Preparation and Characterization of Silver Sulfadiazine–Loaded Polyvinyl Alcohol Hydrogels as an Antibacterial Wound Dressing

In this study, we prepared a series of silver sulfadiazine (AgSD)–loaded polyvinyl alcohol (PVA) hydrogels via electron beam (e-beam) irradiation. Our objective was to explore the influence of e-beam irradiation on the chemical structure and crystallinity of AgSD and the antibacterial properties of AgSD/PVA hydrogels. Prior to irradiation, we mixed AgSD in PVA solution in 2 forms, either suspended in water (WS) or dissolved in ammonia solution (AS). We noted that nano silver was released from AgSD/PVA-AS hydrogels immersed in deionized water, while it would not happen in AgSD/PVA-WS hydrogels. Both kinds of AgSD/PVA hydrogels exhibited good antibacterial activities against gram-negative Escherichia coli and gram-positive Staphylococcus aureus. And their antibacterial activity was not obviously affected by different dosages of e-beam irradiation. Moreover, the antibacterial activity of the AgSD/PVA-WS hydrogels was stronger than that of AgSD/PVA-AS. Accordingly, the cell cytotoxicity of the AgSD/PVA-WS hydrogels was higher than that of AgSD/PVA-AS. Our study results reveal that e-beam irradiation of PVA solution with dispersed AgSD is a simple and efficient way to prepare AgSD/PVA hydrogels, which might be an ideal antibacterial wound dressing.     

Synthesis of nanocapsules blended polymeric hydrogel loaded with bupivacaine drug delivery system for local anesthetics and pain management

Local anesthetics are used clinically for the control of postoperative pain management. This study aimed to develop chitosan (CS) with genipin (GP) hydrogels as the hydrophilic lipid shell loaded poly(ε-caprolactone) (PC) nanocapsules as the hydrophobic polymeric core composites (CS-GP/PC) to deliver bupivacaine (BPV) for the prolongation of anesthesia and pain relief. The swelling ratio, in vitro degradation, and rheological properties enhancement of CS-GP/PC polymeric hydrogel. The incorporation of PC nanocapsules into CS-GP hydrogels was confirmed by SEM, FTIR, and XRD analysis. Scanning electron microscopy results demonstrated that the CS-GP hydrogels and CS-GP/PC polymeric hydrogels have a porous structure, the pore dimensions being non-uniform with diameters between 25 and 300 μm. The in vitro drug release profile of CS-GP/PC polymeric hydrogel has been achieved 99.2 ± 1.12% of BPV drug release in 36 h. Cellular viability was evaluated using the CCK-8 test on 3T3 fibroblast cells revealed that the obtained CS-GP/PC polymeric hydrogel with BPV exhibited no obvious cytotoxicity. The CS-GP/PC polymeric hydrogel loaded with BPV showed significant improvement in pain response compared to the control group animals for at least 7 days. When compared with BPV solution, CS-GP hydrogel and CS-GP/PC polymeric hydrogel improved the skin permeation of BPV 3-fold and 5-fold in 24 h, respectively. In vitro and in vivo results pointed out PC nanocapsules loaded CS-GP hydrogel can act as effective drug carriers, thus prolonging and enhancing the anesthetic effect of BPV. Histopathological results demonstrated the excellent biodegradability and biocompatibility of the BPV-loaded CS-GP/PC polymeric hydrogel system on 7, 14, and 21 days without neurotoxicity.

HIGHLIGHTS

• Preparation and characterization of CS-GP/PC polymeric hydrogel system.
• BPV-loaded CS-GP/PC exhibited prolonged in vitro release in PBS solution.
• Cytotoxicity of BPV-loaded CS-GP/PC polymeric hydrogel against fibroblast (3T3) cells.
• Development of CS-GP/PC a promising skin drug-delivery system for local anesthetic BPV.

