Silibinin solubilization: combined effect of co-solvency and inclusion complex formation.

OBJECTIVE: Belonging to the class II drugs according to the biopharmaceutics classification system, silibinin (SLB) benefits from high permeability but suffers poor solubility that negatively affects the development of any delivery system. This research aimed to improve SLB solubility by combined use of co-solvency and complexation phenomena. METHODS: Solubility studies were performed using the phase solubility analysis according to the shake-flask method in the presence of ethanol and 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) as a co-solvent and inclusion complexing agent, respectively. SLB release studies from chitosan nanoparticles were carried out in double-wall, diffusion cells using the optimized drug release medium. RESULTS: SLB solubility was mathematically optimized constraining to using the lowest concentrations of ethanol and HP-ß-CD. SLB solubility increased linearly with the increase of HP-ß-CD concentration. The solubility in PBS-ethanol mixtures followed a log-linear model. SLB solubility in the presence of the ethanol co-solvent and HP-ß-CD complexing agent was optimized by adopting a genetic algorithm suggesting the phosphate buffer saline solution supplemented by 6%v/v ethanol and 8 mM HP-ß-CD as an optimized medium. The optimized solution was examined to study SLB release from chitosan nanoparticles (4.5 ± 0.2% drug loading) at 37 °C under static conditions. The sigmoidal release profile of SLB from the particles indicated a combination of erosion and diffusion mechanisms governing drug release from the nanoparticles. CONCLUSION: SLB solubility in a buffered solution supplemented by ethanol co-solvent and HP-ß-CD complexing agent is a function of free drug present in the semi-aqueous media, the drug-ligand binary complex, and the drug/ligand/co-solvent ternary complex.

Nanoethosomal formulation of gammaoryzanol for skin-aging protection and wrinkle improvement: a histopathological study.

BACKGROUND: Free radical scavengers and antioxidants, with the main focus on enhanced targeting to the skin layers, can provide protection against skin ageing. OBJECTIVE: The aim of the present study was to prepare nanoethosomal formulation of gammaoryzanol (GO), a water insoluble antioxidant, for its dermal delivery to prevent skin aging. METHODS: Nanoethosomal formulation was prepared by a modified ethanol injection method and characterized by using laser light scattering, scanning electronic microscope (SEM) and X-ray diffraction (XRD) techniques. The effects of formulation parameters on nanoparticle size, encapsulation efficiency percent (EE%) and loading capacity percent (LC%) were investigated. Antioxidant activity of GO-loaded formulation was investigated in vitro using normal African green monkey kidney fibroblast cells (Vero). The effect of control and GO-loaded nanoethosomal formulation on superoxide dismutase (SOD) and malondialdehyde (MDA) content of rat skin was also probed. Furthermore, the effect of GO-loaded nanoethosomes on skin wrinkle improvement was studied by dermoscopic and histological examination on healthy humans and UV-irradiated rats, respectively. RESULTS: The optimized nanoethosomal formulation showed promising characteristics including narrow size distribution 0.17 ± 0.02, mean diameter of 98.9 ± 0.05 nm, EE% of 97.12 ± 3.62%, LC% of 13.87 ± 1.36% and zeta potential value of -15.1 ± 0.9 mV. The XRD results confirmed uniform drug dispersion in the nanoethosomes structure. In vitro and in vivo antioxidant studies confirmed the superior antioxidant effect of GO-loaded nanoethosomal formulation compared with control groups (blank nanoethosomes and GO suspension). CONCLUSIONS: Nanoethosomes was a promising carrier for dermal delivery of GO and consequently had superior anti-aging effect.

Histological assessment of follicular delivery of flutamide by solid lipid nanoparticles: potential tool for the treatment of androgenic alopecia.

