%MiIestonesL in [Drug Therapy
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`Sferie’s Editors
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`%
`
`ProtonPump
`Inhibitors
`
`
`Birkhéiuser %
`
`PZVOOO0000229
`
`

`
`. ;-Jc: :.
`
`~·nr;.j
`I
`I
`
`Editor
`
`Dr. Lars Olbe
`Centre for Gastroenterological Research
`University of GOteborg
`S-41345 G6teborg
`Sweden
`
`Advisory Board
`
`J.C. Buckingham (Imperial College School of Medicine, London, UK)
`D. de Wied (Rudolf Magnus Institute for Neurosciences, Utrecht, The Netherlands)
`F. K. Goodwin (Center on Neuroscience, Washington, USA)
`G. Lambrecht (J. W. Goethe Universit1it, Frankfurt, Germany)
`
`....,
`Library of Congress Cataloging-in-Publicati~u. Data r ~
`A CIP catalogue record for this book is availablb from.the libra4' of Congress,
`'!
`Washington D.C., USA
`
`Deutsche Bibliothek Cataloging-in-Publication Data
`Proton pump inhibitors I ed. by L. Olbe. - Basel ; Boston ; Berlin :
`Birkh1iuser, 1999
`(M:ilestones in drug therapy)
`ISBN 3-7643-5897-1 (Basel ... )
`ISBN 0-8176-5897-1 (Boston)
`
`The publisher and editor can give no guarantee for the informa'tion on drug dosage and administra(cid:173)
`tion contained in this publication. The respective user must check its accuracy by consulting other
`sources of reference in each individual case.
`The use of registered names, trademarks etc. in this publication, even if not identified as such, does
`not imply that they are exempt from the relevant protective laws and regulations or free for general
`use.
`This work is subject to copyright. All rights are reserved, whether the whole or part of the material
`is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation,
`broadcasting, ret'JfOduction on microfilms or in other ways, and storage in date banks. For any kind
`of use permission of the copyright owner must be obtained.
`© 1999 BirkhauserVerlag, P.O. Box 133, CH-4010 Basel, Switzerland
`Printed on acid-free paper produced from chlorine-free pulp. TCF oo
`Printed in Germany
`ISBN 3-7643-5897-1
`ISBN 0-8176-5897-1
`987654321
`
`PZV0000000230
`
`

`
`Proton Pump lnhlt<~tors
`ed by L Olbe
`Q 1999 Bnkhauser Verlag Basel/Switzerland
`
`Pharmaceutical considerations
`
`Ake G. Pilbrant
`Phannaceutical R & D, ASTRA HiissleAB, S~431 83 MOlndal, Sweden
`
`Introduction
`
`Since the launch of the first proton pump inhibitor (PPI), omeprazole, in
`1988 there has been ever increasing mterest in this new chemical class of
`drugs. Now, I 0 years later, there are four compounds on the market, which
`all share common features (Fig. I, Tab. I). The PP!s are substituted benz(cid:173)
`imidazoles which inhibit gastric acid secretion by blocking H+K+ -ATPase
`[I]. They are amphiphilic compounds, that is they are both acids aod bases.
`The pyridine nitrogen is protonised with a pK, of around 4. The positively
`charged ion is rapidly rearraoged to a highly reactive sulphenamide which
`in vivo binds covalently to aod inhibits the proton pump, the WK+ -ATPase
`within the parietal cell [2, 3]. The only place in the body where the pH is
`low enough to cause this rearrangement is the secretory caonaliculi of the
`
`Omeprazole
`
`Lansoprazole
`
`O·CH3
`H,C'C(CH,
`I ""'
`N CH,---s--<;
`N
`H
`
`w ":00-CH,
`
`1
`
`...,;
`
`Pantoprazole
`
`Rabeprazole
`
`,.O.CH,
`CH,
`
`Ftgure 1. Commercially available PPis.
`
`N
`
`II N=o
`
`CH,---~--<;
`N
`H
`
`I
`
`...,;
`
`PZV0000000231
`
`

`
`162
`
`A G Ptlbrant
`
`Table 1 Phystco-chemtcal data of PPh.
