Bioavailability Of Artemether Research Articles

Solubility enhancing lipid-based vehicles for artemether and lumefantrine destined for the possible treatment of induced malaria and inflammation: in vitro and in vivo evaluations

BackgroundThe lipid self-emulsifying system has been advanced as a promising delivery vehicle for improving the solubility and bioavailability of artemether and lumefantrine. However, the observed kinetic instability (propensity of lumefantrine to rapid crystallisation from nano-scale droplets) in aqueous acid has impelled some researchers to incorporate surfactants/solubilizers in the dissolution medium prior to dissolution studies. Thus, in our present work, we sought to prepare micro/large nano-scale (> 100 nm) and yet kinetically stable lumefantrine lipid self-emulsifying system (that would not require an external drug dissolution enhancing agent in the dissolution medium) and palm kernel oil-based 100 nm kinetically stable artemether lipid self-emulsifying system with rapid emulsification time. COVID-19 and Plasmodium falciparum-infected Africans with previous long exposure to malaria have manifested attenuated inflammatory cytokines more than malaria-naive patients. Therefore, the ingestion of artemether-lumefantrine with enhanced solubility may further promote blunting of cytokines. Therefore, this work was aimed at preparing (< 100 nm) stable artemether and aqueous acid-stable micro/large nano-scale (> 100 nm) lumefantrine lipid self-emulsifying system destined for improved antimalarial and anti-inflammatory activities.ResultsThe droplet sizes of all the liquid artemether and lumefantrine formulations were between 8.95–39.88 and 1018–4195 nm, respectively. The loading efficiency for all the formulations was, between 72.91 ± 2.89 and 100.00 ± 0.29%. All the artemether and lumefantrine batches emulsified within the range of 3.90 ± 0.69 to 12.26 ± 0.69 s. Stable and transparent emulsions were formed on aqueous dilution to 1000 ml. The percentage drug released for artemether and lumefantrine ranged from 76.25 ± 2.98 to 99.22 ± 1.61%. The solid lipid self-emulsifying systems produced, had fair and passable flow properties. Differential scanning calorimetry revealed that the solid artemether and lumefantrine lipid self-emulsifying system were amorphous. Solidification with Neusilin FH2 or surfactant replacement with Kolliphor EL and Kollidon VA 64 fine prevented micro-or large nano-scale lumefantrine lipid self-emulsifying system from crystallisation in aqueous acid (pH 1.2). Higher antimalarial activity and remarkable anti-inflammatory effects (P < 0.05) favoured the lipid self-emulsifying formulations.ConclusionOptimal in vitro and in vivo results (enhanced antimalarial and anti-inflammatory activities) were obtained with kinetically stable lumefantrine micro/large nano-scale droplets and kinetically stable palm kernel oil-based (< 50 nm) artemether lipid self-emulsifying system droplets.

Bioavailability Enhancement of Artemether and Lumefantrine by Improving Solubility and Dissolution Rate using Solid Dispersion Technique

Artemether-lumefantrine is World Health Organization approved fixed dose combination for malaria treatment. These drugs have poor bioavailability due to low solubility and dissolution. The objective of this work was to improve bioavailability by increasing solubility and dissolution of both drugs. In this work solid dispersion using hydrophilic carriers like polyvinylpyrrolidone K-30, Soluplus and Lutrol F68 by solvent evaporation technique was prepared and evaluated for solubility, flow property, differential scanning calorimetry, x-ray diffraction analysis, scanning electron microscopy, disintegration and dissolution study. The drugs were determined simultaneously by high performance liquid chromatography method using various surfactants in different dissolution media. Solubility of the drugs was increased in all solid dispersions compared to pure drugs. Flow properties of solid dispersions containing polyvinylpyrrolidone K-30 were better than other carriers and the disintegration time of immediate release tablet containing drug and polyvinylpyrrolidone K-30 (1:0.2) was less than other solid dispersions. X-ray diffraction analysis, differential scanning calorimetry and scanning electron microscopy results indicated decrease in crystalline nature of drugs and their dissolution rate was enhanced than plain drugs and marketed formulations in acidic buffer containing myrj 52 (1 %) as dissolution medium. The pharmacokinetic studies in mice revealed that artemether-lumefantrine solid dispersion immediate release tablet had higher area under the curve, maximum plasma concentration for artemether and lumefantrine than plain and marketed tablet. Thus this technique successfully improved solubility, dissolution rate and hence the bioavailability of artemether and lumefantrine which was determined by single dissolution method.

