PREPARATION, CHARACTERIZATION AND EVALUATION OF HEPATOPROTECTIVE ACTIVITY OF NNDMAC BIODEGRADABLE PARENTERAL SUSTAINED RELEASE MICROSPHERES

The objective of this work was to prepare biodegradable sustained release parenteralmicrospheres of NNDMA-curcumin (NNDMAC), a novel curcumin analogue, characterize theformulation and evaluate the hepatoprotective activity of the microsphere formulation.Microspheres were prepared using solvent evaporation technique using polycaprolactone andwere further characterized for various parameters. In vivo animal studies for 10 days were carriedout for the determination of hepatoprotective activity of the formulation in a CCl4 model.Particles of 12 μm size with 75.41% yield with no drug-polymer interaction were obtained. Thedrug release was sustained for 10 days. Significant hepatoprotection which was better thanrepeated I.V. administration was offered by the microsphere formulation in this 10-day study.Prepared NNDMAC microspheres have potential use in liver toxicity/cirrhosis

SYSTEMIC DELIVERY OF DICLOFENAC SODIUM AFTER TOPICAL APPLICATION OF GELS INCORPORATED WITH DRUG-LOADED SOLID LIPID NANOPARTICLES (SLN)

The aim of this study was to prepare and evaluate gels incorporating solid lipid nanoparticles (SLNs) of diclofenac sodium for systemic delivery of the active after topical application. SLNs were prepared using hot homogenization followed by sonication technique and these were incorporated into freshly prepared carbopol gel. Three different gel formulations (DSL1, DSL2 and DSL3) were prepared and characterized for particle size, charge, viscosity, morphology, and drug-lipid compatibility. The gels were evaluated for in vitro drug release, ex vivo permeation studies and in vivo absorption. The gels enriched with SLN sustained the drug release for 24 h both in vitro and in vivo. The results suggest enhancement in systemic delivery of diclofenac sodium with gels incorporating SLNs

NOVEL SUBCUTANEOUS SUSTAINED RELEASE NANOPARTICLES ENCAPSULATING LOW MOLECULAR WEIGHT HEPARIN (LMWH): PREPARATION, CHARACTERIZATION AND EVALUATION

Objective: The objective of the current research work was to prepare and evaluate novel subcutaneous sustained release polymeric nanoparticles for low molecular weight heparin (LMWH).Methods: In this study, we prepared subcutaneously administered polymeric nanoparticles encapsulating LMWH using different grades of polycaprolactons (PCL) (14k, 45k, 80k) and 0.1% Polyvinyl alcohol (PVA) solution as surfactant by employing water–in-oil in-water (w/o/w) emulsion and evaporation method. The formulated nanoparticles were evaluated for size, shape, zeta potential, in vitro drug release, and in vivo biological activity (anti factor Xa activity) using standard kit, antithrombotic activity in thrombosis induced rat model. Drug and polymer interactions in the nanoparticles were evaluated using Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD).Results: Scanning electron microscopic (SEM) studies on the nanoparticles confirmed the formation of spherical particles with smooth surface. The size of the formed nanoparticles were about 415-495 nm. The % entrapment of nanoparticles was found to be between 69-81%. Nanoparticles showed slow and sustained pattern of release for about 59-65 % in 48 h. Optimized nanoparticles exhibited excellent improvement in pharmacokinetic parameters and showed good antithrombotic activity, Activated partial thromboplastin time (aPTT) activity when compared to free drug. FTIR studies indicated that there was no loss in chemical integrity of the drug upon fabrication into nanoparticles. XRD results demonstrated that the drug changed its physical form in the formulation.Conclusion: The results of this study revealed that subcutaneous nanoparticles were excellent candidates for sustained drug delivery of LMWH to avoid repeated subcutaneous administration.Keywords: Low molecular weight heparin, Subcutaneous, Stability, Polycaprolactone, Venous thrombosis, Activated partial thromboplastin timeÂ

