Drug Delivery Letters - Volume 6, Issue 2, 2016

Background and Objectives: The aim of present study was to prepare quetiapine fumarate (QF) loaded NE and mucoadhesive NE to enhance the uptake of QF to brain via intranasal (i.n.) delivery. Method: On the basis of solubility studies capmul MCM was selected as the oily phase. The NE was optimized using response surface methodology. A numerical optimization technique was employed to determine the optimal values of variables using desirability approach. Effect of independent variables [(Smix water ratio (X1), stirring speed (X2) and stirring time (X3)] on the dependent variables globule size (Y1) and in vitro drug release (Y2) was statistically optimized using 23 full factorial design. The optimized batch of NE and mucoadhesive NE was further characterized and evaluated by morphology, zeta sizer, zeta potential, viscosity, pH, transmittance, conductivity, drug content, in vitro release kinetics, ex-vivo permeation and in vivo biodistributionstudies. In order to investigate the localization of QF in brain and nose, qualitatively confocal laser scanning microscopy technique was carried out using coumarin-6 as a marker. Results: Globule size of formulation was antagonistically effected by the independendent variables, whereas the effect was synergistic on the in vitro drug release. The optimal calculated parameters were found to be Smix water ratio (60:25), stirring speed (1000 rpm) and stirring time (15 min). Conclusion: The results of the present investigation showed that QF can be given through intranasal route. This leads to increase in therapeutic effect with lower dose and reducing the side effects by decreasing the drug concentration in other organs. The formulation was free from nasal ciliotoxicity and a more than 14 folds increase in relative bioavailability of QF as compared to oral NE suggested that formulation provides a better mode of systemic delivery of QF.

Background: This research effort was aimed for the use of edible natural polymers from Dillenia indica and Bora rice for the preparation of palatable dry syrup containing bitter drugs Norfloxacin and Tinidazole for paediatric use. Methods: Bora rice flour and the mucilage extracted from Dillenia indica were characterised by UV and FTIR. They were also evaluated for safety. Norfloxacin-Tinidazole loaded microspheres were prepared using the natural polymers and were evaluated. The dry syrup for pediatrics was formulated and evaluated as per protocol. Results: The natural polymer extracted from Dillenia indica showed presence of pectin and the flour of Bora rice was found to be rich in amylopectin. Both polymers were found to be safe for use in paediatric groups. The release study performed on the microspheres exhibited the release of drugs in the intestine only and not in the stomach. The results of evaluation of the prepared dry syrup were also in conformity and the bitter taste of the drugs was masked. Conclusion: The results of this study demonstrated that the natural polymers from Dillenia indica and Assam Bora rice can be used as pharmaceutical excipient to mask the bitter taste of drugs and to prepare formulation of targeted drug delivery.

Background: Controlled transdermal delivery system for vildagliptin is potentially useful in improving the clinical efficacy and reducing the incidence of adverse side effects. The objective of this study was to develop an adhesive transdermal system for the delivery of vildagliptin. Methods: Vildagliptin-incorporated adhesive patches (P1-P10) were formulated on a polyester-release liner, and laminated with polyethylene-backing membrane. Optimization of the patches was done by conducting ex vivo permeation studies. The effects of varying the type of pressure-sensitive adhesive, drug concentration and chemical enhancer, on the flux was studied. Optimized patch (P8) was prepared with the use of Duro-Tak 87-2516 as pressure-sensitive adhesive, drug concentration of 10% (w/w) and isopropyl myristate as permeation enhancer. In vivo pharmacokinetic parameters were determined in male wistar rats for optimized and control patch and Tmax, Cmax and AUC0-α values were compared. Results: Tmax values were equal for the optimized patches and the control (6 h), while Cmax values was much higher for optimized patches. Vildagliptin was detected in the plasma in first hour of sampling. The AUC0-α value of the optimized patches was 147.5 ± 28.44 ng.h/ml, and this was ~5 folds higher relative to control. Conclusion: These results suggest that transdermal delivery system seems to be promising alternative method for the use of vildagliptin in the management of type 2 diabetes.

