Preliminary investigation on the design of biodegradable microparticles for ivermectin delivery: set up of formulation parameters

The aim was to design sterile biodegradable microparticulate drug delivery systems based on poly(dl-lactide) (PLA) and poly(?-caprolactone) (PCL) and containing ivermectin (IVM), an antiparasitic drug, for subcutaneous administration in dogs. The drug delivery system should: (i) ensure a full 12-month protection upon single dose administration; (ii) be safe with particular attention regarding IVM dosage and its release, in order to prevent over dosage side effects. This preliminary work involves: polymer selection, evaluation of the effects of γ-irradiation on the polymers and IVM, investigation and set up of suitable microparticle preparation process and parameters, IVM-loaded microparticles in vitro release evaluation.

Results of gel permeation chromatography analysis on the irradiated polymers and IVM mixtures showed that combination of IVM with the antioxidant α-tocopherol (TCP) reduces the damage extent induced by irradiation treatment, independently on the polymer type.

Solvent evaporation process was successfully used for the preparation of PLA microparticles and appropriately modified; it was recognized as suitable for the preparation of PCL microparticles. Good process yields were achieved ranging from 76.08% to 94.72%; encapsulation efficiency was between 85.76% and 91.25%, independently from the polymer used. The type of polymer and the consequent preparation process parameters affected microparticle size that was bigger for PCL microparticles (480–800?µm) and solvent residual that was >500?ppm for PLA microparticles. In vitro release test showed significantly faster IVM release rates from PCL microparticles, with respect to PLA microparticles, suggesting that a combination of the polymers could be used to obtain the suitable drug release rate.     

Impact of surfactant selection on the formulation and characterization of microparticles for pulmonary drug delivery

The effect of suspension stabilizers, internal aqueous phase volume and polymer amount were investigated for the production of protein loaded poly(d,l?lactide-co-glycolide) (PLGA) microparticles suitable for pulmonary drug delivery. PLGA microparticles were produced adopting water-in-oil-in-water (W/O/W) solvent evaporation technique and were investigated for surface morphology, particle size, encapsulation efficiency (EE%) and in-vitro release profile. Porous surface morphologies with a narrow size distribution were observed when employing 0.5?ml internal aqueous phase; 23.04?µm (±0.98), 15.05?µm (±0.27) and 22.89?µm (±0.41) for PVA, Tween 80 and oleic acid. Porous microparticles exhibited increased size and reduction in EE% with increasing internal aqueous phase, with non-porous microparticles produced when adopting 2.0?ml internal aqueous phase. The selection of stabilizer influences the size of the pores formed thus offers potential for the aerodynamic properties of the microparticles to be manipulated to achieve suitable aerosolization characteristics for pulmonary delivery of proteins.     

Formulation and characterization of ethylcellulose microparticles containing .l-alanyl- l-glutamine peptide

Context: The l-alanyl-l-glutamine peptide (AGP) has been effective to promote acute glycemia recovery during long-term insulin-induced hypoglycemia (IIH), and the oral administration of AGP is suggested to prevent prolonged hypoglycemia, such as nocturnal hypoglycemia.

Objective: Considering the ability of AGP on glycemia recovery and AGP’s fast metabolism, the aim of current study was to obtain and characterize ethylcellulose microparticles to deliver the drug for a prolonged time.

Materials and Methods: Microparticles were prepared by simple and double emulsification/hardening method and characterized by scanning electron microscopy, thermogravimetry (TG), differential scanning calorimetry (DSC), Fourier transform infra-red (FTIR) and FT-Raman spectroscopy and in vitro release.

Results and Discussion: Spherical structures with a mean diameter between 9.30?µm and 13.19?µm were formed. TG analysis showed that the thermal stability of AGP was even more increased by encapsulation with ethylcellulose. In addition, TG, DSC, FTIR and FT-Raman analyses proved that AGP was encapsulated in a molecular way. Higher values of encapsulation efficiency were observed for the microparticles prepared by double emulsification (57.83–83.67%) than for those prepared by simple emulsification (18.37%). However, the last ones could release the peptide in a quicker and more extensive manner than those prepared by double emulsification.