     

Biocompatible hydrogel based on aldehyde-functionalized cellulose and chitosan for potential control drug release

The present study aimed to prepare cellulose-based biodegradable hydrogel that revealing a potential control of drug release. To achieve this purpose, activation of cellulose was achieved firstly by pretreatment stage using ZnCl₂. Then, selective oxidation of activated cellulose was performed by using sodium periodate to achieve cleavage of the bond between C2 – C3 in the glucose unit generating two active aldehyde groups. The modified cellulose (Dialdehyde cellulose, DAC) was reacted with chitosan, in different molar ratios, via condensation between aldehyde and primary amine groups situated onto cellulose and chitosan, respectively. The activated cellulose, DAC, and produced hydrogels were characterized via FTIR, XRD, and SEM to detect the emerging functional groups as well as the variation of crystallinity and surface morphology features of activated cellulose, DAC, and hydrogels. The swelling capacities of hydrogels showed the optimum value at pH = 7.0. The prepared hydrogels cytotoxicity was investigated toward normal skin fibroblast by MTT assay. It was found that the cells treated with chitosan/DAC hydrogels with ratio 1:1, 1:2, and 1:3 affected by 1.3, 1.8, and 0%, respectively. Streptomycin was incorporated in the prepared hydrogels and its release was evaluated. The DAC ratio was played a key role in controlling the release process. Moreover, further studies were carried out on chitosan (PDB: 2RVA) to evaluate its potential interaction with DAC and streptomycin with binding energies ?4.4 and - 4.3 kcal/mol with short bond lengths 1.3 and 1.944 Å, respectively.     

Structural and biological investigation of chitosan/hyaluronic acid with silanized-hydroxypropyl methylcellulose as an injectable reinforced interpenetrating network hydrogel for cartilage tissue engineering

Cartilage damage continues to pose a threat to humans, but no treatment is currently available to fully restore cartilage function. In this study, a new class of composite hydrogels derived from water-soluble chitosan (CS)/hyaluronic acid (HA) and silanized-hydroxypropyl methylcellulose (Si-HPMC) (CS/HA/Si-HPMC) has been synthesized and tested as injectable hydrogels for cartilage tissue engineering when combined without the addition of a chemical crosslinking agent. Mechanical studies of CS/HA and CS/HA/Si-HPMC hydrogels showed that as Si-HPMC content increased, swelling rate and rheological properties were higher, compressive strength decreased and degradation was faster. Our results demonstrate that the CS and HA-based hydrogel scaffolds, especially the ones with 3.0% (w/v) Si-HPMC and 2.5/4.0% (w/v) CS/HA, have suitable physical performance and bioactive properties, thus provide a potential opportunity to be used for cartilage tissue engineering. In vitro studies of CS/HA and CS/HA/Si-HPMC hydrogels encapsulated in chondrocytes have shown that the proper amount of Si-HPMC increases the proliferation and deposition of the cartilage extracellular matrix. The regeneration rate of the CS/HA/Si-HPMC (3%) hydrogel reached about 79.5% at 21 days for long retention periods, indicating relatively good in vivo bone regeneration. These CS/HA/Si-HPMC hydrogels are promising candidates for tissue compatibility injectable scaffolds. The data provide proof of the principle that the resulting hydrogel has an excellent ability to repair joint cartilage using a tissue-engineered approach.

RESEARCH HIGHLIGHTS

• An injectable hydrogel based on CS/HA/Si-HPMC composites was developed.
• The CS/HA/Si-HPMC hydrogel displays the tunable rheological with mechanical properties.
• The CS/HA/Si-HPMC hydrogel is highly porous with high swelling and degradation ratio.
• Increasing concentration of Si-HPMC promote an organized network in CS/HA/Si-HPMC hydrogels.
• Injectable CS/HA/Si-HPMC hydrogels have a high potential for cartilage tissue engineering.

     

Characterization of pH- and Thermosensitive Hydrogel as a Vehicle for Controlled Protein Delivery

N-[(2-Hydroxy-3-trimethylammonium)propyl] chitosan chloride (HTCC) was chemically modified using glycidyltrimethylammonium chloride (GTMAC). A new composite hydrogel was prepared using the mixture of HTCC and α-β-glycerophosphate (α-β-GP). The gelation of HTCC/GP mainly depended on the concentration and proportion of HTCC and GP. Thermogravimetric analysis exhibited high stability of HTCC/GP hydrogels. Surface morphology assay demonstrated that HTCC/GP hydrogels were well constructed with three-dimensional (3D) porous structures in the range of 5 of 40 μm. The insulin was entrapped during the formation of hydrogel. In vitro, the insulin release was controlled by modifying the composition, drug loading, and pH condition. The hydrogel dissolved and released drug quickly under acidic condition, whereas it absorbed water and released drug slowly under neutral or basic conditions. The hydrogels were biocompatible, and the cells could adhere to and then migrated to the hydrogels. Furthermore, these cells were viable and retained 3D morphology inside the hydrogels. Interestingly, HTCC/GP hydrogel showed both thermo- and pH-sensitive properties. There are potential applications in tissue engineering, cell encapsulation, and intelligent drug delivery systems.     

