Development of an oral formulation of
`omeprazole
`PILBRANT A and CEDERBERG C
`Departments of Pharmaceutics
`and Medicine,
`AB Hassle, Mdlndal, Sweden.
`
`113
`
`Pilbrant A, Cederberg C. Development of an oral formulation of omeprazole.
`Scand J Gastroenterol
`1985;20(suppl 108);113-120,
`
`Omeprazole has a low water solubility and is chemically labile in an acid environment.
`In
`the tormulation of an oral dosage form of omeprazole the possibilities of dissolution rate
`ion degradation must be kept in mind. A water suspen-
`limited absorption and preabsorpt
`sion of omeprazole was tested in a pilot bioavailability
`study. The suspension was
`fasting volunteers on two occasions - together with sodium bicar-
`given to six healthy,
`bonate solution and together with the same volume of water. When the suspension was
`given with water the bioavailability was reduced by about 50 lo owing to preabsorption
`study the slowest of three granule formulations
`In another bioavailability
`degradation.
`with differing in vitro dissolution rates showed a reduced extent of absorption.
`and tested in a
`pellet formulation
`A controlled-release
`(enteric-coated) was formulated
`series of bioavailability
`studies. A single dose given with food resulted in a delayed
`absorption and possibly lower bioavailability
`fasting conditions. When the
`than under
`the length of time
`granules were given on an empty stomach before the morning meal
`administration of a liquid
`between dosage and meal was of no importance. Concomitant
`antacid had no influence on the bioavailability of omeprazole
`
`Key-vrordst Bioavailability; controlled release; dosage form; enteric coating; omeprazole;
`stability
`Ake Pitbrant, Farm. Ltc., Dept of Pharmaceutics, AB HA'ssia,
`S-431 83 MbtndaL Sweden
`
`Introduction
`I) is a substituted
`Omeprazole
`(Figure
`benz-
`imidazole which
`selectively
`the proton
`inhibits
`pump in the gastric mucosa (1, 2). Omeprazole
`is
`very slightly so]uble in water, but
`is very soluble in
`alkaline solutions as the negatively charged ion. It is
`and 8.8
`4 (pyridinium)
`an ampholyte with pKa
`(benzimidazole).
`
`very rapidly in water solu-
`Omeprazole
`degrades
`tions at low pH-values. Figure 2 shows a plot of the
`logarithm of
`for
`rate
`the
`constant
`observed
`as a function of pH. In each experi-
`degradation
`rate of
`pseudo-first-order
`the
`initial,
`ment,
`degradation was calculated from the amount of un-
`(3). The
`changed omepiazoie
`in buffer
`solutions
`rate of degradation proceeds with a half-life of Less
`
`than 10minutes at pH-values below 4. At pH 6.5the
`half-life of degradation is 18 hours; at pH 11 about
`300 days,
`
`Preforrnulation
`studies have shown that moisture,
`solvents and acidic substances have a deleterious ef-
`fect on the stability of omeprazole
`and should be
`avoided in pharmaceutical
`formulations.
`
`CHi
`
`CH„.—8—'
`
`'0l.f,
`
`H 168!68, 5-me!hox;-2-',[(4
`Figure 1. Omeprazole,.
`-1H-
`methoxy-3,5-dimethyl-2-pyridinyl)
`methyl]
`suifiny1]
`benzimidazoie.
`
`Qsgg Q'f g ] i
`
`iu
`
`OOO
`
`gOO 4
`
`g
`
`Ls o,
`O ~
`
`A
`
`Q gU '
`
`O
`
`tn
`
`Page 1
`
`Dr. Reddy's Exh. 1064
`
`

