Formulation of floating tablets containing metronidazole
Doctoral thesesDorottya Kiss
Semmelweis University
Doctoral School of Pharmaceutical Sciences
Supervisor: Dr. Romána Zelkó, Ph.D.
Official reviewers: Dr. Krisztina Ludányi, Ph.D. Dr. Piroska Révész, D.Sc.
President of the final exam committe: Dr. Béla Noszál, D.Sc. Members of the final exam committe: Dr. István Erıs, D.Sc.
Dr. Imre Klebovich, D.Sc.
2 SUMMARY
The aim of the present work was to develop a sustained release, gastroretentive dosage form, which is capable of floating upon the gastric contents, thus providing the site-specific delivery of the active ingredient.
I used metronidazole as a model drug, because its role in the eradication of Helicobacter pylori justifies its application in a dosage form characterized by the above mentioned properties.
In the course of the preformulation studies, I selected the excipients that proved to be compatible with the model drug according to differential scanning calorimetry investigations. I also determined their thermal properties, flowability, compressibility and morphological characteristics, which are of great importance from the aspect of the manufacturing process.
I prepared 36 kinds of tablets using low density foam polymer in half of the formulations and gas-generating excipients in the rest of the tablets in order to assure the appropriate density of the dosage forms. I evaluated the tablets by investigating the effect of the amount of the foam powder, the ratio of the matrix-forming polymers, the amount of the active ingredient and the amount and ratio of the fillers on the hydrodynamic properties and drug release of the formulations.
In the course of the optimization of the composition and production of the tablets, I found that only dosage forms based on gas-generation can be reproduced properly.
Upon investigating the stability of the drug release of the tablets, I found that structural changes of the amorphous region of the matrix-forming agent caused by storage resulted in the increase of the extent of drug release in the case of the low molecular weight matrix-forming polymer.
INTRODUCTION AND AIMS
Along with the growing importance of biopharmaceutics, the interest in novel drug delivery systems has grown, and intensive research and development has started in this field.
Besides the physicochemical properties of active ingredients and excipients, the physiological ascpects of the human body and the consequent challenges are of greater and greater significance in dosage form design. One of these aspects is uncertain gastric residence time, which can range from a couple of minutes to 12 hours depending on the physiological state of the individual and the properties of the dosage form. Another challenge is that very often the active leaves the optimal site of absorption quickly. These factors usually lead to impaired bioavailability and inadequate therapeutic results.
In the case of several active ingredients, gastroretentive drug delivery systems (GRDDSs) can serve as the solution to the above mentioned problems, as they prolong the gastric residence time of the drug, because the passage of the dosage form through the stomach is hindered. The development of such systems started somewhat thirty-five years ago with the invention of Madopar HBS® capsules intended for Parkinson’s disease, and it was hastened by Barry J. Marshall’s and Robin Warren’s discovery of the bacterium known as Helicobacter pylori and its role in certain pathological states of the stomach.
In spite of the difficulties caused by the anatomical and physiological properties of the stomach, numerous technical solutions have been suggested for the realization of gastroretentive dosage forms. One possibility for the prolongation of gastric residence time is the application of low density systems, which are capable of floating upon the contents of the stomach, and thus avoid passing through the pylorus.
4 The aims of my work were the followings:
− selection of an appropriate excipient system for the formulation of sustained release floating tablets,
− formulation of floating tablets containing metronidazole as a model drug using the optimal excipient system,
− investigation of the effect of storage on the drug release characteristics of the tablets.
METHODS
In order to reveal the possible incompatibilities between the active ingredient and the potential excipients, I carried out thermoanalytical investigations by means of differential scanning calorimetry (DSC). The thermograms of the pure substances and 1:1 physical mixtures of the active and the excipients were recorded before and after 1, 2 and 4 weeks of storage using a TA Instruments DSC 2920 type calorimeter. NIR spectroscopic examinations using a Hitachi U-3501 spectrophotometer were also performed in order to find explanation for some phenomena experienced in the course of the compatibility studies.
