covers for pdf 8/14/01 10:28 AM Page 2
`
`Current status
`on targeted
`drug delivery
`to the
`gastrointestinal
`tract
`
`SHORT HILLS (NJ) • APRIL 22
`LONDON • MAY 6
`TOKYO • MAY 14
`1993
`
`BAS 153
`
`

`
`
`
`
`the company’s globalized capsule business.
`is
`Capsugel, a division of Warner Lambert
`Headquartered in USA, Capsugel is the world's largest producer of empty hard gelatin capsules
`devoted to provide the scientific community with high value solutions.
`
`To help the scientists to overcome barriers in oral drug delivery, Capsugel has created a series of
`symposia, a library of documents as well as a computerized literature search. Building upon worldwide
`interest, Capsugel was pleased to present in 1993 another series of symposia to the pharmaceutical
`scientific community. The lectures given in Short Hills (NJ, USA), Tokyo and London are combined
`into these proceedings.
`
`We have also included a poster of the gastrointestinal tract especially designed for this series of
`symposia.
`
`Our ultimate goal in publishing these proceedings is to help you investigate some of the practical
`aspects and development possibilities of targeted drug delivery. Your feedback will tell us if we
`achieved this objective.
`
`We are looking forward to hearing from you.
`
`

`
`P. 9
`
`P. 191
`
`p. 21
`
`p. 35
`
`p. 43
`
`p. 57
`
`p. 65
`
`p. 77
`
`p. 85
`
`p. 95
`
`p. 35
`
`p. 115
`
`p. 121
`
`p. 131
`
`Summary
`
`
`
`SHORT HILLS (NJ) • April 22nd
`
`Gastrointestinal physiology and its relevance to targeted drug delivery
`by Sidney F. PHILLIPS
`
`
`
`Techniques in monitoring functions relevant to drug delivery
`in the gastrointestinal tract
`by Erik P. SANDEFER and Professor George A. DIGENIS
`
`
`
`Gastric emptying; differences among liquid, fiber, polymer
`and solid dosage forms of medications
`by Paul BASS
`
`
`
`Formulation of proton pump inhibitors
`by Åke PILBRANT
`
`
`
`Oral delivery of peptides to the small intestine
`by Randall J. MRSNY
`
`
`
`Recent advances in formulation of poorly-absorbed drugs
`by Joseph R. ROBINSON
`
`
`
`Current issues related to the FDA
`by Roger WILLIAMS
`
`
`
`LONDON • May 6th
`
`Absorption from the gastrointestinal tract
`by Anna-Lena UNGELL
`
`
`
`Gastrointestinal tract physiology and its relevance to drug delivery
`by David F. EVANS
`
`
`
`Floating delivery and other potential gastric retaining systems
`by Professor J. MOËS
`
`
`
`Formulation of proton pump inhibitors
`by Doctor Åke PILBRANT
`
`
`
`The use of computers and microelectronics to control
`drug release from capsules
`by Professor Dr. GRÖNING
`
`
`
`
`
`Possibilities and limitations of peroral bioadhesive
`drug delivery systems
`by Professor Dr. H.E. JUNGINGER
`
`Colonic delivery of drugs
`by Doctor John T. FELL
`
`
`

`
`p. 147
`
`p. 151
`
`p. 161
`
`p. 173
`
`p. 183
`
`P. 191
`
`TOKYO • May 14th
`
`PZ-peptide: a polar, labile peptide with good mucosal
`transport characteristics
`by Professor Vincent H.L. LEE
`
`
`
`
`
`Strategies to improve intestinal membrane transport
`of poorly absorbed drugs and peptides
`by Professor M. HAYASHI
`
`Prospect of oral administration of insulin
`by Professor Y. MACHIDA
`
`
`
`Improvement of drug digestive tract absorption properties
`by Professor T. KIMURA
`
`
`
`Design and evaluation of time-controlled release systems
`for site-specific oral drug delivery to the GI tract
`by H. YOSHINO
`
`
`
`
`Techniques in monitoring functions relevant to drug delivery
`in the gastrointestinal tract
`by Erik P. SANDEFER and Professor George A. DIGENIS
`
`
`

`
`proton pump sheet 8/16/01 4:33 PM Page 1
`
`Formulation of
`proton pump
`inhibitors
`
`Åke PILBRANT, Ph. D.
`
`BAS 153-d
`
`

