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Food Effects on Gastrointestinal Transit Properties of Amphotericin B Solid Lipid Nanoparticles

Food Effects on Gastrointestinal Transit Properties of Amphotericin B Solid Lipid Nanoparticles. NASHIRU BILLA School of Pharmacy University of Nottingham, Malaysia Campus Malaysia.

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Food Effects on Gastrointestinal Transit Properties of Amphotericin B Solid Lipid Nanoparticles

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  1. Food Effects on Gastrointestinal Transit Properties of Amphotericin B Solid Lipid Nanoparticles NASHIRU BILLA School of Pharmacy University of Nottingham, Malaysia Campus Malaysia

  2. Amphotericin B (AmB) is a polyene antifungal agent highly effective in treating life-threatening systemic fungal infections • No oral AmB product currently available for use clinically • Research into oral AmB formulations as alternatives to the currently available yet costly intravenous formulations therefore relevant • Solid lipid nanoparticles (SLNs) have been shown to improve oral bioavailability of hydrophobic drugs (such as AmB) by enhancing lymphatic transport etc • No data on the regional preference to gastrointestinal (GI) absorption & Info on GI transit of AmB dosage forms lacking

  3. Purpose • To formulate AmBin SLNs intended for oral delivery • Study the GI absorption preference for AmB and GI transit properties of AmB SLN • To study the effect of food on the absorption of AmBin stomach, small intestine and colon

  4. Methods • AmB, PAR and SSZ were similarly formulated in SLNs and physically characterised • Size • Surface charge • Morphology • Mobility propensity (in agarose gel) • In-vitro release (PBS – pH 7.4) • Animals • Male Sprague-Dawley rats (250±20 g) – 12/Ethical clearance • Fasted group allowed access to food 8 hr after dosing with the SLNs • Each animal was administered a single-dose oral gavage containing 10 mg/kg each of AmB, PAR and SSZ (freeze-dried SLNs or free drug) dispersed in deionised water • Blood samples withdrawn and analysed for the three drugs

  5. GI transit parameters • Gastric transit time (GTT) of AmB SLN • From plasma PAR absorption-time profiles • Assumption • % PAR absorbed is directly related to the % PAR SLNs emptied from the stomach into the duodenum. • Time for 10% PAR absorption (T10P) ≈ arrival of the SLNs at the small intestine. • Time for complete emptying of the SLNs (T90P) from the stomach was estimated using the time for 90% of PAR absorption in the small intestine • T90P≈ GTT • Small intestinal transit time (SITT) • Plasma SP absorption-time profiles • SITT ≈ T10S - T10P T10S = Time taken for 10% SP absorption in the caecum = caecal arrival of the SLNs

  6. Caecal arrival time (CAT) • CAT = time taken for SLNs to arrive at the caecum • CAT has been estimated as the time for the initial detection of SP in the plasma using the indirect method of estimation • Due to the time lapse in SP production from SSZ released from SSZ SLNs reaching the caecum CAT ≈ T10S • T10Sserves as a better estimate for CAT of the SLNs than the initial SP detection in plasma • Initial SP detection may be mainly due to free SSZ released from the SLNs rather than SSZ released from the intact SSZ SLNs within the caecum • Colonictransit time (CTT) • The CTT was estimated as the time for 90% SP absorption (T90S)

  7. RESULTS

  8. SEM images of the SLNs • All three SLNs shared identical physical characteristics AmB 100 nm Mean particle size and zeta potential of the SLNs 100 nm PAR SSZ 100 nm

  9. Agarose gel (a) before and (b, c) after voltage application In-vitro drug release in phosphate buffer (pH 7.4)

  10. Key assumptions • The SLNs exhibited similar physical characteristics • The assumption was therefore that all three SLNs would transit similarly within the GI tract • The slow in-vitro release from the AmB SLNs was favourable for the aim in improving AmB’s oral bioavailability

  11. Plasma drug concentration of AmB Effect of food on the absorption of PAR SLNs Fasted rats CAT GE

  12. Fasted rats Fed rats * p < 0.05 – statistical significance CAT GE CAT GE

  13. Pharmacokinetic parameters for AmB * p < 0.05 - significantly different from AmB suspension in fasted rats ** p < 0.05 - significantly different from AmB suspension in fed rats # p < 0.05 - significantly different compared with fed rats

  14. Transit times of AmB SLNs in the GI tracts of the rats * p < 0.05 – statistical significance Estimated % absorption of AmB from SLNs in the stomach, small intestines and colon (n = 3)

  15. Key points GTT, SITT, CAT and CTT were longer in the fed rats Only CTT was significantly longer in the fed state Colon++ = Absorption processes in the colon + continued absorption process via lymph in the small intestines Differences in %AmB absorption due to food in the respective GI regions were not statistically significant

  16. Conclusions The use of SLNs significantly enhanced the bioavailability of AmB in both fasted and fed rats Food did not significantly alter the bioavailability of the AmB SLNs Absorption process in SI appears to continue even after ceacal arrival AmB oral formulations should probably be aimed for delayed SI transit

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