113
`
`Development of an oral formulation of
`omeprazole
`
`PILBRANT A and CEDERBERG C
`Departments of Pharmaceutics and Medicine,
`AB Hassle, Molndal, Sweden.
`Pilbrant A, Cederberg C. Development of an oral formulation of omeprazole.
`Scand J Gastroenterol 1985;2O(suppl 108): 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 degradation must be kept in mind. A water suspen-
`sion of omeprazole was tested in a pilot bioavailability study. The suspension was
`given to six healthy, fasting volunteers on two occasions - together with sodium bicar-
`bonate solution and together with the same volume of water. When the suspension was
`given with water the bioavailability was reduced by about 50 Vo owing to preabsorption
`degradation. In another bioavailability study the slowest of three granule formulations
`with differing in vitro dissolution rates showed a reduced extent of absorption.
`A controlled-release pellet formulation (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 length of time
`between dosage and meal was of no importance. Concomitant administration of a liquid
`antacid had no influence on the bioavailability of omeprazole.
`Key-words: Bioavailability; controlled release; dosage form; enteric coating; omeprazole;
`stability
`Ake Pilbrant, Farm. Lic., Dept of Pharmaceutics, AB Hassle,
`S-43183 Molndal. Sweden
`
`Introduction
`Omeprazole (Figure 1) is a substituted benz-
`imidazole which selectively inhibits the proton
`pump in the gastric mucosa (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 pKa-4
`(pyridinium) and 8.8
`(benzimidazole).
`
`Omeprazole degrades very rapidly in water solu-
`tions 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-
`ment,
`the
`initial, pseudo-first-order
`rate of
`degradation was calculated from the amount of un-
`changed omeprazole in buffer
`(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 11 about
`300 days.
`Preformulation 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.
`
`I
`Figure 1. Omeprazole, H 168168, 5-methoxy-2-[[(4-
`methoxy-3,S-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-
`benzimidazole.
`
`Lupin Exh. 1008
`
`

`
`114
`
`The aim was to develop a stable, oral, phar-
`maceutical formulation of omeprazole in doses of
`20-60 mg, with acceptable bioavailability charac-
`teristics.
`Pharmaceutical con-
`siderations
`For a substance which is very slightly soluble in
`water and which rapidly degrades in the acid en-
`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 solutions of the
`drug in order to avoid influences of the dosage form
`on the pharmacokinetics and pharmacodynamics
`of the drug. Omeprazole is, however, only soluble in
`alkaline water solutions with physiologically unac-
`ceptable, high pH-values.
`Suspensions
`In toxicological and phase I clinical studies, suspen-
`sions of omeprazole in water were used. Micronised
`
`omeprazole - particle surface area larger than 2.5
`m2/g - was suspended in a 0.25 Yo water solution
`of methylcellulose also containing sodium bicar-
`bonate as p H 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 To 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:
`0 A conventional oral dosage form from which
`omeprazole is released and absorbed rapidly
`enough to avoid degradation in the stomach.
`0 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.
`
`

`
`An enteric-coated dosage form, which does not
`release the active ingredient for dissolution and ab-
`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
`capsule or granules - is coated with a polymer,
`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 omeprazole 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-
`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
`emptied into the small intestine (4-6). Non-
`disintegrating, coated tablets administered together
`
`%
`
`0
`30min
`20
`10
`Figure 3. Dissolution of omeprazole from three granule
`formulationsin vitro in phosphate buffer, pH= 6.5. The
`cumulative amount dissolved ("0) is plotted as a function
`of time.
`granules, batch H 370-9-1
`A granules, batch H 370-8-1
`V granules, batch H 370-1-1
`
`115
`
`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-
`tying, while enteric-coated granules of a size of
`about 1 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
`omeprazole 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-
`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.
`Formulation and in vitm
`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-
`mulations containing 10 '70 of omeprazole were
`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
`granules corresponding to 10 mg of omeprazole was
`added and the amount dissolved determined from
`the continuous recording of the absorbance at 300
`nm in a spectrophotometer using 1 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 of omeprazole within
`30 minutes.
`
`

`
`116
`
`A pilot bioavailability study showed that the A suspension of micronised omeprazole, 60 mg, in
`two faster dissolving granules were absorbed to the water, 50 ml, also containing 8 mmoles of sodium
`same extent, while the extent of absorption of the
`bicarbonate (pH=9) was administered in the
`more slowly dissolving granules was reduced.
`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 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.
`
`Rapidly dissolving, spherical granules containing
`10 To of omeprazole were enteric-coated with ap-
`proximately 15 To by weight of polymer. The
`coating was sprayed onto the granules from an
`organic solvent solution in a fluidised 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
`SO0 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 To of the initial amount of
`omeprazole was recovered. When tested for dissolu-
`tion rate in vitro in a medium of pH 6.5, more than
`90 To dissolved within 15 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
`
`*mOl
`
`I
`
`Omeprazole capsules have an acceptable storage
`stability when stored in a proper package. The
`stability characteristics of omeprazole - the
`substance 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-
`ment, it is essential to know the magnitude of the
`0
`2
`1
`4 h
`degradation occurring prior to the absorption of an Figure 4. plasma concentration of omeprazo~e in six
`healthy, fasting volunteers, mean + or - SEM after oral
`oral dose. A pilot bioavailability study was
`administration of omeprazole, 60 mg, given as:
`therefore performed using six healthy, male
`buffered suspension
`A suspension without buffer
`volunteers.
`
`.
`
`