`
`proton pump sheet 8/16/01 4:33 PM Page 2
`
`Doctor Åke PILBRANT, Ph. D
`
`Pharmaceutical R&D
`Astra Hässle AB
`S-431 83 MöIndal, Sweden
`
`Introduction
`
`The proton pump inhibitors, or gastric acid pump
`inhibitors, on the market or in late stage clinical studies,
`have the same basic chemical structure, Figure 1.
`Omeprazole, the first proton pump inhibitor, has a rather
`low water solubility of 0.15 mg/ml. It has two pKa-values:
`4.0 (pyridinium) and 8.7 (benzimidazole).
`
`Figure 1. Chemical structure of proton pump inhibitors
`
`The proton pump inhibitors are used in the treatment of
`gastro-intestinal disorders where a reduction of gastric
`acid secretion is beneficial. Omeprazole is, on most mar-
`kets, indicated for treating gastric and duodenal ulcers,
`gastro-oesophageal reflux disease and the Zollinger-
`Ellison syndrome.
`
`Omeprazole administered as a suspension given
`together with pH buffer solution is absorbed rapidly (1).
`Peak plasma concentrations are obtained within 10 to 30
`
`minutes. Omeprazole is distributed and rather rapidly
`metabolised and is cleared from the body with a half-life
`usually less than 1 hour (2). The effect on pentagastrin
`stimulated gastric acid secretion is proportional to the
`dose (1). The proton pump inhibitors have a long dura-
`tion of action. The effect of a single oral 20 mg dose of
`omeprazole on pentagastrin stimulated gastric acid
`secretion is still significantly different from control values
`48 hours after dose (1). This means that the effect on
`gastric acid secretion is not correlated to the plasma
`concentration of omeprazole at any particular time, but
`still correlated to the dose.
`
`The proton pump inhibitors interact with the very final
`step of gastric acid secretion (3). The acid is produced
`by parietal cells situated at the base of the oxyntic glands
`in the gastric mucosa. Hydrogen ions are pumped from
`the cytosol of the parietal cell to the secretory canal in
`exchange for potassium ions by an enzyme, H+K+-
`ATPase, located in the membrane between the cytosol
`and the secretory canal. The acid is emptied into the
`lumen of the gland and then further out into the stomach.
`The pH in the secretory canal must be very low, <pH1,
`since the acid produced by the parietal cell is diluted a
`couple of times before it reaches the stomach where pH
`can be as low as around pH1.
`
`The proton pump inhibitors are pro-drugs. From the
`general circulation they diffuse into the parietal cells like
`they do into most other cells. In the parietal cells, since
`the proton pump inhibitors are weak bases, they partition
`to the acid compartment of the secretory canal, where
`they are trapped as positively charged ions. In the acid
`environment the proton pump inhibitors react to the active
`substance a sulphenamide, which covalently binds to
`sulfhydryl groups of the enzyme and inactivates it (4, 5).
`
`The sulphenamides are very reactive. If there is no
`enzyme available, as is the case in vitro, the substances
`will still react and form degradation products. In acid
`
`