Enhancing Solubility and Bioavailability of Artemether and Lumefantrine through a Self-nano Emulsifying Drug Delivery System

In the present study artemether and lumefantrine self-nano emulsifying drug delivery system formulations were prepared using combination of these drugs with Capmul medical countermeasure, oleic acid and Tween 80. The particle size and zeta potential of these formulations was found to be 15.2 nm and −22.8 mV. The solubility and in vitro dissolution performance of both drugs in self-nano emulsifying drug delivery system formulations was improved significantly as compared to pure drugs and marketed product and the in vivo studies confirmed it. In vivo studies in rats revealed that there was an increase in bioavailability of self-nano emulsifying drug delivery system formulations compared to pure drugs with the area under the curve of artemether from formulation was 598.89±114.33 in comparison to that of pure artemether 190.82±36.57 and the area under the curve for lumefantrine from the formulations was 190.82±36.57 in comparison to that of the pure lumefantrine 68.71±18.63. The Cmax was enhanced for artemether from 13.11±2.22 to 110.31±40.88 and for lumefantrine from 2.39±1.61 to 18.22±2.32.

Effect of Food/Beverage and Selected Drugs on the Oral Absorption of Artemether-Lumefantrine Tablet: an in situ and in vivo Study

Aim: This study aims at assessing the effect of some meals/beverage and selected drugs on oral absorption of artemether (ATM) and lumefantrine (LMF). Methods: In the in situ model, artemether-lumefantrine (AL) tablets were crushed and administered to anesthetized rabbits (n=2) via oral cannula either alone (CTR1) or with food components/beverage [i.e., starch (STC), albumin (ALB), sunflower oil (SFO) or carbonated drinks (CBS)] or drugs [i.e., lamivudine (LMV) or metronidazole (MTN)]. Blood samples were taken from cannulated carotid artery post dose administration. In the in vivo model, forty two healthy human subjects (28 male and 14 female) in groups of six persons received AL tablet alone (CRT2) or “eba” (cassava starch) with melon soup (EMS) or corn pap with milk and “akara” (fried beans cake) (PMA) or fruits (FTS) or CBS or drugs (i.e., LMV or MTN). ATM and LMF plasma concentrations were obtained simultaneously from plasma using reverse phase high pressure liquid chromatographic analysis. Results: There was significant reduction in ATM Ka due to STC, ALB, CBS, MTN and LMV (Ka ≤ 1.371 h-1) compared with CRT1 (3.567 h-1), p < 0.05). LMV and MTN also reduced the Ka and AUC of ATM and LMF, p < 0.05. Similarly, in vivo study showed significantly lower ATM AUC and Ka values for EMS (0.775 µghmL-1 and 0.041 h-1) and CBS (0.248 µghmL-1 and 4.155 h-1) compared with the CRT2 (6.090 µghmL-1 and 0.362 h-1). Conclusion: EMS or CBS resulted in significant reduction in the bioavailability of ATM and LMF and can influence the treatment outcomes.

Formulation design, in vitro characterizations and anti-malarial investigations of artemether and lumefantrine-entrapped solid lipid microparticles

Context: Poor aqueous solubility of artemether and lumefantrine makes it important to seek better ways of enhancing their oral delivery and bioavailability.Objective: To formulate and carry out in vitro and anti-malarial pharmacodynamic evaluations of solidified reverse micellar solutions (SRMS)-based solid lipid microparticles (SLMs) of artemether and lumefantrine for oral delivery and improved bioavailability.Materials and methods: Rational blends of Softisan®154 and Phospholipon®90H lipid matrices, and different concentrations of artemether and lumefantrine were used to formulate several batches of SLMs. Drug-free SLMs were also formulated. Morphology, particle size, encapsulation efficiency (EE%) and pH studies were performed. In vitro release studies were performed in alcoholic buffer, simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) without enzymes. Anti-malarial pharmacodynamic studies were conducted in mice.Results: Stable, smooth and spherical particles with sizes ranging from 4.2 ± 0.02 to 9.3 ± 0.8 µm were formed. EE% of 92.2–97.3% and 30.2–84.7% and pH of 3.0 ± 0.02 to 4.9 ± 0.12 and 3.0 ± 0.02 to 5.8 ± 0.05 were obtained for artemether and lumefantrine SLMs, respectively. Release of 100, 88.28 and 75.49%, as well as 63.26, 34.31 and 56.17% were recorded for artemether and lumefantrine in alcoholic buffer, SGF and SIF, respectively. Pharmacodynamic studies indicated very significant (p < 0.05) clearance of parasitaemia in plasmodium-infected mice by the drug-loaded SLMs.Conclusion: Oral delivery and bioavailability of artemether and lumefantrine could be improved using SRMS-based SLMs.