Long term outcome and EuroSCORE II validation in native valve surgery for active infective endocarditis in a South African cohort

Objectives: To evaluate the major risk factors for adverse short and long term outcomes in patients with active native valve infective endocarditis needing cardiac surgery and to validate the EuroSCORE II in our cohort of patients.Methods: We retrospectively studied 149 patients who underwent native valve surgery for infective endocarditis in June 2000 - May 2011 at our referral centre. Ninety-six patients met the inclusion criteria for the study: 29 aortic valve replacements (AVR), 27 mitral valve replacements (MVR), 28 aortic/mitral (double) valve replacements (DVR) and 12 mitral valve repairs (MV Repair).Results: Mechanical valves were implanted in 68 patients (70.8%), bioprosthetic valves in 16 (16.7%) and mitral annuloplasty rings in 12 (12.5%). The Cox proportional hazard model showed that the most important risk factors for early 30-day mortality were: critical preoperative state, emergency surgery, EuroSCORE II >12%, low cardiac output state (LCOS), HIV positive status, preoperative embolic episodes, vegetation size >1cm and postoperative ventilation >24 hours. The EuroSCORE II underestimated early mortality for the entire cohort. The discriminatory ability was evaluated with the receiver operating characteristic (ROC) curve with an area under the curve of 0.796. The discriminatory ability in the subgroup analysis showed that the AUROC curve was poorer for MVR (0.696), 0.837 for DVR and better for AVR group (0.92).Conclusions: The EuroSCORE II underestimated mortality in the highest risk groups and overestimated mortality in the lowest risk groups. The discriminatory ability and model fit were evaluated to be good and a EuroSCORE II >12% predicted a signifi cantly higher early and medium term mortality

NOVEL NANOPARTICLES FOR THE ORAL DELIVERY OF LOW MOLECULAR WEIGHT HEPARIN: IN VITRO AND IN VIVO ASSESSMENT

Objective: The objective of the present study was to prepare and evaluate a novel oral formulation of nanoparticles for the systemic delivery of low molecular weight heparin (LMWH). Methods: Nanoparticles were prepared by polyelectrolyte complexation (PEC) method using polymers sodium alginate and chitosan. Entrapment efficiency of LMWH in nanoparticles was found to be  ̴88%. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X‑ray diffraction (XRD), Scanning electron microscopy (SEM)  studies carried for nanoparticles. In vitro release studies were performed for the formulations. Ex vivo permeation studies were performed optimized formulation by using small intestine of rat and in vivo studies were conducted on rat model.Results: In vitro release studies demonstrated that the release of LMWH was negligible in the stomach and high in the small intestine. FTIR has indicated that there is no interaction between the ingredients in nanoparticle. DSC and XRD studies confirmed that the amino groups of chitosan interacted with the carboxylic groups of alginate. Invitro % drug release of 95% was shown by formulation AC5. Ex vivo permeation studies have elucidated that ̴ 73% of LMWH was transported across the epithelium. Nanoparticles have shown enhanced oral bioavailability of LMWH as revealed by 4.5 fold increase in AUC of plasma drug concentration time curve.Conclusion: The results suggest that the nanoparticles prepared can result in targeted delivery of LMWH into systemic circulation via intestinal and colon routes. Novel nanoparticles thus prepared in this study can be considered as a promising delivery system.Keywords: Antifactor Xa activity, Chitosan, Differential scanning calorimetry, Sodium alginate, Low-molecular-weight heparin, Oral bioavailability

ENHANCED LIVER DELIVERY AND SUSTAINED RELEASE OF CURCUMIN WITH DRUG LOADED NANOPARTICLES AFTER INTRAVENOUS ADMINISTRATION IN RATS

