Institute of Fundamental Technological Research

Thermoresponsive hydrogels provide a platform for sustained delivery of nanoparticles via nose-to-brain route by resisting mucociliary clearance to the enhanced mean residence time (MRT) of the formulation in the nasal cavity overcoming neurotoxicity induced by uncontrolled delivery of nanoparticles and accumulation in the brain when delivered alone. The reported study presents the synthesis of pullulan (PLN) based nanoparticles (PNP-EHBr) loaded with eletriptan hydrobromide (EHBr) via ionic gelation method having size between 26.65 nm and 29.59 nm after stability studies of 4 h incubation with an average zeta potential of 22.5 ± 0.1 mV and entrapment efficiency of 92.048%. F-127/F-68 based hyaluronic acid-co-pectin hydrogels of EHBr-loaded PLN nanoparticles thermoresponsive hydrogels (HAP-PNP-EHBr/T-Hg) were characterized via Fourier transform infrared spectroscopy (FTIR), X-ray diffraction, thermal analysis (TGA/DSC), and scanning electron microscopy and evaluated for their gelation time, gelation temperature, gel strength, cloud point, sol–gel fraction, ex-vivo permeation, etc. HAP-PNP-EHBr/T-Hg showed drug release in a controlled pattern in both phosphate-buffered saline (PBS) and simulated nasal fluid (SNF) i.e., 90.12 and 87.99, respectively, over 48 h, while PNP-EHBR, 99.44 and 97.53 in PBS and SNF, respectively, over 8 h. The controlled release and absorption of EHBr from HAP-PNP-EHBr/T-Hg and PNP-EHBr was estimated by an in-vivo pharmacokinetic study using high-performance liquid chromatography, MRT and area under the curve (AUC) were increased up to 11.337 ± 0.32 h and 3,104.73 ± 75.841 ng/mL*h, 11.088 ± 0.177 h and 3,906.64 ± 152.86 ng/mL*h in brain and blood respectively after IN administration. This work demonstrates the successful synthesis of a twofold drug delivery system with PLN-based nanoparticles (PNP-EHBr) loaded with EHBr laden F-127/F-68 based hyaluronic acid-co-pectin hydrogels (HAP-PNP-EHBr/T-Hg).

Biodegradable polymers, controlled delivery, nose-to-brain delivery, polymeric nanoparticles, self-assembling micelles, thermoresponsive hydrogels

Oral drug delivery systems have innumerable advantages, despite their precedence, the delivery of lipophilic drugs belonging to biopharmaceutical class II and IV, which has challenges associated with their solubility and permeability, leading to the limitations of this route. To address these barriers, nanocarrier systems combined with biomaterials are considered one of the pre-eminent approaches. Therefore, in this study pH-responsive pullulan-based hydrogels were developed, which were loaded with curcumin nanocrystals, micelles and coarse curcumin. In-vitro characterization studies, including dynamic light scattering, Fourier-transform infrared spectroscopy, proton nuclear magnetic resonance, scanning electron microscopy, thermogravimetric analysis, differential scanning calorimetry, and X-ray diffraction supported the development of hydrogels. The swelling index showed that developed hydrogels have significant swelling at pH 7.4, as the optimized formulation shows a “q value” of 5.938% at higher pH and 2.382% at lower pH. Additionally, the nanocrystal-laden hydrogel showed 86.250% drug release at pH 7.4, and better release than micelles and coarse curcumin-laden hydrogel. Moreover, nanocrystals showed a 1-fold increase in the solubility of curcumin, enhanced physical stability, and 82.81% permeation as compared with formulations. Conclusively, the outcome of the studies distinctly revealed a promising approach for successfully developing Pu-g-MAA hydrogels and the inclusion of lipophilic drugs in them.

