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[Display omitted] The objective of this study was to evaluate the potential of novel poloxamer thermosensitive hydrogels (PTHs) formulations for prolonged release of iron dextran particles (IDP) for intramuscular (IM) injection. The thermosensitive behaviour helps to avoid hepcidin overexpression and toxicity by releasing IDPs without iron accumulation in injection or deposit sites. We hypothesized that novel PTH formulation would prolong iron liberation compared to the commercial iron dextran formulation (FEDEX). PTHs loaded with IDPs were developed with increasing iron content (0.1, 0.2 and 0.4 g of iron/g of poloxamer) and characterized as a prolonged release IM iron supplement. The PTHs had a biocompatible pH for IM injection (6.4) and thermosensitive viscosity, increasing from ∼50 (4 °C) to ∼3000 mPa.s (37 °C). PTHs were successfully injected in the sol state (at 4 °C) into pork meat at 37 °C, transitioning to the gel state in situ (in ∼60–190 s). Structural characterization indicated that there were no PTH-IDP chemical interactions, suggesting that IDP entrapment in PTHs was physical upon gelation. In vitro release studies revealed that iron release from PTH (0.4 g of iron/g of poloxamer) reached 100 % by day 10, whereas 100 % release from FEDEX was complete in 4 h. This novel iron PTH formulation achieved a 60 times long iron release compared to the commercial product. In conclusion, the reported strategy shows adequate IDP entrapment/release properties for prolonged iron release following ex vivo IM injection using biocompatible materials. These results provide a strong basis for future preclinical evaluation to elucidate aspects such as drug release, local irritation, biocompatibility, and efficacy. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The purpose of this work was to develop an in situ thermosensitive electro-responsive mucoadhesive gel loaded with bioactive agent (nanocomposite) meant for nose to brain delivery in a controllable manner when electric stimulation is applied. Nanocomposite was developed using a combinatorial blending of chitosan, hydroxypropylmethylcellulose, pluronic F127 and polyaniline which was then loaded with BCNU-Nano-co-Plex (the bioactive agent). The nanocomposite was a liquid at room temperature but formed an in situ mucogel at a temperature of 27.5 ± 0.5 °C. Furthermore, the nanocomposite possessed a redox element which makes it responsive to electrical stimulation (ES). The stimuli responsiveness enabled the formulation to release the bioactive agent when electrical potential was applied and demonstrated a desired 10.28% release of nanoparticles per application cycle. The results further revealed pore formation within the formulation which accommodated the loaded nanoparticles. The release profile also demonstrated a pulsatile release of the bioactive material when subjected to ES. This formulation may therefore be useful as a nose to brain drug delivery system that can be modulated to deliver bioactive agents to the brain via electro-actuation in an "on-off" drug release kinetics by means of an external ES for a controlled nose-to-brain delivery. [ABSTRACT FROM AUTHOR]

[Display omitted] Injectable hydrogels are a promising treatment option for nervous system injuries due to the difficulty to replace lost cells and nervous factors but research on injectable conductive hydrogels is limited and these scaffolds have poor electromechanical properties. This study developed a chitosan/beta-glycerophosphate/salt hydrogel and added conductive aligned nanofibers (polycaprolactone/gelatin/single-wall carbon nanotube (SWCNT)) for the first time and inspired by natural nerve tissue to improve their biochemical and biophysical properties. The results showed that the degradation rate of hydrogels is proportional to the regrowth of axons and these hydrogels' mechanical (hydrogels without nanofibers or SWCNTs and hydrogels containing these additions have the same Young's modulus as the brain and spinal cord or peripheral nerves, respectively) and electrical properties, and the interconnective structure of the scaffolds have the ability to support cells. [ABSTRACT FROM AUTHOR]