Hydrogels of N-isopropylacrylamide copolymers with controlled release of a model protein

Temperature- and pH-sensitive hydrogels, based on N-isopropylacrylamide (NiPAAm) and itaconic acid (IA), were synthesized by free radical crosslinking copolymerization in the presence of lipase from Candida rugosa. The samples were characterized for their sensitivity to the changes of external conditions and the ability to control the release of a hydrophilic model protein, lipase. These hydrogels were highly responsive to temperature and pH, at constant ionic strength. Parameters, such as the crosslinking degree and non-ionic/ionic (NiPAAm/IA) ratio, were found to impact the hydrogel structure, mechanical properties, morphology and swelling kinetics at different pH and temperatures. The hydrogels demonstrated protein loading efficiency as high as 95 wt%. Release studies of a hydrophilic model protein at a physiological temperature of 37 °C were performed at different pH values. High dependence of lipase release kinetics on hydrogel structure and the environmental pH was found, showing generally low release rates, lower in acidic media (pH 2.20) and higher at higher pHs (6.80). Lipase activity was retained even after treatment conditions that would provoke denaturation of the enzyme if it was not protected in the gel. The obtained hydrogels were found suitable for releasing therapeutic proteins in a controlled manner at specific sites in gastrointestinal tract.     

Thermosensitive hydrogels for nasal drug delivery: The formulation and characterisation of systems based on N-trimethyl chitosan chloride

Towards the development of a thermosensitive drug-delivery vehicle for nasal delivery, a systematic series of N-trimethyl chitosan chloride polymers, synthesised from chitosans of three different average molecular weights, have been co-formulated into a hydrogel with poly(ethylene glycol) and glycerophosphate. Rheological evaluations have shown that hydrogels derived from N-trimethyl chitosan with a low degree of quaternisation and high or medium average molecular weight exhibit relatively short sol-gel transition times at physiologically relevant temperatures. Also, the same hydrogels display good water-holding capacity and strong mucoadhesive potential, and their mixtures with mucus exhibit rheological synergy. An aqueous hydrogel formulation, derived from N-trimethyl chitosan of medium average molecular weight and low degree of quaternisation, appears particularly promising in that it exhibits most favourable rheological and mucoadhesive behaviour and a sol-gel transition that occurs at 32.5 °C within 7 min.     

Incorporation of rosuvastatin-loaded chitosan/chondroitin sulfate nanoparticles into a thermosensitive hydrogel for bone tissue engineering: preparation,characterization, and cellular behavior

Rosuvastatin (RSV) has been shown to have significant impact on the simulation of bone regeneration after local injection. The current study aimed to develop a localized controlled delivery system from RSV by incorporating RSV-loaded chitosan/chondroitin sulfate (CTS/CS) nanoparticles into thermosensitive Pluronic F127/hyaluronic acid (PF127/HA) hydrogel. RSV-loaded CTS/CS nanoparticles were prepared by ionic gelation, and the impact of various formulation variables was assessed using the Box–Behnken design. Consequently, optimized RSV-loaded nanoparticles were incorporated into the PF127/HA hydrogel. Rheological properties, degradation rates of hydrogels, and the release rate of RSV from hydrogel were examined. Mean particle size, zeta potential, entrapment efficiency, and mean release time of the optimized RSV-loaded nanoparticles were confirmed as 283.2?±?16?nm, –31.2?±?6.8?mV, 63.1?±?4.2%, and 6.14?±?0.3?h, respectively. The hydrogel containing 3% w/v CTS/CS nanoparticles existed as a solution with low viscosity at room temperature converted to a semisolid upon increasing the temperature to 35?°C. Hydrogel engrafted with CTS/CS showed controlled release of RSV during 48?h with superior in vitro gel stability. As revealed by cytotoxicity and mineralization assays, incorporation of RSV-loaded particles into PF127/HA hydrogel led to improvement in osteoblast viability and proliferation.     

