Dina Nath Mishra

Nanoparticle mediated brain targeted delivery of gallic acid: in vivo behavioral and biochemical studies for improved antioxidant and antidepressant-like activity

Context: Gallic acid had been reported to possess antidepressant like activity, which may be attributed to its CNS effects like increase in reduced glutathione levels, increased catalase activity and decreased malonaldehyde levels in brain. Objective: This study was designed to enhance the antidepressant-like activity of gallic acid (GA) using nanoparticulate delivery system in swiss male albino mice and to explore the possible underlying mechanisms for this activity. Methods: GA loaded chitosan nanoparticles (GANP) and corresponding tween 80 coated batch (cGANP) were formulated for brain targeting of GA and characterized for physicochemical parameters, morphology, differential scanning calorimetry and in vitro drug release. GA, GANP, cGANP (dose equivalent to GA 10 mg/kg, i.p.) and positive control drug, Fluoxetine (10 mg/kg, i.p.) were administered for successive seven days to male swiss albino mice. Then, the in vivo antidepressant-like activity was evaluated using Despair Swim Test (DST) and Tail Suspension Test (TST); along with the evaluation of MAO-A activity, reduced glutathione, malonaldehyde level, catalase and locomotor activity in mice. Keyfindings: cGANP (equivalent to 10 mg/kg, i.p.) significantly decreased immobility period of mice in DST and TST, indicating significant antidepressant-like activity. There was no significant effect on locomotor activity of the mice by GA and its nanoparticle formulations. cGANP (10 mg/kg, i.p.) significantly decreased Monoamine oxidase-A (MAO-A) activity, malondialdehyde levels, and catalase activity in mice. Conclusions: GA possess significant antidepressant like activity and ligand coated nanoparticle approach with improved brain targeting may serve as an effective approach to enhance such effect.

Piroxicam Bioadhesive Ocular Inserts: Physicochemical Characterization and Evaluation in Prostaglandin-Induced Inflammation

Purpose: An attempt has been made in the present research to formulate piroxicam into bioadhesive ocular inserts with an objective to sustain drug release, reduce frequency of dosing, and enhance ocular bioavailability of piroxicam. Material and Methods: Drug matrices were prepared using film forming polymer, PVP and bioadhesive polymers, HPMC, CMC, and carbopol. Ocular inserts were prepared by film casting method and prepared films were subjected to investigations for their physical and mechanical properties, swelling behaviors, ex vivo bioadhesion, and in vitro drug release. The optimized formulation was tested and compared with eye drops of piroxicam for ocular anti-inflammatory activity in rabbits against PGE2-induced inflammation. Results: The physicochemical, bioadhesive, and swelling properties of films were found to vary significantly depending on the type of the polymers and their combination. The above properties were found to be optimum for all films; however, formulation containing carbopol 0.5% and HPMC 1% was found to be the best film as it shows good adhesion, acceptable pH, and gives a reasonable drug release (99% at 12 hr). Kinetic studies indicated both diffusion and swelling as mechanism of drug release from this matrix. Further in vivo studies with this formulation indicated a significant inhibition of PGE2-induced lid closure and PMN migration as compared to eye drops formulation. Conclusion: Formulation was found promising, as it sustained the drug release and enhanced the ocular bioavailability of piroxicam as compared to piroxicam eye drops.

Azithromycin novel drug delivery system for ocular application

Background: Azithromycin (AZT) is a macrolide antibiotic derived from and similar in structure to erythromycin. Oral administration of AZT is effective for the treatment of trachoma; however, topical formulations are difficult to develop because of the drugs hydrophobicity. The aim of this study is to formulate a novel topical ophthalmic delivery system of AZT. Materials and Methods: In the present study, ocular inserts of AZT are prepared using alginate, carbopol, and hydroxypropyl methylcellulose (HPMC) to solve the said formulation problem of drug and to facilitate ocular bioavailability. Ocular inserts were prepared by film casting method and the prepared films were subjected to investigations for their physical and mechanical properties, swelling behaviors, ex vivo bioadhesion, and in vitro drug release. Ocular irritation of the developed formulation was also checked by hens egg chorioallantoic membrane test for ocular irritation potential. Results: The physicochemical, bioadhesive, and swelling properties of films were found to vary significantly depending on the type of polymers used and their combinations. The alginate films exhibited greater bioadhesion and showed higher tensile strength and elasticity than the carbopol films. HPMC addition to the films significantly affected the properties of ocular inserts. Carbopol:HPMC (30:70)-based ocular inserts sustained drug release for longest span of 6 h. The release profile of AZT showed that drug release was by both diffusion and swelling. The formulation was found to be practically nonirritant in ocular irritation studies. Conclusion: AZT can therefore be developed as an ocular insert delivery system for the treatment of ocular surface infections.

