Novel drug-loaded paper tablets for improved oral drug delivery

The oral route is the most preferred route of drug administration. Tablets are the most prominent oral dosage form as they can provide greater dose precision, higher stability, simplicity and lower cost of manufacturing and suitability for large-scale production. Compressed tablets, which are the mo...

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Bibliographic Details
Main Author: Abolelela, Ayat
Contributors: Keck, Cornelia M. (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2023
Online Access:PDF Full Text
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Summary:The oral route is the most preferred route of drug administration. Tablets are the most prominent oral dosage form as they can provide greater dose precision, higher stability, simplicity and lower cost of manufacturing and suitability for large-scale production. Compressed tablets, which are the most widely used tablets, consist of a blend of one or more active pharmaceutical ingredients (APIs) with suitable excipients. The excipients in tablets, in particular dissolution enhancing excipients, play a vital role in ensuring an efficient oral drug delivery (i.e., high oral bioavailability). These excipients are usually utilized as a part of a solubilization strategy to enhance the drug solubility, and thus its oral bioavailability. However, various excipients in tablets are associated with instability issues, hence, a comprehensive, costly, and time-consuming investigation of excipients is essential to develop stable and efficient tablets. SmartFilms technology is an innovative strategy which enhances the drug aqueous solubility via embedding the drug within a matrix of cellulose-based paper in an amorphous state. Despite its proven effectiveness, smartFilms technology remains unrecognized by the pharmaceutical industry due to the difficulty of large-scale production of paper tablets from paper cut outs with limited flowability. The inadequate flowability might obstruct the compression process due to the adherence of the paper to the tablet press, which might result in dose variation of the tablets. In addition, the influence of the smartFilm tablets on the bioactivity of the loaded drug is still ambiguous. In this thesis, smartFilm tablets were investigated as a potential, industrially feasible approach for an improved solubility and bioactivity of poorly water-soluble APIs. The first part of the thesis investigated the possibility of transforming unloaded smartFilms (i.e., paper) into a flowable physical form and the influence of sucrose as a binder (i.e., amounts and forms) on the behavior of the material under compression as well as the properties of the obtained tablets. Cellulose-based paper utilized in this work was successfully transformed into granules via a wet granulation process. The obtained unloaded paper granules exhibited a slightly elongated shape, demonstrated good flowability and allowed the production of tablets in a continuous mode. The results also showed that using sucrose as a dry powder during the granulation process was the most suitable for obtaining paper granules that can be compressed in large scale into tablets with good pharmaceutical properties (i.e., in accordance with the European Pharmacopoeia). Investigating the mechanical behavior of paper granules under compression indicated that the compaction behavior of these granules was comparable to the behavior of classical binders and compression enhancers. These findings indicate that the obtained paper granules have good flowability, a suitable compression behavior and propose paper granules as suitable intermediate products for the production of tablets made from paper on a large, industrial scale. The second and the third part of the thesis studied the impact of smartFilm tablets on the oral delivery and bioactivity of two poorly water-soluble APIs (i.e., curcumin and norfloxacin) using an ex vivo porcine intestinal model. Curcumin-loaded smartFilms and norfloxacin-loaded smartFilms were successfully transferred into smartFilm granules and smartFilm tablets, respectively. Results also showed that the curcumin-loaded smartFilm granules and smartFilm tablets preserved the amorphous state of the incorporated drug. The obtained tablets also fulfilled the criteria according to the European Pharmacopoeia regarding hardness, friability, content uniformity, mass uniformity, and disintegration time. The incorporation of curcumin or norfloxacin into smartFilm tablets resulted in increasing the dissolution rate (approx. two-fold) especially at the beginning of the release. The ex vivo intestinal permeability of curcumin from the smartFilm tablets was also studied and compared to a physical mixture of curcumin and paper and to a classical and an innovative commercial product, respectively. The innovative product contains curcumin in a micellar form and has previously demonstrated an exceptional oral bioavailability. The findings showed an enhanced intestinal permeability of curcumin from the smartFilm tablets, as compared to the physical mixture tablet and the classical marketed product that contains curcumin as a raw powder (approx. two-fold increase). No difference in the total amount of permeated curcumin was found between the smartFilm tablets and the innovative commercial product (i.e., micellar curcumin). Nevertheless, a trend towards a deeper intestinal permeation of the curcumin from the smartFilm tablets was observed. These outcomes indicate that smartFilm tablets can be equally efficient as innovative and classical curcumin formulation approaches in improving the oral bioavailability of curcumin. The ex vivo bioactivity of norfloxacin from the smartFilm tablets was also investigated and showed a similar trend (i.e., a two-fold higher antibacterial activity of norfloxacin from the smartFilm tablets when compared to the physical mixture tablet). The findings of this thesis provide evidence that smartFilm tablets are a cost-effective, universal, industrially feasible formulation approach for improved solubility and enhanced bioactivity of poorly water-soluble APIs, i.e., BCS class II and IV drugs.
Physical Description:154 Pages