A comparison of commonly used polyethoxylated pharmaceutical excipients on their ability to inhibit P‐glycoprotein activity in vitro

Hugger, Erin; Novak, Barbara; Burton, Philip S.; Audus, Kenneth L.; Borchardt, Ronald T.

doi:10.1002/jps.10176

Cited by 219 publications

(145 citation statements)

References 32 publications

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“…40,41 However, their Moreover, the enhancing effects of 500 µg/mL Tween 80 on the absorptive transport of paclitaxel were only moderate (1.47-fold) in CaCo-2 cells and negligible in MDR1-MDCK cells. 42 Although the contents of Tween 80 and TPGS 1000 incorporated into docetaxel-loaded SLNs are unknown, further enhancement of intestinal absorption of docetaxel from F2 could have been due partly to greater Pgp inhibition by TPGS 1000 than by Tween 80. Taken together, the possible mechanisms for enhancement of intestinal docetaxel absorption by the SLNs include the cellular uptake of intact SLNs (into Peyer's patches and microfold cells) and/or lipid degradation product-based mixed micelles (into enterocytes) to bypass Pgp-mediated efflux (Taxotere versus F1) and the higher Pgp-inhibiting activity of TPGS 1000 compared with that of Tween 80 (F1 versus F2).…”

Section: In Situ Closed-loop Study In Ratsmentioning

confidence: 99%

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

Cho¹,

Park²,

Yoon³

et al. 2014

IJN

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Docetaxel is a potent anticancer drug, but development of an oral formulation has been hindered mainly due to its poor oral bioavailability. In this study, solid lipid nanoparticles (SLNs) surface-modified by Tween 80 or D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS 1000) were prepared and evaluated in terms of their feasibility as oral delivery systems for docetaxel. Tween 80-emulsified and TPGS 1000-emulsified tristearin-based lipidic nanoparticles were prepared by a solvent-diffusion method, and their particle size distribution, zeta potential, drug loading, and particle morphology were characterized. An in vitro release study showed a sustained-release profile of docetaxel from the SLNs compared with an intravenous docetaxel formulation (Taxotere®). Tween 80-emulsified SLNs showed enhanced intestinal absorption, lymphatic uptake, and relative oral bioavailability of docetaxel compared with Taxotere in rats. These results may be attributable to the absorption-enhancing effects of the tristearin nanoparticle. Moreover, compared with Tween 80-emulsified SLNs, the intestinal absorption and relative oral bioavailability of docetaxel in rats were further improved in TPGS 1000-emulsified SLNs, probably due to better inhibition of drug efflux by TPGS 1000, along with intestinal lymphatic uptake. Taken together, it is worth noting that these surface-modified SLNs may serve as efficient oral delivery systems for docetaxel.

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Section: In Situ Closed-loop Study In Ratsmentioning

confidence: 99%

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

Cho¹,

Park²,

Yoon³

et al. 2014

IJN

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“…[6][7][8][9][10][11][12][13][14][15][16] It has been reported that several excipients such as Cremophor EL, Tween 80, n-lauryl-b-D-maltopyranoside (LM), Pluronic P85, vitamin E-TPGS, PEGs, sodium caprate and dimethyl-b-cyclodextrin could inhibit the function of Pgp by in vitro and in vivo methods. [6][7][8][9][10][11][12][13][14][15][16] Among these pharmaceutical excipients, Labrasol is one which has been widely used for the solubilization of hydrophobic drugs.17) Labrasol is obtained from coconut oil and has very low toxicity with an LD 50 of 22 g/kg for rats. Recently, it was reported that Labrasol had a strong absorption enhancing effect and that intestinal absorption of various poorly absorbable drugs including gentamicin, insulin and vancomycin was enhanced in its presence.…”

mentioning

confidence: 99%

Effects of Labrasol and Other Pharmaceutical Excipients on the Intestinal Transport and Absorption of Rhodamine123, a P-Glycoprotein Substrate, in Rats

