Current Drug Delivery (v.10, #5)

Betaxolol Hydrochloride Loaded Chitosan Nanoparticles for Ocular Delivery and their Anti-glaucoma Efficacy by Kunal Jain, R. Suresh Kumar, Sumeet Sood, G. Dhyanandhan (493-499).
Many effective anti-glaucoma drugs available for the treatment of ocular hypertension and open angle glaucomaare associated with rapid and extensive precorneal loss caused by the drainage and high tear fluid turnover. The presentstudy involved design of mucoadhesive nanoparticulate carrier system containing betaxolol hydrochloride for oculardelivery to improve its corneal permeability and precorneal residence time. Nanoparticles were prepared by spontaneousemulsification method and had a particle size of 168-260nm with zeta potential of 25.2-26.4 mV. The in vitro release studiesin simulated tear fluid exhibited biphasic release pattern with an initial burst followed by sustained release upto 12 h.The sterility tests confirmed that formulation was free from viable microorganisms and suitable for ocular delivery. Theocular tolerance of nanoparticles was evaluated using Hen Egg-Chorion Allantoic Membrane (HE-CAM) method and wasfound to be non-irritant. Stability studies of nanoparticles revealed that there was no significant change in particle size anddrug content after storage at 25±2°C/60±5% RH over a period of 3 months. In vivo pharmacodynamic studies were carriedout in dexamethasone induced glaucoma model in rabbits. The developed nanoparticles showed significant decrease in intraocularpressure (IOP) compared to marketed formulation. Optimized formulation of BN3 showed gradual reduction ofIOP reaching peak value of 9.9±0.5mm Hg, equivalent to 36.39±1.84% reduction in IOP compared to control at the end of5 h which was significant (p < 0.05) compared to marketed formulation. Thus, our studies demonstrate that developednanoparticles offer a promising delivery system for the management of glaucoma.

The present study focuses on the formulation of ethosomal gel of ropinirole hydrochloride (ropinirole HCl), ananti-Parkinsonian drug, for delivery as a carrier for transdermal application. The ethosomes were prepared using differentconcentrations of phospholipids (2-5 % w/v), ethanol (20-50 % w/v), ropinirole HCl (5 % w/v) and water. They were optimizedusing 32 full factorial designs to study the effect of independent variables, concentrations of ethanol and lecithinon dependent variables, entrapment efficiency and in-vitro drug release at 24 hrs. The drug release profile exhibited Higuchi’sand zero order kinetics. From the regression analysis, it was observed that independent variables had significant effecton response variables. Formulations were optimized using contour plot and response surface plot. The optimized formulationwas found to be RS10 containing 30 % w/v ethanol and 4% w/v lecithin. The optimized formulation was evaluatedfor assay, particle characteristics, zeta potential, skin retention and stability. Ethosomal gel was prepared by incorporationof optimized ethosomal suspension into gel base. The ethosomal gel was characterized for physical appearance, pH,content uniformity, rheological behaviour, skin-retention, in-vitro and in-vivo drug release and stability. From the results itcan fairly be concluded that ethosomes are capable of delivering ropinirole hydrochloride into systemic circulation bytransdermal route. The amounts thus delivered are also equitable to those delivered orally and are delivered at a rate slowenough to achieve longer blood levels.

A melt dispersion technique was employed to prepare ofloxacin lipospheres, by using cetyl alcohol (polarlipid). Effects of various process parameters such as selection of surfactants (gelatin, Tween 40 and poly vinyl alcohol)and selection of stirring speed were studied. Lipospheres were evaluated for morphology, drug entrapment and in vitrodrug release profiles. The optimized liposphere batch was selected and formulated as tablets and evaluated the in vitrodrug release profile. These studies showed that ofloxacin loaded lipospheres were able to control the drug release for a periodof 16h.

