Production of functional pharmaceutical nano/micro-particles by solvent displacement method using advanced micro-engineered dispersion devices

The rapid advancement of drug delivery systems (DDS) has raised the possibility of using functional engineered nano/micro-particles as drug carriers for the administration of active pharmaceutical ingredients (APIs) to the affected area. The major goals in designing these functional particles are to control the particle size, the surface properties and the pharmacologically active agents release in order to achieve the site-specification of the drug at the therapeutically optimal rate and dose regimen. Two different equipment (i.e. glass capillary microfluidic device and micro-engineered membrane dispersion cell) were utilised in this study for the formation of functional nano/micro-particles by antisolvent precipitation method. This method is based on micromixing/direct precipitation of two miscible liquids, which appear as a straightforward method, rapid and easy to perform, does not require high stirring rates, sonication, elevated temperatures, surfactants and Class 1 solvents can be avoided. Theoretical selection of a good solvent and physicochemical interaction between solvent-water-polymer with the aid of Bagley s two-dimensional graph were successfully elucidated the nature of anti-solvent precipitation method for the formation of desired properties of functional pharmaceutical nano/micro-engineered particles. For the glass capillary microfluidic experiment, the organic phase (a mixture of polymer and tetrahydrofuran/acetone) was injected through the inner glass capillary with a tapered cross section culminated in a narrow orifice. The size of nanoparticles was precisely controlled by controlling phase flow rates, orifice size and flow configuration (two- phase co-flow or counter-current flow focusing). The locations at which the nanoparticles would form were determined by using the solubility criteria of the polymer and the concentration profiles found by numerical modelling. This valuable results appeared as the first computational and experimental study dealing with the formation of polylactide (PLA) and poly(ε-caprolactone) (PCL) nanoparticles by nanoprecipitation in a co-flow glass capillary device. The optimum formulations and parameters interactions involved in the preparation of paracetamol encapsulated nanoparticles (PCM-PCL NPs) using a co-flow microfluidic device was successfully simulated using a 25-full factorial design for five different parameters (i.e. PCL concentration, orifice size, flow rate ratios, surfactant concentration and paracetamol amount) with encapsulation efficiency and drug loading percentage as the responses. PCM-loaded composite NPs composed of a biodegradable poly(ᴅ,ʟ-lactide) (PLA) polymer matrix filled with organically modified montmorillonite (MMT) nanoparticles were also successfully formulated by antisolvent nanoprecipitation in a microfluidic co-flow glass capillary device. The incorporation of MMT in the polymer matrix improved the drug encapsulation efficiency and drug loading, and extended the rate of drug release in simulated intestinal fluid (pH 7.4). The encapsulation of MMT and PCM in the NPs were well verified using transmission electron microscopy (TEM), energy dispersive x-ray spectroscopy (EDS), x-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR). PCL drug-carrier nanoparticles were also produced by rapid membrane micromixing combined with nanoprecipitation in a stirred cell employing novel membrane dispersion. The size of the NPs was precisely controlled by changing the aqueous-to-organic volumetric ratio, stirring rate, transmembrane flux, the polymer content in the organic phase, membrane type and pore morphologies. The particle size decreased by increasing the stirring rate and the aqueous-to-organic volumetric ratio, and by decreasing the polymer concentration in the aqueous phase and the transmembrane flux. The existence of the shear stress peak within a transitional radius and a rapid decline of the shear stress away from the membrane surface were revealed by numerical modelling. Further investigation on the PCL nanoparticles loaded immunosuppressive rapamycin (RAPA) drug were successfully synthesised by anti-solvent nanoprecipitation method using stainless steel (SS) ringed micro-engineered membrane. Less than 10 µm size of monohydrate piroxicam (PRX) micro-crystals also was successfully formed with the application of anti-solvent precipitation method combined with membrane dispersion cell that has been utilised in the formation of functional engineered nanoparticles. This study is believed to be a new insight into the development of integrated membrane crystallisation system

Preparation of biodegradable polymeric nanoparticles for pharmaceutical applications using glass capillary microfluidics

The aim of this study was to develop a new microfluidic approach for the preparation of nanoparticles with tuneable sizes based on micromixing/direct nanoprecipitation in a coaxial assembly of tapered-end glass capillaries. The organic phase was 1 wt% poly(ε-caprolactone) (PCL) or poly(dl-lactic acid) (PLA) in tetrahydrofuran and the antisolvent was Milli-Q water. The size of nanoparticles was precisely controlled over a range of 190–650 nm by controlling phase flow rates, orifice size and flow configuration (two-phase co-flow or counter-current flow focusing). Smaller particles were produced in a flow focusing device, because the organic phase stream was significantly narrower than the orifice and remained narrow for a longer distance downstream of the orifice. The mean size of PCL particles produced in a flow focusing device with an orifice size of 200 μm, an organic phase flow rate of 1.7 mL h−1 and an aqueous-to-organic flow rate ratio of 10 was below 200 nm. The size of nanoparticles decreased with decreasing the orifice size and increasing the aqueous-to-organic phase flow rate ratio. Due to higher affinity for water and amorphous structure, PLA nanoparticles were smaller and exhibited a smoother surface and more rounded shape than PCL particles

Enhanced yield and purity in API crystallisation with a new application of microengineered membrane system for the formation of uniform nanocrystals size distribution and smooth crystal surface

The purpose of this study was to introduce a new approach of micro-engineered membrane system which has a perfect hexagonal array of uniform pores to tailor size of biodegradable and bioresorbable drug-excipient based on the formation of polymeric nanoparticles (NPs) by solventdisplacement (nanoprecipitation) method ...

