Quantifying the Lymphatic Transport of Model Therapeutics from the Brain in Rats.

In recent years, the drainage of fluids, immune cells, antigens, fluorescent tracers, and other solutes from the brain has been demonstrated to occur along lymphatic outflow pathways to the deep cervical lymph nodes in the neck. To the best of our knowledge, no studies have evaluated the lymphatic transport of therapeutics from the brain. The objective of this study was to determine the lymphatic transport of model therapeutics of different molecular weights and lipophilicity from the brain using cervical lymph cannulation and ligation models in rats. To do this, anesthetized Sprague-Dawley rats were cannulated at the carotid artery and cannulated, ligated, or left intact at the cervical lymph duct. Rats were administered 14C-ibuprofen (206.29 g/mol, logP 3.84), 3H-halofantrine HCl (536.89 g/mol, logP 8.06), or 3H-albumin (∼65,000 g/mol) via direct injection into the brain striatum at a rate of 0.5 µL/min over 16 min. Plasma or cervical lymph samples were collected for up to 6-8 h following dosing, and brain and lymph nodes were collected at 6 or 8 h. Samples were subsequently analyzed for radioactivity levels via scintillation counting. For 14C-ibuprofen, plasma concentrations over time (plasma AUC0-6h) were >2 fold higher in lymph-ligated rats than in lymph-intact rats, suggesting that ibuprofen is cleared from the brain primarily via nonlymphatic routes (e.g., across the blood-brain barrier) but that this clearance is influenced by changes in lymphatic flow. For 3H-halofantrine, >73% of the dose was retained at the brain dosing site in lymph-intact and lymph-ligated groups, and plasma AUC0-8h values were low in both groups (<0.3% dose.h/mL), consistent with the high retention in the brain. It was therefore not possible to determine whether halofantrine undergoes lymphatic transport from the brain within the duration of the study. For 3H-albumin, plasma AUC0-8h values were not significantly different between lymph-intact, lymph-ligated, and lymph-cannulated rats. However, >4% of the dose was recovered in cervical lymph over 8 h. Lymph/plasma concentration ratios of 3H-albumin were also very high (up to 53:1). Together, these results indicate that 3H-albumin is transported from the brain not only via lymphatic routes but also via the blood. Similar to other tissues, the lymphatics may thus play a significant role in the transport of macromolecules, including therapeutic proteins, from the brain but are unlikely to be a major transport pathway from the brain for small molecule drugs that are not lipophilic. Our rat cervical lymph cannulation model can be used to quantify the lymphatic drainage of different molecules and factors from the brain.

Use of In silico Methodologies to Predict the Bioavailability of Oral Suspensions: A Regulatory Approach.

BACKGROUND: Oral suspensions are heterogeneous disperse systems, and the particle size distribution, crystalline form of the dispersed solid, and composition of the formulation can be listed as parameters that control the drug dissolution rate and its bioavailability. OBJECTIVE: The aim of this work was to develop a discriminative dissolution test, which, in association with in silico methodologies, can make it possible to safely anticipate bioavailability problems. METHODS: Nimesulide and ibuprofen (BCS class II) and cephalexin (BCS class I) oral suspensions were studied. Previously, solid-state structure and particle size in active pharmaceutical ingredients were characterized and the impact of differences on solubility was evaluated for the choice of discriminative medium. Afterwards, particle size distribution (0.1 to 360 µm), dissolution profile, and in vitro permeability in Caco-2 cell of commercial suspensions, were determined. These parameters were used as input for the establishment of the in vitro-in vivo correlation (IVIVC) for the suspensions using the GastroPlus™ with Wagner-Nelson and Loo- Riegelmann deconvolution approach. RESULTS: The predicted/observed pharmacokinetic model showed good correlation coefficients (r) of 0.960, 0.950, and 0.901, respectively. The IVIVC was established for one nimesulide and two ibuprofen suspensions with r between 0.956 and 0.932, and the percent prediction error (%PE) did not exceed 15%. CONCLUSION: In this work, we have performed a complete study combining in vitro/in silico approaches with the aim of anticipating the safety and efficacy of oral pharmaceutical suspensions in order to provide a regulatory tool for this category of products in a faster and more economical way.

