Impact of formulation parameters on self-assembled liposomes (LeciPlex® III): A detailed investigation.

The present study investigated the feasibility of fabricating self-assembled liposomes, LeciPlex®, a phospholipid-based vesicular nanocarrier using cationic, anionic, and nonionic stabilizers. The phospholipid investigated was soy phosphatidylcholine and the nano-precipitation method based on solvent diffusion was applied as the fabrication technique of liposomes in this study. The effects of various formulation variables, such as lipid and stabilizer concentration, total solid concentration, and solvent type on the self-assembly of vesicles were studied for physical characterization including particle size analysis, differential scanning calorimetry, viscosity, optical transmittance, transmission electron microscopy, and small angle neutron scattering. All three LeciPlex® systems exhibited a direct relationship between particle size and phospholipid concentration. The two categoric variables, solvent, and stabilizer used to prepare LeciPlex® demonstrated a significant effect on particle size for all three LeciPlex® systems. Small angle neutron scattering, and optical transmittance confirmed the formation of micellar systems at a phospholipid: stabilizer ratio of 1:2 and vesicular systems at a ratio of 2:1 for the systems stabilized with anionic and nonionic surfactants. In contrast to this, the LeciPlex® formed with the cationic stabilizer Dioctadecyldimethylammonium bromide (DODAB), formed vesicles at both ratios. From these investigations, it was clear that the formulation space for LeciPlex® was diversified by the addition of cationic, anionic, and non-ionic stabilizers.

Antiproliferative and apoptotic potential of methotrexate lipid nanoparticles in a murine breast cancer model.

Aim: To evaluate the efficacy of novel methotrexate-loaded nanoparticles (MTX-NPs) in vitro and in vivo in the treatment of breast cancer. Materials & methods: MTX-NPs were tested for cellular uptake, cell viability, cell cycle, cellular wound migration and changes in tumor volume using characterized NPs. Results: The solid lipid NPs (SLNPs) showed strong cellular uptake, increased apoptosis, controlled cytotoxicity at lower IC50 of methotrexate and a sizable reduction in tumor burden. Conclusion: MTX-NP oral formulation can be a promising candidate in breast cancer treatment with improved cellular uptake and in vivo efficacy.

Investigation of pre-clinical pharmacokinetic parameters of atovaquone nanosuspension prepared using a pH-based precipitation method and its pharmacodynamic properties in a novel artemisinin combination.

OBJECTIVES: Recently, a growing resistance to antimalarial drugs such as chloroquine, sulfadoxine-pyrimethamine, artemisinin derivatives and mefloquine has been observed. The pharmacokinetic limitation of the current therapy and multi-drug resistance has resulted in an urgent need to study the new antimalarial combinations with existing drugs. This study investigated the activity of a novel triple combination of atovaquone (nanosized)-proguanil-artesunate as an alternative artemisinin combination therapy. Atovaquone in this combination was formulated as a freeze-dried nanosuspension and its pharmacokinetic parameters were also evaluated. METHODS: The suppressive and curative effect of atovaquone nanosuspension, proguanil, and artesunate were studied in a murine model. The in vivo pharmacokinetics of the newly developed atovaquone nanosuspension with particle size less than 200 nm was investigated. RESULTS: Prophylactic efficacy of atovaquone nanosuspension alone at 1/80th the therapeutic dose was proven. In the curative test, atovaquone nanosuspension and proguanil at 1/10th the therapeutic dose was the minimum effective dose that resulted in complete cure of parasitaemia. As a triple combination, atovaquone nanosuspension in combination with proguanil at 1/80th the therapeutic dose of each and 1/5th the therapeutic dose of artesunate resulted in a complete cure. The in vivo pharmacokinetics of the nanosuspension showed a significant (three times) reduction in Tmax value and the area under the curve of the nanosuspension was 1.9 times greater as compared with the plain suspension. CONCLUSIONS: The potential of the synergistic combination of atovaquone nanosuspension-proguanil-artesunate in curing the multi-drug resistant malarial infection at reduced doses of all three drugs could be a solution to pill burden observed with the current therapy.

pH-responsive dual pulse multiparticulate dosage form for treatment of rheumatoid arthritis.