Conclusion: For the first time, microparticles containing AGP were developed and exhibited prolonged in vitro release as well as protection to the drug, and it could be considered as a dosage form for patients who suffer from insulin-induced hypoglycemia and/or nocturnal hypoglycemia.     

Ellipsometric determination of optical properties of carbazole-containing poly(l-glutamate) thin films prepared from different solvents

In this study, the refractive indices (n) and thicknesses of carbazole-containing hole-transport materials such as poly(γ-carbazolylethyl l-glutamate) (PCELG) and poly(N-vinyl carbazole) (PVCz) films were determined by carrying out ellipsometric measurements. The thicknesses of PCELG and PVCz films determined by ellipsometric analysis were in good agreement with those determined by surface profilometry. The dependence of the refractive indices of the PCELG films on film thickness was classified into two types on the basis of the solvent from which the films were prepared: the refractive indices either increased with increasing film thickness, as in the case of PCELG films prepared from 1,2-dichloroethane (DCE) and monochlorobenzene (?-Cl), or were independent of the film thickness, as in the case of films prepared from 1,1,2,2-tetrachloroethane (TCE). A comparison of these results with the structures of the polymers, as determined by ¹H NMR, reveals that the two types of dependences of the refractive indices of the PCELG thin film on the film thickness can be attributed to the two types of aggregation structures and/or orientational characteristics corresponding to the helical conformation of the polymer. In contrast, the refractive indices of PVCz films are governed mainly by the film thickness. Finally, we would like to emphasize that the combination of ellipsometry and other techniques such as NMR and surface profilometry provide information not only on the film thickness and refractive index but also on the aggregation structure in thin films with thicknesses on the order of 50 nm.     

Freeze drying optimization of polymeric nanoparticles for ocular flurbiprofen delivery: effect of protectant agents and critical process parameters on long-term stability

Context: The stabilization of flurbiprofen loaded poly-?-caprolactone nanoparticles (FB-P?CL-NPs) for ocular delivery under accurate freeze-drying (FD) process provides the basis for a large-scale production and its commercial development.

Objective: Optimization of the FD to improve long-term stability of ocular administration’s FB-P?CL-NPs.

Methods: FB-P?CL-NPs were prepared by solvent displacement method with poloxamer 188 (P188) as stabilizer. Freezing and primary drying (PD) were studied and optimized through freeze-thawing test and FD microscopy. Design of experiments was used to accurate secondary drying (SD) conditions and components concentration. Formulations were selected according to desired physicochemical properties. Furthermore, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were used to study interactions components.

Results: Optimized FB-P?CL-NPs, stabilized with 3.5% (w/w) P188 and protected with 8% (w/w) poly(ethylene glycol), was submitted to precooling at +10?°C for 1?h, freezing at ?50?°C for 4?h, PD at +5?°C and 0.140 mbar for 24?h and a SD at +45?°C during 10?h. These conditions showed 188.4?±?1.3?nm, 0.087?±?0.014, 85.5?±?1.4%, 0.61?±?0.12%, ?16.4?±?0.1?mV and 325?±?7 mOsm/kg of average size, polydispersity index, entrapment efficiency, residual moisture, surface charge and osmolality, respectively. It performed a long-term stability >12 months. DSC and XRD spectra confirmed adequate chemical interaction between formulation components and showed a semi-crystalline state after FD.

Conclusions: An optimal freeze dried ocular formulation was achieved. Evidently, the successful design of this promising colloidal system resulted from rational cooperation between a good formulation and the right conditions in the FD process.     

Double-walled microspheres loaded with meglumine antimoniate: preparation,characterization and in vitro release study

Objective: The objective of this study was to fabricate double-walled poly(lactide-co-glycolide) (PLGA) microspheres to increase encapsulation efficiency and avoid rapid release of hydrophilic drugs such as meglumine antimoniate.

Methods: In this study, double-walled and one-layered microspheres of PLGA were prepared using the emulsion solvent evaporation technique to better control the release of a hydrophilic drug, meglumine antimoniate (Glucantime®), which is the first choice treatment of cutaneous leishmaniasis. The effect of hydrophobic coating on microspheres' size, morphology, encapsulation efficiency and drug release characteristics was evaluated. Furthermore, the presence of antimony in meglumine antimoniate made it possible to observe the drug distribution within the microspheres' cross section by means of energy dispersive X-ray spectroscopy.

