Effect of surfactant HLB and different formulation variables on the properties of poly-D,L-lactide microspheres of naltrexone prepared by double emulsion technique

The aim of this work was to investigate the role of HLB of emulsifier as well as volume of the internal aqueous phase (W(1)) and presence of salt in the external aqueous phase (W(2)) on the morphology, size and encapsulation efficiency of poly(D,L-lactide) microspheres containing naltrexone HCl. PLA microparticles containing naltrexone HCl, an effective opiate antagonist, were prepared by a water-in-oil-in-water emulsification-solvent evaporation procedure. One of the five different emulsifiers: span 80, span 20, tween 85, tween 80 and tween 20, with HLB values from 4-17 were added to W(1). Presence of emulsifier in W(1) resulted in smaller particles with a more dense and uniform internal structure. Incorporation of span 80 (HLB 4.3, suitable for W/O emulsions) yield the highest encapsulation efficiency. Increasing the HLB value to 8 or 11 (span 20 or tween 85) decreased the efficiency of naltrexone HCl-loading. HLB values higher than 15 (tween 80 or tween 20) increased encapsulation efficiency unexpectedly, which could be attributed to migration of these emulsifiers to the O/W(2) interface and modifying the surface properties of microparticles. Increasing the internal water phase volume from 0.2-1.8 ml resulted in larger particle size with poor encapsulation efficiency. Addition of 10% w/w NaCl to the W(2) changed the surface morphology of microspheres from a porous form to a smooth surface. It was shown that, by selecting the appropriate HLB value of emulsifier in W(1), addition of salt to W(2) and controlling the volume of W(1), one can control the encapsulation efficiency, size and morphology of microspheres.     

The focused ion beam technique: a useful tool for pharmaceutical characterization

Focused ion beam (FIB) instrumentation, a hybrid of the scanning electron micrsocope, ion milling and computer-aided design systems, has special uses in the electronic and semiconductor industries as a tool for failure analysis and device development. This paper examines the pharmaceutical applications of the FIB, particularly microscopic analysis of microspheres. With the FIB, microsphere structures were peeled off, layer by layer, and the structure of each layer was simultaneously observed under scanning microscopy. The particles had a wrinkled but non-porous surface. Going deeper, some holes appeared, with size and numbers increasing toward the particle center. This unique method precisely investigated the inner structure of particles, layer by layer. Then, by FIB milling, samples were extracted with an accuracy of localization of 50nm from specific parts of the microspheres and prepared to a 200nm uniform thickness film for examination under transmission electron microscopy. The FIB method also has the potential for a wide range of other quantitative and qualitative analysis of dosage forms and materials.     

In vitro release of clomipramine HCl and buprenorphine HCl from poly adipic anhydride (PAA) and poly trimethylene carbonate (PTMC) blends

Controlled drug-delivery technology is concerned with the systematic release of a pharmaceutical agent to maintain a therapeutic level of the drug in the body for modulated and/or prolonged periods of time. This may be achieved by incorporating the therapeutic agent into a degradable polymer vehicle, which releases the agent continuously as the matrix erodes. In this study, poly trimethylene carbonate (PTMC), an aliphatic polycarbonate, and poly adipic anhydride (PAA), an aliphatic polyanhydride, were synthesized via melt condensation and ring-opening polymerization of trimethylene carbonate and adipic acid, respectively. The release of clomipramine HCl and buprenorphine HCl from discs prepared with the use of PTMC-PAA blends in phosphate buffer (pH 7.4) are also described. Clomipramine HCl and buprenorphine HCl were both used as hydrophilic drug models. Theoretical treatment of the data with the Peppas model revealed that release of clomipramine HCl (5%) in devices containing 70% PTMC or more followed a Fickian diffusion model. However, the releases of buprenorphine HCl (5%) in the same devices were anomalous. For devices containing 50% and more PAA, surface erosion may play a significant role in the release of both molecules.     