`

`114
`
`log kobs
`
`~ 1 ~ T—
`
`. 4
`
`'I
`
`1
`
`t
`
`3
`2
`4
`9
`8
`Figure 2. Logarithm of the observed
`h t) for the initial, pseudo-first-order
`rate constant
`(kabt
`in water solution at constant pH, plotted as a function of pH.
`omeprazole
`
`r
`
`t
`
`5
`
`6
`
`7
`
`10
`
`degradation
`
`11 pH
`of
`
`a stable,
`The aim was
`oral, phar-
`to develop
`formulation of omeprazole
`in doses of
`maceutical
`20-60 mg, with acceptable bioavailability
`charac-
`teristics.
`
`con-
`
`Pharmaceutical
`siderations
`soluble
`For a substance which is very slightly
`in
`in the acid en-
`water and which rapidly degrades
`vironment of the stomach,
`there is a limited number
`of options as far as pharmaceutical
`development
`is
`concerned.
`
`Solutions
`and in initial studies in man
`in animal experiments
`it is highly preferable to use water solutions of the
`drug in order to avoid influences of the dosage form
`and pharmacodynamics
`on the pharmacokinetics
`of the drug. Omeprazole is, however, only soluble in
`unac-
`alkaline water solutions with physiologically
`ceptable, high pH-values.
`
`Suspensions
`ln tox'ccnloaical anrl nhace 1 r'linical stttdies
`tutcnen
`sions of omeprazole in water were used. Micronised
`
`- particle surface area larger
`than 2.5
`omeprazole
`m'/g —was suspended
`in a 0,25 %%uo water solution
`of methylcellulose
`sodium bicar-
`also containing
`bonate as pH buffer. The suspensions
`can be stored
`for a week, or stored
`at refrigerator
`temperature
`deep frozen for more than a year, and still
`retain
`99 ttt'o of their
`potency. To avoid
`initial
`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:
`e A conventional
`oral dosage form from which
`is released and absorbed
`omeprazole
`rapidly
`enough to avoid degradation
`in the stomach.
`o An enteric-coated dosage form, which releases
`for
`absorption
`the
`omeprazole
`in
`small
`intestine.
`
`out
`The
`a pilot
`ruled
`option was
`in
`first
`it was
`bioavailability
`(see below), where
`study
`shown that more than half of the omeprazole
`in a
`ranirlly
`in the
`dissolving
`dosage
`form degrades
`stomach.
`
`C)
`
`CO c
`
`d
`
`EOO
`
`O 8 c
`
`cc
`
`Oc
`
`rc
`co
`E ac
`O
`CI
`'a
`
`O EU
`
`Page 2
`
`Dr. Reddy's Exh. 1064
`
`