Results: Drug distribution images confirmed accumulation of the drug within the inner core of double-walled microspheres. In addition, these microspheres encapsulated the drug more efficiently up to 87% and demonstrated reduced initial burst and prolonged release compared to one-layered microspheres. These superiorities make double-walled microspheres an optimum candidate for sustained delivery of hydrophilic drugs.

Conclusion: Double-walled microspheres provide some advantages over traditional microspheres overcoming most of their limitations. Double-walled microspheres were found to be more efficient than their corresponding one-layered microspheres in terms of encapsulation efficiencies and release characteristics.     

Electrochemical characterization of deoxyribonucleic acid on aluminum(III)/poly(l-glutamic acid) film and its application for the detection of phosphinothricin acetyltransferase gene-specific sequence

A simple strategy of transgenic sequence-specific detection without a special amplification procedure was developed on the basis of aluminum(III)/poly(l-glutamic acid) (PLGA) film. An aluminum ion (Al(III)) thin film was assembled on the surface of PLGA via the electrostatic binding of Al(III) with carboxyl, namely Al(III)/PLGA. The immobilization of deoxyribonucleic acid (DNA) was carried out on this Al(III)/PLGA film by Al(III)-single strand DNA (ssDNA) interaction. Surface hybridization between the immobilized ssDNA and its complementary ssDNA was monitored by electrochemical impedance spectroscopy (EIS) using [Fe(CN)₆]^3−/4− as a redox probe. Under the optimal conditions, this DNA electrochemical sensor was applied to determine the specific gene sequence related to phosphinothricin acetyltransferase transgene (PAT) in the transgenic plants by label-free EIS.     

Facile, one-step controlled synthesis of Se nanocrystals in the presence of l-tyrosine

Se with different morphologies was synthesized using l-tyrosine as reducing agent and soft template by means of hydrothermal method. The method was simple and convenient to handle. The reaction process was monitored using ultraviolet-visible spectroscopy (UV-vis) and Fourier-transform infrared spectroscopy (FTIR). The morphology and crystalline phase were determined by transmission electron microscopy (TEM), scanning electronic microscopy (SEM) and X-ray diffraction (XRD) pattern. The results show that the morphologies and the crystalline phases of Se can be easily controlled. By varying the concentration ratio of l-tyrosine to selenious acid, the morphologies and crystalline phases of Se were not changed, but the diameter of Se was different. Se nano-rods are obtained in the lower temperature, and there is a transformation of microspheres into nanorods of Se with the increase of reaction time or reaction temperature. In addition, we discuss the possible mechanism of the reduction of SeO₃²⁻ ions by l-tyrosine. The eco-friendly, biogenic synthesis strategy could be widely used for preparing inorganic/organic biocomposites.     

L-Aspartic acid/L-cysteine/gold nanoparticle modified microelectrode for simultaneous detection of copper and lead

This paper presents an electrochemical microsensor for simultaneous detection of copper (II) and lead (II) using an l-aspartic acid/l-cysteine/gold nanoparticle modified microelectrode. The microelectrode was fabricated by Micro Electro-Mechanical System technique. The complex of gold nanoparticles (AuNPs) and amino acid with carboxyl group was used as the selective ligand for metal ions. The microelectrode was firstly modified with AuNPs to increase the sensitive area of the working electrode. Subsequently, the AuNPs/gold electrode was modified with l-cysteine and then covalently linked with a monolayer of l-aspartic acid using glutaraldehyde. Electrochemical analysis of metal ions was achieved by using square wave voltammetry without stirring. The microsensor exhibited an excellent linear range from 5 μg L^− 1 to 2000 μg L^− 1 with the limit of detection of 1 μg L^− 1. This metal ion detection method based on l-aspartic acid/l-cysteine/gold nanoparticle modified microelectrode is simple, sensitive and it could be used for electrochemical analysis of copper (II) and lead (II).     