Comparison of intravenous ibuprofen pharmacokinetics between Caucasian and Chinese populations using physiologically based pharmacokinetics modeling and simulation.

BACKGROUND: Intravenous ibuprofen, a nonsteroidal anti-inflammatory drug, is widely used as an antipyretic and analgesic in adults and children. This study was designed to evaluate ethnic differences by comparing the pharmacokinetics of intravenous ibuprofen in Caucasian and Chinese populations using physiologically based pharmacokinetics (PBPK) modeling and simulation. METHODS: A PBPK model for intravenous ibuprofen was developed in adults and children utilizing the Simcyp Simulator. The model was tested and verified against published literature and unpublished data obtained from the Caucasian adult population, Caucasian pediatric population and Chinese adult population. RESULTS: The developed PBPK model could adequately pilot the pharmacokinetics of intravenous ibuprofen, and the major observed values were within the 90% prediction interval in both adults and children. Both folding errors of the maximum peak concentration (Cmax) and area under the concentration-time curve (AUC) were 1.5-fold less in the Caucasian and Chinese populations. In addition, no significant differences in weight-normalized Cmax and AUC were observed between the Caucasian and Chinese adult populations. Moreover, there were no obvious pharmacokinetic differences between the Caucasian and Chinese pediatric populations with intravenous infusion (10 minutes) of 10 mg/kg by age group. CONCLUSION: This study indicates that the pharmacokinetic profile and the parameters of intravenous ibuprofen are analogous in Caucasian and Chinese populations, either adults or children. In addition, this study provides effective evidence that the dosing scheme of intravenous ibuprofen in Chinese children can remain the same as the regimen that the original company (Caldolor®) provided.

Chiral pharmacokinetics of ibuprofen enantiomers in Chinese preterm neonates with patent ductus arteriosus using a validated UHPLC-MS/MS method.

Persistent patent ductus arteriosus (PDA) is generally observed in preterm neonates. Oral ibuprofen is the standard treatment for closing PDA in China. To investigate the chiral pharmacokinetics of ibuprofen enantiomers in Chinese premature infants with PDA, a simple, fast, and sensitive analytical enantioselective technology was developed with ultra-performance liquid chromatography (UPLC) - tandem mass spectrometry (MS/MS). Chromatographic separation of (R)-ibuprofen and (S)-ibuprofen was accomplished on a Lux® 3 µm Cellulose-3 (150 mm × 2.0 mm, 3 µm) at a flow rate of 0.2 mL/min within 6 min. UPLC separation was achieved by isocratic elution with a mobile phase consisting of formic acid:water (75:1000000, v/v) and acetonitrile:methanol (1:1, v/v). Only 50 µL of plasma samples were pre-treated with acetonitrile precipitation. Ibuprofen-d3 was used as an internal standard. The standard curves of both enantiomers were linear over a concentration range of 0.0500 µg/mL to 50.00 µg/mL. The method has been validated for selectivity, carryover effect, lower limit of quantification, precision, accuracy, matrix effect, extraction recovery, dilution integrity, and stability based on the existing guidelines of the National Medical Products Administration, the United States Food and Drug Administration, and the European Medicines Agency. This method has been successfully applied to investigate the pharmacokinetics of ibuprofen enantiomers in 9 preterm infants with PDA. Our results showed that a high chiral inversion ratio of (R)- to (S)-ibuprofen exists in Chinese preterm neonates. Further studies should be conducted to monitor drug concentration following oral administration of ibuprofen and to consider the effect of individual variations and ethnic differences in metabolizing enantiomers of ibuprofen in premature neonates with PDA.

Usefulness of the Beagle Model in the Evaluation of Paracetamol and Ibuprofen Exposure after Oral Administration to Pediatric Populations: An Exploratory Study.

