Development and In Vitro-In Vivo Evaluation of Oral Drug Delivery System of Acyclovir Loaded PLGA nanoparticles.

Acyclovir (ACV) is an antiviral drug, used for treatment of herpes simplex virus infections with an oral bioavailability of only 10 to 20 % (limiting absorption in GIT to duodenum and jejunum),half-life about 3 hrs, soluble at acidic pH (pKa 2.27) and distilled water at 37ºC. Polymeric nano drug delivery systems of ACV have been designed and optimized. Poly (lactic-co-glycolic acid) (PLGA) (50:50) was used as polymer and Pluronic F68 was stabilizer. In vitro evaluation of prepared formulations showed drug entrapment up to 90.06 % and particle size from 395nm. Drug: Polymer ratio and concentration of stabilizer were found to influence the particle size and entrapment efficiency of ACV loaded PLGA nanoparticles (NPs). In vitro drug release studies indicated controlled and sustained drug release of drug for a period of 32 hours. In vivo evaluation was carried out for selected formulations in comparison with marketed tablet (Zovirax®) in rabbits. The AUC values for developed formulations clearly indicated two to three fold improvement in bioavailability of ACV when compared to Zovirax® tablets. These preliminary results indicate ACV NPs are superior to marketed tablet Zovirax® as particle size and release rate of entrapped drug is controlled, which results in enhanced bioavailability and probable decrease in dose and dosing frequency. Ultimately increasing adherence to drug therapy and patient comfort

Development and In Vitro-In Vivo Evaluation of Oral Drug Delivery System of Acyclovir Loaded PLGA nanoparticles.

Acyclovir (ACV) is an antiviral drug, used for treatment of herpes simplex virus infections with an oral bioavailability of only 10 to 20 % (limiting absorption in GIT to duodenum and jejunum),half-life about 3 hrs, soluble at acidic pH (pKa 2.27) and distilled water at 37ºC. Polymeric nano drug delivery systems of ACV have been designed and optimized. Poly (lactic-co-glycolic acid) (PLGA) (50:50) was used as polymer and Pluronic F68 was stabilizer. In vitro evaluation of prepared formulations showed drug entrapment up to 90.06 % and particle size from 395nm. Drug: Polymer ratio and concentration of stabilizer were found to influence the particle size and entrapment efficiency of ACV loaded PLGA nanoparticles (NPs). In vitro drug release studies indicated controlled and sustained drug release of drug for a period of 32 hours. In vivo evaluation was carried out for selected formulations in comparison with marketed tablet (Zovirax®) in rabbits. The AUC values for developed formulations clearly indicated two to three fold improvement in bioavailability of ACV when compared to Zovirax® tablets. These preliminary results indicate ACV NPs are superior to marketed tablet Zovirax® as particle size and release rate of entrapped drug is controlled, which results in enhanced bioavailability and probable decrease in dose and dosing frequency. Ultimately increasing adherence to drug therapy and patient comfort

DEVELOPMENT AND VALIDATION OF A HIGHLY SENSITIVE HIGH PERFORMANCE LIQUID CHRMOATOGRAPHY (HPLC) METHOD FOR THE ESTIMATION OF METHOTREXATE (MTX) PURE DRUG AND MARKETED FORMULATION IN SPIKED RAT PLASMA

Objective: Methotrexate (MTX) is used as an anti-tumor agent, and its clinical pharmacokinetics requires an accurate method for estimation of its plasma concentration. We describe a rapid, selective and sensitive HPLC method coupled with UV detection for determination of MTX in rat plasma.Methods: Internal standard (IS; caffeine) was added to plasma aliquots prior to protein precipitation with acetonitrile. MTX and IS were eluted on a Phenomenex C18 column (250 mm × 4.6 mm, 5 μm) protected by a guard column (4 mm × 3 mm ×5 μm) (Torrance, CA, USA). The mobile phase comprised a mixture of aqueous 0.01 M phosphate buffer (pH 3.9)/acetonitrile (89/11%, v/v). To further improve the applicability of the method, a marketed formulation of high dose MTX (Folitrax 10 mg, IPCA) was spiked in rat plasma and the developed method was applied for the detection of MTX.Results: Adequate specificity, precision, and accuracy of the proposed method were demonstrated over the concentration range of 10 to 1000 ng/ml.Conclusion: This developed method was more sensitive and specific than any reported methods for the estimation of MTX and hence was successfully applied to measure plasma MTX concentrations in rat plasma which can be useful to elucidate the pharmacokinetic data of MTX.Keywords: Methotrexate, Folitrax, Protein precipitation, Rat plasma, Caffein

FORMULATION AND EVALUATION OF TACROLIMUS LOADED TRANSFERSOMAL SUBLINGUAL FILMS FOR EFFICIENT MANAGEMENT OF ORGAN REJECTION: IN VITRO AND IN VIVO STUDY

