1 ·-·. - -_ ___ ~ __ --~
`
`0· -
`
`- 1 . -
`
`-2 . -
`
`3. "'
`
`I
`
`r
`I
`
`a
`2
`6
`11 pH
`10
`Figure 2. Logarithm of the observed rate constant (kobs. h"') for the initial, pseudo-first-order degradation of
`omeprazole in water solution al constant pH, plotted as a function of pH.
`
`The aim was to develop a stable, oral, phar(cid:173)
`maceutical formulation of omeprazole in doses of
`20-60 mg, with acceptable bioavailability charac(cid:173)
`teristics.
`
`Pharmaceutical con(cid:173)
`siderations
`For a substance which is very slightly soluble In
`water and which rapidly degrades in the acid en(cid:173)
`vironment of the stomach, there Is a limited number
`of options as far as pharmaceutical development is
`concerned.
`
`Solutions
`In animal experiments and in initial studies in man
`it is highly preferable to use water soluti(>ns of the
`drug in order to avoid influences oft he dosage form
`on the pharmacokinetics and pharmacodynamics
`of the drug. Omeprazole is, however, only soluble in
`alkaline water solutions with physiologically unac(cid:173)
`ceptable, high pH-values.
`
`Suspensions
`In toxicological and phase I clinical studies, suspen(cid:173)
`sions of omeprazole in water were used. Micronised
`
`omeprazole - particle surface area larger than 2.5
`m 2/g- was suspended in a 0.25 fJ!o water solution
`of methylcellulose also containing sodium bicar(cid:173)
`bonate as pH buffer. The suspensions can be stored
`at refrigerator temperature for a week, or stored
`deep frozen for more than a year, and still retain
`99 11Jo of their initial potency. To avoid acidic
`degradation of omeprazole, the suspensions must
`be administered orally together with large amounts
`of pH buffering substances.
`
`Solid dosage forms
`There are two principle options for the formulation
`of an oral, solid dosage form of omeprazole:
`• A conventional oral dosage form from which
`omeprazole is released and absorbed rapidly
`enough to avoid degradation in the stomach.
`• An enteric-coated dosage form, which releases
`omeprazole for absorption
`in
`the small
`intestine.
`
`The first option was ruled out in a pilot
`bioavailability study (see below), where it was
`shown that more than half of the omeprazole in a
`rapidly dissolving dosage form degrades in the
`stomach.
`
`R i G H T S L I N t-1.~)
`
`~
`
`• • •
`
`'
`
`'
`
`•• • • o •
`
`.It
`
`• • I
`
`
`
`An enteric-coated dosage form, which does not
`release the active ingredient for dissolution and ab(cid:173)
`sorption until it has been transported down to the
`neutral reacting part of the small intestine, ofFers
`the best possibilities. The dosage form - a tablet, a
`Is coated with a polymer,
`capsule or granules -
`which is insoluble in acid media but soluble in
`neutral to alkaline media. Depending on the choice
`of polymer and on the thickness of the coated layer,
`the pH-solubility profile of the enteric-coating can
`be controlled.
`
`An enteric-coated dosage form of omcprazole must
`be perfectly coated and acid resistant, since, if any
`drug leaks out of the dosage form in the stomach, It
`is almost immediately degraded. The same is the
`case if an acidic medium can diffuse into the dosage
`form through pin-holes or damage in the enteric(cid:173)
`coating.
