Estimating the maximal potential for intestinal lymphatic transport of lipophilic drug molecules

Efficient delivery of antiretroviral agents to lymph nodes is important to decrease the size of the HIV reservoir within the lymphatic system. Lamivudine (3TC) is used in first-line regimens for the treatment of HIV. As a highly hydrophilic small molecule, 3TC is not predicted to associate with chylomicrons and therefore should have negligible uptake into intestinal lymphatics following oral administration. Similarly, negligible amounts of 3TC are predicted to be transported into peripheral lymphatics following subcutaneous (SC) injection due to the faster flow rate of blood in comparison to lymph. In this work, we performed pharmacokinetic and biodistribution studies of 3TC in rats following oral lipid-based, oral lipid-free, SC, and intravenous (IV) administrations. In the oral administration studies, mesenteric lymph nodes (MLNs) had significantly higher 3TC concentrations compared to other lymph nodes, with mean tissue:serum ratios ranging from 1.4 to 2.9. However, cells and chylomicrons found in mesenteric lymph showed low-to-undetectable concentrations. In SC studies, administration-side (right) draining inguinal and popliteal lymph nodes had significantly higher concentrations (tissue:serum ratios as high as 3.2) than corresponding left-side nodes. In IV studies, lymph nodes had lower mean tissue:serum ratios ranging from 0.9 to 1.4. We hypothesize that following oral or SC administration, slower permeation of this hydrophilic molecule into blood capillaries may result in considerable passive 3TC penetration into lymphatic vessels. Further studies will be needed to clarify the mechanism of delivery of 3TC and similar antiretroviral drugs into the lymph nodes.

Many viruses, bacteria, and parasites rely on the lymphatic system for survival, replication, and dissemination. While conventional anti-infectives can combat infection-causing agents in the bloodstream, they do not reach the lymphatic system to eradicate the pathogens harboured there. This can result in ineffective drug exposure and reduce treatment effectiveness. By developing effective lymphatic delivery strategies for antiviral, antibacterial, and antiparasitic drugs, their systemic pharmacokinetics may be improved, as would their ability to reach their target pathogens within the lymphatics, thereby improving clinical outcomes in a variety of acute and chronic infections with lymphatic involvement (e.g., acquired immunodeficiency syndrome, tuberculosis, and filariasis). Here, we discuss approaches to targeting anti-infective drugs to the intestinal and dermal lymphatics, aiming to eliminate pathogen reservoirs and interfere with their survival and reproduction inside the lymphatic system. These include optimized lipophilic prodrugs and drug delivery systems that promote lymphatic transport after oral and dermal drug intake. For intestinal lymphatic delivery via the chylomicron pathway, molecules should have logP values >5 and long-chain triglyceride solubilities >50 mg/g, and for dermal lymphatic delivery via interstitial lymphatic drainage, nanoparticle formulations with particle size between 10 and 100 nm are generally preferred. Insight from this review may promote new and improved therapeutic solutions for pathogen eradication and combating infective diseases, as lymphatic system involvement in pathogen dissemination and drug resistance has been neglected compared to other pathways leading to treatment failure.

The establishment of latent cellular and anatomical viral reservoirs is a major obstacle to achieving a cure for people infected by HIV. Mesenteric lymph nodes (MLNs) are one of the most important anatomical reservoirs of HIV. Suboptimal levels of antiretroviral (ARVs) drugs in these difficult-to-penetrate viral reservoirs is one of the limitations of current antiretroviral therapy (ART) regimens. This study aimed to design and assess highly lipophilic ester prodrugs of dolutegravir (DTG) formulated with long-chain triglyceride (LCT) for delivery of DTG to the viral reservoir in mesenteric lymph and MLNs. A number of alkyl ester prodrugs of DTG were designed based on the predicted affinity to chylomicrons (CM), and the six most promising prodrugs were selected and synthesised. The synthesised prodrugs were further assessed for their intestinal lymphatic transport potential and biotransformation in biorelevant media in vitro and ex vivo. DTG and the most promising prodrug (prodrug 5) were then assessed in pharmacokinetic and biodistribution studies in rats. Although oral administration of 5 mg/kg of unmodified DTG (an allometrically scaled dose from humans) with or without lipids achieved concentrations above protein binding-adjusted IC₉₀ (PA-IC₉₀) (64 ng/mL) in most tissues, the drug was not selectively targeted to MLNs. The combination of lipophilic ester prodrug and LCT-based formulation approach improved the targeting selectivity of DTG to MLNs 4.8-fold compared to unmodified DTG. However, systemic exposure to DTG was limited, most likely due to poor intestinal absorption of the prodrug following oral administration. In vitro lipolysis showed a good correlation between micellar solubilisation of the prodrug and systemic exposure to DTG in rats in vivo. Thus, it is prudent to include in vitro lipolysis in the early assessment of orally administered drugs and prodrugs in lipidic formulations, even when intestinal lymphatic transport is involved in the absorption pathway. Further studies are needed to clarify the underlying mechanisms of low systemic bioavailability of DTG following oral administration of the prodrug and potential ways to overcome this limitation.

