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Design of in vitro characterization approaches to predict the in vivo performance and to assist the development of orodispersible tablets

  • Oral drug delivery is the preferred route of administration for the majority of drugs. Solid dosage forms arewell-accepted because of ease of administration, accurate dosing and high degree of patient compliance. The orodispersible technology platform has attracted increasing interest. Fast disintegrating in the mouth before swallowing, orodispersible dosage forms like orodispersible tablets (ODTs) address the need for patient-compliant medicines. ODTs represent a convenient alternative to conventional tablets or capsules. ODTs are an interesting approach when a rapid onset of therapeutic action is important. So far, ODTs have often been considered as an innovative variant of conventional oral solid dosage forms. Still, the development of ODT formulations is typically assisted by compendial in vitro test methods. However, the techniques described in international pharmacopoeias are non-specific for ODTs. After administration, the dispersion of an ODT in the mouth may provide effects which might influence the absorption of the drug. The performance of ODTs is more comparable to solutions/suspensions than to traditional tablets. To better guide the development of a new ODT formulation, this lack needs to be addressed. It is the aim of this work to design more specific in vitro test methods helping to improve understanding ODT formulations. To reflect the physiological conditions experienced by an ODT after administration, particular attention was given to the mouth where the ODT disperses and releases the drug before swallowing. In vitro biorelevant test setups simulating in vivo conditions were designed. An electronic tongue system was used to assess taste properties of ODTs. These test methods were applied in different stages of the ODT formulation development. Diclofenac being a poorly soluble and weakly acidic NSAID which is a standard medication for acute painful inflammatory conditions was used as a drug model. Three forms, i.e. the free acid and its sodium/potassium salt, were investigated for the formulation of palatable and fast acting ODTs. In Chapter 1, the development of biorelevant test setup reflecting the physiological conditions experienced by ODTs is described in detail. The newly-designed in vitro models successfully discriminated the different diclofenac forms in successive in vitro compartments simulating the mouth, the stomach and the small intestine. It was possible to identify peculiar dissolution profiles with diclofenac salts. Characterizing in-depth the diclofenac free acid and salt particles provided a better understanding of the peculiar dissolution profiles. Critical behaviors of diclofenac salts on their way from the mouth to the stomach and passing different pH conditions were extensively evaluated. Reasons for pH-dependent API precipitation and particle agglomeration were studied in detail. In pre-formulation studies, the proposed biorelevant test setups succeeded in helping to early identify critical pharmaceutical properties for diclofenac salts and to select diclofenac free acid as the most appropriate drug form providing the most stable in vitro performance. In Chapter 2, the electronic tongue method as an in vitro taste assessment tool for ODTs is proposed. Using the TS-5000Z taste sensing system (Insent Inc., Japan), the method was able to differentiate between the taste/aftertaste qualities and intensities of the three diclofenac candidates. The electronic tongue was also successfully used to differentiate different ODT formulations. The results obtained proved that valuable information can be gained. By this means, the taste perception of the diclofenac drug candidates were classified and rank against each other. For manufacturing taste-masked ODTs, diclofenac free acid, could be selected easily. The electronic tongue found out to be a precious tool in assisting the development of a new ODT product and finding the most appropriate multi-component formulation. Both proposed methods successfully showed their discriminative ability and also their utility in pre-formulation studies of ODTs. In the previous chapters, it was indeed possible to early select diclofenac free acid as the most suitable drug candidate for the targeted product profile. In Chapter 3, said methods were further used to guide the development of the taste masked diclofenac ODT formulation. This study highlights the importance of considering in vitro the physiological aspects which may have an impact on the in vivo performance of ODT dosage forms. The contact of ODTs with the mouth should be simulated in vitro for a better understanding of the in vivo behavior. With feasible biorelevant in vitro dissolution methods, an optimized correlation of in vitro and in vivo results may be achieved. The proposed in vitro test methods may provide data of predictive value and may support the rational development of ODT formulations.
  • La voie orale est la plus populaire. Les formes solides permettent un dosage précis et un haut degré de compliance. Les formes orodispersibles tels que les comprimés orodispersibles (ODTs)répondent à la demande de médicaments plus compliants. Les ODTs représentent une alternative aux comprimés et gélules et offrent de nombreux avantages quand une action thérapeutique rapide est nécessaire. Les ODT sont considérés comme une simple variante de formes conventionnelles et leur développement est assisté par des méthodes in vitro non spécifiques. Dans ce travail ont été concus des méthodes in vitro spécifiques aux formulations ODTs. Une attention particulière a été accordée au lieu où la formulation se disperse. Des tests in vitro simulant les conditions in vivo ont été conçus. Un système de langue électronique a été utilisé pour évaluer les propriétés gustatives. Le diclofénac a été utilisé comme drogue modèle. Le diclofenac acide ainsi que ses sel de sodium/potassium, ont été étudiés pour formuler des ODTs de goût agréable et à action rapide. Dans le chapitre 1, les test sont décrit en détails. Les modèles in vitro discriminent avec succès les différentes formes dans les compartiments successifs simulés in vitro. Des profils de dissolution particuliers ont été identifiés pour les sels de diclofénac. Des comportements critiques des sels de diclofénac selon différentes conditions de pH ont été évalués. Dans le chapitre 2, la langue électronique est utilisée pour évaluer le goût. La langue électronique a aidé à distinguer les qualités de goût. Il a été possible de classer la perception du goût de chaque forme de diclofénac et par conséquent, de les classer les uns par rapport aux autres. Les deux méthodes proposées ont montré avec succès leur capacité discriminative et également leur utilité dans les études de pré-formulation des ODTs. Dans les chapitres précédents, le diclofénac acide a été selectionné. Dans le chapitre 3, ces méthodes sont utilisées pour guider le développement. Le contact des ODTs avec la bouche doit être simulé in vitro pour une meilleure compréhension de leur comportement in vivo. Avec des procédés de dissolution in vitro simulant les conditions biologiques, une corrélation peut être réalisée. Ces méthodes in vitro peuvent être plus prédictives et assister le développement de formulations ODTs.

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Author: Marie Guhmann
Title Additional (German):Darstellung von in-vitro-Charakterisierungsmethode um die in vivo-Wirksamkeit vorherzusagen und um die Entwicklung von Schmelztabletten zu helfen
Advisor:Prof. Dr. Werner Weitschies
Document Type:Doctoral Thesis
Date of Publication (online):2014/06/02
Granting Institution:Ernst-Moritz-Arndt-Universität, Mathematisch-Naturwissenschaftliche Fakultät (bis 31.05.2018)
Date of final exam:2013/12/18
Release Date:2014/06/02
Tag:biorelevant; diclofenac; orodispersible; setups; taste
GND Keyword:diclofenac, Geschmack, Zunge, Charakterisierung
Faculties:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Pharmazie
DDC class:500 Naturwissenschaften und Mathematik / 540 Chemie