`
`Omeprazole
`
`Lansoprazole
`
`Pantoprazolc Rabcprazole
`
`398,87[16]
`40,88[6]
`
`389,87[16)
`4 1, 8 8 [30]
`
`377,82[16] 50,8 g•
`49[31]
`40[31]
`
`105 s [16]
`23h[l6]
`
`85 s [16]
`l3 h [16]
`
`0 06 [5)
`
`195 s [16]
`39 h [16)
`
`80mmb
`
`pK~ 37°C
`pK. 25°C
`Half-hfe of de,b>radatwn
`m water solut10n, 3 7 oc
`atpH2
`at pH 7
`
`Water solublllly, mglml
`
`015 [16]
`
`• Calculated accordmg to Brandstrom et al [4]
`b Astra Hassle AB Data on ftle
`
`stimulated parietal cells. In vitro the rearrangement to the reactive sul(cid:173)
`phonamide can take place when the PPI comes in contact with anything
`reacting acidic whether in solution or in the solid state. The sulphenamide
`will then react further and cause degradation of the PPI to a number of
`usually heavily coloured degradation products [4]. This reactivity together
`with a rather low water solubility and an inherent instability makes the
`pharmaceutical formulation of the PPJs a real challenge. The difficulties
`are mirrored by a great number of patents and patent applications covering
`different aspects of pharmaceutical products and processes.
`
`Physicochemical properties
`
`The PP!s can be protonised in two steps. First, a proton binds to the pyri(cid:173)
`dine nitrogen with a pK, of around 4. At very low pH values another proton
`can bind to the benzimidazole nitrogen. This pK, value is difficult to deter(cid:173)
`mine because of the rapid degradation of the PPis at low pH values. In
`alkaline solutions the benzimidazole hydrogen can leave with a pK, of
`around 9, forming a negatively charged ion.
`The water solubility of the neutral compounds is rather low, less than
`0.1 %. The charged ions have better water solubility, and the PPis are freely
`soluble in sodium hydroxide solutions.
`The stability ofthe PPis in water solution is highly dependent on pH. The
`positively charged ion present in solution at low pH values degrades rapid(cid:173)
`ly. The half-life of degradation of the PPis in dilute solutions at pH 2 IS in
`the range of a few minutes. The uncharged compounds in water solution
`degrade with a half-life of tenths of hours, while the negatively charged
`ionic species are fairly stable in solution; the half-life of degradation is
`close to a year. The kinetics and mechanisms of reaction of omeprazole
`have been thoroughly studied by Briindstrom et al. [4]. A pH/stability pro(cid:173)
`file for lansoprazole has been published [5].
`
`PZV0000000232
`
`

`
`Phannaceutical considerations
`
`163
`
`The solid-state stability of the PP!s is rather good. The pure chemical
`compouuds can be stored for longer periods of time at room temperature,
`although its is preferable to store them at refrigerator temperature or
`in deep freeze. Contact with acidic reacting substances as well as low
`amounts of residual solvents induces degradation [6]. The stability ofPP!s
`in pharmaceutical formulations can be improved by admixing alkaline
`reacting compounds [7-8]. Alkaline anionic salts of PP!s, for example
`potassium, sodium, calcium and magnesium salts, have much better stor(cid:173)
`age stability than the neutral compounds [9].
`
`Characteristics influencing dosage form design
`
`After oral administration of easiiy bioavaiiabie pharmaceutical formula(cid:173)
`tions, the PP!s are rapidly and completely absorbed, with peak blood con(cid:173)
`centrations obtained within 10 to 20 min [6, 10]. They are rapidly eliminat(cid:173)
`ed from the body, with plasma half-lives of about 1 h.
`The susceptibility for degradation in acid media, such as the contents of
`the stomach, precludes the use of conventional oral dosage forms. From the
`low water solubility coupled with the rapid absorption follows that there
`exists a potential for dissolution rate-limited absorption.
