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«Dissertation Zur Erlangung des Doktorgrades der Naturwissenschaften Der Fakultät für Mathematik, Informatik und Naturwissenschaften der ...»

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Characterization of Different

Shellac Types

and

Development of Shellac-Coated

Dosage Forms

Dissertation

Zur Erlangung des

Doktorgrades der

Naturwissenschaften

Der Fakultät für

Mathematik,

Informatik und

Naturwissenschaften

der Universität Hamburg

vorgelegt von

Yassin Farag

aus Hamburg

Hamburg, 2010

Für meine Annina

Reviewer of the dissertation: Professor Dr. Claudia S. Leopold

Professor Dr. Detlef Geffken

Reviewer of the disputation: Professor Dr. Claudia S. Leopold Professor Dr. Sascha Rohn Dr. Werner Pauer Date of disputation : 01.10.2010 The experimental part of this work was prepared from January 2007 until July 2010 in the research group of Professor Dr. Claudia S. Leopold at the Department of Chemistry, Pharmacy, University of Hamburg.

It is my special wish to thank Prof. Dr. Claudia S. Leopold for the opportunity to be a member of her research group, for leaving me this interesting topic and giving me the facility and freedom for the preparation of the present work. I deeply appreciate her help and advice in all concerns and I am especially grateful for her professional and scientific guidance.

Furthermore, I thank Prof. Dr. Detlef Geffken for evaluating my thesis as well as Prof.

Dr. Sascha Rohn and Dr. Werner Pauer for serving as members of my thesis examination committee.

Moreover, I like to thank the members of the pharmaceutical technology research group for the most pleasant and convenient environment to work in. Special thanks to my precious colleagues Tina and Robert who became real friends. I hope we never lose sight of each other.

I thank Professor Dr. Hans R. Kricheldorf from the Institute of Technical and Macromolecular Chemistry as well as Dr. Steffen Weidner from the Federal Institute of Material Research and Testing (Bundesanstalt für Materialforschung und –Testung, BAM) for the preparation and valuable help with the interpretation of the MALDI TOF spectra.

I thank Manfred Penning and especially Dr. Marcel Förster for the donation of shellac samples and helpful discussions about shellac as well as Dr. Fritz Stanislaus and Temmler Ireland for the donation of the theophylline pellets.

I am grateful to the companies Harke Pharma especially Dr. Jörg Brunemann and Stroever Schellack Bremen for giving me financial support for my congress participations.

Thanks go also to Mrs. Renate Walter from the zoological Institute for the preparation of the SEM pictures and to Mrs. Marie Zeise and her scientific workshop team for their helpfulness with the preparation and repair of various instruments.

Very special thanks go to my friends Tim, Jan and Alexander for regularly showing me the world outside the University’s walls and for their effort to keep me an acceptable work-life balance. Jörn, Shirin and especially Björn I like to thank for their invaluable support in times of change.

Most importantly, I thank my parents for giving me the freedom and support to follow and realise my dreams.

–  –  –

Abstract Shellac is the purified product of the natural material lac which is secreted by the small parasitic insect Kerria Lacca on various host trees in India, Thailand and South-eastern Asia. Shellac is non-toxic, physiologically harmless and therefore listed as GRAS by the FDA. This status allows its use in food products such as coating for citrus fruits or confectionaries. Besides its use in the color industry this is its main application.

Shellac for pharmaceutical applications is usually obtained by solvent extraction. With a careful selection of the raw material this refining process allows the production of shellac types with reproducible quality. However, this refining process results in shellac in its acid form which undergoes aging. This aging process leads to changes in the material properties and is the main reason for the decline in pharmaceutical applications.

Since the introduction of aqueous ammoniacal solutions shellac has regained importance. Aqueous solutions are easy to handle and allow the production of films that lack the aging instability.

In the present work different shellac types and batches were characterized with regard to their physicochemical properties and drug release from shellac-coated dosage forms.

It could be shown that the samples differed significantly in their material properties and aging behavior as well as in the drug release profiles of the coated dosage forms.

Besides the origin especially the age of the samples could be identified as a critical factor.

Subsequently, the influence of the aging process on the material properties was investigated. Therefore, shellac samples were artificially aged by thermal stress. Aim of this study was the identification of a suitable parameter for the detection of aged shellac. The determination of the acid value, which is required by the pharmacopoeias for the chemical characterization of shellac, was found to be unsuitable for this purpose.

