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.

Injectable In-Situ Forming Depot Based on PLGA and PLGA-PEG-PLGA for Sustained-Release of Risperidone: In Vitro Evaluation and Pharmacokinetics in Rabbits.

In the current research, novel drug delivery systems based on in situ forming gel (ISFG) (PLGA-PEG-PLGA) and in situ forming implant (ISFI) (PLGA) were developed for one-month risperidone delivery. In vitro release evaluation, pharmacokinetics, and histopathology studies of ISFI, ISFG, and Risperdal CONSTA® were compared in rabbits. Formulation containing 50% (w/w %) of PLGA-PEG-PLGA triblock revealed sustained release for about one month. Scanning electron microscopy (SEM) showed a porous structure for ISFI, while a structure with fewer pores was observed in the triblock. Cell viability in ISFG formulation in the first days was more than ISFI due to the gradual release of NMP to the release medium. Pharmacokinetic data displayed that optimal PLGA-PEG-PLGA creates a consistent serum level in vitro and in vivo through 30 days, and histopathology results revealed nearly slight to moderate pathological signs in the rabbit's organs. The shelf life of the accelerated stability test didn't affect the results of the release rate test and demonstrated stability in 24 months. This research confirms the better potential of the ISFG system compared with ISFI and Risperdal CONSTA®, which would increase patients' compliance and avoid problems of further oral therapy.

Preparation of porous PCL-PEG-PCL scaffolds using supercritical carbon dioxide.

In this study, the Supercritical Carbon Dioxide (scCO2) gas foaming procedure was used in the preparation of scaffolds containing the model drug dexamethasone (DXMT). The method used did not include an organic solvent thus making it a safe method. The ring-opening polymerization of PCL-PEG-PCL (PCEC) triblock was conducted using an organocatalyst [1,8 diazabicyclo [5.4.0] undec-7-ene (DBU)]. After mixing 5.0 g of DXMT with 50.0 g of PCEC, hydraulic pressure was applied to compress the mixed powder into disc-like tablets. The tablet-like scaffold of the triblock containing DXMT was inserted into a scCO2 gas-foaming device. The peak porosity percentage of the synthesized triblock was found to be 55.58 %. Pressure, temperature, soaking time and the time required to depressurize were recorded as 198 bar, 50 °C, 2.0 h, and 28 min respectively. After treatment with scCO2, the scaffolds experienced an almost full release of DXMT in vitro after 30 days (83.74 ± 1.54 % vs 52.24 ± 2.03 % before scCO2 treatment). In conclusion, the results proved that the scCO2 gas foaming procedure could be employed for constructing modifiable PCEC scaffolds with plausible porosity and structural and morphological features which can manipulate drug release.

In-vitro and in-vivo evaluation of sustained-release buprenorphine using in-situ forming lipid-liquid crystal gels.

AIMS: Sustained-release systems reduce the incidence of drug side effects and the need for frequent drug consumption, thus increasing patient compliance with treatment. In this study, we aimed to produce sustained-release buprenorphine (BP) using lipid-liquid crystal gels. MAIN METHODS: The three experimental groups in this study included: group I: lipid-liquid crystal formulation 5 (F5) containing BP, group II: BP-free F5, group III: BP solution in NMP, and group IV: control (no treatment). The formulations were injected subcutaneously into the rabbits' back neck. KEY FINDINGS: The results showed that the time required to reach the drug's maximum concentration (Tmax) was longer in group I than in group III. The maximum BP concentration (Cmax) and the constants of the drug removal rate and drug absorption rate (Ka) were significantly higher in group III compared to group I. The half-life (t1/2) of the drug in blood circulation was significantly longer in group I than in group III. Histopathological analysis revealed no histological abnormalities in the skin and heart in group I (BP-containing F5); however, mild hyperemia was observed in interstitial vessels in group III (BP-containing NMP). The kidney and liver tissues showed normal structure in the control group, as well as groups I and II. However, in the group receiving BP-containing NMP, significant congestion, tissue damage, necrosis, and fibrosis were observed in the kidney and liver. SIGNIFICANCE: The results showed that the lipid-liquid crystal system can be used to design slow-release platforms for BP, minimizing the side effects associated with the use of its conventional forms.

Preparation and in vitro evaluation of injectable formulations of levothyroxine sodium using in situ forming hydrogel temperature-responsive systems based on PLA-PEG-PLA and PLGA-PEG-PLGA triblock copolymers.