Preparation and microscopy examination of alginate-poly-l-lysine-alginate microcapsules

Ca-alginate-poly-l-lysine-alginate (APA-Ca) and Ba-alginate-poly-l-lysine-alginate (APA-Ba) microcapsules were prepared and their thickness and surface were examined by light microscopy and scanning electron microscopy. Specifically, light microscopy with frozen section was used to visualize and quantify the thickness of APA membrane, and monitor temporal changes in the thickness of microcapsules during a month long culture in vitro. The section graph of APA microcapsule represents the accurate measurement of layer thickness of APA-Ca with diameter 900?±?100 and 500?±?100?μm at 6.01?±?1.02 and 9.54?±?2.42?μm (p?p?in vitro. Field emission scanning electron microscopy with freeze drying method was used to detect the surface and thickness of dried microcapsules. From the results, the outer surface of APA-Ca and APA-Ba membrane were smooth and dense, the film thickness of the APA-Ca was about 450–690?nm, while the APA-Ba was approximately 335?nm. In vivo experiment, little significant difference was seen in the change of film thickness of microcapsules in intrapertioneal site for 30 days after transplantation (p?>?0.05), except that the recovery of APA-Ba was higher than the APA-Ca microcapsules. The paper showed an easy method to prepare APA-Ca and APA-Ba, and examine their thickness and surface, which could be utilized to study other types of microcapsules.     

Biomolecule-assisted synthesis of copper indium sulfide microspheres with nanosheets

Copper indium sulfide product was successfully synthesized via a mild solvothermal approach involving CuCl₂·2H₂O as the copper source, InCl₃ as the indium source, l-cysteine as the sulfur source and N,N-dimethylformamide as the reaction medium respectively at 200 °C for 12 h. Morphology, structure, and phase constituents of the as-prepared CuInS₂ powders were characterized by XRD, FE-SEM, XPS, and TEM (HRTEM). Results showed that the synthesized powder consists of microspheres made up of nanosheets and the thickness of the CuInS₂ nanosheets was found to vary from 50 to 100 nm. A possible formation mechanism was put forward and briefly discussed. The proposed solvothermal method using l-cysteine as the sulfur source offers a potential alternative avenue to prepare other ternary semiconductor nanomaterials.     

The Role of Several l-HPCs in Preventing Tablet Capping During Direct Compression of Metronidazole

Several low-hydroxypropyl cellulose (l-HPC) derivatives (LH-11, 21, 22, 31, and 32) differing in granulometric particle size or in hydroxypropyl content were considered in the present study. The l-HPC grades were characterized as pure powders, in order to determine both compression and densification behavior, in presence or in absence of magnesium stearate as lubricant, and then, were physically mixed in different proportions with metronidazole, which was also previously characterized as pure powder. The tabletability and compressibility of these binary mixtures were then evaluated, in presence or in absence magnesium stearate as lubricant at two different compression speeds (20 and 70 mm/sec). It was observed that both binary mixture compression behavior and capping tendency were influenced by compression speed and by the presence of lubricant.

Differences in anti-capping efficiency between the l-HPCs may be related to their hydroxypropyl content. This parameter influences the interaction between the metronidazole and the polymer particles, and consequently the ability of the binary system to undergo densification under compression.     

Development and characterization of new and scalable topical formulations containing N-acetyl-d-glucosamine-loaded solid lipid nanoparticles

N-Acetyl-d-glucosamine (NAG) has been recently considered for topical treatment of hyperpigmentation disorders due to its inhibitory effect on thyrosinase enzymes in melanocytes. NAG is a precursor of hyaluronic acid, increasing its amount in skin, and consequently, preserving the skin hydration and elasticity. It may also act as an emulsion stabilizer.

Solid lipid nanoparticles (SLN) are advanced delivery systems successfully used in pharmaceutical and cosmetic formulations for the improvement of active molecules penetration into the skin. Therefore, this work aimed to develop and characterize stable and scalable topical formulations containing NAG-loaded SLN.

NAG was incorporated in SLN which were prepared by two high shear homogenizers and characterized regarding its morphology and particle size by transmission electron microscopy and photon correlation spectroscopy, respectively. Oil emulgel and hydrogel were used as carriers of NAG-loaded SLN. Several parameters were evaluated, including the droplet size distribution, rheology, pH and topical delivery by different techniques.

