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The aim of this work is to develop and evaluate self-nanoemulsifying drug delivery systems (SNEDDS) containing simvastatin to increase its oral bioavailability. Formulation EO 5 (Ethyl oleate 9.3% w/w: Tween 80 49.4% w/w: Propylene glycol 39.3% w/w) and Formulation CL 14 (Clove oil 54.3% w/w: Tween 80 34.4% w/w: Transcutol-P 9.3% w/w) were thoroughly studied. They showed emulsification time less than 1 min, droplet size in the nanometric range, and almost a complete drug release after 2 h. The in-vitro dissolution profile of both formulations was found to be significant in comparison to the pure drug in pH 1.2 and 7.4 buffers (P < 0.0001). Furthermore, they demonstrated superior anti-hyperlipidemic activity in comparison to simvastatin suspension (10 mg/kg/day). In order to investigate the impact of oil type on oral bioavailability, the selected formulations have been examined in terms of the in-vivo pharmacokinetic study, and formulation EO 5 was found to have higher bioavailability. After oral administration of a single dose (40 mg/kg) of simvastatin-loaded SNEDDS (CL14 and EO 5), a 1.5-fold and 1.95-fold increase in bioavailability were observed, respectively, as compared to simvastatin suspension. Hence, the results indicated that the developed SNEDDS could enhance the therapeutic efficacy and oral bioavailability of simvastatin. [ABSTRACT FROM AUTHOR]

Luteolin (LN), is an herbal bioactive flavone and exhibits many pharmacological activities. However, the bioavailability of LN is limited due to its inadequate solubility and significant first-pass metabolism. The present study developed transdermal LN-loaded invasomes (IVM) gel to improve the therapeutic efficacy. The LN-IVM was prepared and optimized by 2³ factorial designs. LN-IVM was characterized for physicochemical parameters. The optimized LN-IVM (LN-IVMopt) was incorporated into HPMC-K4M gel and evaluated for viscosity, spreadability, and irritation. Further LN-IVM gel was evaluated for drug release, ex-vivo permeation, pharmacokinetic and pharmacodynamics study. LN-IVMopt showed 300.8±2.67 nm of VS, 0.258 of PDI, 89.92±1.29% of EE, and a zeta potential of -18.2 mV. LN-IVM exhibited spherical morphology. FTIR and XRD results demonstrated that LN was encapsulated into IVM matrix. The optimized IVM gel (LN-IVMoptG2) exhibited excellent viscosity, spreadability, and sustained release of LN (91.32±2.95% in 24 h). LN-IVMoptG2 exhibited statistically significant (p < 0.05) higher flux (5.79 µg/h/cm²) than LN-gel (2.09 µg/h/cm²). The apparent permeability coefficient of plain LN gel and LN- IVMoptG was 1.15X10-5 cm/min and 3.22x10-5 cm/min respectively. LN-IVMoptG2 showed no irritation (score 0.0) throughout the study (60 min). The relative bioavailability of LN from LN-IVMopt-G2 (transdermal) was 2.38±0.19 fold as compared to LN-Sus (oral) and 1.81±0.15-fold than plain LN-gel (transdermal). The LN-IVMoptG2 showed a substantial lessening in the paw volume up to 12 h (17.48±1.94% swelling) than plain LN-gel (44.77±2.82% swelling). The finding concluded that the IVM gel is a novel, effective, and safe approach for the delivery of LN transdermally to improve its therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Olmesartan medoxomil (OLM) is a first-line antihypertensive drug with low oral bioavailability (28.6%). This study aimed to develop oleogel formulations to decrease OLM side effects and boost its therapeutic efficacy and bioavailability. OLM oleogel formulations were composed of Tween 20, Aerosil 200, and lavender oil. A central composite response surface design chose the optimized formulation, containing Oil/Surfactant (SAA) ratio of 1:1 and Aerosil % of 10.55%, after showing the lowest firmness and compressibility, and the highest viscosity, adhesiveness, and bioadhesive properties (Fmax and Wad). The optimized oleogel increased OLM release by 4.21 and 4.97 folds than the drug suspension and gel, respectively. The optimized oleogel formulation increased OLM permeation by 5.62 and 7.23 folds than the drug suspension and gel, respectively. The pharmacodynamic study revealed the superiority of the optimized formulation in maintaining normal blood pressure and heart rate for 24 h. The biochemical analysis revealed that the optimized oleogel achieved the best serum electrolyte balance profile, preventing OLM-induced tachycardia. The pharmacokinetic study showed that the optimized oleogel increased OLM's bioavailability by more than 4.5- and 2.5-folds compared to the standard gel and the oral market tablet, respectively. These results confirmed the success of oleogel formulations in the transdermal delivery of OLM. [ABSTRACT FROM AUTHOR]