Objectives: Recently, great attention has been paid to developing new drug delivery systems to manage the rate, time, and site of drug release. We aimed to design a novel drug delivery system to support targeted and gradual delivery of levothyroxine sodium. Materials and Methods: The triblock copolymers of PLA-PEG-PLA and PLGA-PEG-PLGA were constructed using the ring-opening copolymerization method and then purified and characterized by 1H-NMR, DSC, and GPC techniques. The phase transition temperature of the polymers was determined, and levothyroxine sodium stability was investigated in a phosphate-based buffer (pH 7.4). In vitro drug release into the PBS was measured at different concentrations of the triblocks for one month. Results: The results of NMR and GPC showed successful fabrication of the copolymers with low molecular weight dispersion and Tg points of -8.19 °C and -5.19 °C for PLA-PEG-PLA and PLGA-PEG-PLGA, respectively. Stability tests showed that during one month, most of the triblocks' masses degraded at 37 °C while levothyroxine sodium remained stable. Initial burst release of the drug in both copolymers is inversely correlated with the concentration of the polymer. Evaluation of drug release for 35 days showed that PLA-PEG-PLA had a slower drug release rate than PLGA-PEG-PLGA. Conclusion: Considering the low initial burst release, as well as continuous and long-term release kinetics of PLA-PEG-PLA and PLGA-PEG-PLGA copolymers, they can be used to gradually deliver levothyroxine sodium, obviating the need for frequent administrations and concerns over drug-food interactions.

Lipid-liquid crystals for 2 months controlled risperidone release: In-vitro evaluation and pharmacokinetics in rabbits.

In this study, a drug delivery system based on lipid liquid crystal (LLC) was developed for the long-term delivery of risperidone to improve psychological treatment. Optimal LLC formulation was achieved based on maximum release after 60 days with different ratios of phosphatidylcholine (PC) to sorbitol monooleate (PC: SMO), tween grade 80 (w/w %), and tocopherol acetate (TA) (w/w %) using the Box-Behnken method. In vitro and ex vivo studies, pharmacokinetics, and histopathological examination in rabbits were conducted to compare the optimal LLC with Risperdal CONSTA®. The optimum formulation containing the PC to SMO ratio of 58.6%, tween 0.82% w/w, and TA 3.6% w/w was selected because it had the highest drug release percentage (100%) during about two months. Polarized optical microscopy (POM) revealed HII mesophase with a 2-dimensional structure. Cell culture also revealed moderate cytotoxicity for LLC-risperidone. Pharmacokinetic data displayed that the optimal LLC created a more consistent drug serum level within 60 days, and histopathology results demonstrated slight to moderate damage in rabbits' organs. Furthermore, the accelerated stability test confirmed optimum stability for LLC and risperidone. This study confirmed the better pharmacokinetic potentials of SMO-based LLC systems compared with Risperdal CONSTA®, which would promote patient compliance and obviate the difficulties of additional oral 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.

The Impacts of PLGA/PEG Triblock Copolymers with Variable Molecular Weights on the Sustained Release of Buprenorphine.

OBJECTIVE: Current in-situ injectable implants of buprenorphine (BP) such as Sublocade® consist of N-methyl-2-pyrrolidone (NMP)-dissolved PLGA. To control the initial burst release of Sublocade® during the first 24 hours after injection, we here used a BP in-situ forming composite (ISFC) employing different molecular weights of PLGA-PEG-PLGA triblock. METHODS: The triblock was synthesized by Ring-Opening Polymerization (ROP) using PEG molecules with weights of 1500, 3000, and 4000 Da via the melting method. The specifications of the triblocks were evaluated by 1H-NMR, FTIR, GPC, and DSC. The sol-gel, gel-precipitate temperatures, in-vitro release, and composites' morphology, degradation, and toxicity were assessed for determining the features of ISFC 1500, ISFC 3000, and ISFC 4000 formulations. ROP was performed successfully via the melting method. The yields of all polymerization reactions were greater than 83.4%. RESULTS: The PEG 1500 triblock showed both sol-gel and gel-precipitate temperatures, but PEG 3000 and 4000 only showed a sol-precipitate temperature. The values of initial burst release of BP from ISFC 1500, ISFC 3000, and ISFC 4000 were 6.52 ± 0.22%, 12.39 ± 0.61%, and 15.80 ± 0.98%, respectively. BP release from the ISFCs wascompleted over three weeks for ISFC 1500 and 10 days for ISFC 3000 and ISFC 4000. The composites containing PEG 3000 and PEG 4000 were more spongy and porous than PEG 1500. The ISFC 1500 delivered a higher cell viability (95.17 ± 1.15%) compared with ISFC 3000 (86.37 ± 2.25%) and ISFC 4000 (79.70 ± 3.77%). CONCLUSION: These results indicated that ISFC 1500 wasbiocompatible and delivered suitable early initial burst reactions compared with ISFC 3000 and 4000 and might be a good candidate for preparing sustained-release formulation of BP.

