Natalie L. Trevaskis

Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs

Highly potent, but poorly water-soluble, drug candidates are common outcomes of contemporary drug discovery programmes and present a number of challenges to drug development — most notably, the issue of reduced systemic exposure after oral administration. However, it is increasingly apparent that formulations containing natural and/or synthetic lipids present a viable means for enhancing the oral bioavailability of some poorly water-soluble, highly lipophilic drugs. This Review details the mechanisms by which lipids and lipidic excipients affect the oral absorption of lipophilic drugs and provides a perspective on the possible future applications of lipid-based delivery systems. Particular emphasis has been placed on the capacity of lipids to enhance drug solubilization in the intestinal milieu, recruit intestinal lymphatic drug transport (and thereby reduce first-pass drug metabolism) and alter enterocyte-based drug transport and disposition.

Lipid-Based Formulations and Drug Supersaturation: Harnessing the Unique Benefits of the Lipid Digestion/Absorption Pathway

ABSTRACTDrugs with low aqueous solubility commonly show low and erratic absorption after oral administration. Myriad approaches have therefore been developed to promote drug solubilization in the gastrointestinal (GI) fluids. Here, we offer insight into the unique manner by which lipid-based formulations (LBFs) may enhance the absorption of poorly water-soluble drugs via co-stimulation of solubilization and supersaturation. Supersaturation provides an opportunity to generate drug concentrations in the GI tract that are in excess of the equilibrium crystalline solubility and therefore higher than that achievable with traditional formulations. Incorporation of LBF into lipid digestion and absorption pathways provides multiple drivers of supersaturation generation and the potential to enhance thermodynamic activity and absorption. These drivers include 1) formulation dispersion, 2) lipid digestion, 3) interaction with bile and 4) lipid absorption. However, high supersaturation ratios may also stimulate drug precipitation and reduce exposure where re-dissolution limits absorption. The most effective formulations are likely to be those that generate moderate supersaturation and do so close to the site of absorption. LBFs are particularly well suited to these criteria since solubilization protects against high supersaturation ratios, and supersaturation initiation typically occurs in the small intestine, at the absorptive membrane.

Intestinal bile secretion promotes drug absorption from lipid colloidal phases via induction of supersaturation.

The oral bioavailability of poorly water-soluble drugs (PWSD) is often significantly enhanced by coadministration with lipids in food or lipid-based oral formulations. Coadministration with lipids promotes drug solubilization in intestinal mixed micelles and vesicles, however, the mechanism(s) by which PWSD are absorbed from these dispersed phases remain poorly understood. Classically, drug absorption is believed to be a product of the drug concentration in free solution and the apparent permeability across the absorptive membrane. Solubilization in colloidal phases such as mixed micelles increases dissolution rate and total solubilized drug concentrations, but does not directly enhance (and may reduce) the free drug concentration. In the absence of changes to cellular permeability (which is often high for lipophilic, PWSD), significant changes to membrane flux are therefore unexpected. Realizing that increases in effective dissolution rate may be a significant driver of increases in drug absorption for PWSD, we explore here two alternate mechanisms by which membrane flux might also be enhanced: (1) collisional drug absorption where drug is directly transferred from lipid colloidal phases to the absorptive membrane, and (2) supersaturation-enhanced drug absorption where bile mediated dilution of lipid colloidal phases leads to a transient increase in supersaturation, thermodynamic activity and absorption. In the current study, collisional uptake mechanisms did not play a significant role in the absorption of a model PWSD, cinnarizine, from lipid colloidal phases. In contrast, bile-mediated dilution of model intestinal mixed micelles and vesicles led to drug supersaturation. For colloids that were principally micellar, supersaturation was maintained for a period sufficient to promote absorption. In contrast, for primarily vesicular systems, supersaturation resulted in rapid drug precipitation and no increase in drug absorption. This work suggests that ongoing dilution by bile in the gastrointestinal tract may invoke supersaturation in intestinal colloids and promote absorption, and thus presents a new mechanism by which lipids may enhance the oral absorption of PWSD.

Targeted delivery of a model immunomodulator to the lymphatic system: comparison of alkyl ester versus triglyceride mimetic lipid prodrug strategies.

A lipophilic prodrug approach has been used to promote the delivery of a model immunomodulator, mycophenolic acid (MPA), to the lymphatic system after oral administration. Lymphatic transport was employed to facilitate enhanced drug uptake into lymphocytes, as recent studies demonstrate that targeted drug delivery to lymph resident lymphocytes may enhance immunomodulatory effects. Two classes of lymph-directing prodrugs were synthesised. Alkyl chain derivatives (octyl mycophenolate, MPA-C8E; octadecyl mycophenolate, MPA-C18E; and octadecyl mycophenolamide, MPA-C18AM), to promote passive partitioning into lipids in lymphatic transport pathways, and a triglyceride mimetic prodrug (1,3-dipalmitoyl-2-mycophenoloyl glycerol, 2-MPA-TG) to facilitate metabolic integration into triglyceride deacylation-reacylation pathways. Lymphatic transport, lymphocyte uptake and plasma pharmacokinetics were assessed in mesenteric lymph and carotid artery cannulated rats following intraduodenal infusion of lipid-based formulations containing MPA or MPA prodrugs. Patterns of prodrug hydrolysis in rat digestive fluid, and cellular re-esterification in vivo, were evaluated to examine the mechanisms responsible for lymphatic transport. Poor enzyme stability and low absorption appeared to limit lymphatic transport of the alkyl derivatives, although two of the three alkyl chain prodrugs - MPA-C18AM (6-fold) and MPA-C18E (13-fold) still increased lymphatic drug transport when compared to MPA. In contrast, 2-MPA-TG markedly increased lymphatic drug transport (80-fold) and drug concentrations in lymphocytes (103-fold), and this was achieved via biochemical incorporation into triglyceride deacylation-reacylation pathways. The prodrug was hydrolysed rapidly to 2-mycophenoloyl glycerol (2-MPA-MG) in the presence of rat digestive fluid, and 2-MPA-MG was subsequently re-esterified in the enterocyte with oleic acid (most likely originating from the co-administered formulation) prior to accessing the lymphatics and lymphocytes. Importantly, after administration of 2-MPA-TG, the concentrations of free MPA in the mesenteric lymph nodes were significantly enhanced (up to 28 fold) when compared to animals administered equimolar quantities of MPA, suggesting the efficient conversion of the esterified prodrug back to the pharmacologically active parent drug. The data suggest that triglyceride mimetic prodrugs have potential as a means of enhancing immunotherapy via drug targeting to lymphocytes and lymph nodes.

