Fabrication, Evaluation, In Vivo Pharmacokinetic and Toxicological Analysis of pH-Sensitive Eudragit S-100-Coated Hydrogel Beads: a Promising Strategy for Colon Targeting.

The aim of present research aims to fabricate a system of enteric coating of hydrogel beads with pH-sensitive polymer, which shows solubility at pH > 7, and explore their potential to target the colon for drug delivery. Hydrogel beads were fabricated through the extrusion-dripping technique followed by ion gelation crosslinking. Moreover, freeze-thaw cycle was implemented for crosslinking of polyvinyl alcohol (PVA)/Ca-alginate blend beads. The oil-in-oil solvent evaporation method was adopted for the Eudragit coating of hydrogel beads using different coat: core ratios (4:1 or 8:1). Coated and uncoated hydrogel beads were evaluated by in vitro physicochemical properties, swelling and drug release behaviours, and in vivo pharmacokinetics, swelling, and toxicity evaluation. Diclofenac sodium was loaded as an experimental drug. Drug entrapment efficiency for the PVA/Ca-alginate beads was calculated as 98%, and for Ca-alginate beads, it came out to a maximum of 74%. Drug release study at various pH suggested that, unlike uncoated hydrogel beads, the coated beads delay the release of diclofenac sodium in low pH of the gastric and intestinal environment, thus targeting the colon for the drug release. It was concluded that Eudragit S-100-coated hydrogel beads could serve as a more promising and reliable way to target the colon for drug delivery.Graphical abstract.

Synthesis of N,O-Carboxymethyated chitosan and its application in the development of acyclovir loaded nanoparticles.

Objective of the study was to perform a physico-chemical modification of low molecular weight chitosan (CTS) followed by its use in the formulation of nanoparticles carrier of Acyclovir (ACY). Modified polymer was used to develop ACY loaded nanoparticles in order to achieve optimal response and to minimize toxic effects of ACY. CTS were dissolved in varying concentrations of potassium hydroxide solution to synthesize N, O-carboxymethylated chitosan (N,O-CMC). Synthesized derivative was further processed with different concentrations of TPP (0.3%, 0.5% and 1%) and ACY to prepare nanoparticles. N,O-CMC and prepared formulations were characterized by Fourier transform infrared spectroscopy (FTIR). Furthermore, scanning electron microscopy (SEM) was done to observe the surface morphology, zeta size and zeta potential for particle size analysis, in vitro dissolution to find out the release pattern and kinetic modeling was done to observe the release mechanism and pattern of the drug. Result of FTIR was evidence of polymer modification when compared with chitosan which was the parent standard polymer as well as compatibility of the ingredients. Results of zeta size analysis have confirmed that the particles are of nanosized (109-125nm). Good controlled 98.77% over release of 24 h of formulation B observed in phosphate buffer of intestinal pH. Higuchi model with Fickian diffusion was dominating due to the formation of N, O-CMC complex which created smooth surface. All the results were significant and within the p value of 0.001. Conclusively, the modification of the CTS was in nanoparticle showed good sustained release.

The structural, morphological and thermal properties of grafted pH-sensitive interpenetrating highly porous polymeric composites of sodium alginate/acrylic acid copolymers for controlled delivery of diclofenac potassium.

In present investigation new formulations of Sodium Alginate/Acrylic acid hydrogels with high porous structure were synthesized by free radical polymerization technique for the controlled drug delivery of analgesic agent to colon. Many structural parameters like molecular weight between crosslinks (Mc ), crosslink density (Mr ), volume interaction parameter (v2,s ), Flory Huggins water interaction parameter and diffusion coefficient (Q) were calculated. Water uptake studies was conducted in different USP phosphate buffer solutions. All samples showed higher swelling ratio with increasing pH values because of ionization of carboxylic groups at higher pH values. Porosity and gel fraction of all the samples were calculated. New selected samples were loaded with the model drug (diclofenac potassium).The amount of drug loaded and released was determined and it was found that all the samples showed higher release of drug at higher pH values. Release of diclofenac potassium was found to be dependent on the ratio of sodium alginate/acrylic acid, EGDMA and pH of the medium. Experimental data was fitted to various model equations and corresponding parameters were calculated to study the release mechanism. The Structural, Morphological and Thermal Properties of interpenetrating hydrogels were studied by FTIR, XRD, DSC, and SEM.

DEVELOPMENT AND EVALUATION OF IVABRADINE HCI-LOADED POLYMERIC MICROSPHERES PREPARED WITH EUDRAGIT L100-55 (METHACRYLIC ACID-ETHYL ACRYLATE COPOLYMER) AND ETHYL CELLULOSE FOR CONTROLLED DRUG RELEASE.