Nanocrystals, Micelles, Curcumin, Controlled release, pH sensitive, Hydrogels

Biopolymer-based thermoresponsive injectable hydrogels with multifunctional tunable characteristics containing anti-oxidative, biocompatibility, anti-infection, tissue regeneration, and/or anti-bacterial are of abundant interest to proficiently stimulate diabetic wound regeneration and are considered as a potential candidate for diversified biomedical application but the development of such hydrogels remains a challenge. In this study, the Chitosan-CMC-g-PF127 injectable hydrogels are developed using solvent casting. The Curcumin (Cur) Chitosan-CMC-g-PF127 injectable hydrogels possess viscoelastic behavior, good swelling properties, and a controlled release profile. The degree of substitution (% DS), thermal stability, morphological behavior, and crystalline characteristics of the developed injectable hydrogels is confirmed using nuclear magnetic resonance (1H NMR), thermogravimetric analysis, scanning electron microscopy (SEM), and x-ray diffraction analysis (XRD), respectively. The controlled release of cur-micelles from the hydrogel is evaluated by drug release studies and pharmacokinetic profile (PK) using high-performance liquid chromatography (HPLC). Furthermore, compared to cur micelles the Cur-laden injectable hydrogel shows a significant increase in half-life (t1/2) up to 5.92 ± 0.7 h, mean residence time (MRT) was 15.75 ± 0.76 h, and area under the first moment curve (AUMC) is 3195.62 ± 547.99 μg/mL*(h)2 which reveals the controlled release behavior. Cytocompatibility analysis of Chitosan-CMC-g-PF127 hydrogels using 3T3-L1 fibroblasts cells and in vivo toxicity by subcutaneous injection followed by histological examination confirmed good biocompatibility of Cur-micelles loaded hydrogels. The histological results revealed the promising tissue regenerative ability and shows enhancement of fibroblasts, keratinocytes, and collagen deposition, which stimulates the epidermal junction. Interestingly, the Chitosan-CMC-g-PF127 injectable hydrogels ladened Cur exhibited a swift wound repair potential by up-surging the cell migration and proliferation at the site of injury and providing a sustained drug delivery platform for hydrophobic moieties.

Biomaterials,Injectable hydrogels,Wound healing,Chitosan,Carboxymethylcellulose

Hydrogel membrane dressings with multifunctional tunable properties encompassing biocompatibility, anti-bacterial, oxygen permeability, and adequate mechanical strength are highly preferred for wound healing. The present study aimed to develop biopolymer-based hydrogel membranes for the controlled release of therapeutic agent at the wound site. Toward this end we developed Cefotaxime sodium (CTX) loaded keratin (KR)-pullulan (PL) based hydrogel membrane dressings. All membranes show optimized vapor transmission rate (≥1000 g/ m2/day), oxygen permeability >8.2 mg/mL, MTT confirmed good biocompatibility and sufficient tensile strength (17.53 ± 1.9) for being used as a wound dressing. Nonetheless, KR-PL-PVA membranes show controlled CTX release due to enriched hydrophilic moieties which protect the wound from getting infected. In vivo results depict that CTX-KR-PL-PVA membrane group shows a rapid wound closure rate (p < 0.05) with appreciable angiogenesis, accelerated re-epithelization, and excessive collagen deposition at the wound site. These results endorsed that CTX-KR-PL-PVA hydrogel membranes are potential candidates for being used as dressing material in the diabetic wound.

Hydrogel membranes,Keratin,Diabetic wound,Wound healing,Ceftriaxone sodium

Diabetic wound infection often leads to compromised healing with frequent chances of sepsis, amputation and even death. Traditional patient care emphasized on early debridement and fluid resuscitation followed by intravenous antibiotics therapy. However, compromised vasculature often limit the systemic effect of antibiotics. Current study focused formulation of chitosan HCl, κ- carrageenan and PVA based physical cross-linked hydrogel membrane dressings loaded with cefotaxime sodium (CTX), for potential diabetic burn wound healing by adopting solvent casting method. Results of mechanical strength shows tensile strength and % elongation of 12.63 0.25 and 48 respectively. Water vapor transmission rate (WVTR) depicts that despite of formulation KCP3 and KCP6, all hydrogel membranes have WVTR value in range of ideal dressing i.e., 2000–2500 g/m2/day. Whereas, all hydrogel membranes have oxygen permibility values more than 8.2 mg/ml. Bacterial penetration analysis confirms the barrier property of formulated membranes. Drug loaded hydrogel membrane showed control release up to 24 hr which provide protection against bacterial proliferation. Present study aims to constructs diabetic burn rat model which demonstrate that CTX loaded hydrogel membrane shown significantly rapid wound closure higher re-epithelization and numerous granulation tissue formation as compared to positive and negative control group. Conclusively, it is confirmed that formulated hydrogel membranes are beneficial and can be considered as a promising membrane dressing to treat diabetic burn wound.