Dissolving microneedles (DMN) have been studied as a drug delivery system to enhance the transport of drug molecules across the skin with almost no pain. However, the poor dissolving ability of microneedles in the skin and low drug loading have limited their potential application. The aim of this study was to develop a novel dissolving microneedle system with improved dissolving ability for the delivery of poorly water soluble contraception drug, levonorgestrel (LNG). Chitosan and beta-sodium glycerophosphate (β-GP) were incorporated in the formulation of microneedles. It was found that 69.32 ± 4.23% of the microneedles penetrated through the skin and dissolved within the first 2 h, which was almost 2-fold higher than that of the conventional microneedles. In addition, drug loading was significantly increased by packaging LNG into the molecules of hydroxypropyl beta cyclodextrin (HP-β-CD) to form LNG-HP-β-CD inclusion compounds. The use of chitosan and β-GP together with HP-β-CD inclusion compounds was shown to enhance the bioavailability of LNG transdermally. This novel DMN system resulted in a similar pharmacokinetic profile as that following oral administration. In addition to similar C max and AUC values, drug concentrations in the blood were more consistent following the DMN in comparison to oral administration. [ABSTRACT FROM AUTHOR]

Conventional formulations of human calcitonin (hCT), a peptide drug, normally suffer from limited therapeutic efficacy with low stability and short half-life. We have found that the fibrillation of highly amyloidogenic hCT can be inhibited by cucurbit[7] (CB[7]), an amphiphilic small molecule. Meanwhile, a thermogelling copolymer was found to be a suitable candidate for sustained delivery of peptide/protein drugs. Herein, we report a long-term delivery formulation composed of hCT-CB[7] complex and biodegradable thermogel of poly(D,L-lactic acid- co -glycolic acid)- b -poly(ethylene glycol)- b -poly(D,L-lactic acid − co -glycolic acid) (PLGA-PEG-PLGA). A 20 wt% PLGA-PEG-PLGA solution exhibited a temperature-sensitive sol-gel transition at 35 °C in phosphate buffer solution and slowly degraded over one month at neutral pH. Both the mass fraction of PLGA-PEG-PLGA copolymer and the complexation of hCT-CB[7] moderated the release process. hCT was sustainedly released over three weeks in the 20 wt% hydrogel with hCT-CB[7] complex at the ratio of 1:10 or 1:25. Further considering its low cytotoxicity, the delivery system is potential for the clinical application of hCT. [ABSTRACT FROM AUTHOR]

To obtain wound dressings which could be removed easily without secondary injuries, we prepared thermoresponsive electrospun fiber mats containing poly(di(ethylene glycol) methyl ether methacrylate) (PDEGMA). Blend fibers of PDEGMA and poly( l -lactic acid-co-ε-caprolactone) (P(LLA-CL) were fabricated via electrospinning, and analogous fibers containing the antibiotic ciprofloxacin (CIF) were also prepared. Smooth cylindrical fibers were obtained, albeit with a small amount of beading visible for the ciprofloxacin-loaded fibers. X-ray diffraction showed the drug to exist in the amorphous physical form post-electrospinning. The composite fibers showed distinct thermosensitive properties and gave sustained release of CIF over more than 160 h in vitro . The fibers could promote the proliferation of fibroblasts, and by varying the temperature cells could easily be attached to and detached from the fibers. Antibacterial tests demonstrated that fibers loaded with ciprofloxacin were effective in inhibiting the growth of E. coli and S. aureus . In vivo investigations on rats indicated that the composite PDEGMA/P(LLA-CL) fibers loaded with CIF had much more potent wound healing properties than a commercial gauze and CIF-loaded fibers made solely of P(LLA-CL). These results demonstrate the potential of PDEGMA/P(LLA-CL)/ciprofloxacin fibers as advanced wound dressing materials. [ABSTRACT FROM AUTHOR]

