Optimization and Characterization of a Parenteral In Situ Forming Gel Formulation of Tramadol to Use in Chronic Pains

Introduction: Targeted delivery systems such as smart polymers based on in situ forming gel can form controlled release formulations. These smart polymers based on in situ forming gel are thermosensitive and converse to gel in the site of injection and body temperature. Tramadol is an opiate-like analgesic that has tendency to μ-receptors of opioids. It inhibits the re-uptake of monoamines and serotonin in the central nervous system. In this research our goal is preparation, optimization and characterization of a parenteral in situ forming gel formulation of tramadol to use in chronic pains. Methods and Results:Optimization of formulation done by a D-optimal method. We found the effect of different factors such as; polymers’ concentrations, type and concentration of gelating agent on gelation time. The prepared in situ forming gel formulation in vitro were fully characterized. Morphologic study such as AFM and drug release in PBS environment with Franz cell were done. The release kinetics study was also performed. In optimum situation, the resulted concentration of chitosan, glycerophosphate, poloxamer F-127 and TPP are 1%, 14.5%, 20% and 0.5%. Gelation time and temperature were validated and the results show about 1.5 minutes and 37 ℃ respectively. The drug release profile of free drug showed the fastest release rate with about 100% at 8 h whereas the formulations with TPP and without TPP were about 94% and 38% at 28 h respectively. Conclusions: A parenteral in situ forming gel formulation was designed and in vitro evaluation showed that our gel formulation has a uniform texture and can release drug through its nanostructured pores, properly. So, it can be useful in chronic pains, according to its features and reduces the frequency of consumption.&nbsp

The effect of size, morphology and surface properties of mesoporous silica nanoparticles on pharmacokinetic aspects and potential toxicity concerns

Mesoporous silica nanoparticles (MSNs) are considered as suitable delivery vehicles considering their unique characteristics. Various physicochemical characteristics of MSNs govern their pharmacokinetic parameters which affect the disposition of these nanoparticles in the body. Along with the advantages of MSNs, the toxicity of nanoparticles entering the body is a major concern. Various factors such as particle size, surface charge, route of administration, etc., may affect organ toxicity of MSNs. The main target organs involved in the metabolism and elimination of MSNs are the kidney and the liver as well as the hematopoietic system. In this review, we first introduced the physicochemical characteristics of MSNs which affect the pharmacokinetic properties including drug absorption and bio-distribution. Thereafter, we discussed the mechanisms by which organ toxicity may occur. In this regard, the effects of various factors on organ-based MSNs toxicities and molecular mechanisms have been summarized. At last, we emphasized on the role of the physicochemical parameters on organ-based toxicities, and the proposed approaches to prevent or at least diminish MSN-related toxicities are discussed in detail

Data on cell growth inhibition induced by anti-VEGF siRNA delivered by Stealth liposomes incorporating G2 PAMAM-cholesterol versus Metafectene® as a function of exposure time and siRNA concentration

AbstractIn this data article, carboxyfluorescein-loaded liposomes were prepared and purified from free carboxyfluorescein using gel filtration chromatography in the first part. In the next part, following preparation of anti-VEGF siRNA loaded liposomes incorporating hydrophobically modified G2 PAMAM dendrimer (G2-Chol40%) (Golkar et al., 2016) [1], the cell growth inhibition induced by the formulations (siRNA/Metafectene complexes and siRNA loaded liposomes incorporating hydrophobic G2) was evaluated at two exposure times through MTT assay in a breast cancer cell (SKBR-3) and compared by two-way ANOVA

Chitosan Dextran Microparticles as the Potential Carrier for Colon Specific Delivery of 5- Fluorouracil

