The Effects of Lyophilization on the Physico-Chemical Stability of Sirolimus Liposomes

Purpose: The major limitation in the widespread use of liposome drug delivery system is its instability. Lyophilization is a promising approach to ensure the long-term stability of liposomes. The aim of this study was to prepare sirolimus-loaded liposomes, study their stability and investigate the effect of lyophilization either in the presence or in the absence of lyoprotectant on liposome properties. Methods: Two types of multi-lamellar liposomes, conventional and fusogenic, containing sirolimus were prepared by modified thin film hydration method with different ratio of dipalmitoylphosphatidylcholine (DPPC), cholesterol and dioleoylphosphoethanolamine (DOPE), and were lyophilized with or without dextrose as lyoprotectant. Chemical stability investigation was performed at 4°C and 25°C until 6 months using a validated HPLC method. Physical stability was studied with determination of particle size (PS) and encapsulation efficiency (EE %) of formulations through 6 months. Results: Chemical stability test at 4°C and 25°C until 6 months showed that drug content of liposomes decreased 8.4% and 20.2% respectively. Initial mean EE % and PS were 72.8 % and 582 nm respectively. After 6 months mean EE % for suspended form, lyophilized without lyoprotectant and lyophilized with lyoprotectant were 54.8 %, 62.3% and 67.1 % at 4°C and 48.2%, 60.4 % and 66.8 % at 25°C respectively. Corresponding data for mean PS were 8229 nm, 2397 nm and 688nm at 4°C and 9362 nm, 1944 nm and 737 nm at 25°C respectively. Conclusion: It is concluded that lyophilization with and without dextrose could increase shelf life of liposome and dextrose has lyoprotectant effect that stabilized liposomes in the lyophilization process

An in vitro aerosolization efficiency comparison of generic and branded salbutamol metered dose inhalers

Background: Due to the high rate of pulmonary diseases, respiratory drug delivery systems have been attracted excessive attention for the past decades. Because of limitations and growing drug bill, physicians are encouraged to prescribe generically whenever possible. The purpose of this study was to evaluate whether there was any significant difference in aerosolization performance between a reference brand Salbutamol (A) Metered Dose Inhalers (MDIs) and two generic products (B and C). Methods: The aerosolization performance of MDIs was evaluated by calculating aerosolization indexes including fine particle fraction (FPF), fine particle dose (FPD), geometric standard deviation (GSD) and mass median aerodynamic diameters (MMAD) by using the next generation impactor. Results: Although aerosolization indexes of MDI A were superior than the Iranian brands, but the differences were not statistically significant. Conclusion: These results verified that generic MDIs deliver similar quantities of Salbutamol to the reference brand and aerosolization performance parameters of generic Salbutamol MDIs did not differ significantly from the reference brand

Application of lactobionic acid and nonionic surfactants as solubilizing agents for parenteral formulation of clarithromycin

Purpose: The purpose of this paper is to enhance the solubility of clarithromycin (CLR) using nonionic surfactants and some type of acids for preparation of the new formulations. Methods: Myrj 52 and chremophor (2.5 and 5% w/v) were used in two concentrations. To investigate solubility, the formulations were shaken for 48 hours at room temperature. For stability test, lyophilized samples were maintained in refrigerator at 4° C, and in oven at 40° C. Drug analysis was performed by reverse phase high performance liquid chromatography (HPLC) with ultraviolet detection. Results: Solubility tests indicated that lactobionic acid was the most effective to increase clarithromycin solubility and chremophor showed higher enhancing effect than myrj 52 on CLR solubility. The stability tests results also confirmed that shelf-lives of all formulations have been the equivalent to 24 months. Conclusion: On the whole, formulations described in this article may be very suitable for industrial-scale manufacturing and clinical application

Formulation of Menthol-Loaded Nanostructured Lipid Carriers to Enhance Its Antimicrobial Activity for Food Preservation

Purpose: Due to the antimicrobial property, menthol have significant potential for food preservation and foodstuff shelf life improvement. Nevertheless, menthol instability, insolubility, and rapid crystallization in aqueous media make it unsuitable for used in food products. This work was aimed to prepare menthol-loaded nanostructured lipid carriers (NLCs) to enhance its antimicrobial activity. Methods: Morphology, particle size and size distribution, encapsulation efficiency percent (EE%), and physical stability of the optimized formulation, prepared by hot melt homogenization method, were characterized by scanning electron microscopy, particle size analyzing, gas chromatography, and X-ray diffraction (XRD) methods. Minimum inhibitory concentration and minimum bactericidal concentration of menthol-loaded NLCs were evaluated and compared with conventional menthol emulsion against various Gram-positive (Staphylococcus aureus, Bacillus cereus) and Gram-negative bacteria (Escherichia coli), as well as one fungus (Candida albicans). Results: Menthol-loaded NLCs were spherically shaped nanosized (115.6 nm) particles with narrow size distribution (PDI = 0.2), suitable menthol EE% (98.73%), and appropriate physical stability after 90 days of storage period. XRD results indicated that menthol was in the amorphous form in the nanoparticles matrix. Antibacterial assay results revealed that the menthol-loaded NLCs exhibited significantly higher in vitro antimicrobial property than conventional menthol emulsion. The results also indicated that menthol-loaded NLCs had better effect on fungi than bacteria, and furthermore, antibacterial efficiency on Gram-positive bacteria was higher than Gram-negative bacteria. Conclusion: In conclusion, NLCs could be a promising carrier for improvement of antimicrobial activity and preservation efficacy of essential oils in foodstuffs