Application of Design of Experiments to Optimizing Novel Gastroretentive Drug Delivery of Simvastatin by Swati Jagdale, Prasad Kurhe, Bhanudas Kuchekar, Aniruddha Chabukswar (527-541).
Context: Simvastatin is a hypolipidemic drug used in atherosclerosis. It has short elimination half life (2-3hours) and narrow absorption window. It is mainly absorbed from stomach. Objective: The objective of this research wasto develop gastroretentive floating tablets of Simvastatin using combination of release retardant polymers like PolyoxWSR 205, Polyox WSR N12K and HPMC K4M. Material and methods: 32 full Factorial design was applied to design theexperiments and tablets were prepared by direct compression. Prepared floating tablets were evaluated for hardness, floatingtime, friability, % drug content, swelling index, in-vitro drug release study and mean gastric retention period by invivoX-ray study. Statistical analysis was done using design expert software and model fitting was carried out using PCPDISSO. Design expert software was validated by comparing predicted results with observed results. Results and conclusion:Statistical analysis data revealed that tablets from formulation batch D3 (containing HPMC K4M 10% and POLYOXWSR 205 35%) and formulation batch E2 (HPMC K4M 10% and Polyox WSR N12K 25%) were promising system exhibitingexcellent floating properties and drug release pattern. Stability studies revealed that all formulations were physicallyand chemically stable. In-vivo X-ray imaging of formula D3 and formula E2 shows mean gastric retention time of6 ± 0.5 hours.

Amphotericin B (AmB) is a poorly water soluble polyene antifungal antibiotic which is negligibly absorbedfrom the gastro intestinal tract after oral administration. The objective of this research work was to study the oralbioavailability and stability of a self-emulsifying drug delivery system (SEDDS) of amphotericin B (AmB). The SEDDSformulation consisted of glyceryl monooleate, tween 80, polyethylene glycol 400 (PEG 400) and propylene glycol andhad AmB content of about 8 mg per ml. The stability of the SEDDS formulation was studied in simulated gastric fluid(SGF) and simulated intestinal fluid (SIF) in comparison to pure drug. Oral bioavailability of the SEDDS formulation wasstudied in rats in comparison to the pure drug. The formulation was filled in two different types of capsule shell, namelyHPMC capsule and hard gelatin capsule and stability of the formulation was studied for 3 months. The SEDDSformulation resulted in a mean AUC value of 40.57µg/ml.hr with mean peak plasma concentration of 6.17 µg/ml reachedafter 2 hours after oral administration in rats, whereas concentration of AmB in plasma was not detectable afteradministration of the pure drug. The formulation filled in hard gelatin capsule shell was physically and chemically stablefor more than 3 months under refrigeration (4°C). The study demonstrates that SEDDS approach can be successfullyutilized for oral delivery of AmB.

Compritol®888 ATO a Lipid Excipient for Sustained Release of Highly Water Soluble Active: Formulation, Scale-up and IVIVC Study by Shilpa N. Patere, Neha S. Desai, Ankitkumar S. Jain, Prashant P. Kadam, Urmila M. Thatte, Nithya Gogtay, Chhanda J. Kapadia, Nabil Farah, Mangal S. Nagarsenker (548-556).
The potential of Compritol®888 ATO as a release modifier to retard the release of highly water soluble drug,metoprolol succinate (MPL) was exploited. Different ratios of Compritol®888 ATO versus MPL were utilized and the effectof various formulation methods was evaluated to sustain the release of MPL. MPL: Compritol®888 ATO in 1:2 ratiocould successfully retard the release of MPL. Melt granulation method “as hot process” was found to be effective whencompared to direct compression and wet granulation. The in vitro release characteristics of tablets were studied in pH 6.8phosphate buffer at 50 rpm using USP Type II apparatus. Formulation F7 retarded MPL release with ~90% release after20h. Stability studies showed no significant difference (f2>;50) in MPL release profile after three months of storage periodat 25±2°C/60±5% RH and 40±2°C/75±5% RH. The bioavailability of sustained release tablets, F7 was compared withcommercially available tablets, MetXL50 in 12 healthy human volunteers in a crossover design. Plasma concentration ofMPL was determined using HPLC with fluorescence detector. IVIVC correlation was obtained by deconvoluting theplasma concentration-time curve using a model independent Wagner-Nelson method. Correlations of fraction of drug dissolvedin vitro and fraction of drug absorbed in vivo displayed a significant linear relationship for sustained release tabletsof MPL.