Factorial analyses of photopolymerizable thermoresponsive composite hydrogels for protein delivery

A smart protein delivery system for wound healing applications was developed using composite nanoparticle hydrogels that can release protein in a temperature-responsive manner. This system can also be formed in situ in the presence of ultraviolet light and Irgacure 2959 photoinitiator. The system consists of temperature-sensitive poly(N-isopropylacrylamide-co-acrylamide) (PNIPAM-AAm) nanoparticles embedded in a poly(ethylene glycol) diacrylate (PEGDA) matrix. A factorial analysis was performed to evaluate the effects of PEGDA concentration (10% and 15% w/v) and PEGDA molecular weight (MW; 3.4 kDa and 8 kDa), as well as PNIPAM-AAm nanoparticle concentration (2% and 4% w/v) and temperature (23°C and 40°C) on the protein release profiles and swelling ratios of the hydrogels. Results indicate that PNIPAM-AAm nanoparticle concentration and temperature were the most important factors affecting the protein release during the burst release phase. Additionally, PEGDA MW was the most important factor affecting the protein release in the plateau region. It was also important in controlling the hydrogel swelling ratio. A dual-layered hydrogel was further developed to produce a protein delivery system with a better sustained release. These findings have improved our understanding of the composite hydrogel systems and will help in tailoring future systems with desired release profiles.From the Clinical EditorA smart protein delivery system for wound healing applications using composite nanoparticle hydrogels that can release protein in a temperature-responsive manner is reported in this paper. Systems like this may aid in optimal would healing in the surgical and trauma-related settings.     

Novel semi-interpenetrating hydrogel networks with enhanced mechanical properties and thermoresponsive engineered drug delivery,designed as bioactive endotracheal tube biomaterials

Thermoresponsive polymeric platforms are used to optimise drug delivery in pharmaceutical systems and bioactive medical devices. However, the practical application of these systems is compromised by their poor mechanical properties. This study describes the design of thermoresponsive semi-interpenetrating polymer networks (s-IPNs) based on cross-linked p(NIPAA) or p(NIPAA-co-HEMA) hydrogels containing poly(ε-caprolactone) designed to address this issue. Using DSC, the lower critical solution temperature of the co-polymer and p(NIPAA) matrices were circa 34 °C and 32 °C, respectively. PCL was physically dispersed within the hydrogel matrices as confirmed using confocal scanning laser microscopy and DSC and resulted in marked changes in the mechanical properties (ultimate tensile strength, Young’s modulus) without adversely compromising the elongation properties. P(NIPAA) networks containing dispersed PCL exhibited thermoresponsive swelling properties following immersion in buffer (pH 7), with the equilibrium-swelling ratio being greater at 20 °C than 37 °C and greatest for p(NIPAA)/PCL systems at 20 °C. The incorporation of PCL significantly lowered the equilibrium swelling ratio of the various networks but this was not deemed practically significant for s-IPNs based on p(NIPAA). Thermoresponsive release of metronidazole was observed from s-IPN composed of p(NIPAA)/PCL at 37 °C but not from p(NIPAA-co-HEMA)/PCL at this temperature. In all other platforms, drug release at 20 °C was significantly similar to that at 37 °C and was diffusion controlled. This study has uniquely described a strategy by which thermoresponsive drug release may be performed from polymeric platforms with highly elastic properties. It is proposed that these materials may be used clinically as bioactive endotracheal tubes, designed to offer enhanced resistance to ventilator associated pneumonia, a clinical condition associated with the use of endotracheal tubes where stimulus responsive drug release from biomaterials of significant mechanical properties would be advantageous.     

Thermosensitive hydrogels of poly(methyl vinyl ether-co-maleic anhydride) – Pluronic® F127 copolymers for controlled protein release

Thermosensitive hydrogels are of a great interest due to their many biomedical and pharmaceutical applications. In this study, we synthesized a new series of random poly (methyl vinyl ether-co-maleic anhydride) (Gantrez^® AN, GZ) and Pluronic^® F127 (PF127) copolymers (GZ–PF127), that formed thermosensitive hydrogels whose gelation temperature and mechanical properties could be controlled by the molar ratio of GZ and PF127 polymers and the copolymer concentration in water. Gelation temperatures tended to decrease when the GZm/PF127 ratio increased. Thus, at a fixed GZm/PF127 value, sol–gel temperatures decreased at higher copolymer concentrations. Moreover, these hydrogels controlled the release of proteins such as bovine serum albumin (BSA) and recombinant recombinant kinetoplastid membrane protein of Leishmania (rKMP-11) more than the PF127 system. Toxicity studies carried out in J774.2 macrophages showed that cell viability was higher than 80%. Finally, histopathological analysis revealed that subcutaneous administration of low volumes of these hydrogels elicited a tolerable inflammatory response that could be useful to induce immune responses against the protein cargo in the development of vaccine adjuvants.     