CONTEXT: Flutamide is a potent anti-androgen with the several unwanted side effects in systemic administration, therefore, it has attracted special interest in the development of topically applied formulations for the treatment of androgenic alopecia. OBJECTIVE: The purpose of this study was to prepare and characterize the solid lipid nanoparticles (SLNs) of Flutamide for follicular targeting in the treatment of the androgenic alopecia. METHODS: Flutamide-loaded SLNs, promising drug carriers for topical application were prepared by hot melt homogenization method. Drug permeation and accumulation in the exercised rat skin and histological study on the male hamsters were performed to assess drug delivery efficiency in vitro and in vivo, respectively. RESULTS: The optimized Flutamide-loaded SLNs (size 198 nm, encapsulation efficiency percentage 65% and loading efficiency percentage 3.27%) exhibited a good stability during the period of at least 2 months. The results of X-ray diffraction showed Flutamide amorphous state confirming uniform drug dispersion in the SLNs structure. Higher skin drug deposition (1.75 times) of SLN formulation compared to Flutamide hydroalcoholic solution represented better localization of the drug in the skin. The in vivo studies showed more new hair follicle growth by utilizing Flutamide-loaded SLNs than Flutamide hydroalcoholic solution which could be due to the higher accumulation of SLNs in the hair follicles as well as slowly and continues release of the Flutamide through the SLNs maximizing hair follicle exposure by antiandrogenic drug. CONCLUSION: It was concluded Flutamide-loaded SLN formulation can be used as a promising colloidal drug carriers for topical administration of Flutamide in the treatment of androgenic alopecia.

Protective effect of pioglitazone on morphine-induced neuroinflammation in the rat lumbar spinal cord.

BACKGROUND: Morphine-induced tolerance is associated with the spinal neuroinflammation. The aim of this study was to explore the effects of oral administration of the pioglitazone, the peroxisome proliferator activated receptor gamma (PPAR-γ) agonist, on the morphine-induced neuroinflammation in the lumbar region of the male Wistar rat spinal cord. RESULTS: Co-administration of the pioglitazone with morphine not only attenuated morphine-induced tolerance, but also prevented the up-regulation of pro-inflammatory cytokines (tumor necrosis factor alpha, interleukin-1beta, and interleukin 6) and nuclear factor-kappa B activity. Administration of the GW-9662 antagonized the above mentioned effects of the pioglitazone. CONCLUSIONS: It is concluded that oral administration of the pioglitazone attenuates morphine-induced tolerance and the neuroinflammation in the lumbar region of the rat spinal cord. This action of the pioglitazone may be, at least in part, due to an interaction with the spinal pro-inflammatory cytokine expression and the nuclear factor-kappa B activity.

Fusogenic liposomal formulation of sirolimus: improvement of drug anti-proliferative effect on human T-cells.

CONTEXT: Fusogenic liposomes are unique delivery vehicles capable of introducing their contents directly and efficiently into the cytoplasm. OBJECTIVE: The objective of this study was to evaluate the potential of fusogenic liposomes containing Sirolimus to improve its anti-proliferative effect on T-lymphocyte cells. MATERIALS AND METHODS: Conventional liposomes containing Sirolimus were prepared from Dipalmitoylphosphatidylcholine (DPPC) and cholesterol using the modified ethanol injection method. To prepare fusogenic liposomes, dioleoylphosphatidylethanolamine (DOPE) was added to the conventional liposome formulation. The liposomes were characterized by their size, zeta potential, encapsulation efficiency percent (EE%) and chemical stability during 6 months. The in vitro release of liposomes, anti-proliferative effect and liposome uptake of both types of liposomes with optimized formulations were studied on human T-lymphocyte cells employing the MTT assay and fluorescein isothiocyanate-loaded liposomes. RESULTS AND DISCUSSION: The particle size of the liposomes was evaluated between 138 and 650 nm and mean zeta potential was in the range of -32.95 to -45.60 mV. The average EE% of the prepared conventional and fusogenic liposomes were 76.9% and 80.5%, respectively. Liposomal formulations released only 10-20% of encapsulated drug without any burst effect. In vitro immunosuppressive evaluation on T-cells showed that fusogenic liposomes have the best anti-proliferative effects and uptake on T-lymphocyte cell compared to the conventional liposomes. CONCLUSION: Our results indicated that fusogenic liposomes can be useful carriers for improving the inhibition of T-cell proliferation.

Histopathological evaluation of caffeine-loaded solid lipid nanoparticles in efficient treatment of cellulite.