`Since the PP!s bind covalently to the proton pump, the effect on gastric
`acid secretion is long lasting and depends on the total amount of the PPl
`absorbed and is not proportional to the blood concentration of the PPI at
`any particular time. This also means that the rate of absorption is not
`critical for the long-term effect- only the total amount absorbed.
`
`Oral dosage forms
`
`Formulation principles
`
`There are two main options for getting arouud the risk of acid-catalysed
`degradation of the PPI in the stomach after oral administration.
`I. To secure a neutral/alkaline gastric pH by coadministration of pH buf(cid:173)
`fering substances. This was done in early human pharmacological
`studies with omeprazole [6] but can hardly be applied to a marketable
`pharmaceutical formulation for longer use.
`2. To ensure that the active drug is not released in the stomach by using
`an enteric coating which dissolves only in solutions with a pH of 5.5 or
`higher, such as is the case in the small intestine.
`
`An enteric-coating can be applied on whole tablets or onto individual pel(cid:173)
`lets/particles/granules which then are dispensed into gelatin capsules or
`mixed with tablet excipients and compressed into tablets.
`
`PZV0000000233
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`

`
`164
`
`A. G Pilbrant
`
`Astra, the pwneer of the PPI area, mvented a pharmaceutical formulation
`of omeprazole: individually enteric-coated pellets dispensed in hard gelatin
`capsules [7]. Lansoprazole is presented in a similar capsule formulation
`[8], wheras pantoprazole [II] and rabeprazole [12] are formulated as
`single-unit enteric-coated tablets. In some markets Astra has recently also
`introduced a tablet containing a multitude of small, individually enteric(cid:173)
`coated pellets [13].
`
`Gastric emptying of enteric-coated dosage forms
`
`Single-unit enteric-coated dosage forms must be swallowed whole, and
`they do not dissolve in the stomach. It is well known that insoluble enteric(cid:173)
`coated tablets of a size > 3-5 mm in diameter may reside in the stomach
`during quite some time if they are administered together with food [14],
`whereas a multiple dose unit of small enteric-coated pellets will show a
`much less variable gastric emptying time [15]. This may affect the time re(cid:173)
`quired to obtain a response on gastric acid secretion after the first dose. The
`effect on gastric acid secretion after a single dose of a PPI is long lasting,
`and during continuous dosing tt is of less importance when - during a
`dosage interval - the absorption actually takes place. The pharmacody(cid:173)
`namic effects at steady state after administration of enteric-coated whole
`tablets or capsules containing enteric-coated pellets will not differ [16].
`
`Pharmacopoeial requirements
`
`Pharmacopoeial requirements on enteric-coated articles include testing of
`the function of the enteric coating in vitro. The test article is placed in
`0.1 M hydrochloric acid at 3 7 oc for 2 h. The amount of drug released to
`the medium should be less than I 0% - that is testing the integrity of the
`enteric coating. The pH of the medium is then shifted to pH 6.8, and the
`release of the drug to this medium should reach a certain minimum value
`within a specified time- a test to show that the enteric coating dissolves at
`a pH resembling that of the small intestine. Since the PP!s degrade rapidly
`in acid solution to a cascade of degradation products, the first part of the
`test, the acid stage, cannot be applied as such. It is possible to perform the
`testing in two separate steps. First, a number of enteric-coated units are
`individually exposed to acid for 2 h, the tablets or pellets are collected and
`dissolved in alkaline solution, and the amount of drug remaining intact
`after acid exposure is determined. Another set of enteric-coated units are
`then frrst exposed to acid during 2 h, the pH of the medium is shifted to
`pH 6.8 and the amount of drug released to the medium after a specified
`time is determined. However, because of the rapid degradation of the PP!s
`in acid solution, it is suffiCient to perform only the second part of the test.
`The same mformation about the function of the enteric coating is gained.