`

`An enteric-coated
`dosage form, which does not
`for dissolution and ab-
`release the active ingredient
`it has been transported
`sorption until
`down to the
`reacting part of the small
`neutral
`intestine, offers
`the best possibilities. The dosage form —a tablet, a
`capsule or granules —is coated with a polymer,
`which is insoluble
`in acid media but
`soluble
`in
`to alkaline media. Depending on the choice
`neutral
`of polymer and on the thickness of the coated layer,
`the pH-soiubility profile of the enteric-coating can
`be controlled.
`
`An enteric-coated dosage form of omeprazole must
`since, if any
`be perfectly coated and acid resistant,
`drug leaks out of the dosage form in the stomach,
`it
`is almost
`degraded. The same is the
`immediately
`case if an acidic medium can diffuse into the dosage
`form through pin-holes or damage in the enteric-
`coating.
`
`Solid particles of a size exceeding 2-4 mm, such as
`enteric-coated tablets or capsules, are known to re-
`main in the stomach for a long time before they are
`{4—6). Non-
`emptied
`into
`the
`small
`intestine
`coated tablets administered
`disintegrating,
`together
`
`0/
`
`100
`
`80
`
`60
`
`'0
`
`20 "
`
`0"
`
`30min
`
`10
`20
`Figure 3. Dissolution of omeprazole
`from three granule
`formntattnnsin
`vi(ro in phosphate buffer, pH= 6.5. The
`amount dissolved (%)is plotted as a function
`cumulative
`of time,
`L Ltl
`,n
`lAA1
`"«es, vnacu xz
`Iv-w-r
`X granules, batch H 370-8-1
`V granules, batch H 370-1-1
`
`1]5
`
`with food were found to stay rn the stomach for
`more
`(7). Enteric-coated
`than
`14 hours
`aspirin
`tablets showed a prolonged and erratic gastric emp-
`granules of a size of
`tying, while enteric-coated
`about
`1 mm dispensed
`in hard gelatine
`capsules
`in the content of the stomach
`dispersed
`and
`in to the small
`in a
`graradually
`emptied
`intestine
`reproducible way {5),
`
`of coated
`In the pharmaceutical
`manufacture
`to coat every single
`it is impossible
`dosage forms,
`fraction of units
`in a batch perfectly. A small
`unit
`coating, or else be damaged
`will have imperfect
`during further handling and transport. For a single
`dosage form of omeprazoie,
`unit, enteric-coated
`e.g, a tablet,
`there is always a small
`risk that all
`contained in the dose can be degraded
`orneprazole
`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-
`tained in a few pellets out of a total of hundreds
`is
`lost. Our efforts were,
`therefore,
`concentrated
`on
`developing an enteric-coated granule formulation.
`
`and in vitro
`
`Formulation
`testing
`of a solid dosage
`ln the formulation
`form of
`having a low water solubility of 0.1
`orneprazole,
`the risk of dissolution rate
`there is always
`mg/ml,
`absorption. Three spherical
`limited
`for-
`granule
`10 Vo of omeprazole were
`mulations
`containing
`manufactured
`and classified, The fraction with a
`diameter between 0.7- 1,0 mm was used for further
`studies.
`
`The dissolution ratein vitro was determined using a
`slightly modified beaker method according to Levy
`and Hayes (8). 500 ml of deaerated phosphate buff-
`er pH 6.5, ionic strength 0.1, was kept at +37'C
`and stirred at a rate of 100 rpm. An amount of
`to 10mg of omeprazole was
`granules corresponding
`added and the amount dissolved determined
`from
`recording of the absorbance at 300
`the continuous
`nm in a spectrophotometer
`using I cm flow cells.
`The cumulative
`amount
`dissolved is plotted as a
`function of time in Figure 3. All three formulations
`released most of their content ofomeprazole within
`30 minutes.
`
`IPt 4 Gl 14 T 8;; 1 &'d its~
`
`Page 3
`
`Dr. Reddy's Exh. 1064
`
`

