Preparation of multivesicular liposomes for the loco-regional delivery of Vancomycin hydrochloride using active loading method: drug release and antimicrobial properties.

Over the last few years, among controlled-release delivery systems, multivesicular liposomes (MVLs) have attracted attention due to their unique benefits as a loco-regional drug delivery system. Considering the clinical limitations of the current treatment strategies for osteomyelitis, MVLs can be a suitable carrier for the local delivery of effective antibiotics. This study aimed to prepare vancomycin hydrochloride (VAN HL) loaded MVLs using the active loading method which to the best of our knowledge has not been previously reported. Empty MVLS were prepared by the double emulsion (w/o/w) method and VAN HL was loaded into the prepared liposomes by the ammonium gradient method. After full characterization, the release profile of VAN HL from MVLs was assessed at two different pH values (5.5 and 7.4), and compared with the release profile of the free drug and also passively loaded MVLs. In vitro antimicrobial activities were evaluated using the disc diffusion method. Our results demonstrated that the encapsulation efficiency was higher than 90% in the optimum actively loaded MVL. The free VAN HL was released within 6-8 h, while the passively loaded MVLs and the optimum actively loaded MVL formulation released the drug in 6 days and up to 19 days, respectively. The released drug showed effective antibacterial activity against osteomyelitis-causing pathogens. In conclusion, the prepared formulation offered the advantages of sustained-release properties, appropriate particle size as well as being composed of biocompatible materials, and thus could be a promising candidate for the loco-regional delivery of VAN HL and the management of osteomyelitis.

Amphotericin B Pharmacokinetics: Inter-strain Differences in Rats Following Intravenous Administration of the Most Commonly Marketed Formulations of the Drug.

Background: Amphotericin B (AmB) is the first-line drug to treat invasive fungal infections. However, its delivery to the body and clinical use faces many challenges because of its poor solubility, poor pharmacokinetics, and severe nephrotoxicity. Objectives: Due to the necessity for designing safer and more effective nanocarriers for AmB and the importance of preclinical pharmacokinetic studies in evaluating these novel drug delivery systems, the present study was framed to explore the influence of rat strain on the pharmacokinetic profile of this drug. Methods: Twenty-four Wistar and Sprague-Dawley (SD) rats were intravenously injected with 1 mg/kg AmB as Fungizone or AmBisome, which are the two most commonly marketed formulations of the drug. Blood samples were collected before and at regular intervals up to 24 h after administration. Drug concentration was analyzed by a validated HPLC method, and pharmacokinetic parameters were determined by the non-compartmental method. Results: Irrespective of the type of formulation, the AUC0-t and AUC0-∞ values were significantly higher (P < 0.001), and Cl as an important PK parameter was markedly lower (P < 0.001) in SD rats compared to the Wistar strain. For Fungizone, the mean Cl values in SD and Wistar rats were 206.90 and 462.95 mL/h/kg (P < 0.001), respectively. The apparent volume of distribution (Vss) was also lower in SD rats compared to Wistar; however, for AmBisome, the difference in Vss was not statistically significant. Our further investigation suggested that the higher amount of total protein in the SD strain may justify the higher plasma concentrations and lower Cl and Vss of amphotericin B in this strain compared to the Wistar strain. Conclusions: Overall, following intravenous administration of AmB, there were significant differences in the pharmacokinetic parameters of the drug between two rat strains for both formulations. The obtained data is important for correctly interpreting experimental data from different research groups.

Biocompatible phospholipid-based mixed micelles for posaconazole ocular delivery: Development, characterization, and in - vitro antifungal activity.

Current study intended to prepare and evaluate phospholipid-based, mixed micelles (MMs) to improve the ocular delivery of posaconazole (POS), a broad-spectrum antifungal drug. For this, MMs based on egg phosphatidylcholine (EPC), as the main component, in combination with various bile salts (sodium cholate (NaC), sodium deoxycholate (NaDC), sodium taurocholate (NaTC)) or non-ionic surfactants (Pluronic® F-127, Pluronic® F-68, Tween 80, Labrasol® ALF, and d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS)) were prepared. Particle size, polydispersity index, zeta potential and entrapment efficiency were evaluated to optimize the composition and preparation method of the MMs. Finally, morphology, stability, in vitro release pattern, and in vitro antifungal activity of the optimized formulation were investigated. Among the prepared MMs, vesicles composed of EPC: TPGS with a molar ratio of 70:30, prepared by the thin-film hydration method, showed more appropriate features. Among the prepared MMs, vesicles composed of EPC: TPGS with a molar ratio of 70:30 showed more appropriate features, including an entrapment efficiency (EE) greater than 80%, spherical shape morphology, an average particle size of about 58 nm, desirable stability over a month, slow-release without a noticeable initial burst, and a significantly higher in vitro antifungal activity in comparison with the drug suspension. Therefore, this formulation was selected as the optimal MMs and could be considered as a promising carrier for topical ocular delivery of POS.