`
`PZV0000000234
`
`

`
`Pharmaceuttcal constderattons
`
`165
`
`Dissolution rate-limited absorption
`
`Although the PPis are rapidly absorbed from a solution, their low solubility
`in water coupled with the susceptibility of degradation in solutions of acid
`to near-neutral pH-values indicate that the rate of dissolution from a dosage
`form can limit the rate and extent ofbioavailability [6].
`
`Influence of food
`
`Absorption from a controlled-release dosage form has a greater potential
`of being influenced by concomitant food intake than that from an imme(cid:173)
`diate release formulation. Absorption from enteric-coated dosage forms,
`which dissolve first in the small intestine, are of course influenced by
`gastric emptying. In this respect enteric-coated tablets, due to their size,
`show a greater variability than small, individually enteric-coated multiple(cid:173)
`unit formulations. The presence of food can also interfere with the dissolu(cid:173)
`tion and absorption ofthe active drug. When single oral doses ofpantopra(cid:173)
`zole sodium sesquihydrate enteric-coated tablets were given to 19 healthy
`subjects prior to a high caloric breakfast, the area under the plasma con(cid:173)
`centration vs time curve (AUC) and the maximum plasma concentration
`(Cm~) were the same as when the tablets were given in the fasting state [17].
`The gastric emptying of the tablets given together with food were much
`more variable, resulting in an increased variability in time [lmall) to reach
`C~,. This delay in gastric emptying is of no clinical importance during
`continuous dosing, although it may delay the effect on gastric acid secre(cid:173)
`tion after the first dose of a treatment. The influence of food on the absorp(cid:173)
`tion of omeprazole from a multiple-unit enteric-coated pellet formulation
`(Losee® capsules) was studied in 12 healthy subjects. In two periods of
`7 days the capsules were given either before or after breakfast. When the
`capsules were given after the meal, the time for appearance of omeprazole
`in blood plasma seemed to be prolonged, but the total amount absorbed was
`not affected [18]. Different results were found for Jansoprazole capsules,
`with Cm,. reduced about 50% andAUC reduced about 27% when the cap(cid:173)
`sules were given together with a standard meal [19]. In another study in 12
`healthy male subjects single doses oflansoprazole 30 mg capsules contain(cid:173)
`ing enteric-coated pellets were administered with or without breakfast.
`When co-administered with breakfast, 1m, was doubled, and the AUC and
`Cmu were decreased by approximately 50% [20].
`
`Influence of antacids
`
`In the clinical situation, where treatment with a PPI is indicated, antacids
`are often used for symptom relief. Antacids increase the pH of the stomach
`
`PZV0000000235
`
`

`
`166
`
`A G P1lbrant
`
`contents to pH values where the enteric coating of PPI dosage forms is
`soluble. Antacids usually have a short-term effect on gastric pH. If a PPI
`dosage form is taken together with antacids, there is a risk that the enteric
`coating will dissolve or partly dissolve while the dosage form still remains
`in the stomach. If the gastric pH returns to normal, the remaining PPI will
`rapidly degrade. It has been shown for omeprazole [21, 22] and panto(cid:173)
`prazole [23] that this is not the case. The bioavailability ofthese two drugs
`is not influenced by concomitant administration of antacids. For lansopra(cid:173)
`zole capsules, however, the bioavailability was slightly decreased when the
`capsules were given together with antacids [19, 24]. When antacids were
`administered 1 h before the lansoprazole capsules, there was no influence
`on lansoprazole bioavailability [19].
`
`Dispersion of enteric-coated dosage forms in liquids
`
`For the PP!s, which degrade rapidly in acidic media, it is essential that the
`enteric coating functions. It is also important that the dosage forms be swal(cid:173)
`lowed intact. They cannot be crushed or chewed. For patients having dif(cid:173)
`ficulties swallowing tablets or capsules, for example patients with erosive
`reflux oesophagitis, this can be a real challenge. Dosage forms containing
`small individually enteric-coated units can be dispersed, preferably in an
`acid-reacting fruit juice, before intake [25]. If the enteric-coated units are
`small enough, it is also possible to feed a dispersion through a nasogastric
`tube. For enteric-coated whole tablets there is no such opportunity.