The objective of this study was to prepare and evaluate ivabradine HCl-loaded microspheres consisting of Eudragit LIOO-55 and ethyl cellulose prepared by oil-in-oil solvent evaporation method. Ivabradine HCl was encapsulated into microspheres by in situ method. The resultant microspheres were characterized with respect to drug loading, flow properties, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffractometry (XRD), thermal analysis and release behavior. Chemical stability of IBH after being encapsulated into microspheres was confirmed by FTR, DSC and XRD. FTIR spectra reflect- ed no interaction between drug and excipients. TGA indicates that prepared microspheres showed much better thermal stability than pure drug ivabradine. SEM images showed formulation of microspheres in spherical shape. The maximum perceniage entrapment efficiency was found to be 81 ± 2.15 and percentage yield was 88 ± 2.65. The maximum in vito drug release was 94.5% for the pH 7.4 and demonstrated that all drug-loaded formulations had a pH-dependent drug release. The cumulative drug release data were analyzed by applying different kinetic models. Korsmeyer-Peppas equation was used to determine value of n which follows non-Fickian diffusion.

FABRICATION AND IN VITRO EVALUATION OF 5-FLOROURACIL LOADED CHONDROITIN SULFATE-SODIUM ALGINATE MICROSPHERES FOR COLON SPECIFIC DELIVERY.

Chondroitin sulfate and sodium alginate were incorporated in different ratios to prepare glutaraldehyde (GA) crosslinked microspheres by water-in-oil emulsion crosslinking method for delivery of 5-flurouracil (5-FU) to colon. Chemical interaction, surface morphology, thermal degradability, crystallinity evaluation, elemental analysis and drug release results were computed by using FTIR, SEM, DSC and TGA, PXRD, EXD and dissolution studies at pH 1.2, pH 6.8 and pH 7.4, respectively. Results revealed an acetal ring formation, non-porous surfaces, stability up to 450 degrees C with mass loss of 84.31%, variation in carbon and oxygen contents and targeted release at pH 7.4. Different kinetic models were applied on release studies i.e., zero order, first order, Higuchi and Korsmeyer-Peppas. Higuchi model was declared as best fit model based on r2 value (0.99) and mechanism of release was non-Fickian diffusion. A potential approach for colonic delivery of 5-FU was successfully developed.

PREPARATION AND EVALUATION OF pH RESPONSIVE POLY(2-HYDROXYETHYL METHACRYLATE-CO-ITACONIC ACID) MICROGELS FOR CONTROLLED DRUG DELIVERY.

In this study, a series of pH sensitive microgels (MGs) were prepared by modified free radical suspension polymerization of 2-hydroxyethyl methacrylate (HEMA) and itaconic acid (IA), using ethylene glycol dimethacrylate (EGDMA) as crosslinker. Equilibrium swelling technique was employed for esomeprazole magnesium trihydrate (EMT) loading. Prepared microgels were characterized through Fourier transforms infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), dynamic light scattering technique (DLS), scanning electron microscopy (SEM), equilibrium swelling and in vitro drug release kinetics. FTIR and TGA confirmed the formation of copolymeric p(HEMA-co-IA) network. SEM and DLS revealed smooth, round and uniformly distributed microspheres with particle size up to 10 µm. Developed microgels found to be pH responsive in nature. All the formulations (HIDI - HID5) followed Higuchi model with non-Fickian diffusion mechanism of drug release. It was concluded that p(HEMA-co-IA) microgels have potential to be used as drug carriers for site specific and controlled drug delivery.

Methods of synthesis of hydrogels A review.

Hydrogels are being investigated recently for the bioactive molecules (in particular pharmaceutical proteins) controlled release, such as matrices, and for the living cells encapsulation. Biodegradable nature of hydrogels has created much interest for drug delivery systems. The original three-dimensional structure disintegrates into nontoxic substances to ascertain an excellent biocompatibility of the gel. Chemical cross-linking is the highly resourceful method for the formation of hydrogels having an excellent mechanical strength. Cross-linkers used in hydrogel preparation should be extracted from the hydrogels before use due to their reported toxicity. Physically cross-linked methods for preparation of hydrogel are the alternate solution of cross-linker toxicity.

Chemically cross-linked poly(acrylic-co-vinylsulfonic) acid hydrogel for the delivery of isosorbide mononitrate.

