Naser Tavakoli

Introduction: Zaringiah (Dracocephalum kotschyi) is a famous Iranian herbal plant with anti-inflammatory and spasmolytic activities. There is no standard drug dosage form for the D. kotschyi extract on the market. The objective of this project was to design a suitable oral dosage form for the hydroalcoholic extract of D. kotschyi. Methods: Standard granules were prepared using the moist granulation technique. Physical properties of the granules were determined before filling the capsule with fixed doses of the drug (25 mg and 50 mg). Syrup was prepared in sucrose solution at 5 mg/mL concentration. Bioactivity and phytochemical assays were used for dosage form stability and uniformity evaluations before and after 3- and 6- months incubation. Pharmacological bioassay method was designed to determine the bioactivity of the products before and after incubation. Pharmacological effects of the prepared capsule and syrup were determined on rat isolated ileum and intestinal meal transit, respectively. Results: In this study, D. kotschyi extract was effectively formulated as capsule and syrup for oral consumption. Environmental and aging factors had no significant effect on the total flavonoid or phenolic contents or bioactivity of the manufactured products. Furthermore, the ingredients used in the formulation had no effect on the bioactivity of the active substances in the extract. Conclusion: The standard oral dosage forms prepared from D. kotschyi extract can be used for clinical trials. In addition, we introduced a reliable bioassay technique, which might be applied for the evaluation of herbal medicines with antispasmodic activities.

A dual pH- and time-dependent polymeric coated capsule was developed to achieve the site specificity of simvastatin (SIM) release in the colon. To improve the SIM solubility, soluplus-based nanosuspension of the drug were prepared by applying the anti-solvent crystallization technique; this was then followed by lyophilization. Particle size, polydispersity index, and saturation solubility were evaluated. The optimized nanosuspension was combined with SLS and freeze-dried before filling into hard gelatin capsules. Drug release characteristics of the coated capsules were studied in HCl 0.1 N, the phosphate buffers 6.8 and 7.4, and the simulated colonic fluid (pH 6.8). The in-vitro cytotoxic effects of SIM nanoparticles against HT29 cells were then evaluated using the MTT assay. The prepared nanoparticles were spherical with a mean size of 261.66 nm, the zeta potential of −18.20 and the dissolution efficiency of 59.71%. X-ray diffraction and differential scanning calorimetry studies showed that the nanosizing technique transformed the crystalline drug into the more soluble amorphous form. The coated capsules had no release in the gastric media, providing the specific delivery of SIM in the colon. The cytotoxic effect of the SIM nanoparticles was significantly increased, as compared to the free SIM. The findings, therefore, showed that the coated capsules using the two polymers of ethyl cellulose and Eudragit S100 could be suitable for the colon target delivery of SIM. Graphical Abstract

The objective of this study was to develop an in‐situ gel containing lorazepam (LZM) loaded nanostructured lipid carriers (NLCs) for direct nose‐to‐brain delivery in order to increase drug therapeutic efficacy in the treatment of epilepsy. Accordingly, LZM loaded NLCs were formulated using emulsification solvent diffusion and evaporation method; then the effects of the formulation variables on different physicochemical characteristics of NLCs were investigated. Thermosensitive in‐situ gels containing LZM‐NLCs were prepared using a combination of chitosan and β‐glycerol phosphate (β‐GP). The anticonvulsant efficacy of LZM‐NLCs‐Gel was then examined using the pentylenetetrazole (PTZ) model. The optimised NLCs were spherical, showing the particle size of 71.70 ± 5.16 nm and the zeta potential of −20.06 ± 2.70 mV. The pH and gelation time for the chitosan solution with 15% (w/v) β‐GP were determined to be 7.12 ± 0.03 and 5.33 ± 0.58 min, respectively. The in‐vivo findings showed that compared with the control group and the group that received LZM‐Gel, the occurrence of PTZ‐induced seizures in the rats was significantly reduced by LZM‐NLCs‐Gel after intranasal administration. These results, therefore, suggested that the LZM‐NLCs‐Gel system could have potential applications for brain targeting through nasal route and might increase LZM therapeutic efficacy in the treatment of epilepsy.

In the current study, floating dosage form containing acyclovir was developed to increase its oral bioavailability. Effervescent floating tablets containing 200 mg acyclovir were prepared by direct compression method with three different rate controlling polymers including Hydroxypropyl methylcellulose K4M, Carbapol 934, and Polyvinylpyrrolidone. Optimized formulation showed good floating properties and in vitro drug release characteristics with mean dissolution time and dissolution efficacy of about 4.76 h and 54.33%, respectively. X-ray radiography exhibited that the tablet would reside in the stomach for about 5 ± 0.7 h. After oral administration of floating tablet containing 200 mg acyclovir, the C_max, T_max, and AUC_0–∞ of optimized gastroretentive formulation were found to be 551 ± 141 ng/mL, 2.75 ± 0.25 h and 3761 ± 909.6 ng/mL/h, respectively.

