Determination of Mucoadhesion of Polyvinyl Alcohol Films to Human Intestinal Tissue

Abstract

The absorption of drugs with narrow absorption windows in the upper small intestine can be improved with a mucoadhesive drug delivery system such as enteric films. To predict the mucoadhesive behaviour in vivo, suitable in vitro or ex vivo methods can be performed. In this study, the influence of tissue storage and sampling site on the mucoadhesion of polyvinyl alcohol film to human small intestinal mucosa was investigated. Tissue from twelve human subjects was used to determine adhesion using a tensile strength method. Thawing of tissue frozen at −20 °C resulted in a significantly higher work of adhesion (p = 0.0005) when a low contact force was applied for one minute, whereas the maximum detachment force was not affected. When the contact force and time were increased, no differences were found for thawed tissue compared to fresh tissue. No change in adhesion was observed depending on the sampling location. Initial results from a comparison of adhesion to porcine and human mucosa suggest that the tissues are equivalent.

Introduction

An ideal drug substance should be absorbed uniformly throughout the small intestine. Some drugs are poorly absorbed due to narrow absorption areas, also known as absorption windows. These are usually located in the upper part of the small intestine. Poor absorption may be caused by specific transport mechanisms such as active transport or active excretion. Several drug delivery approaches have been developed to overcome this challenge, such as mucoadhesive films, which can be a highly beneficial drug delivery system (DDS) for site-specific applications, such as in the upper intestine. Examples of drugs that are only absorbed in the upper small intestine are furosemide [1], acyclovir [2,3] and gabapentin [4]. Other possible drugs that could benefit from prolonged residence time through mucoadhesion are therapeutic peptides and proteins [5,6]. These macromolecules mostly have very low oral bioavailability due to their high molecular weight and vulnerable structure. The specific amino acid sequence essential for drug activity can be destroyed by the chemical, physical and proteolytic nature of the gastrointestinal tract [7]. An ideal DDS for peptides and proteins should protect and preserve the drug structure and release it at the highly vasculated specific absorption site [8].

To predict the adhesion of the dosage form in vivo during formulation development, appropriate in vitro methods can be useful. In vitro methods have the advantage of good reproducibility and avoidance of biological tissues. Many biomimetic materials have been described in literature to mimic and replace tissue. They include, for example, simple hydrogels such as gelatin [9] or agar gels [10] and more complex hydrogels such as HEMA-AGA hydrogels [11] or mucin compacts [12]. The disadvantage of these biomimetic materials is that they may not adequately represent the inter-individual variability of ex vivo and in vivo studies. This can lead to biased prediction of in vivo behavior by in vitro methods. Therefore, ex vivo methods using tissue can be very helpful to get an idea of the variability in vivo. Ideally, the tissue used should represent as closely as possible the application site of the DDS under development.

Tissues from animal sources are mainly used as ex vivo substrates, such as chicken pouch [13], porcine tissue [14] or bovine tissue [15]. Although animal tissues are often used in ex vivo studies, there is the ethical drawback that animals have to be slaughtered to obtain the tissue. Along with these ethical concerns, the choice of suitable animal tissue is another issue. When it comes to mucoadhesion studies in the small intestine, rodents are known to be poor model animals. Not only the anatomy and physiology have been found to be different from humans [16,17] but also the pH and water content [18]. Therefore, large animal models such as pigs are often used to study the small intestine. However, although the pig anatomy is quite similar to that of humans, there are still some differences. Mucus thickness and composition are known to influence mucoadhesion [19]. In pigs, the average thickness of the small intestinal mucus is about 26 to 31 µm [19], whereas in humans the gastroduodenal mucus layer is of variable thickness [20]. These differences may affect mucoadhesion and the in vitro-in vivo correlation of mucoadhesion studies. Therefore, the ideal tissue for mucoadhesion studies is potentially human tissue. Patients taking medicines are usually elderly people suffering from more than one disease [21]. Their gastrointestinal tract may further differ from that of animals used in animal models. Theoretically, tissue from the target patient population should ideally be used to obtain the most predictive results.

Despite the choice of tissue, tissue preparation and storage may also affect the outcome of studies. In previous studies, mucoadhesion was found to be higher on thawed porcine small intestine tissue than on fresh tissue [22]. As these results may not be applicable to human tissue, further mucoadhesion studies on human small intestinal mucosa are needed. To the best of our knowledge, there is no ex vivo mucoadhesion study on human intestinal tissue. In this study, several questions will be addressed, the first of which is whether tissue storage has an effect on mucoadhesion in two different test setups. Secondly, the effect on the sampling site was investigated. Finally, a comparison was made with results on porcine tissue obtained in previous studies [22] using the same methodology. The results should indicate that the choice and storage of the tissue and the experimental design of each mucoadhesion study are very important variables that need to be investigated in order to understand the underlying mechanisms of mucoadhesion and to achieve predictive results for respective DDS.

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Materials

The water-soluble polyvinyl alcohol quality EMPROVE® ESSENTIAL PVA 18–88 (PVA 18–88, Mw ≈ 96,000 g/mol, Merck KGaA, Darmstadt, Germany) with a degree of hydrolysis of 88% was used as the mucoadhesive polymer for the preparation of the mucoadhesive films. Anhydrous glycerol (AppliChem GmbH, Darmstadt, Germany) was used as a plasticizer. The chemicals were dissolved in demineralized water.

Müller, L.; Rosenbaum, C.; Rump, A.; Grimm, M.; Klammt, F.; Kleinwort, A.; Busemann, A.; Weitschies, W. Determination of Mucoadhesion of Polyvinyl Alcohol Films to Human Intestinal Tissue. Pharmaceutics 2023, 15, 1740. https://doi.org/10.3390/pharmaceutics15061740

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