Significance and clinical value of the transitional zone volume (TZV) or index (TZI) in assessing the degree of lower urinary tract obstruction: Revisited

Introduction

A lot of diagnostic tools are present for assessing the degree of LUTs. Pressure-flow studies are invasive and cannot be justified in all patients suffering from LUTs. From here came the clinical importance of searching for another clinical tool, to help in assessing the degree of LUTS.

Electrochemical determination of naltrexone on the surface of glassy carbon electrode modified with Nafion-doped carbon nanoparticles: Application to determinations in pharmaceutical and clinical preparations

A new sensitive and selective electrochemical sensor was developed for determination of naltrexone (NAL) in pharmaceutical dosage form and human plasma. Naltrexone is an opioid antagonist which is commonly used for the treatment of narcotic addiction and alcohol dependence. A voltammetric study of naltrexone has been carried out at the surface of glassy carbon electrode (GCE) modified with Nafion-doped carbon nanoparticles (CNPs). The electrochemical oxidation of naltrexone was investigated by cyclic and differential pulse voltammetric techniques. The dependence of peak currents and potentials on pH, concentration and the potential scan rate was investigated. The electrode characterization by electrochemical methods and atomic force microscopy (AFM) showed that CNPs enhanced the electroactive surface area and accelerated the rate of electron transfer. Application of the modified electrode resulted in a sensitivity enhancement of more than 20 times, relative to the bare GCE, in detection of NAL and a considerable negative shift in peak potential was achieved. Two linear dynamic ranges of 1–10 μM and 10–100 μM with a detection limit of 0.1 μM was obtained in phosphate buffer of pH = 3. Differential pulse voltammetry as a simple, rapid, sensitive and selective method was developed for the determination of NAL in dosage form and human plasma without any treatments. No electroactive interferences were found in biological fluids from the endogenous substances and additives present in capsules.     

Cost-effectiveness of different interferon beta products for relapsing-remitting and secondary progressive multiple sclerosis: Decision analysis based on long-term clinical data and switchable treatments

Background

Multiple sclerosis (MS) is a highly debilitating immune mediated disorder and the second most common cause of neurological disability in young and middle-aged adults. Iran is amongst high MS prevalence countries (50/100,000). Economic burden of MS is a topic of important deliberation in economic evaluations study. Therefore determining of cost-effectiveness interferon beta (INF β) and their copied biopharmaceuticals (CBPs) and biosimilars products is significant issue for assessment of affordability in Lower-middle-income countries (LMICs).

Methods

A literature-based Markov model was developed to assess the cost-effectiveness of three INF βs products compared with placebo for managing a hypothetical cohort of patients diagnosed with relapsing remitting MS (RRMS) in Iran from a societal perspective. Health states were based on the Kurtzke Expanded Disability Status Scale (EDSS). Disease progression transition probabilities for symptom management and INF β therapies were obtained from natural history studies and multicenter randomized controlled trials and their long term follow up for RRMS and secondary progressive MS (SPMS). A cross sectional study has been developed to evaluate cost and utility. Transitions among health states occurred in 2-years cycles for fifteen cycles and switching to other therapies was allowed. Calculations of costs and utilities were established by attachment of decision trees to the overall model. The incremental cost effectiveness ratio (ICER) of cost/quality adjusted life year (QALY) for all available INF β products (brands, biosimilars and CBPs) were considered. Both costs and utilities were discounted. Sensitivity analyses were done to assess robustness of model.

Results

ICER for Avonex, Rebif and Betaferon was 18712, 11832, 15768 US Dollars ($) respectively when utility attained from literature review has been considered. ICER for available CBPs and biosimilars in Iran was $847, $6964 and $11913.

Conclusions

The Markov pharmacoeconomics model determined that according to suggested threshold for developing countries by world health organization, all brand INF β products are cost effective in Iran except Avonex. The best strategy among INF β therapies is CBP intramuscular INF β-1a (Cinnovex). Results showed that a policy of encouraging accessibility to CBPs and biosimilars could make even high technology products cost-effective in LMICs.     