Impaired Clinical Response in a Patient with Uncomplicated Falciparum Malaria Who Received Poor-Quality and Underdosed Intramuscular Artemether

We describe an adult with uncomplicated Plasmodium falciparum malaria who did not improve clinically despite 5 days of intramuscular artemether therapy. He was prescribed a lower dose (kg body weight) than that recommended, and a vial from the packet contained only 74% of the artemether dose as stated by the manufacturer. The combination of underdosing, poor-quality drug, and the intrinsic low bioavailability of artemether may have contributed to his poor clinical response. Analysis of the packaging and chemical "fingerprinting" of the artemether suggested that the drug was genuine but was either substandard or had deteriorated after manufacture.

The pharmacokinetics and bioavailability of dihydroartemisinin, arteether, artemether, artesunic acid and artelinic acid in rats.

The pharmacokinetics and bioavailability of dihydroartemisinin (DQHS), artemether (AM), arteether (AE), artesunic acid (AS) and artelinic acid (AL) have been investigated in rats after single intravenous, intramuscular and intragastric doses of 10 mg kg(-1). Plasma was separated from blood samples collected at different times after dosing and analysed for parent drug. Plasma samples from rats dosed with AM, AE, AS and AL were also analysed for DQHS which is known to be an active metabolite of these compounds. Plasma levels of all parent compounds decreased biexponentially and were a reasonable fit to a two-compartment open model. The resulting pharmacokinetic parameter estimates were substantially different not only between drugs but also between routes of administration for the same drug. After intravenous injection the highest plasma level was obtained with AL, followed by DQHS, AM, AE and AS. This resulted in the lowest steady-state volume of distribution (0.39 L) for AL, increasing thereafter for DQHS (0.50 L), AM (0.67 L), AE (0.72 L) and AS (0.87 L). Clearance of AL (21-41 mL min(-1) kg(-1)) was slower than that of the other drugs for all three routes of administration (DQHS, 55-64 mL min(-1) kg(-1); AM, 91-92 mL min(-1) kg(-1); AS, 191-240 mL min(-1) kg(-1); AE, 200-323 mL min(-1) kg(-1)). In addition the terminal half-life after intravenous dosing was longest for AL (1.35 h), followed by DQHS (0.95 h), AM (0.53 h), AE (0.45 h) and AS (0.35 h). Bioavailability after intramuscular injection was highest for AS (105%), followed by AL (95%) and DQHS (85%). The low bioavailability of AM (54%) and AE (34%) is probably the result of slow, prolonged absorption of the sesame-oil formulation from the injection site. After oral administration, low bioavailability (19-35%) was observed for all five drugs. In-vivo AM, AE, AS and AL were converted to DQHS to different extents; the ranking order of percentage of total dose converted to DQHS was AS (25.3-72.7), then AE (3.4-15.9), AM (3.7-12.4) and AL (1.0-4.3). The same ranking order was obtained for all formulations and routes of administration. The drug with the highest percentage conversion to DQHS was artesunic acid. Because DQHS has significant antimalarial activity, relatively low DQHS production could still contribute significantly to the antimalarial efficacy of these drugs. This is the first time the pharmacokinetics, bioavailability and conversion to DQHS of these drugs have been directly compared after different routes of administration. The results show that of all the artemisinin drugs studied the plasma level was highest for artelinic acid; this reflects its lowest extent of conversion to DQHS and its slowest rate of elimination.