[Display omitted] • Injectable chitosan-based thermosensitive nanocomposite hydrogels were prepared using graphene oxide nano sheets. • Graphene oxide modulated the physicochemical properties of the nanocomposite hydrogels in a concentration-dependent manner. • Incorporation of graphene oxide enhanced the mechanical properties of the chitosan-based thermosensitive hydrogels. • Graphene oxide/chitosan thermosensitive nanocomposite hydrogel controlled the release of bupivacaine hydrochloride in vitro and in vivo. Local anesthetics are commonly used for the management of intraoperative and postoperative acute and chronic pain caused by small invasive procedures. However, their short half-life and duration of action limit their clinical benefits. In this study, we proposed the incorporation of graphene oxide (GO) nanosheets to chitosan (CS)/β-glycerophosphate (GP) thermosensitive hydrogel system to form an injectable nanocomposite hydrogel (NCH) with improved mechanical properties and better control over the release of bupivacaine hydrochloride (BH). The prepared NCHs were characterized for their gelation time, porosity, swelling ratio, injectability, mechanical strength and in vitro drug release. In vivo , the efficacy of the prepared NCH containing 0.5 % w/v BH was evaluated using a thermal nociceptive assay in a rat model. The incorporation of GO significantly enhanced the physicochemical and mechanical properties of the hydrogel scaffolds in a concentration-dependent manner. Inclusion of 0.1% w/v GO resulted in 84% reduction in gelation time and 16% and 40% decrease in the porosity and swelling ratio of the NCHs, respectively. The mechanical strength of the CS/GP hydrogel scaffolds was also significantly improved in presence of GO. BH was slowly released from the NCHs containing 0.1% w/v GO and resulted in a 55% and 86.43% drug release after 6 and 24 h, respectively. In vivo studies showed that BH-loaded NCH significantly prolonged the local anesthetic effect and resulted in a 6.5-fold increase in blocking the pain sensory reflex compared to BH solution. These results indicate that the incorporation of GO significantly improved the physical and mechanical properties of CS/GP thermosensitive hydrogels and successfully sustained the effect of local anesthesia for more effective pain management. [ABSTRACT FROM AUTHOR]

Abstract: The present study aimed to prepare a chemically and physically stable formulation of baicalein (Ba) in an in situ thermally sensitive hydrogel for vaginal administration. An inclusion complex of Ba and hydroxypropyl-γ-cyclodextrin (HP-γ-CD) was first developed to increase the stability and solubility of Ba in an aqueous solution. The formation of the Ba-HP-γ-CD complex was characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray powder diffractometry (XRPD). Poloxamers 407, 188 (P407, P188), sodium alginate (SA), hydroxypropylmethylcellulose (HPMC), and benzalkonium bromide were mixed to obtain a hydrogel with an appropriate gelation temperature for vaginal use. Among the formulations examined, P407/Ba-HP-γ-CD/HPMC/P188/benzalkonium bromide (18/0.96/0.5/4.0/0.02%) represented the appropriate gelation temperature and acceptable drug release rate at the administration site. Release of Ba-HP-γ-CD from the poloxamer hydrogel followed Peppas equation, which suggests that it occurred through coupled corrosion-diffusion mechanism, and the corrosion-release curve showed that corrosion was the primary mode of release. In animal study, treatment by using Ba-HP-γ-CD thermosensitive hydrogel could produce a restoration of damaged tissues. Thermosensitive hydrogel formulation of the Ba-HP-γ-CD complex appears to be a promising treatment for cervicitis. [Copyright &y& Elsevier]

Abstract: Poloxamer 407 has excellent thermo-sensitive gelling properties. Nevertheless, these gels possess inadequate poor bioadhesiveness and high permeability to water, which limited its’ application as a thermoresponsive matrix. The main aim of the present investigation was to develop thermosensitive and mucoadhesive rectal in situ gel of nimesulide (NM) by using mucoadhesive polymers such as sodium alginate (Alg–Na) and HPMC. These gels were prepared by addition of mucoadhesive polymers (0.5%) to the formulations of thermosensitive gelling solution containing poloxamer 407 (18%) and nimesulide (2.0%). Polyethylene glycol (PEG) was used to modify gelation temperature and drug release properties. The gelation temperature and drug release rate of the prepared in situ gels were evaluated. Gelation temperature was significantly increased with incorporation of nimesulide (2.0%) in the poloxamer solution, while the addition of the mucoadhesive polymers played a reverse role on gelation temperature. The addition of PEG polymers increased the gelation temperature and the drug release rate. Among the formulations examined, the poloxamer 407/nimesulide/sodium alginate/PEG 4000 (18/2.0/0.5/1.2%) exhibited the appropriate gelation temperature, acceptable drug release rate and rectal retention at the administration site. Furthermore, the micrographic results showed that in situ gel, given at the dose of 20mg/kg, was safe for no mucosa irritation. In addition, it resulted in significantly higher initial serum concentrations, C max and AUC of NM compared to the solid suppository. [Copyright &y& Elsevier]

