FORMULATION FORUM - Lymphatic versus Portal Drug Delivery: An Understanding of Drug Oral Absorption & Food Effect

KEYWORDS: Lipid nanoparticles, SEDDS, lymphatic absorption, portal absorption, drug transport pathways, poorly soluble drugs, oral bioavailability, solubilization technologies, food effects, GMP manufacturing.

INTRODUCTION

As the industry facing challenges with new chemical entities due to their poor solubility and bioavailability, the applications of novel excipients and delivery technologies and their mechanisms by which the drug molecules get absorbed into systemic circulation via oral drug delivery, are still subject of continued interest.¹ Oral low bioavailability of drugs stems from low solubility, poor permeability, enzymatic degradation in the stomach and gastrointestinal (GI) tract, and the hepatic first-pass metabolism.² The first-pass metabolism remains one of the main impediments for enhancing absorption and bioavailability of many drugs. Even though there is a lot known about first-pass (pre-systemic) metabolism, there are still reasons not clearly understood, especially how the lymphatic pathway absorption impacts oral bioavailability. Other barriers also include Pgp transport pumps and limited permeability across intestinal lumen in the GI tract. To by-pass first-pass metabolism for enhancing the absorption of lipophilic drugs, lipids have been used to increase the oral bioavailability via intestinal lymphatic system as shown in Figure 1.³

These two pathways, upon molecules transit across the enterocytes in epithelial cells, play an important role for drug absorption; one in which the molecules enter blood capillaries through the portal vein, and the other one by lymph capillaries through the lymphatic system. Soluble, small molecules preferably transported through the portal vein get metabolized, leading to lower concentrations in the plasma. Lipophilic drugs with logP >5, on the other hand, are preferentially transported through the intestinal lymphatic system that leads to greater absorption and bioavailability. The greater association with lipoproteins and chylomicrons assemblies due to inherent lipophilicity of molecules gets into enterocytes and then transported to plasma through the intestinal lymphatic system. Less lipophilic molecules with logP <5 get transported via the portal system. For example, macromolecules like insulin and GLP-1 are preferably transported through the portal vein (Figure 1).

The lymphatic system is a network of capillaries and small vessels, nodes, and organs, that is filled with fluids that play an important role in modulating immune functions as well as also help facilitate the lipid absorption, a key mechanism to overcome the portal absorption and by-pass the first metabolism in liver. This distinctive route is essential for drug transport and delivery of large and lipophilic molecules by alleviating the challenges in penetrating blood capillaries. Composed of a single layer of epithelial cells, filled with interstitial fluids, these capillaries are distributed throughout the body and allow the entry of dissolved substance into the lymphatic system that enter the bloodstream via drainage and filtration of lymphatic fluid into lymph nodes. The filtration of lymphatic fluid eliminates bacteria, viruses, or any other foreign particles. Lymph nodes are important in fighting invasion of foreign particulates and help protect the immune response by triggering the lymphocytes to produce antibodies to fight infections.

LIPID NANOPARTICLES

Lipid-based formulations, composed of lipid aggregates with varied structure and compositions, are one of the important routes for delivery of drugs though lymphatic systems to by-pass the liver metabolism. Designed to enhance solubility and stability, the lipid assemblies protect drug from degradation as they transit through GI tract. These lipid aggregates are further categorized as liposomes, solid nanoparticles, nanostructured lipid carriers, cubosomes, self-emulsifying nano- and microemulsions (SNEDDS/ SMEDDS). Drugs with higher logP have shown higher solubilization than those with lower logP by this formulation approach.⁴ Lipophilic drugs dissolved in SNEDDS does not necessarily improve the absorption. In fact, lipid suspensions have also shown the improvement of bioavailability of drugs like griseofulvin, and others.⁵ Like lipids, proteins also play an important role in enhancing oral bioavailability by lymphatic pathway. Proteins engineered with certain receptors can target lymphatic endothelial cells, and hence, allowing more uptake by the lymphatic system. For instance, albumin and immunoglobin G (IgG)-based nanoparticles can lead to improved stability and controlled systemic release due to lymphatic absorption as well. Conjugation of drug with proteins can lead to improved pharmacokinetic properties by facilitating the interactions with lymphatic transporters and receptors and enhancing the drug accumulation in the lymphatic tissues.