In the present research study, we formulate bilosomes (BMs) of diclofenac (DC) for oral delivery for enhancement of therapeutic efficacy (anti-inflammatory disease). The BMS were prepared by thin film hydration method and optimized by Box–Behnken design (BBD) using cholesterol (A), lipid (B), surfactant (C), and bile salt (D) as formulation factors. Their effects were evaluated on vesicle size (Y1) and entrapment efficacy (Y2). The optimized DC-BMs-opt showed a vesicle size of 270.21 ± 3.76 nm, PDI of 0.265 ± 0.03, and entrapment efficiency of 79.01 ± 2.54%. DSC study result revealed that DC-BMs-opt exhibited complete entrapment of DC in BM matrix. It also depicted significant enhancement (p < 0.05) in release (91.82 ± 4.65%) as compared to pure DC (36.32 ± 4.23%) and DC-liposomes (74.54 ± 4.76%). A higher apparent permeability coefficient (2.08 × 10−3 cm/s) was also achieved compared to pure DC (6.6 × 10−4 cm/s) and DC-liposomes (1.33 × 10−3 cm/s). A 5.21-fold and 1.43-fold enhancement in relative bioavailability was found relative to pure DC and DC liposomes (DC-LP). The anti-inflammatory activity result showed a significant (p < 0.05) reduction of paw edema swelling compared to pure DC and DC-LP. Our findings revealed that encapsulation of DC in BMs matrix is a good alternative for improvement of therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Due to poor bioavailability and chemical instability, the effectiveness of curcumin is negligible in the treatment of numerous diseases. Solid lipid nanoparticles (SLNs) increase the bioavailability of lipophilic compounds and protect the drug from gastrointestinal degradation. The objective of our study is the utilization of SLNs to improve the pharmacokinetics and pharmacodynamics of curcumin in the management of diabetes mellitus. Central composite design was used to prepare curcumin-loaded SLNs (Cur-SLN). The analysis of independent variables like drug concentration, lipid concentration, and surfactant concentration was carried out using analysis of variance (ANOVA) to obtain the optimized batch (optimized Cur-SLN) having the desired values of dependent variables particle size and entrapment efficiency. In vitro release, differential scanning calorimeter (DSC), transmission electron microscopy (TEM), and Fourier Transform Infra-Red (FTIR) studies of optimized Cur-SLN were carried out and then its pharmacokinetic and pharmacodynamic studies were performed. The model was found to be significant for particle size and entrapment efficiency based on F-value and p-value. The optimized batch's predicted values were in close agreement with the actual values of particle size and entrapment efficiency. TEM results confirm mono-dispersion and spherical shape of particles in the formulation. The DSC results confirmed the changing of drug from crystalline to amorphous form. Burst release followed by the sustained release was obtained in the in vitro release studies. The pharmacokinetic study shows enhanced bioavailability of optimized Cur-SLN compared with a plain drug suspension. The optimized Cur-SLN achieved higher antidiabetic activity in streptozotocin-induced diabetes mellitus rats than the plain drug suspension. SLNs can be used as a promising technique for delivering curcumin in the management of diabetes mellitus. [ABSTRACT FROM AUTHOR]

During the last decades, much attention has been focused on SNEDDS approach to resolve concerns of BCS II class drugs with accentuation on upgrading the solubility and bioavailability. The present hypothesis confirms the theory that SNEDDS can reduce the impact of food on Candesartan solubilization, thereby offering the potential for improved oral delivery without co-administration with meals. The present studies describe quality-by-design-based development and characterization of Candesartan loaded SNEDDS for improving its pharmacodynamic potential. D-optimal mixture design was used for systematic optimization of SNEDDS, which showed globule size of 13.91 nm, more rapid drug release rate of >90% in 30 min and 16 s for self-emulsification. The optimized formulations were extensively evaluated, where an in vitro drug release study indicated up to 1.99- and 1.10-fold enhancement in dissolution rate from SNEDDS over pure drug and marketed tablet. In vivo pharmacodynamic investigation also showed superior antihypertensive potential of SNEDDS in normalizing serum lipid levels as compared to pure drug and marketed tablet that was executed on male Wistar rats. Overall, this paper reports successful systematic development of candesartan-loaded SNEDDS with distinctly improved biopharmaceutical performance. This research work interpreted a major role of SNEDDS for enhancing the rate of dissolution and bioavailability of poorly water soluble drugs. [ABSTRACT FROM AUTHOR]