Amino-functionalized poloxamer 407 with both mucoadhesive and thermosensitive properties: preparation,characterization and application in a vaginal drug delivery system

Lack of mucoadhesive properties is the major drawback to poloxamer 407 (F127)-based in situ hydrogels for mucosal administration. The objective of the present study was to construct a novel mucoadhesive and thermosensitive in situ hydrogel drug delivery system based on an amino-functionalized poloxamer for vaginal administration. First, amino-functionalized poloxamer 407 (F127-NH₂) was synthesized and characterized with respect to its micellization behavior and interaction with mucin. Then using acetate gossypol (AG) as model drug, AG-loaded F127-NH₂-based in situ hydrogels (NFGs) were evaluated with respect to rheology, drug release, ex vivo vaginal mucosal adhesion, in vivo intravaginal retention and local irritation after vaginal administration to healthy female mice. The results show that F127-NH₂ is capable of forming a thermosensitive in situ hydrogel with sustained drug release properties. An interaction between positively charged F127-NH₂ and negatively charged mucin was revealed by changes in the particle size and zeta potential of mucin particles as well as an increase in the complex modulus of NFG caused by mucin. Ex vivo and in vivo fluorescence imaging and quantitative analysis of the amount of AG remaining in mouse vaginal lavage all demonstrated greater intravaginal retention of NFG than that of an unmodified F127-based in situ hydrogel. In conclusion, amino group functionalization confers valuable mucoadhesive properties on poloxamer 407.     

New amphiphilic and pH-sensitive hydrogel for controlled release of a model poorly water-soluble drug

This paper presents the development of new pH-sensitive, amphiphilic and biocompatible hydrogels based on alginate-g-PCL, cross-linked with calcium ions to form beads, prepared for controlled delivery of poorly water-soluble drug. We have focused our study on the effect of the length of PCL chains (530 and 1250 g mol⁻¹). Swelling profiles obtained clearly indicated that these hydrogels swell slightly (10–14%) in a simulated gastric fluid (pH 1.2), and strongly (700–1300% before disintegration) in a simulated intestinal fluid (pH 6.8). In both media, rates of swelling were lower for beads based on amphiphilic derivatives than for alginate/Ca²⁺ ones due to the hydrophobic PCL grafts, and decreased when hydrophobic character increased. A model drug, theophylline, was entrapped into these hydrogels and release studies were carried out. The drug was protected in acidic fluid (only 14–20% of release for alginate-g-PCL hydrogel against 35% of release for alginate hydrogel during 350 min). The drug is released completely in neutral fluid due to ion exchanges and disintegration of the hydrogel. PCL leads to decrease in the release kinetics in SIF (2 h for alginate-g-PCL/Ca²⁺ beads against 1 h for alginate/Ca²⁺ beads). It was demonstrated that the establishment of clusters inside beads by intramolecular interactions between PCL grafts of 530 g mol⁻¹ in salt media allowed to retain the drug and to slow down its release considerably.     

Note on the formulation of thermosensitive and mucoadhesive vaginal hydrogels containing the miniCD4 M48U1 as anti-HIV-1 microbicide

The miniCD4 M48U1 was formulated into thermosensitive and mucoadhesive pluronic^® hydrogels as anti-HIV-1 microbicide. The release kinetics of M48U1 from F127/HPMC (20/1 wt%) and F127/F68/HPMC (22.5/2.5/1 wt%) studied during 24 h by using Franz diffusion cells showed that HEC hydrogel (1.5 wt%) used as control released 93% of the peptide, while about 25% of M48U1 remained in pluronic^® hydrogels. The formulation of M48U1 in pluronic^® hydrogels ensures a local delivery because no diffusion of the peptide was detected through vaginal Cynomolgus macaque mucosa using Ussing chamber. Finally, toxicological studies showed no significant difference in the HeLa cell viability of the pluronic^® hydrogels in comparison with HEC and phosphate buffer saline.     