3’-O-Retinoyl-5-fluoro-2’-deoxyuridine (RFUdR) is a putative dual-acting, mutually-masking (DAMM) prodrugfor the treatment of cancer. As part of the proof of principle for the DAMM concept, the concentrations of RFUdRand its post-hydrolysis active metabolites, 5-fluoro-2’-deoxyuridine (FUdR) and all-trans-retinoic acid (RA), were determinedin plasma and selected tissues following either bolus intravenous (i.v.; 12.5 μmol/kg) or oral (p.o.; 13.7 μmol/kg)doses of RFUdR to mice bearing EMT6 murine mammary tumors. The concentrations of RFUdR and its primary metaboliteswere measured by high-performance liquid chromatography. A three compartment model provided the best fit forplasma RFUdR after an i.v. bolus, whereas FUdR and RA data were best fit by a one compartment model. The terminalhalf-life of RFUdR in plasma was 9 hours. The AUC of RFUdR in tumor (3400 μmol/L min) was estimated to be about 4-fold higher than its AUC in the plasma (809±241 μmol/L min). A short-duration, saturated elimination phase for RFUdRwas observed in both liver and kidney following an i.v. bolus. Neither unchanged RFUdR nor RA was detected in urine.The high bioavailability (~90%) following oral dosing with RFUdR indicates that this DAMM prodrug may be suitablefor oral dosing to deliver FUdR and RA for cancer chemotherapy.

In the present investigation chitosan microspheres loaded with flurbiprofen (FLB) were prepared by oil/oilemulsification method for colon specific drug delivery. FLB was entrapped in chitosan microspheres, following coatingwith Eudragit S-100 utilizing the benefits of pH dependent solubility of Eudragit S-100, so as to prevent the premature releaseof FLB in upper GIT. Different batches of FLB microspheres were prepared by varying FLB: chitosan ratio (1:1 to1:4). The effect of chitosan concentration on size, entrapment efficiency, percent drug loading and degree of swelling wasevaluated. DSC studies revealed the dispersion of FLB in the matrix of chitosan microspheres. SEM analysis indicated thenearly smooth surface and spherical shape of the prepared microspheres X-ray diffract gram of FLB microspheresshowed less intense peaks as compared to free FLB. In vitro release studies of uncoated FLB- chitosan microspheresshowed burst release in initial 4 h, while Eudragit S-100 coated microspheres prevented the premature release of FLB andshowed controlled release for 12 h following Higuchi model, thus suitable for colon specific drug delivery.

Studies on Ocular and Parenteral Application Potentials of Azithromycin- Loaded Anionic, Cationic and Neutral-Charged Emulsions by Shunmugaperumal Tamilvanan, Ramona Khanum, Sudalimuthu Ramachandran Senthilkumar, Marimuthu Muthuraman, Thenrajan Rajasekharan (572-586).
Ocular and parenteral application potentials of azithromycin-containing, non-phospholipid-based cationicnanosized emulsion in comparison to the phospholipid-based anionic and neutral-charged nanosized emulsions were investigated.Various physical, chemical, nonclinical toxicity and antimicrobial activity studies (mean droplet diameter, surfacecharge, creaming index, entrapment efficiency, accelerated, long-term and freeze-thaw cycling stabilities, TLC study,modified hen’s egg chorioallantoic membrane (HET-CAM) test, in vitro hemolysis test, in vitro and in vivo myotoxicity,and in vitro antimicrobial activity) were conducted for assessing the potentials of these three types of emulsions. Followingautoclave sterilization, all of these emulsions exhibited a nanometer range mean particle diameter (200 ± 29 to 434 ±13 nm). While the anionic and cationic emulsions did show high negative (-34.2 ± 1.23 mV) and positive zeta potential(42.6 ± 1.45 mV) values, the neutral-charged emulsion did not. Even with 5 freeze-thaw cycles, the cationic emulsion remainedstable whereas other two emulsions underwent phase-separation. The hen?s egg chorioallantoic membrane test revealedan irritation score value that was higher for the anionic emulsion than for cationic or neutral-charged emulsion. Asignificantly higher % hemolysis value was also noticed for the anionic emulsion when compared to the % hemolysisvalue of cationic emulsion (ANOVA, P ‹ 0.05). However, all of the emulsions showed a lesser intracellular creatinekinase (CK) release/plasma CK level in comparison to the positive control (phenytoin) indicating their lesser myotoxicityat the injection site . When compared to anionic and neutral-charged emulsions, the possible controlled drug release fromcationic emulsion delayed the in vitro antimicrobial action against H.influenzae and S.pneumoniae.

