In-situ forming biodegradable implants for sustained Fluocinolone acetonide release to the posterior eye: In-vitro and in-vivo investigations in rabbits.

Delivering medication to the posterior segment of the eye presents a significant challenge. Intravitreal injection has emerged as the preferred method for drug delivery to this area. However, current injectable non-biodegradable implants for fluocinolone acetonide (FA) require surgical removal after prolonged drug release, potentially affecting patient compliance. This study aimed to develop an in-situ forming biodegradable implant (ISFBI) optimal formulation containing PLGA504H and PLGA756S (50:50 w/w%) with the additive NMP solvent. The goal was to achieve slow and controlled release of FA over a two-month period with lower burst release, following a single intravitreal injection. Through morphology, rheology, stability and in-vitro release evaluations, the optimal formulation demonstrated low viscosity (0.12-1.25 Pa. s) and sustained release of FA at a rate of 0.36 µg/day from the third day up to two months. Furthermore, histopathology and in-vivo studies were conducted after intravitreal injection of the optimal formulation in rabbits' eye. Pharmacokinetic analysis demonstrated mean residence time (MRT) of 20.02 ± 0.6 days, half-life (t1/2) of 18.80 ± 0.4 days, and clearance (Cl) of 0.29 ± 0.03 ml/h for FA in the vitreous humor, indicating sustained and slow absorption of FA by the targeted retinal tissue from vitrea over the two-month period and eliminating through the anterior section of the eye, as revealed by its presence in the aqueous humor. Additionally, FA exhibited no detection in the blood and no evidence of systemic side effects or damage on the retinal layer and other organs. Based on these findings, it can be concluded that in-situ forming injectable biodegradable PLGA implants can show promise as a long-acting and controlled-release system for intraocular drug delivery.

Development of Sustained Release Formulations Based on Lipid-Liquid Crystal to Control the Release of Deoxycholate: In Vitro and In Vivo Assessment.

Subcutaneous injections of phosphatidylcholine (PC), sodium deoxycholate (NADC), and a mixture of them were found to be an effective option for treating cellulite. However, it is noteworthy that the injection of NADC may result in inflammation as well as necrosis in the injection area. The preparation of a sustained release formulation based on lipid-liquid crystal that controls the release of NADC could be a potential solution to address the issue of inflammation and necrosis at the site of injection. To present a practical and validated approach for accurately determining the concentration of NADC in LLC formulations, spectrofluorimetry was used based on the International Council for Harmonization (ICH) Q2 guidelines. Based on the validation results, the fluorometric technique has been confirmed as a reliable, efficient, and economical analytical method for quantifying NADC concentrations. The method demonstrated favorable attributes of linearity, precision, and accuracy, with an r2 value of 0.999. Furthermore, it exhibited excellent interday and intraday repeatability, with RSD values below 4%. The recovery percentages ranged from 97 to 100%, indicating the method's ability to accurately measure NADC concentrations. The subcutaneous injection of the LLC-NADC demonstrated a reduction in inflammation and tissue necrosis in skin tissue, along with an increase in fat lysis within 30 days, when compared to the administration of only NADC solution. Moreover, the histopathological assessment confirmed that the use of the LLC formulation did not result in any detrimental side effects for kidney or heart tissue.

Prolonged local delivery of doxorubicin to cancer cells using lipid liquid crystalline system.

Exploring efficient strategies to eradicate the tumor tissue and enhance patient outcomes still remained a serious challenge. Systemic toxicity of the current chemotherapeutics and their low concentration in the tumor site limited reaching a practical approach in their administration and combinational therapy. Besides, complicated delivery platforms could not receive the marketing approval due to difficulties in scale up procedures. To this aim, we developed a simple injectable local delivery platform which provided a sufficient dose of the chemotherapeutic in the cancerous tissue with sustained release properties. Herein, various injectable in situ forming LLC formulations loaded with doxorubicin (DOX) were developed. Although there were many previous studies on lipid liquid crystal (LLC) based formulations, their performance as an injectable intratumoral depot system for local chemotherapy has not been extensively investigated yet. In the current study we developed 18 formulations of DOX loaded LLCs using Box-Behnken method via different ratios of phosphatidyl choline: sorbitan monooleate (PC: SMO), N-Methyl-2-pyrrolidone (NMP), and tween 80. The physicochemical properties of the formulations were investigated and their in vivo tumor inhibition efficiencies in C26 tumor bearing mouse model was further studied. The results indicated that DOX loaded PC: SMO/NMP/Tween 80 (50:50/50/2 w/w%) and DOX loaded PC: SMO/NMP (50:50/50 w/w%) formulations were syringeable with pseudoplastic behavior. Also, they could release the cargo in a sustained manner for 60 days. Compared to intravascular administration of DOX, intratumoral injection of the developed formulations led to a significant decrease in tumor volume and enhancement of the survival rate in murine tumor model. Additionally, animal imaging studies proved their prolonged accumulation in the tumor site. Histopathological studies showed that treatment with the DOX-loaded LLC formulations did not cause any systemic toxicity to vital organs. Taken together, we believe that the developed simple and efficient local delivery platform can be further used in combinational therapies and treatment of various solid tumors.

Hybrid in situ- forming injectable hydrogels for local cancer therapy.