The present study aimed to explore the usefulness of beagle dogs in combination with physiologically based pharmacokinetic (PBPK) modeling in the evaluation of drug exposure after oral administration to pediatric populations at an early stage of pharmaceutical product development. An exploratory, single-dose, crossover bioavailability study in six beagles was performed. A paracetamol suspension and an ibuprofen suspension were coadministered in the fasted-state conditions, under reference-meal fed-state conditions, and under infant-formula fed-state conditions. PBPK models developed with GastroPlus v9.7 were used to inform the extrapolation of beagle data to human infants and children. Beagle-based simulation outcomes were compared with published human-adult-based simulations. For paracetamol, fasted-state conditions and reference-meal fed-state conditions in beagles appeared to provide adequate information for the applied scaling approach. Fasted-state and/or reference-meal fed-state conditions in beagles appeared suitable to simulate the performance of ibuprofen suspension in pediatric populations. Contrary to human-adult-based translations, extrapolations based on beagle data collected under infant-formula fed-state conditions appeared less useful for informing simulations of plasma levels in pediatric populations. Beagle data collected under fasted and/or reference-meal fed-state conditions appeared to be useful in the investigation of pediatric product performance of the two investigated highly permeable and highly soluble drugs in the upper small intestine. The suitability of the beagle as a preclinical model to understand pediatric drug product performance under different dosing conditions deserves further evaluation with a broader spectrum of drugs and drug products and comparisons with pediatric in vivo data.

Population Pharmacokinetic Modelling of Acetaminophen and Ibuprofen: the Influence of Body Composition, Formulation and Feeding in Healthy Adult Volunteers.

BACKGROUND AND OBJECTIVE: Combined acetaminophen and ibuprofen are common antipyretic and analgesic drugs. Formulation and feeding affect drug absorption. Drug clearance has a nonlinear relationship with total body weight. The covariate effect of fat mass on acetaminophen and ibuprofen pharmacokinetics remains unexplored. This study sought to quantify acetaminophen and ibuprofen pharmacokinetics with intravenous, tablet, sachet and oral suspension formulations in fed and fasted states. METHODS: Pooled time-concentration data for acetaminophen and ibuprofen were available from fasting and fed healthy adults. Data from intravenous, tablet, sachet and suspension formulations were analysed using nonlinear mixed-effects models. Body composition was considered as a covariate on clearances and volumes of distribution (Vd). Size metrics investigated were total body weight, fat and fat-free mass. Theory-based allometry was used to scale pharmacokinetic parameters to a 70 kg individual. A factor on absorption half-life and lag time quantified delays due to feeding for oral formulations. Pharmacokinetic-pharmacodynamic simulations were used to explore the time courses of pain response for acetaminophen and ibuprofen for each formulation. RESULTS: Pooled data included 116 individuals (18-49 years, 49-116 kg) with 6095 acetaminophen and 6046 ibuprofen concentrations available for analysis. A two-compartment pharmacokinetic model with first-order elimination described disposition for both drugs. Normal fat mass was the best covariate to describe acetaminophen clearance (CL), with a factor for fat contribution (FFATCL) of 0.816. Acetaminophen volume of distribution was described using total body weight. Normal fat mass was the best covariate to describe ibuprofen clearance (FFATCL = 0.863) and volume of distribution: (FFATV = 0.718). Clearance and central volume of distribution were 24.0 L/h/70 kg and 43.5 L/h/70 kg for acetaminophen. Ibuprofen clearance and central volume of distribution were 3.79 L/h/70 kg and 10.5 L/h/70 kg. Bioavailability and absorption half-life were 86% and 12 min for acetaminophen and 94% and 27 min for ibuprofen. Absorption lag times were 5.3 min and 6.7 min for acetaminophen and ibuprofen, respectively. Feeding increased both absorption half-life and absorption lag time when compared to the tablet formulation under fasting conditions. Feeding had the most pronounced effect on the lag time associated with tablet formulation for both drugs. Time to a pain score reduction of 2 points (visual analogue score, 0-10) differed by only 5-10 min across all formulations for acetaminophen and ibuprofen. CONCLUSION: Fat mass was an important covariate to describe acetaminophen and ibuprofen pharmacokinetics. The absorption half-lives of acetaminophen and ibuprofen were increased in fed states. The delay in absorption, quantified by a lag time, was protracted for both drugs.

