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

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Presentation on theme: "Food Effects on Gastrointestinal Transit Properties of Amphotericin B Solid Lipid Nanoparticles NASHIRU BILLA School of Pharmacy University of Nottingham,"— Presentation transcript:

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 AmB in 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 AmB in 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10 mg/kg each of AmB, PAR and SSZ (freeze-dried SLNs or free drug) dispersed in deionised water Blood samples withdrawn and analysed for the three drugs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 T10S serves 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 Colonic transit time (CTT) The CTT was estimated as the time for 90% SP absorption (T90S)

7 RESULTS

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

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

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 CAT GE Fasted rats

12 * p < 0.05 – statistical significance
CAT GE Fasted rats GE CAT Fed rats Rats Tmax (hr) Cmax (ng/mL) AUC (ng.hr/mL) Fasted 0.50±0.25 3616.3±68.4* ± Fed 0.75±0.29 2383.3±747.9 ±5712.2 * p < 0.05 – statistical significance

13 Pharmacokinetic parameters for AmB
Group Dose (mg/kg) Tmax (hr) Cmax (ng/mL) AUC (ng.hr/mL) Fasted rats AmB SLNs 10 8.00±0.00* 534.7±122.5* 7953.0±551.2* Control 1.50±0.71 205.3±9.6# 4412.5±376.9 Fed rats 9.33±4.62** 323.2±44.0 ** 7565.3± ** 0.38±0.18 173.8±27.9 3343.0±209.3 * p < significantly different from AmB suspension in fasted rats ** p < significantly different from AmB suspension in fed rats # p < significantly different compared with fed rats

14 Transit times of AmB SLNs in the GI tracts of the rats
Parameter  Fasted rats Fed rats GTT (hr) 1.71±0.61 2.25±0.46 SITT (hr) 1.65±0.86 1.79±1.29 CAT (hr) 1.80±0.81 1.90±1.29 CTT (hr) 15.50±3.20* 24.60±2.60 * p < 0.05 – statistical significance Estimated % absorption of AmB from SLNs in the stomach, small intestines and colon (n = 3) Fasted rats Fed rats Stomach (%) Small intestine (%) Colon (%) Stomach (%) Colon++ (%) Mean 2.8 44.1 53.1 3.2 37.2 59.6 SD 1.1 10.7 10.6 1.2 16.0 17.1

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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