Impact of grinding balls on the size reduction of Aprepitant in wet ball milling procedure.

One of the widely used approaches for improving the dissolution of poorly water-soluble drugs is particle size reduction. Ball milling is a mechanical, top-down technique used to reduce particle size. The effect of ball number, ball size, and milling speed on the properties of milled Aprepitant is evaluated. A full factorial design was employed to investigate the influence of affecting factors on particle size reduction. The initial suspension was made by suspending the drug in distilled water using excipients followed by milling in a planetary ball mill. Ball size, ball number, and milling speed modulated particle size distribution of Aprepitant. Increasing the number of balls from minimum to maximum for each ball size led to approximately a 28% reduction in mean particle size, a 37% decrease in D90%, and a 25% decrease in the ratio of volume mean particle diameter to numeric mean particle diameter. On average, using 10 mm balls instead of 30 mm balls reduced mean particle size by 1.689 µm. As a result, ball size, ball number, and milling speed are three effective factors in the process of ball milling. By increasing the ball number and decreasing the ball size, efficient micronization of drug particles takes place and the particle size is more uniform.

Carrier-Free Inhalable Dry Microparticles of Celecoxib: Use of the Electrospraying Technique.

Upregulation of cyclooxygenase (COX-2) plays an important role in lung cancer pathogenesis. Celecoxib (CLX), a selective COX-2 inhibitor, may have beneficial effects in COVID-19-induced inflammatory storms. The current study aimed to develop carrier-free inhalable CLX microparticles by electrospraying as a dry powder formulation for inhalation (DPI). CLX microparticles were prepared through an electrospraying method using a suitable solvent mixture at two different drug concentrations. The obtained powders were characterized in terms of their morphology, solid state, dissolution behavior, and aerosolization performance. Electrosprayed particles obtained from the ethanol-acetone solvent mixture with a drug concentration of 3 % w/v exhibited the best in vitro aerosolization properties. The value of the fine particle fraction obtained for the engineered drug particles was 12-fold higher than that of the untreated CLX. When the concentration of CLX was increased, a remarkable reduction in FPF was obtained. The smallest median mass aerodynamic diameter was obtained from the electrosprayed CLX at a 3% concentration (2.82 µm) compared to 5% (3.25 µm) and untreated CLX (4.18 µm). DSC and FTIR experiments showed no change in drug crystallinity or structure of the prepared powders during the electrospraying process. The findings of this study suggest that electrospraying has potential applications in the preparation of DPI formulations.

S1PR1 modulators in multiple sclerosis: Efficacy, safety, comparison, and chemical structure insights.

Multiple sclerosis (MS) is a neurological disease that leads to severe physical and cognitive disabilities. Drugs used in the treatment of MS vary from small synthetic molecules to large macromolecules such as antibodies. Sphingosine 1-phosphate receptor modulators are frequently used for the treatment of MS. These medicines prevent the egress of lymphocytes from secondary lymphoid organs leading to immune system suppression. Currently, four S1PR modulators are on the market and several potential drug candidates are in clinical trials for the treatment of MS. These compounds differ in chemical structure, adverse effects, and efficacy points of view. The current article reviews the latest studies on S1PR1 modulators and compares them with other MS drugs in terms of efficacy, tolerability, and safety. A special focus was dedicated to discussing the structure-activity relationships of these compounds and performing a three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis to gain better insight into the ligand-receptor interaction mode.

Dry Powder Formulation of Simvastatin Nanoparticles for Potential Application in Pulmonary Arterial Hypertension.

It has been hypothesized that simvastatin could be used to treat pulmonary arterial hypertension (PAH). This study is intended to formulate a simvastatin nanoparticle dry powder inhalation (DPI) formulation. Simvastatin nanoparticles were prepared via an emulsification and homogenization-extrusion method, followed by spray drying of the colloidal suspension of simvastatin nanoparticles containing mannitol to get it into a respirable size. Particle size distribution, morphology, and crystallinity of the fabricated nanoparticles of the obtained microparticles for DPI formulation were assessed by dynamic light scattering (DLS), scanning electron microscopy (SEM), and X-ray diffraction pattern (XRPD), respectively. Aerosolization performance of the DPI formulation was assessed by the Next Generation Impactor (NGI) equipped with an Aerolizer®. Simvastatin nanoparticles were around 100 nm with a very narrow size distribution (PDI = 0.105). The X-ray diffraction pattern revealed that the crystallinity of simvastatin was decreased by the spray drying procedure. Microscopic images displayed that gathered nanoparticles were in the suitable inhalable range and had the appropriate shape and surface properties for pulmonary delivery. Aerosolization assessment by the NGI indicated a suitable inhalation performance (fine particle fraction of 20%). In conclusion, the results confirmed that the spray drying technique for simvastatin can be optimized to obtain simvastatin aggregated nanoparticles without any coarse carrier to be used in DPI formulation for better deposition of the drug in the lungs for local treatment of PAH.