Mechanochemical prepared ibuprofen-Polygonatum sibiricum polysaccharide drug delivery system for enhanced bioactivity with reduced renal injury induced by NSAIDs.

Ibuprofen (IBU) was a widely used NSAID (a type of nonsteroidal anti-inflammatory drug) worldwide, and many drug deliveries had been reported to enhance bioavailability. However, higher bioavailability would increase the danger of renal injury caused by oxidative stress. This study prepared IBU-Polygonatum sibiricum polysaccharide (IBU-PSP) drug delivery system via mechanochemical method. Due to drug delivery and renal protection effect of Polygonatum sibiricum polysaccharide (PSP), the solubility of IBU-PSP was increased 8.22 times, and the bioavailability was increased 2.52 times compared with IBU, carrageenin-induced rat paw edema test also increased. Meanwhile, short-term and long-term renal injuries induced by IBU were notable decreases. In conclusion, IBU-PSP was a multifunctional drug delivery system with superior anti-inflammatory and renal protection effects. It will benefit from developing high-efficiency NADIs preparations with safer clinical applications while providing an efficient and energy-saving technology for polysaccharide drug delivery.

Dissolution Challenges Associated with the Surface pH of Drug Particles: Integration into Mechanistic Oral Absorption Modeling.

The present work aimed to differentiate between in vitro dissolution profiles of ibuprofen as input for GastroPlus™ and to see the impact on systemic exposure. In vitro dissolution profiles of ibuprofen obtained under low- and high-buffered dissolution media were used as input using the z-factor approach. In a second step, a customized surface pH calculator was applied to predict the surface pH of ibuprofen under these low- and high-buffered dissolution conditions. These surface pH values were adopted in GastroPlus™ and simulations were performed to predict the systemic outcome. Simulated data were compared with systemic data of ibuprofen obtained under fasted state conditions in healthy subjects. The slower dissolution rate observed when working under low-buffered conditions nicely matched with the slower dissolution rate as observed during the clinical aspiration study and was in line with the systemic exposure of the drug. Finally, a population simulation was performed to explore the impact of z-factor towards bioequivalence (BE) criteria (so-called safe space). Concerning future perspectives, the customized calculator should be developed in such a way to make it possible to predict the dissolution rate (being informed by the particle size distribution) which, in its turn, can be used as a surrogate to predict the USP2 dissolution curve. Subsequently, validation can be done by using this profile as input for PBPK platforms.

Novel strategy to personalise use of ibuprofen for closure of patent ductus arteriosus in preterm neonates.

OBJECTIVE: Exploration of a novel therapeutic drug monitoring (TDM) strategy to personalise use of ibuprofen for closure of patent ductus arteriosus (PDA) in preterm neonates. DESIGN: Prospective, single-centre, open-label, pharmacokinetics study in preterm neonates. SETTING: Neonatal intensive care unit at McMaster Children's Hospital. PATIENTS: Neonates with a gestational age ≤28+6 weeks treated with oral ibuprofen for closure of a PDA. METHODS: Population pharmacokinetic parameters, concentration-time profiles and exposure metrics were obtained using pharmacometric modelling and simulation. MAIN OUTCOME MEASURE: Association between ibuprofen plasma concentrations measured at various sampling time points on the first day of treatment and attainment of the target exposure over the first 3 days of treatment (AUC0-72h >900 mg·hour/L). RESULTS: Twenty-three preterm neonates (median birth weight 780 g and gestational age 25.9 weeks) were included, yielding 155 plasma ibuprofen plasma samples. Starting from 8 hours' postdose on the first day, a strong correlation between ibuprofen concentrations and AUC0-72h was observed. At 8 hours after the first dose, an ibuprofen concentration >20.5 mg/L was associated with a 90% probability of reaching the target exposure. CONCLUSION: We designed a novel and practical TDM strategy and have shown that the chance of reaching the target exposure (AUC0-72h >900 mg·hour/L) can be predicted with a single sample collection on the first day of treatment. This newly acquired knowledge can be leveraged to personalise ibuprofen dosing regimens and improve the efficacy of ibuprofen use for pharmacological closure of a PDA.