The particle size distribution of the materials was determined by a method based on laser diffraction with a Sympatec particle size analyzator. The flowability of the different powders was measured using an ASTM-funnel and a stopper, whereas the apparent volume before and after settling was determined using a STAV 2003 type settling apparatus equipped with an Omron HFCX-A4 counter. The examination of the morphological characteristics was carried out by means of scanning electronmicroscopy (SEM, Philips XL30 microscope).
The tablets were compressed directly with a Diaf type single punch tablet press after homogenization of the components. The uniformity of mass and friability of the tablets was measured according to Ph. Hg. VIII. using a Precisa XB 160M type laboratory balance and an Erweka TAP 25 701 friability apparatus. The resistance of tablets to crushing was determined with an Erweka TBH 200TD type apparatus, while the floating lagtime was observed visually in 150 ml hydrochloric acid in a beaker.
The dissolution tests were carried out in an Erweka DT6RE type apparatus, and the active ingredient (metronidazole) conent of the samples was determined based on the UV-spectrophotometric method in Ph. Hg. VIII.
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The dissolution curves were analyzed by fitting four different models to the drug release profiles using linear regression and the Solver function of Microsoft Excel®. The correlation coefficients of the fittings were also calculated, and the comparison of the dissolution profiles was carried out based on the difference and similarity factors proposed by the FDA.
In order to elucidate the phenomena behind the changes in drug release in the course of storage, the structural alterations of the matrix-forming polymer were followed by DSC and SEM methods and positron annihilation lifetime spectroscopy.
RESULTS
New scientific results:
− In the course of the preformulation studies, I have clarified which of the excipients intended for application in the tablets proved to be compatible with metronidazole used as a model drug.
− After screening 36 kinds of compositions based on low densitiy foam powder or gas-generating excipients, I have chosen the optimal ones from the aspect of hydrodynamical properties. The floating behaviour of the low density systems proved to be better, but the compositions containing gas-generating agents were more advantageously tablettable.
− The optimization of the compositions and manufacturing process revealed that the hydrodynamic properties of the systems containing foam powder cannot be maintained in the course of reproduction. In the case of tablets based on gas-generation, the amount of CO2-producing agents proved to be critical from the
aspect of hydrodynamic characteristics.
− Upon assessing the stability of drug release, the dissolution profiles exhibited changes because of the structural alterations of the amorphous regions of poly(ethylene oxide) type matrix-forming agents applied in the formulations.
− The above phenomenon was more pronounced in the case of the lower molecular weight polymer. Thus, it is advisable to apply the higher molecular weight form at least in 1:1 ratio, or to assure the airtight packaging and controlled-temperature storage of the dosage form.
8 Practical relevance of the results:
− The conclusions concerning the practical relevance of the above investigations were drawn on the basis of experiments carried out with a model drug. By the development of other floating dosage forms, the properties of the active ingredient that influence hydrodynamic behaviour (density, dose, etc.) must be taken into account. Still, the results of the above studies allow some general conclusions to be drawn about the development of floating drug delivery systems.
− The findings of the physical preformulation studies can be used in the formulation of gastroretentive dosage forms based on the investigated matrix-forming, gas-generating and low density excipients, irrespective of the active ingredient of the formulation.
− The compatibility studies revealed that most of the examined excipients can be applied in metronidazole-containing systems, and at the same time the interaction of the model drug with Emcompress® was newly detected.
− The investigation of tablets containing low density polypropylene foam powder showed that the relatively large particle size of the material disadvantageously influences its homogenization with the model drug and other excipients. The porous structure of the material gets compressed in the course of tabletting, which is unfavourable from the aspect of the final density of the tablet. Based on these findings, the applicability of polypropylene in floating tablets is questionable.
− In the case of systems based on gas generation, I have determined the optimal amount of gas-generating components needed for the appropriate hydrodynamic properties.
− I have pointed out that among several matrix-forming polymers, poly(ethylene oxides) are mostly applicable to ensure appropriate hydrodynamic properties and nearly linear drug release kinetics. I have also shown that dissolution rate can be regulated through the molecular weight of the matrix-forming polymer.
