Lipid-Based Formulations for Oral Administration: Opportunities for Bioavailability Enhancement and Lipoprotein Targeting of Lipophilic Drugs

Porter, Christopher John; Charman, William Neil

doi:10.1081/rrs-100107429

Cited by 44 publications

(19 citation statements)

References 143 publications

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“…7 In addition, a formed o/w microemulsion could be delivered by lymphatic transport to avoid first-pass metabolism in the liver, thus improving BA of the drug. 8 Nevertheless, SMEDDS have several shortcomings for practical drug product development. First, the volume of solubilizing vehicle, including oil and surfactants, is generally too large to accommodate the usual dose of the drug in a unit dosage form.…”

Section: Introductionmentioning

confidence: 99%

Enhanced oral bioavailability of valsartan using a polymer-based supersaturable self-microemulsifying drug delivery system

Yeom¹,

Chae²,

Son³

et al. 2017

IJN

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A novel, supersaturable self-microemulsifying drug delivery system (S-SMEDDS) was successfully formulated to enhance the dissolution and oral absorption of valsartan (VST), a poorly water-soluble drug, while reducing the total quantity for administration. Poloxamer 407 is a selectable, supersaturating agent for VST-containing SMEDDS composed of 10% Capmul ® MCM, 45% Tween ® 20, and 45% Transcutol ® P. The amounts of SMEDDS and Poloxamer 407 were chosen as formulation variables for a 3-level factorial design. Further optimization was established by weighting different levels of importance on response variables for dissolution and total quantity, resulting in an optimal S-SMEDDS in large quantity (S-SMEDDS_LQ; 352 mg in total) and S-SMEDDS in reduced quantity (S-SMEDDS_RQ; 144.6 mg in total). Good agreement was observed between predicted and experimental values for response variables. Consequently, compared with VST powder or suspension and SMEDDS, both S-SMEDDS_LQ and S-SMEDDS_RQ showed excellent in vitro dissolution and in vivo oral bioavailability in rats. The magnitude of dissolution and absorption-enhancing capacities using quantity-based comparisons was in the order S-SMEDDS_RQ > S-SMEDDS_LQ > SMEDDS > VST powder or suspension. Thus, we concluded that, in terms of developing an effective SMEDDS preparation with minimal total quantity, S-SMEDDS_RQ is a promising candidate.

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Section: Introductionmentioning

confidence: 99%

Enhanced oral bioavailability of valsartan using a polymer-based supersaturable self-microemulsifying drug delivery system

Yeom¹,

Chae²,

Son³

et al. 2017

IJN

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“…Conversely, plasma esterases are unlikely to play a significant role in MU to M conversion. Halofantrine is also converted to a less lipophilic and poorly lymphatically transported metabolite desmethylhalofantrine (Khoo, 2002) within the enterocyte (Porter and Charman, 2001b). However, halofantrine is not a high extraction efficiency drug; therefore, the extent of enterocyte-based conversion of halofantrine to desbutylhalofantrine is considerably lower than that of MU to M.…”

Section: Discussionmentioning

confidence: 98%

Lymphatic Transport of Methylnortestosterone Undecanoate (MU) and the Bioavailability of Methylnortestosterone Are Highly Sensitive to the Mass of Coadministered Lipid after Oral Administration of MU

White¹,

Nguyen²,

Charman³

et al. 2009

The Journal of Pharmacology and Experimental Therapeutics

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The contribution of lymphatic transport to the oral bioavailability of methylnortestosterone (M) after oral administration of the lipophilic prodrug methylnortestosterone undecanoate (MU) has been evaluated, and the sensitivity of lymphatic MU transport to lymphatic lipid transport has been investigated. M and MU were administered intravenously and orally to greyhound dogs to determine absolute bioavailability after oral dosing of MU. MU was also administered orally with differing quantities of food (lipid) to lymph duct-cannulated greyhound dogs to investigate the relative roles of lymph versus blood transport on M bioavailability and the effect of lipid load on systemic exposure. The relationship between lymphatic lipid and MU transport was further investigated in anesthetized rats. The oral bioavailability of M after administration of MU was found to be highly dependent on coadministration of food, and the bioavailability of M increased approximately 700% in fed versus fasted animals. In both cases, lymph diversion resulted in negligible systemic exposure of M, indicating almost complete dependence on lymphatic transport of MU for systemic exposure of M. Lymphatic transport of MU was even more highly dependent on the quantity of coadministered lipid and increased more than 50-fold with increasing lipid load. Therefore, increasing the quantity of food or lipid coadministered with MU stimulated a significant increase in the lymphatic transport of MU and systemic exposure of M. The lipid sensitivity of lymphatic transport of MU is significantly higher than previously observed for more metabolically stable compounds, suggesting a role for coadministered lipid in promoting avoidance of enterocyte-based cleavage of MU.

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“…Previous studies have demonstrated that the plasma ratio of desbutyl-halofantrine to halofantrine is significantly higher after oral as opposed to i.v. administration and that the metabolism of halofantrine after oral administration can be reduced by coadministration with the cyto-chrome p450 3A inhibitor, ketoconazole (Porter and Charman, 2001b). Coadministration of halofantrine with food also results in a reduction in the desbutyl-halofantrine to halofantrine plasma ratios (Humberstone et al, 1996).…”

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confidence: 91%

An Examination of the Interplay Between Enterocyte-Based Metabolism and Lymphatic Drug Transport in the Rat

Trevaskis¹,

Porter²,

Charman³

2006

Drug Metabolism and Disposition

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ABSTRACT: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 enterocytebased 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.After oral delivery, drugs may be transported from the intestine to the systemic circulation via the intestinal lymph or the portal blood (Porter and Charman, 2001a). Drugs that are significantly transported via the intestinal lymphatic system usually do so in association with the lipid-rich lipoprotein fraction of lymph (Sieber et al., 1974;Porter and Charman, 2001a). For this reason, only highly lipophilic drugs (typically log P Ͼ 5, triglyceride solubility Ͼ 50 mg/g) (Charman and Stella, 1986a), which can associate with developing lipoproteins during transport through the enterocyte, are appreciably transported via the intestinal lymphatic system.Relatively little has been published detailing the processes that dictate the association of lipophilic drugs with enterocyte-based lipoproteins; however, a recent study from our laboratory (Trevaskis et al., 2006) has shown that the size and dynamics of the LLPP seems to dictate the rate and extent of lymphatic transport of a highly lipophilic drug (halofantrine). The LLPP consists of multiple droplets of lipid situated in the smooth endoplasmic reticulum (SER) and Golgi of the enterocyte. The lipids in the LLPP are destined for assembly into lipoproteins, which are subseque...

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Lipid-Based Formulations for Oral Administration: Opportunities for Bioavailability Enhancement and Lipoprotein Targeting of Lipophilic Drugs

Cited by 44 publications

References 143 publications

Enhanced oral bioavailability of valsartan using a polymer-based supersaturable self-microemulsifying drug delivery system

Enhanced oral bioavailability of valsartan using a polymer-based supersaturable self-microemulsifying drug delivery system

Lymphatic Transport of Methylnortestosterone Undecanoate (MU) and the Bioavailability of Methylnortestosterone Are Highly Sensitive to the Mass of Coadministered Lipid after Oral Administration of MU

An Examination of the Interplay Between Enterocyte-Based Metabolism and Lymphatic Drug Transport in the Rat

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