Pharmacodynamic/pharmacokinetic correlation of optimized ibuprofen nanosuspensions having enhanced anti-inflammatory and antinociceptive activity.

OBJECTIVES: The main objective of this study was to evaluate the antinociceptive and anti-inflammatory activity of ibuprofen (IB) nanoformulations which were developed in our previous study and showed enhanced in-vitro dissolution rate compared with the marketed formulation. METHODS: The in-vivo pharmacodynamic (PD) studies were performed in mice. The antinociceptive effect of the formulations was evaluated using the formalin test, whereas the anti-inflammatory activity was evaluated by measuring oedema caused by formalin test. KEY FINDINGS: The optimized formulation exhibited nanosized particles with rapid dissolution compared with IB in water and marketed product. The antinociceptive and anti-inflammatory activity of IB was significantly improved in optimized nanosuspension compared with other formulations. A good correlation was observed between the pharmacokinetic and PD data: nanosuspension > freeze-dried nanoparticles > marketed product > unhomogenized formulation > IB suspension in water. There was a significantly good correlation between percentage inhibition of paw oedema with peak serum concentration (Cmax) and time at which the Cmax is observed (Tmax) but not area under the curve (AUC), whereas there was a good correlation between percentage inhibition of formalin-induced nociception in phase II, but not phase I, with AUC and Cmax but not Tmax. CONCLUSIONS: The development of IB nanoformulation by ultra-homogenization technique improved its dissolution and PD properties.

Solubility and dissolution rate enhancement of ibuprofen by cyclodextrin based carbonate nanosponges.

In the present study nanotechnology approach, i.e., a cyclodextrin (CD) based carbonate nanosponge was used to improve the solubility and dissolution of ibuprofen. Solvent and ultrasound assisted methods were used to prepare nanosponges using two CDs (ß-CD and 2-hydroxypropyl-ß-CD (2HP-ß-CD)) and a cross-linker (CL) diphenyl carbonate (DPC) in varying molar ratios. Nanosponges were investigated for their solubilizing efficiency and phase solubility studies. Structural analysis by Fourier transform infrared (FTIR) and powder X-ray diffraction (PXRD), thermo-analytical characterization by differential scanning calorimetry (DCS), morphology by scanning electron microscopy (SEM). In-vitro drug release followed by in-vivo analgesic and anti-inflammatory studies were performed. 2HP-ß-CD based nanosponges (molar ratio 0.01:0.04) prepared by ultrasound assisted method showed the highest solubilizing efficiency (i.e., 4.28 folds). Stability constant values showed that all complexes were stable. Inclusion complexes of drug was confirmed by PXRD and DSC. SEM images showed porous structures confirming the formation of cross-linked network. Particle size was in the range of 296.8±64 to 611.7±32nm. In-vitro release studies showed enhanced dissolution profile from nanosponge formulation (~94% from I11) as compared to the pure drug (~45% Ibuprofen) in 120min. Significant (p<0.05) extent of pain inhibition and anti-inflammatory activity was observed for nanosponge formulation when compared with the pure drug. CD based carbonate nanosponges with better solubility, enhanced release profile, improved analgesic and anti-inflammatory activity were successfully formulated for ibuprofen.

Confectionery Xylitol Gum-Containing Tablets for Medical Application and the Sintering Effect on Gum Tablets.