Biomimetic membranes,Biopolymer,PVA,Diabetic wound,Wound healing Ceftriaxone

Injectable hydrogel with multifunctional tunable properties comprising biocompatibility, anti-oxidative, anti-bacterial, and/or anti-infection are highly preferred to efficiently promote diabetic wound repair and its development remains a challenge. In this study, we report hyaluronic acid and Pullulan-based injectable hydrogel loaded with curcumin that could potentiate reepithelization, increase angiogenesis, and collagen deposition at wound microenvironment to endorse healing cascade compared to other treatment groups. The physical interaction and self-assembly of hyaluronic acid-Pullulan-grafted-pluronic F127 injectable hydrogel were confirmed using nuclear magnetic resonance (1H NMR) and Fourier transformed infrared spectroscopy (FT-IR), and cytocompatibility was confirmed by fibroblast viability assay. The CUR-laden hyaluronic acid-Pullulan-g-F127 injectable hydrogel promptly undergoes a sol-gel transition and has proved to potentiate wound healing in a streptozotocin-induced diabetic rat model by promoting 93% of wound closure compared to other groups having 35%, 38%, and 62%. The comparative in vivo study and histological examination was conducted which demonstrated an expeditious recovery rate by significantly reducing the wound healing days i.e. 35 days in a control group, 33 days in the CUR suspension group, 21 days in unloaded injectable, and 13 days was observed in CUR loaded hydrogel group. Furthermore, we suggest that the injectable hydrogel laden with CUR showed a prompt wound healing potential by increasing the cell proliferation and serves as a drug delivery platform for sustained and targeted delivery of hydrophobic moieties.

Bioactive polymers,Tissue regeneration,In situ injectable hydrogel,Diabetic wound healing,Hyaluronic acid

Wounds are often recalcitrant to traditional wound dressings and a bioactive and biodegradable wound dressing using hydrogel membranes can be a promising approach for wound healing applications. The present research aimed to design hydrogel membranes based on hyaluronic acid, pullulan and polyvinyl alcohol and loaded with chitosan based cefepime nanoparticles for potential use in cutaneous wound healing. The developed membranes were evaluated using dynamic light scattering, proton nuclear magnetic resonance, Fourier transform infrared spectroscopy, thermogravimetric analysis, and scanning electron microscopy. The results indicated the novel crosslinking and thermal stability of the fabricated hydrogel membrane. The in vitro analysis demonstrates that the developed membrane has water vapors transmission rate (WVTR) between 2000 and 2500 g/m2/day and oxygen permeability between 7 and 14 mg/L, which lies in the range of an ideal dressing. The swelling capacity and surface porosity to liberate encapsulated drug (cefepime) in a sustained manner and 88% of drug release was observed. The cefepime loaded hydrogel membrane demonstrated a higher zone of inhibition against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli and excisional rat model exhibit expeditious recovery rate. The developed hydrogel membrane loaded with cefepime nanoparticles is a promising approach for topical application and has greater potential for an accelerated wound healing process.

Controlled drug delivery,Biomaterials,Hydrogel membranes,Nanoparticles,Wound healing

Objectives: The study aimed to develop safe, effective, and targeted drug delivery system for administration of nonsteroidal anti-inflammatory drugs (NSAIDs) in the form of microgels. We developed pH responsive microgels to overcome the mucosal damage caused by traditional immediate release dosage forms. Colon targeting and controlled release formulations have the potential to improve efficacy and reduce undesirable effects associated with NSAIDs.