`
`Solid particles of a size exceeding 2-4 mm, such as
`enteric-coated tablets or capsules, are known to re(cid:173)
`main in the stomach for a long time before they are
`emptied into the small Intestine (4-6). Non(cid:173)
`disintegrating, coated tablets administered together
`
`%
`
`0 -r--.,-----.--·..---r--.-- ---,-
`20
`0
`10
`l"isurc J. Dis5olution of omeprn1.ote from tin-e~ granule
`fom1ul~1Jon~ /JJ vlrro in phosphate buff~r, pH= 6.5. The
`cumula tive omounl dissolved (lifo) is plotted as a function
`of time,
`o granules, batch H 370-9-1
`A granules, batch H 370-8-1
`'Y granules, batch H 370-1-1
`
`1!5
`
`with food were found to stay in the stomach for
`more than 14 hours (7). Enteric-coated aspirin
`tablets showed a prolonged and erratic gastric emp(cid:173)
`tying, while enteric-coated granules or a size of
`about I mm dispensed in hard gelatine capsules
`dispersed in the content of the stomach and
`gradually emptied in to the small intestine in a
`reproducible way (5),
`
`In the pharmaceutical manufacture of coated
`dosage forms, it Is impossible to coat every single
`unit in a batch perfectly. A small fraction of units
`will have imperfect coating, or else be damaged
`during further handling and transport. For a single
`unit, enteric-coated dosage form of omeprazole,
`e.g, a tablet, there is always a small risk that all
`omeprazola contained in the dose can be degraded
`in the stomach. For a multiple unit, enteric-coated
`dosage form, e.g, enteric-coated granules dispensed
`in a hard gelatine capsule, only the omeprazole con(cid:173)
`tained in a few pellets out of a total of hundreds is
`lost. Our efforts were, therefore, concentrated on
`developing an enteric-coated granule formulatlon.
`
`Formulation and 1n vitro
`testing
`In the formulation of a solid dosage form of
`omeprazole, having a low water solubility of 0.1
`mg/ml, there is always the risk of dissolution rate
`limited absorption. Three spherical granule for(cid:173)
`mulations containing 10 f!/o of omeprazole were
`manufactured and classified. The fraction with a
`diameter between 0. 7 - 1.0 mm was used for further
`studies.
`
`The dissolution rate in vitro was determined using a
`slightly modified beaker method according to Levy
`and Hayes (8). 500 ml of deaerated phosphate buff(cid:173)
`er pH 6.5, ionic strength 0.1, was kept at + 37 o C
`and stirred at a rate of 100 rpm. An amount of
`granules corresponding to lO mg of omeprazole was
`added and the amount dissolved determined from
`the continuous recording of the absorbance at 300
`nm in a spectrophotometer using J em flow cells.
`The cumulative amount dissolved is plotted as a
`function oftime in Figure 3. All threeformulations
`released most oftheir content of omeprazole within
`30 minutes.
`
`
`
`IJ6
`
`A pilot bioavailability study showed that the
`two faster dissolving granules were absorbed to the
`same extent, while the extent of absorption of the
`more slowly dissolving granules was reduced.
`
`Rapidly dissolving, spherical granules containing
`10 "'o of omeprazole were enteric-coated with ap(cid:173)
`proximately 15 o/o by weight of polymer. The
`coating was sprayed onto the granules from an
`organic solvent solution in a fluldised bed ap·
`paratus. After drying, the coated granules were
`analysed and dispensed in hard gelatine capsules.
`
`The granules were tested for acid resistance in vitro
`in the following way: An amount of granules cor·
`responding to 10 mg of omeprazole was dispersed in
`500 ml of 0.1 molar hydrochloric acid at a
`temperature of +37 •c. Stirring was done with a
`paddle at a rate of 100 rpm. After two hours the
`granules were removed from the vessel, rinsed with
`water, dried and analysed for omeprazole by liquid
`chromatography. After two hours exposure to
`acid more than 85 O!o of the initial amount of
`omeprazole was recovered. When tested for dissolu(cid:173)
`tion rate in vitro in a medium of pH 6.5, more than
`90 ll/o dissolved within 15 minutes.
`
`Omeprazole capsules have an acceptable storage
`stability when stored in a proper package. The
`stability characteristics of omeprazole -
`t.he
`~ubstance is sensitive to moisture- necessitate the
`presence of a desiccant in the package.