It could be shown, that the glass transition temperature is a more sensitive indicator for the detection of aged shellac.

Abstract

ii Furthermore, the influence of process parameters during the production of shellaccoated dosage forms was investigated. It could be shown that the inlet air temperature of the fluid bed coating process has a large influence on the quality of the final product.





Whereas high inlet air temperatures led to continuous coating films, a reduction of the temperature resulted in cracks in the coating film and thus a loss of film integrity with most samples. The temperature sensitivity of the coating process was found to be different for the investigated shellac types.

Finally, a new concept for the formulation of shellac-coated sustained release formulations is presented. A subcoat containing different substances that interact with shellac was applied to drug pellets which were subsequently coated with shellac. It could be shown that the application of modifying subcoats is an effective means to obtain sustained release from shellac-coated formulations. The choice of a suitable substance and concentration allows tailor-made release profiles.

Shellac is a very interesting material with a broad spectrum of applications. However, different shellac types may differ widely in their material properties. These differences are even more pronounced with aged shellac. This variability in the physicochemical and mechanical properties also affects the processibility of the material and has to be considered if shellac is used in pharmaceutical applications.

However, due to its regulatory status shellac may be of interest for coating applications especially for food products where the use of other coating materials is not allowed.

Hence, the subcoat formulations presented in this work offer an interesting approach for the development of sustained release drug and dietary supplement formulations.

Zusammenfassung iii

Zusammenfassung

Schellack ist die aufgereinigte Form des Harzes Lac, welches von dem kleinen, parasitischen Insekt Kerria Lacca auf verschiedene Wirtsbäume in Indien, Thailand und Südostasien sezerniert wird. Schellack ist ungiftig, physiologisch gut verträglich und deshalb als Lebensmittelzusatzstoff zugelassen. Diese Eigenschaft ermöglicht den Einsatz als Überzugsmittel für Lebensmittel wie Zitrusfrüchte und Süßwaren, worin Schellack neben der Verwendung in der Farbindustrie seine Hauptanwendung findet.

Schellack für pharmazeutische Anwendungen wird überwiegend durch Lösemittelextraktion gewonnen. Bei einer sorgfältigen Auswahl der Rohmaterialien erlaubt es dieses Aufreinigungsverfahren Schellack mit gleichbleibender Qualität herzustellen. Endprodukt dieses Verfahrens ist jedoch Schellack in seiner Säureform, die einem Alterungsprozess unterliegt. Dieser Alterungsprozess führt zu Veränderungen in den Materialeigenschaften, was einer der Hauptgründe dafür ist, dass die Verwendung von Schellack in pharmazeutischen Anwendungen stark zurückgegangen ist.

Seit der Einführung wässrig-ammoniakalischer Lösungen konnte Schellack wieder Bedeutung gewinnen. Wässrige Schellacklösungen lassen sich leicht verarbeiten und daraus hergestellte Filme zeigen nur geringe Alterungserscheinungen.

Im Rahmen dieser Arbeit wurden unterschiedliche Schellacksorten und -chargen hinsichtlich ihrer physikochemischen Eigenschaften sowie der Wirkstofffreisetzung aus schellack-überzogenen Arzneiformen untersucht. Dabei konnte gezeigt werden, dass sich die einzelnen Proben sowohl stark in ihren Materialeigenschaften und ihrem Alterungsverhalten als auch in den Wirkstofffreisetzungsprofilen der überzogenen Arzneiformen unterschieden. Neben dem verschiedenen Ursprung wurde dabei vor allem das Alter der Schellackprobe als kritischer Faktor identifiziert.

Im Folgenden wurde geklärt, welchen Einfluss der Alterungsprozess auf die Materialeigenschaften hat. Dazu wurden Schellackproben unter Stressbedingungen künstlich gealtert. Im Rahmen dieser Untersuchung sollte eine geeignete Kenngröße gefunden werden, um gealterten Schellack zu erkennen. Die Säurezahl, die vom Arzneibuch als einzige Kennzahl für die chemische Charakterisierung gefordert wird, Zusammenfassung iv hat sich dabei als ungünstig erwiesen. Es konnte gezeigt werden, dass die Glasübergangstemperatur einen viel empfindlicheren Indikator für die Erkennung von gealtertem Schellack darstellt.