`
`proton pump sheet 8/16/01 4:33 PM Page 3
`
`media the most common degradation products are two
`isomers (Figure 2) with fully conjugated electron systems,
`which make them very strong chromophores (6). The
`pure drug substances or pharmaceutical formulations
`containing them are discoloured by the degradation prod-
`ucts when these are present in amounts of less than 1 %.
`
`Figure 2. Degradation products of omeprazole
`
`Figure 3. Degradation of omeprazole in water solution.
`Logarithm of the observed first-order rate constant for
`degradation at constant pH plotted as a function of pH
`
`The rate of degradation of omeprazole in water solution
`is dependent on pH. Figure 3 shows the logarithm of the
`observed, initial, first order rate constant for degradation
`at constant pH plotted as a function of pH. In acid solu-
`tion the rate is almost independent on pH and the reac-
`tion proceeds rapidly. The half-life of degradation at pH
`
`2, room temperature, is less than 10 minutes; at pH 7
`the half-life is about 40 hours, and at pH 11 around 300
`days. Reaction mechanisms and rates of reactions have
`been studied in detail (7). A similar profile was recently
`published for lansoprazole (8). The rate of degradation at
`37 °C of the three proton pump inhibitors is given in
`Table 1. Lansoprazole degrades with the highest rate fol-
`lowed by omeprazole and pantoprazole.
`
`Omeprazole
`
`Lansoprazole
`
`Pantoprazole
`
`pH 2
`
`pH 7
`
`105 sec
`
`23 hours
`
`85 sec
`
`13 hours
`
`195 sec
`
`39 hours
`
`Table 1. Half-life of degradation in water solution, + 37 °C
`
`What type of oral dosage form?
`
`To sum up the background information.
`
`The proton pump inhibitors:
`
`- have rather low water solubility
`
`- degrade rapidly in contact with acids to intensely
`coloured degradation products
`
`- have better stability in neutral/alkaline media
`
`- are absorbed rapidly and are metabolised rapidly
`
`- have a long duration of action
`
`There are, in principle, three options to formulate an
`oral dosage form of the proton pump inhibitors:
`
`1. A dosage form which is dissolved and absorbed so
`rapidly that acid catalysed degradation in the stomach
`will be insignificant.
`
`2. A dosage form which contains a sufficient amount of
`pH-buffering substances to buffer the pH of the stomach
`content to near neutral or alkaline values during the
`absorption phase.
`
`3. An enteric coated formulation, which is insoluble in
`acid media but soluble in near neutral or alkaline media,
`such as in the small intestine.
`
`

`
`proton pump sheet 8/16/01 4:33 PM Page 4
`
`given together with an American breakfast containing
`eggs, toast, cheese, milk and coffee. The plasma con-
`centration curves are given in Figure 5. We concluded
`that the gastric pH after breakfast was not high enough
`for omeprazole since more than 80 % of the dose was
`lost.
`
`To test the first option a pilot bioavailability study with
`micronised omeprazole suspended in water or in sodium
`bicarbonate solution was performed (9). Fasting healthy
`volunteers were first given 50 ml of sodium bicarbonate
`solution (8 mmoles = 0.67 g in 50 ml) 5 minutes prior to
`dose. The suspension of omeprazole in 50 ml of sodium
`bicarbonate solution was rinsed down with another 50 ml
`of sodium bicarbonate solution followed by further 50 ml
`portions of bicarbonate solution 10, 20 and 30 minutes
`after the dose; i.e. in total 300 ml of sodium bicarbonate
`solution. In a cross-over experiment omeprazole suspen-
`sion was administered according to the same experi-
`mental procedure but the sodium bicarbonate solution
`was replaced by water. Frequent blood samples were
`taken and analysed for omeprazole, Figure 4.
`
`Figure 5. Mean plasma concentrations of omeprazole
`after administration of omeprazole suspension with buffer
`solution and after administration of a rapidly dissolving
`tablet given together with a meal to six healthy volunteers
`
`The second option, to give omeprazole together with a
`sufficient amount of pH buffering substances in order to
`control the pH of the stomach to near neutral values dur-
`ing the absorption phase, would probably mean about
`one gram or more of sodium bicarbonate - i.e. too much
`for an ordinary tablet.
`
`Remains an enteric-coated dosage form.
`
`What is the best dosage form for proton pump
`inhibitors? A single unit dosage form? Or a multiple unit
`dosage form? Such as individually enteric-coated parti-
`cles dispensed in a capsule.
`
`Non-disintegrating, enteric-coated tablets given with
`food may stay in the stomach for long times, 10 to 15
`hours, before they are emptied into the small intestine.
`Small particles, on the other hand - particle diameter less
`than about 3 mm -, are emptied from the stomach much
`more regularly, regardless of whether they are given with
`food or not (10).
`
`Figure 4. Mean plasma concentrations of omeprazole
`after administration of suspensions of micronised
`omeprazole to six healthy volunteers
`
`Omeprazole was obviously rapidly emptied from the
`stomach to the small intestine and rapidly absorbed, dis-
`tributed and eliminated. Peak plasma concentrations
`were found after 10 to 20 minutes in both experiments
`but the area under the plasma concentration versus time
`curve (AUC) was reduced by more than 50 % when the
`suspension was given without buffer protection. Without
`having the absolute evidences we assume that the
`reduced extent of bioavailability was due to acid catal-
`ysed degradation of omeprazole in the stomach.
`
`What happens if we give omeprazole with a meal
`which increases the pH of the stomach content? In
`another cross-over pilot study we compared the micro-
`nised suspension given according to the “bicarbonate
`solution scheme” above with a rapidly dissolving tablet
`
`

