Solid State Characterization Studies Research Articles

Quality by Design (QbD) Approach to Develop Colon-Specific Ketoprofen Hot-Melt Extruded Pellets: Impact of Eudragit® S 100 Coating on the In Vitro Drug Release.

A pelletizer paired with hot-melt extrusion technology (HME) was used to develop colon-targeted pellets for ketoprofen (KTP). Thermal stability and side effects in the upper gastrointestinal tract made ketoprofen more suitable for this work. The pellets were prepared using the enzyme-triggered polymer Pectin LM in the presence of HPMC HME 4M, followed by pH-dependent Eudragit® S 100 coating to accommodate the maximum drug release in the colon by minimizing drug release in the upper gastrointestinal tract (GIT). Box-Behnken Design (BBD) was used for response surface optimization of the proportion of different independent variables like Pectin LM (A), HPMC HME 4M (B), and Eudragit® S 100 (C) required to lower the early drug release in upper GIT and to extend the drug release in the colon. Solid-state characterization studies revealed that ketoprofen was present in a solid solution state in the hot-melt extruded polymer matrix. The desired responses of the prepared optimized KTP pellets obtained by considering the designed space showed 1.20% drug release in 2 h, 3.73% in the first 5 h of the lag period with the help of Eudragit® S 100 coating, and 93.96% in extended release up to 24 h in the colonic region. Hence, developing Eudragit-coated hot-melt extruded pellets could be a significant method for achieving the colon-specific release of ketoprofen.

Development and Evaluation of Amorphous Solid Dispersion of Riluzole with PBPK Model to Simulate the Pharmacokinetic Profile.

In the current work, screening of polymers viz. polyacrylic acid (PAA), polyvinyl pyrrolidone vinyl acetate (PVP VA), and hydroxypropyl methyl cellulose acetate succinate (HPMC AS) based on drug-polymer interaction and wetting property was done for the production of a stable amorphous solid dispersion (ASD) of a poorly water-soluble drug Riluzole (RLZ). PAA showed maximum interaction and wetting property hence, was selected for further studies. Solid state characterization studies confirmed the formation of ASD with PAA. Saturation solubility, dissolution profile, and in vivo pharmacokinetic data of the ASD formulation were generated in rats against its marketed tablet Rilutor. The RLZ:PAA ASD showed exponential enhancement in the dissolution of RLZ. Predicted and observed pharmacokinetic data in rats showed enhanced area under curve (AUC) and Cmax in plasma and brain with respect to Rilutor. Furthermore, a physiologically based pharmacokinetic (PBPK) model of rats for Rilutor and RLZ ASD was developed and then extrapolated to humans where physiological parameters were changed along with a biochemical parameter. The partition coefficient was kept similar in both species. The model was used to predict different exposure scenarios, and the simulated data was compared with observed data points. The PBPK model simulated Cmax and AUC was within two times the experimental data for plasma and brain. The Cmax and AUC in the brain increased with ASD compared to Rilutor for humans showing its potential in improving its biopharmaceutical performance and hence enhanced therapeutic efficacy. The model can predict the RLZ concentration in multiple compartments including plasma and liver.

Solubility enhancement of terbinafine hydrochloride by hydrotropic technique

Terbinafine hydrochloride is an antifungal drug belonging to the class of allylamines. The drug exhibits poor aqueous solubility and thus results in decrease in oral bioavailability. In the present study, an attempt was made to enhance the solubility of terbinafine hydrochloride using hydrotropic solubilization technique employing different hydrotropesnamely sodium benzoate and ureain different proportions and their combinations. The different hydrotropes were selected based on the saturation solubility exhibited by the drug. Among them best batches of the drughydrotrope combinations of varying concentrations of 5% w/v, 10% w/v and 15% w/v were further subjected for the in vitro dissolution studies and solid-state characterization studies. The results so obtained were an indicative of solubility enhancement of terbinafine hydrochloride in combination of 10% urea, and combinationhydrotropes of 10% urea and 15% sodium benzoate. Thus, the experimental investigation concluded that there is an 1.53, 3.77 fold increase in dissolution profile for drug with 10% urea and combination of drug with 10% urea and 15% sodium benzoate respectively at the end of 120 minutes

Solubility Enhancement and Inhalation Delivery of Cyclodextrin-Based Inclusion Complex of Delamanid for Pulmonary Tuberculosis Treatment.