`

`116
`
`bioavailability
`A pilot
`the
`showed
`that
`study
`two faster dissolving granules were absorbed to the
`same extent, while the extent of absorption of the
`more slowly dissolving granules was reduced.
`
`spherical granules
`containing
`Rapidly dissolving,
`10 % of omeprazole were enteric-coated with ap-
`15% by weight of polymer. The
`proximately
`sprayed onto the granules
`coating was
`from an
`solution
`soivent
`organic
`in a fluidised
`bed ap-
`paratus. After drying,
`the coated granules were
`analysed and dispensed in hard geiatine capsules.
`
`The granules were tested for acid resistancein virro
`in the following way: An amount of granules cor-
`responding to 10mg of omeprazole was dispersed in
`500 ml of 0,1 molar
`acid at a
`hydrochloric
`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
`After
`to
`two hours
`exposure
`chromatography.
`acid more than 85 % of the initial
`amount of
`omeprazole was recovered. When tested for dissolu-
`tion rate in virro in a medium of pH 6.5, more than
`90 % dissolved within 15 minutes.
`
`have an acceptable storage
`Omeprazole
`capsules
`stored in a proper package. The
`stability when
`of omeprazole — the
`characteristics
`stability
`to moisture —necessitate the
`substance is sensitive
`presence of a desiccant
`in the package.
`Bioavailability evaluation of
`dosage forms
`Omeprazole
`suspension
`given
`with and without pH-buffers
`of
`The
`and
`solubility
`stability
`properties
`the use of water solutions as the
`omeprazole prevent
`formulation
`reference
`in
`and
`animal
`human
`of
`studies. A rapidly
`dissolving
`suspension
`micronised omeprazole is the second best choice as
`reference
`formulation.
`the
`since
`However,
`omeprazole
`rapidly in an acid environ-
`degrades
`to know the magnitude of the
`it is essential
`ment,
`degradation occurring prior to the absorption of an
`dose. A pilot
`oral
`bioavailability
`study was
`therefore
`performed
`six healthy, male
`using
`volunteers.
`
`A suspension of micronised omeprazole, 60 mg,
`in
`water, 50 ml, also containing 8 mmoles of sodium
`(pH=9) was
`bicarbonate
`administered
`in the
`following way: In the morning,
`after fasting for at
`least ten hours,
`the volunteers were given a solution
`of 8 mmoles of sodium bicarbonate
`in 50 ml of
`water. Five minutes
`took the
`the volunteers
`later
`and rinsed it down with
`omeprazoie
`suspension
`another 50ml of sodium bicarbonate solution. 10,
`later, a further 50 ml of sodium
`20, and 30 minutes
`solution was taken. The amount of
`bicarbonate
`to buffer the pH of
`sodium bicarbonate is sufficient
`to neutral values for at least 45
`the gastric content
`minutes,
`
`In another experiment, a suspension of omeprazole
`in water (pH adjusted to 9 by sodium hydroxide)
`according to the same protocol as
`was administered
`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
`blood
`hours
`and
`for
`was
`plasma
`analysed
`(9).
`omeprazole
`by liquid chromatography
`
`The results of the plasma analyses
`are shown in
`Figure 4. The absorption of omeprazole proceeds
`and peak plasma
`concentrations
`rapidly
`were
`
`I
`
`ttmot
`6
`
`5
`
`3
`
`2
`
`1
`
`3
`0
`2
`of omeprazole
`concentration
`Figure &t. Plasma
`in six
`fasting volunteers, mean + or —SEM after oral
`healthy,
`admtttlstraiio&n& o& o&»eplazo&c, 5u r&og& giver& atc
`~ buffered suspension
`A suspension without buffer
`
`lPt I 43 Ft T 6 th 1
`
`i"4 ti',tl~
`
`Page 4
`
`Dr. Reddy's Exh. 1064
`
`

`

`117
`
`From this experiment,
`it can be concluded that
`the
`in vitro
`dissolution
`rate method
`used
`can dis-
`between 'cceptable
`criminate
`non-accept-
`and
`able batches.
`to be fully absorbed,
`In order
`the
`rate should be as high as, or
`in vitro dissolution
`that of granules H 370-8-1.
`than,
`higher
`Bioavailability of enteric-coated
`granules
`Six, healthy, male volunteers participated in a three-
`way, cross-over bioavailability
`study. They received,
`oral doses of
`in random order, 60 mg single,
`either as a buffered suspension
`omeprazole
`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-
`together with a meal.
`sules
`In each experiment,
`standardised meals were served 2.5 and 6 hours
`after administration of the dose. Venous blood was
`for four hours (suspension) or
`sampled frequently
`seven hours (granules). Blood plasma was analysed
`for omeprazole
`accord-
`by liquid chromatography
`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
`10 — 20
`concentrations
`reached within
`were
`minutes. After administration of the enteric-coated
`
`umolx
`5 '
`
`I
`
`2
`
`C
`
`reached after a mean of 13 minutes
`in both ex-
`periments. The area under
`the plasma concentra-
`tion time
`curve
`(AUC) was
`calcula'fed
`by the
`up to four hours
`after ad-
`trapezoidal method
`ministration
`to infinity
`extrapolated
`and
`by
`last plasma
`dividing
`the
`concentration
`by the
`slope of the terminal,
`linear part of the
`negative
`log/linear
`plasma concentration time curve.
`
`When
`the
`orneprazole
`suspension
`was
`given
`together with sodium bicarbonate buffer,
`the mean
`(range 2.8 —8.8) With-
`AUC was 4.8 pmol x h/I
`out
`the buffer protection the AUC was
`reduced
`to a mean of 2.1 pmol x h/I
`(44 c/o),
`indicating
`that more than half of the dose was lost due to
`degradation
`in the acidic stomach.
`
`analysis of the
`A straight-forward
`pharmacokinetic
`data showed that the absorption of omeprazole was
`and completed within
`rapid
`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
`owing to preabsorption
`bioavailability
`degrada-
`tion of omeprazole in the stomach.
`Bioavailability of granules —in-
`fluence of dissolution rate
`A pilot
`bioavailability
`study
`in
`six,
`healthy
`volunteers was performed in order to clarify the in-
`fluence of the dissolmion rate on the absorption of
`formulations — the
`Three granule
`omeprazole.
`curves are shown in Figure 3 —were
`dissolution
`tested using buffered suspension
`as the reference
`In order to avoid problems with the
`formulation.
`degradation of omeprazole,
`doses of 60 mg were
`given together with sodium bicarbonate, as describ-
`ed above. Venous blood was frequently sampled and
`blood plasma
`for omeprazole
`analysed
`(9), The
`AVC for
`the
`faster
`two
`dissolving
`granules
`(H 370-9-1 and H 370-8-1) relative to that of the
`reference formulation was 95 and 92 4/o, respective-
`ly. The granules with the lowest
`in vitro dissolu-
`tion rate (H 370-1-1)were absorbed to a lower extent
`and had a mean relative AUC of 73 c/o only. The
`
`0C
`CD
`
`CD
`
`0 c
`
`s
`
`JD
`
`E8 u0
`
`00CCC
`E-CCC0cE 0
`E 0,0
`
`0 n
`
`&3
`'0
`
`M
`
`for the other two granule
`formulations
`a iower
`also indicating
`suspension,
`sorption,
`
`and for the
`rate of ab-
`
`orat doses of omeprszole as:
`bccffc reel sccsnension
`8 enteric-coated granules before breakfast
`enteric-coated granules with breakfast
`
`R I Gi R T B I. I
`
`iu K4~
`
`Page 5
`
`Dr. Reddy's Exh. 1064
`
`