There are several approaches to increase drug transport to lymphatic system.3

1. Postprandial state – a diet-based inclusion of drug with food
2. Lipid prodrug- drug is covalently linked with lipid moieties like long chain fatty acids, glyceride and phospholipids making drugs to be more lipophilic
3. Lipid nanoparticles (LNPs) – administration of drug with lipid-based assemblies comprised of lipids, solubilizers and/or surfactants can lead to significant lymphatic transport of drugs

In postprandial state, the chylomicrons level increases after consuming fatty foods with increased lipoproteins synthesis in the lymphatics. For example, halofantrine, an antimalarial drug, when administered with food in postprandial state, increased the lymphatic uptake in dog by 54% as opposed to only 1.3% increase in fasted state.⁶ Like postprandial, lipid conjugates with covalently liked drugs, making the drug more lipophilic, results in association with lipoproteins/ chylomicrons that leads to faster uptake by lymphatics and greater bioavailability. For example, valproic acid conjugated with phospholipids, especially with longer fatty acid lipids, shows greater association with chylomicrons and absorption in enterocytes leading to higher bioavailability compared with short chain lipids.⁷ Mefenamic acid modified with glycerides as a prodrug also shows higher plasma concentration compared to free drug, suggesting that lipid prodrugs increase bioavailability and reduce the adverse effect in the GI tract.⁸

ROLE OF LIPIDS IN LYMPHATIC DRUG TRANSPORT

Lipid nanoparticles (LNPs) improve the stability of drugs by encapsulating into interior aqueous and hydrophobic bilayers. Composed of a different class of lipids, short- and long-chain phospholipids, the liposomes or different lipid assemblies protect drugs from harsh conditions in the GI tract and minimize the degradation by enzymes. Phospholipids (and cholesterol) are digested in the intestine. Once the bile salt is released into the small intestine, phosphocholines are hydrolyzed to lyso-phospholipid and fatty acids by Phospholipase A2. Thus, drugs like cefotaxime incorporated in liposomes are stable and showed higher concentrations in lymph and plasma as compared to solution state, further supporting the fact that lymphatic transport plays an important role in increasing the oral bioavailability of this drug.⁹ Surface-modified liposomes containing cyclosporine A with a positive charged stearyl amine showed better muco-adhesion than chitosan and much higher lymphatic absorption.¹⁰

As previously shown in Figure 1, the first-pass metabolism is the result of efficient uptake and hepatic metabolism of drugs by liver. The blood filters through the GI tract and is collected in the portal vein and then passes through liver where all substances get absorbed with blood and distributed to other organs. To circumvent the passage through port vein and divert to lymphatic system, structural modifications are commonly practiced for improving the oral bioavailability. As shown in Table 1, testosterone’s oral bioavailability is low, but on modification as prodrug with a fatty acid (undecanoic acid), oral bioavailability improved about 3% resulting from >95% contribution from lymphatic transport.¹² Docetaxel modified with an oleic acid also showed about 2-fold increase in oral bioavailability in SNEDDS formulation as compared to unconjugated drug.¹³

FOOD EFFECT ON DRUG TRANSPORT

Food effect also known as food-drug interaction, plays an important role in determining efficacy and bioavailability of drugs. This is clinically relevant, specifically in cases to prevent the undesired adverse effect and reduce drug overdosing. A majority of compounds are prone to food effects belong to BCS class II and/or Class IV, especially the positive food effect. Only a few have shown the negative food effect. A typical dosage is susceptible to fed and fasted state. Increasing plasma concentration of a drug with food (low or high fat diets) is referred to as positive food effect, while lowering plasma concentration of a drug with food referred to as negative food effect, as shown in Figure 2.²³

After consuming food, the gastric pH is raised from about 2 to 4 and remains elevated about 4.5 hours. As the food travels in duodenum and small intestine, the pH does not fluctuate as much as stomach and remains around 6-8. Fluid volumes could elevate in stomach to 500 ml or higher and in small intestine may increase from 200 ml to 1000 ml. The solubility of drugs is increased by bile salts secreted from gall bladder. In addition, increasing in viscosity could hamper the release of drugs, making them less available for systemic absorption. Drug absorption is also affected by inhibition of transporters. For example, grapefruit juice when co-administered with drug leads to higher bioavailability due to inhibition of cytochrome P450 3A4. On the other hand, with lipophilic molecules, the lymphatic uptake route leads to increasing the bioavailability with fatty food diet.