Chemo-photothermal immunotherapy for eradication of orthotopic tumors and inhibition of metastasis by intratumoral injection of polydopamine versatile hydrogels

Cancer remains one of the leading causes of death globally and metastasis always leads to treatment failure. Here, we develop a versatile hydrogel loading photothermal agents, chemotherapeutics, and immune-adjuvants to eradicate orthotopic tumors and inhibit metastasis by combinational therapy. Hydrogel networks were synthesized via the thiol-Michael addition of polydopamine (PDA) with thiolated hyaluronic acid. PDA acted as a cross-linking agent and endowed the hydrogel with excellent photothermal property. Meanwhile, a chemotherapeutic agent, doxorubicin (DOX), was loaded in the hydrogel via π?π stacking with PDA and an immune-adjuvant, CpG-ODN, was loaded via electrostatic interaction. The release of DOX from the hydrogel was initially slow but accelerated due to near infrared light irradiation. The hydrogels showed remarkably synergistic effect against 4T1 cancer cells and stimulated plenty of cytokines secreting from RAW264.7 cells. Moreover, the hydrogels eradicated orthotopic murine breast cancer xenografts and strongly inhibited metastasis after intratumoral injection and light irradiation. The high anticancer efficiency of this chemo-photothermal immunotherapy resulted from the strong synergistic effect of the versatile hydrogels, including the evoked host immune response. The combinational strategy of chemo-photothermal immunotherapy is promising for highly effective treatment of breast cancer.     

Neem (Azadirachta Indica) and silk fibroin associated hydrogel: Boon for wound healing treatment regimen

Background & ObjectivesWound healing is the complex physiological process of replacing damaged cells or tissue layers. The neem (Azadirachta Indica) has a variety of biological activities, which may hasten the rate at which the wound healing mechanism occurs. Silk fibroin is a biomaterial that is reported for its tissue regeneration activity. So, the present study was designed to assess the effectiveness of a hydrogel comprising neem and silk fibroin biomaterials for the treatment of wounds.MethodsTopical neem hydrogels (N-HG) with and without silk fibroin (N-SFB-HG) were prepared using neem extract, silk fibroin, and guar gum, which act by entrapping the components by forming a gel. Evaluation tests such as Fourier transform infrared spectroscopy (FT-IR), visual emergence, pH, rheological behavior, spreading capacity, drug content, skin irritation, anti-microbial action, in vivo wound healing activity, and stability were carried out.ResultsThe FT-IR results showed no chemical interaction between the constituents. The formed hydrogels had pH values of 5.87 ± 0.3 for N-HG and 5.76 ± 0.2 for N-SFB-HG. The preferred topical gel viscosity was observed in the N-HG (54.2 ± 3.2cPs) and N-SFB-HG (59.9 ± 4.8cPs) formulations. The formulated hydrogels were sterile and did not irritate the skin. The in vivo wound healing investigation results reveal that the N-SF-HG treatment speeds up the regeneration of the injured area faster when compared to control and N-HG treated groups.Interpretation & ConclusionThese results support the efficacy of the topical hydrogel formulation, including neem and silk fibroin. Therefore, the neem-silk fibroin hydrogel formulation is a therapeutically viable choice that, following necessary clinical research, might be utilized in novel formulations for managing chronic wounds.     

Studies on controlled release of indomethacin from PVA hydrogel

The polyvinyl alcohol (PVA) hydrogel containing 1-methyl-2-pyrrolidinone (MP) and sorbitol was preapred by the freeze and thaw method. The release rate of indomethacin from PVA hydrogel was used as a criterion for deciding the optimum formula of hydrogel using the computer optimization technique. The hydrogel of optimum formula was composed of PVA (10 w/v%), MP (0 w/v%), and sorbitol (40 w/v%) and the release rate of indomethacin was 1.981 μg/ml·min^1/2.     