Modified Gadonanotubes as a promising novel MRI contrasting agent

Background and purpose of the study

Carbon nanotubes (CNTs) are emerging drug and imaging carrier systems which show significant versatility. One of the extraordinary characteristics of CNTs as Magnetic Resonance Imaging (MRI) contrasting agent is the extremely large proton relaxivities when loaded with gadolinium ion (Gd_n³⁺) clusters.

Methods

In this study equated Gd_n³⁺ clusters were loaded in the sidewall defects of oxidized multiwalled (MW) CNTs. The amount of loaded gadolinium ion into the MWCNTs was quantified by inductively coupled plasma (ICP) method. To improve water solubility and biocompatibility of the system, the complexes were functionalized using diamine-terminated oligomeric poly (ethylene glycol) via a thermal reaction method.

Results

Gd_n³⁺ loaded PEGylated oxidized CNTs (Gd_n³⁺@CNTs-PEG) is freely soluble in water and stable in phosphate buffer saline having particle size of about 200 nm. Transmission electron microscopy (TEM) images clearly showed formation of PEGylated CNTs. MRI analysis showed that the prepared solution represents 10% more signal intensity even in half concentration of Gd³⁺ in comparison with commerciality available contrasting agent Magnevist®. In addition hydrophilic layer of PEG at the surface of CNTs could prepare stealth nanoparticles to escape RES.

Conclusion

It was shown that Gd_n³⁺@CNTs-PEG was capable to accumulate in tumors through enhanced permeability and retention effect. Moreover this system has a potential for early detection of diseases or tumors at the initial stages.     

Postprandial lipemia under treatment with Allium sativum. Controlled double-blind study of subjects with reduced HDL2-cholesterol]

Postprandial Lipaemia under Treatment with Allium sativum/Controlled double-blind study in healthy volunteers with reduced HDL2-cholesterol levels. The effectiveness of a standardized garlic powder preparation (Sapec, Kwai) on alimentary hypertriglyceridaemia after intake of a standardized fatty test meal containing 100 g butter was analyzed in a randomized placebo-controlled double-blind study. 24 volunteers with HDL2-cholesterol concentrations in plasma of less than 10 mg/dl (men) respectively 15 mg/dl (women) participated in the study. The volunteers received 3 times 1 tablet daily over a period of 6 weeks equivalent to a daily dosage of 900 mg garlic powder in the active treated group. Control measurements were made on the 1st, 22nd and 43rd day of treatment and 0, 3 and 5 h after intake of the meal. The postprandial increase of triglycerides was clearly reduced under garlic medication as compared to placebo treatment. The determined AUC-values for the triglycerides were up to 35% lower in the garlic group compared to the placebo group. The regular intake of the garlic preparation over the period of 6 weeks showed a significant lowering of the fasting values of triglycerides in comparison to placebo. Under garlic medication HDL2-cholesterol increased more than under placebo in tendency.     

Crystal modification of phenytoin using different solvents and crystallization conditions

Phenytoin crystals having different types of habits, were prepared by recrystallization from ethanol and acetone solutions under different conditions (cooling rate or crystallization temperature, solvent evaporation and watering-out techniques). Scanning electron microscopy, X-ray powder diffractometry, FT-IR spectrometry and differential scanning calorimetry were used to investigate the physical characteristics of the crystals. The dissolution behavior and compaction properties of various batches of crystals were also studied. It was found that using watering-out technique as a crystallization method, produced thin plate crystals, while the crystals obtained by other methods were needle shape for alcoholic solutions and rhombic for acetone solutions. X-ray diffraction spectra and differential scanning calorimetry studies, did not show any polymorphic change. The dissolution rate of different crystals was lower than that of untreated samples. The compacts of phenytoin crystals produced from alcohol or acetone (especially those made by watering-out method) had higher crushing strengths than untreated phenytoin compacts due to the lower porosity and the lower elastic recovery.