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Fulltext A gastrointestinal transit study on amphotericin B-loaded solid lipid nanoparticles in rats

Amekyeh H, Billa N, Yuen KH, Chin SL

AAPS PharmSciTech, 2015 Aug;16(4):871-7.
PMID: 25588365 DOI: 10.1208/s12249-014-0279-4

The gastrointestinal (GI) transit behavior of and absorption from an amphotericin B (AmB) solid lipid nanoformulation (SLN) in rats was investigated. We aimed to estimate the gastric emptying time (GET) and cecal arrival time (CAT) of AmB SLN in rats as animal models. From these two parameters, an insight on the absorption window of AmB was ascertained. Three types of SLNs, AmB, paracetamol (PAR), and sulfasalazine (SSZ), were similarly formulated using beeswax/theobroma oil composite as the lipid matrix and characterized with regard to size, viscosity, density, migration propensity within agarose gel, in vitro drug release, morphology, gastrointestinal transit, and in vivo absorption. The GET and CAT were estimated indirectly using marker drugs: PAR and sulfapyridine (SP). All three types of SLNs exhibited identical properties with regard to z-average, viscosity, relative density, and propensity to migrate. PAR was absorbed rapidly from the small intestine following emptying of the SLNs giving the T50E (time for 50% absorption of PAR) to be 1.6 h. SP was absorbed after release and microbial degradation of SSZ from SLN in the colon with a lag time of 2 h post-administration, serving as the estimated cecal arrival time of the SLNs. AmB within SLN was favorably absorbed from the small intestine, albeit slowly.

Matched MeSH terms: Acetaminophen/pharmacokinetics
Fulltext Optimizing supercritical antisolvent process parameters to minimize the particle size of paracetamol nanoencapsulated in L-polylactide

Kalani M, Yunus R, Abdullah N

Int J Nanomedicine, 2011;6:1101-5.
PMID: 21698077 DOI: 10.2147/IJN.S18979

The aim of this study was to optimize the different process parameters including pressure, temperature, and polymer concentration, to produce fine small spherical particles with a narrow particle size distribution using a supercritical antisolvent method for drug encapsulation. The interaction between different process parameters was also investigated.

Matched MeSH terms: Acetaminophen/pharmacokinetics
Fulltext Effect of supercritical fluid density on nanoencapsulated drug particle size using the supercritical antisolvent method

Kalani M, Yunus R

Int J Nanomedicine, 2012;7:2165-72.
PMID: 22619552 DOI: 10.2147/IJN.S29805

The reported work demonstrates and discusses the effect of supercritical fluid density (pressure and temperature of supercritical fluid carbon dioxide) on particle size and distribution using the supercritical antisolvent (SAS) method in the purpose of drug encapsulation. In this study, paracetamol was encapsulated inside L-polylactic acid, a semicrystalline polymer, with different process parameters, including pressure and temperature, using the SAS process. The morphology and particle size of the prepared nanoparticles were determined by scanning electron microscopy and transmission electron microscopy. The results revealed that increasing temperature enhanced mean particle size due to the plasticizing effect. Furthermore, increasing pressure enhanced molecular interaction and solubility; thus, particle size was reduced. Transmission electron microscopy images defined the internal structure of nanoparticles. Thermal characteristics of nanoparticles were also investigated via differential scanning calorimetry. Furthermore, X-ray diffraction pattern revealed the changes in crystallinity structure during the SAS process. In vitro drug release analysis determined the sustained release of paracetamol in over 4 weeks.

Matched MeSH terms: Acetaminophen/pharmacokinetics
Reliability of the reported ingested dose of acetaminophen for predicting the risk of toxicity in acetaminophen overdose patients

Zyoud SH, Awang R, Sulaiman SA

Pharmacoepidemiol Drug Saf, 2012 Feb;21(2):207-13.
PMID: 21812068 DOI: 10.1002/pds.2218

The present study examines the relationship between the dose of acetaminophen reported to have been ingested by patients and the occurrence of serum acetaminophen levels above the 'possible toxicity' line in patients presenting at the hospital after acetaminophen overdose. The prognostic value of patient-reported dosage cut-offs of 8, 10 and 12 g was determined.