`

`118
`
`a certain time was
`1'or gastric
`granules
`required
`emptying and for dissolution of the enteric-coating
`before absorption of omeprazole
`started,
`In most
`cases, gastric emptyitig occurred in connection with
`the meal served 2.5 hours after the dose. ln one sub-
`ject, when enteric-coated granules were given with
`food, gastric emptying of granules did not start un-
`in connection with the second meal, served six
`til
`hours after the dose.
`
`concentration-time
`The plasma
`curves obtained
`of emeric-coated
`after
`administration
`granules
`were flat and broad, and peak plasma concentra-
`absorbed,
`low, The total amount
`tions were
`as
`only de-
`by the AUC, was, however,
`reflected
`creased by 14 'Vo when the granules were given on an
`empty stotnach in comparison with the buffered
`for
`en-
`The
`corresponding
`suspension.
`figure
`teric-coated
`administered
`a meal
`with
`granules
`of omeprazole
`absorption
`since
`but
`is higher,
`was not completed
`in all subjects when the ex-
`the exact
`figure is un-
`terminated,
`periment was
`con-
`is not
`known. Although
`this
`study
`fully
`clusive regarding the bioavailability of omeprazole
`that ome-
`is recommended
`food,
`given with
`it
`be taken in the morning
`before
`should
`prazole
`breakfast.
`
`The effect of omeprazole on gastric acid secretion is
`long lasting (10).The effect is not a direct. function
`of blood concentration of omeprazole
`at any time,
`is rather a function of the total amount of
`but
`i.e„
`the general
`circulation,
`omeprazole
`reaching
`to the AUC (2, 10). This
`directly proportional
`effect
`the same pharmacological
`that
`means
`is
`achieved with dosage forms of omeprazole produc-
`ing equal AUCs, The shapes of the plasma concen-
`curves are of no importance.
`tration-time
`Bioavailability of enteric-
`coated granules
`administered
`times before
`at different
`breakfast
`Vr'hen omeprazole enteric-coated granules are given
`the rate of absorption of omeprazole is
`with a meal,
`are therefore
`recommended
`reduced. Patients
`to
`take the dose on an empty stomach before the morn-
`ptactice
`clinicai
`ing meal. However,
`in
`is
`ic
`length of time is required
`necessary to know what
`
`dosing and food intake. To be able to
`between
`a bioavail-
`answer
`the question, we performed
`enteric-
`omeprazole
`ability
`comparing
`study
`coated granules
`the
`before
`15 minutes
`given
`the same dose given
`breakfast with
`2 minutes
`before
`the meal. A buffered
`suspension
`was
`reference
`as
`formulation.
`again
`the
`used
`participated
`volunteers
`the
`Twelve
`healthy
`in
`study. The doses were given as described above,
`Standardised meals were served after 2.5, 6, 10
`13 hours, Blood samples were
`and
`collected
`over a period of 6 hours
`and 24
`(suspension)
`hours (granules).
`Eleven of the subjects completed the study and are
`included in the results. The resulting mean plasma
`time curves are shown in Figures 6
`concentration
`and 7, It is in teresting to note that the absorption of
`omeprazole
`from the enteric-coated
`in
`granules
`some subjects started as early as 30 minutes
`after
`the dose and that most subjects had a second plas-
`ma concentration
`peak shortly after
`the second
`meal served 2.5 hours after dose.
`
`The AVC, relative to that of the reference formula-
`tion, was very similar
`in the two experiments with
`
`f
`
`umccl
`7
`
`0
`
`0
`of omeprazole, mean
`Figure 6. Plasma
`concentration
`+ or —SEM, in eleven healthy volunteers
`given a 60 mg
`single, oral dose of omeprazole
`as a buffered susptmsian
`under
`fasting conditions.
`
`Oc
`OC
`
`0
`
`68 5
`
`!
`
`O C
`
`CC O
`ctC OM
`E CCC
`O a
`CC 0M
`g O.
`O c
`O
`a
`
`O8
`
`'a
`
`N
`ca
`
`Page 6
`
`Dr. Reddy's Exh. 1064
`
`