Carrier Effect in Development of Rifampin Loaded Proliposome for Pulmonary Delivery: A Quality by Design Study.

Purpose: Pulmonary tuberculosis (TB) is a worldwide life-threatening infection. Therecommended anti-TB regimen contains oral administration of classical first-line drugs suchas rifampin for 6-24 months which often leads to low patient compliance due to high adverseeffects; therefore, lung localized pulmonary delivery of anti-TB agents may be a suitablealternative. Proliposomes free-flowing powders are well-known carriers for lung delivery sincethey can form liposomes by hydration. Liposomes are safe and useful carriers for lung deliverydue to their phospholipid structure. Methods: Porous lactose and mannitol as proliposome carriers were prepared by spray dryingtechnique using sucrose and citric acid as templating agents. Design Expert® software wasused to develop forty formulations based on the porous and non-porous carriers, which werecharacterized with respect to their weight yield, density, and flowability. Rifampin-loadedhydrated liposomes were produced and evaluated for size, morphology, loading capacityand encapsulation efficiency. The optimized proliposomes in vitro release and aerosolizationproperties were evaluated. Solid-state analysis was confirmed by differential scanningcalorimetry (DSC). Results: Porous lactose surface area was 80 folds higher than non-porous one, respectively.Optimized porous-based proliposome indicated the acceptable aerosolization properties,including mass median aerodynamic diameter (MMAD) of 6.21 ± 0.36 µm and fine particlefraction (FPF) of 9.17 ± 0.18% with a fast rifampin release (80%) within one hour. DSC resultsproved that there was no change in the solid-state of rifampin during the production process. Conclusion: Hence, it seems; rifampin loaded inhalable proliposomes may be a suitable systemfor delivering liposomal rifampin into the lungs.

A mechanistic perspective, clinical applications, and phage-display-assisted discovery of TNFα inhibitors.

TNFα participates in a variety of physiological processes, but at supra-physiological concentrations it has been implicated in the pathology of inflammatory and autoimmune diseases. Therefore, much attention has been devoted to the development of strategies that overcome the effects of aberrant TNFα concentration. Promising strategies include drugs that destabilize the active (trimeric) form of TNFα and antagonists of TNFα receptor type I. Underpinning these strategies is the successful application of phage-display technology to identify anti-TNFα peptides and antibodies. Here, we review the development of inhibitors of the TNFα-TNF receptor system, with particular focus on the phage-display-assisted identification of molecules that interfere with this system by acting as inhibitors of TNFα or by sequestering TNFα away from its receptor.

A quantitative approach to predicting lung deposition profiles of pharmaceutical powder aerosols.

Dry powder inhalers (DPI) are widely used systems for pulmonary delivery of therapeutics. The inhalation performance of DPIs is influenced by formulation features, inhaler device and inhalation pattern. The current review presents the affecting factors with great focus on powder characteristics which include particle size, shape, surface, density, hygroscopicity and crystallinity. The properties of a formulation are greatly influenced by a number of physicochemical factors of drug and added excipients. Since available particle engineering techniques result in particles with a set of modifications, it is difficult to distinguish the effect of an individual feature on powder deposition behavior. This necessitates developing a predictive model capable of describing all influential factors on dry powder inhaler delivery. Therefore, in the current study, a model was constructed to correlate the inhaler device properties, inhalation flow rate, particle characteristics and drug/excipient physicochemical properties with the resultant fine particle fraction. The r2 value of established correlation was 0.74 indicating 86% variability in FPF values is explained by the model with the mean absolute errors of 0.22 for the predicted values. The authors believe that this model is capable of predicting the lung deposition pattern of a formulation with an acceptable precision when the type of inhaler device, inhalation flow rate, physicochemical behavior of active and inactive ingredients and the particle characteristics of DPI formulations are considered.

Co-electrospraying technology as a novel approach for dry powder inhalation formulation of montelukast and budesonide for pulmonary co-delivery.