Abstract: To develop an industrially practical thermosensitive injectable hydrogel that is easy to administer, gels quickly in the body and allows sustained release of the drug, poloxamer-based hydrogels containing piroxicam as a model drug were prepared with poloxamer, sodium hydroxide and sodium chloride using the cold method. Their rheological characterization, dissolution and pharmacokinetics after intramuscular administration to rabbits were evaluated. Among the ingredients tested, sodium hydroxide and piroxicam decreased the viscosity and retarded the gelation time of the injectable gel. However, sodium chloride did the opposite. The thermosensitive injectable gel composed of 2.5% piroxicam, 15% P 407, 17% P 188, 0.01% sodium hydroxide and 1.6% sodium chloride was instantly applied to practical industrial product, since it was easy to administer intramuscularly and gelled quickly in the body. The drug was dissolved out of the hydrogels by Fickian diffusion through the extramicellar aqueous channels of the gel matrix. Sodium chloride barely affected the dissolution mechanism or dissolution rate of the drug from the injectable gels. Furthermore, it maintained the plasma concentrations of drug for 4 days and gave a 150-fold higher AUC compared to piroxicam solution. Thus, it would be practically useful for delivering piroxicam in a pattern that allows sustained release for a long time, leading to better bioavailability. [Copyright &y& Elsevier]

Abstract: Sucrose esters (SEs) are non-toxic, biodegradable, non-ionic surfactants. They have a wide range of hydrophilic–lipophilic balance values (1–16) and are usually applied as surfactants, or as solubility or penetration enhancers. The aims of this work were to study the gelling behaviour of SEs and the effects of this property on drug release. The gelling characteristics of two different SEs (P1670 and S970) were investigated by rheological measurements, and compared with each other. The effects of the gel-forming SEs on model drug (paracetamol) release were evaluated by in vitro drug release studies. The kinetics of the dissolution process were studied by analysing the dissolution data through the use of various kinetic equations. The results revealed that the gelling of the SEs is temperature- and concentration-dependent. The examined sucrose stearate (S970) has a stronger gel structure than that of sucrose palmitate (P1670) and this behaviour has a significant effect on the drug release. The analysis of the dissolution kinetic data in this study revealed that the dissolution follows the Korsmeyer–Peppas (paracetamol–P1670) or Higuchi (paracetamol–S970) equations. [Copyright &y& Elsevier]

Abstract: Thermosensitive magnetoliposomes (TMs) encapsulated with methotrexate (MTX) were prepared with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol by reverse-phase evaporation. Encapsulation efficiency of MTX and hydrophilic magnetite Fe2O3-glu, liposome particle size, ζ-potential, and in vitro and in vivo drug release were studied. More than 80% of loaded MTX was released from TMs within 30min when the environmental temperature increased from 37°C to 41°C, while 60% of the drug was remained inside TMs for up to 24h at 37°C. Furthermore, the pharmacokinetics and tissue distribution study showed that TMs significantly increased the accumulation of MTX in the skeletal muscular tissue when exposed to an external constant magnetic field and heated to 41°C compared to the absence of the magnetic field and heating. Therefore, the results in this study suggested that TMs prepared by reverse-phase evaporation can archive a good magnetic targeting effect and fast drug release in response to hyperthermia, which implies their great potential of application in cancer therapy. [Copyright &y& Elsevier]