A new approach for the preparation of functional pharmaceutical nanoparticles using glass capillary millifludic devices

Functional pharmaceuticals nanoparticles are solid carriers with a mean size of less than 1 μm, which are capable to dissolve, entrap, encapsulate or attach active ingredients (drug) to its nanoparticle matrix. In this study, a new approach for the formation of acetaminophen (PCM) encapsulated poly(ɛ-caprolactone) (PCL) nanoparticles with controllable size dependent has been performed in a glass capillary milifluidic device by nanoprecipitation (“diffusion-stranding”) method

A new approach to control nucleation of crystals based on engineered drug carrier nanoparticles using a co-flow microfluidic device

A new approach to control nucleation of crystals based on engineered drug carrier nanoparticles using a co-flow microfluidic devic

Encapsulation and controlled release of rapamycin from polycaprolactone nanoparticles prepared by membrane micromixing combined with antisolvent precipitation

Rapamycin loaded polycaprolactone nanoparticles (RAPA-PCL NPs) with a polydispersity index of 0.006−0.073 were fabricated by anti-solvent precipitation combined with micromixing using a ringed stainless steel mem-brane with 10-μm diameter laser-drilled pores. The organic phase composed of 6 g L−1 of PCL and 0.6−3.0 g L-1 of RAPA in acetone was injected through the membrane at 140 L m−2 h−1 into 0.2 wt% aqueous polyvinyl alcohol solution stirred at 1300 rpm, resulting in a Z-average mean of 189−218 nm, a drug encapsulation efficiency of 98.8−98.9 % and a drug loading in the NPs of 9−33 %. The encapsulation of RAPA was confirmed by UV‐Vis spectroscopy, XRD, DSC, and ATR-FTIR. The disappearance of sharp characteristic peaks of crystalline RAPA in the XRD pattern of RAPA-PCL NPs revealed that the drug was molecularly dispersed in the polymer matrix or RAPA and PCL were present in individual amorphous domains. The rate of drug release in pure water was negligible due to low aqueous solubility of RAPA. RAPA-PCL NPs released more than 91 % of their drug cargo after 2.5 h in the release medium composed of 0.78−1.5 M of the hydrotropic agent N,N-diethylnicotinamide, 10 vol% of ethanol, and 2 vol% of Tween 20 in phosphate buffered saline. The dissolution of RAPA was slower when the drug was embedded in the PCL matrix of the NPs than dispersed in the form of pure RAPA nanocrystals

Enhancement of BDNF Concentration and Restoration of the Hypothalamic-Pituitary-Adrenal Axis Accompany Reduced Depressive-Like Behaviour in Stressed Ovariectomised Rats Treated with Either Tualang Honey or Estrogen

A possible interaction between glucocorticoids and estrogen-induced increases in brain-derived-neurotrophic factor (BDNF) expression in enhancing depressive-like behaviour has been documented. Here we evaluated the effects of Tualang honey, a phytoestrogen, and 1

Formation of functional pharmaceutical nanoparticles using membrane dispersion cell combined with solvent displacement method

Formation of functional pharmaceutical nanoparticles using membrane dispersion cell combined with solvent displacement metho

Zoophilia in a Patient with Frontotemporal Dementia

Objective: A 65-year-old divorced man who presented with a 4-year history of personality and behavioural changes with inappropriate sexual behaviour was studied. Result: Cognitive impairment was indicated by low scores in MMSE and RUDAS. Neuropsychological assessment showed poor melokinetic ability, delayed response, personality change and, poor visual learning and memory signifying frontal lobe with predominantly right temporal deficits. CT brain showed multifocal cerebellar infarction and old right occipital infarct. However, brain MRI was not done as the patient could not afford it. Conclusion: A patient with bvFTD and hypersexuality is at risk of zoophilia if they also have the traditional risk factors of zoophilia such as low education, residing in a rural area and lack of opportunities to have sex with human partners

The Potential Role of Melatonin on Memory Function: Lessons from Rodent Studies

Pineal melatonin biosynthesis is regulated by the circadian clock located in the suprachiasmatic nucleus of the hypothalamus. Melatonin has been found to modulate the learning and memory process in human as well as in animals. Endogenous melatonin modulates the process of newly acquired information into long-term memory, while melatonin treatment has been found to reduce memory deficits in elderly people and in various animal models. However, the mechanisms mediating the enhancing effect of melatonin on memory remain elusive. This review intends to explore the possible mechanisms by looking at previous data on the effects of melatonin treatment on memory performance in rodents