Matched MeSH terms: Acetaminophen/pharmacokinetics
Significance of lipid matrix aging on in vitro release and in vivo bioavailability

Choy YW, Khan N, Yuen KH

Int J Pharm, 2005 Aug 11;299(1-2):55-64.
PMID: 15955645

A polyglycolised glyceride carrier, Gelucire 50/13, was incorporated with paracetamol as a model drug, filled into hard gelatin capsules and stored at three different temperatures for various lengths of time. The resultant solidified matrix within the capsule was subjected to thermal analysis using differential scanning calorimetry (DSC) to ascertain its supramolecular structure. Polymorphic transformations towards more stable gelucire forms were observed upon aging the matrices, with samples stored at a temperature near the melting range of the lower temperature gelucire melting fraction showing the most profound changes. The increase in the rate of drug release from aged samples could be correlated to the alterations to the supramolecular structure of the gelucire. Accelerated drug release from aged samples could also be seen from in vivo studies using healthy human volunteers, although the extent of absorption was not affected. Therefore, even though the sustainability of release may be compromised by aging the gelucire matrices, the bioavailability of the incorporated drug is unlikely to be affected.

Matched MeSH terms: Acetaminophen/pharmacokinetics*
Fulltext A randomized single-dose, two-period crossover bioequivalence study of two fixed-dose Paracetamol/Orphenadrine combination preparations in healthy volunteers under fasted condition

Cheah KY, Mah KY, Pang LH, Ng SM, Wong JW, Tan SS, et al.

BMC Pharmacol Toxicol, 2020 06 23;21(1):45.
PMID: 32576287 DOI: 10.1186/s40360-020-00416-3

BACKGROUND: Paracetamol/Orphenadrine is a fixed dose combination containing 35 mg orphenadrine and 450 mg paracetamol. It has analgesic and muscle relaxant properties and is widely available as generics. This study is conducted to investigate the relative bioavailability and bioequivalence between one fixed dose paracetamol/orphenadrine combination test preparation and one fixed dose paracetamol/orphenadrine combination reference preparation in healthy volunteers under fasted condition for marketing authorization in Malaysia.
METHOD: This is a single-center, single-dose, open-label, randomized, 2-treatment, 2-sequence and 2-period crossover study with a washout period of 7 days. Paracetamol/Orphenadrine tablets were administered after a 10-h fast. Blood samples for pharmacokinetic analysis were collected at scheduled time intervals prior to and up to 72 h after dosing. Blood samples were centrifuged, and separated plasma were kept frozen (- 15 °C to - 25 °C) until analysis. Plasma concentrations of orphenadrine and paracetamol were quantified using liquid-chromatography-tandem mass spectrometer using diphenhydramine as internal standard. The pharmacokinetic parameters AUC0-∞, AUC0-t and Cmax were determined using plasma concentration time profile for both preparations. Bioequivalence was assessed according to the ASEAN guideline acceptance criteria for bioequivalence which is the 90% confidence intervals of AUC0-∞, AUC0-t and Cmax ratio must be within the range of 80.00-125.00%.
RESULTS: There were 28 healthy subjects enrolled, and 27 subjects completed this trial. There were no significant differences observed between the AUC0-∞, AUC0-t and Cmax of both test and reference preparations in fasted condition. The 90% confidence intervals for the ratio of AUC0-t (100.92-111.27%), AUC0-∞ (96.94-108.08%) and Cmax (100.11-112.50%) for orphenadrine (n = 25); and AUC0-t (94.29-101.83%), AUC0-∞ (94.77-101.68%) and Cmax (87.12-101.20%) for paracetamol (n = 27) for test preparation over reference preparation were all within acceptable bioequivalence range of 80.00-125.00%.
CONCLUSION: The test preparation is bioequivalent to the reference preparation and can be used interchangeably.
TRIAL REGISTRATION: NMRR- 17-1266-36,001; registered and approved on 12 September 2017.