`
`proton pump sheet 8/16/01 4:33 PM Page 5
`
`It is not attractive to have a dosage form of an acid
`labile compound staying in the stomach for long periods
`of time, since a small damage of the enteric-coating can
`allow acid solution to enter into the core and destroy the
`active compound. A long gastric residence time will of
`course also delay the pharmacological effect.
`
`Dissolution rate limited absorption
`
`Omeprazole has a rather low water solubility, 0.15
`mg/ml, which indicates that dissolution might reduce rate
`or extent of absorption. To test this possibility and in
`order to set quality limits we formulated small beads con-
`taining omeprazole by extrusion and spheronisation (9).
`The in vitro dissolution rate at pH 6.5 of three formula-
`tions is given in Figure 6.
`
`Their absorption characteristics were tested in a small
`pilot bioavailability study, where the pellets were given
`according to the “bicarbonate solution scheme”. The
`slower of the pellet formulations showed a somewhat
`slower absorption, with the peak plasma concentration
`occurring later, as well as a reduced AUC (73 %). The
`two faster dissolving formulations had their peak plasma
`concentration at the same time as the reference suspen-
`sion and the AUC was not significantly different from the
`suspension, 92 and 95 % relative AUC respectively.
`
`Figure 6. Dissolution in vitro of three pellet formulations of
`omeprazole. USP dissolution apparatus N. 2 (paddle), 37
`°C, 100 rpm, 500 mI phosphate buffer pH = 6.5
`
`The dosage form
`
`Omeprazole
`
`Micronised omeprazole mixed with fillers, binders and
`pH-buffering substances is formulated into rounded
`beads, diameter 1.0-1.6 mm, by extrusion and spheroni-
`sation. After drying and sieving the beads are coated.
`We have used fluidized-bed technique and applied
`hydroxypropyl methylcellulose phthalate (HPMCP) from
`an organic solvent solution. For environmental reasons
`we are now switching to aqueous based coating with
`Metharylic acid copolymer (Eudragit® L3OD).
`
`Enteric-coating polymers have free carboxyl groups. If
`the coating is applied directly to the omeprazole-contain-
`ing cores the carboxyl groups will interact with the active
`substance at the surface of the core and cause discol-
`oration during the coating process or during storage.
`This discoloration can be avoided by applying some type
`of separating layer between the core and the enteric-
`coating (11). Finally, the enteric-coated pellets are dis-
`pensed into hard gelatine capsules.
`
`Lansoprazole
`
`The dosage form used for lansoprazole on some
`European markets is constructed in a similar way (12).
`Inert cores, nonpareils 20-28 mesh, are charged into a
`roto-granulator. A solution of hydroxypropylcellulose
`(HPC) in water is sprayed onto the cores and a first pow-
`der mixture of lansoprazole, MgC03, sucrose, corn
`starch and low substituted HPC is added as a dusting
`powder, followed by a second powder mixture of
`sucrose, corn starch and L-HPC. Pellets are then
`enteric-coated with Metharylic acid copolymer and finally
`dispensed into hard gelatine capsules.
`
`Pantoprazole
`
`The pantoprazole dosage form used in clinical studies
`is an enteric-coated tablet.
`
`Packaging and stability
`
`Enteric-coated pellets of omeprazole dispensed in hard
`gelatine capsules are sensitive to moisture:
`
`- capsules stored at 25 °C and 50 % r.h. are stable for
`one year
`
`- capsules stored at 25 °C and 65 % r.h. are stable for
`three months
`
`- capsules stored at 25 °C and 80 % r.h. are stable for
`two weeks, where “stable” means less than 1.5 % of
`degradation products
`
`