Celecoxib is used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, joint inflammation and sport injuries. Long term administration of the drug results in such complications as gastrointestinaland renal disturbances and cardio-vascular complications. The main objective of the present study was to investigate the feasibility of delivering celecoxib incorporated in gel formulations by iontophoresis. Sodium alginate, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose (HPMC) and carbopol 934P were used to develop topical gel formulations of celecoxib. The gel formulations were evaluated for macroscopic and microscopic properties, pH determination, spreadability, rheological behaviour, and drug release characteristics both in vitro and ex vivo. Drug release was evaluated in the presence of iontophoresis field (0.1 to 0.5 mA/cm2) or without electrical current (passive diffusion) and celecoxib was measured spectrophotometrically at 252 nm. Most gel formulations showed acceptable physicochemical properties. Amongst formulations, gel formulation containing HPMC K4M which indicated greater performance in drug release behaviour was selected for further in vivo studies. The cumulative percent of drug released in vitro at the end of each experiment was 36%, 63%, and 89.7% for passive diffusion, direct electric current (DC) current density of 0.3 mA/cm2, and 0.5 mA/cm2, respectively. The findings of ex vivo drug transport across rat skin also showed a significantly higher release of celecoxib compared to passive flux for both AC and DC currents. A 0.5 mA/cm2 of DC current increased drug flux to 73% compared to 41.5% of passive diffusion. It can be concluded from the results of this study that the application of iontophoresis enhances the flux of celecoxib, as compared to the passive diffusion.

The purpose of the present study was to compare the stabilizing effect of four disaccharides alone or in combination on the lactoperoxidase (LP) derived from bovine milk during lyophilization. Sucrose, lactose, maltose, and trehalose at different concentrations (5-500 mM) were used to compare their protective effects on LP activity. The activity of lyophilized and native LP enzyme was evaluated using the procedure of Schindler with slight modifications. The antibacterial activity of the lyophilized enzyme against Pseudomonas aeroginosa, Escherichia coli, and Staphylococcus aureus was also investigated using the antimicrobial effectiveness test. Trehalose at concentration of 500 mM was the most effective cryoprotectant in protecting the enzyme activity. It preserved LP activity for 40 days, while the native enzyme lost its activity after 6 days. Combinations of disaccharides resulted in an increment in the stability of the enzyme, compared to the native enzyme. Combination of 200 mM trehalose and 200 mM sucrose were found most effective cryoprotectant in freeze-drying of LP. The lyophilized LP decreased the growth rate of Ps.aeroginosa, E.coli, and S.aureus between up to 30.8% in 106 cfu/ml and 53.3% in 105 cfu/ml. Antimicrobial efficacy of LP was more pronounced when 105 cfu/ml was used as compared to 106 cfu/ml.

The inflammation and pain associated with osteoarthritis are treated with nonsteroidal anti‐inflammatory drugs (NSAIDs). This treatment is accompanied by several side effects; therefore local intra articular (IA) NSAID injection can be more efficient and safe than systemic administration or topical use. In this study, alginate−chitosan−pluronic nanoparticles were considered as a new vehicle for IA meloxicam delivery. These novel nanoparticles were prepared using an ionotropic gelation method and were optimized for variables such as alginate to chitosan mass ratio, pluronic concentration, and meloxicam concentration using a 3‐factor in 3‐level Box‐Behnken design. To optimize the formulation, the dependent variables considered were particle size, zeta potential, entrapment efficiency, and mean dissolution time (MDT). The nanoparticles morphology was characterized by FESEM and AFM. The potential interactions of the drug‐polymers were investigated by ATR‐FTIR and DSC, and the delivery profile of meloxicam from the nanoparticles was obtained. The average particle size of the optimized nanoparticles was 283 nm, the zeta potential was −16.9 mV, the meloxicam entrapment efficiency was 55%, and the MDT was 8.9 hours. The cumulative released meloxicam amount from the composite nanoparticles was 85% at pH 7.4 within 96 h. The release profile showed an initial burst release followed by a sustained release phase. The release mechanism was non‐Fickian diffusion. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci.2015,132, 42241.