Liver targeting drug delivery systems can improve thedelivery of several drugs useful in the treatment of liverdisorders such as cirrhosis and liver cancer. Theobjective of this study was to prepare the biodegradablenanoparticles containing curcumin, a well-knownhepatoprotective agent and further to evaluate the livertargetability and sustained release of curcumin with thedeveloped nanoformulation. Curcumin nanoparticleswere prepared by double emulsion (w/o/w) solventevaporation method using different drug polymer ratios.Poly-ε-caprolactone was used in the preparation. Theprepared formulations were evaluated for particles size,surface potential, entrapment efficiency, in vitro release,drug polymer interaction. Four different formulationsCNP1, CNP2, CNP3 and CNP4 were prepared.Optimized formulation (CNP3) was evaluated forpharmacokinetics and hepatoprotective activity in CCl4induced liver toxicity model after i.v. administration.Optimized formulation was selected based on the size,entrapment efficiency and release characteristics.Curcumin i.v. solution and oral suspension form wereused as the reference. Particle size of all formulationswas in the range of 300-470 nm and the entrapmentefficiencies were in the range of 75-85 %. Drug releasefrom the nanoparticles was sustained both in vitro and invivo. Nanoparticle formulation tested in vivodemonstrated better pharmacokinetics andpharmacodynamics compared to the reference. Druglevels in the liver were significantly higher withnanoparticular formulation. Thus, this studysuccessfully prepared a nanoparticular formulationcontaining curcumin with polycaprolactone as thepolymer. With the developed formulation better livertargetability was achieved

DEVELOPMENT OF ROPINIROLE (FREE BASE) TRANSDERMAL PATCH US ING BLENDS OF HYDROXYPROPYL METHYLCELLULOSE/EUDRAGITS AND IT’ S IN VITRO/ IN VIVO CHARACTERIZATION

The objective of this study was toprepare and evaluate a matrix type transdermal patch ofropinirole using blends ofhydroxypropylmethylcellulose (HPMC) and EudragitRL 100 and HPMC and Eudragit ERS100. Materialsand Methods: Ropinirole free based used as the drugentity was prepared from its hydrochloride salt.Suitability of the polymers in the form of drug-excipientcompatability was determined prior to formulationdevelopment using FTIR. Patches were developed usingsolvent evaporation technique. Limonene was used asa penetration enhancer. Moisture absorption,moisture content and mechanical properties, drugcontent, in vitro drug release, drug-excipient compatibility,in vitro skin permeation were the in vitro parametersmeasured. Short-term stability, skin irritation andin vivo drug release were measured with oneoptimized formulation. Results and discussion:Ropinirole free base was used successfully in thepreparation of the patches. FTIR studies indicated nointeraction between the drug and the polymers of thisstudy. Formulations developed were strong and notbrittle with uniform drug release. Patches containinghigher HPMC generally showed higher drug releaseand permeation. Drug release and permeation decreasedwith increase in the concentrations of Eudragits. Drugrelease studies indicated Higuchi model for all thepatches with a diffusion mechanism of non-fickian type.Short-term stability studies indicated that ropinirolewas stable in the patches. Patches did not cause any skinirritation. In vivo the optimized patch sustained drugrelease for 24 hours upon one time administration.Conclusion: Clinically viable ropinirole transdermalpatch can be successfully prepared from its base formusing HPMC/Eudragits

SYNTHESIS OF PRODRUGS OF MEFENAMIC ACID AND THEIR IN VIVO EVALUATION

Objective: The purpose of the study was to synthesize prodrugs of mefenamic acid, to be used as Anti inflammatory drug with fewer adverse effects. Methods: The drug was covalently bonded to PEG 1500 (polyethylene glycol) and PEG 6000 as such and with a linker glycine. The prodrugs were characterized by FT-I.R and N.M.R. For the drug release studies, all the prodrugs were subjected to pH 1.2 and pH 7.2. For the anti inflammatory activity, Carrageenan induced rat paw edema method was followed and for Ulcer protecting activity, Pylorus ligation method was used, the prodrugs were administered to male Sprague-Dawley rats. Results: The results suggested that the prodrugs of mefenamic acid, the drug release was higher at pH 7.2 than at pH 1.2. The result obtained for anti inflammatory activity was comparable to the standard drug of mefenamic acid. For ulcers, the prodrugs were found to possess Ulcer curing property higher than the standard drug. Conclusion: The prodrugs thus synthesized possess anti inflammatory activity as well as good ulcer protecting activity, can be used instead of standard drug