This investigation aimed to design, develop, and optimize intranasal nanoemulsion for brain targeted delivery of lurasidone hydrochloride for the management and treatment of schizophrenia. The design of experiment supported optimization of high-pressure homogenization (HPH) process was executed for the manufacturing of lurasidone loaded nanoemulsion. The nanoemulsion comprising of lurasidone hydrochloride (10 mg/mL), 20% Oilmix, 25% surfactant and, 55% aqueous phase (w/w) was processed with HPH at optimized conditions to get droplet size in the nano range. The droplet size of optimized nanoemulsion was found to be 48.07 ± 3.29 nm with a polydispersity index of 0.31 ± 0.01. The optimized translucent nanoemulsion (% transmittance of 88.56 ± 2.47) was found to be non-toxic to sheep nasal mucosa and stable for six months. The results of ex vivo diffusion study revealed the improvement in drug diffused by mucoadhesive nanoemulsion (MLNE) (1.41 × 10−4 ± 1.11 × 10−5 cm2/min) as compared to the solution (1.15 × 10−4 ± 1.35 × 10−5 cm2/min). The results of pharmacodynamic studies in mice uncover the highest inhibition of compulsive behavior (64.63%) and spontaneous locomotor activity (60.87%) shown by MLNE. This may be due to increased bioavailability in a brain, and possibly confirms the potential of nanoemulsion in targeting the brain through nasal route in the treatment of schizophrenia. [ABSTRACT FROM AUTHOR]

Purpose: Etoposide is one of the principal chemotherapeutic agents used for the treatment of small cell lung cancer (SCLC). There are some disadvantages of currently available etoposide injections (EI) such as low LD50, necessary dilution before clinical application, thus, etoposide lipid emulsion (ELE) was developed and expected to have a comparable or better effect on SCLC. Methods: ELE was prepared through high-pressure homogenization method, and a series of evaluations such as encapsulation efficiency (EE%), in vitro release, stability studies, pharmacokinetics study, safety assessment and pharmacodynamic study were systematically performed. Results: ELE had high EE% and good stability. Pharmacokinetics study revealed ELE had a longer T1/2 F compared with EI, which is in agreement with in vitro release in which ELE released slower than EI (EI released over 80% within 12 h, while ELE released 50%). Safety tests showed there was no hematology or significant tendency of accumulated toxicity, and LD50 of ELE was higher than EI. Furthermore, percentage of tumor inhibition (TI%) of ELE was comparable with EI in the same dose. Conclusions: Unlike EI, ELE could further increase the dose, which endowed etoposide with a greater potential for cytotoxic agent. LE is a promising delivery system for etoposide. [ABSTRACT FROM AUTHOR]

the aim of the present research work was to formulate and evaluate colon targeted pellets of lornoxicam for the pain management of rheumatoid arthritis. the product and process parameters were optimized by screening methods. Pellets were prepared by extrusion spheronization method using microcrystalline cellulose (MCC) as spheronizing aid and ethyl cellulose (EC) as controlled release polymer, in different ratios. Based on the physical appearance, sphericity and % in vitro drug release, batch B17 containing EC: MCC (6:4) was optimized for core pellets. the site specificity was obtained by screening Eudragit FS30D and Eudragit S100 as coating polymers and the core pellets were coated with Eudragit S100. the batch C4 (6%) showed appropriate physical appearance and % in vitro drug release upto 24 h, indicating controlled release property. the pharmacodynamic studies performed on rat model indicated the anti-inflammatory activity of pellet formulation. thus, it is concluded that the coated pellets can be a good candidate for site specific delivery of lornoxicam to colon by decreasing the gastric irritation, reducing dose frequency and improving patient compliance. [ABSTRACT FROM AUTHOR]