Tuberculosis (TB) is a contiguous airborne disease caused by Mycobacterium tuberculosis (M.tb), primarily affecting the human lungs. The progression of drug-susceptible TB to drug-resistant strains, MDR-TB and XDR-TB, has become a global challenge toward eradicating TB. Conventional TB treatment involves frequent dosing and prolonged treatment regimens predominantly by an oral or invasive route, leading to treatment-related systemic adverse effects and patient's noncompliance. Pulmonary delivery is an attractive option as we could reduce dose, limit systemic side-effects, and achieve rapid onset of action. Delamanid (DLD), an antituberculosis drug, has poor aqueous solubility, and in this study, we aim to improve its solubility using cyclodextrin complexation. We screened different cyclodextrins and found that HP-β-CD resulted in a 54-fold increase in solubility compared to a 27-fold and 13-fold increase by SBE-β-CD and HP-ɣ-CD, respectively. The stability constant (265 ± 15M-1) and complexation efficiency (8.5 × 10-4) suggest the formation of a stable inclusion complex of DLD and HP-β-CD in a 2:1 ratio. Solid-state characterization studies (DSC, PXRD, and NMR) further confirmed successful complexation of DLD in HP-β-CD. The nebulized DLD-CD complex solution showed a mass median aerodynamic diameter of 4.42 ± 0.62μm and fine particle fraction of 82.28 ± 2.79%, suggesting deposition in the respiratory airways. In bacterial studies, minimum inhibitory concentration of DLD-CD complex was significantly reduced (four-fold) compared to free DLD in M.tb (H37Ra strain). Furthermore, accelerated stability studies confirmed that the inclusion complex was stable for 4weeks with 90%w/w drug content. In conclusion, we increased the aqueous solubility of DLD through cyclodextrin complexation and improved its efficacy in vitro.

Solid dispersions of atorvastatin with Kolliphor RH40: Enhanced supersaturation and improvement in a hyperlipidemic rat model

Atorvastatin is a potent lipid-lowering drug with poor solubility and high presystemic clearance that limits its therapeutic efficacy. The aim of this study was to develop solid dispersions and micellar systems to obtain fast-dissolving atorvastatin systems that enhances their anti-hyperlipidemic effect. Solubility and wettability studies allow the development of solid dispersions with low proportions of croscarmellose sodium as hydrophilic carrier. Solid state characterization studies indicated that the addition of Kolliphor® RH40 surfactant to solid dispersions increases intermolecular hydrogen bonding between drug and polymer chains. Dissolution studies in biorelevant Fasted State Simulate Intestinal Fluid (FaSSIF pH 6.5) medium showed for atorvastatin solid dispersion a supersaturation peak of atorvastatin followed by an aggregation/precipitation process. Only the presence of a surfactant such as Kolliphor® RH40 in atorvastatin micellar system, promotes the presence of micelles that achieve delayed recrystallization. Efficacy studies were carried out using a hyperlipidemic model of rats fed with a high- fat diet. The atorvastatin micellar system at doses of 10 mg/kg, revealed a significant improvement in serum levels of total cholesterol, low-density lipoproteins, and triglycerides compared to atorvastatin raw material. This micellar system also exhibited more beneficial effects on liver steatosis, inflammation and ballooning injury.