`Bioavailability evaluation of
`dosage forms
`Omeprazole suspension given
`with and without pH-buffers
`The
`solubility and
`stability properties of
`omeprazole prevent the use of water solutions as the
`reference
`formulation
`in animal and human
`studies. A rapidly dissolving suspension of
`micronised omeprazole is the second best choice as
`the
`reference
`formulation. However,
`since
`omeprazole degrades rapidly in an acid environ·
`menl, it is essential to know the magnitude of the
`degradation occurring prior to the absorption of an
`oral dose. A pilot bioavailability study was
`therefore performed using six healthy, male
`volunteers.
`
`A suspension of micronised omeprazole, 60 mg, in
`water, 50 ml, also containing 6 mmoles of sodium
`bicarbonate (pH=9) was administered in the
`following way: In the morning, after fasting for at
`least ten hours, the volunteers were given a solution
`of 8 mmoles or sodium bicarbonate in 50 ml of
`water. Five minutes later the volunteers took the
`omeprazole suspension and rinsed it down with
`another 50 ml of sodium bicarbonate solution. 10,
`20, and 30 minutes later, a further 50 ml of sodium
`bicarbonate solution was taken. The amount of
`sodium bicarbonate Is sufficient to buffer the pH of
`the gastric content to neutral values for at least 45
`minutes.
`
`In another experiment, a suspension of omeprazole
`in water (pH adjusted to 9 by sodium hydroxide)
`was administered according to the same protocol as
`above but with the sodium bicarbonate solutions
`replaced by water. Doses were given in random
`order with a week's Interval between doses. Venous
`blood was sampled frequently over a period of four
`hours and blood plasma was analysed
`for
`omeprazole by liquid chromatography (9).
`
`The results of the plasma analyses are shown in
`Figure 4. The absorption of omeprazole proceeds
`rapidly and peak plasma concentrations were
`
`.~
`
`3
`4 h
`2
`0
`Figure 4. Plasma concentration of omcprazole in six
`healthy, fasting volunteers, mean + or- SEM after oral
`administration of omeprazole, 60 mg, given as:
`• buffered suspension
`4 suspension without buffer
`
`IJ.'I: l G H l' S ll. l i'..l k>~~}
`... .. .. ..... ...
`
`
`
`117
`
`From this experiment, it can be concluded that the
`in vitro dissolution rate method used can dis(cid:173)
`criminate between ·acceptable and non-accept(cid:173)
`able batches. In order to be fully absorbed, the
`in vitro dissolution rate should be as high as, or
`higher than, that of granules H 370-8-1.
`
`Bioavailability of enteric-coated
`granules
`Six, healthy, male volunteers participated in a three(cid:173)
`way, cross-over bioavailability study. They received,
`in random order, 60 mg single, oral doses of
`omeprazole either as a buffered suspension given
`together with sodium bicarbonate solution, or as
`enteric-coated granules dispensed in hard gelatine
`capsules given together with 300 ml of water on an
`empty stomach or as enteric-coated granules in cap(cid:173)
`sules together with a meal. In each experiment,
`standardised meals were served 2.5 and 6 hours
`after administration of the dose. Venous blood was
`sampled frequently for four hours (suspension) or
`seven hours (granules). Blood plasma was analysed
`for omeprazole by liquid chromatography accord(cid:173)
`ing to Persson et al (9).
`
`The results of the plasma analyses are shown in
`Figure 5. The absorption of omeprazole after the
`suspension was given was rapid, and peak plasma
`concentrations were reached within 10 -
`20
`minutes. After administration of the enteric-coated
`
`1Jmolll
`5 •
`
`---------------- -------------4
`
`reached after a mean of 13 minutes in both ex(cid:173)
`periments. The area under the plasma concentra(cid:173)
`tion time curve (AUC) was calculated by the
`trapezoidal method up to four hours after ad(cid:173)
`ministration and extrapolated
`to
`infinity by
`dividing the last plasma concentration by the
`negative slope of the terminal, linear part of the
`log/linear plasma concentration time curve.