Docetaxel encapsulation in nanoscale assembly micelles of folate-PEG-docetaxel conjugates for targeted fighting against metastatic breast cancer in vitro and in vivo.

Due to the high frequency and mortality of breast cancer, developing efficient targeted drug delivery systems for frightening against this malignancy is among cancer research priorities. The aim of this study was to synthesize a targeted micellar formulation of docetaxel (DTX) using DTX, folic acid (FA) and polyethylene glycol (PEG) conjugates as building blocks. In the current study, two therapeutic polymers consisting of FA-PEG-DTX and PEG-DTX conjugates were synthesized and implemented to form folate-targeted and non-targeted micelles. Dissipative particle dynamics (DPD) method was used to simulate the behavior of the nanoparticle. The anti-cancer drug, DTX was loaded in to the micelles via solvent switching method in order to increase its solubility and stability. The cytotoxicity of the targeted and non-targeted formulations was evaluated against 4T1 and CHO cell lines. In vivo therapeutic efficiency was studied using ectopic tumor model of metastatic breast cancer, 4T1, in Female BALB/c mice. The successful synthesis of therapeutic polymers, FA-PEG-DTX and PEG-DTX were confirmed implementing 1HNMR spectral analysis. The size of DTX-loaded non-targeted and targeted micelles were 176.3 ± 8.3 and 181 ± 10.1 nm with PDI of 0.23 and 0.17, respectively. Loading efficiencies of DTX in non-targeted and targeted micelles were obtained to be 85% and 82%, respectively. In vitro release study at pH = 7.4 and pH = 5.4 showed a controlled and continuous drug release for both formulations, that was faster at pH = 5.4 (100% drug release within 120 h) than at pH = 7.4 (80% drug release within 150 h). The targeted formulation showed a significant higher cytotoxicity against 4T1 breast cancer cells (high expression of folate receptor) within the range of 12.5 to 200 µg/mL in comparison with no-targeted one. However, there was no significant difference between the cytotoxicity of the targeted and non-targeted formulations against CHO cell line as low-expressed cell line. In accordance with in vitro investigation, in vivo studies verified the ideal anti-tumor efficacy of the targeted formulation compared to Taxotere and non-targeted formulation. Based on the obtained data, FA-targeted DTX-loaded nano-micelles significantly increased the therapeutic efficacy of DTX and therefore can be considered as a new potent platform for breast cancer chemotherapy.

Retinoprotective Effects Of Crocin And Crocetin via Anti-Angiogenic Mechanism in High Glucose-Induced Human Retinal Pigment Epithelium Cells.

BACKGROUND: Diabetic retinopathy (DR) is one of the most common side effects of diabetes. We aimed to investigate the effects of crocin and crocetin (as a deglycosylated form of crocin in blood stream) in gene expression or protein levels of vascular endothelial growth factor (VEGF), vascular endothelial growth factor-receptor1 (VEGFR-1), matrix metalloproteinases2 (MMP-2), matrix metalloproteinases9 (MMP-9) and thrombospondin-2 (TSP-2) in high glucose cell culture media. METHODS: The retinal pigment epithelium (RPE) cells were exposed to high glucose (HG, 30 mM glucose concentration) and normal glucose (NG, 24.5 mM mannitol + 5.5 mM glucose) for six days. RPE cells were treated in four treatment groups (crocin, crocetin, Bevacizumab, and crocin + Bevacizumab). Gene expressions were measured using quantitative real-time PCR, and protein levels were evaluated by western blot. RESULTS: Findings showed that VEGF gene expression and protein level significantly decreased in all treatment groups. In addition, reduction in VEGFR1 gene expression was significantly higher in Bevacizumab and crocin + Bevacizumab groups than other groups. Only crocin and crocetin could reduce the gene levels of MMP-2 and MMP-9. In addition, TSP-2 protein levels increased when HG cells were exposed to crocin or crocin + Bevacizumab groups. CONCLUSION: Our data showed that crocin and crocetin have anti-VEGF function similar to Bevacizumab, act as an anti-angiogenic agent. Also, crocin and crocetin could decrease MMP-2 and MMP-9 gene levels being inflammatory and angiogenesis factors. As a result, crocin and crocetin have protective effects against angiogenesis and inflammation in DR.