Post-Synthesis Strategies to Prepare Mesostructured and Hierarchical Silicates for Liquid Phase Catalytic Epoxidation

Olefin epoxidation is an important transformation for the chemical valorization of olefins, which may derive from renewable sources or domestic/industrial waste. Different post-synthesis strategies were employed to introduce molybdenum species into mesostructured and hierarchical micro-mesoporous catalysts of the type TUD-1 and BEA, respectively, to confer epoxidation activity for the conversion of relatively bulky olefins (e.g., biobased methyl oleate, DL-limonene) to epoxide products, using tert-butyl hydroperoxide as an oxidant. The influences of (i) the type of metal precursor, (ii) type of post-synthesis impregnation method, (iii) type of support and (iv) top-down versus bottom-up synthesis methodologies were studied to achieve superior catalytic performances. Higher epoxidation activity was achieved for a material prepared via (post-synthesis) incipient wetness impregnation of MoO2(acac)2 (acac = acetylacetonate) on (pre-treated) siliceous TUD-1 and calcination; for example, methyl oleate was converted to the corresponding epoxide with 100% selectivity at 89% conversion (70 °C). Catalytic and solid-state characterization studies were conducted to shed light on material stability phenomena.

Factorial Design-Based Nanocarrier Mediated Formulation of Efavirenz and Its Characterization

Efavirenz (EFV) suffers from poor aqueous solubility which results in low bioavailability of the drug. Nanocarrier-based drug delivery systems offer a suitable alternative for improving the physico-chemical properties of the drug and hence its efficacy. Nanosuspension (NS) of EFV was formulated by solvent-anti solvent precipitation method using PVP K-30 as stabilizer and sodium lauryl sulphate (SLS) as the wetting agent. Multi-level factorial design was applied to select the optimal formulation which was further characterized. The optimal batch exhibited mean particle size of 305[Formula: see text]nm and polydispersity index (PDI) of 0.345. Solid-state characterization studies of the NS conducted using scanning electron microscopy, Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction, and differential scanning calorimetry (DSC) revealed compatibility between the drug and the excipients and modest alteration in the crystallinity of the drug. There was progressive increase in the solubility of the drug when incorporated in NS from 17.39[Formula: see text][Formula: see text]g/ml to 256[Formula: see text][Formula: see text]g/ml. Further, drug release studies showed significantly better and controlled drug release pattern in comparison to the free drug due to the presence of nanosized particles in the formulation.

Direct cyclodextrin-based powder extrusion 3D printing for one-step production of the BCS class II model drug niclosamide

Niclosamide (NCS) is a drug that has been used as an anthelmintic and anti-parasitic drug for about 40 years. Recently, some studies have highlighted its potential in treating various tumors, allowing a repositioning of this drug. Despite its potential, NCS is a Biopharmaceutical Classification System (BCS) Class II drug and is consequently characterized by low aqueous solubility, poor dissolution rate and reduced bioavailability, which limits its applicability. In this work, we utilize a very novel technique, direct powder extrusion (DPE) 3D printing, which overcomes the limitations of previously used techniques (fused deposition modelling, FDM) to achieve direct extrusion of powder mixtures consisting of NCS, hydroxypropyl methylcellulose (HPMC, Affinisol 15 LV), hydroxypropyl-β-cyclodextrin (HP-β-CD) and polyethylene glycol (PEG) 6000. For the first time, direct printing of powder blends containing HP-β-CD was conducted. For all tablets, in vitro dissolution studies showed sustained drug release over 48 h, but for tablets containing HP-β-CD, the release was faster. Solid-state characterization studies showed that during extrusion, the drug lost its crystal structure and was evenly distributed within the polymer matrix. All printed tablets have exhibited good mechanical and physical features and a stability of the drug content for up to 3 months. This innovative printing technique has demonstrated the possibility to produce personalized pharmaceutical forms directly from powders, avoiding the use of filament used by FDM.Graphical abstract

Formulation of Chitosan-Coated Piperine NLCs: Optimization, In Vitro Characterization, and In Vivo Preclinical Assessment