We report synthesis, characterization, and drug release attributes of a series of novel pH-sensitive poly(acrylic-co-vinylsulfonic) acid hydrogels. These hydrogels were prepared by employing free radical polymerization using ethylene glycol dimethacrylate (EGDMA) and benzyl peroxide (BPO) as cross-linker and initiator, respectively. Effect of acrylic acid (AA), polyvinylsulfonic acid (PVSA), and EGDMA on prepared hydrogels was investigated. All formulations showed higher swelling at high pHs and vice versa. Formulations containing higher content of AA and EGDMA show reduced swelling, but one with higher content of PVSA showed increased swelling. Hydrogel network was characterized by determining structural parameters and loaded with isosorbide mononitrate. FTIR confirmed absence of drug polymer interaction while DSC and TGA demonstrated molecular dispersion of drug in a thermally stable polymeric network. All the hydrogel formulations exhibited a pH dependent release of isosorbide mononitrate which was found to be directly proportional to pH of the medium and PVSA content and inversely proportional to the AA contents. Drug release data were fitted to various kinetics models. Results indicated that release of isosorbide mononitrate from poly(AA-co-VSA) hydrogels was non-Fickian and that the mechanism was diffusion-controlled.

Improved physicochemical characteristics of artemisinin-nicotinamide solid dispersions by solvent evaporation and freeze dried methods.

Artemisinin (ARMN) is a drug of choice against drug-resistant malaria especially due to Plasmodium falciparum. Being poorly soluble in water, its solid dispersions with nicotinamide (NA) were prepared at various drug-carrier ratios (1:1, 1:4, 1:6, 1:8, 1:10) by solvent evaporation and freeze drying methods. These solid dispersions were characterized by differential scanning calorimetery (DSC), fourier transform infrared spectroscopy (FTIR), X-ray diffraction patterns (XRD), phase solubility and dissolution studies. Artemisinin and nicotinamide both were found completely crystalline as shown by their XRD patterns. Physical mixtures (PMs) showed decreased intensity in their XRD patterns while solid dispersions by solvent evaporation method (SLVPs) exhibited displaced angles and decreased intensity whereas freeze dried solid dispersions (FDSDs) showed least number of peaks having low intensity and maximum displaced angles. DSC thermograms of drug-carrier ratios at 1:1-1:4 showed lower melting temperature than artemisinin and nicotinamide in all preparations. Endothermic temperature of artemisinin in PMs and SLVPs increased with rise of nicotinamide content upto 1:6 ratio followed by decline. All samples showed crystallization temperature below the artemisinin except drug-carrier ratio 1:6 of PMs while δH value was minimum at this ratio. FDSDs produced lowest endothermic temperature than corresponding PMs and SLVPs. SLVPs exhibited band shifting in both functional and fingerprint region compared to respective PMs as exhibited by their FTIR spectra. FDSDs and SLVPs showed different nature of bonding among artemisinin and nicotinamide. FDSDs produced strongest CONH(2) bonding followed by SLVPs and PMs respectively. PMs produced significantly higher aqueous solubility and rate of dissolution as compared to artemisinin alone. SLVPs exhibited improved solubility and dissolution profile corresponding to PMs. FDSDs showed highest release rate and aqueous solubility followed by SLVPs and PMs at all ratios. PMs and SLVPs showed their highest dissolution profile at 1:6 drug-carrier ratio followed by gradual decrease while FDSDs progressed in dissolution rate with increase of nicotinamide content successively upto maximum at 1:10 ratio.

Preparation, characterization and release of verapamil hydrochloride from polycaprolactone/acrylic acid (PCL/AA) hydrogels.

In this study pH sensitive, biocompatible and controlled released hydrogels were prepared and their localized drug delivery effect was analyzed. Polycaprolactone and acrylic acid (PCL/AA) were reacted by free radical polymerization and developed inter penetrating polymeric network (IPN) hydrogels. Benzylperoxide was used as initiator and N, N methylenebisacrylamide [NNMBisAm] was employed as a cross-linking agent. Different concentrations of monomer, polymer and cross-linking agent were used and the reaction parameters were optimized. The obtained PCL/AA hydrogels were fully characterized by Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and thermogravimetric analysis (TGA) that determined the polymer structure, its morphology and strength respectively. Verapamil, a calcium channel blocker was loaded by incubation of polymerization method. Controlled release Verapamil hydrogel was developed due to its low solubility; low permeability and having very short half life of 1.2-2 h. The dynamic swelling, equilibrium swelling and drug release were carried out in a buffer solution of pH 1.2, 4.5 and 6.8. Concentration of Acrylic acid showed direct, while Polycaprolactone inverse relation to swelling and drug release due to their hydrophilic and hydrophobic nature respectively. Cross-linking agent also had the contrary effect on swelling. Diffusion coefficient (D) of hydrogels was determined by using Flory-Rehner theory. Drug release and swelling data were analyzed by different kinetic models, like Zero order, First order, Higuchi, Korsmeyer's and Peppas. The release and diffusion was best described by the first order kinetics where n value was <0.5 for all the formulations indicating Fickian drug release mechanism.