BACKGROUND: Dual pulse multiparticulate systems may provide relief from circadian disorder rheumatoid arthritis. AIM: The aim of this study was to develop a pH-responsive dual pulse multiparticulate dosage form containing a model drug ketoprofen, a nonsteroidal anti-inflammatory drug used for rheumatoid arthritis. METHOD: The pellets were prepared by using extrusion-spheronization method and the core pellets were coated with a pH-sensitive poly(methyl) acrylate copolymer (Eudragit® L100-55, Eudragit® S100) to achieve site-specific drug release with a lag time. The formulated pellets were characterized for shape and size uniformity, friability, surface morphology studies, coating uniformity, and drug-excipient compatibility studies. In vitro dissolution test was used for comparison of drug release profiles of various coated pellets. RESULTS: The particle size of core and polymer-coated pellets was found to be in the range of 0.95-1.3 and 1.42-1.61 mm, respectively. The pellets were spherical in shape with smooth texture and uniformity in size. The dual pulse was aimed at release after a lag time of 2 and 5 hours. In vitro dissolution tests were carried out for the first and second dose pellets in a USP type II dissolution apparatus in media-simulating pH conditions of the gastrointestinal tract. The first dose release of the ketoprofen from the formulated pellets was established in pH 1.2 for a period of 2 hours, followed by pH 6.8. The second dose pellets were passed through pH 1.2, pH 6.8 followed by pH 7.5 for the rest of the study. CONCLUSION: The study concluded that the formulated multiparticulate dosage form of ketoprofen was able to relieve circadian symptoms of rheumatoid arthritis during midnight and early morning.

Advances in polymeric micelles for drug delivery and tumor targeting.

A plethora of formulation techniques have been reported in the literature for targeting drugs to specific sites. Polymeric micelles (PMs) can be targeted to tumor sites by passive as well as active mechanisms. Some inherent properties of PMs, including size in the nanorange, stability in plasma, longevity in vivo, and pathological characteristics of tumor allow PMs to be targeted to the tumor site by a passive mechanism called the enhanced permeability and retention effect. PMs formed from an amphiphilic block copolymer are suitable for encapsulation of poorly water-soluble, hydrophobic anticancer drugs. Other characteristics of PMs such as separate functionality at the outer shell are useful for targeting the anticancer drug to tumor by active mechanisms. PMs can be conjugated with many ligands such as antibody fragments, epidermal growth factors, α(2)-glycoprotein, transferrin, and folate to target micelles to cancer cells. Application of heat or ultrasound are the alternative methods to enhance drug accumulation in tumoral cells. Targeting using micelles can also be directed toward tumor angiogenesis, which is a potentially promising target for anticancer drugs. PMs have been used for the delivery of many anticancer agents in preclinical and clinical studies. This review summarizes recently available information regarding targeting of anticancer drugs to the tumor site using PMs.

Buccal drug delivery of pravastatin sodium.

The purpose of this study was to develop and optimize formulations of mucoadhesive bilayered buccal tablets of pravastatin sodium using carrageenan gum as the base matrix. The tablets were prepared by direct compression method. Polyvinyl pyrrolidone (PVP) K 30, Pluronic(R) F 127, and magnesium oxide were used to improve tablet properties. Magnesium stearate, talc, and lactose were used to aid the compression of tablets. The tablets were found to have good appearance, uniform thickness, diameter, weight, pH, and drug content. A 2(3) full factorial design was employed to study the effect of independent variables viz. levels of carrageenan gum, Pluronic F 127 and PVP K30, which significantly influenced characteristics like in vitro mucoadhesive strength, in vitro drug release, swelling index, and in vitro residence time. The tablet was coated with an impermeable backing layer of ethyl cellulose to ensure unidirectional drug release. Different penetration enhancers were tried to improve the permeation of pravastatin sodium through buccal mucosa. Formulation containing 1% sodium lauryl sulfate showed good permeation of pravastatin sodium through mucosa. Histopathological studies revealed no buccal mucosal damage. It can be concluded that buccal route can be one of the alternatives available for the administration of pravastatin sodium.

Mucoadhesive bilayered patches for administration of sumatriptan succinate.

The purpose of this study was to develop and optimize formulations of mucoadhesive bilayered buccal patches of sumatriptan succinate using chitosan as the base matrix. The patches were prepared by the solvent casting method. Gelatin and polyvinyl pyrrolidone (PVP) K30 were incorporated into the patches, to improve the film properties of the patches. The patches were found to be smooth in appearance, uniform in thickness, weight, and drug content; showed good mucoadhesive strength; and good folding endurance. A 3(2) full factorial design was employed to study the effect of independent variables viz. levels of chitosan and PVP K30, which significantly influenced characteristics like swelling index, in-vitro mucoadhesive strength, in vitro drug release, and in-vitro residence time. Different penetration enhancers were tried to improve the permeation of sumatriptan succinate through buccal mucosa. Formulation containing 3% dimethyl sulfoxide showed good permeation of sumatriptan succinate through mucosa. Histopathological studies revealed no buccal mucosal damage. It can be concluded that buccal route can be one of the alternatives available for administration of sumatriptan succinate.