In the present research work, surface-modified nanostructured lipid carriers (NLCs) with chitosan (CH) were prepared to improve the therapeutic efficacy of piperine (PP). NLCs were developed and optimized (CH-PP-NLCs-opt) by design expert software and the selected NLCs surface was coated with chitosan (0.2% w/v). CH-PP-NLCs-opt have shown a particle size of 149.34 ± 4.54 nm and entrapment efficiency of 80.65 ± 1.23%. The results of the solid-state characterization study exhibited that PP enclosed in lipids and present amorphous form. It might be due to the nanoparticle size of NLCs. The drug release study revealed PP-NLCs-opt and CH-PP-NLCs-opt exhibited significant (P < 0.05) difference in PP release (88.87 ± 5.23% and 76.34 ± 4.54%) as compared to pure PP (19.02 ± 2.87%). CH-PP-NLCs-opt exhibited strong bioadhesion than PP-NLCs-opt which has a positive influence the drug permeation and absorption. CH-PP-NLCs-opt showed higher permeation (1083.34 ± 34.15 μg/ cm2) than pure PP (106.65 ± 15.44 μg/cm2) and PP-NLCs-opt (732.45 ± 28.56 μg/ cm2). The significantly enhanced bioavailability of PP was observed from CH-PP-NLCs-opt (3.76- and 1.21-fold) than PP-dispersion and PP-NLCs-opt. The diabetes was induced in rats by a single intraperitoneal administration of streptozotocin (STZ, 40 mg/kg, citrate buffer pH 4.5), and results revealed that PP-NLCs-opt and CH-PP-NLCs-opt reduce the blood glucose level (28.26% and 36.52% respectively) as compared to PP-dispersion (10.87%). It also helps to maintain the altered biochemical parameters. In conclusion, CH-PP-NLC can be a novel oral nanocarrier for the management of diabetes.

Study of Different Crystal Habits of Aprepitant: Dissolution and Material Attributes

In the present study, aprepitant (APT) was selected to find its suitable crystal habit, which can improve its existing poor dissolution and manufacturing processability. Solvents were screened out for solubility analysis of APT and further crystal habit modification. Solid-state characterization studies like powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and Fourier infrared spectroscopy (FTIR) distinguished that tabular crystal habit was generated from acetone (APT-AC) and long tabular crystal habit was generated from ethyl acetate (APT-EA). Kawakita analysis and powder flow property studies showed that APT-EA is cohesive, has poor flow property and low bulk density compared to APT-AC (p &lt; 0.05). Heckel plots reflected that APT-EA shows higher fragmentation and particle rearrangement during the initial stages as indicated by the higher intercept values. Higher slopes in APT-EA and APT-AC confirmed better plasticity but lower yield pressure in APT-AC proved good plastic deformation compared to APT-EA (p &lt; 0.05). The dissolution profile of the APT-EA was found to be better than that of APT-AC. Overall, it can be concluded that APT-AC crystal habit has a better flow rate, tensile strength, and plasticity whereas APT-EA has better dissolution.

Repurposing Bedaquiline for Effective Non-Small Cell Lung Cancer (NSCLC) Therapy as Inhalable Cyclodextrin-Based Molecular Inclusion Complexes.

There is growing evidence that repurposed drugs demonstrate excellent efficacy against many cancers, while facilitating accelerated drug development process. In this study, bedaquiline (BDQ), an FDA approved anti-mycobacterial agent, was repurposed and an inhalable cyclodextrin complex formulation was developed to explore its anti-cancer activity in non-small cell lung cancer (NSCLC). A sulfobutyl ether derivative of β-cyclodextrin (SBE-β-CD) was selected based on phase solubility studies and molecular modeling to prepare an inclusion complex of BDQ and cyclodextrin. Aqueous solubility of BDQ was increased by 2.8 × 103-fold after complexation with SBE-β-CD, as compared to its intrinsic solubility. Solid-state characterization studies confirmed the successful incorporation of BDQ in the SBE-β-CD cavity. In vitro lung deposition study results demonstrated excellent inhalable properties (mass median aerodynamic diameter: 2.9 ± 0.6 µm (<5 µm) and fine particle fraction: 83.3 ± 3.8%) of BDQ-CD complex. Accelerated stability studies showed BDQ-CD complex to be stable up to 3 weeks. From cytotoxicity studies, a slight enhancement in the anti-cancer efficacy was observed with BDQ-cyclodextrin complex, compared to BDQ alone in H1299 cell line. The IC50 values for BDQ and BDQ-CD complex were found to be ~40 µM in case of H1299 cell line at 72 h, whereas BDQ/BDQ-CD were not found to be cytotoxic up to concentrations of 50 µM in A549 cell line. Taken together, BDQ-CD complex offers a promising inhalation strategy with efficient lung deposition and cytotoxicity for NSCLC treatment.