`
`Storage stability
`
`Given the physicochemical characteristics of the PPls, it is difficult to
`develop dosage forms with good long-term stability with regard to chemi(cid:173)
`cal stability as well as biopharmaceutical properties. The pharmaceutical
`products must be capable of being stored and handled at elevated tempera(cid:173)
`tures and at high relative humidity. Functional and well-designed packages
`are important for good storage stability. According to current guidelines, a
`pharmaceutical product which can be stored at 40'C/75% relative humidi(cid:173)
`ty during 6 months without changes in its physicochemical characteristics
`can be assigned a shelf-life of3 years. The market acceptance of the PP!s
`and especially omeprazole has created great interest, and a vast number of
`omeprazole products of different origin are available. All of these do not
`live up to the quality ofthe Astra brand-name products. A number of ome(cid:173)
`prazole products available in different countries were tested regarding their
`storage stability at 40°C/75% relative humidity [26, 27]. After storage for
`6 months less than 20% of the products had acceptable quality with regard
`to potency, content of degradation products, discoloration and in vitro
`
`PZV0000000236
`
`

`
`Pharmaceutical constderatlons
`
`167
`
`dissolution rate. The use of some of these products will certainly lead to
`suboptimal treatment results.
`
`Parenteral dosage forms
`
`The stability characteristics of the PPis precludes the development of ready(cid:173)
`to-use solutions for parenteral administration. In alkaline water solutions,
`where the PPis are present mainly in anionic form, the stability (and solu(cid:173)
`bility) is sufficient for the preparation of a solution which can be filtered
`sterile, dispensed aseptically into sterile injection vials and freeze-dried.
`For stability and solubility reasons the pH of the concentrated dispensing
`solution needs to be above pH II. If the lyophilised substance is recon(cid:173)
`stituted with a small amount of water, the solution will have a high pii
`which might be given by slow intravenous injection; but this is accom(cid:173)
`panied by a high risk of causing pain at the injection site or even thrombo(cid:173)
`phlebitis. It is recommended to dissolve the lyophilised substance in 50 to
`I 00 ml of saline or 5% dextrose for infusion. The dilute solution in saline
`will have a pH of about 10 and can be given as a short-term infusion over
`20 to 30 min without problems. Omeprazole (Losee'") is available both
`as a lyophilised substance for infusion (for reconstitution in I 00 ml of
`saline or 5% dextrose for infusion) and as a lyophilised substance for intra(cid:173)
`venous injection. For the latter a solvent ampoule (water/polyethylene
`glycol) containing pH-buffering substances is provided. The pH of the
`injection solution, 10 ml containing 40 mg of omeprazole, is adjusted to
`pH 9. This solution can be given as an intravenous injection over at least
`2.5 minutes. Lansoprazole [28] and pantoprazole [27] have also been
`formulated as lyophilised substances for extemporaneous reconstitution.
`These products are available only in a few countries.
`The reconstituted solutions are stable for short periods oftime. The lyo(cid:173)
`philised substances should only be reconstituted in the recommended solu(cid:173)
`tions. The PP!s cannot be added to other infusion solutions. Parenteral
`nutritional solutions have too low a pH, causing rapid degradation of the
`active drug. Other solutions for infusion contain different metal ions which
`will precipitate the PPI out of solution.
`
`Formulations for other routes of administration
`
`Many other routes of administration for the PP!s have been discussed, for
`example rectal, transdennal, nasal and so on. However, the chemical struc(cid:173)
`ture of the PP!s is such that the active substances might cause allergic
`contact skin reactions. This property of the PP!s prohibits the develop(cid:173)
`ment of pharmaceutical preparations for most routes other than oral and
`parenteral.