`
`the omeprazole suspension was given
`When
`together with sodium bicarbonate buffer, the mean
`AUC was 4.8 jlmol x h/1 (range 2.8- 8.8). With(cid:173)
`out the buffer protection the AUC was reduced
`lo a mean of 2.1 pmol x h/1 (44 "lo), indicating
`that more than half of the dose was lost due to
`degradation in the acidic stomach.
`
`A straight-forward pharmacokinetic analysis ofthe
`data showed that the absorption of omeprazo!e was
`rapid and completed within the period during
`which the stomach was neutral. The results clearly
`show that a conventional, non-buffered, oral
`dosage form of omeprazole will have a low systemic
`bioavailability owing to preabsorption degrada(cid:173)
`tion of omepruole in the stomach.
`Bioavailability of granules - in(cid:173)
`fluence of dissolution rate
`A pilot bioavailability study in six, healthy
`volunteers was performed in order to clarify the in·
`fluence of the dissolution rate on the absorption of
`omeprazole. Three granule formulations -
`the
`dissolution curves are shown in Figure 3 - were
`tested using buffered suspension as the reference
`formulation. In order to avoid problems with the
`degradation of omepruolc, doses of 60 mg were
`given together with sodium bicarbonate, as describ(cid:173)
`ed above. Venous blood was frequently sampled and
`blood plasma analysed for omeprazole (9). The
`AUC for the
`two faster dissolving granules
`(H 370-9-1 and H 370-8-1) relative to that of the
`reference formulation was 95 and 92 %, respective(cid:173)
`ly. The granules with the lowest in vitro dissolu(cid:173)
`tion rate (H 370-1-1) were absorbed to a lower extent
`and had a mean relative AUC of 73 OJo only. The
`
`for the other two granule formulations and for the
`suspension, also indicating a lower rate oi ab(cid:173)
`sorption.
`
`oral doses of omeprazole as:
`• buffered suspension
`• enteric-coated granules before breakfast
`A enteric-coated granules with breakfast
`
`
`
`118
`
`granules a certain time was required !'or gastric
`emptying and for dissolution of the enteric-coating
`before absorption of omeprazole started. In most
`cases, gastricemptyirlg occurred in conm:ction with
`the meal served 2.5 hours after the dose. In one sub(cid:173)
`ject, when enteric-coated granules were given with
`food, gastric emptying of granules did not start un(cid:173)
`til in connection with the second meal, served six
`hours after the dose.
`
`The plasma concentration-time curves obtained
`after administration of enteric-coated granules
`were nat and broad, and peak plasma concentra(cid:173)
`tions were low, The total amount absorbed, as
`reflected by the AUC, was, however, only de(cid:173)
`creased by 14 D!o when the granules were given on an
`empty stomach in comparison with the buffered
`suspension. The corresponding figure for en(cid:173)
`teric-coated granules administered with a meal
`is higher, but since absorption of omeprazole
`was not completed in all subjects when the ex(cid:173)
`periment was terminated, the exact figure is un(cid:173)
`ktlown. Although this study is not fully con(cid:173)
`clusive regarding the bioavailability of omeprazole
`given with food, it is recommended that ome(cid:173)
`prazole should be taken in the morning before
`breakfast.
`
`The effect of omcprazole on gastric acid secretion is
`long lasting (10). The effect is not a direct function
`of blood concentration of omeprazole at any time,
`but i~ rather a function of the total umoum of
`omeprazole reaching the general circulation, i.e.,
`directly proportional to the AUC (2, 10). This
`means that the same pharmacological effect is
`achieved with dosage forms of omeprazole produc(cid:173)
`ing equal AUCs. The shapes of the plasma concen(cid:173)
`tration-time curves are of no importance.