`

`119
`
`ttmot/I
`
`1.5 ~
`
`0.5
`
`I
`1
`6
`4
`2
`Figure 7. Plasma concentration of omeprazole, men + or
`—SEM, in eleven healthy given 60 mg single, oral doses of
`omeprazole as:
`
`t
`
`I
`
`8
`24
`~ enteric-coated granules 15 minutes before breakfast
`L enteric-coated granules 2 minutes before breakfast
`
`65.5 Vo when
`l5
`enteric-coated
`granules;
`given
`minutes before breakfast and 66.6 oro when given 2
`before breakfast. The variability
`in the
`minutes
`AUC between doses within subjects was small, as
`can be seen in Figure 8. The conclusion of this study
`the omeprazole dose can be given before the
`is that
`there is no need to specify
`morning meal, and that
`any time between the administration
`and the start
`of the morning meal.
`
`Bioavailability of entexic-
`- interaction
`coated granules
`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
`cause
`form and
`of the coating in the stomach. For
`dissolution
`this could mean an increased risk of
`omeprazole
`1111 CC o4
`CC o C
`ccu aaa auavau usa u uaC
`uCgf
`ucaatuna ma uaCSCOrunaeu,
`influence of a liquid antacid on the bioavailability
`of omeprazole enteric-coated granules.
`
`Six healthy
`in random
`volunteers
`given,
`were
`order, enteric-coated
`granules with and without
`of an aluminium-
`concomitant
`administration
`suspension. The
`magnesium hydroxide/carbonate
`dose was given on an empty stomach and venous
`blood samples collected during a period of seven
`In one
`hours.
`subjects were
`experiment
`the
`pretreated with antacid the day before the orne-
`10 ml doses of a liquid ant-
`prazole administration.
`capacity of 85 mmol
`acid with an acid-binding
`per dose (Novaluzid~, AB Hassle, 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 10ml dose was given just prior
`to the dose of omeprazole enteric-coated granules.
`In the other experiment omeprazole enteric-coated
`antacid treat-
`granules were administered without
`ment.
`The results of the plasma analyses are summarised
`in Figure 9, which shows the individual
`and mean
`Can nvv VVaS Praetieaaay iucaaaia.aa iu
`the two experiments. As can be seen in Figure 9, the
`variability m the AUC within each subject is small,
`
`R I Gi R "tr eg IL l
`
`I'ar ac&4/
`
`Oa
`
`Oa
`
`0 c
`
`s
`
`0
`
`E8 c
`
`sO+
`
`co O
`E 00 a
`Ct 0
`'0
`
`8 z
`
`c
`lg
`
`Q'
`
`0 M
`
`Page 7
`
`Dr. Reddy's Exh. 1064
`
`