Des Weiteren wurde der Einfluss von Prozessparametern bei der Herstellung schellacküberzogener Arzneiformen untersucht. Hierbei konnte gezeigt werden, dass die Zulufttemperatur beim Überzugsprozess einen erheblichen Einfluss auf die Qualität der überzogenen Arzneiform hat. Während bei hohen Temperaturen intakte Überzüge hergestellt werden konnten, führte eine Absenkung der Temperatur bei den meisten Proben zur Ausbildung von Rissen im Überzug und damit zu einem Verlust der Filmintegrität. Es stellte sich heraus, dass die Temperaturabhängigkeit des Überzugsprozesses stark von der verwendeten Schellacksorte abhängt.

Schließlich wurde ein neues Konzept zur Entwicklung schellack-überzogener Retardarzneiformen entwickelt. Arzneistoffpellets wurden mit einem Zwischenüberzug versehen, der verschiedene Substanzen enthielt, die mit Schellack wechselwirken.

Anschließend wurden die Pellets mit Schellack überzogen. Es konnte gezeigt werden, dass die Verwendung modulierender Zwischenüberzüge eine effektive Methode ist, eine verlängerte Wirkstofffreisetzung mit schellack-überzogenen Arzneiformen zu erhalten. Durch die Auswahl der entsprechenden Substanz sowie deren Konzentration können auf diese Weise Arzneiformen mit maßgeschneiderten Freisetzungsprofilen hergestellt werden.

Schellack ist ein Material mit vielfältigen Anwendungsmöglichkeiten. Einzelne Schellacksorten können sich jedoch deutlich in ihren Eigenschaften unterscheiden.

Diese Unterschiede sind umso stärker ausgeprägt je älter die Schellackproben sind.

Diese Variabilität in den Materialeigenschaften beeinflusst auch die Verarbeitbarkeit des Materials und muss bei der Verwendung von Schellack in Arzneiformen berücksichtigt werden.

Im Gegensatz zu den meisten anderen Überzugsmaterialien ermöglicht der Status als Lebensmittelzusatzstoff eine Anwendung von Schellack in Lebensmitteln. Die in dieser Arbeit vorgestellten Retardformulierungen eröffnen daher einen interessanten Ansatz für die Entwicklung verlängert freisetzender Arzneiformen und Nahrungsergänzungsmittel.

Contents v

–  –  –

1.1. Coated dosage forms Film coating has become a routine operation in the production of solid oral dosage forms. There are numerous reasons for the application of film coatings to drug formulations. Polymeric film coatings can be applied to pharmaceutical solids for decorative purposes to provide gloss [1]. The incorporation of dyes and pigments into the coating films allows coloration of the dosage form e.g. to facilitate product differentiation [2-4]. Film coatings are also applied to improve the mechanical stability and reduce abrasion of the dosage form during manufacturing, shipping and storage [5, 6]. Sensitive drug formulations are film-coated to protect the ingredients from light or humidity [7]. Film coatings can mask unpleasant taste as well as odor and facilitate swallowing [8] which will improve the patient’s compliance during drug therapy.

Another important function of film coatings manifests itself once the dosage form reaches the GI tract. By selection of specific coating materials the film coating allows controlled release of the drug in the GI tract: So-called enteric coatings are applied to solid oral dosage forms to protect the drug from the acidic milieu of the stomach or vice versa. Sustained release coatings deliver the drug over a long time period and allow a reduction of daily intake frequency and thus improve the compliance of the patient.

Especially for such coated controlled release formulations a consistent quality of the film coating is essential to maintain reproducible release profiles and to avoid the risk of dose dumping or loss of efficacy.

The large number of applications for film coatings, the variety of coating materials and the need for reliable coating processes explains the great research effort on coated dosage forms.

Introduction 3

1.2. Film coating materials For each desired application a variety of different coating materials with tailor-made physicochemical properties is available. Most commonly used are polymers such as polymethacrylates [9], povidones [10] and cellulose esters and ethers [11, 12].

Povidones and polymethacrylates are synthetic polymers which are obtained by emulsion polymerisation [13, 14]. The properties of the final polymer can be adjusted by selection of specific monomers. Cellulose derivatives are semisynthetic polymers gained either by esterification or etherification of natural cellulose. The type of substituent and the degree of substitution defines the properties of the final polymer.

Besides these major film coating polymers there are few other materials used for film coating applications. One of them is shellac.

The chemical properties of the coating material define the functionality of the coating film and thus the drug release characteristics of the final dosage form.



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