`
`proton pump sheet 8/16/01 4:33 PM Page 6
`
`So moisture is critical for the long-term stability of
`omeprazole capsules and the normal moisture level of
`hard gelatine capsules, 15 to 17 % moisture, is too high
`for omeprazole and must be reduced. It is not possible
`to dry the empty capsules before the capsule filling oper-
`ation. Dry capsules are just too brittle. At Astra we have
`solved the problem in the following way:
`
`- Empty hard gelatine capsules are supplied with a
`moisture level of 15 ± 1 %.
`
`- Capsules are filled and handled in an area with con-
`trolled humidity.
`
`- Capsules are dispensed into tight bottles together
`with a balanced amount of a desiccant.
`
`After 2 to 4 weeks an equilibrium moisture level is
`reached where the capsules have the desired water
`content.
`
`Figure 7. Mean plasma concentrations of omeprazole
`after administration of Losec® 20 mg capsules with and
`without food to 12 healthy volunteers
`
`Using this package configuration an expiration dating of
`three years at maximum 30 °C is no problem. There are,
`of course, other ways to reach the same moisture level
`and stability.
`
`Bioavailability - influence of food
`
`The omeprazole capsule formulation was given to
`healthy volunteers in a single dose, cross-over study to
`document the effect of food (13). The blood plasma con-
`centrations were similar, Figure 7. The mean plasma con-
`centration curve for fasting conditions has two peaks.
`Some volunteers have a short gastric emptying time
`when capsules are given on an empty stomach, while
`others empty in connection with next meal, given 2.5
`hours after dose. The AUC was practically identical for
`the two administrations, and food has little influence on
`the extent of bioavailability.
`
`Enteric-coated tablets
`
`We have also developed single-unit enteric-coated
`tablets of omeprazole. These are rapidly dissolving 7 mm
`diameter tablets cores coated first with a separating
`coating then with an entericcoating. The enteric coating
`protects tablets from dissolving in synthetic gastric juice
`during more than 16 hours. They still dissolve within 30
`minutes when they are removed and tested in a medium
`of pH 6.8.
`
`A comparative bioavailability study in 24 healthy, fasting
`volunteers showed that the enteric-coated tablets gave a
`similar mean AUC, but of course much more variation in
`time to reach peak plasma concentration than omepra-
`zole capsules. According to regulatory guidelines enteric-
`coated single-unit tablets can never be bioequivalent with
`multiple-unit enteric-coated dosage forms. There will
`always be differences in peak plasma concentration and
`time to reach peak plasma concentration. A tablet is
`either in the stomach where it is insoluble or it is in the
`small intestine where it dissolves, while one part of a
`multiple-unit dosage form can be in the stomach and
`another part in the small intestine. The absorption phase
`for a multiple-unit dosage form will on average be longer
`and the plasma concentration versus time curve will be
`flatter.
`
`

`
`proton pump sheet 8/16/01 4:33 PM Page 7
`
`Patient No
`
`Capsule Tablet
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`Average
`
`76
`
`76
`
`73
`
`37
`
`92
`
`94
`
`82
`
`43
`
`89
`
`42
`
`54
`
`61
`
`68
`
`78
`
`74
`
`75
`
`44
`
`92
`
`95
`
`74
`
`63
`
`79
`
`53
`
`52
`
`68
`
`71
`
`Table 2. Inhibition of stimulated gastric acid secretion,
`on day 6, 25-28 hours after last dose, % inhibition of
`pre-study value
`
`A multiple-unit enteric-coated dosage form of a proton
`pump inhibitor cannot be bioequivalent with a single-unit
`enteric-coated dosage form (Same AUC, Cmax and
`tmax), but can they be considered therapeutically equiva-
`lent? The pharmacological effect of the proton pump
`inhibitors, which is most important for the clinical efficacy,
`is, of course, their ability to reduce gastric acid secretion.
`And so we designed a cross-over study in duodenal
`ulcer patients in remission. The patients, aged between
`39 and 79 years, were administered omeprazole 20 mg
`enteric-coated tablets or enteric-coated pellets in cap-
`sules once daily with breakfast during five days. Before
`the study and during day six the rate of gastric acid
`secretion during intravenous pentagastrin stimulation was
`measured. Blood plasma was sampled frequently during
`days one and five.
`
`The plasma concentrations after administration of cap-
`sules day one were the expected. There was a slight
`tendency towards a somewhat slower gastric emptying
`among the patients in comparison to young healthy vol-
`unteers. When tablets were administered on day one,
`two of twelve patients had no plasma concentrations of
`omeprazole during the blood sampling interval (blood
`was sampled every half hour during nine hours after
`dose), and one patient had his first measurable plasma
`concentration nine hours after dose. Once emptied into
`the small intestine the tablets were rapidly absorbed. It is
`quite obvious that enteric-coated tablets administered
`together with a meal will show a variable and prolonged
`gastric emptying rate in comparison with small enteric-
`coated pellets. During day five all patients emptied the
`tablets more regularly but still more variably than cap-
`sules.
`
`The effect was measured as the maximum inhibition of
`pentagastrin stimulated gastric acid secretion during day
`6, approximately 25 hours after the last dose. As is obvi-
`ous from the data given in Table 2 there is no difference
`between tablets and capsules with regard to their effect
`on peak acid output during repeated dosing.
`
`Still, I would like to say that a multiple-unit dosage form
`is the preferred dosage form for proton pump inhibitors.
`
`

