ABSTRACT
The lymphatic system plays a crucial role in the absorption of lipophilic drugs, making it an important route for drug delivery. In this study, an in vitro model using Intralipid® was developed to investigate the lymphatic uptake of drugs. The model was validated using cannabidiol, halofantrine, quercetin, and rifampicin. Remarkably, the uptake of these drugs closely mirrored what would transpire in vivo. Furthermore, adding peanut oil to the model system significantly increased the lymphatic uptake of rifampicin, consistent with meals containing fat stimulating lymphatic drug uptake. Conversely, the inclusion of pluronic L-81 was observed to inhibit the lymphatic uptake of rifampicin in the model. This in vitro model emerges as a valuable tool for investigating and predicting drug uptake via the lymphatic system. It marks the first phase in developing a physiologically based predictive tool that can be refined further to enhance the precision of drug interaction predictions with chylomicrons and their subsequent transport via the lymphatic system. Moreover, it can be employed to explore innovative drug formulations and excipients that either enhance or hinder lymphatic drug uptake. The insights gained from this study have significant implications for advancing drug delivery through the lymphatic system.
ABSTRACT
Background and purpose: Lysosomal-targeted drug delivery can open a new strategy for drug therapy. However, there is currently no universally accepted simulated or artificial lysosomal fluid utilized in the pharmaceutical industry or recognized by the United States Pharmacopeia (USP). Experimental procedure: We prepared a simulated lysosomal fluid (SLYF) and compared its composition to a commercial artificial counterpart. The developed fluid was used to test the dissolution of a commercial product (Robitussin®) of a lysosomotropic drug (dextromethorphan) and to investigate in-vitro lysosomal trapping of two model drugs (dextromethorphan and (+/-) chloroquine). Findings/Results: The laboratory-prepared fluid or SLYF contained the essential components for the lysosomal function in concentrations reflective of the physiological values, unlike the commercial product. Robitussin® passed the acceptance criteria for the dissolution of dextromethorphan in 0.1 N HCl medium (97.7% in less than 45 min) but not in the SLYF or the phosphate buffer media (72.6% and 32.2% within 45 min, respectively). Racemic chloroquine showed higher lysosomal trapping (51.9%) in the in-vitro model than dextromethorphan (28.3%) in a behavior supporting in-vivo findings and based on the molecular descriptors and the lysosomal sequestration potential of both. Conclusion and implication: A standardized lysosomal fluid was reported and developed for in-vitro investigations of lysosomotropic drugs and formulations.
ABSTRACT
Dissolution testing is important in assessing the in vitro drug release performance for oral administration dosage forms. However, currently, a simple and efficient in vitro test to investigate critical factors that may impact the drug release and bioavailability at the development stage of a drug-loaded nanoemulsion (NE) is lacking. Thus, in this study, we developed a new combined biphasic and modified cylinder (BP + MC) method to evaluate the dissolution profile of NEs. Flubendazole (FLZ), a Biopharmaceutical Classification System (BCS) Class II drug, offers a new prospective for drug repositioning for treating lung cancer and cryptococcal meningitis. We compared the drug release profiles of three different FLZ formulations (micronized as a suspension, loaded in NE, and solubilized in oil) by using three different methods (dialysis bag, modified cylinder method, and a new BP + MC method). The results showed potential higher drug release of FLZ from the suspension compared to FLZ-loaded NE at pH 1.2, and higher drug release from FLZ-loaded NE compared to other forms in octanol phase. These results correlate well with the in vivo test performed in mice carried out in our previous works. Furthermore, the partition mechanism of the drug released from the NE is discussed in-depth in this article, as well as the advantage of drug-loaded NEs over other preparations in creating supersaturable conditions. Based on the results, we provide new insights into how dissolution methods for a poorly water-solubility drug can be designed. Therefore, we present this new combined BP + MC method as a potential new discriminative dissolution test for future studies when developing drug-loaded NE and comparing with other dosage forms.
Subject(s)
Solubility , Mice , Animals , Pharmaceutical Preparations , Prospective Studies , Drug Liberation , Drug Compounding , Administration, OralABSTRACT
The uniqueness of structure and physiology of the lymphatic system make it challenging to delineate all its contributions in the maintenance of our health. However, in the past two decades, the understanding of the importance of the function of this system has evolved and more appreciation has been drawn to the distinctive role it plays in health and disease. The lymphatic system has been linked to the pathophysiology of numerous ailments including cancer, various metabolic diseases, inflammatory conditions, and infections. Moreover, it has also been revealed that lymphatic targeted formulations can enhance the delivery of drugs through the lymphatic system to the bloodstream, bypassing the hepatic first-pass metabolism if taken orally, thus increasing the bioavailability, and improving the pharmacokinetic and toxicological profiles in general. Engineering lymphotropic preparations requires the understanding of many factors, the most important one being that of the physiological environment which they will encounter. Therefore, in this review, we detail the basic structure of the lymphatic system, then highlight the therapeutic and the pharmacokinetic benefits of drug delivery into the lymphatic system. The criteria for drugs and formulations used for lymphotropic delivery are also detailed with a contemporary overview of various studies undertaken in this field.