`
`117
`
`From this experiment, it can be concluded that the
`in vitro dissolution rate method used can dis-
`criminate between acceptable and non-accept-
`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-
`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-
`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-
`ing to Persson et a1 (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
`
`reached after a mean of 13 minutes in both ex-
`periments. The area under the plasma concentra-
`tion time curve (AUC) was calculated by the
`trapezoidal method up to four hours after ad-
`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.
`When
`the omeprazole suspension was given
`together with sodium bicarbonate buffer, the mean
`AUC was 4.8 pmol x h/l (range 2.8 - 8.8). With-
`out the buffer protection the AUC was reduced
`to a mean of 2.1 pmol x h/l (44 Vo), indicating
`that more than half of the dose was lost due to
`degradation in the acidic stomach.
`A straight-forward pharmacokinetic analysis of the
`data showed that the absorption of omeprazole 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-
`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 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 omeprazole, doses of 60 mg were
`given together with sodium bicarbonate, as describ-
`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 Vo, respective-
`ly. The granules with the lowest in vilro dissolu-
`tion rate (H 370-1-1) were absorbed to a lower extent
`and had a mean relative AUC of 73 Vo only. The
`^ ^ - 1
`
`I-^_
`
`sorption.
`
`A enteric-coated granules with breakfast
`
`

`
`118
`
`granules a certain time was required for gastric
`emptying and for dissolution of the enteric-coating
`before absorption of omeprazole started. In most
`cases, gastric emptying occurred in connection with
`the meal served 2.5 hours after the dose. In one sub-
`ject, when enteric-coated granules were given with
`food, gastric emptying of granules did not start un-
`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 flat and broad, and peak plasma soncentra-
`tions were low. The total amount absorbed, as
`reflected by the AUC, was, however, only de-
`creased by 14 070 when the granules were given on an
`empty stomach in comparison with the buffered
`suspension. The corresponding figure for en-
`reric-coated granules administered wirh a meal
`is higher, but since absorption of omeprazole
`was not completed in all subjects when the ex-
`periment was terminated, the exact figure is un-
`known. Although this study is not fully con-
`clusive regarding the bioavailability of omeprazole
`given with food, it is rxommended that ome-
`prazole should be taken in the morning before
`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,
`but is rather a function of the total amount of
`orneprazole 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-
`ing equal AUCs. The shapes of the plasma concen-
`tration-time curves are of no importance.
`Bioavailability of enteric-
`coated granules administered
`at different times before
`break fast
`When omeprazole enteric-coated granules are given
`with a meal, the rate of absorption of omeprazole is
`reduced. Patients are therefore recommended to
`take the dose on an empty stomach before the morn-
`ing meal. However, in
`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-
`ability study comparing omeprazole enteric-
`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.
`Twelve healthy volunteers participated
`in the
`study. The doses were given as described above.
`Standardised meals were served after 2.5, 6, 10
`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 theabsorption 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 plas-
`ma concentration peak shortly after the second
`meal served 2.5 hours after dose.
`
`The AUC, relative to that of the reference formula-
`tion, was very similar in the two experiments with
`
`prnol I
`7
`
`6
`
`5
`
`4
`
`3
`
`2
`
`1
`
`0
`
`i
`i,
`4
`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.
`
`

`
`119
`
`pmolil
`1.5
`
`1
`
`0.5
`
`0
`
`4
`2
`6
`0
`Figure 7. Plasma concentration of omeprazole, men + or
`- SEM, in eleven healthy given 60 mg single, oral doses of
`omeprazole as:
`
`enteric-coated granules; 65.5 070 when given 15
`minutes before breakfast and 66.6 070 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 between the administration and the start
`of the morning meal.
`Bioavailability of enteric-
`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.
`
`i
`8
`
`24
`h
`12
`10
`enteric-coated granules 15 minutes before breakfast
`A enteric-coated granules 2 minutes before breakfast
`
`Six healthy volunteers were given, in random
`order, enteric-coated granules with and without
`concomitant administration of an aluminium-
`magnesium hydroxidekarbonate 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-
`prazole administration. 10 ml doses of a liquid ant-
`acid with an acid-binding capacity of 85 mmol
`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 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
`
`lpniol I h I
`
`prnol x hi1
`
`coated
`
`'
`
`buffered
`suwersion
`
`granules
`enteric
`15 rnn
`2 min
`belore
`betore
`breakfast
`breakfasr
`Figure 8. AUC (umolx h/l) 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
`whereas
`substantial.
`
`subjects
`
`is
`
`Conclusion: Co-administration of antacids has no
`influence on the bioavailability of omeprazole
`given as enteric-coated granules.
`
`WI t hou t
`antacids
`antacids
`Figure 9. AUC (umolxh/l) in six healthy volunteers
`given 60 mg single, oral doses of omeprazole enteric-
`coated granules with and without antacids.
`- individual values
`_ _
`- - mean values
`
`2.
`
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