`
`Bioavailability of enteric(cid:173)
`coated granules administered
`at different times before
`breakfast
`When omeprazole enteric-coated granules are given
`with a meal, the rate of absorption of omeprazolc is
`reduced. Patients are therefore recommended to
`take the dose on an empty stomach before the morn(cid:173)
`it1g meal. However,
`in clinical practice it
`is
`necessary to know what length of time is required
`
`between dosing and food intake. To be able to
`answer the question, we performed a bioavail(cid:173)
`ability study comparing omeprazole enteric(cid:173)
`coated granules given 15 minutes before the
`breakfast with the same dose given 2 minutes
`before the meal. A buffered suspension was
`again used
`as
`the
`reference
`formulation.
`1\velve healthy volunteers participated in
`the
`study. The doses were given as described above.
`Standardised meals were served after 2.5, 6, lO
`and 13 hours. Blood samples were collected
`over a period of 6 hours (suspension) and 24
`hours (granules).
`
`Eleven of the subjects completed the study and are
`included In the results. The resulting mean plasma
`concentration time curves are shown in Figures 6
`and 7. It Is interesting to note that the absorption of
`omeprazole from the enteric-coated granules in
`some subjects started as early as 30 minutes after
`the dose and that most subjects had a second pla~
`ma concentration peak shortly after the second
`meal served 2.5 hours after dose.
`
`The AUC, relative to that of the reference formula(cid:173)
`tion, was very similar in the two experiments with
`
`,_.mol l
`7
`• '"'' . , ..
`
`.. .. .. . -
`
`·- - - - - - · · · · · .. ·-;--- ,,._ .... .
`
`6
`
`5
`
`•
`
`4
`
`-
`
`2
`
`"
`
`I
`
`.
`
`0
`
`0
`6 h
`Figure 6. Plasma concentration of omeprazole, mean
`+ or - SEM, in eleven healthy volunteers given a 60 mg
`single, oral dose of omeprazole as a buffered suspension
`under fasting conditions.
`
`
`
`f,lmol/1
`1.5 . -- - - - - --- - - - - - - - - - - - - - - - - - - - - - - - - ..
`
`119
`
`0.5
`
`0
`
`r--j~--i-~,._ ...... ,_
`1-- - - . - - ---,.---.,-----r-------r-- --r-l l-r,"-- - --'1
`0
`2
`4
`6
`8
`10
`12
`24
`h
`Figure 7, Plasma concentration of omeprazQie, men + or
`- SEM, in eleven healthy given 60 mg single, oral doses of
`omeprazolc as:
`
`• enteric-coated gmnules lS minutes before breakfast
`A enteric·coated granules 2 minutes before breakfast
`
`enteric-coated granules; 65.5 % when given 15
`minutes before breakfast and 66.6 DJo when given 2
`minutes before breakfast. The variability in the
`AUC between doses within subjects was small, as
`can be seen in Figure 8. The conclusion of this study
`is that the omeprazole dose can be given before the
`morning meal, and that there is no need to specify
`any time bet weer. the administration and the start
`of the morning meal.
`
`Bioavailability of enteric(cid:173)
`coated granules - interaction
`with antacids
`In the clinical treatment of ulcer, antacids are often
`prescribed together with inhibitors of gastric acid
`secretion. Antacids may interfere with the function
`of an enteric-coated dosage form and cause
`dissolution of the coating in the stomach. For
`omeprazole this could mean an increased risk of
`degradation in the stomach. We therefore tested the
`influence of a liquid antacid on the bioavailability
`of omeprazole enteric-coated granules.
`
`Six healthy volunteers were given, in random
`order, enteric-coated granules with and without
`concomitant administration of an aluminium(cid:173)
`magnesium hydroxide/carbonate suspension. The
`dose was given on an empty stomach and venous
`blood samples collected during a period of seven
`hours. In one experiment the subjects were
`pretreated with antacid the day before the ome(cid:173)
`prazole administration. 10 ml doses of a liquid ant(cid:173)
`acid with an acid-binding capacity of 85 mmol
`per dose (Novaluzidlil, AB Hlissle, Sweden) were
`given one and three hours after each meal and at
`bed time; a total of seven doses. On the morning of
`the next day, another 10 ml dose was given just prior
`to the dose of omeprazole enteric-coated granules.
