Current Drug Delivery (v.9, #5)

The objective of present project was to improve the dissolution profile of gliclazide by developing floating alginate beads using various biodegradable polymers like gelatin, pectin and hydroxypropylmethylcellulose (HPMC). The floating beads were prepared by a simple ionotropic gelatin method using calcium carbonate as gas generating agent. The developed beads were characterized by Fourier transform infrared spectroscopy analysis, differential scanning calorimetry, X-ray diffraction analysis and scanning electron microscopy (SEM). The prepared beads showed good in vitro floatation, which was dependent on the concentration of gas-forming agent. SEM photomicrographs confirmed that the developed beads were spherical in shape and had particle size in the range of 730 to 890 &#x3BC;m. The incorporation efficiency was found to be in the range of 59.96 to 85.1%. The cumulative percent drug release from the beads after 10 h dissolution study at pH 1.2 and pH 5.8 was in the range of 33 to 46% and 82 to 95% respectively. The concentration of the gas generating agent was found to influence the release rate. The mechanism of drug release was Fickian diffusion with swelling. The in vivo sub-acute hypoglycemic study in high fat diet induced diabetic C57BL/6J mice demonstrated significant (p < 0.05) hypoglycemic effect over a period of 12 h and 24 h, respectively, with HPMC and pectin beads. A significant (p < 0.05) reduction in fasting and non-fasting blood glucose levels, reduction in fasting plasma insulin level and a significant improvement in glucose tolerance were observed in animals treated with formulations. The developed beads were suitable carriers for improving the systemic absorption of gliclazide and maintaining reduced blood glucose levels.

Preparation and Evaluation of Isosorbide Mononitrate Hydrogels for Topical Fissure Treatment by Krassimira Yoncheva, Irini Doytchinova, Ludmila Tankova (452-458).
The aim of the present study was to prepare and evaluate hydrogels containing 0.1% isosorbide mononitrate (ISMN) for topical treatment of anal fissure. The hydrogels were prepared on the base of Carbopol 940, Poloxamer 407 or their combination. The highest viscosity and significant thyxotropy were observed for the combined hydrogel, which corresponded with slow drug release. Drug release from Poloxamer hydrogel was slow probably due to the heterogeneous structure of the gel – hydrophobic polyoxypropylene domains and hydrophilic polyoxyethylene domains. Drug release form Carbopol hydrogel was faster, which was associated with the lower viscosity and homogeneous gel structure. Further, Carbopol gel containing 0.1% ISMN (wt/wt) was tested on 21 patients with two applications daily for a period of 6 weeks. The results showed that chronic anal fissures healed in 71% of the patients. The formulation based on Carbopol seemed to be appropriate and efficient for the topical mononitrate treatment of anal fissures.

Design Porosity Osmotic Tablet for Delivering Low and pH-Dependent Soluble Drug Using An Artificial Neural Network by Alpesh Patel, Tarak Mehta, Mukesh Patel, Kanu Patel, Natvarlal Patel (459-467).
In this paper formulation of porosity osmotic tablet containing isradipine (model drug) as a low and pH dependent solubility was optimized based on the simultaneous optimization technique in which an artificial neural network (ANN) was incorporated. Nonlinear relationships between the causal factors and the response variables were represented well with the response surface predicted by ANN. Three causal factors, i.e., drug, osmotic pressure promoting agent rate (Lactose: Fructose), PEG400 content in coating solution and coating weight, were evaluated based on their effects on drug release rate. In vitro dissolution profile time profiles at four different sampling times (1, 12, 20 and 24h) were chosen as output variables. Commercially available STATISTICA 7 (Stat soft, USA) was used throughout the study. The optimize values for the factors X1-X3 were 1.25:0.75, 22% and 2.5% respectively. Calculated difference (f1 = 11.19) and similarity (f2 = 70.07) factors indicate that there is no difference between predicted and experimental observed drug release profile. Artificial neural network technique can be particularly suitable in the pharmaceutical technology of controlled release dosage forms where systems are complex and nonlinear relationships between independent and dependent variables often exist.

The permeation of ionic compounds through lipophilic skin membrane can be enhanced by converting the impermeable ionized drug into a more permeable unionized form with pH-adjusting excipients. The osmotic influx of water into the device core, upon application on the human skin, dissolve the drug and pH-adjusting adjuvant allowing the partitioning and subsequent permeation of unionized drug from the transdermal device core. The present investigation was aimed to evaluate the feasibility of water activated pH-controlled pseudolatex films for transdermal delivery of zidovudine by ex vivo tests. The monolithic pseudolatex transdermal film of zidovudine was prepared by solvent change followed by solvent casting technique using Eudragit RL 100 and Eudragit RS 100 in varying proportions with pH 7.4 in the device core. The prepared films were of desired physicochemical properties. The SEM photomicrographs of drug loaded formulations exhibited uniformity with rough surface and no traces of crack or pores. The ex vivo skin permeation study across pig ear epidermis in Keshary-Chien glass diffusion cell showed that the drug permeability was controlled by the osmotic influx of water into the device core and consequent partition of dissolve drug into and diffusion through the skin. The formulation F2a with 10 % w/w of zidovudine dispersed in the polymer matrix composed of Eudragit RL 100 and Eudragit RS 100 at the ratio of 1:2, respectively, showed nearly the desired flux at 239.09 &#x3BC;g/cm2/h. A patch area of 117.48 cm2 would be required for transdermal delivery of zidovudine to obtain therapeutic plasma concentration at 0.3 &#x3BC;g/ml.

