Piyasi Mukhopadhyay

pH-sensitive chitosan/alginate core-shell nanoparticles for efficient and safe oral insulin delivery

Chitosan-alginate (CS/ALG) nanoparticles were prepared by formation of an ionotropic pre-gelation of an alginate (ALG) core entrapping insulin, followed by chitosan (CS) polyelectrolyte complexation, for successful oral insulin administration. Mild preparation process without harsh chemicals is aimed at improving insulin bio-efficiency in in vivo model. The nanoparticles showed an average particle size of 100-200 nm in dynamic light scattering (DLS), with almost spherical or sub-spherical shape and ∼ 85% of insulin encapsulation. Again, retention of almost entire amount of encapsulated insulin in simulated gastric buffer followed by its sustained release in simulated intestinal condition proved its pH sensitivity in in vitro release studies. Significant hypoglycemic effects with improved insulin-relative bioavailability (∼ 8.11%) in in vivo model revealed the efficacy of these core-shell nanoparticles of CS/ALG as an oral insulin carrier. No systemic toxicity was found after its peroral treatment, suggesting these core-shell nanoparticles as a promising device for potential oral insulin delivery.

pH sensitive N-succinyl chitosan grafted polyacrylamide hydrogel for oral insulin delivery.

pH sensitive PAA/S-chitosan hydrogel was prepared using ammonium persulfate (APS) as an initiator and methylenebisacrylamide (MBA) as a crosslinker for oral insulin delivery. The synthesized copolymer was characterized by Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) study; morphology was observed under scanning electron microscope (SEM). The PAA/S-chitosan with ∼ 38% of insulin loading efficiency (LE) and ∼ 76% of insulin encapsulation efficiency (EE), showed excellent pH sensitivity, retaining ∼ 26% of encapsulated insulin in acidic stomach pH 1.2 and releasing of ∼ 98% of insulin in the intestine (pH 7.4), providing a prolonged attachment with the intestinal tissue. The oral administration of insulin loaded PAA/S-chitosan hydrogel was successful in lowering the blood glucose level of diabetic mice. The bioavailability of insulin was ∼ 4.43%. Furthermore, no lethality or toxicity was documented after its peroral administration. Thus, PAA/S-chitosan hydrogel could serve as a promising oral insulin carrier in future.

Oral insulin delivery by self-assembled chitosan nanoparticles: in vitro and in vivo studies in diabetic animal model.

We have developed self-assembled chitosan/insulin nanoparticles for successful oral insulin delivery. The main purpose of our study is to prepare chitosan/insulin nanoparticles by self-assembly method, to characterize them and to evaluate their efficiency in vivo diabetic model. The size and morphology of the nanoparticles were analyzed by dynamic light scattering (DLS), atomic force microscopy (AFM) and scanning electron microscopy (SEM). The average particle size ranged from 200 to 550 nm, with almost spherical or sub spherical shape. An average insulin encapsulation within the nanoparticles was ~85%. In vitro release study showed that the nanoparticles were also efficient in retaining good amount of insulin in simulated gastric condition, while significant amount of insulin release was noticed in simulated intestinal condition. The oral administrations of chitosan/insulin nanoparticles were effective in lowering the blood glucose level of alloxan-induced diabetic mice. Thus, self-assembled chitosan/insulin nanoparticles show promising effects as potential insulin carrier system in animal models.

Quercetin in anti-diabetic research and strategies for improved quercetin bioavailability using polymer-based carriers – a review

With numerous pharmacological and biological functions bio-flavonoids gain appreciable attention in diabetes and other therapeutic research. Among several beneficial flavonoids quercetin exhibits impressive hypoglycemic effects, with significant improvement, stabilization of long sustaining insulin secretion and regeneration of human islets in the pancreas without producing serious health hazards. However, in oral delivery poor solubility, stability in biological milieu, low permeation, short biological half-life, and insignificant bioavailability limit its wide application in anti diabetic research. Over the last few decades polymeric carrier systems have been widely studied for improvement of quercetin bioavailability. Natural polymers are more preferred in this regard as they possess several favourable properties like biocompatibility, biodegradability, mucoadhesiveness, non-immunogenicity and non-toxicity. This review focuses on quercetin in anti-diabetic research and the progress in the synthesis of polymer-based formulations for efficient quercetin delivery, with an emphasis on producing an improved biological efficacy of the flavonoid. Diabetic complications, probable mechanisms of quercetin absorption, regulation and anti diabetic effects, obstacles to produce desired bio-efficacy and possible remedies are also brought into focus. To overcome these barriers encapsulation of quercetin within various safe polymeric vehicles are discussed. Further, this review sheds light on enhancing the efficacy of quercetin in novel ways for successful diabetes treatment and others.