Introduction: Colorectal cancer is one of the most commonly diagnosed cancers in the world. The main and classic treatment of this cancer is 5-fluorouracil (5-Fu) that its cytotoxicity and low systemic absorption restricted its therapeutic efficacy. To overcome these problems, mucoadhesive and colonic microbially degradable formulations based on chitosan and dextran sulphate hydrogels could be effective. Methods and Results: 5-Fu loaded hydrogel microparticles were formed via polyelectrolyte complexation technique using chitosan and dextran sulphate solutions. It was optimized by a systematic multi-objective optimization approach in terms of the particle size and loading efficiency of the resulting microparticles. Under this condition, the molecular weight of chitosan and 5-Fu concentration are the two factors which significantly influence the particle size and loading efficiency, respectively. Then the optimized microparticles were prepared and were characterized based on particle size, zeta potential, drug loading and drug release behavior. Finally the cytotoxicity of optimized microparticles was assessed by MTT assay (SW742 cell line) compare to free drug solution. Therefore, spherical particles of 51.33±0.95 μm mean diameter and a narrow size distribution were obtained under optimal conditions. The zeta potential, loading efficiency and loading capacity of optimized microparticles were 18.1±0.87mv, 26.96±0.38 and 13.12±0.65%, respectively. The in vitro drug release profile was fitted on Higuchi model and the cytotoxicity MTT results indicated the higher cytotoxicity of studied formulation on cells compare to free drug. The hydrogel microparticles were further lyophilized to prepare the enteric coated tablets and all tests endorsed that the coating process was suited. Conclusions: The designed formulations have provided appropriate properties and offer a potential mean for colon specific delivery of 5-Fu via oral administration

Mechanistic Assessment of Functionalized Mesoporous Silica-Mediated Insulin Fibrillation

Insulin, which is a small protein hormone consisting of 51 amino acids, rapidly fibrillates under stressogenic conditions. This biotechnological/ medical problematic reaction quickly accelerates in the presence of some particles, while there are several other particles that slow down the kinetic process. To address the unexplored demand of the particles that modulate protein fibrillation, we have synthesized two amino-based particles and a chitosan-coated mesoporous silica particle (MS-NH2, MS-3NH2, and MS-chitosan) to investigate insulin fibrillation. While these particles were fairly similar in size, they are differ in their net positive charge and surface hydrophobicity. To monitor the exact role of the hydrophobic interaction between the protein and MS-chitosan during the fibrillation, we have also co- and preincubated insulin with cholesterol and the particles under stressogenic conditions. The results indicate that MS-NH2 and MS-3NH2, due to their high positive charges and lack of surface hydrophobicity, repel the positively charged unfolded insulins at pH 2.0. Moreover, MS-chitosan with 25% surface hydrophobicity stacks partially unfolded insulins to its surface and induces some α-helix to β-sheet structural transitions to the protein. Consequently, both amino- and chitosan-based particles slow down the kinetics of the fibrillation. We also showed that cholesterol can structurally participate in insulin fibril architecture as a hydrophobic bridge, and extraction of this molecule from the preformed fibrils may disrupt the fibril structure

Recent Advances in Designing 5-Fluorouracil Delivery Systems: A Stepping Stone in the Safe Treatment of Colorectal Cancer

5-Fluorouracil (5-FU) has become one of the most widely employed antimetabolite chemotherapeutic agents in recent decades. It is considered a first line antineoplastic agent for the treatment of colorectal cancer. Unfortunately, chemotherapy with 5-FU has several limitations, including its short half-life, high cytotoxicity and low bioavailability. In order to overcome the drawbacks of 5-FU and enhance its therapeutic efficiency, many scientific groups have focused on designing a new delivery system to successfully deliver 5-FU to tumor sites. We provide a comprehensive review on different strategies to design effective delivery systems, including nanoformulations, drug-conjugate formulations and other strategies for the delivery of 5-FU to colorectal cancer. Furthermore, co-delivery of 5-FU with other therapeutics is discussed. This review critically highlights the recent innovations in and literature on various types of carrier system for 5-FU

Enhanced Intestinal Permeation of Doxorubicin Using Chitosan Nanoparticles

Purpose: Due to limited oral bioavailability of doxorubicin (Dox) many efforts during the last decades focused on the development of novel delivery systems to overcome these limitations. In the present study, Dox encapsulated chitosan nanoparticles were prepared to evaluate the intestinal permeation of Dox via oral administration. Methods: Nanoparticles were fabricated based on ionic gelation method using tripolyphosphate. Some physicochemical properties, such as nanoparticle size and morphology, loading efficiency and in vitro drug release in 3 different pH values (5.0, 6.8 & 7.4) were evaluated. Intestinal permeations of free Dox and Dox loaded in nanoparticles were assessed using rat intestinal sac model. Results: The nanoparticles were spherical shape with average size of 150 10 nm. The entrapment and loading efficiency of Dox were up to 40% and 23%, respectively. According to the release profiles, up to 30% of loaded drug was released within 6hrs and the remaining amount of Dox was released more gradually, but this pattern was related to pH of the medium. The amount of drug released at acidic condition (pH 5.0) was greater than other pHs. The intestinal permeation of Dox increased nearly up to 90% by loading in chitosan nanoparticles. Conclusion: Using chitosan nanoparticles presents a potential safe drug delivery system for oral administration of Dox. In vivo studies and the determined pharmacokinetic and pharmacodynamic of Dox loaded chitosan nanoparticles after oral administration are planned for future studies

