Experimental Solubility, Thermodynamic/Computational Validations, and GastroPlus-Based In Silico Prediction for Subcutaneous Delivery of Rifampicin.

We focused to explore a suitable solvent for rifampicin (RIF) recommended for subcutaneous (sub-Q) delivery [ethylene glycol (EG), propylene glycol (PG), tween 20, polyethylene glycol-400 (PEG400), oleic acid (OA), N-methyl-2-pyrrolidone (NMP), cremophor-EL (CEL), ethyl oleate (EO), methanol, and glycerol] followed by computational validations and in-silico prediction using GastroPlus. The experimental solubility was conducted over temperature ranges T = 298.2-318.2 K) and fixed pressure (p = 0.1 MPa) followed by validation employing computational models (Apelblat, and van't Hoff). Moreover, the HSPiP solubility software provided the Hansen solubility parameters. At T = 318.2K, the estimated maximum solubility (in term of mole fraction) values of the drug were in order of NMP (11.9 × 10-2) ˃ methanol (6.8 × 10-2) ˃ PEG400 (4.8 × 10-2) ˃ tween 20 (3.4 × 10-2). The drug dissolution was endothermic process and entropy driven as evident from "apparent thermodynamic analysis". The activity coefficients confirmed facilitated RIF-NMP interactions for increased solubility among them. Eventually, GastroPlus predicted the impact of critical input parameters on major pharmacokinetics responses after sub-Q delivery as compared to oral delivery. Thus, NMP may be the best solvent for sub-Q delivery of RIF to treat skin tuberculosis (local and systemic) and cutaneous related disease at explored concentration.

Thermodynamic, Computational Solubility Parameters in Organic Solvents and In Silico GastroPlus Based Prediction of Ketoconazole.

The study aimed to select a suitable solvent capable to solubilize ketoconazole (KETO) and serve as a permeation enhancer across the skin. Experimental solubility and Hansen solubility parameters were obtained in ethanol, dimethyl sulfoxide (DMSO), ethylene glycol, oleic acid, span 80, limonene, eugenol, transcutol (THP), labrasol, and propylene glycol. Thermodynamic functional parameters and computational models (van't Hoff and Apelblat) validated the determined solubility in various solvents at T = 298.2 K to 318.2 K and P = 0.1 MPa. The HSPiP software estimated the solubility parameters in the solvents. The maximum mole fractional solubility values of KETO were found to be in an order as oleic acid (8.5 × 10-3) > limonene (7.3 × 10-3) > span 80 (6.9 × 10-2) > THP (4.9 × 10-2) > eugenol (4.5 × 10-3) at T = 318.2 K. The results of the apparent thermodynamic analysis confirmed that the dissolution rate was endothermic and entropy driven. The GastroPlus program predicted significantly high permeation of KETO (79.1%) in human skin from the KETO-THP construct as compared to drug solution (38%) and excellent immediate release from THP-solubilized construct (90% < 1 h). Hence, THP could be a better option for topical, transdermal, and oral formulation.

Solidified self nano-emulsifying drug delivery system of rosuvastatin calcium to treat diet-induced hyperlipidemia in rat: in vitro and in vivo evaluations.

The present work focuses on preparing a solidified self nano-emulsifying drug-delivery system (S-SNEDDS) to improve the in vitro dissolution of rosuvastatin and to evaluate its antihyperlipidemic activity. Powder flow characterization demonstrated good flow properties. The drug-excipient compatibility study indicates no possible interaction. Transmission electron microscopy and scanning electron microscopy revealed nonaggregated, spherical nanosized globules. The globule-size analysis revealed droplet size in nanorange (∼100 nm). S-SNEDDS exhibited improved drug release (∼95%) as compared with rosuvastatin powder (51.89%) at 60 min. Upon antihyperlipidemic study, S-SNEDDS after 14th day of treatment revealed significant reduction in cholesterol (33.47%), triglycerides (40.77%) and atherogenic index (81.28%), while high-density lipoprotein (118.43%) was increased. The study indicates the great potential of S-SNEDDS for improving oral absorption of such poorly soluble drugs and their pharmacodynamic efficacy.

Elastic liposome-based gel for topical delivery of 5-fluorouracil: in vitro and in vivo investigation.

OBJECTIVE: This investigation has focused to characterize the elastic liposome containing 5-fluorouracil (5-FU) and to enhance drug permeation across stratum corneum (SC) of the skin (rat) using various surfactants and in vivo dermal toxicity evaluation. METHODOLOGY: 5-FU-loaded elastic liposomes were developed, prepared and characterized for their entrapment efficiency, vesicle size, number of vesicles, morphological characteristics, surface charge and turbidity. In vitro drug release profile, in vitro skin permeation potential and in vitro hemolytic ability of the formulation have been evaluated to compare with drug solution for 24 h. In vitro skin permeation potential was also compared with marketed cream. Furthermore, in vivo skin irritation potential, drug penetration into the skin using confocal laser scanning microscopy (CLSM) and in vivo toxicity studies were performed. RESULTS AND CONCLUSIONS: The optimized elastic liposomes demonstrated maximum drug entrapment efficiency, optimum vesicular size and considerable elasticity. In vitro skin permeation studies showed the highest drug permeation flux like 77.07 ± 6.34, 89.74 ± 8.5 and 70.90 ± 9.6 µg/cm(2)/h for EL3-S60, EL3-S80 and EL3-T80, respectively, as compared to drug solution (8.958 ± 6.9 µg/cm(2)/h) and liposome (36.80 ± 6.4 µg/cm(2)/h). Drug deposition of optimized elastic liposome EL3-S80 was about three fold higher than drug solution. Skin irritation and CLSM studies suggested that optimized gel was free from skin irritation and capable to deliver 5-FU into the epidermal area for enhanced topical delivery than drug solution. The in vitro study showed minimum hemolysis in the optimized formulation. Finally, in vivo toxicity studies followed with hisptopathological assessment showed that elastic liposome was able to extract SC to improve drug permeation without changing general anatomy of the skin.