Toxicological study of the Primaquine phosphate loaded chitosan nanoparticles in mice

Primaquine (PQ) shows activity against the late hepatic stages and latent tissue forms of Plasmodium vivax and Plasmodium ovale. However, liver targeted PQ delivery may be useful to minimize the dose-limiting blood toxicities and side-effects of PQ. The prime objective of this study was the preparation of PQ loaded chitosan nanoparticles (PQ-CS-NPs) in order to enhance drug tolerance and to reduce dose frequency. The morphological analysis of the chitosan NPs displayed particle size in the range 287-686 nm, polydispersity index in the range 0.338-0.430 and zeta potential between 9.21 and 22.80 mV which indicated good stability. PQ-CS-NPs exhibited EE and LC as 64.28 ± 1.85% and 33.18 ± 0.975%, respectively. The in vitro drug release (Batch C7) was 97.80 ± 0.65% after 24 h. After intravenous injection of PQ-CS-NPs in mice, the lethal dose of the PQ significantly reduced when compared to that of free PQ solution.

Unfolding type gastroretentive film of Cinnarizine based on ethyl cellulose and hydroxypropylmethyl cellulose

The present work was based on the development and characterization of unfolding type gastro retentive dosage form appropriate for controlled release of Cinnarizine (CNZ), a drug with narrow therapeutic window. The drug loaded polymer film of biological macromolecules, i.e., ethyl cellulose (EC) and hydroxypropylmethyl cellulose (HPMC K15) was folded into hard gelatin capsules. The film was folded in different patterns for characterizing their unfolding behavior. The polymeric film revealed a fast release during the first hour followed by a more gradual drug release during a 12-h period following a non-Fickian diffusion process. Tensile strength of polymeric film was optimized using different amount (0.2-0.7 ml) of polyethylene glycol (PEG 400). Various physical parameters were studied for evaluating their performance as a gastroretentive dosage form. Drug and polymers were found to be compatible as revealed by differential scanning calorimetry (DSC) study and scanning electron micrograph (SEM) study revealed uniform dispersion of CNZ in polymeric matrices. The results indicate that unfolding type gastro retentive drug delivery system holds lots of potential for drug having stability problems in alkaline pH or are which mainly absorbed in acidic pH.

Effect of ampicillin and chloroquine on humoral immune response elicited by bovine albumin encapsulated in liposomes

Effect of ampicillin and chloroquine on humoral immune response elicited by bovine albumin encapsulated in liposomes Immune suppression resulting from chemoprophylaxis and potential drug interaction were investigated in experimental animals pre-medicated with ampicillin and chloroquine followed by immunization with bovine serum albumin bearing liposomes prepared by the reverse phase evaporation method. The prepared liposomes were evaluated for particle size, entrapment efficiency and in vitro release. Humoral immune response was measured in terms of systemic IgG antibody titre by the ELISA method. The present study showed that 7:3 molar ratio of soya phosphatidylcholine and cholesterol produced liposomes of mean diameter of 235.4 ± 10.3 nm and entrapment efficiency of 41.3 ± 3.2%. Ampicillin significantly (p < 0.05) decreased the antibody titre whereas chloroquine did not reduce the antibody titre significantly. The study will help in programming a new drug management and in characterization of vaccine-drug interaction. Učinak ampicilina i klorokina na humoralnu imunošku reakciju na goveđi albumin kapsuliran u liposome Na eksperimentalnim životinjama koje su prvo tretirane ampicilinom i klorokinom a zatim imunizirane goveđim serumskim albuminom s liposomima praćena je supresija imunološkog sustava i potencijalna interakcija lijekova. Liposomi su pripravljeni metodom reverzno-fazne evaporacije, a određena im je veličina čestica, količina supstancije koju mogu inkorporirati i oslobađanje in vitro. Humoralna imunološka reakcija praćena je određivanjem titra IgG antitijela ELISA metodom. Rezultati rada pokazuju da liposomi s fosfatidilkolinom iz soje i kolesterolom u molnom omjeru 7:3 imaju prosječni promjer 235.4 ± 10.3 nm i sposobnost inkorporacije 41.3 ± 3.2%. Ampicilin je značajno (p < 0.05) smanjio titar antitijela, a klorokin nije. Ovi će rezultati biti korisni u programiranju novog režima primjene lijekova i u praćenju interakcije između cjepiva i lijeka.