CONTEXT: Cellulite refers to dimpled appearance of the skin, usually located in the thighs and buttocks regions of most adult women. OBJECTIVE: The aim of this study was to formulate topically used caffeine-loaded solid lipid nanoparticle (SLN) for the treatment of cellulite. METHODS: SLNs were prepared by hot homogenization technique using Precirol® as lipid phase. The physical characterization and stability studies of SLNs as well as in vitro skin permeation and histological studies in rat skin were conducted. RESULTS: The mean particle size, encapsulation efficiency and loading efficiency percentages for optimized SLN formulation were 94 nm, 86 and 28%, respectively. In vitro drug release demonstrated that caffeine-loaded SLN incorporated into carbopol made hydrogel (caffeine-SLN-hydrogel) exhibited a sustained drug release compared to the caffeine hydrogel over 24 h. Caffeine-loaded SLNs showed a good stability during 12 months of storage at room temperature. The DSC and XRD results showed that caffeine was dispersed in SLN in an amorphous state. In vitro permeation studies illustrated higher drug accumulation in the skin with caffeine-SLN-hydrogel compared to caffeine hydrogel. The flux value of caffeine through rat skin in caffeine-SLN-hydrogel was 3.3 times less than caffeine hydrogel, representing lower systemic absorption. In contrast with caffeine hydrogel, the histological studies showed the complete lysis of adipocytes by administration of caffeine-SLN-hydrogel in the deeper skin layers. CONCLUSION: Results of this study indicated that SLNs are promising carrier for improvement of caffeine efficiency in the treatment of cellulite following topical application on the skin.

Effect of anionic macromolecules on intestinal permeability of furosemide.

CONTEXT: Furosemide is an anionic molecule and has very low absorption in gastro intestinal tract. OBJECTIVE: The aim of this study was to investigate the effect of anionic macromolecules on the intestinal permeability of Furosemide. MATERIALS AND METHODS: The intestinal permeability of Furosemide was determined using single-pass intestinal perfusion technique in rats. Briefly a jejunal segment of ∼10 cm was isolated and cannulated in both ends for inlet and outlet solution. The perfusate was collected every 10 min and samples were analyzed using the RP-HPLC method. Test samples containing furosemide and two anionic macromolecules, sodium carboxy methyl cellulose and sodium alginate, at different concentrations were used. RESULTS: The obtained data showed that existence of Sodium carboxy methyl cellulose significantly increased the Peff values in all three investigated concentrations (p < 0.05) but sodium alginate only in concentrations <0.1% increased drug permeability. DISCUSSION: It is concluded that the anionic macromolecules at specific concentrations could alter the permeability of anionic drugs across the biological membranes. CONCLUSIONS: Donnan phenomenon and chelating property of macromolecules could be attributed to the observed effect.

Plasma stable, pH-sensitive non-ionic surfactant vesicles simultaneously enhance antiproliferative effect and selectivity of Sirolimus.

OBJECTIVE: The purpose of the present investigation was to prepare a plasma stable, pH-sensitive niosomal formulation to enhance Sirolimus efficacy and selectivity. MATERIALS AND METHODS: pH-sensitive niosomal formulations bearing PEG-Poly (monomethyl itaconate)-CholC6 (PEG-PMMI-CholC6) copolymers and cholesteryl hemisuccinate (CHEMS) were prepared by a modified ethanol injection method and characterized with regard to pH-responsiveness and stability in human serum. The ability of pH-sensitive niosomes to enhance the Sirolimus cytotoxicity was evaluated in vitro using human erythromyeloblastoid leukemia cell line (K562) and compared with cytotoxicity effect on human umbilical vein endothelial cells (HUVEC). RESULTS AND DISCUSSION: This study showed that both formulations can be rendered pH-sensitive property and were found to rapidly release their contents under mildly acidic conditions. However, the CHEMS-based niosomes lost their pH-sensitivity after incubation in plasma, whereas, PEG-PMMI-CholC6 niosomes preserved their ability to respond to pH change. Sirolimus encapsulated in pH-sensitive niosomes exhibited a higher cytotoxicity than the control conventional formulation on K562 cell line. On the other hand, both pH-sensitive niosomes showed lower antiproliferative effect on HUVEC cells. CONCLUSION: Plasma stable, pH-sensitive PEG-PMMI-CholC6-based niosomes can improve the in vitro efficiency and also reduce the side effects of Sirolimus.