Xanthan Gum and Its Derivatives as a Potential Bio-polymeric Carrier for Drug Delivery System by Hemant R. Badwaik, Tapan Kumar Giri, Kartik T. Nakhate, Pranita Kashyap, Dulal Krishna Tripathi (587-600).
Xanthan gum is a high molecular weight natural polysaccharide produced by fermentation process. It consistsof 1, 4-linked β -D-glucose residues, having a trisaccharide side chain attached to alternate D-glucosyl residues. Althoughthe gum has many properties desirable for drug delivery, its practical use is mainly confined to the unmodified forms dueto slow dissolution and substantial swelling in biological fluids. Xanthan gum has been chemically modified by conventionalchemical methods like carboxymethylation, and grafting such as free radical, microwave-assisted, chemoenzymaticand plasma assisted chemical grafting to alter physicochemical properties for a wide spectrum of biological applications.This article reviews various techniques utilized for modification of xanthan gum and its applications in a range of drug deliverysystems.

Malaria is one of the major public health problems in the developing countries. Numbers of drugs are availablefor the treatment of malaria but chloroquine diphosphate still remains a drug of choice. The aim of this study is to developand characterize a suitable drug delivery system of antimalarial drug for prophylactic use. A depot system for controlledrelease of antimalarial drug was prepared. Drug loaded heat cross-linked gelatin microspheres were prepared by singleemulsion thermal gelation technique. These were characterized by optical microscopy, scanning electron microscopy(SEM), percentage yield (63.20% to 86.13%), drug content (22.95% to 28.02%), encapsulation efficiency (41.46% to68.26%), differential scanning calorimetry (DSC) and in vitro studies. Sizes of the microspheres as observed by opticalmicroscopy were in the range of 44.06±6.98 μm to 54.70±8.19 μm, DSC pattern showed the absence of drug and polymerinteraction. The gelatin microspheres were below 60 μm and spherical in shape as evidenced by the SEM photographs.Encapsulated chloroquine diphosphate was released slowly for 24?1 hrs. The study indicated optimum drug release behavior(84.5% ± 0.96) in 25 hrs.

The present investigation describes development and optimization of pioglitazone-loaded jackfruit seed starch(JFSS)-alginate beads by ionotropic-gelation using 32 factorial design. The effect of polymer-blend ratio and CaCl2concentration on the drug encapsulation efficiency (DEE, %), and cumulative drug release after 10 hours (R10h, %) wasoptimized. The DEE (%) of these beads were 64.80 ± 1.92 to 94.07 ± 3.82 % with sustained in vitro drug release of64.±1.83 to 92.66 ± 4.54 % over 10 hours. The in vitro drug release from these beads followed controlled-releasepattern with super case-II transport. Particle size range of these beads was 0.77 ± 0.04 to 1.24 ± 0.09 mm. The beads werealso characterized by SEM and FTIR. The swelling of these beads was influenced by pH of the test medium. Theoptimized pioglitazone-loaded JFSS-alginate beads showed significant hypoglycemic effect in alloxan-induced diabeticrats over prolonged period after oral administration.

Formulation and Evaluation of Non-Effervescent Floating Tablets of Losartan Potassium by Anil Getyala, H. V. Gangadharappa, M. Sarat Chandra Prasad, M. Praveen Kumar Reddy, T. M. Pramod Kumar (620-629).
The aim of the work is to modify the solubility and bioavailability of Losartan potassium, by employing noneffervescentfloating drug delivery (tablet dosage forms). Non-effervescent systems are a type of floating drug deliverysystems, that have been used to boost the gastric residence and the floatation time in the gastro intestinal tract. The studyincluded formulation of floating tablets using polymers like Chitosan and Karaya gum as matrix forming agents. Accurel®MP 1000 was used as floating agent. The tablets were prepared by direct compression technique. FTIR, DSC studiesconformed that there was no incompatibility between the polymer and the drug. Tablet preformulation parameters werewithin the Pharmacopoeial limit. Tablet showed zero lag time, contisnuance of buoyancy for >;12 h. The tablet showedgood in vitro release. Drug release was through swelling and abided by the gellation mechanism. In vivo X-ray studiesdepicted that tablets continued to float in the GIT for 12 h. Accelerated stability showed that, tablets were stable for over 6month. Thus the prepared non-effervescent floating tablet of Losartan potassium can be used for the treatment ofhypertension for more than 12 h with single dose administration.