`
`proton pump sheet 8/16/01 4:33 PM Page 8
`
`8. T. Tabata, T. Makino, T. Kashihara, S. Hirai, N.
`Kitamori and H. Toguchi, Stabilization of a new
`antiuIcer drug (lansoprazole) in the solid dosage
`forms, Drug Dev. Ind. Pharm., 18: 1437-1447
`(1992).
`
`9. Å. Pilbrant and C. Cederberg, Development of an
`oral formulation of omeprazole, Scand. J.
`Gastroenterol., 20: (Suppl. 108) 113-120 (1985).
`
`10. C. Bogentoft, I. Carlsson, G. Ekenved and A.
`Magnusson, Influence of food on the absorption of
`acetylsalicylic acid from enteric-coated dosage
`forms, Eur. J. Clin. Pharmacol. 14: 351-355 (1978).
`
`11. K. Lövgren, Å. Pilbrant, M. Yasumura, S. Morigaki,
`M. Oda and N. Ohishi, New pharmaceutical prepa-
`ration for oral use, United States Patent, 4, 786,
`505 (1988).
`
`12. T. Makino, T. Tabata and S.I. Hirai, Spherical gran-
`ules having core and their production, European
`Patent Application EP 0 277 741 (1988).
`
`13. T. Andersson, K. Andrén, C. Cederberg, A
`Heggelund, P. Lundborg and K. Röhss,
`Bioavailability of omeprazole as enteric coated (EC)
`granules in conjunction with food on the first and
`seventh day of treatment, Drug Invest., 2: 184-188
`(1990).
`
`References
`
`1. T. Lind, C. Cederberg, G. Ekenved, U. Haglund and
`L. Olbe, Effect of omeprazole - a gastric proton
`pump inhibitor on pentagastrin stimulated gastric
`acid secretion in man, Gut., 24: 270-276 (1983).
`
`2. C.G. Regardh, Pharmacokinetics and metabolism of
`omeprazole in man, Scand. J. Gastroenterol., 21:
`(Suppl. 118), 99-104 (1986).
`
`3. E. Fellenius, T. Berglindh, G. Sachs, L. Olbe, B.
`Elander, S.E. Sjöstrand and B. Wallmark,
`Substituted benzimidazoles inhibit gastric acid
`secretion by blocking H+K+ATPase, Nature, 290:
`159-161 (1981).
`
`4. B. Wallmark, A. Brändström and H. Larsson,
`Evidence for acid-induced transformation of
`omeprazole into an active inhibitor of (H+K+)-ATPase
`within the parietal cell, Biochim. Biophys. Acta, 778:
`549-558 (1984).
`
`5. P. Lindberg, P. Nordberg, T. Alminger, A. Brändström
`and B. Wallmark, The mechanism of action of the
`gastric acid secretion inhibitor omeprazole, J. Med.
`Chem., 29:1327-1329 (1986).
`
`6. A. Brändström, P. Lindberg, N.Å. Bergman I.
`Grundevik, L. Tekenbergs-Hjelte and K. Ohlson,
`Chemical reactions of omeprazole and omeprazole
`analogues. VI. The reactions of omeprazole in the
`absence of 2-mercapto-ethanol, Acta Chem.
`Scand., 43: 595-611 (1989).
`
`7. A. Brädndström, P. Lindberg, N.Å. Bergman, T.
`Alminger, K. Ankner, U. Ljunggren, B. Lamm, P.
`Nordberg, M. Erickson, I. Grundevik, I. Hagin, K.J.
`Hoffmann, S. Johansson, S. Larsson, I. Liöfberg, K.
`Ohlson, B. Persson, I. Skanberg and L. Tekenbergs-
`Hjelte, Chemical reactions of omeprazole and
`omeprazole analogues, Acta Chem. Scand., 43:
`536-611 (1989).