Background: Microwave assisted grafting of natural materials enables their use for specific drug delivery application. Microwave assisted reactions have numerous advantages like rapid reactions, improved yields, high purity products, simple, safe, efficient and ease of scale up. Methods: In the present study graft copolymers of n-vinyl-2-pyrrolidone and locust bean gum were prepared by microwave assisted graft copolymerization using ceric ammonium nitrate as redox initiator. The grafted procedure was optimized in terms of irradiation time, amount of initiator and n-vinyl-2- pyrrolidone by using constant amount of the gum. Characterization of the grafted gum was carried out by FTIR, XRD, DSC, elemental analysis and swelling studies. In vitro release behaviour of graft copolymer was comparatively evaluated with ungrafted gum by formulating the matrix tablets for colon specific delivery of budesonide. Results: Results of FTIR, XRD, DSC confirmed grafting of the gum. Elemental analysis of pure gum showed negligible amount of nitrogen in it (0.942%) but grafted gum showed good quantity of nitrogen content (2.48%), which confirmed the successful grafting of locust bean gum. The grafted gum was employed to prepare controlled release tablets of budesonide which were evaluated for colon specific drug delivery. Conclusion: Microwave assisted grafting of locust gum was performed successfully. The in vitro drug release revealed that the grafted gum has application for the development of colonic drug delivery system.

Background: Flunarizine Dihydrochloride (FDC) is used as a Prophylaxis to a migraine. It has solubility issues and it is practically insoluble in water and alcohol. FDC is widely prescribed for a migraine which is available in the form of tablets, and capsules. It is advantageous to deliver FDC as a nasal drug delivery system in the form of the nanoemulsion. Nanoemulsion increases the solubility of the poorly soluble drug as well as increases the transport of drug delivery through nasal mucosa by which it may offer quick onset of action. The high vasculation and permeability of nasal mucosal influence the drug absorption by which it can be easily accessible to blood capillaries then the therapeutic response may be faster which is desirable in migraine treatment. Methods: In this research, FDC Nanoemulsions were prepared by using IPM, β cyclodextrin, tween 80, polyethylene glycol, GMS and poloxamer 407. The prepared nanoemulsions were optimized by varying the concentration of surfactant, Co surfactant, IPM and GMS ratios. The best formulation was characterized by using XRD, Master Sizer, Zeta Sizer, and Zeta Potential. Further the prepared nanoemulsions were studied for in vitro drug release profile by using Simulated Nasal Fluid (SNF). The release profile was analyzed by suitable pharmacokinetic models. Results: The mean particle size of FN2 was found to be 242.3±211.8 as compared to FN4 which is larger 351.7±162.9. So it was demonstrated from the results that FN2 was found to be the best formulation with the lowest mean particle size with the diameter of 155.7 nm whereas FN4 got 288.4 nm size which is higher than FN2. The PDI was found to be less which is 0.317 for FN2 and 0.164 for FN4. The drug release profile was consistent and reproducible in in vitro studies conducted in SNF (simulated nasal fluid). Conclusion: The nanoemulsions shown the variation in particle size, % EE, in vitro dissolution profile. The prepared nanoemulsions increased the solubility of Flunarizinedihydrochloride as it is poorly soluble drug as well as the nanoemulsions can be delivered through the nose for better therapeutic action. The emusions were stable during the short term stability studies.