Formulation and In-Vitro Characterization of Solidified Nebivolol Self-Nanoemulsion using Liquisolid Technique

Recently, supersaturable self-nanoemulsion (Su-SNE) is an advanced approach that can address low oral bioavailability issues. The antihypertensive drug, nebivolol (NBH), has low bioavailability, about 12%, due to its poor solubility and extensive pre-systematic metabolism. This work aimed to convert liquid nebivolol Su-SNE to powder using a liquisolid technique for exploiting the privileges of both Su-SNE and liquisolid approaches. Liquid NBH-loaded Su-SNE composed of imwitor 988, cremophor EL, propylene glycol and soluplus was adsorbed onto avicel PH101 and aerosil 200 admixture. The powder flow properties and in-vitro dissolution tests were carried out. Furthermore, the solid-state of optimized formula was characterized by SEM, DSC, X-ray diffraction, FT-IR analysis, and mean droplets size after redispersion in 0.1N HCl. The optimum liquisolid formula (SL-F8) revealed good flowability and significant dissolution improvement with 98.8% ± 0.99 drug dissolved compared to 23.1% ± 1.5 of pure NBH at 60 min. The solid-state characterization study of formula (SL-F8) showed an amorphous state of NBH within the solidified nanosystem without any interactions with the excipient used. Also, it gave nanoemulsion with mean droplets size about 47.77nm ±1.58 and PDI 0.289± 0.03, which was close to liquid Su-SNE with 55.27nm ± 1.22 droplets size and PDI 0.294± 0.01. Consequently, the liquisolid technique is a promising strategy for solidification of a liquid self-emulsifying system with improving dissolution rate and maintaining nanoemulsion properties.

In vitro evaluation of mucoadhesive in situ nanogel of celecoxib for buccal delivery

The research aims for finding the possibility of buccal delivery of celecoxib from an in situ mucoadhesive nanogel, and in vitro evaluation of the gel to evidence the enhanced permeation of drug from buccal mucosa. Six formulations of celecoxib loaded NLCs were prepared using stearic acid and oleic acid in different ratio in aqueous solution of poloxamer by emulsion solvent evaporation technique. The physicochemical evaluations of the celecoxib loaded NLC (CeL-NLC) were carried out. The formulation F4 was selected as the best and subjected for FTIR, DSC, PXRD, and surface morphology study. In situ mucoadhesive gel was prepared with F4 in HPC, HPMC and Carbopol 934 gelling systems. The gels were evaluated for their mechanical and rheological properties and in vitro permeation studies through rabbit oral mucosa. The selected process at high shear homogenization could yield nanoparticles of desired physiochemical properties. The drug and excipients were compatible as disseminated from FTIR study. Transformation of the crystal form to amorphous form of celecoxib was revealed by the solid-state characterization studies. The AFM study unfold the formation of discrete asymmetric nano particles. All mucoadhesive gels found to have good mucoadhesion and rheological property with good in vitro permeation of drug. A comparative study and statistical analysis unveiled that gel containing Carbopol 934 was found to be the best mucoadhesive in situ gel of nano particles of celecoxib with enhanced permeation parameters. Therefore, the above in vitro evaluation of in situ mucoadhesive nano gel proved the potential of the formulation as a promising buccal delivery of celecoxib.