A reversed-phase high performance liquid chromatography approach for analysis of 5-Fluorouracil

A reproducible, sensitive, accurate and selective high performance liquid chromatographic (HPLC) method with ultraviolet absorbance detection has been developed and validated to quantitate 5-Fluorouracil (5-FU), an antimetabolite chemotherapeutic agent used in treatment of colorectal cancer as a drug of choice. Chromatographic separations were performed on a C18 column (Eurosphar 100-5, 150 mm × 4.6 mm) as the reversed stationary phase, eluted with a mobile phase composed of deionized water and methanol (95:5) with the flow rate of 1.0 mL/min. The UV wavelength was set at 261nm. The method produced linear responses throughout 5-fluorouracil range of 25-500 ng/ml with a correlation coefficient of 0.998. A limit of quantitation (LOQ) was established at 25 ng/ml. The within-day and between-day precision and accuracy were both in acceptable ranges. The outcomes of these tests indicate a proper separation efficacy as well as accuracy and sensivity of method which is a potential tool in many pharmaceutical studies such as drug delivery of this anti-cancer agent. </p

Antiulcer Activity after Oral Administration of the Wormwood Ethanol Extract on Lesions due to Leishmania major Parasites in BALB/C Mice

Herbal extracts were used to investigate the in vivo efficacy of Artemisia absinthium on the treatment of cutaneous leishmaniasis in susceptible mice. A total of 40 BALB/c mice were subjected to assays. In each, 3-5×103 amastigotes of standard Leishmania major strain were inoculated subcutaneously into the tail base of mice. Groups of mice were assigned as: I-negative control, II-positive control, III-Glucantime®, IV-ointment twice a day, V-ointment with oral medicine, VI-oral medicine on parasite injection, VII-oral medicine once ulcer develops, and VIII-ointment-based crème on ulcer. The gold standard of clinical infection control was based on ulcer size measurement using a Vernier scale weekly during 4 weeks Post-Ulcer Development (PUD). The mean ulcer sizes in different groups were compared using the post hoc Dunnett's 3 statistical analyses. There was a significant difference between the two groups of ointment with medicine (V) and medicine on parasite inoculation (VI) (P ≤ 0.027). Antiulcer activity and healing was noted after oral treatment with aqueous extract on parasite injection. There was a significant difference between data from positive control group and local ointment with oral medicine (P ≤ 0.045) indicating that ointment use facilitated ulcer growth. There was also a significant difference between data from Glucantime® use and ointment with medicine group (P ≤ 0.039) which showed the deteriorating effect of oil-based ointment use. The oral administration of extract had an effect similar to Glucantime® use and led to the repair of ulcer. A. absinthium extract as oral feeder appeared to cause modulation of host responses, ulcer size reduction and tissue repair

A Reversed-phase High Performance Liquid Chromatography (HPLC) method for bio-analysis of Methotrexate

Methotrexate (MTX) is a chemotherapeutic agent used in treatment of many disorders including autoimmune diseases and cancers. The availability of a reliable analysis method for drug assay in biological fluids of interest  is  a  prerequisite  for  all  pharmacokinetic  studies  in  humans  or  animal  models. Considering the complex matrices of the biological specimens as well as the low concentrations of the majority of the drugs in biological fluids, the development of an available while sensitive method for the bioanalytical studies is often a challenging issue.For drug assay in aqueous, plasma, animal brain and liver tissue environments in a concentration range of 25-600 ng/ml, a reverse phase high performance liquid chromatography (RP-HPLC) was developed.System suitability tests were indicating a method with acceptable analytic separation efficiency and peak shape proving method’s selectivity. Limit of detection (LOD) and limit of quantification (LOQ) determined to be 10 ng/ml and 25ng/ml, which reflect method sensitivity. Regression analysis showed a linear correlation between area under curve (AUC) of peaks and corresponding MTX concentrations. The within-day and between-day precision and accuracy was both in acceptable ranges. Recovery index of method for median concentration (200 ng/ml) is also about 74%.The developed method was accorded to the acceptable criteria of analytical method validation. The sensitivity of the method in all the tested matrices made the method suitable in terms of detection and quantitation of low concentration samples throughout the study. Also, the assay method had fairly short run-time and lacks any significant interference. </p