Improved drug delivery of poorly soluble actives with smartFilms® & tablets made from paper
Introduction
Many active pharmaceutical ingredients (APIs) and especially new chemical entities, possess poor aqueous solubility. This leads to poor bioavailability, not only after oral, but also after dermal, pulmonal or ocular administration. Issues being associated with poor solubility of APIs are not novel and various galenic approaches are already known to overcome poor aqueous solubility and low bioavailability. Most prominent techniques to improve the kinetic solubility, dissolution rate and/or the bioavailability of poorly soluble APIs include nanocrystals, mixed crystals, liposomes, solid dispersions or the use of cyclodextrins [1].
Another trend for improved drug delivery of poorly soluble actives is the use of mesoporous materials in which APIs can be loaded in amorphous state. Examples of so far exploited porous materials include silica, calcium carbonate as well as titanium dioxide [2-5]. A recent study could now confirm that a cellulose matrix, that means commercially available paper, can also be used for the stabilization of APIs in amorphous state [6]. The loading is performed by dissolving the API in a solvent and by soaking the paper with the solution. The drug loaded paper, which is referred to be a “smartFilm®”, is obtained upon complete evaporation of the solvent. The method is simple, cost effective and can be seen as a universal formulation approach for all kinds of poorly soluble APIs. SmartFilms can be produced from different and very diverse types of commercially available paper. The drug loading capacity depends on the type of paper used. Data by now yielded loading capacities to up to 25%w/w for the API in amorphous state [6-9]. After loading in smartFilms APIs possess an improved kinetic solubility and increased dissolution rate when compared to crystalline bulk material. Thus, in theory, leading to an increased bioavailability of poorly soluble APIs. A recent study could already demonstrate the superiority of the smartFilms in regard to dermal and transdermal penetration of a poorly soluble, fluorescent model API (Fig. 1).
However, oral administration of paper might not be convenient. Of course, hard capsules would enable the encapsulation of small amounts of paper, but larger quantities cannot be encapsulated by this. One possibility to enable the administration of larger quantities might be the compression of the paper and smartFilms into tablets. The possibility to transfer paper and smartFilms into tablets was therefore investigated in this study.
Experimental Methods
In the first step of the study, different and diverse types of paper were cut into small pieces and manually compressed by a single punch tablet press (EK0, Korsch, Germany). The properties of the resulting tablets were determined by using the standard methods for the testing of tablets according to the European Pharmacopeia (Ph. Eur.). In the second step, paper and smartFilms were transferred into freely flowable intermediate products, that means pellets and powder, to allow for an automated production of tablets in a larger, industrial scale process. Finally, a proof of concept study was conducted to prove that not only smartFilms, but also tablets made from smartFilms are suitable to improve the kinetic solubility and dissolution rate of poorly soluble APIs. For detailed experimental procedures, see [8, 9].
Results and Discussion
Manual production of tablets made from paper
All types of paper led to intact tablets with a smooth surface (Fig. 2) and possessed properties being conform to the requirements of the Ph. Eur [8, 9]. Unfortunately, disintegration of non-coated tablets was found to be very fast (< 30 s), which could possibly impair the swallowing of the tablets. However, coating of the tablets was found to circumvent the fast disintegration (Fig. 3). Thus, allowing easy and safe swallowing of the tablets made from paper.
The first part demonstrated that paper can be compressed into tablets with good pharmaceutical quality. However, manual compression is not feasible for industrial scale production. Therefore, the next step of the study aimed at transferring paper into a freely flowable formulation, that can be filled into the filling shoe of a tablet press. Thus, allowing for an automated production of tablets made from paper. For this paper was milled by using different types of mills. Depending on the mill used, milled paper and smartFilms resulted in the formation of flakes or powder (Fig. 4). The flakes could be transferred into freely flowable pellets, which were then used for automated tablet production. However, tablets obtained were too soft and brittle, which was due to a high content of air within the pellets [9]. The addition of sucrose to the binding material resulted in denser pellets, which could be transferred into tablets with sufficient pharmaceutical properties (Fig. 4 upper). The powder obtained upon milling of paper and smartFilms was found to be even suitable for direct compression (Fig. 4 lower).
Determination of crystalline state and drug release of a poorly soluble model API from tablets made from smartFilms
Previous studies already proved that poorly soluble APIs can be loaded into commercially available paper in amorphous state. Thus, leading to an increased solubility and dissolution rate of the API when compared to crystalline bulk material. However, the aim of this study was to investigate if the compression of smartFilms into tablets alters the amorphous state and/or the release kinetics of the API. Results show that compression did not alter the crystalline state of the API (Fig. 5 left).
The drug release of the poorly soluble API was improved by the smartFilms when compared to the bulk material. Compression of the smartFilms into tablets resulted in a small delay in drug release but did not hamper the absolute release of the API (Fig. 5 right). Results indicate that the pores of the paper in tablets are compressed, but swell upon contact with water or body fluids, finally leading to a similar drug release when compared to the non-compressed smartFilms.
Conclusions
SmartFilms and tablets made from paper present a novel drug delivery system for improved delivery of poorly soluble actives. SmartFilms can be used for improved dermal delivery of poorly soluble actives but are not convenient to swallow. This study confirmed that paper and smartFilms can be transferred into tablets. The tablets possess good pharmaceutical quality and automated production is also possible by transferring paper or smartFilms prior to compression into pellets or powder. Crystalline state and drug release of API are also not altered by compression of smartFilms into tablets. Coating of the tablets made from paper is suggested to allow for an easy and convenient swallowing of the tablets.
Perspectives
Paper is a renewable resource and can contribute to the production of sustainable pharmaceutical products in the future. Data by now indicate that smartFilms and tablets made from smartFilms are a universal formulation strategy for poorly soluble APIs. The production is simple, cost-effective and can be performed by well-known and established pharmaceutical large-scale GMP processes. Hence, a transfer of the technology from basic research into real products seems to be not only innovative but also feasible. Due to these features, smartFilms and tablets made from paper were lately awarded with the Marburg Biotechnology and Nanotechnology Award (MarBiNa) for outstanding scientific work in the field of biotechnology and / or nanotechnology with high innovative and realization potential.
References
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