Bypassing P-glycoprotein mediated efflux of afatinib by cyclodextrin complexation – Evaluation of intestinal absorption and anti-cancer activity

A cyclodextrin complex of afatinib, a FDA-approved pan–ErbB inhibitor and known P-gp substrate, was developed to enhance its bio-activity while also reducing p-glycoprotein (P-gp) efflux, thereby improving its transport across the intestinal membrane. A sulfobutyl ether derivative of β-cyclodextrin (SBE-β-CD, pharmaceutical grade) was selected based on preliminary phase solubility studies and molecular modeling to prepare an afatinib-cyclodextrin inclusion complex. Various solid-state characterization studies were performed to confirm complex formation and to evaluate its physicochemical properties. Results showed that complexation with SBE-β-CD enhanced afatinib's stability in PBS (pH 7.4), as well as in simulated gastric (pH 2.0) and intestinal fluids (pH 6.5). In addition, the cytotoxicity (reduced IC50 after complexation across multiple cancer cell lines with varied P-gp expression) and tumor volume retraction ability (in-vitro 3D-spheroids of P-gp overexpressing cell lines) of afatinib were both enhanced through cyclodextrin complexation. CD complexation effect of afatinib on P-gp efflux as well as transport was assessed using in-vitro permeability studies (Caco-2 and EpiIntestinal® tissue models). Results demonstrated that cyclodextrin complexation significantly increased the transport of afatinib across the gut membrane while also reducing its efflux ratio, indicating its vital role in P-gp efflux modulation.

ENHANCED INTESTINAL ABSORPTION AND BIOAVAILABILITY VIA PRONIOSOMES FOR BAZEDOXIFENE ACETATE DRUG

Objective: The main objective of the present study was to develop proniosomal formulations to enhance the oral bioavailability of bazedoxifene acetate by improving solubility, dissolution and intestinal permeability.&#x0D; Methods: Proniosomal powder formulations were prepared with bazedoxifene acetate drug varying the span 60 and cholesterol ratio in the range of 0.8:0.2 to 0.2:0.8 using maltodextrin as carrier by slurry method. The prepared proniosomal powder was filled into capsules. The bioavailability enhancement of proniosomes loaded with drug was studied focusing on non-ionic surfactants composition and drug: span 60 ratio. Prepared proniosomes were characterized for their particle size distribution, zeta potential, entrapment efficiency, in vitro dissolution study and thermal characteristics to understand the phase transition behavior. Further, the formulated proniosomes were subjected to stability behavior, ex vivo permeation studies using rat intestine followed by in vivo studies.&#x0D; Results: Physico-chemical studies among various formulations helped in optimization of batch. Good flow properties confirmed from angle of repose values indicate easy filling into capsules. Enhancement in dissolution is due to incorporation of bazedoxifene acetate into the non-ionic surfactant and change in the physical state from crystalline to amorphous, thus improving oral bioavailability. Solid state characterization studies prove the transformation to amorphous form with small particle size improving permeation. No drug excipient interaction was observed and sample is stable in refrigerated conditions. Ex vivo studies show significant permeation enhancement across gastrointestinal membrane compared to control. Invivo studies proved enhanced absorption of bazedoxifene acetate drug by oral route.&#x0D; Conclusion: In conclusion, proniosomes provide a powerful and functional way of distribution of inadequately soluble bazedoxifene acetate drug which is proved from in vivo studies based on the enhanced oral delivery.