Preparation, Characterization and in vivo Evaluation of Parenteral Sustained Release Microsphere Formulation of Zopiclone

The aim of this study was to prepare zopiclone-loaded polycaprolactone microspheres by emulsion solvent evaporation technique with different drug-to-carrier ratios {MP 1 (1:1), MP 2 (1:2), MP 3 (1:3), and MP 4 (1:4)}, characterize and evaluate the in vivo performance. The microspheres were characterized for particle size, surface morphology, drug excipient compatibility, percentage yield, drug entrapment, and in vitro release kinetics. Pharmacokinetics and pharmacodynamics were evaluated after parenteral administration so as to determine the sustained action of the drug after one-time administration of the formulation in a rat model. Of four formulations prepared, MP 2, i.e., 1:2 (drug–polymer) ratio was selected as the optimized formulation based on particle size, particle shape, and the release behavior. The size of microspheres was found to be ranging from 5.4 to 12.1 µm. The shape of microspheres was found to be spherical by SEM. Among the four formulations, MP 2 (1:2) showed maximum percentage yield of 75% ± 2.68%. There was no interaction between drug and polymer by FT-IR study. In the in vitro release study, formulation MP 2 (1:2) showed 86.5% drug release and was found to be sustained for 10 days. The microsphere formulations were able to sustain the release of drug both in vitro and in vivo. Pharmacodynamic study (Maze apparatus) indicated that the anxiolytic activity shown by zopiclone microspheres was significant when compared to the zopiclone solution given daily

Long term outcome and the validity of EuroSCORE II in native-valve surgery for active endocarditis in a South African cohort

Infective endocarditis was initially described in the early 16th century and only methodically reviewed after the 19th century when Osler gave the drive to the Royal College of Physicians in 1885 through his contribution. The last 25 years has not shown much change in the mortality from infective endocarditis (IE) despite diagnostic and therapeutic advances. The current in-hospital mortality rate for patients with IE is 15% to 20%, with 1-year mortality approaching 40%. The morbidity associated with infective endocarditis includes valvular incompetence, embolization, cerebrovascular accidents and congestive heart failure and this has influenced the surgical options to a great extent. The EuroSCORE II is the current model available for predicting the early mortality after cardiac surgery. HYPOTHESIS: Infective endocarditis has a high risk for mortality due to certain risk factors and the currently available EuroSCORE II model may not predict early mortality accurately and may not be suitable for our patient population. OBJECTIVES: To evaluate the major risk factors for adverse short and long term outcomes in patients with active native valve infective endocarditis needing cardiac surgery, and to validate the EuroSCORE II in our cohort of patients. PATIENTS AND METHODS: A retrospective review will be undertaken on patients with infective endocarditis requiring cardiac surgery from 2000-2012 at the Christian Barnard Division of Cardiothoracic surgery (Groote Schuur Hospital, UCT Private Academic Hospital) and follow-up with respect to mortality, re-operation and major adverse cardiac events, as well as an evaluation of the validity of the EuroSCORE II. DATA COLLECTION AND ANALYSIS: The standardized data extraction form in the appendix will be used for extracting data from various databases and telephonic interviews. Data will be analyzed using STATA to determine the most significant predictors of adverse outcome and conducting Kaplan Meier actuarial analysis for early and late survival and freedom from adverse events. The EuroSCORE II will be evaluated and validated to our cohort of patients