Lack of suitable formulations often obscures the potential of natural medicine. Moreover, the presence of myriad of constituents with varied physicochemical properties makes fabrication of stable phyto-formulation extremely difficult. Bee propolis is one such material that suffers inadequate clinical application, despite having diverse pharmacological activities, solely attributed to deficit of appropriate formulations. In this study, we have presented a possibility of fabricating liposomes as a platform nano-formulation for enhancement of hepatoprotective activity of propolis. Hepatoprotective efficacy of the propolis is limited by its poor oral absorption. Moreover, the exact composition of the propolis being yet undefined, indeed unconfined, it cannot be administered parenterally. In order to address the foregoing issue, propolis liposomes suitable for oral administration and having higher entrapment efficiency were formulated through a modified ethanol injection method. Effect of phospholipids (PL) and cholesterol (CH) concentration on the formulation characteristics was checked statistically by 32 factorial approach. Liposomes were characterized for vesicle diameter (Dv), entrapment efficiency (EE), zeta potential (&#x3B6; p), TEM and drug release kinetics. Clinical efficacy of the formulation was assessed using acetaminophen induced hepatotoxicity in rat model. Biochemical parameters such as AST, ALT, ALP and TBARS, as well as histopathological aspects were studied. Stable unilamellar vesicles were formed according to 32 factorial approach. Dv, EE and &#x3B6; p were ranging between 216 to 437 nm, 79.53 to 93.01% No. -27.8 to -31.2 mV, respectively. Marked positive effect of PL and CH and propolis concentrations was seen on Dv as well as EE. Release of propolis in acidic media followed zero order kinetics while in alkaline media it followed 1st order kinetics. Formulation was able to suppress AST, ALT, ALP & TBARS levels in hepatotoxicity induced experimental animals and promote tissue healing, in a manner more effective than plain EEP as well as silymarin. In conclusion, suitability of liposomes as a fundamental formulation for enhancing hepatoprotective activity of multi-component propolis was justified.

Purpose: The potential of sucrose fatty acid esters (SEs) to enhance intestinal absorption was investigated in order to identify their utility for the intestinal absorption of water-soluble high molecular weight compounds. Methods: Fluorescein isothiocyanate-labeled dextran (FD) with a molecular weight (MW) of 4,000 (FD-4) was used as a model compound, and several SEs were tested as absorption enhancers. After FD-4 was administered intra-duodenally at 10 % (w/v) with the non-loop method in situ in rats in the absence or presence of SEs, the plasma concentration-time profiles of FD-4 were examined. As to sucrose laurate (L-1695), the relationship between concentration and enhancement effect was investigated. In addition, the enhancement effect after dosing into the different small intestinal regions, the effect on FDs with different MWs and the influence of N-acetyl-cysteine (NAC) co-existence were examined. Results: Low watersoluble SEs exhibited slight and/or slow absorption enhancement effects, while L-1695, being highly water-soluble, had good potential to enhance the absorption rate and extent. The enhancement effect became greater as the concentration of L1695 increased. L-1695 displayed high enhancement potential in wide intestinal areas. The enhancement effect of L-1695 (10 %, w/v) depended on MWs of FDs; the mean values of the area under the plasma concentration curve from 0-120 min (AUC0-120 mins) increased by 14 and 8 times for FD-4 and FD-10 (MW 10,000), while it was hardly changed as for FD-70 (MW 70,000). The enhancement effect of L-1695 (10 %, w/v) was similar to that of sodium caprate (10 %, w/v), and was influenced to some extent by the co-existence of NAC (5 %, w/v). Conclusion: The absorption enhancement potential of SEs depended on their water-solubility. L-1695, being highly water-soluble, showed a good enhancement effect, and its absorption profiles were elucidated. This study proposes the possibility of SEs, in particular, L-1695, as intestinal absorption enhancers. As far as the present non-loop method is concerned, the intestinal damage was not observed macroscopically with the addition of L1695 at 2.5-20 % (w/v).