Matched MeSH terms: Acetaminophen/pharmacokinetics*
Fabrication of composite poly(d,l-lactide)/montmorillonite nanoparticles for controlled delivery of acetaminophen by solvent-displacement method using glass capillary microfluidics

Othman R, Vladisavljević GT, Thomas NL, Nagy ZK

Colloids Surf B Biointerfaces, 2016 May 01;141:187-195.
PMID: 26852102 DOI: 10.1016/j.colsurfb.2016.01.042

Paracetamol (PCM)-loaded composite nanoparticles (NPs) composed of a biodegradable poly(d,l-lactide) (PLA) polymer matrix filled with organically modified montmorillonite (MMT) nanoparticles were fabricated by antisolvent nanoprecipitation in a microfluidic co-flow glass capillary device. The incorporation of MMT in the polymer improved both the drug encapsulation efficiency and the drug loading, and extended the rate of drug release in simulated intestinal fluid (pH 7.4). The particle size increased on increasing both the drug loading and the concentration of MMT in the polymer matrix, and decreased on increasing the aqueous to organic flow rate ratio. The drug encapsulation efficiency in the NPs was higher at higher aqueous to organic flow rate ratio due to faster formation of the NPs. The PCM-loaded PLA NPs containing 2 wt% MMT in PLA prepared at an aqueous to organic flow rate ratio of 10 with an orifice size of 200 μm exhibited a spherical shape with a mean size of 296 nm, a drug encapsulation efficiency of 38.5% and a drug loading of 5.4%. The encapsulation of MMT and PCM in the NPs was confirmed by transmission electron microscopy, energy dispersive X-ray spectroscopy, X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis and attenuated total reflection-Fourier transform infrared spectroscopy.

Matched MeSH terms: Acetaminophen/pharmacokinetics*
Fulltext A metabolomic analysis of thiol response for standard and modified N-acetyl cysteine treatment regimens in patients with acetaminophen overdose

Dear JW, Ng ML, Bateman DN, Leroy Sivappiragasam P, Choi H, Khoo BBJ, et al.

Clin Transl Sci, 2021 Jul;14(4):1476-1489.
PMID: 33742775 DOI: 10.1111/cts.13009

N-acetylcysteine (NAC) is an antidote to prevent acetaminophen (paracetamol-APAP)-induced acute liver injury (ALI). The 3-bag licensed 20.25 h standard regimen, and a 12 h modified regimen, are used to treat APAP overdose. This study evaluated the redox thiol response and APAP metabolites, in patients with a single APAP overdose treated with either the 20.25 h standard or 12 h modified regimen. We used liquid chromatography tandem mass spectrometry to quantify clinically important oxidative stress biomarkers and APAP metabolites in plasma samples from 45 patients who participated in a randomized controlled trial (SNAP trial). We investigated the time course response of plasma metabolites at predose, 12 h, and 20.25 h post-start of NAC infusion. The results showed that the 12 h modified regimen resulted in a significant elevation of plasma NAC and cysteine concentrations at 12 h post-infusion. We found no significant alteration in the metabolism of APAP, mitochondrial, amino acids, and other thiol biomarkers with the two regimens. We examined APAP and purine metabolism in overdose patients who developed ALI. We showed the major APAP-metabolites and xanthine were significantly higher in patients with ALI. These biomarkers correlated well with alanine aminotransferase activity at admission. Receiver operating characteristic analysis showed that at admission, plasma APAP-metabolites and xanthine concentrations were predictive for ALI. In conclusion, a significantly higher redox thiol response with the modified NAC regimen at 12 h postdose suggests this regimen may produce greater antioxidant efficacy. At baseline, plasma APAP and purine metabolites may be useful biomarkers for early prediction of APAP-induced ALI.

Matched MeSH terms: Acetaminophen/pharmacokinetics