Purpose: The genetic makeup of each individual varies among each other and has changed the pharmacokinetics. Thus, pharmacokinetics of every region has variations, due to the changes in genetic expression of various genes. Allopurinol inhibited xanthine oxidase that declined the uric acid from body. The pattern for pharmacokinetics of allopurinol in Pakistani males was calculated and the bioequivalence was compared for two brands of allopurinol drug. Tab. Zyloric® 300 mg, GlaxoSmith- Kline, Karachi, Pakistan was used as reference drug and Tab. Zynol® 300 mg, Pharmedic Laboratories, Lahore, Pakistan was utilized as a test drug. Method: A single dose per period, crossover, open label, two period study was conducted on 08 healthy adult volunteers. Sampling comprised of two study periods, each was separated by interval of 1 week. Volunteers received a single oral dose of allopurinol 300 mg on sampling day. Blood was collected at 0, 0.5, 1.0, 1.5, 2, 2.5, 3, 4, 5 and 6 hours of dose administration and blood sampling was analyzed by the HPLC method. Results and Conclusion: The calculation of volume of distribution, elimination half life, clearance, maximum concentration of drug, time required to achieve maximum concentration, area under curve and mean residence time was determined by using pharmacokinetics software (APO). The observed Cmax was 2.44 μg/ml and Tmax was calculated to be 1.33 hr, respectively. AUC calculated by trapezoidal rule was 8.62 h.μg/ml. Vd was known to be 1.32 L/kg. Clearance was amounted at 0.45 L/hr. 2.88 hr was found to be mean residence time of allopurinol inside the body. Upon calculation of bioequivalence parameters, it was sorted out that AUC (8.62:8.74 h.μg/ml; Zyloric Vs Zynol) Cmax (2.44:2.50 h.μg/ml; Zyloric Vs Zynol) and Tmax (1.33:1.35 h.μg/ml; Zyloric Vs Zynol) were found to be in FDA determined bioequivalence criteria. Allopurinol, oxypurinol and allopurinol riboside showed maximum binding affinity with Xanthine Oxidoreductase. Docking analyses elucidated that Ser-425, Lys-433, Gly-502, Met-504, Leu-1209, Glu-1210, Glu-1211, His-1213, Thr-1227, Thr-1228, Lys-1229, Thr- 1302, Thr-1329 are critical residues for ligand-receptor interactions.

Background: Previously, we demonstrated a similar adsorption of the vaccine candidate TERAVAC against HIV-1 to the aluminum hydroxide and aluminum phosphate adjuvants but the subcutaneous administration with aluminum hydroxide promoted a better Th1 response than the aluminum phosphate. Objective: The present study examined whether a differential three-dimensional (3D) adsorption of the multiantigenic formulation TERAVAC to these adjuvants has an impact on the generation of IgG antibodies against the gp120 protein. Methods: Groups of mice were subcutaneously inoculated with TERAVAC adjuvated with aluminum hydroxide or aluminum phosphate hydrated gels. At the end of the schedule of immunization sera from animals were collected and the recognition of HIV antigens assessed by western blot. Results: We found that subcutaneous immunization of TERAVAC with aluminum hydroxide, and not with aluminum phosphate, stimulated a gp120-specific IgG response. A possible explanation for this finding is discussed. Conclusion: This result revealed a previously unappreciated difference when the multiantigenic formulation TERAVAC is inoculated with these adjuvants. Taken together, this finding and previous studies suggest that selection of the best aluminum-containing adjuvant for mixtures of antigens must be based on experimental evidences.

Background: Tamoxifen (TMX) has been in clinical use for over 40 years and can be considered the standard for breast cancer chemoprevention in high-risk patients. Unfortunately, patient compliance to treatment is low due to systemic toxicity. Objective: The present study demonstrates the use of a nanochannel Delivery System (nDS) for controlled and sustained local release of TMX in mammary tissue. Method: TMX release in vitro from the nDS was assessed using two different concentrations of the solubilizer PEG400. The optimal configuration was then studied in 9-week old NMU-treated Sprague Dawley rats, and the release profile of TMX analyzed with LC-MS/MS. Systemic and organ toxicity was evaluated. Results: Although highly water insoluble, we showed that through utilization of PEG400, we were able to sustain the release of TMX in vitro for 2 months. In vivo, we released TMX from nDS implants and reached relevant plasma concentrations (>50 ng/ml). Our study showed sustained low dose delivery of TMX over several months from the implant placed adjacent to the mammary gland, thereby minimizing whole-body exposure and associated side effects. Compared to the oral TMX treated group, the nDSTMX group maintained higher body weight and showed lower uterine weight. Compared to the sham group, TMX treatment reduced the number of mammary gland aggregates without affecting liver weight. Conclusion: We demonstrate that the nDS is a valid technology for long-term delivery of TMX. Additional tests are required to prove if the nDS is applicable for breast cancer prevention to offer an avenue to reduce the incidence of estrogen sensitive breast cancer.