Improving the in-vivo biological activity of fingolimod loaded PHBV nanoparticles by using hydrophobically modified alginate.

Uncontrolled distribution of nanoparticles (NPs) within the body can significantly decrease the efficiency of drug therapy and is considered among the main restrictions of NPs application. The aim of this study was to develop a depot combination delivery system (CDS) containing fingolimod loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) NPs dispersed into a matrix of oleic acid-grafted-aminated alginate (OA-g-AAlg) to minimize the nonspecific biodistribution (BD) of PHBV NPs. OA-g-AAlg was synthesized in two step; First, Alg was aminated by using adipic dihydrazide (ADH). The degree of hyrazide group substitution of Alg was determined by trinitro-benzene-sulfonic acid (TNBS) assay. Second, OA was attached to AAlg through formation of an amide bond. Chemical structure of OA-g-AAlg was confirmed with FTIR and HNMR spectroscopy. Furthermore, rheological properties of OA-g-AAlg with different grafting ratios were evaluated. In-vitro release studies indicated that 47% of fingolimod was released from the CDS within 28 days. Blood and tissue samples were analyzed using liquid chromatography/tandem mass spectrometry following subcutaneous (SC) injection of fingolimod-CDS into Wistar rats. The elimination phase half-life of CDS-fingolimod was significantly higher than that of fingolimod (∼32 d vs. ∼20 h). To investigate the therapeutic efficacy, lymphocyte count was assessed over a 40 day period in Wistar rats. Peripheral blood lymphocyte count decreased from baseline by 27 ± 8% in 2 days after injection. Overall, the designed CDS represented promising results in improving the pharmacokinetic properties of fingolimod. Therefore, we believe that this sustained release formulation has a great potential to be applied to delivery of various therapeutics.

A Comparative Study on Different Pharmaceutical Industries and Proposing a Model for the Context of Iran.

Medication is known as the main and the most effective factor in improving public health. On the other hand, having a strong and effective pharmaceutical industry will, to a very large extent, guarantee people's health. Therefore, this study was prospected to review the different pharmaceutical industries around the world and propose a model for the context of Iran. This is a qualitative as well as a comparative study which was carried out in 2015. At the first stage, using the World Bank website, countries were divided into four groups of low-income, lower-middle-income, upper-middle-income, and high-income economies. Then, four countries of Afghanistan, India, Brazil, and Canada were chosen from these four groups, respectively. Secondly, data gathered from these countries were given to two 12-member expert panels. Finally, using the articles and the results of expert panel groups, useful and effective policies were extracted for the growth and development of Iran's pharmaceutical industry. Findings of the study indicated that the following seven items are the essential policies for the context of Iran: establishment of high academic centers as well as research institutes, using weak patent law, supporting research and development centers at universities and pharmaceutical companies, backing national pharmaceutical companies up, implementing generic rules, gradual economic liberalization, and membership in world trade organization. Since, pharmaceutical industry is an effective and inseparable part of every health system, proper and evidence-based policies should be taken into account in order to develop this industry and, ultimately, meet the public needs.

Nanoparticulate fingolimod delivery system based on biodegradable poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV): design, optimization, characterization and in-vitro evaluation.

This study was focused on the fabrication, statistical optimization and in vitro characterization of poly (hydroxybutyrate-co-hydroxyvalerate) (PHBV) nanoparticles loaded with fingolimod. PHBV-based fingolimod nanoparticles were prepared by single and double evaporation methods; the incorporation efficiency of fingolimod was higher with the single emulsion evaporation method in the nanosize range particles. Fingolimod HCL was neutralized with NaOH in order to slow down the release of the highly soluble fingolimod. The encapsulation efficiency of neutralized fingolimod was much higher (53-73%) due to the insoluble form of the drug used in encapsulation. It was found that the amount of fingolimod, concentration of PHBV and polyvinyl alcohol (PVA) would influence the encapsulation efficiency significantly. The effect of these parameters on the Particle size, PdI, loading capacity and loading efficacy was studied. The optimum conditions were 1.32% PHBV, 0.42% PVA and 5 mg fingolimod. The average size of optimized nanoparticles which measured with the aid of the Box-Behnken experimental design was 250 nm and entrapment efficiency of 73(%). Drug-release from the nanospheres over a four-week period has shown a characteristic triphasic release pattern with an initial burst effect.

Treatment with pioglitazone is associated with decreased preprandial ghrelin levels: a randomized clinical trial.

The effects of metformin and pioglitazone on ghrelin, a physiologic regulator of appetite and food intake, have not been clearly established. In a randomized clinical trial, we randomly assigned 60 type 2 diabetic patients to either metformin (Group A; n=30) or pioglitazone (Group B; n=30) treatment groups. The groups were similar in their baseline characteristics. A standard fasting 75 g oral glucose tolerance test was performed at time zero before starting metformin or pioglitazone, and 3 months later. After 3 months of treatment, pioglitazone, but not metformin, was significantly associated with weight gain. Both groups experienced a significant reduction in fasting plasma glucose (p<0.01), hemoglobin A1c (p<0.01 in Group A and p<0.05 in Group B), and insulin resistance (p<0.01). The effect of metformin on preprandial ghrelin and its response to glucose challenge was not significant, while the pioglitazone group had a significant reduction in preprandial ghrelin levels after treatment (p<0.05). The effect of pioglitazone on ghrelin was independent of changes in body weight, body mass index, glucose control, insulin resistance, and plasma insulin. In conclusion, treatment with pioglitazone is associated with a decrease in preprandial ghrelin levels and therefore, the weight gain and increased food intake related to pioglitazone use cannot be explained by its effects on ghrelin. The effect of pioglitazone on ghrelin is independent of changes in body weight, body mass index, plasma insulin, insulin resistance, or glucose control.

HPLC analysis of orlistat and its application to drug quality control studies.

In this study, a high performance liquid chromatography method with UV detection was developed for determination of orlistat. The chromatographic system consisted of a Nova-Pack C18 column, an isocratic mobile phase of phosphoric acid 0.1%-acetonitrile (10 : 90, v/v) and UV detection at 205 nm. Orlistat was eluted at about 6 min with no interfering peak from excipients used for preparation of dosage form. The method was linear over the range of 10-160 microg/ml orlistat (r2 > 0.9999). The within-day and between-day precision values were also in the range of 0.10-0.59%. The appropriate dissolution conditions were also determined and applied to evaluate the dissolution profile of orlistat capsules. Optimal conditions were 1000 ml of 3% SLS in water as dissolution medium and paddle at 100 rotation per minute. The proposed method was applied successfully to the determination of orlistat content in capsules and in vitro dissolution studies.

Validated HPLC method for determination of carboxylic acid metabolite of clopidogrel in human plasma and its application to a pharmacokinetic study.

A new, simple, and reproducible method for determination of carboxylic acid metabolite of clopidogrel in human plasma has been developed. After liquid-liquid extraction in acidic medium with chloroform, samples were quantified on a Nova-pak C(8), 5 microm column using a mixture of 30 mM K(2)HPO(4)-THF-acetonitrile (pH = 3, 79:2:19, v/v/v) as mobile phase with UV detection at 220 nm. The flow rate was set at 0.9 mL/min. Ticlopidine was used as internal standard and the total run time of analysis was about 12 min. The method was linear over the range of 0.2-10 microg/mL of clopidogrel metabolite in plasma (r(2) > 0.999). The within-day and between-day precision values were in the range 1.0-4.8%. The limit of quantification of the method was 0.2 microg/mL. The method was successfully used to study the pharmacokinetics of clopidogrel in healthy volunteers.