− I have also pointed out that the stability of drug release of the optimized compositions is not sufficient in the case of the lower molecular weight poly(ethylene oxide). This phenomenon can be attributed to the storage-induced changes of the amorphous regions of the polymer. This justifies the application of the higher molecular weight forms, as well as the necessity of such investigations of dosage forms containig these polymers.
− Based on in vitro drug release and hydrodynamic investigations, the proposed floating tablets can be applied for sustained and localized delivery of metronidazole in the stomach. This can be advantageous in the eradication of Helicobacter pylori through the maintenance of high drug concentration at the site of action.
10 LIST OF PUBLICATIONS
Papers connected to the theses
− Kiss D, Zelkó R. (2005) Gasztroretentív hatóanyag-leadó rendszerek jellemzése. Acta Pharm Hung, 75(3):169-176.
− Kiss D, Zelkó R, Novák Cs, Éhen Zs. (2006) Application of DSC and NIRS to study the compatibility of metronidazole with different pharmaceutical excipients. J Therm Anal Cal, 84(2):447–451. IF: 1,438
− Kiss D, Süvegh K, Marek T, Dévényi L, Novák Cs, Zelkó R. (2006) Tracking the physical aging of poly(ethylene oxide): a technical note. AAPS PharmSciTech, 7 (4):article 95. (www.aapspharmscitech.org, DOI: 10.1208/pt070495) IF: 0,857
− Zelkó R, Kiss D. (2005) Amorf polimer segédanyagok fizikai öregedése I. Fizikai-kémiai alapok. Acta Pharm Hung 75(4):213-222.
− Zelkó R, Kiss D. (2006) Amorf polimer segédanyagok fizikai öregedése II. Az öregedés nyomon követése. Acta Pharm Hung 76(1):55-63.
− Zelkó R, Kiss D. (2006) Amorf polimer segédanyagok fizikai öregedése III. Az öregedés lehetséges következményei. Acta Pharm Hung 76(2):105-113.
− Zelkó R, Kiss D, Süvegh K. Effects of physical ageing on polymer structure and function – a pharmaceutical approach. Sent and accepted upon request from the editorial board of “Polymer Degradation and Stability Research Trends”.
Lectures connected to the theses published in extenso
− Kiss D, Süvegh K, Marek T, Zelkó R. (2005) Effect of physical ageing on the physicochemical characteristics of poly(ethylene oxides). Eur J Pharm Sci, 25(S1):S132-S134.
− Kiss D, Süvegh K, Novák Cs, Dévényi L, Zelkó R. Tracking and consequences of physical ageing of poly(ethylene oxide). Proc. 5th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, Geneva, 27-30 March 2006, P-37.
− Kiss D, Berlier P-H, Roussel L, Zelkó R. (2006) Effect of physical ageing on the drug release characteristics of poly(ethylene oxide) matrices. 1st BBBB Conference on Pharmaceutical Sciences, Siófok, 26-28 September 2005, P-24, pp. 157-160.
Lectures connected to the theses
− Kiss D. Preformulációs vizsgálatok szabályozott hatóanyag-leadású tabletta készítéséhez. (Semmelweis Egyetem Ph.D. Tudományos Napok, Budapest, 2005. április 14-15., E-VII/8, absztr.:68)
− Kiss D, Süvegh K, Marek T, Zelkó R. Effect of physical ageing on the physicochemical characteristics of poly(ethylene oxides). (6th Central European Symposium on Pharmaceutical Technology and Biotechnology, Siófok, 2005. május 25-27.)
− Kiss D, Berlier P-H, Roussel L, Zelkó R. Effect of physical ageing on the drug release characteristics of poly(ethylene oxide) matrices. (1st BBBB Conference
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− Kiss D. Physical ageing of poly(ethylene oxide): tracking and consequences. (Semi-centennial conference of Semmelweis University, Faculty of Pharmacy, Budapest, 2005. október 12-14., L-12.)