Cerasome Versus Liposome: A Comparative Pharmacokinetic Analysis Following Intravenous Administration into Rats.

Background: Cerasomes, due to their external siloxane network, demonstrate markedly higher physicochemical stability and, therefore, easier handling and storage than liposomes. Objectives: The main objective of this study was to compare the pharmacokinetics (PK) of cerasome and liposome following intravenous administration. The PK of PEGylated and non-PEGylated cerasomes was also compared to see whether the presence of a hydrophilic siloxane network on the surface of cerasomes can play the role of polyethylene glycol (PEG) in increasing the blood circulation of these vesicles. Methods: Silver sulfide (Ag2S) quantum dots (Qds)-loaded PEGylated and non-PEGylated cerasomes and PEGylated liposomes were fabricated and thoroughly characterized in terms of particle size, polydispersity index, zeta potential, entrapment efficiency, and in vitro stability. For pharmacokinetic evaluation, the free Qds and the selected formulations were intravenously injected into rats, and blood samples were collected for up to 72 hours. Pharmacokinetic parameters were calculated by the non-compartmental method. Results: Both cerasomal and liposomal carriers significantly improved the PK of Qds. For example, the elimination half-life (t1/2) and the area under the plasma concentration-time curve from time 0 to time infinity (AUC0-∞) for the free Qds were 4.39 h and 8.01 µg/mL*h and for cerasomal and liposomal formulations were 28.82 versus 26.95 h and 73.25 versus 62.02 µg/mL*h, respectively. However, compared to each other, the plasma concentration-time profiles of PEGylated cerasomes and liposomes displayed similar patterns, and the statistical comparison of their pharmacokinetic parameters did not show any significant difference between the two types of carriers. For PEGylated cerasomes, t1/2 and AUC0-∞ values were respectively 1.6 and 3.3 times greater than the classic cerasome, indicating that despite the presence of a hydrophilic siloxane network, the incorporation of PEG is necessary to reduce the clearance of cerasomes. Conclusions: The comparable PK of PEGylated cerasomes and liposomes, along with the higher physicochemical stability of cerasomes, can be considered an important advantage for the clinical application of cerasomes. Additionally, the easy surface functionalizing ability of cerasomes confers a dual advantage over liposomes. The study findings also showed that the presence of a hydrophilic siloxane network on the surface of cerasomes alone is not enough to make them circulate long.

Doxorubicin-Loaded Multivesicular Liposomes (DepoFoam) as a Sustained Release Carrier Intended for Locoregional Delivery in Cancer Treatment: Development, Characterization, and Cytotoxicity Evaluation.

Background: Despite the advantages of direct intratumoral (IT) injection, the relatively rapid withdrawal of most anti-cancer drugs from the tumor due to their small molecular size limits the effectiveness of this method of administration. To address these limitations, recently, increasing attention has been directed to using slow-release biodegradable delivery systems for IT injection. Objectives: This study aimed to develop and characterize a doxorubicin-loaded DepoFoam system as an efficient controlled-release carrier to be employed for locoregional drug delivery in cancer treatment. Methods: Major formulation parameters, including the molar ratio of cholesterol to the main lipid [Chol/egg phosphatidylcholine (EPC)], triolein (TO) content, and lipid-to-drug molar ratio (L/D), were optimized using a two-level factorial design approach. The prepared batches were evaluated for encapsulation efficiency (EE) and percentage of drug release (DR) after 6 and 72 hours as dependent variables. The optimum formulation (named DepoDOX) was further evaluated in terms of particle size, morphology, zeta potential, stability, Fourier-transform infrared spectroscopy, in vitro cytotoxicity, and hemolysis. Results: The analysis of factorial design indicated that TO content and L/D ratio had a negative effect on EE; between these two, TO content had the greatest effect. The TO content was also the most significant component, with a negative effect on the release rate. The ratio of Chol/EPC showed a dual effect on the DR rate. Using a higher percentage of Chol slowed down the initial release phase of the drug; nevertheless, it accelerated the DR rate in the later slow phase. DepoDOX were spherical and honeycomb-like structures (≈ 9.81 µm) with a desired sustained release profile, as DR lasted 11 days. Its biocompatibility was confirmed by the results of cytotoxicity and hemolysis assays. Conclusions: The in vitro characterization of optimized DepoFoam formulation demonstrated its suitability for direct locoregional delivery. DepoDOX, as a biocompatible lipid-based formulation, showed appropriate particle size, high capability for encapsulating doxorubicin, superior physical stability, and a markedly prolonged DR rate. Therefore, this formulation could be considered a promising candidate for locoregional drug delivery in cancer treatment.