Methods: The pH sensitive oral hydrogel demonstrates the potential to target the colon. Cellulose acetate phthalate (CAP) and hydroxyethyl methacrylate (HEMA) based microgel particles were produced using a free radical polymerization technique using ammonium persulfate (APS) initiator and methylenebisacrylamide (MBA) as the crosslinking agent. Swelling and in-vitro drug release studies were performed at a range of pH conditions. The produced formulations were characterized using Fourier transform infrared spectroscopy, thermogravimetric analysis, differential scanning calorimetry, scanning electron microscopy (SEM), and X-ray diffraction. Biocompatibility of the microgels was analyzed in cytotoxicity studies.

Key findings: The swelling and release rate were negligible at pH 1.2, which confirmed the pH-responsiveness of CAP-co-poly(HEMA). The co-polymeric system prevents the release of ketoprofen sodium in the stomach owing to limited swelling at gastric pH, whilst promoting release at the basic pH observed in the colon. SEM images confirmed porous nature of the microgels that facilitate effective drug diffusion through the polymeric matrix. Cytotoxicity studies revealed biocompatibility of hydrogels.

Conclusion: These investigations showed that that the controlled drug release and gastro-protective drug delivery of NSAIDS was achieved using CAP-co-poly(HEMA) microgel particles.

Biomaterials, microgels, cellulose acetate phthalate, hydrogel, pH sensitive

Ulcerative colitis (UC) is an inflammatory disease of the colon that severely affects the quality of life of patients and usually responds well to anti-inflammatory agents for symptomatic relief; however, many patients need colectomy, a surgical procedure to remove whole or part of the colon. Though various types of pharmacological agents have been employed for the management of UC, the lack of effectiveness is usually predisposed to various reasons including lack of target-specific delivery of drugs and insufficient drug accumulation at the target site. To overcome these glitches, many researchers have designed and characterized various types of versatile polymeric biomaterials to achieve target-specific delivery of drugs via oral route to optimize their targeting efficiency to the colon, to improve drug accumulation at the target site, as well as to ameliorate off-target effects of chemotherapy. Therefore, the aim of this review was to summarize and critically discuss the pharmaceutical significance and therapeutic feasibility of a wide range of natural and synthetic biomaterials for efficient drug targeting to colon and rationalized treatment of UC. Among various types of biomaterials, natural and synthetic polymer-based hydrogels have shown promising targeting potential due to their innate pH responsiveness, sustained and controlled release characteristics, and microbial degradation in the colon to release the encapsulated drug moieties. These characteristic features make natural and synthetic polymer-based hydrogels superior to conventional pharmacological strategies for the management of UC.

Ulcerative colitis, Biomaterials, Hydrogels, Biomedical applications , Ulcerative colitis

Cellulose acetate phthalate-based pH-responsive hydrogel was synthesized for fabrication of polymeric matrix tablets for gastro-protective delivery of loxoprofen sodium. Cellulose acetate phthalate (CAP) was cross-linked with methacrylic acid (MAA) using free radical polymerization technique. Fourier transform infrared (FTIR) spectra confirmed the formation of cross-linked structure of CAP-co-poly(methacrylic acid). Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) confirmed the thermal stability of polymeric networks, and scanning electron microscopy (SEM) and energy-dispersive X-ray spectrum (EDS) images unveiled that the prepared formulations were porous in nature and thus the developed formulations had shown better diffusibility. Swelling and in vitro drug release was performed at various pHs and maximum swelling and release was obtained at pH 7.4, while swelling and release rate was very low at pH 1.2 which confirmed the pH-responsive behavior of CAP-co-poly(MAA). CAP-co-poly(MAA) copolymer prevents the release of loxoprofen sodium into the stomach due to reduced swelling at gastric pH while showing significant swelling and drug release in the colon. Cytotoxicity studies revealed higher biocompatibility of fabricated hydrogel. Acute oral toxicity studies were performed for the evaluation and preliminary screening of safety profile of the developed hydrogels. Matrix tablets were evaluated for release behavior at simulated body pH. The investigations performed for analysis of hydrogels and fabricated matrix tablets indicated the controlled drug release and gastro-protective drug delivery of CAP-co-poly(MAA) hydrogels and pH-sensitive matrix tablets for targeted delivery of gastro-sensitive/irritative agents.

