Fine excipient materials in carrier-based dry powder inhalation formulations: The interplay of particle size and concentration effects.

The contributions of fine excipient materials to drug dispersibility from carrier-based dry powder inhalation (DPI) formulations are well recognized, although they are not completely understood. To improve the understanding of these contributions, we investigated the influences of the particle size of the fine excipient materials on characteristics of carrier-based DPI formulations. We studied two particle size grades of silica microspheres, with volume median diameters of 3.31 µm and 8.14 µm, as fine excipient materials. Inhalation formulations, each composed of a lactose carrier material, one of the fine excipient materials (2.5% or 15.0% w/w), and a drug (fluticasone propionate) material (1.5% w/w) were prepared. The physical microstructure, the rheological properties, the aerosolization pattern, and the aerodynamic performance of the formulations were studied. At low concentration, the large silica microspheres had a more beneficial influence on the drug dispersibility than the small silica microspheres. At high concentration, only the small silica microspheres had a beneficial influence on the drug dispersibility. The results reveal influences of fine excipient materials on mixing mechanics. At low concentration, the fine particles improved deaggregation and distribution of the drug particles over the surfaces of the carrier particles. The large silica microspheres were associated with a greater mixing energy and a greater improvement in the drug dispersibility than the small silica microspheres. At high concentration, the large silica microspheres kneaded the drug particles onto the surfaces of the carrier particles and thus impaired the drug dispersibility. As a critical attribute of fine excipient materials in carrier-based dry powder inhalation formulations, the particle size demands robust specification setting.

Molecular modeling of novel 2-aminopyridine derivatives as potential JAK2 inhibitors: a rational strategy for promising anticancer agents.

Janus kinase 2(JAK2) is a potential target for anticancer drugs in the treatment of numerous myeloproliferative diseases due to its central role in the JAK/STAT signaling cascade. In this study, the binding behavior of 2 amino-pyridine derivatives as JAK2 inhibitors was investigated by using multifaceted strategies including 3D-QSAR, molecular docking, Fingerprint analysis, MD simulations, and MM-PBSA calculations. A credible COMFA (q2 = 0.606 and r2 = 0.919) and COMSIA (q2 = 0.641 and r2 = 0.992) model was developed, where the internal and external validation revealed that the obtained 3D-QSAR models could be capable of predicting bioactivities of JAK2 inhibitors. The structural criteria provided by the contour maps of model were used to computationally develop more potent 100 new JAK2 inhibitors. Docking studies were conducted on the model data set and newly developed compounds (in-house library) to demonstrate their binding mechanism and highlight the key interacting residues within JAK2 active site. The selected docked complexes underwent MD simulation (100 ns), which contributed in the further study of the binding interactions. Binding free energy analyses (MMGB/PBSA) revealed that key residues such as Glu930, Leu932 (hinge region), Asp939 (solvent accessible region), Arg980, Asn981and Asp994 (catalytic site) have a significantly facilitate ligand-protein interactions through H-bonding and van der Waals interactions. The preliminary in-silico ADMET evaluation revealed encouraging results for all the modeled and in-house library compounds. The findings of this research have the potential to offer valuable recommendations for the advancement of novel, potent, and efficacious JAK2 inhibitors. Overall, this work has successfully employed a wide range of computer-based methodologies to understand the interaction dynamics between 2-amino-pyridine derivatives and the JAK2 enzyme, which is a crucial target in myeloproliferative disorders.Communicated by Ramaswamy H. Sarma.

Strategies to improve the stability of amorphous solid dispersions in view of the hot melt extrusion (HME) method.

Oral administration of drugs is preferred over other routes for several reasons: it is non-invasive, easy to administer, and easy to store. However, drug formulation for oral administration is often hindered by the drug's poor solubility, which limits its bioavailability and reduces its commercial value. As a solution, amorphous solid dispersion (ASD) was introduced as a drug formulation method that improves drug solubility by changing the molecular structure of the drugs from crystalline to amorphous. The hot melt extrusion (HME) method is emerging in the pharmaceutical industry as an alternative to manufacture ASD. However, despite solving solubility issues, ASD also exposes the drug to a high risk of crystallisation, either during processing or storage. Formulating a successful oral administration drug using ASD requires optimisation of the formulation, polymers, and HME manufacturing processes applied. This review presents some important considerations in ASD formulation, including strategies to improve the stability of the final product using HME to allow more new drugs to be formulated using this method.

A review on taste masked multiparticulate dosage forms for paediatric.

Taste refers to those sensations perceived through taste buds on the tongue and oral cavity. The unpleasant taste of drugs leads to the refusal of taking the medicine in the paediatric population. It is widely known that a pharmaceutical product's general acceptability is the result of numerous contributing components such as swallowability, palatability (taste, flavour, texture, and mouthfeel), appearance, ease of administration, and patient characteristics. Multiparticulate as a dosage form is a platform technology for overcoming paediatrics' incapacity to swallow monolithic dosage forms, masking many medications' inherent nasty taste, and overcoming the obstacles of manufacturing a commercially taste masked dosage form. This review will discuss the considerations that must be taken into account to prepare taste masked multiparticulate dosage forms in the best way for paediatric use.

Particle Engineering by Nano Spray Drying: Optimization of Process Parameters with Hydroethanolic versus Aqueous Solutions.