Enhanced stability and permeation potential of nanoemulsion containing sefsol-218 oil for topical delivery of amphotericin B.

AIM: To characterize the enhanced stability and permeation potential of amphotericin B nanoemulsion comprising sefsol-218 oil at varying pH and temperature of aqueous continuous phase. METHODOLOGY: Several batches of amphotericin B loaded nanoemulsion were prepared and evaluated for their physical and chemical stability at different pH and temperature. Also, a comparative study of ex vivo drug permeation across the albino rat skin was investigated with commercial Fungisome® and drug solution at 37 °C for 24 h. The extent of drug penetrated through the rat skin was thereby evaluated using the confocal laser scanning microscopy (CLSM). RESULTS AND CONCLUSIONS: The optimized nanoemulsion demonstrated the highest flux rate 17.85 ± 0.5 µg/cm(2)/h than drug solution (5.37 ± 0.01 µg/cm(2)/h) and Fungisome® (7.97 ± 0.01 µg/cm(2)/h). Ex vivo drug penetration mechanism from the developed formulations at pH 6.8 and pH 7.4 of aqueous phase pH using the CLSM revealed enhanced penetration. Ex vivo drug penetration studies of developed formulation comprising of CLSM revealed enhanced penetration in aqueous phase at pH 6.8 and 7.4. The aggregation behavior of nanoemulsion at both the pH was found to be minimum and non-nephrotoxic. The stability of amphotericin B was obtained in terms of pH, optical density, globular size, polydispersity index and zeta potential value at different temperature for 90 days. The slowest drug degradation was observed in aqueous phase at pH 7.4 with shelf life 20.03-folds higher when stored at 4 °C (3.8 years) and 5-fold higher at 25 °C (0.951 years) than at 40 °C. The combined results suggested that nanoemulsion may hold an alternative for enhanced and sustained topical delivery system for amphotericin B.

Cardioprotective effect of green tea extract on doxorubicin-induced cardiotoxicity in rats.

The in vivo antioxidant properties of green tea extract (GTE) were investigated against doxorubicin (DOX) induced cardiotoxicity in rats. In this experiment, 48 Wistar albino rats (200-250 g) were divided into eight groups (n = 6). Control group received normal saline for 30 days. Cardiotoxicity was induced by DOX (20 mg/kg ip.), once on 29th day of study and were treated with GTE (100, 200 and 400 mg/kg, p.o.) for 30 days. Aspartate aminotransferase (AST), creatinine kinase (CK), lactate dehydrogenase (LDH), lipid peroxidation (LPO), cytochrome P450 (CYP), blood glutathione, tissue glutathione, enzymatic and non-enzymatic antioxidants were evaluated along with histopathological studies. DOX treated rats showed a significant increased levels of AST, CK, LDH, LPO and CYP, which were restored by oral administration of GTE at doses 100, 200 and 400 mg/kg for 30 days. Moreover, GTE administration significantly increased the activities of glutathione peroxidase (GPX), glutathione reductase (GR), glutathione s-transferase (GST), superoxide dismutase (SOD) and catalase (CAT), in heart, which were reduced by DOX treatment. In this study, we have found that oral administration of GTE prevented DOX-induced cardiotoxicity by accelerating heart antioxidant defense mechanisms and down regulating the LPO levels to the normal levels.

Formulation by design of felodipine loaded liquid and solid self nanoemulsifying drug delivery systems using Box-Behnken design.

OBJECTIVE: To design and develop liquid and solid self-nanoemulsifying drug delivery systems (SNEDDS and S-SNEDDS) of felodipine (FLD) using Box-Behnken design (BBD). METHODS: Solubility study was carried out in various vehicles. Ternary phase diagram was constructed to delineate the boundaries of the nanoemulsion domain. The content of formulation variables, X1 (Acconon E), X2 (Cremophor EL) and X3 (Lutrol E300) were optimized by assessment of 15 formulations (as per BBD) for mean globule sizes in Millipore water (Y1), 0.1 N HCl (Y2), phosphate buffer (pH 6.4) (Y3); emulsification time (Y4) and T85% (Y5). The responses (Y1-Y5) were evaluated statistically by analysis of variance and response surface plots to obtain optimum points. The optimized formulations were solidified by adsorption to solid carrier technique using Aerosil 200 (AER). RESULTS AND DISCUSSION: Transmission electron microscopy images confirmed the spherical shape of globules with the size range concordant with the globule size analysis by dynamic light scattering technique (<60 nm). The surface morphology of S-SNEDDS (before release) by scanning electron microscopy and atomic force microscopy indicated that SNEDDS are adsorbed uniformly on the surface of AER. The dried residue of S-SNEDDS (after release) revealed the presence of nanometric pores vacated by the previously adsorbed SNEDDS onto AER. Differential scanning calorimetry and X-ray powder diffraction studies illustrated the change of FLD from crystalline to amorphous state. CONCLUSION: This study indicates that owing to nanosize, SNEDDS and S-SNEDDS of FLD have potential to enhance its absorption and may serve an efficient oral delivery.