Injectable in situ forming hydrogels are amongst the efficient local drug delivery systems for cancer therapy. Providing a 3D hydrogel network within the target tissue capable of sustained release of the chemotherapeutics made them attractive candidates for increasing the therapeutic index. Remarkable swelling properties, mechanical strength, biocompatibility, wide composition variety and tunable polymeric moieties have led to preparation of injectable hydrogels which also could be used as cavity adaptive chemotherapeutic-loaded implants to prevent post -surgical cancer recurrence. Implementation of various polymers, nanoparticles, peptide and proteins and different crosslinking chemistry facilitated the fabrication of hybrid hydrogels with favorable characteristics such as stimuli sensitive platforms or multifunctional systems. In the current review, we focused on design and fabrication strategies of injectable in situ forming hydrogels and summarized recent hybrid hydrogels used for local cancer therapy.

Comparison of lipid liquid crystal formulation and Vivitrol® for sustained release of Naltrexone: In vitro evaluation and pharmacokinetics in rats.

Camurus' FluidCrystal® injection depot is a lipid liquid crystal (LLC) phase formation-based method, comprising of glycerol dioleate (GDO) and soy phosphatidylcholine (SPC), together with minute quantities of N-methyl-2-pyrrolidone solvent (NMP). The present study aimed to develop a method for LLC using sorbitan monooleate (LLC-SMO) instead of GDO to prepare a one-month sustained-release formulation of naltrexone (NTX) that is applied for the treatment of autism and treating alcohol dependence. The optical characteristics of the LLC were assessed by polarizing light microscopy (PLM) to reveal the presence of lamellar, hexagonal, and cubic mesophases. Furthermore, in vitro release of NTX and NMP, degradation, pharmacokinetics, and histopathology of LLC-GDO and LLC-SMO in rats were evaluated and compared to those of Vivitrol®. The PLM images revealed that the structure of LLC-SMO is hexagonal, similar to LLC-GDO. The in vitro release of NTX and its pharmacokinetic results in rats indicted that the LLC-SMO system is more uniform than LLC-GDO and Vivitrol® during 35 days. Histopathological results of LLC-GDO and LLC-SMO confirmed the biocompatibility of our LLC delivery systems. Taken together these data demonstrate that the LLC-SMO-based method, was efficient enough to sustain the release of NTX in vitro and in vivo, confirming the biocompatible nature of this delivery system.

Randomized clinical trial comparing of transcranial direct current stimulation (tDCS) and transcutaneous electrical nerve stimulation (TENS) in knee osteoarthritis.

BACKGROUND: Due to the limitations of pharmacological and surgical management of knee osteoarthritis (OA), several non-pharmacologic approaches including transcutaneous electrical nerve stimulation (TENS) and transcranial direct current stimulation (tDCS) have been introduced, with promising results. OBJECTIVE: We aimed to investigate and compare the therapeutic effects of TENS and tDCS for the treatment of patients with knee OA. METHODS: In this double-blinded randomized controlled trial, a total of 40 adult patients with knee OA were randomly allocated to either the TENS or the tDCS group. Patients in either group received 6 sessions of the TENS or tDCS for 2 weeks. Knee strengthening exercises were performed twice daily for the entire treatment period. Patients were evaluated using the visual analogue scale (VAS) and Western Ontario and McMaster Universities (WOMAC). RESULTS: Significant improvement was observed in all outcomes in both TENS and tDCS groups at each follow up compared to baseline although the early improvement (first follow-up) in the WOMAC index was not significant in the TENS group. Based on the within-subject analysis, the behavior of two treatment groups did not differ regarding the changes in the course of the VAS, WOMAC score and its subscales, i.e. stiffness, pain and function (p = 0.263, 0.051, 0.198, 0.075, and 0.146, respectively). CONCLUSIONS: Based on the results of this study, the effect of tDCS and TENS was not significantly different on pain and function of patients with knee OA.

Molecular characteristics and antibiotic resistance pattern of Staphylococcus aureus nasal carriage in tertiary care hospitals of Isfahan, Iran.

Carriage of S. aureus in the anterior nares seems to play a significant role in the pathogenesis of infection. This study aimed to determine the molecular characteristics and antibiotic susceptibility pattern of S. aureus isolates obtained from the nasal carriage of health care workers (HCWs). This study was performed during July 2014 to July 2015 at three tertiary care hospitals. Nasal samples were collected from the nasal cavity of HCWs. Standard microbiological methods were used for identification of S. aureus isolates. Antibiotic susceptibility pattern was determined by the disc diffusion method. Determination of SCCmec typing and virulence genes was performed by the PCR method. From the isolates of 340 nasal swab samples of HCWs, 65 S. aureus strains (19%) including 22 (33.8%) MRSA were isolated. The highest sensitivity for MRSA isolates was towards vancomycin and rifampicin, each with 90.9%. Overall, 17% (11/65) and 92.3% (60/65) of S. aureus isolates were positive for pvl and hla genes, respectively. The rates of SCCmec types II, III, IV, V and I among MRSA isolates were 36.4 %, 22.7 %, 22.7 %, 9.1% and 4.5% respectively. The results of the present study indicate that S. aureus nasal carriage with potential virulence ability still remains a significant healthcare problem, especially in hospital environments.