Efficient oral insulin delivery by dendronized chitosan: in vitro and in vivo studies

The development of efficient and bio-safe polymeric carriers for oral insulin delivery is a major thrust in biomedical research. In this paper, dendronized chitosan (DCTS) is prepared using a Michael-type addition reaction by grafting polyamidoamine (PAMAM) onto chitosan to improve its water solubility, pH sensitivity, and insulin encapsulation efficiency for enhanced bioavailability of the oral insulin. The self-assembled dendronized chitosan nanoparticles are prepared using a mild coacervation method, in which almost sub-spherically shaped nanoparticles of 85–150 nm size are produced, with an insulin encapsulation of approx. 95%. In vitro release study confirms a pH-sensitive and self-sustained release of insulin, where the oral administration of these nanoparticles exhibits a pronounced hypoglycemic effect in diabetic mice, producing a relative bioavailability of ∼9.19%. As no systemic toxicity is observed with its peroral delivery, these DCTS nanoparticles can effectively serve as a promising device in the efficient administration of oral insulin.

Chitosan-graft-PAMAM–alginate core–shell nanoparticles: a safe and promising oral insulin carrier in an animal model

The development of efficient, biodegradable and bio-safe polymeric nanocarriers for oral insulin delivery is a major goal in the biomedical field. PAMAM grafted chitosan (CS-g-PAMAM) was prepared using a Michael type addition reaction to graft polyamidoamine (PAMAM) onto native chitosan to improve the water solubility, pH responsiveness, and insulin encapsulation efficiency for the enhancement of the relative oral bioavailability of insulin. The insulin loaded nanoparticles were prepared by the formation of an ionotropic pre-gel with an alginate (ALG) core that entrapped insulin, followed by PAMAM grafted chitosan (CS-g-PAMAM) polyelectrolyte complexation. The mild preparation process not involving harsh chemicals is aimed to improve insulin bio-efficiency in vivo. The nanoparticles had an excellent core–shell architecture with an average particle size of 98–150 nm as shown by dynamic light scattering (DLS), with ∼97% insulin encapsulation and 27% insulin loading capacity. In vitro release data confirm a pH sensitive and self-sustained release of encapsulated insulin, protecting it from enzymatic deactivation in the gastrointestinal tract. The oral administration of these nanoparticles exhibits a pronounced hypoglycaemic effect in diabetic mice, producing a relative bioavailability of ∼11.78%. As no acute systemic toxicity is observed with peroral treatment, these core–shell nanoparticles can effectively serve as an efficient carrier of oral insulin in a mouse model.

Alginate coated chitosan core-shell nanoparticles for efficient oral delivery of naringenin in diabetic animals—An in vitro and in vivo approach

The chemical synthesis of this study targets for development of a bio-safe polymeric nano-vehicle for improvising the solubility of the flavanone naringenin in antidiabetic animal study. Nanoparticles were prepared from two cost-effective carbohydrate biopolymers - chitosan and alginate for successful encapsulation of naringenin. Dual crosslinked nanoparticles were synthesized by using Na2SO4 and CaCl2 as crosslinkers. The nanoparticles were characterized by DLS, FTIR, XRD and SEM. The prepared nano-formulations exhibited significant naringenin entrapment of >90% and pH-responsive slow and sustained release of the flavonoid. In-vivo studies revealed significant hypoglycemic effect after oral delivery of the nanoparticles to streptozotocin-induced diabetic rats. Histopathology and several blood parameters indicated that oral administrations of nanoparticles were free from toxicity. Other studies also suggested that polymeric formulations were quite effective for oral delivery of the flavonoid as a therapeutic agent in the treatment of dyslipidemia, hyperglycemia and haemoglobin iron-mediated oxidative stress in type 1 diabetic model.