Transdermal delivery of selegiline from alginate-Pluronic composite thermogels

The present work was carried out to design a practical, controlled-release transdermal system for selegiline using thermosensitive hydrogels. The copolymers of alginate and Pluronic F127 (PF127) were used to design thermogels by either physical blending (A+P) or chemical grafting (AP). The thermogels were characterized in terms of the sol-gel temperature, scanning electron microscopy (SEM), degradation ratio, and skin permeation behavior. The chemical grafting of alginate to PF127 could delay the sol-gel temperature from 24.1 to 30.4°C, which is near the temperature of the skin surface. The gelling temperature of the physical mixture of alginate and PF127 (A+P) did not significantly differ. The porosity of the A+P structure was greater compared to that of the AP structure. AP thermogels were regularly degraded, with 60% of the gel matrix remaining after a 48-h incubation. PF127 and A+P hydrogels showed almost no degradation. The results of skin permeation across porcine skin and nude mouse skin suggested that the thermogels could produce sustained selegiline release, with AP showing the most-sustained permeation. AP hydrogels exhibited linear permeation properties for the transdermal delivery of selegiline. Inter-subject variations in skin permeation were reduced by incorporation of the thermogel. Such a thermosensitive hydrogel can be advantageous as a topical therapeutic formulation for selegiline.     

PHARMACEUTICAL NANOTECHNOLOGY: A Novel Composite Hydrogel Based on Chitosan and Inorganic Phosphate for Local Drug Delivery of Camptothecin Nanocolloids

In attempt to overcome the problem of low water solubility and severe toxicity of camptothecin (CPT) after intravenous administration, a novel drug carrier system based on chitosan (CS) and dibasic sodium phosphate (DSP) has been developed in this paper to encapsulate CPT intending for local administration. Nanocolloids of CPT with size about 500 nm were first prepared, followed by encapsulation in the chitosan/dibasic sodium phosphate (CS/DSP) formulation. The formulation was sol state below 37°C and transformed to nonflowing gel state at 37°C. Encapsulation of CPT nanocolloids had greatly effect on the gelling time as well as the micro-structure of hydrogel. In vitro and in vivo degradation studies revealed that the developed CS/DSP hydrogel was biodegradable and biocompatible. In vitro release study revealed that CPT released from CS/DSP hydrogel in an extended period with about 70% of total CPT released from hydrogel after 18 days. Furthermore, nearly 90% of CPT in the chitosan hydrogels could be preserved in the lactone form (active form) even after 7 days's storage at 37°C. Furthermore, in vitro cytotoxicity of CPT nanocolloids on SKOV3 human ovarian cancer cells suggested the well anti-tumor cell efficiency could be gained at a lower concentration.     

Intranasal delivery of Clozapine using nanoemulsion-based in-situ gels: An approach for bioavailability enhancement

Limited solubility and hepatic first-pass metabolism are the main causes of low bioavailability of anti-schizophrenic drug, Clozapine (CZP). The objective of the study was to develop and validate nanoemulsion (NE) based in-situ gel of CZP for intranasal administration as an approach for bioavailability enhancement. Solubility of CZP was initially investigated in different oils, surfactants and co-surfactants, then pseudoternary phase diagrams were constructed to select the optimized ratio of oil, surfactant and co-surfactant. Clear and transparent NE formulations were characterized in terms of droplet size, viscosity, solubilization capacity, transmission electron microscopy, in-vitro drug release and compatibility studies. Selected NEs were incorporated into different in-situ gel bases using combination of two thermosensitive polymers; Pluronic® F-127 (PF127) and F-68 (PF68). NE-based gels (NG) were investigated for gelation temperature, viscosity, gel strength, spreadability and stability. Moreover, selected NGs were evaluated for ex-vivo permeation, mucoadhesive strength and nasal ciliotoxicity. Peppermint oil, tween 80 and transcutol P were chosen for NE preparation owing to their maximum CZP solubilization. Clear NE points extrapolated from tween 80:transcutol P (1:1) phase diagram and passed dispersibility and stability tests, demonstrated globule size of 67.99 to 354.96 nm and zeta potential of −12.4 to −3.11 mV with enhanced in-vitro CZP release (>90% in some formulations). After incorporation of the selected N3 and N9 formulations of oil:Smix of 1:7 and 2:7, respectively to a mixture of PF127 and PF68 (20:2% w/w), the resultant NG formulations exhibited optimum gelation temperature and viscosity with enhanced CZP permeation and retention through sheep nasal mucosa. Ciliotoxicity examinations of the optimum NGs displayed no inflammation or damage of the lining epithelium and the underlying cells of the nasal mucosa. In conclusion, NE-based gels may be a promising dosage form of CZP for schizophrenia treatment.