ABSTRACT
OBJECTIVES: To evaluate the in-vivo efficacy of solid SMEDDS containing combination of artemether and lumefantrine. METHODS: Formulation development of solid SMEDDS containing combination of artemether and lumefantrine was carried out using spray drying technique. These S-SMEDDS were evaluated for reduction in parasitemia and mortality as well as subacute toxicity in mice. Haematology, biochemical parameters and histopathology were performed for evaluating safety of formulation. Pharmacokinetic characterization of both drugs was performed after oral administration in rats. KEY FINDINGS: Optimized solid SMEDDS containing low, medium and high dose were more effective in reducing parasitemia and mortality of mice as compared to marketed tablets containing high dose of these drugs. Single oral administration of solid SMEDDS containing high-dose combination could maintain plasma concentration of lumefantrine above the minimum effective concentration for ≈4 days. CONCLUSIONS: Solid SMEDDS containing low-, medium- and high-dose combination of artemether and lumefantrine are more effective than marketed tablets.
Subject(s)
Antimalarials/administration & dosage , Artemisinins/administration & dosage , Drug Delivery Systems , Ethanolamines/administration & dosage , Fluorenes/administration & dosage , Administration, Oral , Animals , Antimalarials/pharmacokinetics , Antimalarials/toxicity , Artemether, Lumefantrine Drug Combination , Artemisinins/pharmacokinetics , Artemisinins/toxicity , Chemistry, Pharmaceutical , Dose-Response Relationship, Drug , Drug Combinations , Drug Compounding , Emulsions , Ethanolamines/pharmacokinetics , Ethanolamines/toxicity , Female , Fluorenes/pharmacokinetics , Fluorenes/toxicity , Male , Mice , Rats , Rats, Wistar , TabletsABSTRACT
AIM: The low aqueous solubility of artemether and lumefantrine makes them less bioavailable. It is expected that by formulating self-microemulsifying drug-delivery systems (SMEDDS), their aqueous solubility and absorption will thus be enhanced. Results & methodology: Optimized liquid SMEDDS containing artemether and lumefantrine was adsorbed on Neusilin US2® employing spray drying technique to convert it into solid SMEDDS. Almost 90% of both drugs were released within 15 min in their respective official dissolution media. Drug assay and dissolution rate of solid SMEDDS remained unaltered after 3-month storage at 40°C and 75% relative humidity. CONCLUSION: Reconstitution of solid SMEDDS in water yielded microemulsion with a globule size of 67.74 nm. Complete and faster in vitro release of both drugs from solid SMEDDS was observed as compared with that from marketed tablets.
Subject(s)
Antimalarials/chemistry , Drug Delivery Systems , Administration, Oral , Antimalarials/administration & dosage , Biological Availability , Emulsions , Humans , Malaria/drug therapy , SolubilityABSTRACT
Excipients or formulation variables have often been exploited to improve stability, modify release, or improve physicochemical properties of dosage forms. In pharmaceutical field, it is generally expected that excipients work at macromolecular level where they might influence the crystal structure of a solid. These polymers/colloidal particles may modify the rate and direction of crystal growth. It has also been observed, that different polymorphic crystals exhibit different colors on exposure to same colorant, predominantly due to difference in surface pH of different crystal lattices. Apart from physicochemical affect, crystal habit also influences pharmacokinetic parameters of the dosage form. Crystals with smaller size or lower lattice energy have shown to exhibit higher bioavailability with faster rate of release.
Subject(s)
Chemistry, Pharmaceutical , Crystallization , Excipients/chemistry , Pharmacokinetics , Drug Liberation , Humans , Hydrophobic and Hydrophilic Interactions , Solvents/chemistry , TemperatureABSTRACT
The active pharmaceutical ingredient (API) of a dosage form is affected by number of mechanical and environmental factors which have a tendency to alter its crystalline state. Polymorphic transitions have been observed to occur during various unit operations like granulation, milling and compression. Forces of pressure, shear and temperature have an ability to induce alterations in crystal habit. A conversion in polymorphic form during a unit operation is very likely to affect the handling of API in the subsequent unit operation. Transitions have also been observed during storage of formulations where the relative humidity and temperature play a major role. An increase in temperature during storage can dehydrate or desolvate the crystal and hence produce crystal defects, whilst, high humidity conditions produce higher molecular mobility leading to either crystallization of API or alteration of its crystalline form.
Subject(s)
Pharmaceutical Preparations/chemistry , Chemistry, Pharmaceutical , Crystallization , Drug Stability , Drug Storage , Humidity , Pressure , Surface Properties , Technology, Pharmaceutical/methods , Temperature , Time Factors , Water/chemistryABSTRACT
Microemulsions are thermodynamically stable, optically transparent isotropic solutions of oil and water successfully formulated by using a combination of suitable surfactant and cosurfactant. The solubilization power of microemulsions for lipophilic, hydrophilic and amphiphilic solutes form a viable approach for enhancing the bioavailability of hydrophobic drugs and percutaneous permeation of poorly permeable drugs, mainly due to the large area per volume ratio available for mass transfer. Microemulsions have emerged as novel vehicles for drug delivery due to their versatile applications. They allow sustained release for topical, oral, nasal, intravenous, ocular, parenteral and other administration routes of drugs. They also offer a relevant application platform for improving target specificity, therapeutic activity, and reducing toxicity of drugs.
Subject(s)
Drug Delivery Systems/methods , Emulsions , Administration, Cutaneous , Administration, Intranasal , Administration, Intravaginal , Administration, Oral , Animals , Cosmetics , Drug Carriers , Humans , Infusions, Parenteral , Ophthalmic SolutionsABSTRACT
Microemulsions (MEs) are thermodynamically stable, optically transparent isotropic solutions of oil and water successfully formulated by using a combination of suitable surfactant and cosurfactant. While the selection of oil is based primarily on the solubility of drug in it, surfactant is generally selected on the basis of its hydrophilic-lipophilic balance value. MEs are characterized by ultra-low interfacial tension between the immiscible phases and offer the advantage of spontaneous formation, thermodynamic stability and ease of manufacture. The solubilization power of MEs for lipophilic, hydrophilic and amphiphilic solutes form a viable approach for enhancing bioavailability of hydrophobic drugs and percutaneous permeation of poorly permeable drugs, mainly due to the large area to volume ratio available for mass transfer.