Yang

Shen

Katsumi

et al. 2007

Biological & Pharmaceutical Bulletin

102

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P-Glycoprotein (P-gp) is a plasma membrane glycoprotein of about 170 kDa that belongs to the superfamily of ATPbinding cassette (ABC) transporters. P-gp is extensively expressed in tumor cells, liver, intestinal brush border membranes, kidney, brain, and adrenal glands.1) It can actively pump drugs out of cells, thus reducing the oral bioavailability of a wide range of drugs such as digoxin, vinca alkaloids, and b-adrenergic agonists.It has been reported that some P-glycoprotein inhibitors such as verapamil and cyclosporin A could enhance the bioavailability of P-gp substrate drugs.2-4) But it is well known that these drugs themselves have pharmacological activities. Therefore, it is important to find a P-gp inhibitor which does not have pharmacological activities. It has been demonstrated that a number of excipients could inhibit the function of P-gp, thereby increasing the absorption of P-gp substrate drugs. 5) These excipients include polyethylene glycols (PEGs), nonionic surfactants, fatty acids and bile salts. [6][7][8][9][10][11][12][13][14][15][16] It has been reported that several excipients such as Cremophor EL, Tween 80, n-lauryl-b-D-maltopyranoside (LM), Pluronic P85, vitamin E-TPGS, PEGs, sodium caprate and dimethyl-b-cyclodextrin could inhibit the function of Pgp by in vitro and in vivo methods. [6][7][8][9][10][11][12][13][14][15][16] Among these pharmaceutical excipients, Labrasol is one which has been widely used for the solubilization of hydrophobic drugs.17) Labrasol is obtained from coconut oil and has very low toxicity with an LD 50 of 22 g/kg for rats. Recently, it was reported that Labrasol had a strong absorption enhancing effect and that intestinal absorption of various poorly absorbable drugs including gentamicin, insulin and vancomycin was enhanced in its presence. [18][19][20] However, few studies examined the effect of Labrasol on the function of P-gp in the intestine and the intestinal absorption of P-gp substrates. Cornaire et al. (2004) examined the effect of Labrasol on the transport of digoxin by an in vitro everted sac experiment, and reported that 0.5% Labrasol increased the transport of digoxin in this experiment.21) However, they demonstrated that 0.5% Labrasol could increase the lactate dehydrogenase (LDH), and so the increase in digoxin transport might be due to the intestinal membrane damage, and not to the inhibition of P-gp function in the intestine. Furthermore, they did not study the different regional effects of Labrasol on the transport of P-gp substrate and in situ or in vivo intestinal absorption of P-gp substrate with or without Labrasol.In this study, therefore, we studied the effect of Labrasol on the function of P-gp using two different intestinal absorption experiments. We first adopted an in vitro diffusion chamber system using the isolated rat intestinal membrane to evaluate the effects of Labrasol and other pharmaceutical excipients, Gelucire44/14 and Transcutol P on the intestinal transport of rhodamine123, a P-gp substrate. In addition, the intestinal mem...

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“…Tween 80 is a suitable surfactant for EZT and ATR because it inhibits P-gp efflux. 20) Furthermore, Tween 80 inhibits both hepatic and intestinal CYP3A4 activity, which may have enhanced the bioavailability of ATR. 21,22) Mean Droplet Size of Blank SMEDDS One of the most important physical properties of a microemulsion system is mean droplet size.…”

Section: Solubility Of Atr and Ezt In Various Excipients (Mean±sdmentioning

confidence: 99%

Formulation and <i>in Vitro</i> Evaluation of Self-microemulsifying Drug Delivery System Containing Fixed-Dose Combination of Atorvastatin and Ezetimibe

Hwang

Park

Kim

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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This paper focuses on the development and physicochemical characterization of a self-microemulsifying drug delivery system (SMEDDS) containing a fixed-dose combination of atorvastatin (ATR) and ezetimibe (EZT). The solubility of both drugs was determined in excipient screening studies. Ternary-phase diagrams were drawn for 27 systems composed of different surfactants, cosurfactants, and oils at different surfactantto-cosurfactant (S/CoS) ratios, and the system exhibiting the largest percentage area of the self-microemulsifying region was selected. The optimum oil ratio in the SMEDDS was selected by evaluating the mean droplet size of the resultant microemulsions. The underlying mechanism of the lower ATR loading capacity compared with EZT was elucidated by measurement of the zeta potential and UV absorption analysis. The results implied that ATR was located exclusively in the surfactant-cosurfactant layer, whereas EZT was located both in the microemulsion core and the surfactant-cosurfactant layer. In vitro dissolution studies showed that the SMEDDS had higher initial dissolution rates for both drugs when compared with marketed products. More importantly, EZT had a significantly increased dissolution profile in distilled water and pH 4.0 acetate buffer, implying enhanced bioavailability.Key words self-microemulsifying drug delivery system; fixed-dose combination; ezetimibe; atorvastatin calcium; solubilization Atorvastatin (ATR) is a fully synthetic drug that lowers cholesterol level by competitively blocking 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase. However, it has an absolute bioavailability of only 14% due to rapid clearance by CYP3A4 in gastrointestinal mucosa and liver. 1) Ezetimibe (EZT) is a lipid-lowering drug that inhibits intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat-soluble nutrients. However, EZT has a very low solubility and dissolution rate resulting in highly variable bioavailability, which is also in part due to extensive efflux by p-glycoprotein (P-gp). 2,3)When co-administered with statins, EZT provides significant incremental reductions in low density lipoprotein (LDL)-cholesterol and triglycerides and increases in high density lipoprotein (HDL)-cholesterol when compared with statin monotherapy.4) Co-administration of EZT and ATR is well tolerated with no serious adverse effects. 5) Therefore, the addition of 10 mg EZT to low-dose ATR therapy may significantly reduce the risk of severe side effects, such as myopathy, while increasing its efficacy.Despite the clear synergism of the two drugs, incorporating both drugs in one drug delivery system poses some challenges due to different physicochemical properties. ATR is a weak acid with a solubility of 0.8 mg/mL and pK a of 4.46. 6) On the contrary, EZT is a practically insoluble and weakly basic compound with solubility of 0.012 mg/mL, and pK a of 9.75. 7)Therefore, it may be difficult for both drugs to be solubilized using a single solubilizing agent or strategy (e.g., pH-modifying...

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A comparison of commonly used polyethoxylated pharmaceutical excipients on their ability to inhibit P‐glycoprotein activity in vitro

Cited by 219 publications

References 32 publications

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

Effects of Labrasol and Other Pharmaceutical Excipients on the Intestinal Transport and Absorption of Rhodamine123, a P-Glycoprotein Substrate, in Rats

Formulation and <i>in Vitro</i> Evaluation of Self-microemulsifying Drug Delivery System Containing Fixed-Dose Combination of Atorvastatin and Ezetimibe

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