Buccal mucoadhesive systems among novel drug delivery systems have attracted great attention in recent years due to their ability to adhere and remain on the oral mucosa and to release their drug content gradually. Buccal mucoadhesive films can improve the drug therapeutic effect by enhancement of drug absorption through oral mucosa increasing the drug bioavailability via reducing the hepatic first pass effect. The aim of the current study was to formulate the drug as buccal bioadhesive film, which releases the drug at sufficient concentration with a sustain manner reducing the frequency of the dosage form administration. One of the advantagees of this formulation is better patient compliances due to the ease of administration with no water to swallow the product. The mucoadhesive films of glibenclamide were prepared using hydroxypropyl methylcellulose (HPMC) K4M, K15M and Eudragit RL100 polymers and propylene glycol as plasticizer and co-solvent. Films were prepared using solvent casting method, and were evaluated with regard to drug content, thickness, weight variations, swelling index, tensile strength, ex vivo adhesion force and percentage of in vitro drug release. Films with high concentrations of HPMC K4M and K15M did not have favorable appearance and uniformity. The formulations prepared from Eudragit were transparent, uniform, flexible, and without bubble. The highest and the lowest percentages of swelling were observed for the films containing HPMC K15M and Eudragit RL100, respectively. Films made of HPMC K15M had adhesion force higher than those containing Eudragit RL100. Formulations with Eudragit RL100 showed the highest mean dissolution time (MDT). Drug release kinetics of all formulations followed Higuchi's model and the mechanism of diffusion was considered non-Fickian type. It was concluded that formulations containing Eudragit RL100 were more favorable than others with regard to uniformity, flexibility, rate and percentage of drug release.

Glibenclamide (GLIB) is a poorly soluble drug with formulation-dependent bioavailability. Therefore, we attempted in this study to improve GLIB dissolution rate by preparing drug solid dispersions by solvent evaporation (SE) and supercritical fluid solvent-antisolvent techniques (SCF-SAS). A D-optimal mixture design was used to investigate the effects of different ratios of HPMCE5 (50-100%), PEG6000 (0-40%), and Poloxamer407 (0-20%) on drug dissolution from different solid dispersion (SD) formulations prepared by SE. The ratios of carriers used in SCF-SAS method were HPMCE5 (fixed at 60%), PEG6000 (20-40%), and Poloxamer407 (0-20%). A constant drug: carrier weight ratio of 1:10 was used in all experiments. The SDs obtained were physically characterized and subjected to the dissolution study. The major GLIB bands in FTIR spectra were indicative of drug integrity. The reduced intensity and the fewer number of peaks observed in X-ray diffractograms (XRD) of GLIB formulations was the indicative of at least partial transformation of crystalline to amorphous GLIB. This change and/or dilution of drug in much higher amounts of carriers present caused disappearance of distinctive endothermic peaks in differential scanning calorimetry thermograms of GLIB formulations. The model generated according to the results of the D-optimal mixture design indicated that GLIB formulations comprising HPMC (50%-60%), PEG (34-40%), and poloxamer (6-10%) had enhanced dissolution performances. As compared to SE method, the SCF-SAS technique produced formulations of higher dissolution performances, likely due to the effects of solution and the supercritical CO2 (SC-CO2) on enhanced plasticization of polymers and thus increased diffusion of the drug into the polymer matrix.

The pH‐sensitive poly(acrylamide‐co‐maleic acid)/montmorillonite (P(AAm‐MA)/MMT) nanocomposite hydrogels were synthesized through in situ polymerization. The chemical structure and morphology of nanocomposites were characterized by Fourier transform infrared spectroscopy, X‐ray diffraction, and transmission electron microscopy. The resulted disks were then loaded by caffeine, a moderately soluble model drug, using soaking method. The swelling and the drug release experiments were carried out in enzyme‐free simulated gastric and intestinal fluids. The release experiments showed that with the addition of MMT, the burst effect is well controlled, and the barrier property of nanocomposite hydrogels is improved. The effects of some compositional parameters including maleic acid to acrylamide (MA/AAm) molar ratio (MA_R), weight percent of MMT (MMT%), cross‐linker/AAm molar ratio (C_R), and also the influence of pH of medium on the equilibrium swelling ratio (Q) as well as caffeine release behavior of disks were studied by Taguchi method. The results indicated that shifting the pH value from 1.2 to 7.4 leads to a greater Q. The Q value and the release percentage (P%) increased with increasing the MA_R in the structure of disks at pH 7.4. The amounts of P% and Q in both external media decreased with increasing both MMT% and C_R. Mathematical behavior of release process was well represented by Peppas Power law model (at short times) and a two‐dimensional Fickian mass transfer model (at long times). The caffeine release behavior in both media was corresponded to the non‐Fickian transport mechanism.