Purpose: Triple solid dispersion adsorbates (TSDads) and spherical agglomerates (SA) present new techniques that extensively enhance dissolution of poorly soluble drugs. The aim of the present study is to hasten the onset of hypoglycemic effect of glimepiride through enhancing its rate of release from tablet formulation prepared from either technique. Methods: Drug release from TSDads or SA tablets with different added excipients was explored. Scanning electron microscopy (SEM) and effect of compression on dissolution were illustrated. Pharmacodynamic evaluation was performed on optimized tablets. Results: TSDads & SA tablets with Cross Povidone showed least disintegration times of 1.48 and 0.5 min. respectively. Kinetics of drug release recorded least half-lives (54.13 and 59.83min for both techniques respectively). Cross section in tablets displayed an organized interconnected matrix under SEM, accounting for the rapid access of dissolution media to the tablet core. Components of tablets filled into capsules showed a similar release profile to that of tablets after compression as indicated by similarity factor. The onset time of maximum reduction in blood glucose in male albino rabbits was hastened to 2h instead of 3h for commercial tablets. Conclusion: After optimization of tablet excipients that interacted differently with respect to their effect on drug release, we could conclude that both amorphisation and spheronization were equally successful in promoting in vitro dissolution enhancement as well as providing a more rapid onset time for drug action in vivo. [ABSTRACT FROM AUTHOR]

Objective: The objective of present study was to develop and evaluate paliperidone (PALI) loaded microemulsion (PALI-ME) for intranasal delivery in the treatment of schizophrenia. Material and methods: The PALI-ME was formulated by the spontaneous microemulsification method and characterized for physicochemical parameters. Pharmacodynamic assessments (apomorphine-induced compulsive behavior and spontaneous motor activity) were performed using mice. All formulations were tagged with99mTc (technetium). Pharmacokinetic evaluation of PALI in the brain was investigated using Swiss albino rats. Brain scintigraphy imaging was performed in rabbits. Results and discussion: PALI-ME was found stable with average droplet size of 20.01 ± 1.28 nm. In pharmacodynamic studies, significant (p < 0.05) deference in parameters estimated, were found between the treated and control groups.99mTc-tagged PALI solution (PALI-SOL)/PALI-ME/PALI muco-adhesive ME (PALI-MME) was found to be stable and suitable forin vivostudies. Brain-to-blood ratio at all sampling points up to 8 h following intranasal administration of PALI-MME compared to intravenous PALI-ME was found to be 6–8 times higher signifying greater extent of distribution of the PALI in brain. Rabbit brain scintigraphy demonstrated higher intranasal uptake of the PALI into the brain. Conclusion: This investigation demonstrates a prompt and larger extent of transport of PALI into the brain through intranasal PALI-MME, which may prove beneficial for treatment of schizophrenia. [ABSTRACT FROM AUTHOR]

The objective of this study was to develop and evaluate olanzapine (OZP) -loaded microemulsions (OZPME) for intranasal delivery in the treatment of schizophrenia. The OZPME was formulated by the spontaneous microemulsification method and characterized for physicochemical parameters. Pharmacodynamic assessments (apomorphine – induced compulsive behavior and spontaneous locomotor activity) were performed using mice. All formulations were radiolabeled with technetium-99 (99mTc), and biodistribution of drug in the brain was investigated using Swiss albino rats. Brain scintigraphy imaging in rabbits was performed to determine the uptake of the OZP into the brain. OZPME were found clear and stable with average globule size of 23.87 ± 1.07 nm. In pharmacodynamic assessments, significant (p < 0.05) difference in parameters estimated were found between the treated and control groups.99mTc-labeled OZP solution (OZPS)/OZPME/OZP mucoadhesive microemulsion (OZPMME) were found to be stable and suitable forin vivostudies. Brain/blood ratio at all sampling points up to 8 h following intranasal administration of OZPMME compared to intravenous OZPME was found to be five to six times higher signifying larger extent of distribution of the OZP in brain. Drug targeting efficiency and direct drug transport were found to be highest for intranasal OZPMME, compared to intravenous OZPME. Furthermore, rabbit brain scintigraphy also demonstrated higher intranasal uptake of the OZP into the brain. This investigation demonstrates a prompt and larger extent of transport of OZP into the brain through intranasal OZPMME, which may prove beneficial for treatment of schizophrenia. [ABSTRACT FROM AUTHOR]