Development of solid lipid microparticles by melt-emulsification/spray-drying processes as carriers for pulmonary drug delivery

The aim of this study was to optimize the parameters of the complex melt-emulsification process coupled with the spray-drying, in order to maintain the balance between solid lipid microparticles (SLMs) powders aerodynamic performance and salbutamol sulfate release rate. Quality target product profile was identified and risk management and principal component analysis were used to guide formulation development. Obtained dry powders for inhalation (DPIs) were evaluated in terms of SLMs size distribution, morphology, true density, drug content, solid state characterization studies, in vitro aerosol performance and in vitro drug release. SLMs micrographs indicated spherical, porous particles. Selected powders showed satisfactory aerosol performance with a mean mass aerodynamic diameter of around 3 μm and acceptable fine particle fraction (FPF). Addition of trehalose positively affected SLMs aerodynamic properties. The results of in vitro dissolution testing indicated that salbutamol sulfate release from the tested SLMs formulations was modified, in comparison to the raw drug release. In conclusion, SLMs in a form of DPIs were successfully developed and numerous factors that affects SLMs properties were identified in this study. Further research is required for full understanding of each factor's influence on SLMs properties and optimization of DPIs with maximized FPFs.

Enhanced solubility, stability, permeation and anti-cancer efficacy of Celastrol-β-cyclodextrin inclusion complex

Celastrol (Cela), a pentacyclic triterpenoid, has been explored widely due to its broad therapeutic activity such as antioxidant, chemotherapeutic, neuroprotective etc. However, poor aqueous solubility, limited permeability, and instability in physiological conditions result in reduced therapeutic efficacy of Cela and thereby hinder its potential clinical translation. In this exploration, we demonstrate the impact of FDA approved β-cyclodextrin (βCD) derivatives complexation with Cela in overcoming its existing limitations. In-silico molecular modeling studies and phase solubility results indicated superior activity of sulfobutyl-βCD (SBE-βCD; Dexolve®) in improving the aqueous solubility of Cela. Formation of inclusion complex was confirmed using spectroscopic and solid-state characterization studies. In-vitro permeability was assessed using EpiIntestinal® 3D small intestine tissue model and the results demonstrated improved permeability of Cela-SBE-βCD complex across the intestinal tissue. The stability of Cela was found to be greatly increased in phosphate buffer saline (pH 7.4) and biological matrices; rat plasma and human plasma upon complexation with SBE-βCD.In-vitro EpiIntestinal® tissue permeability results demonstrated improved permeability of Cela-SBE-βCD inclusion complex. Moreover, the in-vitro anti-cancer studies on human lung cancer cells showed that SBE-βCD complexation of Cela resulted into enhanced cytotoxic efficacy as compared to free Cela with significant reduction in IC50 values (p < 0.0001). Our results provide valuable insights on the effectiveness of SBE-βCD complexation as a potential strategy to improve the characteristics of Cela for its extended clinical application.

Repurposing Losartan as Dry Powder Inhalation (DPI) for Asthma Related Cardiovascular Complications

Our previous work published suggests that systemic administration of losartan is effective against asthma and asthma related implications. Dry powder inhalation (DPI) formulations as dosage forms are gaining momentum because of their propellant‐free nature, improved physical and chemical stability, low drug dose requirements and high systemic absorption. We developed a dry powder inhalation (DPI) formulation of losartan to treat the symptoms of asthma‐related cardiovascular complications. In this study, we evaluated the compatibility of some common DPI excipients with losartan and their ability to improve critical aerodynamic properties of the formulation to make it suitable for pulmonary drug delivery. There are different manufacturing techniques available for developing DPI formulations including milling, freeze‐drying, and spray drying (SD). We used SD in the current study to develop our formulation. The screening studies were performed by following one factor at a time approach (OFAT). We used amino acids and sugars, either alone or in combination to develop the DPI formulation by using SD technique. The SD conditions were kept constant at 110°C inlet temperature, 100% aspiration, 10% (approx. 3ml/min) pump rate, and 601 liters/hour gas flow rate. The developed formulations were characterized for their physicochemical, aerodynamic, and solid‐state properties. Particle size (&lt;5μm) is critical to understand the deposition behavior of the DPI. Our formulations have the particle size distribution of the 50% of the particles (Dx50) below the respirable range that is &lt;6μm. The fine particle fraction (2.2 – 3.4μm) of our formulation is 53.72%, which is the amount of dose that is actually reaching the lungs and shows therapeutic activity. The respirable fraction (3.4 – 5.3 μm) of our formulation is 70.90%, which is the amount of drug that is within the inhalable range. The solid‐state characterization studies, including differential scanning calorimetry, powder X‐ray diffraction studies indicate the drug in the formulation is amorphous, and the excipients and carrier used help to keep the formulation stable. The drug‐excipient compatibility was proved by quantitatively and qualitatively analyzing the samples using High‐Performance Liquid Chromatography (HPLC) and Fourier Transform Infrared Spectroscopic (FT‐IR). The developed formulations showed good aerosol performance and can be used for preclinical work for further evaluation of therapeutic efficacy of the losartan in asthma models.