`In the other experiment omeprazole enteric-coated
`granules were administered without antacid treat·
`ment.
`
`The results of the plasma analyses are summarised
`in Figure 9, which shows the individual and mean
`AUCs. The mean AUC was practically identical in
`the two experiments. As can be seen in Figure 9, the
`variability in the AUC within each subject is small,
`
`
`
`\
`
`120
`
`fJnlOI • hI
`
`~molxh/1
`
`I
`I
`
`.
`
`10-
`
`coated
`
`5-
`
`--- _.;.. ___ ...
`
`0
`
`bullered
`susoens1on
`
`enterrc
`granules
`15 mm
`2 m•n
`before
`belore
`breakfast
`breakfast
`Figure 8. AUC (Jimol x h/1) in eleven healthy volunteers
`given 60 mg single, oral doses of omeprazole as a buffered
`suspension and enteric-coated granules 15 or 2 minutes
`before breakfast.
`- - individual values
`• . • • - mean values
`
`the variability between subjects
`whereas
`sub~tantial.
`
`is
`
`Concluston: Co-administration of antacids has no
`inOuence on the bioavailability of omeprazole
`given as enteric-coated granules.
`
`0 -~------------------------~
`Without
`Wilh
`antac1ds
`antactds
`Figure 9. AUC (Jimolxh/1) in six healthy volunteers
`given 60 mg single, oral doses of omeprazole enteric·
`coated granules with and without antacids.
`- - individual values
`- - - - · mean values
`
`References
`Walhnark B, Berglindh T, Mardh S 1·t al. The
`mechanism of action of omeprazolc. Scand J
`Gastroenteroll985;20(suppl 108):37-51.
`2. Larsson H, Mal!sson H, Sundell G, Carlsson E.
`Animal pharmacodynamics of omeprazole. A
`survey of the pharmacological projlenies of
`omeprazole in animals. Scand J Gastroenterol
`19B5;20(suppl 108):23-35.
`3. Erickson GEM. Unpublished result£ 198(1.
`.J. Blythe RH, Grass GM, MacDonell OR. The for(cid:173)
`mulation and evaluation of enteric-coated aspirin
`iablets. Am J Pharm 1959;!31:206·16.
`5. Hogen toft C, Carlsson I, Ekenved G, Magnusson A.
`lnnucnce of
`food on
`the
`absorption of
`acetylsalicylic acid from enteric-coaled dosage
`forms. Ilur J Clin Pharmacoll978;J4:351-5.
`
`6. Bechgaard H. Critical
`influencing
`factors
`gastrointestinal absorption - What is the role of
`pellets? Acta Pharm Technolog I 982;28: 149-57.
`7. Bogentoft C, Jonsson UE, Eriksson R, Alpsten M
`Gastric emptying of pellets and tablets in healthy
`subjects under fasting and nonfasting conditions.
`43rd International Congress of Pharmaceutical
`Sciences FlP, Montreux 1983, p 102.
`8. Levy 0, Hayes BA. Physicochemical basis of the
`buffered acetylsalicylic acid controversy. N Eng! J
`Med 1960;262: 1053-8.
`9. Persson B-A, Lagerstrllm P-0, Grundevik I. Deter(cid:173)
`mination of omepratole and ruetaboli!es in plasma
`and urine. Scand J Gastroenterol 1985;20(suppl
`108):71-7.
`
`10. Cederberg C, Ekenved G, Lind T, Olhe L. Acid in(cid:173)
`hibitory characteristics of omeprazolc in man.
`Scand J Gastrocnteroll985;201suppl IOB):IOS-12.
`
`R t G H 1'' 9
`
`lt. I r·~ ~<~)