It was observed that SLN size was significantly dependent on NAG incorporation and homogenization process. Most tested SLN parameters appeared to be quite suitable, that is, spherical and well-defined SLN with approximately 258?nm and ?30?mV. Hereafter, both gels containing SLN presented a pseudoplastic flow. Emulgel formulation containing NAG-loaded SLN allowed a higher NAG permeation through the SC compared to the respective control (about 0.8 μgcm^?2?h^?1).

According to the results obtained, it can be suggested that NAG acts as an emulsion stabilizer. This stabilization was also particularly dependent on the homogenizer type which is quite important for scale-up process. This study demonstrated the potential of scalable SLN formulations to improve NAG topical delivery contributing to the improvement of skin properties on several skin disorders.     

In vitro bioactivity of chitosan/poly (d,l-lactide-co-glycolide) composites

Porous composites scaffolds of chitosan/poly(d,l-lactide-co-glycolide) were fabricated for tissue engineering applications by thermally induced phase separation and lyophilization techniques. The in vitro bioactivity evaluation of the scaffolds was carried out by analyzing the apatite layers produced on them using SBF as incubation medium. The apatite formation was analyzed using FTIR spectroscopy and Field emission scanning electron microscopy coupled to energy-dispersive electron X-ray spectroscopy. The cumulative results obtained from the IR spectra and SEM-EDS suggest that the developed composites might have potential applications in tissue engineering.     

Enhanced efficacy of clindamycin hydrochloride encapsulated in PLA/PLGA based nanoparticle system for oral delivery

Clindamycin hydrochloride (CLH) is a clinically important oral antibiotic with wide spectrum of antimicrobial activity that includes gram‐positive aerobes (staphylococci, streptococci etc.), most anaerobic bacteria, Chlamydia and certain protozoa. The current study was focused to develop a stabilised clindamycin encapsulated poly lactic acid (PLA)/poly (D,L‐lactide‐co‐glycolide) (PLGA) nano‐formulation with better drug bioavailability at molecular level. Various nanoparticle (NPs) formulations of PLA and PLGA loaded with CLH were prepared by solvent evaporation method varying drug: polymer concentration (1:20, 1:10 and 1:5) and characterised (size, encapsulation efficiency, drug loading, scanning electron microscope, differential scanning calorimetry [DSC] and Fourier transform infrared [FTIR] studies). The ratio 1:10 was found to be optimal for a monodispersed and stable nano formulation for both the polymers. NP formulations demonstrated a significant controlled release profile extended up to 144 h (both CLH‐PLA and CLH‐PLGA). The thermal behaviour (DSC) studies confirmed the molecular dispersion of the drug within the system. The FTIR studies revealed the intactness as well as unaltered structure of drug. The CLH‐PLA NPs showed enhanced antimicrobial activity against two pathogenic bacteria Streptococcus faecalis and Bacillus cereus. The results notably suggest that encapsulation of CLH into PLA/PLGA significantly increases the bioavailability of the drug and due to this enhanced drug activity; it can be widely applied for number of therapies.Inspec keywords: drug delivery systems, biomedical materials, antibacterial activity, nanoparticles, nanomedicine, microorganisms, polymers, nanofabrication, differential scanning calorimetry, encapsulation, drugs, scanning electron microscopy, Fourier transform infrared spectraOther keywords: Streptococcus faecalis, Bacillus cereus, DSC, stable nanoformulation, monodispersed nanoformulation, pathogenic bacteria, FTIR spectra, molecular dispersion, thermal behaviour, controlled release profile, Fourier transform infrared spectra, differential scanning calorimetry, scanning electron microscopy, drug loading, encapsulation efficiency, polymer concentration, solvent evaporation method, molecular level, drug bioavailability, stabilised clindamycin encapsulated poly lactic acid‐poly (D,L‐lactide‐co‐glycolide) nanoformulation, protozoa, Chlamydia, anaerobic bacteria, gram‐positive aerobes, antimicrobial activity, oral antibiotics, oral delivery, PLA‐PLGA based nanoparticle system, clindamycin hydrochloride     

Microspheres for the oral delivery of insulin: preparation,evaluation and hypoglycaemic effect in streptozotocin-induced diabetic rats