− Kiss D, Süvegh K, Marek T, Zelkó R. Effect of physical ageing on the physicochemical characteristics of poly(ethylene oxides). (Semi-centennial Conference of Semmelweis University, Faculty of Pharmacy, Budapest, 2005. október 12-14., P-53.)
− Kiss D, Zelkó R. Effect of physical ageing on the physicochemical and drug relaese characteristics of poly(ethylene oxides). (II. PhD Joint Meeting on Biomedical Sciences, Budapest, 2005. november 6-7.)
− Kiss D, Süvegh K, Novák Cs, Dévényi L, Zelkó R. Tracking and consequences of physical ageing of poly(ethylene oxide). (5th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, Genf, 2006. március 27-30.).
− Kiss D. Polimer segédanyagok fizikai öregedése. (MGYT Ipari Szervezete szakmai napja, Budapest, 2006. április 5.)
− Kiss D, Zelkó R. Poli(etilén-oxid) alapú mátrixtabletták stabilitásvizsgálata. (Semmelweis Egyetem Ph.D. Tudományos Napok, Budapest, 2006. április 13-14., E-IV/6, absztr.:37 – EGIS-különdíj.)
− Kiss D, Süvegh K, Zelkó R. Effects of physical ageing on polymer structure and function – a pharmaceutical approach. (1st European Chemistry Congress, Budapest, 2006. augusztus 28-31., absztr.:288.)
− Kiss D, Zelkó R. Amorf polimerek fizikai öregedésének nyomonkövetése és következményei gyógyszer-stabilitási szempontból. (Gyógyszerkémiai és Gyógyszertechnológiai Szimpózium, Eger, 2006. szeptember 18-19.)
− Kiss D, Mátyus P, Balogh B, Zelkó R. Stability of poly(ethylene oxide) matrices – effects of storage and active ingredient structure. (European Network of Doctoral Studies in Pharmaceutical Sciences – 3rd Annual Meeting, Catania, 2006. november 3-4.)
− Kiss D. Gasztroretentív, úszó gyógyszerformák formulálásának szempontjai. (VIII. Clauder Ottó Emlékverseny, Budapest, 2007. április 12-13. – I. helyezés)
− Zelkó R, Kiss D. A fizikai öregedés nyomon követésének jelentısége a gyógyszerek stabilitás-vizsgálata során. (Congressus Pharmaceuticus Hungaricus XIII., Budapest, 2006. május 25-27., P-78, Gyógyszerészet Kongresszusi Különszám:87.)
Other papers
− Balogh J, Berta Gy, Hankó B, Hankó Z, Hermetz I, Kenéz M, Kiss D, Mészáros Á, Rixer A, Vincze Z (szerk.), Zelkó R. Gyógyszerügyi Szervezéstan. Részletes szervezési ismeretek. Semmelweis Kiadó, Budapest, 2004. (egyetemi jegyzet)
− Balogh J, Bubenik J, Dredán J, Csempesz F, Kiss D, Zelkó R. (2005) The effect of structured triglycerides on the kinetic stability of total nutrient admixtures. J Pharm Pharm Sci, 8(3):552-557. (www.cspscanada.org)
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− Balogh J, Kiss D, Dredán J, Csempesz F, Puskás I, Zelkó R. (2006) Tracking of the kinetic stability of 2 types of total nutrient admixtures containing different lipid emulsions. AAPSPharmSciTech, 7(4):article 98.
(www.aapspharmscitech.org, DOI: 10.1208/pt070498) IF: 0,857
− Csóka G, Gelencsér A, Kiss D, Pásztor E, Klebovich I, Zelkó R.(2007) Comparison of the fragility index of different Eudragit polymers determined by activation enthalpies. J Therm Anal Cal, 87(2):469-473. IF: 1,438
− Patai K, Kiss D, Dévényi L, Zelkó R. (2007) In utero incrustation of intrauterine systems – consequent complications and monitoring. Fertil Steril, 87(5):1210-1211. IF: 3,277
− Farkas E, Kiss D, Zelkó R. Study on the release of chlorhexidine base and salts from different liquid crystalline structures. Int J Pharm, közlés alatt. IF: 2,212
Other lectures
− Kiss D. TPN oldatkeverékek fizikai stabilitásának vizsgálata. (VII. Clauder Ottó Emlékverseny, Visegrád, 2004. október 14-15. absztr.:28– különdíj.)