Nanostructured Lipid Carrier for Topical Application of N-Acetyl Glucosamine

Purpose: Hyperpigmentation occurs when melanin is overproduced in certain spots on the skin and is one of the most challenging skin conditions to treat. Although it is usually harmless, for cosmetic reasons, it is dreadfully bothersome to those who undergo it. It was reported that N-acetyl-glucosamine (NAGA) prevents melanin synthesis and alters the expression of numerous genes related to pigmentation. In spite of these advantages, NAGA cannot be employed in topical formulations due to its extremely polar characteristics. Nanoparticles, especially lipid-based ones, have been introduced as an efficient carrier for dermal drug delivery. Methods: The aim of the present study was to load adequate hydrophilic NAGA to the lipophilic nanostructured lipid carriers (NLCs) for potential dermal application. Methods: NAGA-loaded NLCs were formulated, using hot homogenization technique, and the characteristics of the optimized formulation were analyzed by laser light scattering, X-ray diffraction, and scanning electron microscopy methods. Loading capacity percentage and in vitro release study were carried out by applying a validated HPLC method. The optimum formulation was utilized for the in vivo skin lightening evaluations in healthy volunteers. Results: NAGA-loaded NLCs demonstrated promising results (the size of 190 nm, narrow size distribution, loading capacity of 9%, and appropriate NAGA release profile) suitable for dermal delivery. XRD results exhibited a dramatic reduction in the crystalline structure of encapsulated NAGA. Dermoscopy images indicated a considerable decline in melanin distribution pattern in the majority of the cases treated with NAGA-loaded NLCs. Conclusion: Thus, this study has opened new horizons for the potential use of lipid based nanoparticles in the managing of hyperpigmentation

Development and Validation of an HPLC Method for the Analysis of Sirolimus in Drug Products

Purpose: The aim of this study was to develop a simple, rapid and sensitive reverse phase high performance liquid chromatography (RP-HPLC) method for quantification of sirolimus (SRL) in pharmaceutical dosage forms. Methods: The chromatographic system employs isocratic elution using a Knauer- C18, 5 mm, 4.6 × 150 mm. Mobile phase consisting of acetonitril and ammonium acetate buffer set at flow rate 1.5 ml/min. The analyte was detected and quantified at 278nm using ultraviolet detector. The method was validated as per ICH guidelines. Results: The standard curve was found to have a linear relationship (r2 > 0.99) over the analytical range of 125–2000ng/ml. For all quality control (QC) standards in intraday and interday assay, accuracy and precision range were -0.96 to 6.30 and 0.86 to 13.74 respectively, demonstrating the precision and accuracy over the analytical range. Samples were stable during preparation and analysis procedure. Conclusion: Therefore the rapid and sensitive developed method can be used for the routine analysis of sirolimus such as dissolution and stability assays of pre- and post-marketed dosage forms

Development and characterization of solid dispersion of piroxicam for improvement of dissolution rate using hydrophilic carriers

Introduction: The main objective of this study was preparation and characterization of solid dispersion of piroxicam to enhance its dissolution rate. Methods: Solid dispersion formulations with different carriers including crospovidone, microcrystalline cellulose and Elaeagnus angustifolia fruit powder and with different drug: carrier ratios were prepared employing cogrinding method. Dissolution study of the piroxicam powders, physical mixtures and solid dispersions was performed in simulated gastric fluid and simulated intestinal fluid using USP Apparatus type II. The physical characterization of formulations were analyzed using powder X ray diffraction (PXRD), particle size analyzer and differential scanning calorimetry (DSC). Interactions between the drug and carriers were evaluated by Fourier transform infrared (FT-IR) spectroscopic method. Results: It was revealed that all of three carriers increase the dissolution rate of piroxicam from physical mixtures and especially in solid dispersions compared to piroxicam pure and treated powders. PXRD and DSC results were confirmed the reduction of crystalline form of piroxicam. FT-IR analysis did not show any physicochemical interaction between drug and carriers in the solid dispersion formulations. Conclusion: Dissolution rate was dependent on the type and ratio of drug: carrier as well as pH of dissolution medium. Dissolution data of formulations were fitted well in to the linear Weibull as well as non-linear logistic and a suggested models

Enhanced Transdermal Delivery of Diclofenac Sodium via Conventional Liposomes, Ethosomes, and Transfersomes

The aim of this study was to improve the transdermal permeation of Diclofenac sodium, a poorly water-soluble drug, employing conventional liposomes, ethosomes, and transfersomes. The prepared formulations had been characterized for the loaded drug amount and vesicle size. The prepared vesicular systems were incorporated into 1% Carbopol 914 gel, and a survey of in vitro drug release and drug retention into rat skin has been done on them using a modified Franz diffusion cell. The cumulative amount of drug permeated after 24 h, flux, and permeability coefficient were assessed. Stability studies were performed for three months. The size of vesicles ranged from 145 to 202 nm, and the encapsulation efficiency of the Diclofenac sodium was obtained between 42.61% and 51.72%. The transfersomes and ethosomes provided a significantly higher amount of cumulative permeation, steady state flux, permeability coefficient, and residual drug into skin compared to the conventional liposomes, conventional gel, or hydroethanolic solution. The in vitro release data of all vesicular systems were well fit into Higuchi model (RSD > 0.99). Stability tests indicated that the vesicular formulations were stable over three months. Results revealed that both ethosome and transfersome formulations can act as drug reservoir in skin and extend the pharmacologic effects of Diclofenac sodium