Injectable In-Situ Forming Depot of Doxycycline Hyclate/α-Cyclodextrin Complex Using PLGA for Periodontitis Treatment: Preparation, Characterization, and In-Vitro Evaluation.

BACKGROUND: Doxycycline (DOX) is used in treating a bacterial infection, especially for periodontitis treatment. OBJECTIVE: To reduce irritation of DOX for subgingival administration and increase the chemical stability and against enzymatic, the complex of α-cyclodextrin with DOX was prepared and loaded into injectable in situ forming implant based on PLGA. METHODS: FTIR, molecular docking studies, X-ray diffraction, and differential scanning calorimetry was performed to characterize the DOX/α-cyclodextrin complex. Finally, the in-vitro drug release and modeling, morphological properties, and cellular cytotoxic effects were also evaluated. RESULTS: The stability of DOX was improved with complex than pure DOX. The main advantage of the complex is the almost complete release (96.31 ± 2.56 %) of the drug within 14 days of the implant, whereas in the formulation containing the pure DOX and the physical mixture the DOX with α-cyclodextrin release is reached to 70.18 ± 3.61 % and 77.03 ± 3.56 %, respectively. This trend is due to elevate of DOX stability in the DOX/ α-cyclodextrin complex form within PLGA implant that confirmed by the results of stability. CONCLUSION: Our results were indicative that the formulation containing DOX/α-cyclodextrin complex was biocompatible and sustained-release with minimum initial burst release.

Pharmacological Effects of Saffron and its Constituents in Ocular Disorders from in vitro Studies to Clinical Trials: A Systematic Review.

INTRODUCTION: Some medicinal plants have shown promising therapeutic potential for the management of the diseases. We aimed to systematically review the literature wherein the therapeutic effects of saffron have been studied on eye disorders. METHODS: A systematic literature search was performed in PubMed, Scopus, Web of Science, Google scholar and other databases using eye disorders and saffron as key terms. No strict inclusion criteria were defined, and almost all clinical studies, as well as in vivo and in vitro studies were included. The reported data in each study were extracted and then qualitatively described. RESULTS: Finally, 78 articles were found but only 29 relevant articles were included. Nine articles were clinical trials and 20 articles were studies conducted on cellular and molecular aspects of saffron on eye disorders. According to the included studies, crocin prevented the pro-inflammatory response in retinal cells and decreased glucose levels in diabetic mice. Also, crocetin prevented retinal degeneration and saffron protected photoreceptors from light-induced damage in retinal cells. Saffron also improved visual function in age-related macular edema and decreased intraocular pressure in patients with glaucoma. In addition, it was shown that crocin can improve best corrected visual acuity and decrease central macular thickness in patients with diabetic maculopathy. CONCLUSION: The results of this review indicated that saffron and its main ingredients such as crocin could be a potential candidate for the treatment of ocular disease especially eye inflammation; however, further clinical studies are needed to confirm such efficiency.

Effect of Pleurotus ostreatus and Trametes versicolor on triclosan biodegradation and activity of laccase and manganese peroxidase enzymes.

INTRODUCTION: Triclosan (TCS) is an extensively used antibacterial agent which has been frequently detected in different environmental compartments. Because of TCS inhibition effect on vast majority of bacterial species, it is important to explore fungal species and their involved enzymes in TCS biodegradation. The aim of this study was to compare the potential of two white rot fungi Pleurotus ostreatus and Trametes versicolor for TCS biodegradation through the whole cell culture of fungi in an aqueous culture medium. Additionally, the changes in ligninolytic enzyme activities and possible correlations and contributions of degradative enzymes during TCS biodegradation process were monitored. MATERIAL AND METHODS: This study was carried out using a factorial experiment with a completely randomized design in three replications. factorial design in The experimental factors included: two white rot fungi Pleurotus ostreatus and Trametes versicolor and uninoculated controls which were subjected to five levels of TCS concentrations (0, 5, 10, 20, 30 and 50 µg mL-1) to assess ligninolytic enzymatic activity during biodegradation of TCS. Samples were harvested periodically at three time intervals (4, 7 and 10 days). An AB SCIEX 3200 QTRAP LC-MS/MS system was used in order to analyze the biodegradation of TCS in liquid medium. RESULTS: Results suggested that the two white rot fungi responded differently when exposed to the different concentrations of TCS. In general, P. ostreatus exhibited more potential and ligninolytic enzymatic activity compared to T. versicolor. LC-MS/MS analyses also showed that P. ostreatus degraded TCS with higher efficiency compared to T. versicolor. In addition, almost all P. ostreatus biodegradation activity was completed within the first day of sampling. Contrasting, less efficient degradation was observed by T. versicolor, reaching around 88% of TCS biodegradation at concentration of 20 µg mL-1after 10 days. At higher TCS concentrations (≥30 µg mL-1), the growth of T. versicolor severely inhibited and led to a drop in enzymatic activity and biodegradation. Furthermore, laccase and manganese peroxidase (MnP) were determined as more involved enzymes which significantly correlated to TCS biodegradation by T. versicolor and P. ostreatus, respectively. CONCLUSION: P. ostreatus might be considered as efficient fungus in biodegradation of high amount of TCS in environmental matrices. The results of the present study might provide insights for future investigations on potential of fungi for applications in bioaugmentation-based strategies to remove TCS from wastewater and activated sludge.