Micro-porous surfaces in controlled drug delivery systems: design and evaluation of diltiazem hydrochloride controlled porosity osmotic pump using non-ionic surfactants as pore-former.

The major problem associated with conventional drug delivery systems is unpredictable plasma concentrations. The aim of this study was to design a controlled porosity osmotic pump (CPOP) of diltiazem hydrochloride to deliver the drug in a controlled manner. CPOP tablets were prepared by incorporation of drug in the core and subsequent coating with cellulose acetate as semi-permeable membrane. Non-ionic surfactants were applied as pore-formers as well. The effect of pore-formers concentration on the in vitro release of diltiazem was also studied. The formulations were compared based on four comparative parameters, namely, total drug released after 24 h (D24 h), lag-time (tL), squared correlation coefficient of zero order equation (RSQzero) and mean percent deviation from zero order kinetic (MPDzero). Results of scanning electron microscopy studies exhibited formation of pores in the membrane from where the drug release occurred. It was revealed that drug release rate was directly proportional to the concentration of the pore-formers. The value of D24 h in the formulations containing Tween 80 (10%) and Brij 35 (5%) were found to be more than 94.9%, and drug release followed zero order kinetic (RSQzero > 0.99 and MPDzero < 8%) with acceptable tL (lower than 1 h).

Fusogenic pH sensitive liposomal formulation for rapamycin: improvement of antiproliferative effect.

CONTEXT: Liposomes are increasingly employed to deliver chemotherapeutic agents, antisense oligonucleotides, and genes to various therapeutic targets. OBJECTIVE: The present investigation evaluates the ability of fusogenic pH-sensitive liposomes of rapamycin in increasing its antiproliferative effect on human breast adenocarcinoma (MCF-7) cell line. MATERIALS AND METHODS: Cholesterol (Chol) and dipalmitoylphosphatidylcholine (DPPC) (DPPC:Chol, 7:3) were used to prepare conventional rapamycin liposomes by a modified ethanol injection method. Dioleoylphosphatidylethanolamine (DOPE) was used to produce fusogenic and pH-sensitive properties in liposomes simultaneously (DPPC:Chol:DOPE, 7:3:4.2). The prepared liposomes were characterized by their size, zeta potential, encapsulation efficiency percent (EE%), and chemical stability during 6 months. The antiproliferative effects of both types of rapamycin liposomes (10, 25, and 50 nmol/L) with optimized formulations were assessed on MCF-7 cells, as cancerous cells, and human umbilical vein endothelial cells (HUVEC), as healthy cells, employing the diphenyltetrazolium bromide (MTT) assay for 72 h. RESULTS AND DISCUSSION: The particle size, zeta potential, and EE% of the liposomes were 165 ± 12.3 and 178 ± 15.4 nm, -39.6 ± 1.3, and -41.2 ± 2.1 mV as well as 76.9 ± 2.6 and 76.9 ± 2.6% in conventional and fusogenic pH-sensitive liposomes, respectively. Physicochemical stability results indicated that both liposome types were relatively stable at 4 °C than 25 °C. In vitro antiproliferative evaluation showed that fusogenic pH-sensitive liposomes had better antiproliferative effects on MCF-7 cells compared to the conventional liposomes. Conversely, fusogenic pH-sensitive liposomes had less cytotoxicity on HUVEC cell line.

A Rapid Mercury Droplet Electrode Polarography Method for Determination of Blood Lead Level in Lead Poisoned People.

BACKGROUND: Lead is a hazardous heavy metal, which causes many problems in the human body. Unfortunately, recent reports showed that smugglers and opium sellers add lead to drugs during the production procedure in order to increase its weight and cost. PURPOSE: The aim of this study was development of a rapid and accurate method for measurement of blood lead levels (BLL) in the oral and inhaled opiate abuser people. METHODS: BLL in samples obtained from the oral and inhaled opium addicted patients referring to Sina Hospital in Tabriz, Iran, during 2017 was compared with healthy control group (N=15). The wet digestion method was used to prepare whole blood and Mercury Droplet Electrode Polarography (MDEP) method was utilized for measurement of the lead content of digested samples. RESULTS: Results showed that there were significant differences between the BLL of samples obtained from oral (17.12±74.61 µg/dL, p<0.0003) and inhaled (19.33±2.257 µg/dL, p<0.0001) opium addicted groups in comparison with healthy control group (4.669±0.3367 µg/dL). CONCLUSION: Based on the results of this study it was observed that BLL in opium addicted people needs to be measured as soon as possible. Furthermore, screening of blood lead concentrations in opium-addicted people with a rapid and accurate MDEP method is very necessary and important.