Nano spray drying has emerged as an outstanding platform for engineering micro- and nanoparticles, with growing applications in various areas of drug delivery. As a new technology involving distinct technical design, parameters of the nano spray drying process are not fully elucidated. In a quality-by-design approach, the aim of the current study was to gain thorough understanding of critical determinants of product characteristics in the Büchi Nano Spray Dryer B-90. Following a factorial experimental design, a series of spray drying experiments were conducted to gain new insights into the influences of the inlet temperature, the spray solvent, and the solute concentration in the spray solution on the yield, the moisture content, and the particle size of the nano spray-dried powder material. Special consideration was given to the potential of using hydroethanolic in comparison with aqueous solvent systems and to particle engineering for pulmonary drug delivery. Lactose and mannitol, widely used as excipients in dry powder inhalation formulations, were used as model materials. Lactose and mannitol are known to spray dry in amorphous and crystalline forms, respectively. The yields of spray drying of lactose and mannitol amounted generally to 71.1 ± 6.6% w/w and 66.1 ± 3.5% w/w, respectively. The spray-dried materials exhibited generally a number-weighted median particle diameter of 1.6 ± 0.2 µm and a volume-weighted median particle diameter of 5.1 ± 1.0 µm. A detailed analysis of the results improved understanding of the interplay between process parameters in the Nano Spray Dryer. The results demonstrate that optimization of spray generation is the key to yield optimization. On the other hand, particle size is determined by the spray mesh pore size and the spray solution degree of saturation. Selection of an appropriate spray solvent and using spray solution additives could optimize spray flow. In parallel, the spray solvent and the solute concentration in the spray solution determine the degree of saturation. Guidance on optimization of particle engineering by nano spray drying is provided.

Stability of Paracetamol Instant Jelly for Reconstitution: Impact of Packaging, Temperature and Humidity.

The stability of the medicinal product is a major concern in the pharmaceutical industry and health authorities, whose goal is to guarantee that drugs are delivered to patients without loss of therapeutic properties. This study aims to evaluate the effect of environmental conditions and packaging on the stability of paracetamol instant jelly sachets based on both chemical and physical stability. The paracetamol instant jelly was packaged in plastic sachets (packaging 1) and sealed aluminium bags in screw-capped amber glass bottles (packaging 2), which were stored in real-time and accelerated stability chambers for 3 months. Samples were taken out from the chambers and were characterised for appearance, moisture content, texture, viscosity, in vitro drug release, paracetamol content, and 4-aminophenol level at different time points. The real-time storage condition at a lower temperature maintained the stability of the paracetamol instant jelly, while the accelerated condition led to a significant change in the formulation properties. In addition, the proper packaging of paracetamol instant jelly maintained the paracetamol's stability, regardless of environmental conditions, for three months. The results show that the environmental conditions and packaging play a significant role in maintaining paracetamol instant jelly stability.

Ibuprofen-Loaded Chitosan-Lipid Nanoconjugate Hydrogel with Gum Arabic: Green Synthesis, Characterisation, In Vitro Kinetics Mechanistic Release Study and PGE2 Production Test.

Ibuprofen is a well-known non-steroidal anti-inflammatory (NSAID) medicine that is often used to treat inflammation in general. When given orally, it produces gastrointestinal issues which lead to lower patient compliance. Ibuprofen transdermal administration improves both patient compliance and the efficacy of the drug. Nanoconjugation hydrogels were proposed as a controlled transdermal delivery tool for ibuprofen. Six formulations were prepared using different compositions including chitosan, lipids, gum arabic, and polyvinyl alcohol, through ionic interaction, maturation, and freeze-thaw methods. The formulations were characterised by size, drug conjugation efficiency, differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR). Further analysis of optimised hydrogels was performed, including X-ray diffraction (XRD), rheology, gel fraction and swelling ability, in vitro drug release, and in vitro macrophage prostaglandin E2 (PGE2) production testing. The effects of ibuprofen's electrostatic interaction with a lipid or polymer on the physicochemical and dissolution characterisation of ibuprofen hydrogels were evaluated. The results showed that the S3 (with lipid conjugation) hydrogel provided higher conjugation efficiency and prolonged drug release compared with the S6 hydrogel.

Inhalable, Spray-Dried Terbinafine Microparticles for Management of Pulmonary Fungal Infections: Optimization of the Excipient Composition and Selection of an Inhalation Device.

Terbinafine is a broad-spectrum antifungal agent with therapeutic potential against pulmonary aspergillosis. The main aim of the current study was to investigate the potential of l-leucine, alone and in combination with mannitol, to improve the performance of spray-dried terbinafine microparticles for inhalation. The study also aimed to investigate the potential of the low resistance Cyclohaler® and the high resistance Handihaler® as inhalation devices for spray-dried microparticles. To this end, eight powder inhalation formulations of terbinafine were prepared by nano spray drying via a factorial experimental design. The formulations were evaluated in vitro for their potential to deliver the antifungal drug to the lungs using the Cyclohaler® and the Handihaler®. Leucine was superior as an excipient to mannitol and to mixtures of leucine and mannitol. Using leucine as an excipient resulted in formulations with fine particle fractions of up to 60.84 ± 0.67% w/w and particle mass median aerodynamic diameters of down to 1.90 ± 0.20 µm, whereas using mannitol as an excipient resulted in formulations with fine particle fractions of up to 18.75 ± 3.46% w/w and particle mass median aerodynamic diameters of down to 6.79 ± 0.82 µm. When leucine was used as an excipient, using 50% w/w rather than 25% w/w ethanol in water as a spray solvent enhanced the dispersibility of the particles, with a mean absolute increase in the formulation fine particle fraction of 9.57% w/w (95% confidence interval = 6.40-12.73% w/w). This was potentially underlain by enrichment of the particle surfaces with leucine. The Cyclohaler® outperformed the Handihaler® as an inhalation device for the developed formulations, with a mean absolute increase in the fine particle fraction of 9.17% w/w (95% confidence interval = 8.17-10.16% w/w).