In the current study electrospraying methodology was used for particle engineering of montelukast and budesonide to prepare a combined inhalable dry powder formulation applicable as a smart regimen in asthma treatment. For this, electrospraying was carried out using different solvents and drug concentrations. No carrier was added for the formulation of montelukast-budesonide combination as montelukast played the role of both active ingredient and carrier. Scanning electron microscopy, particle size analysis, gas chromatography, powder X-ray diffraction, Fourier transform infrared spectroscopy, and differential scanning calorimetry were used to evaluate the physicochemical properties of the produced drug particles. In vitro drug deposition pattern was assessed using next generation impactor, and the dissolution profile of the selected formulations was characterized via modified diffusion franz cell method. The FPF value for the co-electrosprayed carrier free formulation of montelukast-budesonide was 38% with a significantly enhanced dissolution rate for budesonide compared to the budesonide alone formulations. The pharmacological effects of hypothesized combined formulation was assessed by measuring its power to inhibit the production of reactive oxygen species in human normal lung cells. The results showed that the combination of montelukast and budesonide can exert a synergistic effect. The findings in the current study emphasize that using montelukast as a carrier for budesonide not only has greatly improved the aerosolization behavior and dissolution rate of budesonide but also has resulted in synergistic pharmacological effects, indicating the suitability of this combination as an anti-asthmatic therapeutic.

Dry powder inhaler aerosol deposition in a model of tracheobronchial airways: Validating CFD predictions with in vitro data.

Effective drug delivery into the lungs plays an important role in management of pulmonary diseases that affect millions all around the world. The main objective of this investigation is to study airflow structure, as well as transport and deposition of micron-size particles at different inhalation flow rates in a realistic model of human tracheobronchial airways. The airway model was developed based on computed tomography (CT) images of a healthy 48-years-old female, which includes extrathoracic, trachea, and bronchial airways up to fourth generations. Computational fluid dynamics (CFD) simulations were performed to predict transport and deposition of inhaled particles and the results were compared to our previous in vitro experiments. Airflow structure was studied through velocity contours and streamlines in the extrathoracic region, where the onset of turbulence, reverse flow and subsequently vortex formation, and laryngeal jet are found to be critical phenomenons in the formation of airflow and deposition patterns. The deposition data was presented by deposition efficiency (DE) and deposition fraction (DF) against impaction parameter and Stokes number. At all of the inhalation flow rates, highest values of deposition fractions were devoted to the mouth-throat (MT), tracheobronchial tree (TB), and trachea (Tra), respectively (At 60 L/min: MT = 6.7%, TB = 5.3%, Tra = 1.9%). The numerical deposition data showed a good agreement with the experimental deposition data in most of the airway regions (e.g. less than 10% difference between the deposition fractions in the tracheobronchial region). Enhancing inhalation flow rate in all of the airway regions led to an uptrend in deposition rate due to the increase of particles inertia and turbulence level. In addition, the increase of particle deposition with enhancing inhalation flow rate in all of the sections including extrathoracic, trachea, and tracheobronchial tree suggesting that inertial impaction is the dominant deposition mechanism due to the increase of inertial force. In conclusion, the validated CFD model provided an opportunity to cover the limitations of our previous experimental investigation on aerosol deposition of commercial inhalers and became an efficient method for further studies.

Development of a Carrier Free Dry Powder Inhalation Formulation of Ketotifen for Pulmonary Drug Delivery.

BACKGROUND: Pulmonary drug delivery route is gaining much attention because it enables to target the active ingredients directly to lung both for local and systemic treatments, which maximize the therapeutic effect and minimize unwanted systemic toxicity. Dry powder inhaler (DPI) systems for asthma therapy have shown several merits to the other pulmonary delivery systems such as nebulizers and metered dose inhalers. PURPOSE: The present study aims to develop and optimize a DPI formulation for Ketotifen fumarate through spray drying technique. METHODS: Particles size and morphology, crystallinity, and drug-excipient interaction of fabricated DPI formulations were evaluated by scanning electron microscopy, X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier Transform Infrared Spectroscopy methods, respectively. The aerosolization indexes and aerodynamic properties of dry powders were determined by next generation impactor. The powder flowability was assessed by measuring the Hausner ratio and compressibility index. RESULTS: Among solvent systems, ethanol-water mixture produced the most desirable powder property for inhalation after spray drying. Although co-spray dried formulations with ammonium bicarbonate resulted in the porous structure, it was not beneficial for DPI formulations due to the interaction with Ketotifen. DSC and XRD experiments proved the amorphous structure of prepared powders, which were stable for 12 months. CONCLUSION: The results of this study demonstrate the potential of Ketotifen DPI formulation and pave a way to use it easily in an industrial scale.