Nanophytosomes for enhancement of rutin efficacy in oral administration for diabetes treatment in streptozotocin-induced diabetic rats.

Rutin is a natural antioxidant compound with several therapeutic benefits. However, the application of this bioactive compound is limited due to its low stability and bioavailability. To overcome these limitations, this study aimed to encapsulate rutin into nanophytosomes (NPs) and evaluate the therapeutic potency of this nanocarrier in streptozotocin (STZ)-induced diabetic rats. The particle size, zeta potential, and encapsulation efficiency of the prepared NPs were 72.72 nm, -22 mV, and 93.7%, respectively. The in vivo study showed that the oral administration of rutin-loaded NPs (containing 25 mg rutin/kg per day) for 4 weeks was more effective than free rutin in the control of hyperglycemia and hyperlipidemia in the STZ-induced diabetic rats. Additionally, the administration of rutin-loaded NPs regulated the activities of liver marker enzymes and the levels of total hemoglobin and glycated hemoglobin in the diabetic rats. The antioxidant defenses in the diabetic rats were increased by the administration of rutin-loaded NPs more than free rutin. Moreover, the histopathological study showed that the administration of rutin-loaded NPs restored the diabetes-induced damages in kidney, liver, and pancreas. In conclusion, encapsulation of rutin with phytosomes is an effective technique to benefit from its therapeutic potential, especially to attenuate diabetic complications.

Mesenchymal Stem Cells: A New Generation of Therapeutic Agents as Vehicles in Gene Therapy.

In recent years, mesenchymal stem cells (MSCs) as a new tool for therapeutic gene delivery in clinics have attracted much attention. Their advantages cover longer lifespan, better isolation, and higher transfection efficiency and proliferation rate. MSCs are the preferred approach for cell-based therapies because of their in vitro self-renewal capacity, migrating especially to tumor tissues, as well as anti-inflammatory and immunomodulatory properties. Therefore, they have considerable efficiency in genetic engineering for future clinical applications in cancer gene therapy and other diseases. For improving therapeutic efficiency, targeted therapy of cancers can be achieved through the sustained release of therapeutic agents and functional gene expression induction to the intended tissues. The development of a new vector in gene therapy can improve the durability of a transgene expression. Also, the safety of the vector, if administered systemically, may resolve several problems, such as durability of expression and the host immune response. Currently, MSCs are prominent candidates as cell vehicles for both preclinical and clinical trials due to the secretion of therapeutic agents in several cancers. In the present study, we discuss the status of gene therapy in both viral and non-viral vectors along with their limitations. Throughout this study, the use of several nano-carriers for gene therapy is also investigated. Finally, we critically discuss the promising advantages of MSCs in targeted gene delivery, tumor inhibition and their utilization as the gene carriers in clinical situations.

Development of a Carrier Free Dry Powder Inhalation Formulation of Ketotifen for Pulmonary Drug Delivery.

BACKGROUND: Pulmonary drug delivery route is gaining much attention because it enables to target the active ingredients directly to lung both for local and systemic treatments, which maximize the therapeutic effect and minimize unwanted systemic toxicity. Dry powder inhaler (DPI) systems for asthma therapy have shown several merits to the other pulmonary delivery systems such as nebulizers and metered dose inhalers. PURPOSE: The present study aims to develop and optimize a DPI formulation for Ketotifen fumarate through spray drying technique. METHODS: Particles size and morphology, crystallinity, and drug-excipient interaction of fabricated DPI formulations were evaluated by scanning electron microscopy, X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier Transform Infrared Spectroscopy methods, respectively. The aerosolization indexes and aerodynamic properties of dry powders were determined by next generation impactor. The powder flowability was assessed by measuring the Hausner ratio and compressibility index. RESULTS: Among solvent systems, ethanol-water mixture produced the most desirable powder property for inhalation after spray drying. Although co-spray dried formulations with ammonium bicarbonate resulted in the porous structure, it was not beneficial for DPI formulations due to the interaction with Ketotifen. DSC and XRD experiments proved the amorphous structure of prepared powders, which were stable for 12 months. CONCLUSION: The results of this study demonstrate the potential of Ketotifen DPI formulation and pave a way to use it easily in an industrial scale.