Preparation and in vitro in vivo evaluation of aceclofenac loaded alginate microspheres: An investigation of effects of polymer using multiple comparison analysis by Madhusmruti Khandai, Santanu Chakraborty, Priyanka Nayak, N. Bala Murali Krishna, Gandepalli Chakravarthi, Biswajit Acharjya, Ashoke Kumar Ghosh (495-505).
The aim of this present research work was to prepare and evaluate alginate microspheres of aceclofenac by ionic gelation method for targeting the drug release in intestinal region and decrease distinct tissue protection in the stomach. This method offers to prepare microspheres which are important in controlling the release rate and the absorption of aceclofenac from the intestinal region. Variation in polymer concentration was studied systemically for their influence on the encapsulation efficacy, particle size and in vitro drug release. The enteric nature of the microspheres showed very less amount of drug released in acidic medium. The mucoadhesion property was strongly dependent on the pH of the medium and the polymer concentration in the formulations. In vitro drug release study proposed a mixed drug release mechanism, partially involving the sphere matrix disintegration and drug diffusion of the microspheres. Holm-Sidak multiple comparison analysis suggested a significant difference in measured t50% values among all the microsphere formulations. In vivo studies revealed that the anti-inflammatory effect induced by the aceclofenac loaded alginate microspheres was significantly high and prolonged than that induced by the pure aceclofenac. So, this aceclofenac loaded alginate microspheres exhibited promising properties to improve the patient compliance by controlling and prolonging the systemic absorption of aceclofenac along with a distinct tissue protection in the stomach.

Comparative Studies of Lamivudine-zidovudine Nanoparticles for the Selective Uptake by Macrophages by V. Sankar, Parmar Nilaykumar Nareshkumar, Gohel Nishit Ajitkumar, Shalini Devi Penmetsa, Sivaram Hariharan (506-514).
The present study investigates the specific drug targeting of anti retroviral drugs, such as lamivudine and zidovudine, after intraperitoneal (i.p) injection by incorporation into polymeric nanoparticles (PNs) and solid lipid nanoparticles (SLNs). Our results showed that Glyceryl Monosterate-Poloxamer 188 SLNs (average diameter of 522.466 nm) showed slow drug release rates (63.18% of lamivudine and 62.37% of zidovudine were released in 12 hrs) among all the SLN formulations. For Poly lactic-co-glycolic acid (PLGA)-Poloxamer 188 PNs (average diameter of 70.348 nm), there were faster release rates of both lamivudine and zidovudine (97% and 94.06%, respectively, in 12 hrs). Tissue distribution studies were carried out in mice and concentrations of drugs in different organs were determined using high performance liquid chromatography (HPLC) after i.p. administration. Glyceryl Monosterate-Poloxamer 188 SLNs and PLGAPoloxamer 188 PNs showed increase in the distribution of lamivudine and zidovudine to liver and spleen when compared to the drugs in solution. Also, Glyceryl Monosterate-P 188 SLNs showed higher concentration of drugs in RES organs than PLGA-P 188 PNs.

Formulation, Antimicrobial and Toxicity Evaluation of Bioceramic based Ofloxacin Loaded Biodegradable Microspheres for Periodontal Infection by Tariq Jamal, Md. Akhlaquer Rahman, Mohd. Aamir Mirza, A. K. Panda, Sushama Talegaonkar, Zeenat Iqbal (515-526).
In the present study an attempt has been made to load Poly (Lactic-Co-glycolic acid) microspheres with hydroxyapatite (HA) and ofloxacin and propose the composite microspheres to be used as local drug delivery system with the drug releasing capability for periodontitis treatment. A modified single emulsion method has been used for the preparation of microspheres. Experiments were conducted to optimize the formulation by RSM-Box-Behnken Method, which is an independent quadratic design involving three or four independent variables against a pre determined set of dependant parameters. The particle size of composite microspheres was analyzed and the average size was found to be 22.05 &#x3BC;m. Photomicrographs and scanning electron micrographs showed that the composite microspheres are spherical in shape and porous in nature. The microbiological activity of optimized formulation was evaluated using strain: S. aureus-ATCC- 29213 and E. coli–ATCC-25922. In vivo/in situ toxicity evaluation of the formulation was assessed by MTT assay and the formulation was found to be biocompatible.

Novel chitosan-carrageenan nanoparticles were produced through the process of ionotropic gelation for the encapsulation and controlled release of recombinant human erythropoietin (rHu-EPO). The effects of chitosan concentration, chitosan to carrageenan mass ratio and solution pH on the nanoparticle diameter, polydispersity and surface charge were explored through both screening and response surface modeling (RSM) methods. The chitosan-carrageenan nanoparticles created had particle diameters between 200 and 1000nm, surfaces charges between 40 and 55mV, and polydispersity between 0.2 and 0.35. RSM optimized chitosan-carrageenan nanoparticles demonstrated an increased rHu-EPO encapsulation efficiency of 47.97±4.10% and a more sustained in vitro release of ~50% over a 2 week period when compared to previous nano/microparticle delivery systems. Studies on the effect of surface charge and chitosan molecular weight on the encapsulation and controlled release of rHu-EPO revealed that increasing either led to improved encapsulation efficiency and reduced release rate.