O-Carboxymethylated chitosan; A promising tool with in-vivo anti-inflammatory and analgesic properties in albino rats.

In the present study chitosan derivative, O-carboxymethylated chitosan (O-CMC) was synthesized by simple and cost-effective technique and scrutinized for in-vivo anti-inflammatory and analgesic activities. Na-carboxymethyl intermediate was prepared by acidification of chitosan with monochloroacetic acid and neutralized with 0.5 M NaOH which was further converted into O-CMC by using 0.2 M HCl. Resulted O-CMC was confirmed by FTIR spectroscopy. Inflammation was induced in albino rats by carrageenan and anti-inflammatory property of synthesized O-CMC was confirmed by calculating paw volume, %age inflammation and %age inhibition of inflammation. Analgesic properties were confirmed by %age analgesia and latency time. The results revealed that the synthesized O-CMC derivative of chitosan showed stretched peaks at 2891 cm-1, 1631 cm-1, 1060 cm-1 of -OH, -NH and -CO respectively. Formulation V was optimized due to its of percentage inflammation, 45.5 ± 0.02% inhibition of inflammation and decrease in paw volume, as well as a positive control on % age analgesia and latency time as compared to chitosan by applying statistics. O-CMC may be considered a remarkable anti-inflammatory and analgesic agent which may provide adjunctive effect with other active pharmaceutical ingredients.

pH responsive cross-linked polymeric matrices based on natural polymers: effect of process variables on swelling characterization and drug delivery properties.

Introduction: The current work was aimed to design and synthesize novel crosslinked pH-sensitive gelatin/pectin (Ge/Pec) hydrogels using different polymeric ratios and to explore the effect of polymers and degree of crosslinking on dynamic, equilibrium swelling and in vitro release behavior of the model drug (Mannitol). Methods: The Ge/Pec based hydrogels were prepared using glutaraldehyde as the crosslinker. Various structural parameters that affect their release behavior were determined, including swelling study, porosity, sol-gel analysis, average molecular weight between crosslinks (Mc), volume fraction of polymer (V2,s), solvent interaction parameter (χ) and diffusion coefficient. The synthesized hydrogels were subjected to various characterization tools like Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and DSC differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). Results: The hydrogels show highest water uptake and release at lower pH values. The FTIR spectra showed an interaction between Ge and Pec, and the drug-loaded samples also showed the drug-related peaks, indicating proper loading of the drug. DSC and TGA studies confirmed the thermal stability of hydrogel samples, while SEM showed the porous nature of hydrogels. The drug release followed non-Fickian diffusion or anomalous mechanism. Conclusion: Aforementioned characterizations reveal the successful formation of copolymer hydrogels. The pH-sensitive swelling ability and drug release behavior suggest that the rate of polymer chain relaxation and drug diffusion from these hydrogels are comparable which also predicts their possible use for site-specific drug delivery.

Effect of ethylene glycol dimethacrylate on swelling and on metformin hydrochloride release behavior of chemically crosslinked pH-sensitive acrylic acid-polyvinyl alcohol hydrogel.

BACKGROUND: The present work objective was to prepare and to observe the effect of ethylene glycol dimethacrylate on swelling and on drug release behavior of pH-sensitive acrylic acid-polyvinyl alcohol hydrogel. METHODS: In the present work, pH sensitive acrylic acid-polyvinyl alcohol hydrogels have been prepared by free radical polymerization technique in the presence of benzoyl peroxide as an initiator. Different crosslinker contents were used to observe its effect on swelling and on drug release. Dynamic and equilibrium swelling studies of prepared hydrogels were investigated in USP phosphate buffer solutions of pH 1.2, 5.5, 6.5 and 7.5 with constant ionic strengths. Hydrogels were evaluated for polymer volume fraction, solvent interaction parameter, molecular weight between crosslinks, number of links per polymer chain, diffusion coefficient, sol-gel fraction and porosity. To demonstrate the release pattern of the drug, zero-order, first-order, higuchi and korsmeyer-peppas models were applied. Quality and consistency of hydrogels was examined by FTIR and surface morphology of hydrogels was examined by SEM. RESULTS: Decrease in swelling and in drug release was seen by increasing content of ethylene glycol dimethacrylate. A remarkable high swelling was observed at high pH indicating the potential of this hydrogel for delivery of drugs to intestine. By increasing the concentration of ethylene glycol dimethacrylate, porosity decreased. Order of release was observed first order in all cases and the mechanism was non-fickian diffusion. FTIR confirmed the formation of network. SEM results showed the incorporation of drug. CONCLUSION: The prepared hydrogels can be suitably used for targeted drug delivery to the intestine.