Objective: Patients travailing with end-stage organ failure can benefit from life-saving treatment protocol called organ transplantation that also rallies eminence of life. Tacrolimus plays important role in maintaining the healthy status of the organ transplanted, but its widespread clinical application is constrained due to low oral bioavailability which can be the limiting factor for the reduction in life span of transplanted healthy organ. Methods: To overcome the drawbacks of tacrolimus and to maximize its therapeutic efficiency, tacrolimus was formulated as transfersomes using thin film hydration method using soyalecithin and  Tween-80,optimized by Central composite designs and characterized for Particle size, deformability index (DI), entrapment efficiency(EE%) and Zeta potential. The selected transfersome formulation was incorporated into sublingual films using Hydroxy Propyl Methyl Cellulose (HPMC) as film-forming polymer and Polyethylene Glycol (PEG-400) as Plasticizer. The physical characteristics (average weight, pH, uniformity of weight and thickness) of the prepared films were studied, in addition they were evaluated for the in vitro drug release, ex vivo permeation, Differential Scanning Calorimetry (DSC), Attenuated Reflectance Spectroscopy (ATR), Scanning Electronic Microscopy (SEM), stability and in vivo pharmacokinetics in rats to prove the effect of flexibility provided by vesicle formation through sublingual route for enhanced systemic availability of tacrolimus. Results: Designed and optimized transfersomal vesicles showed the vesicle size of 139±2.1 nm with Deformability Index of 8.53±1.9%, Entrapment Efficiency of 86.66±1.2% and zeta potential of -23.6 mV respectively. Optimized Tacrolimus-loaded transfersomal vesicles (TAC-TFs) showed controlled release with more than 80±3.4% for extended period of time compared to pure drug Tacrolimus. The average weight of all prepared transfersomal sublingual film (TAC_TF_SL films), batches were found in the range of 55.8±1.45 to 94.2±1.42 mg with mean thickness in the range of 0.23+0.1 to 0.52±0.2 mm indicating uniform cast of respective batches. The surface pH was found to be in the range of 6.9 to 7.0 which was close to saliva pH. Optimized transfersomal sublingual films as well as nanovesicular dispersions found to be followed Zero order, diffusion coupled with polymer relaxation. Ex vivo studies revealed the improved permeation of 6.51±0.04µg drug through sublingual mucosa than pure drug of 1.2±0.01 µg depicting the significant role of soyalecithin and edge activator in the formulations. Transfersomal sublingual films exhibited controlled release with higher plasma concentration of 9.16±2.34 µg/ml at Tmax of 1.29±1.51hr in comparison with 7.99±1.23 µg/ml at Tmax of 0.75±1.78hr (oral marketed dosage form Pengraf capsules) embarking the higher rate of controlled absorption after sublingual delivery of optimized sublingual films with significant increase in AUC of 129.87±2.40 μg/ml*hr when compared to AUC of marketed dosage form of 69.19 ±1.46 μg/ml*hr. In addition the absolute bioavailability of the drug following sublingual administration was found to be 70.77±2.92% in comparison with that after oral administration 40.60±2.34%. Conclusion: Designed Tacrolimus loaded transfersomal sublingual films can be a promising carrier for delivering tacrolimus through sublingual route by enhancing drug bioavailability efficiently which can be a boon to organ transplanted patients

Response surface methodology and process optimization of sustained release pellets using Taguchi orthogonal array design and central composite design

Furosemide is a powerful diuretic and antihypertensive drug which has low bioavailability due to hepatic first pass metabolism and has a short half-life of 2 hours. To overcome the above drawback, the present study was carried out to formulate and evaluate sustained release (SR) pellets of furosemide for oral administration prepared by extrusion/spheronization. Drug Coat L-100 was used within the pellet core along with microcrystalline cellulose as the diluent and concentration of selected binder was optimized to be 1.2%. The formulation was prepared with drug to polymer ratio 1:3. It was optimized using Design of Experiments by employing a 32 central composite design that was used to systematically optimize the process parameters combined with response surface methodology. Dissolution studies were carried out with USP apparatus Type I (basket type) in both simulated gastric and intestinal pH. The statistical technique, i.e., the two-tailed paired t test and one-way ANOVA of in vitro data has proposed that there was very significant (P≤0.05) difference in dissolution profile of furosemide SR pellets when compared with pure drug and commercial product. Validation of the process optimization study indicated an extremely high degree of prognostic ability. The study effectively undertook the development of optimized process parameters of pelletization of furosemide pellets with tremendous SR characteristics

Cocrystals of Hydrochlorothiazide: Solubility and Diffusion/Permeability Enhancements through Drug-Coformer Interactions

Hydrochlorothiazide (HCT) is a diuretic and a BCS class IV drug with low solubility and low permeability, exhibiting poor oral absorption. The present study attempts to improve the physicochemical properties of the drug using a crystal engineering approach with cocrystals. Such multicomponent crystals of HCT with nicotinic acid (NIC), nicotinamide (NCT), 4-aminobenzoic acid (PABA), succinamide (SAM), and resorcinol (RES) were prepared using liquid-assisted grinding, and their solubilities in pH 7.4 buffer were evaluated. Diffusion and membrane permeability were studied using a Franz diffusion cell. Except for the SAM and NIC cocrystals, all other binary systems exhibited improved solubility. All of the cocrystals showed improved diffusion/membrane permeability compared to that of HCT with the exception of the SAM cocrystal. When the solubility was high, as in the case of PABA, NCT, and RES cocrystals, the flux/permeability dropped slightly. This is in agreement with the expected interplay between solubility and permeability. Improved solubility/permeability is attributed to new drug-coformer interactions. Cocrystals of SAM, however, showed poor solubility and flux This cocrystal contains a primary sulfonamide dimer synthon similar to that of HCT polymorphs, which may be a reason for its unusual behavior. Hirshfeld surface analysis was carried out in all cases to determine whether a correlation exists between cocrystal permeability and drug-coformer interactions