Protective effect of Rheum ribes extract against lead-induced hepatotoxicity in male rats

Abstract The effects of Rheum ribes on lead acetate levels and hepatic biochemical factors due to lead acetate toxicity were investigated. Forty male Wistar rats were designated into four groups: Control; lead acetate (receiving in drinking water at 0.6 g/L, daily); hydroalcoholic extract groups (200 and 400 mg/kg doses, gavage, once daily). Treatments were conducted for 10 days. On the 11th day, blood samples were collected to measure lead acetate levels and biochemical factors. Liver tissue samples were examined for histopathological changes. Lead serum levels were increased in lead acetate-treated rats (p<0.001). Lead acetate treatment was associated with a significant increase in liver tissue damage (p<0.001), while R. ribes extract prevented liver tissue damage (p<0.05). The levels of alanine aminotransferase and aspartate aminotransferase were significantly lower in the groups lead acetate + extract (two doses) than in the lead acetate group (p<0.001 and P<0.01, respectively), but alkaline phosphatase level, prothrombin time, partial thromboplastin time and international normalized ratio were not different between the lead acetate + extract groups and the lead acetate group. The results showed the inhibitory role of R. ribes on lead-induced hepato-toxicity. The results make Rhubarb a good candidate to protect against the deleterious effect of chronic lead intoxication after complementary studies

Multivesicular liposomal depot system for sustained delivery of risperidone: development, characterization, and toxicity assessment.

OBJECTIVE: Considering the limitations of conventional risperidone (RSP) therapies, the present research characterizes the usefulness of multivesicular liposomes (MVLs) as an efficient controlled-release carrier for this widely used antipsychotic drug, to be employed for the treatment of schizophrenia. METHODS: A 23 full factorial design based on three independent variables was implemented to plan the experiments: the molar ratios of lipid to the drug, triolein to phospholipid, and cholesterol to phospholipid. The impacts of these parameters on the risperidone encapsulation efficiency and its release pattern within the first 24 and 48 h were investigated as dependent variables. Then, the optimized liposomal system was further in-depth analyzed in terms of size, morphological and structural features, release profile over 15 days, biocompatibility, and stability. RESULTS: Optimized formulation parameters gave rise to MVLs possessing a spherical morphology with a median diameter of about 8 µm, a relatively narrow size distribution (span value of 1.49), and an encapsulation efficiency of 57.6%. These carriers not only exhibited a sustained-release behavior in vitro, lasting until the end of the 15 days but also underwent a negligible change in their size and RSP incorporation over two months at refrigerator condition. Furthermore, in vitro cytotoxicity and hemolysis assessments revealed that the optimized MVL formulation is biocompatible. CONCLUSION: This study revealed the potential of MVLs as a promising system for the delivery of RSP and could open a new vista for the successful management of schizophrenia.

Psychometrics properties of the Iranian version of fertility quality of life tool: A cross- sectional study.

BACKGROUND: Clinical measurement of quality of life (QoL) for assessing reproductive problems should be considered as a standard investigation at the initial and continuing medical consultations with infertile people. OBJECTIVE: The purpose of this study was comprehensive testing the psychometric properties of the Iranian version of fertility quality of life (FertiQoL). MATERIALS AND METHODS: This cross-sectional study was conducted on300 women referred to infertility clinic. After linguistic validation, a semi-structured interview was conducted to assess face validity. Consequently exploratory factor analysis was performed to indicate the scale constructs. Discriminate validity was assessed using the known groups comparison. Convergent validity was evaluated by assessing the correlation between similar content on the 12-Item Short Form Health Survey (SF12), Hospital Anxiety and Depression Scale and FertiQol. In addition, reliability analysis was carried out with internal consistency. RESULTS: The reliability of the Iranian version of the FertiQoL was satisfactory in all dimensions (0.77-0.83). Six factors (emotional, mind/body, relational, social, environmental, and tolerability) were extracted from the results of exploratory factor analysis. Discrimination validity showed that FertiQoL can differentiate between female patients with differing duration of infertility and number of children. Moreover, the results of convergent validity showed a favorable correlation between the related dimensions of SF12 (0.43-0.68), Hospital Anxiety and Depression Scale (0.47-0.52) and FertiQoL. CONCLUSION: The Iranian version of FertiQoL is valid and reliable for assessing infertility problems and the effects of treatment on QoL of infertile patients referred for diagnosis and treatment at infertility clinic.

