The effect of chitosan on the bioaccessibility and intestinal permeability of acyclovir.

Chitosan is object of pharmaceutical research as a candidate permeability enhancer. However, chitosan was recently shown to reduce the oral bioavailability of acyclovir in humans. The effect of chitosan on two processes determining the oral bioavailability of acyclovir, bioaccessibility and intestinal absorption, was now investigated. Acyclovir's bioaccessibility was studied using the dynamic TNO gastro-Intestinal Model (TIM-1). Four epithelial models were used for permeability experiments: a Caco-2 cell model in absence and presence of mucus and both rat and porcine excised intestinal segments. Study concentrations of acyclovir (0.8 g/l) and chitosan (1.6 g/l and 4 g/l) were in line with those used in the aforementioned human study. No effect of chitosan was measured on the bioaccessibility of acyclovir in the TIM-1 system. The results obtained with the Caco-2 models were not in line with the in vivo data. The tissue segment models (rat and porcine intestine) showed a negative trend of acyclovir's permeation in presence of chitosan. The Ussing type chamber showed to be the most biopredictive, as it did point to an overall statistically significantly reduced absorption of acyclovir. This model thus seems most appropriate for pharmaceutical development purposes, in particular when interactions between excipients and drugs are to become addressed.

The Influence of Chitosan on the Oral Bioavailability of Acyclovir--a Comparative Bioavailability Study in Humans.

PURPOSE: The effects of chitosan hydrochloride on the oral absorption of acyclovir in humans were studied to confirm the absorption enhancing effects reported for in vitro and rat studies, respectively. METHODS: A controlled, open-label, randomized, 3-phase study was conducted in 12 healthy human volunteers. Zovirax 200 mg dispersible tablets co-administered with doses of 400 and 1000 mg chitosan HCl were compared with Zovirax only. RESULTS: The expected increased absorption of acyclovir was not observed. On the contrary, mean area under the plasma concentration-time curve (AUC0-12 h) and maximal plasma concentration (Cmax) decreased following concomitant chitosan intake (1402 versus 1017 and 982.0 ng ∙ h/ml and 373 versus 208 and 235 ng/ml, respectively). In addition, Tmax increased significantly in presence of 1000 mg of chitosan from 1 to 2 h. CONCLUSIONS: The results of this study in human volunteers did not confirm an absorption enhancing effect of chitosan. Reference values were comparable to literature data, whereas addition of chitosan resulted in significant opposite effects on Cmax, Tmax and AUC. Additional studies are needed to investigate the cause of the discrepancy. The observed variability and complex potential interactions may complicate the use of chitosan HCl in oral pharmaceutical formulations.

Novel insights into excipient effects on the biopharmaceutics of APIs from different BCS classes: Lactose in solid oral dosage forms.

Excipients encompass a wide range of properties that are of importance for the resulting drug product. Regulatory guidelines on biowaivers for immediate release formulations require an in depth understanding of the biopharmaceutic effects of excipients in order to establish bioequivalence between two different products carrying the same API based on dissolution tests alone. This paper describes a new approach in evaluating biopharmaceutic excipient effects. Actually used quantities of a model excipient, lactose, formulated in combination with APIs from different BCS classes were evaluated. The results suggest that companies use different (relative) amounts depending on the characteristics of the API. The probability of bioinequivalence due to a difference in lactose content between test and reference products was classified as low for BCS class I APIs and medium for BCS class II and III APIs, whereas a high probability was assigned to the combination of lactose and BCS class IV APIs. If repeated for other excipients, this retrospective, top-down approach may lead to a new database and more widespread applications of the biowaiver approach.

In vivo methods for drug absorption - comparative physiologies, model selection, correlations with in vitro methods (IVIVC), and applications for formulation/API/excipient characterization including food effects.

This review summarizes the current knowledge on anatomy and physiology of the human gastrointestinal tract in comparison with that of common laboratory animals (dog, pig, rat and mouse) with emphasis on in vivo methods for testing and prediction of oral dosage form performance. A wide range of factors and methods are considered in addition, such as imaging methods, perfusion models, models for predicting segmental/regional absorption, in vitro in vivo correlations as well as models to investigate the effects of excipients and the role of food on drug absorption. One goal of the authors was to clearly identify the gaps in today's knowledge in order to stimulate further work on refining the existing in vivo models and demonstrate their usefulness in drug formulation and product performance testing.

The impact of the EMA change in definition of "dose" on the BCS dose-solubility ratio: a review of the biowaiver monographs.

The Biopharmaceutics Classification System (BCS) defines the solubility characteristics of an active pharmaceutical substance based on its dose-solubility ratio: for highly soluble drugs this ratio is less than 250 mL over a defined pH range. Prior to the revision of the European Medicines Agency (EMA, formerly EMEA) guideline in 2010, the "dose" in this ratio was consistently defined by the US FDA, the EMA, and the WHO biowaiver guidelines as the highest dosage strength. However, in the revised EMA guideline, the dose is defined as the highest single dose administered according to the Summary of Product Characteristics. The new EMA criterion for highly soluble may be closer to the actual conditions of use, but it is not in line with the dose that would be used in the in vivo bioequivalence study. This paper evaluates the impact on the BCS classification of the active pharmaceutical ingredients of the published biowaiver monographs and discusses the consequences of the possible change in classification on biowaiver recommendations. Using the current definition of dose by the EMA, the biowaiver recommendations for metoclopramide hydrochloride and verapamil hydrochloride are no longer valid according to EMA criteria. For prednisolone and prednisone, a reevaluation of the biowaiver recommendation, taking into account the usual dosing levels, seems appropriate.

Risk analysis in bioequivalence and biowaiver decisions.

This article evaluates the current biowaiver guidance documents published by the FDA, EU and WHO from a risk based perspective. The authors introduce the use of a Failure Mode and Effect Analysis (FMEA) risk calculation tool to show that current regulatory documents implicitly limit the risk for bioinequivalence after granting a biowaiver by reduction of the incidence, improving the detection and limiting the severity of any unforeseen bioinequivalent product. In addition, the authors use the risk calculation to expose yet unexplored options for future extension of comparative in vitro tools for biowaivers.

A phytochemical study of lignans in whole plants and cell suspension cultures of Anthriscus sylvestris.

In the roots of Anthriscus sylvestris 12 different lignans were detected. Arctigenin, dimethylmatairesinol, dimethylthujaplicatin, podophyllotoxin, 7-hydroxyyatein and 7-hydroxyanhydropodorhizol have not been previously reported to be present in A. sylvestris. In the cell suspension cultures, which were initiated for this study, trace amounts of deoxypodophyllotoxin could be detected. With these cell suspension cultures we carried out feeding experiments using deoxypodophyllotoxin, yatein and, anhydropodorhizol. Yatein had a toxic effect on the cell cultures and was, like anhydropodorhizol, not converted into any detectable product. Deoxypodophyllotoxin, in contrast, was converted into podophyllotoxin, yielding significantly higher concentration than measured in whole plants.