`

`120
`
`nn)ol
`
`h I
`
`0 -~bufiered
`
`suscen sion
`
`coated
`
`granules
`Z min
`be!ore
`break!est
`
`entenc
`15 min
`be!ore
`breaklast
`Figurc 8. AUC (pmol x h/I)
`in eleven healthy volumeers
`given 60 mg single, oral doses of omeprazole as a buffered
`15 or 2 minutes
`and enteric-coated granules
`suspension
`before breakfast,
`values
`individual
`- ~ - ~ - mean values
`
`whereas
`substantial.
`
`the
`
`variability
`
`between
`
`subjects
`
`is
`
`Conclusion: Co-administration
`on the bioavailability
`in()uence
`given as enteric-coated granules.
`
`of antacids has no
`of omeprazole
`
`a QC
`
`) a
`
`Kl
`
`C)
`E
`
`'8 a
`a a
`IQ u
`
`V&
`
`8oCll
`E a,0 a
`'a4aa
`
`aan dBQ"
`
`a M
`
`References
`I Wallmark B, Berglindh T, Mgrdh S et al. The
`mechanism of action of omeprazole.
`I
`Scand
`1985;20(suppl 108):37-51.
`Gastroenterol
`2. Larsson H, Mattsson H, Sundell G, Carlsson E.
`of omeprazole.
`pharmacodynamics
`Animal
`A
`of
`the
`pharmacological
`properties
`survey
`Scand J Gastroenterol
`animals.
`in
`1985;20(suppl 108).'23-35.
`3. Erickson GEM. Unpublished
`results 1980.
`lvlacDonell DR. The for-
`Blythe RH, Grass GM,
`and evaluation of enteric-coated
`mulation
`aspirin
`tablets. Am J Pharm 1959;131:206-16.
`S. Bogentoi't C, Carlsson I, Ekenved G, Magnusson A.
`of
`food
`of
`on
`Influence
`absorption
`the
`acid
`from enteric-coated
`acetylsalicylic
`dosage
`forms. Eur J Clin Pharmacol 1978;14:35I-5.
`
`ot'meprazole
`
`H.
`
`6. Bechgaard
`Critical
`factors
`influencing
`absorption —What
`is the role of
`gastrointestinal
`pellets? Acta Pharm Technolog 1982;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.
`of Pharmaceutical
`43rd International
`Congress
`Sciences FIP, Montreux 1983, p 102.
`8. Levy G, Hayes BA. Physicochemical
`basis of the
`buffered acetylsalicylic
`acid comroversy. N Fngl J
`Med 1960;262:1053-8.
`9. Pcrsson B-A, Lagerstrdm P-O, Grundevik
`I. Deier-
`minaiion of omeprazole
`and metaboliies
`in plasma
`and urine, Scand J Gastroenterol
`1985;20(suppl
`108):71-7.
`10. Cederberg C, Ekenved G, I.ind T, Othe L. Acid in-
`of omeprazolc
`characteristics
`hibitory
`in man.
`Scand J Gasirocnterol
`1985;20/suppl 108):105-12,
`
`I!mal x h/I
`
`l
`
`10-
`
`5-
`
`0-
`
`Wlgi
`antacids
`
`without
`antacids
`Figure 9. AUC (pmoixh/I)
`in six healthy
`volunteers
`given 60 mg single, oral doses of omeprazole
`enteric-
`
`coated granules with and without antacids,—individual
`
`values
`-- -- - mean values
`
`Page 8
`
`Dr. Reddy's Exh. 1064
`
`