Confectionery ingredients are expected to enhance the medication adherence of pediatric patients taking bitter-tasting drugs when adequate pediatric medicines are not available in practical settings. Gum is a familiar confectionery, and several drug-loaded gums are on the market as medicated chewing gums. In this study, medical gum tablets composed of confectionery xylitol gum and a drug (ibuprofen or acetaminophen) were prepared and evaluated for the purpose of potential hospital applications. The effect of the sintering process, a heating treatment, on the physical properties of the solid materials was also examined. The sintering process markedly improved the hardness of the gum tablets. The sintering temperature and time affected the hardness of both ibuprofen- and acetaminophen-loaded gum tablets, whereas heat treatment around the melting point of ibuprofen or xylitol and longer heat treatment resulted in failure of the preparation or a reduction in hardness. The sintered gum tablets exhibited a delayed drug release profile in artificial saliva after an in vitro chewing test. The current results provide basic and useful information about the preparation of gum-containing tablets in future clinical settings.

New potential application of hydroxypropyl-ß-cyclodextrin in solid self-nanoemulsifying drug delivery system and solid dispersion.

The purpose of this study was to use hydroxypropyl-ß-cyclodextrin (HP-ß-CD) as a novel carrier in solid SNEDDS and solid dispersions to enhance the solubility and oral bioavailability of poorly water-soluble dexibuprofen. The novel dexibuprofen-loaded solid SNEDDS was composed of dexibuprofen, corn oil, polysorbate 80, Cremophor® EL, and HP-ß-CD at a weight ratio of 45/35/50/15/100. This solid SNEDDS spontaneously formed a nano-emulsion with a size of approximately 120 nm. Unlike the conventional solid SNEDDS prepared with colloidal silica as a carrier, this dexibuprofen-loaded solid SNEDDS exhibited a spherical structure. Similar to the dexibuprofen-loaded solid dispersion prepared with HP-ß-CD, the transformation of the crystalline drug to an amorphous state with no molecular interactions were observed in the solid SNEDDS. Compared to the solid dispersion and dexibuprofen powder, solid SNEDDS significantly enhanced drug solubility and AUC. Therefore, HP-ß-CD is a novel potential carrier in SNEDDS for improving the oral bioavailability of dexibuprofen.

Repurposing ibuprofen-loaded microemulsion for the management of Alzheimer's disease: evidence of potential intranasal brain targeting.

Studies have shown the use of non-steroidal anti-inflammatory drugs, such as ibuprofen could reduce the risk of Alzheimer's disease. The drug-repurposing strategy offers a bright opportunity for these patients. Intranasal administration through the olfactory pathway provides noninvasive and direct drug delivery to the target brain. A novel ibuprofen microemulsion was prepared, characterized and assessed the brain uptake in rats. The solubility of ibuprofen in various oils, surfactants, co-surfactants, and different ratios of surfactant/co-surfactant mixtures was screened and the phase diagrams were constructed. The colloidal particle size was 166.3 ± 2.55 nm and the zeta potential was -22.7 mV. Conductivity and dilution test identified an O/W type microemulsion with pH 4.09 ± 0.08. The rheological study showed a Newtonian flow behavior with cP 10.633 ± 0.603 (mPa⋅s). A steady drug release and linear permeation profiles were observed and showed a 90% permeation rate from the released drug. Ibuprofen microemulsion showed excellent stability in 3-months accelerated storage conditions, heating-cooling and freeze-thaw cycles, accelerated centrifugation, and 6- and 12-months long-term storage conditions. In vivo studies in rats further demonstrated a 4-fold higher brain uptake of ibuprofen from the microemulsion compared to the reference solution and nearly 4-fold and 10-fold higher compared to the intravenous and oral administrations. This study provides an exciting repurposing strategy and new administration route for the treatment of Alzheimer's disease.

The Impacts of Crystalline Structure and Different Surface Functional Groups on Drug Release and the Osseointegration Process of Nanostructured TiO2.