The aim of the present research work was to investigate the potential of polyamidoamine (PAMAM) dendrimers as oral drug delivery carriers for quercetin, a Biopharmaceutical Classification System (BCS) class II molecule. The aqueous solubility of quercetin was investigated in different generations of dendrimers, i.e. G0, G1, G2 and G3, with varying concentrations (0.1, 0.5, 1, 2 and 4 µM). Then, it was successfully incorporated in PAMAM dendrimers and they were characterized for incorporation efficacy, nature of nanoformulations, size, size distribution, surface morphology and stability.In vitrorelease characteristics of quercetin from all quercetin-PAMAM complexes were studied at 37 °C in phosphate buffer saline (PBS; pH 7.4). Furthermore, the efficacy of quercetin-loaded PAMAM dendrimer was assessed by pharmacodynamic experiment, namely, a carrageenan-induced paw edema model to evaluate the acute activity of this nanocarrier in response to inflammation. It was observed that both generation and the respective concentrations of PAMAM dendrimers showed potential positive effects on solubility enhancement of quercetin. All the quercetin-PAMAM complexes were found to be in nanometeric range (<100 nm) with narrow polydispersity index.In vitrostudy revealed a biphasic release pattern of quercetin which was characterized by an initial faster release followed by sustained release phase and pharmacodynamic study provided the preliminary proof of concept about the potential of quercetin-PAMAM complexes. The study concludes that the dendrimer-based drug delivery system for quercetin has enormous potential to resolve the drug delivery issues associated with it. [ABSTRACT FROM AUTHOR]

Context: Skin cancer has turned into global epidemic leading to higher incidences among cancer stricken population. Objective: The aim of the present investigation is to evaluate the anticancer potential and intracellular uptake of a novel nanovesicular formulation of 5-FU. Materials and methods: Detailed intracellular uptake study in conjunction with estimation of intracellular reactive oxygen species was done using skin melanoma cell lines (A375) along with cytotoxicity studies. To further obtain the mechanistic insights into inhibition of tumor cell proliferation, cell-cycle arrest studies were conducted. The preclinical anticancer activity was carried out employing in vivo DMBA-croton oil-induced skin cancer model in mice. Results and discussion: Significant reduction in the number of papillomas was observed in skin cancer-bearing mice on treatment with nanovesicular formulation (51.4 ± 3.2%) in comparison with marketed formulation (21.3 ± 2.1%) of 5-FU. Tumor volume was found to be reduced to 46.3 ± 3.5% with prepared formulation, whereas the marketed formulation-treated group showed the reduction of 18.6 ± 1.8% in comparison with the control (untreated) group. Conclusion: The results of present study demonstrated that nanovesicular formulation of 5-FU possessed the enhanced anticancer activity which could be attributed to better intracellular uptake, cellular retention, and sustained release of drug. [ABSTRACT FROM AUTHOR]

Background Low basal lower esophageal sphincter ( LES) pressure and transient LES relaxations are major causes of gastroesophageal reflux disease ( GERD). Pumosetrag, a novel selective partial 5 HT3 receptor agonist, showed a promising effect on reducing reflux events in health. We aimed to evaluate the effect of pumosetrag on changes in reflux episodes, lower esophageal sphincter pressure ( LESP), and specific symptoms in patients with GERD receiving a refluxogenic meal. Methods Patients with GERD, who developed heartburn and/or regurgitation after ingestion of a refluxogenic meal, were randomized to 1 of 3 dose levels of pumosetrag (0.2, 0.5, or 0.8 mg) or placebo. Before and after 7 days of treatment, patients underwent manometry, intraesophageal multichannel, intraluminal impedance and pH after a standard refluxogenic meal. Key Results A total of 223 patients with GERD [125 (56%) women, mean (SD) age = 36 (12) years] were enrolled. No overall treatment effects were detected for the total number of reflux episodes (acidic and weakly acidic) (p > 0.5); however, significant treatment effects (p < 0.05) on the number of acid reflux episodes were observed with lower values on pumosetrag 0.2 mg (10.8 ± 1.1), 0.5 mg (9.5 ± 1.1), and 0.8 mg (9.9 ± 1.1) compared with placebo (13.3 ± 1.1). Significant treatment effects (p < 0.05) were also observed for the percentage of time pH was <4, with less time for pumosetrag at 0.5 mg (10%) and 0.8 mg (10%) compared with placebo (16%). Conclusions & Inferences In GERD, the partial 5 HT3 agonist pumosetrag significantly reduced the rate of acid reflux events but did not result in a significant change in LESP or symptomatic improvement over a 1-week treatment period. [ABSTRACT FROM AUTHOR]