Insulin-loaded microspheres were prepared by alternating deposition film layers that were composed of insulin and poly(vinyl sulfate) potassium on the surface of poly(lactic acid) (PLA) microspheres. The preparation of the insulin-loaded microspheres was optimized by an orthogonal test design, and the relationship between drug loading (DL) and film layers was studied. The particle size, DL and encapsulation efficiency of the obtained insulin-loaded microspheres with 10 films were 5.25?±?0.15?µm, 111.33?±?1.15?mg/g and 33.7?±?0.19%, respectively. Following this, the physical characteristics of the insulin-loaded microspheres were investigated. The results from scanning electron microscopy and a laser particle size analyzer (LPSA) indicated the spherical morphology, rough surface and increasing particle sizes of the insulin-loaded microspheres, which were compared to those of PLA microspheres. An in vitro release study showed that the insulin-loaded microspheres were stable in HCl solution (pH 1.0) and released insulin slowly in phosphate-buffered solution (pH 6.8). Finally, the drug efficacy of the prepared insulin-loaded microspheres via oral administration was evaluated in rats with diabetes induced by streptozotocin, and an obvious dose-dependent hypoglycemic effect was observed. This preliminary data could illustrate the prospect of using microspheres for the oral delivery of insulin.     

A Multi-Criteria Decision Analysis Technique for Stochastic Task Criticality in Project Management

Inherent in project management is the risk that a project fails to meet planned completion deadlines due to delays experienced in individual tasks. As such, certain critical tasks may be candidates for risk management (e.g., the allocation of additional resources such as labor, materials, and equipment) to prevent delays. A common means to identify such critical tasks is with the critical path method (CPM), which identifies a path of tasks in a project network that, when delayed, result in project delays. This work offers a complementary, stochastic approach to CPM that ranks tasks according to their effect on the project completion time distribution, when the distributions of task completion time are delayed. The new hybrid approach is based on the use of a Monte Carlo simulation and a multi-criteria decision analysis technique. Monte Carlo simulation allows for approximating the cumulative distribution function of the total duration of the project, while the multi-criteria decision analysis technique is used to compare and rank the tasks across percentiles of the resulting project completion time distributions. Doing so allows for different percentile weighting schemes to represent decision maker risk preferences. The suggested approach is applied to two project network examples. The examples illustrate that the proposed approach highlights some tasks as risky, which may not always lie on the critical path as identified by CPM. This is valuable for practicing managers as it allows them to properly consider their risk preferences when determining task criticality based on the distribution of project completion time (e.g., emphasizing median vs. upper tail completion time).     

Self-assembly of silver nanoparticles into dendritic flowers from aqueous solution

Similar to folding of proteins into three-dimensional (3D) structure, self-assembly of metallic nanoparticles (NPs) into dendritic or other supramolecular structures is of greater interest, yet less understood. We observed spontaneous, template-free organisation of silver NPs into 3D, dendritic, elegant, flower-like structures from an aqueous solution containing AgNO₃ and L-cysteine (Cys). The resultant NPs and dendritic structures were characterised using UV–Vis spectroscopy and scanning and transmission electron microscopy. The process initiated most likely by diffusion-limited aggregation in the liquid phase, which were further grown into elegant, dendritic flowers probably by evaporation of residual wetting layer of larger NPs. Electrostatic attraction between –COO^? and –NH₃ ⁺ groups of L-Cys on the surface of silver NPs may also have a role in their growth.     

Facile and controllable one-step fabrication of selenium nanoparticles assisted by l-cysteine

A simple and solution-phase approach for large-scale synthesis of selenium nanoparticles (Nano-Se) by reducing sodium selenite (Na₂SeO₃) with l-cysteine has been demonstrated in this study. l-cysteine was used as both the reducing agent and surface modifier to control the formation of Nano-Se. The effects of reactant concentrations and ratios, and reaction time on the size and stability of Nano-Se were also investigated. The morphology and chemical composition of Nano-Se were characterized using various spectroscopic and microscopic methods. The results showed that varying the concentration ratio of l-cysteine to Na₂SeO₃ could control the diameter and morphology of Nano-Se, but not affecting their crystalline phases and chemical compositions. Monodisperse and homogeneous spherical Nano-Se with an average diameter of about 100 nm could be synthesized with the concentration ratio of l-cysteine to Na₂SeO₃ at 4:1. A striking feature of the as-synthesized Nano-Se was their good stability when dispersed in the reaction solutions, which indicates their potential in medical applications.