Self-nanoemulsifying Drug Delivery Systems: Formulation Insights, Applications and Advances

Abhijit A Date; Neha Desai; Rahul Dixit; Mangal Nagarsenker

Disclosures

Nanomedicine. 2010;5(10) 

In This Article

Factors Limiting Oral Bioavailability of Drugs & Potential of SNEDDS in Oral Drug Delivery

Dissolution Rate-limited Absorption

As presviously described, approximately 40% of the existing therapeutic agents have poor solubility in physiological milieu. These therapeutic agents belong to BCS class II and IV (e.g., cyclosporine, celecoxib and artemether, among others). The poor dissolution rate of these compounds is responsible for the poor absorption from the GI tract. The components used for the fabrication of SNEDDS have high solubilization potential for various hydrophobic drugs. The drug solubilized in SNEDDS has a very high dissolution velocity compared with the pure drug. Furthermore, SNEDDS spontaneously present the drug in very fine nanodroplets offering very high surface area for absorption. This helps with quick absorption of the drug and improves oral bioavailability.

Poor Permeability

Poor permeability is also one of the major factors that limits oral bioavailability of several drugs, such as atenolol and acyclovir (BCS class III). Owing to poor permeability, such drugs have to be administered at significantly higher doses. Interestingly, several SNEDDS components have the ability to enhance the membrane permeation of the therapeutic agents. For example, oily phases (e.g., oleic acid, monoglycerides of caprylic acid and propylene glycol esters of caprylic acid[46]), surfactants (e.g., Labrasol®, vitamin E tocopheryl polyethylene glycol 1000 succinate [TPGS] and polysorbate 80[75–77]) and cosurfactants (e.g., PEG 400, Transcutol and alcohol[78]) are known to have permeation-enhancing properties. Bruesewitz et al. have evaluated the effect of poloxamer-based nanoemulsions on Caco-2 permeability of various drugs, such as danazol (BCS class II), atenolol (BCS class III) and metoprolol (BCS class I).[79] Interestingly, they observed that nanoemulsions could significantly improve the Caco-2 permeability of all these drugs without causing any appreciable damage/toxicity to Caco-2 cells. This clearly indicates the potential of SNEDDS in oral delivery.

High Degree of Presystemic & Hepatic First-pass Metabolism

Oral bioavailability of a vast number of molecules, such as antihypertensive and cardiovascular agents (β-blockers, calcium-channel blockers and angiotensin-converting enzyme inhibitors), antihyperlipidemic agents (3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors), antidiabetic agents (repaglinide) and antibiotics (cephalosporins), is limited by presystemic and/or hepatic first-pass metabolism. Several SNEDDS components including Gelucire® 44/14 (lauroyl macrogol glycerides) and Labrasol (caprylocaproyl macrogol glycerides) have the ability to modulate/inhibit activity of cytochrome P450 and gut metabolizing enzymes,[56,80,81] whereas long-chain tri- and mono-glycerides (glyceryl monooleate) have demonstrated the ability to improve the intestinal lymphatic transport of the hydrophobic drugs.[44,45] Both these mechanisms are responsible for reducing/preventing the first-pass or presystemic metabolism of the drug resulting in improvement of oral bioavailability; for example, the oral bioavailability of cefpodoxime proxetil (an antibiotic with a high degree of gut metabolism) showed twofold improvement after encapsulation in submicronic emulsions.[9] We and others have also demonstrated that SNEDDS can improve the therapeutic efficacy/bioavailability of ezetimibe, a lipid-lowering agent with a high degree of presystemic metabolism.[13,82]

P-glycoprotein Efflux

P-glycoprotein (P-gp) is an efflux pump present at several sites in the body, including the GI tract. P-gp prevents the entry of the drugs in the systemic circulation, thus hampering the oral bioavailability of the drugs. A considerable number of molecules, such as amphotericin B, paclitaxel, digoxin and doxorubicin, are known P-gp substrates and their bioavailability is hampered owing to the P-gp-mediated efflux. Many surfactants, for example vitamin E TPGS, Solutol® HS 15, Labrasol, Cremophor EL, Gelucire 44/14 (lauroyl macrogol glycerides) and Polysorbate 80, and oily phases, including Imwitor® 742 and Akoline MCM® (mono-, and di-glyceride of caprylic acid) and Peceol® (glyceryl monooleate), have the potential to inhibit P-gp efflux.[57,83–86] Hence, SNEDDS can also inhibit the P-gp efflux process and improve oral bioavailability of drugs.

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