− Kiss D. A mesterséges táplálás gyógyszerészi vonatkozásai. (XL. Rozsnyay Mátyás Emlékverseny, Gyula, 2005. május 12-14., absztr.:36 – V. helyezés.)
− Kiss D, Vajna M, Zelkó R. Diclofenac-készítmények hatóanyag-leadásának vizsgálata a hibás gyógyszer-alkalmazás szempontjából. (Congressus Pharmaceuticus Hungaricus XIII., Budapest, 2006. május 25-27., P-56, Gyógyszerészet Kongresszusi Különszám:80.)
− Kiss D, Vajna M, Zelkó R. Nifedipin-készítmények hatóanyagleadásának vizsgálata a hibás gyógyszer-alkalmazás szempontjából. (Gyógyszer az Ezredforulón VI. Továbbképzı Konferencia, Sopron, 2006. november 9-11.)
− Balogh J, Nikolics M, Farkas E, Kiss D, Vincze Z, Zelkó R. Egyedi összetételő "all-in-one" oldatok stabilitásával, inkompatibilitásával kapcsolatos összefüggések vizsgálata. (Magyar Kórházi Gyógyszerészek XIV. Kongresszusa, Debrecen, 2004. május 13-15.)
− Balogh J, Dredán J, Csempesz F, Kiss D, Nikolics M, Zelkó R. Strukturált trigliceridek hatása teljes parenterális táplálásra szánt oldatkeverékek fizikai stabilitására. (Magyar Mesterséges Táplálási Társaság 2005. évi Kongresszusa, Budapest, 2005. november 18-19., absztr.:1.)
− Zelkó R, Kiss D, Patai K. Intrauterin terápiás rendszer in vivo fizikai öregedésének hatása a hormon-felszabadulásra. (Farmakokinetika és Gyógyszermetabolizmus Továbbképzı Szimpózium, Mátraháza, 2006. április 20-22.)
16 ACKNOWLEDGEMENTS
Firstly, I wish to thank my supervisor, Dr. Romána Zelkó, who helped and encouraged my work to the uttermost of her patience. It was her professional calling that inspired me to start dealing with pharmaceutical technology, and she has always endeavoured to let me realize my own ideas.
I owe thanks to Professor Béla Noszál, who has paid attention to my studies since my first year at the Faculty of Pharmacy, and offered me the opportunity to participate in the cooperation between the Faculty and Richter Ltd.
I would like to thank Dr. György Thaler for allowing my participation in the Ph.D. program and for being concerned about the progress. I also owe thanks to Dr. Attila Bódis, who gave all the help needed to maintain the balance between the academic and industrial sides.
Furthermore, I wish to thank Professor Zoltán Vincze for letting me start my R&D activity in the University Pharmacy Department of Pharmacy Administartion. I owe many thanks to my colleagues in the University Pharmacy Department of Pharmacy Administartion for their help and support; with special concern to Magdolna Gregor-Lipóczki, Dr. Judit Kovács-Balogh, Mária Schwáb and Márton Vajna, who made the daily routine pleasant and human.
The help of the staff of the Department of Pharmaceutics is greatly acknowledged, as well.
I am highly grateful to Dr. László Dévényi, Dr. Csaba Novák, Dr. Imre Pozsgai and Dr. Károly Süvegh, who have been of great help in the experimental work. Finally, I would like to dedicate the last lines to my parents, who ensured the undisturbed background needed for my studies and work. I am grateful for their love, the encouragement they gave, the calm family atmosphere they have created, and that they have always let me follow my own way.