AN EXAMINATION OF THE INTERPLAY BETWEEN ENTEROCYTE-BASED METABOLISM AND LYMPHATIC DRUG TRANSPORT IN THE RAT

The current study has examined whether drugs that are transported to the systemic circulation via the intestinal lymph (and therefore associate with lipoproteins within the enterocyte) are accessible to enterocyte-based metabolic processes. The impact of changes to the mass of lipid present within the enterocyte-based lymph lipid precursor pool (LLPP) on the extent of enterocyte-based drug metabolism has also been addressed. Low (5 mg oleic acid/h) or high [20 mg oleic acid/5.2 mg lyso-phosphatidylcholine/h] lipid dose formulations containing halofantrine (which is lymphatically transported and metabolized) or dichlorodiphenyltrichloroethane (DDT) (which is lymphatically transported and relatively metabolically inert) and radiolabeled oleic acid were infused into the duodenum of lymph duct-cannulated rats. After 5 h, drug and radiolabeled oleic acid were removed from the infusions, allowing calculation of the first order turnover rate constants describing drug and oleic acid transport from the LLPP into lymph from the washout profiles. In one group of animals, bolus doses of ketoconazole were also administered to inhibit cytochrome P450-based metabolism. The rate constant describing halofantrine transport from the LLPP into the lymph was lower than that of oleic acid, whereas these differences were abolished in the presence of ketoconazole. DDT and oleic acid exhibited similar turnover rate constants. The data therefore suggest that enterocyte-based metabolism removes halofantrine from the LLPP before transport into the lymph. Furthermore, enhancing the lymphatic transport of halofantrine by coadministration of larger quantities of lipid reduced the difference between the turnover rate constant for halofantrine and oleic acid and seemed to reduce the extent of enterocyte-based metabolism.

Targeted drug delivery to lymphocytes: a route to site-specific immunomodulation?

Lymphocytes are central to the progression of autoimmune disease, transplant rejection, leukemia, lymphoma and lymphocyte-resident viral diseases such as HIV/AIDs. Strategies to target drug treatments to lymphocytes, therefore, represent an opportunity to enhance therapeutic outcomes in disease states where many current treatment regimes are incompletely effective and promote significant toxicities. Here we demonstrate that highly lipophilic drug candidates that preferentially access the intestinal lymphatics after oral administration show significantly enhanced access to lymphocytes leading to improved immunomodulatory activity. When coadministered with such drugs, lipids enhance lymphocyte targeting via a three tiered action: promotion of drug absorption from the gastrointestinal tract, enhancement of lymphatic drug transport and stimulation of lymphocyte recruitment into the lymphatics. This strategy has been exemplified using a highly lipophilic immunosuppressant (JWH015) where coadministration with selected lipids led to significant increases in lymphatic transport, lymphocyte targeting and IL-4 and IL-10 expression in CD4+ and CD8+ lymphocytes after ex vivo mitogen stimulation. In contrast, administration of a 2.5-fold higher dose of JWH015 in a formulation that did not stimulate lymph transport had no effect on antiinflammatory cytokine levels, in spite of equivalent drug exposure in the blood. The current data suggest that complementary drug design and delivery strategies that combine highly lipophilic, lymphotropic drug candidates with lymph-directing formulations provide enhanced selectivity, potency and therapeutic potential for drug candidates with lymphocyte associated targets.

Intestinal Lymphatic Transport Enhances the Post-Prandial Oral Bioavailability of a Novel Cannabinoid Receptor Agonist Via Avoidance of First-Pass Metabolism

PurposeTo examine the effect of food on the oral bioavailability of a highly lipophilic, cannabinoid receptor agonist (CRA13) and to explore the basis for the food effect in lymph-cannulated and non-cannulated dogs.MethodsOral bioavailability was assessed in fasted and fed human volunteers and in lymph-cannulated dogs. In fasted dogs, the extent of absorption and oral bioavailability was also examined following administration of radiolabelled CRA13.ResultsFood had a substantial positive effect on the oral bioavailability of CRA13 in human volunteers (4.3–4.9 fold increase in

The Potential for Drug Supersaturation during Intestinal Processing of Lipid-Based Formulations May Be Enhanced for Basic Drugs

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