Enhancement of ketorolac tromethamine permeability through rat skin using penetration enhancers: An ex-vivo study.

Introduction: Ketorolac tromethamine (KT), a nonsteroidal anti-inflammatory drug, when given orally causes gastrointestinal disturbances. Its transdermal drug delivery may reduce such side effects associated with them. The present investigation was aimed at evaluating the efficiency of various penetration enhancers for improved permeation of KT through the skin. Materials and Methods: A concentration of 1 mg/mL of the drug solution with enhancers was used to evaluate diffusion through the rat skin using a Franz diffusion cell assembly. 20 different penetration enhancers were selected for this study. Results: Saturated fatty acids like stearic and palmitic acid were found to increase the permeation rate of the drug to a great extent whereas unsaturated fatty acid viz. oleic acid exhibited maximum permeation. Increase in permeability efficiency of various penetration enhancers was observed in the following order: Oleic acid > stearic acid > palmitic acid > isopropyl myristate > tween 80 > span 80 > span 40 > span 20 > l-limonene > l-menthol > fenchone > α-pinene > urea > dimethyl sulfoxide (DMSO) > triton X-100 > tween 20 > dimethyl formamide > acetone > control > citric acid > ascorbic acid. Ascorbic acid and citric acid had no effect on permeation rate. Conclusion: The results revealed that the permeation of KT through the skin can maximally be enhanced using oleic acid-an unsaturated fatty acid.

Failure of calcium gluconate internal gelation for prolonging drug release from alginate-chitosan-based ocular insert of atenolol

Background: The aim of the investigation was to develop and evaluate ocular polymeric film of atenolol for the management of glaucoma. Materials and Methods: Fixed concentration blends of sodium alginate (NaAlg) and chitosan were combined with the varying concentration of calcium gluconate and the resulting hydrogels were casted as ocular films. Various physicochemical studies and in vitro release tests of the prepared films were carried out to study the effect of calcium gluconate addition to alginate-chitosan blend films. Results: Cumulative % drug released from the formulations ranged from 95 to 99% within 5- to 12-hour period. The drug release enhanced with incorporation of higher ratios of calcium gluconate. F1 (2% NaAlg and 1% chitosan without calcium gluconate) sustained the drug release for the longest period of time (12 hours). Addition of calcium gluconate to the formulation resulted in faster drug release rather than sustained drug release. Conclusion: The results showed that the addition of calcium gluconate leads to a change in the release capacities of the matrices. Despite the presence of calcium ions and thus the possibility of an ionic interaction, the internal gelation of the polymer matrix lead to enhanced drug release and poor sustaining of drug. The sustained release effect of NaAlg-chitosan matrices alone was the best among the formulations studied.

Nose to brain delivery of galantamine loaded nanoparticles: In-vivo pharmacodynamic and biochemical study in mice

BACKGROUND Presence of blood brain barrier is one of the major hurdle in drug delivery to brain for the treatment of neurological diseases. Alternative and more effective drug delivery approaches have been investigated for the drug targeting to brain in therapeutic range. OBJECTIVE The present investigation was carried out to improve the galantamine bioavailability in brain by intranasal drug delivery through thiolated chitosan nanoparticles and compared to nasal and oral delivery of its solution using pharmacodynamic activity as well as biochemical estimation. METHODS Thiolated chitosan (modified) nanoparticles were fabricated using modified ionic gelation method and intranasal delivery is evaluated by reversal of scopolamine induced amnesia and biochemical estimation of acetylcholinesterase activity in Swiss albino mice brain. Scopolamine (0.4 mg/kg, i.p.) was used to induce amnesia. Piracetam (400mg/kg, i.p.) was used as positive control. Mice were treated with galantamine solution (4mg/kg) by oral and nasal route and formulated galantamine nanoparticles (equivalent to 4mg/kg) by intranasal administration for 7 successive days and the results were compared statistically. RESULTS Intranasal delivery of galantamine loaded thiolated chitosan nanoparticles was found significant (p<0.05) as compared to oral and nasal administration of its solution, by pharmacodynamic study and biochemical estimation of acetylcholinesterase activity in Swiss albino mice brain. CONCLUSION Significant recovery in amnesia induced mice model by intranasal administration of galantamine loaded thiolated chitosan nanoparticles established the relevance of nose to brain delivery over the conventional oral therapies for the treatment of Alzheimers disease.