In implantable materials, surface topography and chemistry are the most important in the effective osseointegration and interaction with drug molecules. Therefore, structural and surface modifications of nanostructured titanium dioxide (TiO2) layers are reported in the present work. In particular, the modification of annealed TiO2 samples with -OH groups and silane derivatives, confirmed by X-ray photoelectron spectroscopy, is shown. Moreover, the ibuprofen release process was studied regarding the desorption-desorption-diffusion (DDD) kinetic model. The results proved that the most significant impact on the release profile is annealing, and further surface modifications did not change its kinetics. Additionally, the cell adhesion and proliferation were examined based on the MTS test and immunofluorescent staining. The obtained data showed that the proposed changes in the surface chemistry enhance the samples' hydrophilicity. Moreover, improvements in the adhesion and proliferation of the MG-63 cells were observed.

Development and Evaluation of Cocoa Butter Taste Masked Ibuprofen Using Supercritical Carbon Dioxide.

Masking the unpleasant taste of the pharmaceutically active ingredients plays a critical role in patient acceptance, particularly for children. This work's primary objective was the preparation of taste-masked ibuprofen microparticles using cocoa butter with the assistance of supercritical fluid technology. Microparticles were prepared by dissolving ibuprofen in melted cocoa butter at 40 °C. The solution was then introduced into a supercritical fluid unit and processed at 10 MPa CO2 pressure for 30 min. The product was collected after depressurizing the system. The effect of the drug to cocoa butter ratio and the supercritical fluid units' configuration on product quality was evaluated and compared with the sample prepared by a conventional method. Physicochemical characterization of the prepared product, including particle size, crystallinity, entrapment efficiency, in vitro drug release, and product taste using a human volunteer panel was conducted. The produced microparticles were in the range of 1.42 to 15.28 µm. The entrapment efficiency of the formulated microparticles ranged from 66 to 81%. The drug:polymer ratio, the configuration of the supercritical fluid unit, and the method of preparation were found to have a critical role in the formulation of ibuprofen microparticles. Taste evaluation using human volunteers showed that microparticles containing 20% drug and processed with supercritical fluid technology were capable of masking the bitter taste of ibuprofen. In conclusion, the dispersion of ibuprofen in cocoa butter using supercritical fluid technology is a a promising innovative method to mask the bitter taste of ibuprofen.

Nanocellulose as template to prepare rough-hydroxy rich hollow silicon mesoporous nanospheres (R-nCHMSNs) for drug delivery.

Drug-delivery technology is an effective way to promote drug absorption and efficacy. Mesoporous hollow silica material and small-molecule drug ibuprofen were used as a carrier model and as model drug, respectively. By quantum chemical calculation (density functional theory and frontier orbital theory), it was found that the content of geminal silanols on the material surface played a decisive role in the release of the different drugs. The rough hollow materials are easily adsorbed and have a large loading capacity, and so we fabricated a mesoporous hollow silica material (R-nCHMSNs) with a rough surface and rich geminal silanols by using hydroxyl-rich nanocellulose as a template. The content and types of hydroxyl groups on the material surface were studied by 29Si NMR. The loading and delivery of ibuprofen and lysozyme were studied in detail. Materials with rich geminal silanols exhibited excellent delivery properties for different drugs, which shows great potential and research value for drug delivery.

Formulation of solid dispersion to improve dissolution and oral bioavailability of poorly soluble dexibuprofen.