Abstract: In situ gellable thermosensitive poly(N-isopropylacrylamide-co-acrylamide) (designated as PNIP/AAm) nanogel aqueous dispersions were prepared through precipitation polymerization. Their thermosensitive volume phase transition and in situ gel-forming behavior were investigated. 5-Fluorouracil (5-Fu) and bovine serum albumin (BSA) were used as model drugs. The drug-loading properties of PNIP/AAm nanogel particles and release behavior from in situ gelatinized PNIP/AAm nanogel aqueous dispersions were investigated. The prepared PNIP/AAm nanogel particles and aqueous dispersions show good thermosensitivity. The presence of the drugs in the systems has no significant influence upon the thermosensitivity of the systems. In addition, the amount of cross-linker used in the preparation of the PNIP/AAm nanogel has little influence upon the drug-loading capability of PNIP/AAm nanogel particles and also on the release behavior from gelatinized dispersions. It was found that the drug-loading efficacy and entrapment efficiency of PNIP/AAm nanogel particles for low molecular weight 5-Fu was higher than that for biomacromolecular BSA. Furthermore, the cumulative release ratios of 5-Fu from in situ gelatinized PNIP/AAm nanogel aqueous dispersions were distinctly higher than that of BSA. These results imply potential application of prepared thermosensitive nanogel dispersions as embolizing and tissue engineering materials. [Copyright &y& Elsevier]

Abstract: The objective of this research is to develop injectable polymers solution based controlled release delivery systems for testosterone (TSN), using phase sensitive and thermosensitive polymers. A combination of poly(lactide) (PLA) and solvents mixture of benzyl benzoate (BB) and benzyl alcohol (BA) was used in the phase sensitive polymer delivery system. The effects of solvents system and drug loading on the in vitro TSN release were evaluated. In the case of thermosensitive polymer delivery systems, a series of low-molecular-weight poly(lactide-co-glycolide)–poly(ethylene glycol)–poly(lactide-co-glycolide) (PLGA–PEG–PLGA) triblock copolymers with varying ratio of lactide/glycolide (LA/GA, 2.0–3.5) were studied to control the release of TSN. The effects of varying block length of copolymers 1–4 on the in vitro TSN release were evaluated. Phosphate buffer saline (pH 7.4) containing 0.5% (w/v) Tween-80 was used as in vitro release medium. The amount of the released TSN was determined by an HPLC method. A controlled (zero-order) in vitro release of TSN was observed from both the phase sensitive and thermosensitive polymer delivery systems. Addition of BA (15%, v/v) in solvents system significantly (p <0.05) increased the release rate of TSN (0.33±0.01mg/ml) from phase sensitive delivery system in comparison to solvent without BA (0.27±0.00mg/day). Increasing drug loading also increased release rate. In the case of thermosensitive polymer delivery system, increasing the hydrophobic PLGA block length of copolymers significantly (p <0.05) decreased the release rate of TSN. It is evident from this study that the phase sensitive and thermosensitive polymers are suitable for developing prolong-release injectable implant delivery systems for TSN. [Copyright &y& Elsevier]

Abstract: The purpose of this study was to synthesize and characterize biodegradable and thermosensitive triblock copolymers for delivering protein at controlled rate in biologically active form for longer duration of time. A series of thermosensitive triblock copolymers with different block lengths (PLGA–PEG–PLGA) were synthesized by ring-opening polymerization of d,l-lactide and glycolide with polyethylene glycol (PEG) in the presence of stannous octoate. Compositions and molecular weight of triblock copolymers were characterized by 1H NMR spectrometry and gel permeation chromatography, respectively. A single test-tube inverting method was employed to determine the sol–gel transition temperature. Lysozyme was used as a model protein. Lysozyme solution formulation was prepared with different triblock copolymers for in vitro release. Lysozyme concentration and its biological activity in the released sample were determined using a standard MicroBCA method and bacterial cell lysis method, respectively. The effects of varying block lengths and concentrations of copolymers on the in vitro release of lysozyme were evaluated. The release profiles from formulations showed a higher initial release followed by slower release up to 4 weeks. Increasing the block lengths of copolymers decreased burst release of lysozyme from 41.2±5.4% to 16.1±3.9%. Increasing copolymer concentrations decreased the drug release. Lysozyme in the 4 weeks released samples retained most of its biological activity (>80%). It is feasible to deliver protein in biologically active form for longer duration by varying block lengths and concentrations of triblock copolymers. [Copyright &y& Elsevier]