Enhanced Dissolution of Luteolin by Solid Dispersion Prepared by Different Methods: Physicochemical Characterization and Antioxidant Activity.

Luteolin (LT) is a poorly soluble bioactive compound that suffered bioavailability problems after oral administration. Hence, the aim of the proposed research work was to formulate and investigate various solid dispersions (SDs) of LT in order to enhance its dissolution and bioactivity. LT-SD was prepared using polyethylene glycol 4000 (PEG 4000) as a carrier at the mass ratios of 1:1, 1:2, and 1:4. LT-SD was prepared using different methods including fusion (FU), solvent evaporation (SE), and microwave irradiation (MI) methods. The prepared LT-SD was duly characterized in terms of differential scanning calorimetry (DSC), X-ray diffraction (XRD), scanning electron microscopy (SEM), infrared (IR) spectroscopy, and nuclear magnetic resonance (NMR) and evaluated for dissolution and in vitro antioxidant activity. The results of DSC, XRD, SEM, IR, and NMR suggested the formation of LT-SD. After 90 min of the dissolution study, the results displayed that the % release of LT from prepared SD was significantly higher compared with the pure LT and its physical mixture dispersion (PMD). LT-SD prepared using the MI method displayed the maximum release of LT (i.e., 97.78 ± 4.41%) at a 1:2 mass ratio of LT:PEG 4000. The LT-SD prepared using the SE method displayed the maximum release of 93.78 ± 3.98% at a mass ratio of 1:4 of LT:PEG 4000. The SD prepared by the MI method showed enhanced dissolution due to higher aqueous solubility and the reduction of particle size. The solid-state characterization studies (DSC, XRD, SEM, IR, and NMR studies) suggested the morphological conversion of LT into the amorphous form from the crystalline state. The results of the antioxidant study revealed that the formation LT-SD displayed significantly higher radical scavenging activity than the pure LT. Therefore, SD obtained using PEG 4000 could be a potential strategy for maximizing the solubility, in vitro dissolution, and therapeutic efficacy of LT.

Molecular simulation driven experiment for formulation of fixed dose combination of Darunavir and Ritonavir as anti-HIV nanosuspension

In this study, we designed a fixed-dose combination (FDC) for Darunavir (DRV) and Ritonavir (RTV) using molecular simulations as a tool. Molecular modeling allowed us to choose the solvent and antisolvent required for the formation of nanosuspension by estimating the solubility parameter. Molecular dynamics simulations and the analysis of the same provided useful information at the molecular level. Hydrogen bonding interactions, radial distribution functions, the radius of gyration, diffusion coefficient, and density profile analysis allowed us to see the formation of particles virtually. With the information obtained from the simulations, we were able to design our experiments and found that the results from experiments complemented the findings from the simulations. Nanosuspension was prepared by using high-speed homogenization (HSH) followed by probe sonication. The solid-state characterization studies demonstrated that both the drugs remain in the amorphous form with absence of any intermolecular interactions. The pharmacokinetic study indicated a significant improvement in the oral bioavailability of DRV/RTV nanosuspension compared to the pure drug combination. Thus, the studies demonstrated that the developed FDC nanosuspension could be a useful alternative dosage form for treating human immunodeficiency virus (HIV) infected patients.