`
`PZV0000000237
`
`

`
`168
`
`References
`
`A. G. Ptlbrant
`
`Fellenius E, Berglindh T, Sachs G, Olbe L, Elander B, Wallmark B (1981) Substituted
`benzimidazoles inhibit gastric acid secretion by blocking (HtK+)ATPase. Nature 290:
`159-161
`2 Wallmark B, BriindstrOm A, Larsson H (1984) Evidence for acid~induced transformation
`of omeprazole into an active inhibitor of (H'K')-ATPase within the parietal cell. Biochem
`Biophys Acta 778: 549-558
`3 Lindberg P, Nordberg P, Alminger T, BdndstrOm A, Wallmark 8 ( 1986) The mechanism of
`action of the gastric acid secretion inhibitor omeprazole. J Med Chern 29: 1327-1329
`4 BriindstrOm A, Lindberg P, Bergman N-A, Alminger T, Ankner K, Junggren U, Lamm B,
`Norberg P, Erickson M, Grundevik I et al (1989) Chemical reactions of omeprazole and
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`6 Pilbrant A, Cederberg C (I 985) Development of an oral formulation of omeprazole. Scand
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`12 Saeki Y, Koyama N, Aoki S (1989) Peroral preparation of an acid-unstable compound.
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`18 Andersson T, Andren K., Cederberg C, Heggelund A, Lundborg P, ROhss K (1990) Rio(cid:173)
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`and seventh days oftreabnent. Drug Invest 2: 184-188
`19 Delhotal-Landes B, Cournot A, Vermerien N, Dellatolas F, Benoit M, Flouvat B (1991)
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`20 Bergstrand R, Grind M, Nyberg G, Olofsson B (1995) Decreased oral bioavailability of
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`lnvest9; 67-71
`21 Howden CW, Reid JL ( 1988) The effect of antacids and metoclopramide on omeprazole
`absorption and disposition. Brit J Clin Pharmacol25: 779-781
`22 Tuynman HARE, Festen IIPM, ROhss K, Meuwissen SGM (1987) Lack of effect of antacids
`on plasma concentrations of omeprazole given as enteric-coated granules. Br J Clin
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`23 Hartmann M, Bliesath H, HuberR, Koch H, Steinijans VW, Wurst W (1994) Simultaneous
`intake of antacids has no influence on the phannacokinetcs of the gastric H+K+-ATPase
`inhibitor pantoprazole. Gut 35 (Suppl 4): A 76
`
`PZV0000000238
`
`

`
`Pharmaceuttcal considerations
`
`169
`
`24 Gerloff J, Barth H, Mtgnot A, Fuchs W, 1-Iemtze K (1993) Does the proton pump
`mhtbttor lansoprazole mteract wtth antactds? Naunyn Schmredebergs Arch Pharmacol
`347 (Suppl) R31
`25 Chun AHC, Eason CJ, Slu III!, Cavanaugh JH (1995) Lansoprazole an altemattve method
`of adtrumstratlon of a capsule dosage formulation Clm Ther 17 441-447
`26 DaVIdson AG, McCallum A (1996) A survey of the stabthty of omeprazole products from
`13countnes DrugDevlndPharm22 1173-1185
`27 Karlsson A, Lmdqvtst J, Lovgren K, Rosen L, TIVert A-M (1996) An mvesbgatlOn of
`the phannaceuttcal quality of non-Astra authonsed omeprazole products - a comparative
`study IntPharmJIO 210-213
`28 Takeclu N, Hamagucht N (1995) InJectable solutions contammg antt-ulcer benztmtdazoles
`and amJdes Eur PatAppl 0 649 655Al
`29 Dtetnch R (1996) Method of producmg a pantoprazole 1yoph1.hsate PCT Pat Appl WO
`96/17607
`30 Knstl A, Vrecer F (1996) Investlgatwn of the ac1do-bastc and partition properttes of the
`proton pump mhibttor lansoprazole Eur J Pharm Scr 4 (Suppl) S 117
`31 Huber R, Kohl B, Sachs G, Senn-Bilfmger J, Simon WA, Sturm E (1995) Review arttcle
`the contmumg de-velopment of proton pu.up u-J:-ubttors With. particular reference to par;,to(cid:173)
`prazole Aliment Pharmacu/ Ther 9 363-378
`
`PZV0000000239