Sensitization of MDA-MBA231 breast cancer cell to docetaxel by myricetin loaded into biocompatible lipid nanoparticles via sub-G1 cell cycle arrest mechanism.

The harmful dose-dependent side effects of chemotherapy drugs have caused the discovery of novel perspective to evaluate chemotherapy protocols. In this study, the potential application of Compritol was investigated as a major scaffold into nanostructured lipid careers to highlight myricetin efficiency in treatment of breast cancer cells along with codelivery of docetaxel (DXT). Characterization of myricetin-loaded NLCs was carried out by measuring the particle size and zeta potential, using the scanning electron microscopy. MTT, DAPI staining, flow cytometric, and RT-PCR (real-time) assays were used to recognize novel formulation behavior on cell cytotoxicity as well as recognizing molecular mechanism of formulation concerning apoptosis phenomenon. Myricetin-loaded NLCs reduced the cell viability from 50 ± 2.3 to 40 ± 1.3% (p < 0.05). Percentage of apoptosis improved with combination treatment of myricetin-loaded NLCs and DXT in the MDA-MBA231 breast cancer cells. Expression of antiapoptotic genes (survivin, Cyclin B1, and Mcl1) indicated a significant reduction in factor along with increment in proapoptotic factor Bax and Bid mRNA rates. Overall, our results represented that the NLC delivery system could be a promising strategy to enhance the effect of anticancer agents such as DXT on breast cancer.

A multilayer hollow nanocarrier for pulmonary co-drug delivery of methotrexate and doxorubicin in the form of dry powder inhalation formulation.

Lung cancer is the number one cause of cancer deaths in the global population and remains difficult to treat mainly because of the absence of targeted drug delivery stages and restrictions related with delivery of drugs to deep lung tissues. The aim of the present study was to develop a noninvasive, patient-convenient formulation for the targeted delivery of chemotherapeutics to cancer cells located in the deep lung tissue. A PEGylated paramagnetic hollow-nanosphere was fabricated, fully characterized and used as a nanocarrier for pulmonary co-delivery of Doxorubicin (DOX) and Methotrexate (MTX). In first step, magnetic-silica nanoparticles were synthesized and then coated with amino/acrylate groups and derivatized with polyethylene glycol (PEG). Finally, silica was removed to provide hollow structured nanoparticles. The biocompatibility of blank carriers and the efficiency of MTX-DOX-loaded carriers were also approved by MTT assay and DAPI staining. The aerosolization performance of nanoparticles embedded microspheres were assessed by next generation impactor. The almost natural zeta potential and obvious decrease in silica content observed by EDX and removal of intense silica characteristic peak at FTIR analyses approved the successful removal of silica layer and preparation of hollow-nanospheres. The successful PEGylation of multilayer magnetic hollow-nanospheres catalyzed by boric acid was confirmed by presence of amide groups in FTIR spectra. The developed polymeric nanoparticle showed quite appropriate loading capacity for both DOX and MTX (48%) because of designing adequate negatively and positively charged sites for both drugs. The cytotoxicity assays proved the safety of blank nanoparticles and efficacy of drugs-loaded nanoparticles on lung cancer A549 cell lines. The developed dry powder inhalation formulation of nanoparticles showed appropriate aerosolization performance (fine particle fraction around 22%). It was concluded that these outcomes may open the potentials for efficient pulmonary co-delivery of MTX and DOX to the carcinogenic tissues.

Skin toxicity of topically applied nanoparticles.

Nowadays, nanoproducts have found numerous applications, allowing them to enter the human body in different ways. Skin is a major body organ that acts as the first-line barrier between the internal organs and external environment. Although the inhalation and ingestion of nanoparticles is more dangerous compared with skin exposure, there are noteworthy information gaps in skin exposure to nanoparticles that need much attention. Despite the few reviews in the literature on the cytotoxic effects of nanoparticles, no research has reviewed the clinical side effects of nanoparticles following topical admonition, including skin inflammation, skin cancer and genetic toxicity.