Characterization and evaluation of curcumin loaded guar gum/polyhydroxyalkanoates blend films for wound healing applications

The present paper explores the ‘in situ’ fabrication of guar gum/polyhydroxyalkanoates-curcumin blend (GPCC) films in view of their increasing applications as wound dressings and antibacterial materials. Curcumin is incorporated to assess its bactericidal activity and to enhance the production and accumulation of the extracellular matrix in the healing process. In order to characterize the nature of the polymer network in the blend, FTIR/ATR spectra analysis and TGA are performed. The results reveal that the rigidity of the guar gum/PHBV blend improves with the increase of PHBV content due to the formation of non-covalent interactions, especially H-bonds, between these molecules. Electron microscopy analyses reveal the homogenecity of the blends and surface roughness of the blended films, favoring cell attachment and cell proliferation compared with the film without curcumin. The anti-microbial study demonstrate that the bactericidal activity is more effective against Gram-positive strains than Gram-negative strains. Results of the in vivo wound healing study in an animal model demonstrates that the developed curcumin loaded guar gum/PHBV blend film shows markedly enhanced wound healing compared to the control one.

Assessment of in vivo chronic toxicity of chitosan and its derivates used as oral insulin carriers

Considering public health protection, the carrier system for oral insulin must be safe. Hence, in the present study, the chronic oral toxicity of chitosan derivates was investigated in a mouse model. Oral administration of polymers did not cause any significant change in the behavioural pattern, body weight, and clinical symptoms of the treated mice. There were also no significant alterations in the biochemical parameters of blood serum and urine. Further, histopathological examination revealed an almost normal architecture, suggesting no significant adverse effects on the liver, kidney and intestine of the treated animals. An in vitro haemolysis assay proved that chitosan and its derivatives were blood compatible. Finally, intestinal luminal bacteria were able to biodegrade the polymers completely. Overall, the results suggested that the oral administration of the derivatives of chitosan in mice did not produce any significant toxicity in chronic treatment. Hence, these polymers could be utilized as safe devices for oral delivery of insulin and also other drugs.

Viper and Cobra Venom Neutralization by Alginate Coated Multicomponent Polyvalent Antivenom Administered by the Oral Route

Background Snake bite causes greater mortality than most of the other neglected tropical diseases. Snake antivenom, although effective in minimizing mortality in developed countries, is not equally so in developing countries due to its poor availability in remote snake infested areas as, and when, required. An alternative approach in this direction could be taken by making orally deliverable polyvalent antivenom formulation, preferably under a globally integrated strategy, for using it as a first aid during transit time from remote trauma sites to hospitals. Methodology/Principal Findings To address this problem, multiple components of polyvalent antivenom were entrapped in alginate. Structural analysis, scanning electron microscopy, entrapment efficiency, loading capacity, swelling study, in vitro pH sensitive release, acid digestion, mucoadhesive property and venom neutralization were studied in in vitro and in vivo models. Results showed that alginate retained its mucoadhesive, acid protective and pH sensitive swelling property after entrapping antivenom. After pH dependent release from alginate beads, antivenom (ASVS) significantly neutralized phospholipaseA2 activity, hemolysis, lactate dehydrogenase activity and lethality of venom. In ex vivo mice intestinal preparation, ASVS was absorbed significantly through the intestine and it inhibited venom lethality which indicated that all the components of antivenom required for neutralization of venom lethality were retained despite absorption across the intestinal layer. Results from in vivo studies indicated that orally delivered ASVS can significantly neutralize venom effects, depicted by protection against lethality, decreased hemotoxicity and renal toxicity caused by russell viper venom. Conclusions/Significance Alginate was effective in entrapping all the structural components of ASVS, which on release and intestinal absorption effectively reconstituted the function of antivenom in neutralizing viper and cobra venom. Further research in this direction can strategize to counter such dilemma in snake bite management by promoting control release and oral antivenom rendered as a first aid.