Lipid-based formulation (LBF) has attracted more and more attention as it can significantly improve the efficiency of oral delivery of poorly soluble drugs by exploiting the specific absorption pathway of lipids in the intestinal lymphatic system. Based on the structure and function of the intestinal lymphatic system, this article describes the advantages and strategies of oral LBF delivery through this system, highlights the research progress of oral LBF (lipid-based nanocarriers, lipid-based prodrugs) based on this system in recent years, and briefly outlines the experimental model to study the intestinal lymphatic delivery of drugs, providing methods and ideas for the development and utilization of poorly soluble drugs and the rational design of LBF.

Clofazimine (CFZ) is an important component of the World Health Organization's (WHO) recommended all-oral drug regimen for treatment of multi-drug resistant tuberculosis (MDR-TB). However, the lack of a dividable oral dosage form has limited the use of the drug in pediatric populations, who may require lowering of the dose to reduce the likelihood of adverse drug events. In this study, pediatric-friendly CFZ mini-tablets were prepared from micronized powder via direct compression. Rapid disintegration and maximized dissolution in GI fluids was achieved using an iterative formulation design process. Pharmacokinetic (PK) parameters of the optimized mini-tablets were obtained in Sprague-Dawley rats and compared against an oral suspension of micronized CFZ particles to examine the effect of processing and formulation on the oral absorption of the drug. Differences in maximum concentration and area under the curve between the two formulations were non-significant at the highest dosing level tested. Variability between rats prevented bioequivalence from being determined according to guidelines outlined by the Food and Drug Administration (FDA). These studies provide an important proof-of-concept for an alternative, low-cost formulation and processing approach for the oral delivery of CFZ in manner that is suitable for children as young as 6 months of age.

Clofazimine, an anti-leprosy drug, has been anticipated for a candidate to treat tuberculosis, cryptosporidiosis, and coronavirus infection, but its low oral bioavailability is considered a reason for its limited activity. In the current study, we have tried to improve the oral bioavailability of clofazimine by several SNEDDS formulations and characterized the absorption behavior from various aspects. Among four SNEDDS formulations prepared, SNEDDS A, prepared with castor oil as an oil component, provided the highest bioavailability (around 61%) and SNEDDS D, prepared with Capryol 90, gave the second highest bioavailability. SNEDDS A formed the finest nanoparticles, which were maintained under gastric and intestinal luminal conditions. The comparison in oral bioavailability between the SNEDDS formulation and its corresponding preformed nanoemulsion suggested that SNEDDS A would efficiently form nanoemulsion in the gastrointestinal tract after oral administration. AUC of mesenteric lymph node concentration was the highest for SNEDDS A, which would be one of the reasons for SNEDDS A to reveal the highest oral bioavailability. A cycloheximide-treated oral absorption study and single-pass perfusion study by utilizing a vascular–luminal perfused small intestine–liver preparation clearly indicated that over 90% of clofazimine absorbed to systemic circulation should be derived from lymphatic transport for both SNEDDS A and D. Furthermore, the fraction of dose absorbed was around 65% for SNEDDS D, but SNEDDS A achieved around 94%, indicating the excellent performance of SNEDDS A.