Anti-tumor Effect of Quercetin Loaded Chitosan Nanoparticles on Induced Colon Cancer in Wistar Rats.

Purpose: This study was aimed to evaluate the site-specific drug delivery of 5-FU with chitosan (CS) as a carrier and quercetin (Qu) against induced colon cancer in Wistar rats. Methods: Cross-linked CS-Qu nanoparticles (NPs) were prepared by ionotropic gelation method. Physicochemical characterization of NPs was performed by Fourier-transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), in vitro drug release, and drug loading efficiency (LE). 1, 2-Dimethylhydrazine (DMH) and dextran sulfate sodium (DSS) were applied to induce adenocarcinoma tumors on inbred male Wistar rats' colon. The treatment group of rats was administered through enema with NPs dispersion. Hematoxylin and eosin staining were performed to the histopathological examination of tumors. Results: Zeta potential and particle size for NPs were +53.5 ± 5 mV and 179 ± 28 nm, respectively. About 96% Qu LE was obtained with a maximum release of 5.63 ±1.59% and 4.62 ± 1.33% after 24 hours in PB solution with pH values of 6 and 7.4, respectively. The numbers of 8 to 21 tumors were observed in all rats administered with DMH and DSS. Significantly decreasing of microvascular density and mitosis count was detected in the treatment group in comparison with cancerous group (P = 0.032 for the former compared to P = 0.016 for the later), respectively. Furthermore, the treatment group showed a high apoptosis rate (P = 0.038). Conclusion: The developed Qu-loaded CS NPs were good candidates for site-specific and sustained drug release in enema treatment. Decreasing of microvascular density and mitosis count, along with increasing the apoptosis percent in the treatment group proved that the NPs could have promising results in site-specific and sustained drug delivery against colorectal cancer.

Experimental investigation of aerosol deposition through a realistic respiratory airway replica: An evaluation for MDI and DPI performance.

PURPOSE: In the present work, a comparison between MDI and DPI for evaluating performance of the devices were carried out by experimentally investigating the deposition parameters through a realistic airway replica. METHODS: Computed tomography (CT) images of the respiratory airway of a healthy subject were used to develop the realistic model. The airway replica was included extrathoracic, trachea, and tracheobronchial tree up to fourth generations which was fabricated by rapid prototyping. Afterward, in vitro experiments were performed to validate the airway model by comparing the total deposition (G0 to G3) of present replica with available data in the literature. Drug deposition (Salbutamol) in the model was measured by determining concentration of the segments sample by High Performance Liquid Chromatography (HPLC) assay. RESULTS: Deposition parameters were used for investigating the deposition patterns of the inhaled particles. Results showed that inertial impaction is the dominant mechanism in the most regions of the replica. It was found that the MDI delivered more drug to the tracheobronchial tree compared to the DPI for three different flow rate. CONCLUSION: The developed realistic respiratory airways model provided an opportunity to more accurately evaluate the performance of drug delivery devices and studying mechanisms of the drug deposition.

Application of Spray Drying Technique for Flowability enhancement of Divalproex Sodium.

BACKGROUND: Tablets and capsules are the most accepted and widely used solid dosage forms in the medical therapy. Flow property of the powders is playing a key role in the various pharmaceutical fields especially in the fomulation of tablets and capsules. The high hygroscopic crystalline structure of anhydrous Divalproex sodium (DVX) makes it to be appear as waxy white flakes with almost no powder flowability which cause serious problems during the tabletting and capsule filling procedures. PURPOSE: The main objective of this study was to improve the flowability of DVX powder. METHODS: DVX was mixed with mannitol or lactos in different ratios, dissolved in water and differet binary mixtures of ethanol:water, and finally spray dried with different spray drying conditions. Particle size and powders morphology were assessed by Scanning Electron Microscopy (SEM). The poweder flowability was assessed by measurmet of Hausner ratio (HR), Carr's index (CI) and angle of repose (AOR) indexes. Furthermore, the content uniformity of DVX in spray-dried powders was determined by using a validated HPLC technique. RESULTS: The results showed that spray drying technique improved DVX flowability by forming spherical particles with narrow size distribution AOR value of DVX was decrease from not flowable to 36.1° in spray dried solid dispersion indicating the improvmet of powder flowability from very poor to fair/good condition. CONCLUSION: Findings suggest that the spray drying technique improves DVX flowability and may pave the way for improvement in the tabletting procedure of DVX.