Synthesis of a novel PEGylated colon-specific azo-based 4- aminosalicylic acid prodrug.

OBJECTIVES: 4-aminosalicylic acid (4-ASA) is an isomer of mesalazine that has recently been shown to be effective against inflammatory bowel disease (IBD), and more specifically, ulcerative colitis. However, the majority of orally administered 4-ASA is readily and extensively absorbed from the stomach and small intestine, so only a small amount is transported to the colon. A mutual ester and azo prodrug of 4-ASA was synthesized with polyethylene glycol (PEG) and dimethylaniline, respectively , to overcome this issue. MATERIALS AND METHODS: The 4-ASA prodrug was synthesized via a two-step process and then characterized by 1H-NMR. The stability of the prodrug was evaluated in simulated gastric fluid (pH 1.2). Furthermore, the in vitro release profiles of the drug conjugate was evaluated at pH 1.2, as well as pH 6.8 in the absence or presence of rat cecal content. RESULTS: The prepared prodrug was stable at pH 1.2, indicating that it could be protected from the acidic environment of the stomach. Also, the results of drug release at pH 6.8 showed that the amount of 4-ASA released was 63% within 12 hr in the absence of rat cecal content, while in the presence of rat cecal content, 97% of 4-ASA was released from the prodrug in 6 hr. CONCLUSION: Overall, the synthesized PEGylated azo-based 4-ASA prodrug could be a potential candidate for targeted drug delivery to the inflamed gut tissue in IBD.

In-vitro Release Evaluation of Growth Hormone from an Injectable In-Situ Forming Gel Using PCL-PEG-PCL Thermosensitive Triblock.

OBJECTIVE: An injectable long acting In-Situ Forming Gel (ISFG) of human Growth Hormone (hGH) was prepared by using triblock PCL-PEG-PCL (Mw 1500-1500-1500). Ring-Opening Polymerization (ROP) of triblock using microwave was applied. METHODS: The BCA protein assay Kit was used to determine the concentration of hGH in the in-vitro release medium. Finally, Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis (SDS-PAGE) tests and Circular Dichroism (CD) spectrum were done to approve the stability of released hGH. The result of ROP demonstrated that the proportion of PCL to PEG accorded with the initial molar ratio of the monomers. The cross-section of the Surface Electron Microscopy (SEM) indicated the porous framework of the hydrogel could load the drug into its tridimensional matrixes structure. There is the low initial burst release of hGH from the supramolecular hydrogel. RESULTS: The maximum in-vitro release of hGH was 71.2 % ± 1.5 that were due to hGH degrading after this time (21 days). The CD spectrum and SDS-PAGE results confirmed the stability of hGH during invitro release evaluation. CONCLUSION: The results suggest that the sustained-release formulation using PCL-PEG-PCL can be applied to control the release of hGH.

Docetaxel-Loaded Mixed Micelles and Polymersomes Composed of Poly (caprolactone)-Poly (ethylene glycol) (PEG-PCL) and Poly (lactic acid)-Poly (ethylene glycol) (PEG-PLA): Preparation and In-vitro Characterization.

