Ezetimibe-Loaded Nanostructured Lipid Carrier for Oral Delivery: Response Surface Methodology; In Vitro Characterization and Assessing the Antihyperlipidemic Effect in Rats.

Among the independent risk factors for the occurrence of cardiovascular diseases like atherosclerosis is hyperlipidemia. To decrease cardiovascular events and patient mortality, antihyperlipidemia therapy is crucial. Our study aimed to enhance the solubility of the poorly soluble lipid-lowering agent ezetimibe (EZ), a member of class II as per the Biopharmaceutics Classification System (BCS). The drug was formulated as a nanostructured lipid carrier (NLC) employing the ultrasonication technique. A response surface D-optimal design was employed to study the effect of changing the liquid lipid type and the percentage of liquid lipid with respect to total lipid amount on the particle size, zeta potential, percentage entrapment efficiency, and percentage of drug released after 24 h. Nine NLC formulations were prepared and pharmaceutically evaluated, and the optimized NLC formulation was selected, further characterized, and evaluated as well. Optimized EZ-NLC was assessed in the high-fat diet model to induce hyperlipidemia in rats in comparison with the EZ suspension. The results of the optimized formulation showed that the prepared NLCs were spherical with no aggregation having a particle size of 204.3 ± 19.17 nm, zeta potential equal to -32 ± 7.59 mV, and entrapment efficiency of 81.5 ± 3.58% and 72.15 ± 4.58% drug released after 24 h. EZ-NLC significantly decreased the elevated serum lipid parameters, including total cholesterol, triglycerides, and LDL-C, but significantly normalized serum HDL-C levels of rats kept on a high-fat diet. The results demonstrated the improved efficacy of EZ-NLC in ameliorating the elevated serum lipid parameters compared to EZ.

Formulation and Characterization of Acetazolamide/Carvedilol Niosomal Gel for Glaucoma Treatment: In Vitro, and In Vivo Study.

Acetazolamide (ACZ) is a diuretic used in glaucoma treatment; it has many side effects. Carvedilol (CAR) is a non-cardioselective beta-blocker used in the treatment of elevated intraocular pressure; it is subjected to the first-pass metabolism and causes fluids accumulation leading to edema. This study focuses on overcoming previous side effects by using a topical formula of a combination of the two previous drugs. Sixty formulations of niosomes containing Span 20, Span 60, Tween 20, and Tween 60 with two different ratios were prepared and characterized. Formulation with the lowest particle size (416.30 ± 0.23), the highest zeta potential (72.04 ± 0.43 mv), and the highest apparent coefficient of corneal permeability (0.02 ± 0.29 cm/h) were selected. The selected formula was incorporated into the gel using factorial design 23. Niosomes (acetazolamide/carvedilol) consisting of Span 60 and cholesterol in the molar ratio (7:6), HMPC, and carbopol with two different ratios were used. The selected formula was subjected to an in vivo study of intraocular pressure in ocular hypertensive rabbits for 60 h. The sustained gel formula of the combination decreased (IOP) to normal after 1 h and sustained efficacy for 4 days. Histological analysis of rabbit eyeballs treated with the selected formula showed improvement in glaucomatous eye retinal atrophy.

Intranasal brain-targeted clonazepam polymeric micelles for immediate control of status epilepticus: in vitro optimization, ex vivo determination of cytotoxicity, in vivo biodistribution and pharmacodynamics studies.

Clonazepam (CZ) is an anti-epileptic drug used mainly in status epilepticus (SE). The drug belongs to Class II according to BCS classification with very limited solubility and high permeability and it suffers from extensive first-pass metabolism. The aim of the present study was to develop CZ-loaded polymeric micelles (PM) for direct brain delivery allowing immediate control of SE. PM were prepared via thin film hydration (TFH) technique adopting a central composite face-centered design (CCFD). The seventeen developed formulae were evaluated in terms of entrapment efficiency (EE), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and in vitro release. For evaluating the in vivo behavior of the optimized formula, both biodistrbution using 99mTc-radiolabeled CZ and pharmacodynamics studies were done in addition to ex vivo cytotoxicty. At a drug:Pluronic® P123:Pluronic® L121 ratio of 1:20:20 (PM7), a high EE, ZP, Q8h, and a low PDI was achieved. The biodistribution studies revealed that the optimized formula had significantly higher drug targeting efficiency (DTE = 242.3%), drug targeting index (DTI = 144.25), and nose-to-brain direct transport percentage (DTP = 99.30%) and a significant prolongation of protection from seizures in comparison to the intranasally administered solution with minor histopathological changes. The declared results reveal the ability of the developed PM to be a strong potential candidate for the emergency treatment of SE.

Novel non-ionic surfactant proniosomes for transdermal delivery of lacidipine: optimization using 2(3) factorial design and in vivo evaluation in rabbits.

CONTEXT: Proniosomes offer a versatile vesicle drug delivery concept with potential for delivery of drugs via transdermal route. OBJECTIVES: To develop proniosomal gel using cremophor RH 40 as non-ionic surfactant containing the antihypertensive drug lacidipine for transdermal delivery so as to avoid its extensive first pass metabolism and to improve its permeation through the skin. MATERIALS AND METHODS: Proniosomes containing 1% lacidipine were prepared by the coacervation phase separation method, characterized, and optimized using a 2(3) full factorial design to define the optimum conditions to produce proniosomes with high entrapment efficiency, minimal vesicle size, and high-percentage release efficiency. The amount of cholesterol (X1), the amount of soya lecithin (X2), and the amount of cremophor RH 40 (X3) were selected as three independent variables. RESULTS AND DISCUSSION: The system F4 was found to fulfill the maximum requisite of an optimum system because it had minimum vesicle size, maximum EE, maximum release efficiency, and maximum desirability. The optimized system (F4) was then converted to proniosomal gel using carbopol 940 (1% w/w). In vitro permeation through excised rabbit skin study revealed higher flux (6.48 ± 0.45) for lacidipine from the optimized proniosomal gel when compared with the corresponding emulgel (3.04 ± 0.13) mg/cm(2)/h. The optimized formulation was evaluated for its bioavailability compared with commercial product. Statistical analysis revealed significant increase in AUC (0 - α) 464.17 ± 113.15 ng h/ml compared with 209.02 ± 47.35 ng h/ml for commercial tablet. Skin irritancy and histopathological investigation of rat skin revealed its safety. CONCLUSIONS: Cremophor RH 40 proniosomal gel could be considered as very promising nanocarriers for transdermal delivery of lacidipine.