Physicochemical characterization of artemether solid dispersions with hydrophilic carriers by freeze dried and melt methods.

Solid dispersions of artemether (ARM), a poorly soluble drug, were prepared using polyvinylpyrrolidone (PVPK25, MW 25000) and polyethyleneglycol (PEG4000, MW 4000) as excipients. These dispersions were studied by physical mixture, freeze-drying, and melting methods. They were characterized by X-ray diffraction pattern, fourier transform infrared spectrophotometry, differential scanning calorimetery, and dissolution studies. X-ray diffraction pattern revealed the complete crystalline nature of artemether, whereas physical mixtures, melt mixtures (MM), and freeze-dried solid dispersions (FDSD) of ARM-PVP and ARM-PEG showed reduced peak intensities with increased PVP/PEG content. PEG showed lower decreases in intensity than PVP preparations. Differential scanning calorimetery also confirmed this finding by showing either a small or absent endotherm. Red shifts in O-H stretching vibrations of ARM were higher in the MM of ARM-PVP than its FDSD as exhibited by fourier transform infrared spectrophotometry. The carbonyl peak of PEG was blue shifted in MM and FDSD, whereas the C=O peak of PVP was red shifted in FDSD and MM, indicating different H-bonding by PEG and PVP with ARM. The rate of dissolution (phosphate buffer at pH 4.5) was improved up to 4-fold in MM and FDSD compared to artemether, and up to 50% compared to physical mixtures. The preparation of solid dispersions influenced the rate of dissolution at various drug-carrier ratios, i.e., the dissolution order of 1:1-1:4 ratio was MM > FDSD; FDSD > MM at 1:6-1:8 ratios of both ARM-PVP and ARM-PEG; and FDSD of ARM-PEG > FDSD of ARM-PVP > MM of ARM-PEG > MM of ARM-PVP at a 1:10 ratio.

pH-sensitive polyvinylpyrrolidone-acrylic acid hydrogels: Impact of material parameters on swelling and drug release

In this study, we fabricated pH-sensitive polyvinylpyrrolidone/acrylic acid (PVP/AA) hydrogels by a free-radical polymerisation method with variation in the content of monomer, polymer and cross-linking agent. Swelling was performed in USP phosphate buffer solutions of pH 1.2, 5.5, 6.5 and 7.5 with constant ionic strength. Network structure was evaluated by different parameters and FTIR confirmed the formation of cross-linked hydrogels. X-ray crystallography showed molecular dispersion of tramadol HCl. A drug release study was carried out in phosphate buffer solutions of pH 1.2, 5.5 and 7.5 for selected samples. It was observed that swelling and drug release from hydrogels can be modified by changing composition and degree of cross-linking of the hydrogels under investigation. Swelling coefficient was high at higher pH values except for the one containing high PVP content. Drug release increased by increasing the pH of the medium and AA contents in hydrogels while increasing the concentration of cross-linking agent had the opposite effect. Analysis of the drug release mechanism revealed non-Fickian transport of tramadol from the hydrogels.

Nesse estudo, preparamos hidrogéis de polivinilpirrolidona/ácido acrílico(PVP/AA), sensíveis ao pH, por meio de método de polimerização de radical livre, com variações no conteúdo de monômero, de polímero e de agente de ligação cruzada. O inchamento foi realizado em soluções tampão fosfato USP pH 1,2, 5,5, 6,5 e 7,5, com força iônica constante. A estrutura reticular foi avaliada por diferentes parâmetros e o FTIR confirmou a formação de hidrogéis de ligação cruzada. A cristalografia de raios X mostrou dispersão molecular do cloridrato de tramadol. Realizou-se estudo de liberação do fármaco em soluções tampão fosfato pH 1,2, 5,5 e 7,5 para amostras selecionadas. Observou-se que o inchamento e a liberação do fármaco dos hidrogéis podem ser modificados mudando-se a composição e o grau de ligação cruzada dos hidrogéis em estudo. O coeficiente de inchamento foi alto em pH mais altos, exceto para um deles com alto conteúdo de PVP. A liberação do fármaco aumentou com o aumento do pH do meio e do conteúdo em AA nos hidrogéis, enquanto que o aumento na concentração do agente de ligação cruzada apresentou efeito oposto. A análise do mecanismo de liberação do fármaco revelou transporte não Fickiano do tramadol dos hidrogéis.