Acute toxicity, Cellulose acetate phthalate, Controlled release, Gastro-protective, Hydrogel

Non-healing, chronic wounds place a huge burden on healthcare systems as well as individual patients. These chronic wounds especially diabetic wounds will ultimately lead to compromised mobility, amputation of limbs and even death. Currently, wounds and limb ulcers associated with diabetes remain significant health issues; the associated healthcare cost ultimately leads to the increased clinical burden. The presence of diabetes interrupts a highly coordinated cascade of events in the wound closure process. Advances in the understanding of pathophysiological conditions associated with diabetic wounds lead to the development of drug delivery systems which can enhance wound healing by targeting various phases of the impaired processes. Wound environments typically contain degradative enzymes, along with an elevated pH and demonstrate a physiological cascade involved in the regeneration of tissue, which requires the application of an effective delivery system. This article aims to review the pathophysiological conditions associated with chronic and diabetic wounds. The delivery systems, involved in their treatment are described, highlighting potential biomaterials and polymers for establishing drug delivery systems, specifically for the treatment of diabetic wounds and the promotion of the associated mechanisms involved in advanced wound healing. Emerging approaches and engineered devices for effective wound care are reported. The discussion will give insight into the mechanisms relevant to all stages of wound healing.

Biomaterials, Diabetes, Diabetic wound healing, Hydrogels, Polymers

Oral drug delivery is natural, most acceptable and desirable route for nearly all drugs, but many drugs like NSAIDs when delivered by this route cause gastrointestinal irritation, gastric bleeding, ulcers, and many undesirable effects which limits their usage by oral delivery. Moreover, it is almost impossible to control the release of a drug in a targeted location in body. We developed thermo-responsive chitosan-co-poly(N-isopropyl-acrylamide) injectable hydrogel as an alternative for the gastro-protective and controlled delivery of loxoprofen sodium as a model drug. A free radical polymerization technique was used to synthesize thermo-responsive hydrogel by cross-linking chitosan HCl with NIPAAM using glutaraldehyde as cross-linker. Confirmation of crosslinked hydrogel structure was done by Fourier transform infrared spectra (FTIR). The thermal stability of hydrogel was confirmed through thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The scanning electron microscopy (SEM) was performed to evaluate the structural morphology of cross-linked hydrogel. To evaluate the rheological behavior of hydrogel with increasing temperature, rheological study was performed. Swelling and in vitro drug release studies were carried out under various temperature and pH conditions. The swelling study revealed that maximum swelling was observed at low pH (pH 1.2) and low temperature (25 °C) compared to the high range of pH and temperature and it resulted in quick release of the drug. The high range of pH (7.4) and temperature (37 °C) however caused controlled release of the drug. The in vivo evaluation of the developed hydrogel in rabbits demonstrated the controlled release behavior of fabricated system.

Thermosensitive hydrogels, Chitosan, NIPAAM, In vivo study, Biomaterials

The aim of this study was to develop and characterize a pH sensitive, biodegradable, interpenetrating polymeric network (IPNs) for colon specific delivery of sulfasalazine in ulcerative colitis. It also entailed in-vitro and in-vivo evaluations to optimize colon targeting efficiency, improve drug accumulation at the target site, and ameliorate the off-target effects of chemotherapy. Pectin was grafted with polyethylene glycol (PEG) and methacrylic acid (MAA) by free radical polymerization. Fourier transformed infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), energy dispersion X-ray (EDX) and powder X-ray diffraction (XRD) results confirmed the development of stable pectin-g-(PEG-co-MAA) hydrogels. The swelling and release studies exhibited that the hydrogels were capable of releasing drug specifically at colonic pH (pH 7.4). The toxicological potential of polymers, monomers and hydrogel was investigated using the Balb/c animal model, that confirmed the safety of the hydrogels. In vitro degradation of the hydrogel was evaluated using pectinase enzyme in various simulated fluids and the results showed that the hydrogels were susceptible to biodegradation by the natural microflora of the colon. In-vivo study was performed using Dextran sulphate sodium (DSS) rat model proved the hydrogels to be effective in the management of UC.

Semi-IPN hydrogel, Pectin, Sulfasalazine colon targeting, Ulcerative colitis, In vitro degradation studies, In vivo toxicity, colon targeting, colon targeting