Attenuation of Morphine-Induced Tolerance and Dependence by Pretreatment with Cerebrolysin in Male rats.

BACKGROUND: Dependence and tolerance to morphine are major problems which limit its chronic clinical application. PURPOSE: This study was aimed to investigate the attenuation effect of Cerebrolysin, a mixture of potent growth factors (BDNF, GDNF, NGF, CNTF etc,), on the development of Morphine-induced dependence and tolerance. METHODS: Male Wistar rats were selected randomly and divided into different groups (n=8) including: a control group, groups received additive doses of morphine (5-25 mg/kg, ip, at an interval of 12 h until tolerance completion), and groups pretreated with Cerebrolysin (40, 80 and 160 mg/kg, ip, before morphine administration). Development of tolerance was assessed by tail-flick test and the attenuation effect of Cerebrolysin on morphine-induced dependence was evaluated after injection of naloxone (4 mg/kg, ip, 12 h after the morning dose of morphine). Seven distinct withdrawal signs including: jumping, rearing, genital grooming, abdominal writhing, wet dog shake and teeth grinding were recorded for 45 min and total withdrawal score (TWS) was calculated. RESULTS: Results showed that administration of Cerebrolysin could prolonged development (10 and 14 days in administration of 80 mg/kg and 160 mg/kg Cerebrolysin) and completion (4, 10 and 14 days in administration of 40, 80 and 160 mg/kg Cerebrolysin, respectively) of tolerance. Results also indicated that administration of Cerebrolysin (40, 80 and 160 mg/kg) could significantly decreased the TWS value (62±2, 77±4 and 85±6%, respectively). CONCLUSION: In conclusion, it was found that pretreatment with Cerebrolysin could attenuated morphine-induced tolerance and dependence.

Improvement of dermal delivery of tetracycline using vesicular nanostructures.

The objective of this investigation was to study the potential use of nanoliposomes and nanotransfersomes in dermal delivery of tetracycline hydrochloride (TC) for acne treatment. Vesicular nanostructures were prepared by thin film hydration method and evaluated for their size, zeta potential, morphology, and entrapment efficiency. Minimal inhibitory concentration values of TC-loaded vesicles were evaluated and compared with TC aqueous solution against Staphylococcus epidermis. In vitro drug release and ex vivo drug permeation through the excised rat skin were performed to assess drug delivery efficiency. Particle size, zeta potential, and entrapment efficiency of prepared nanoliposomes and nanotransfersomes were found to be 75 and 78 nm, 17 and 7 mV, and 45 and 55%, respectively. Antimicrobial analysis indicated that there was no difference between vesicular formulations and aqueous solution of TC. In vitro drug release study indicated that nanoliposomes could release TC 2.6 folds more than nanotransfersomes, and skin permeation study showed that the permeability of TC-loaded nanotransfersomes was 1.6 times higher than nanoliposomes which was also confirmed by fluorescence microscope imaging. These findings concluded that nanoliposomal and especially nanotransfersomal formulations could be proposed as the potential approach for better therapeutic performance of TC against acne.

The effect of different coating materials on the prevention of powder bounce in the next generation impactor.

In the process of quality control of pulmonary drug delivery products, aerosolization efficiency is mainly determined using impactors, e.g. next generation impactor (NGI). However, particle bounce may interfere with the validity and accuracy of results due to the overestimation of the respirable fraction. It is suggested that the coating of impactor's stages may prevent the particle bounce. Therefore, coating materials may influence the results of the aerosolization indexes of pulmonary dosage forms. The aim of this study was to investigate if the aerosolization indices are affected differently by using the different coating materials. In this study, the effects of using different materials including Span® 85, Tween® 80, silicon® oil, glycerin and Brij® 35/glycerin mixture recommended for the coating of NGI stages on the aerosolization indices such as fine particle fraction, fine particle dose, mass median aerodynamic diameter, and geometric standard deviation of salbutamol emitted from a commercial metered dose inhaler (MDI), were assessed. Three statistically different results were obtained on using Tween® 80, Span® 85 and silicon oil, and glycerin and Brij®35/glycerin mixture. It can be concluded that the type of coating material influenced the aerosolization indices of the examined MDI in NGIs.