Many drugs are food dependent, and a majority belong to Class II with some Class IV, and also Class I, and Class III. They are also recommended to be taken with and without food and/or in an empty stomach before the meal. Taken collectively, the food effects on drug absorption can be neither be avoided nor exploited. Undesirable food effects can lead to exposure and increased toxicity or reduced therapeutic efficacy. Hydrocortisone, for example, when taken with food leads to delayed release by reducing Cmax and prolonged Tmax as opposed to fasted state. Therefore, hydrocortisone should be taken with empty stomach before breakfast and to be more clinically relevant.²⁴ On the exploitation, co-administration with food is required to increase solubility and absorption of drugs and to achieve the desired bioavailability. For example, rivastigmine when taken with food, led to 30% AUC and 30% decrease in Cmax with 1.5 h delay in Tmax to achieve the desired bioavailability.²⁵ In many cases, the food intake is required and recommended to prevent the adverse effects, such as gastric irritation, bleeding, nausea among others, which are all clinically relevant.

CONCLUSION & FUTURE PERSPECTIVES

Lymphatic absorption remains as an alternative and an ideal approach to enhance the oral bioavailability of poorly soluble molecules, especially those belonging to BCS II and IV. We expect more molecules being discovered will be utilizing the lymphatic system versus portal system for delivery of poorly soluble and permeable drugs to target sites.

Food intake can impact drug transport and may divert the transport via lymphatic or portal vein or could be preferential favoring one over other. There are no obvious reasons to believe which of the 2 transport routes will be preferred and to what extent it will be impacted. There are pharmacokinetic models to evaluate the food effect on bioavailability of drugs. Lower absorption and bioavailability are taken as markers for hepatic first metabolism.

Ascendia’s enabling technologies (LipidSol™, EmulSol®, NanoSol®, and AmorSol®) offer a range of formulation choices to design better and smarter dosages, oral liquids, and solids to mitigate the food effect and improve the oral bioavailability by finding the appropriate class of lipids and surfactants, and oils to achieve the desired outcomes. This is essential and required for new chemical entities with solubility challenges and for improving their bioavailability by directing them to lymphatic pathways.

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Shauket Ali, PhD
Sr. Director, Scientific Affairs & Technical Marketing
Ascendia Pharmaceutical Solutions
sali@ascendicdmo.com
www.ascendiacdmo.com

Dr. Shaukat Ali joins Ascendia Pharmaceutical Solutions as Senior Director of Scientific Affairs and Technical Marketing after having worked in the pharma industry for many years. His areas of expertise include lipid chemistry, liposomes, lipid nanoparticles, surfactant-based drug delivery systems, SEDDS/SMEDDS, oral and parenteral, topical and transdermal drug delivery, immediate- and controlled-release formulations. He earned his PhD in Organic Chemistry from the City University of New York and carried out his post-doctoral research in Physical Biochemistry at the University of Minnesota and Cornell University. He has published extensively in scientific journals and is inventor/co-inventor of several US and European patents.

Jim Huang, PhD
Founder & CEO
Ascendia Pharmaceutical Solutions
jhuang@ascendiacdmo.com
www.ascendiacdmo.com

Dr. Jim Huang is the Founder and CEO of Ascendia Pharmaceutical Solutions. He earned his PhD in Pharmaceutics from the University of the Sciences in Philadelphia (formerly Philadelphia College of Pharmacy and Sciences) under Joseph B. Schwartz. He has more than 20 years of pharmaceutical experience in preclinical and clinical formulation development, manufacturing, and commercialization of oral and parenteral dosage forms. His research interests are centered on solubility/bioavailability improvement and controlled delivery of poorly water-soluble drugs through nano-based technologies.