Microwave irradiation was used to synthesize poly (caprolactone)-poly (ethylene glycol) (PEG-PCL) and poly (lactic acid)-poly (ethylene glycol) (PEG-PLA) copolymers that are composed of biodegradable polymers including PEG, PLA, and PCL. These copolymers were used for loading docetaxel in nanoparticles. Single emulsion-solvent evaporation technique was applied for preparing the PEG-PLA and PEG-PCL mixed nanoparticles (micelles and polymersomes) with different proportions, including 0:1, 1:1, 3:1, 1:3, and 1:0. The unimodal gel permeation chromatography curve showed low polydispersity of the di-block copolymers. The in-vitro drug release curves of formulations were compared. Micelles and polymersomes of 75% PEG-PCL and 25% PEG-PLA (P5 and M5) have the lowest burst release (5%) at the same period compared to the other copolymers. The dynamic light scattering and TEM results clarified that the size and shape of the formulations are uniform. The cytotoxicity effect of P5 and M5 was evaluated in different cell lines. The best one was found to P5 with half maximal inhibitory concentration (IC50) between 1.48-11.79 µg/mL. The pro-apoptotic effect of P5 was confirmed with flow cytometry study. These mixed micelles (M5) and polymersomes (P5) was found to be superior formulations than non-mixed ones.

In-vitro, ex-vivo, and in-vivo evaluation of buprenorphine HCl release from an in situ forming gel of PLGA-PEG-PLGA using N­methyl­2­pyrrolidone as solvent.

An in situ forming gel (ISFG) of buprenorphine (BP) was prepared using PLGA-PEG-PLGA (triblock) and N­methyl­2­pyrrolidone as solvent for decreasing the initial burst release. Supercritical CO2 method was used for ring opening polymerization of triblock. The optimum formulation of ISFG was achieved based on a minimum initial burst release of BP in the in-vitro release media using Box-Behnken design. In-vitro, ex-vivo, and in-vivo studies of ISFG were compared with an in situ forming implant (ISFI) composed of copolymer PLGA 504H (similar to RBP-6000). The initial burst release from in vitro media for the ISFG (6.19 ±â€¯0.31%) was significantly lower than that for the ISFI (13.45 ±â€¯1.14%) because the thermosensitive property of the triblock and hydrogen bonding between the NMP molecules and the PEG of the triblock prevented the NMP from diffusing rapidly into the release medium. The Cmax of BP (6.95 ±â€¯0.98 ng/mL) from the ISFG was significantly (p < 0.05) lower than those from the ISFI (8.19 ±â€¯1.02). Furthermore, the AUC, the range of serum concentration (C) of BP for the ISFG (AUC = 2721.38 ±â€¯69, C = 1.87-7.12) formulation were similar to those for ISFI (AUC = 2727.36 ±â€¯71, C = 1.75-10). The results suggest that the ISFG can be used as a new type of sustained-release injection formulation with a smaller initial burst release than the ISFI.

An In Vitro Study on the Effect of Amorphous Calcium Phosphate and Fluoride Solutions on Color Improvement of White Spot Lesions.

The ability of remineralizing agents to improve the color of white spot lesions (WSL) is an important aspect that should be investigated. The aim of this study was to evaluate the effects of 0.05% amorphous calcium phosphate (ACP), 0.5% ACP, and 0.05% fluoride solutions, as well as artificial saliva on the color improvement of white spot lesions (WSLs). In this in vitro study, 50 human premolar teeth were randomly classified into five groups. At baseline, all the samples were assessed by using a colorimeter (E0). Then, white spot lesions were induced on the surface of the teeth by means of a pH-cycling model, and the colorimeter was used again (E1). Afterwards, samples of the 1st and 2nd groups were kept in 0.05% ACP and 0.5% ACP solutions for 1 min/day, respectively. The 3rd group specimens were placed in 0.05% fluoride solution for 1 min/day. The other two groups were kept in artificial saliva and distilled in water separately. All the samples were assessed by the colorimeter for a third time (E2). We found no significant difference between the groups in ∆E1. There was also no significant difference among 0.05% ACP solution, 0.5% ACP solution, 0.05% fluoride solution, and artificial saliva considering ∆E2. However, a significant difference was noted between the above-mentioned solutions and distilled water in ∆E2. With respect to ∆E3, there were considerable differences between ACP solution and artificial saliva. The same results were obtained for the difference between fluoride solution and artificial saliva. However, no significant difference was found among 0.05% ACP, 0.5% ACP, and 0.05% fluoride solutions in terms of ∆E3. In Conclusion, ACP is as effective as fluoride in the color improvement of WSLs and the recommended treatment for this purpose is daily use of 0.05% ACP, 0.5% ACP or 0.05% fluoride solutions.