Dexibuprofen (DEXI) belongs to BCS class II drug with poor aqueous solubility resulting in poor bioavailability. To enhance solubility and bioavailability of DEXI, DEXI-loaded solid dispersion (SD) was formulated. DEXI-SDs were prepared by melting method and solvent evaporation method. Amphipathic polymer poloxamer 407 (pol 407) was selected based on solubility and dissolution tests. The ratio of DEXI:pol 407 was optimized as 1:2. The physicochemical properties, dissolution, and oral bioavailability of SD3 and SD6 were evaluated to compare preparation methods. The dissolution rate of DEXI from SD formulations was higher at pH 6.8 and pH 7.2 than at pH 1.2. Following oral administration in rats, the Cmax and AUClast of SD3 and SD6 formulations were significantly higher compared with raw DEXI. In addition, the SD6 formulation showed increased Cmax and AUClast by 1.34- and 1.33-fold, compared with those of SD3 formulation, respectively. These results demonstrated that SD formulation has excellent potential as a formulation for poorly soluble drug DEXI.

Application of Aquasolv Lignin in ibuprofen-loaded pharmaceutical formulations obtained via direct compression and wet granulation.

AS (Aquasolv) Lignin produced via Liquid Hot Water Pretreatment and Enzymatic Hydrolysis has shown potential as an active pharmaceutical ingredient and/or excipient in solid dosage forms. Moreover, lignin is safe to consume and presents antioxidant and antidiabetic capacity, properties that can add to solid dosage forms in pharmaceuticals. This work aimed to evaluate the performance of tablets produced via direct compression and wet granulation when lignin is used in combination with commercial excipients. In order to find optimal tablet performance, different lignin formulations were assessed, and the concentrations were given by extreme vertices mixture design (13 formulations). The blends were composed of AS Lignin, Microcrystalline Cellulose, and Lactose monohydrate and the optimized blend was found to be 14.53 w/w% of disintegrant, 26.57 w/w% of binder and 58.9 w/w% of AS lignin. This proportion was further used to evaluate the performance of lignin-based tablets in drug release, using Ibuprofen as a drug model (50 w/w% and 70 w/w%) and for comparison of direct compression with wet granulation. Direct compressed tablets resulted in higher drug dissolution rates when compared with wet granulation, nevertheless; both tableting techniques showed promising results for lignin. More than 5 formulations tested in this work are compliant with International Pharmacopoeia regulations for solid dosage pharmaceutical forms, thus AS Lignin shows potential to be used as an excipient in pharmaceutical formulations. INDUSTRIAL RELEVANCE: Industrially, AS Lignin appears as promising excipient in the pharmaceutical technologies as well as boost in the biorefining technologies in the following years. Lignin produced is free of sulfur, can be labelled as clean and environmentally-friendly and in this study, was proven this non-cytotoxic AS lignin can be used for excipients and drug carriers. The findings in this paper showed the use of product formulation for life science purposes, thus stressing one of possibilities for lignin valorization in biorefineries.

Effect of ibuprofen entrapment procedure on physicochemical and controlled drug release performances of chitosan/xanthan gum polyelectrolyte complexes.

The effect of the entrapment procedure of a poorly water soluble drug (ibuprofen) on physicochemical and drug release performances of chitosan/xanthan polyelectrolyte complexes (PECs) was investigated to achieve controlled drug release as the ultimate goal. The formation of PECs for two drug entrapment procedures (before or after the mixing of polymers) at pH 4.6 and 5.6 and three chitosan-to-xanthan mass ratios (1:1, 1:2 and 1:3) was observed by continuous decrease in conductivity during the PECs formation and increased apparent viscosity and hysteresis values. The most extensive crosslinking was observed with ibuprofen added before the PECs formation at pH 4.6 and chitosan-to-xanthan mass ratio 1:1. The PECs prepared at polymers' mass ratios 1:2 and 1:3 had higher yield and drug entrapment efficiency. DSC and FT-IR analysis confirmed ibuprofen entrapment in PECs and the partial disruption of its crystallinity. All ibuprofen release profiles were similar, with 60-70% of drug released after 12 h, mainly by diffusion, but erosion and polymer chain relaxation were also included. Potentially optimal can be considered the PEC prepared at pH 4.6, ibuprofen entrapped before the mixing of polymers at chitosan-to-xanthan mass ratio 1:2, which provided controlled drug release by zero-order kinetics, high yield, and drug entrapment efficiency.