Dorzolamide Loaded Niosomal Vesicles: Comparison of Passive and Remote Loading Methods.

Glaucoma is a common progressive eye disorder and the treatment strategies will benefit from nanoparticulate delivery systems with high drug loading and sustained delivery of intraocular pressure lowering agents. Niosomes have been reported as a novel approach to improve drug low corneal penetration and bioavailability characteristics. Along with this, poor entrapment efficiency of hydrophilic drug in niosomal formulation remains as a major formulation challenge. Taking this perspective into consideration, dorzolamide niosomes were prepared employing two different loading methodologies (passive and remote loading methods) and the effects of various formulation variables (lipid to drug ratio, cholesterol percentage, drug concentration, freeze/thaw cycles, TPGS content, and external and internal buffer molarity and pH) on encapsulation efficiency were assessed. Encapsulation of dorzolamide within niosomes increased remarkably by the incorporation of higher cholesterol percentage as well as increasing the total lipid concentration. Remote loading method showed higher efficacy for drug entrapment compared to passive loading technique. Incorporation of TPGS in bilayer led to decrease in EE; however, retarded drug release rate. Scanning electron microscopy (SEM) studies confirmed homogeneous particle distribution, and spherical shape with smooth surface. In conclusion, the highest encapsulation can be obtained using phosphate gradient method and 50% cholesterol in Span 60 niosomal formulation.

Enhanced Permeability of Etoposide across Everted Sacs of Rat Small Intestine by Vitamin E-TPGS.

Etoposide, a widely used anticancer drug, exhibits low and variable oral bioavailability mainly because of being substrate for the efflux transporter, P-glycoprotein (P-gp). Therefore, the present study was aimed to investigate the effect of D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and PEG 400 as P-gp inhibitors on the intestinal absorption of etoposide. Everted sacs of rat small intestine were incubated in Krebs buffer solution which contained etoposide in the absence or presence of various concentrations of TPGS or PEG 400. The effect of verapamil as a known P-gp inhibitor on the absorption of drug was also studied. The absorptive transport of etoposide was significantly enhanced (p < 0.001) in the presence of verapamil (100 µg/mL) and TPGS (over the concentration range of 0.002- 0.1 mg/mL), suggesting that the inhibition of P-gp located in the intestine may be involved in the enhancement of etoposide absorption. However, the addition of PEG 400 at various concentrations (0.05, 0.1 and 0.5% w/v) had no effect on the etoposide transport. No significant difference was found between the permeability values in the absence and presence of the maximum concentration of TPGS for two transport markers, lucifer yellow and imipramine, indicating that the enhancement in etoposide permeability in the presence of TPGS was not due to the compromise in tight junctions or membrane integrity of epithelial cells. The results of the study suggest that the use of TPGS as a safe excipient in etoposide formulations may enhance the oral bioavailability of etoposide and result in a predictable oral absorption.

Accelerated blood clearance of PEGylated PLGA nanoparticles following repeated injections: effects of polymer dose, PEG coating, and encapsulated anticancer drug.

PURPOSE: To investigate accelerated blood clearance (ABC) induction upon repeated injections of PLGA-PEG nanoparticles as a commonly used polymeric drug carrier. METHODS: Etoposide-loaded PLGA-PEG NPs were developed and administered as the test dose to rats pre-injected with various NP treatments at certain time intervals. Pharmacokinetic parameters of etoposide and production of anti-PEG IgM antibody were evaluated. RESULTS: A notable ABC effect was induced by a wide range of polymer doses (0.1 to 20 mg) of empty NPs, accompanied by IgM secretion. However, a further increase in polymer dose resulted not only in the abrogation of the observed ABC induction but also in distinctly a higher value for AUC of the NPs relative to the control. The data from the PEG-negative group verified the fundamental role of PEG for ABC induction. The first injection of etoposide-containing PEGylated nanoparticles (a cell cycle phase-specific drug) produced a strong ABC phenomenon. Three sequential administrations of etoposide-loaded NPs abolished ABC, although a high level of IgM was still detected, which suggests saturation with insignificant poisoning of immune cells. CONCLUSION: The presented results demonstrate the importance of clinical evaluations for PLGA-PEG nanocarriers that consider the administration schedule in multiple drug delivery, particularly in cancer chemotherapy.