Modification of microenvironmental pH of nanoparticles for enhanced solubility and oral bioavailability of poorly water-soluble celecoxib.

This study aimed to develop a novel pH-modified nanoparticle with improved solubility and oral bioavailability of poorly water-soluble celecoxib by modifying the microenvironmental pH. After assessing the impact of hydrophilic polymers, surfactants and alkaline pH modifiers on the drug solubility, copovidone, sodium lauryl sulfate (SLS) and meglumine were chosen. The optimal formulation of solvent-evaporated, surface-attached and pH-modified nanoparticles composed of celecoxib/copovidone/SLS/meglumine at weight ratios of 1:1:0.2:0, 1:0.375:1.125:0 and 1:1:1:0.2:0.02, respectively, were manufactured using spray drying technique. Their physicochemical characteristics, solubility, dissolution and pharmacokinetics in rats were evaluated compared to the celecoxib powder. The solvent-evaporated and pH-modified nanoparticles converted a crystalline to an amorphous drug, resulting in a spherical shape with a reduced particle size compared to celecoxib powder. However, the surface-attached nanoparticles with insignificant particle size exhibited the unchangeable crystalline drug. All of them gave significantly higher solubility, dissolution, and oral bioavailability than celecoxib powder. Among them, the pH-modified nanoparticles demonstrated the most significant improvement in solubility (approximately 1600-fold) and oral bioavailability (approximately 4-fold) compared to the drug powder owing to the alkaline microenvironment formation effect of meglumine and the conversion to the amorphous drug. Thus, the pH-modified nanoparticle system would be a promising strategy for improving the solubility and oral bioavailability of poorly water-soluble and weakly acidic celecoxib.

Impact of carrier hydrophilicity on solid self nano-emulsifying drug delivery system and self nano-emulsifying granule system.

The purpose of this study was to investigate the impact of carrier hydrophilicity on solid self nano-emulsifying drug delivery system (SNEDDS) and self nano-emulsifying granule system (SEGS). The mesoporous calcium silicate (Ca-silicate) and hydroxypropyl-ß-cyclodextrin (HP-ß-CD) were utilised as hydrophobic carrier and hydrophilic carrier, respectively. The liquid SNEDDS formulation, composed of Tween80/Kollipohr EL/corn oil (35/50/15%) with 31% (w/w) dexibuprofen, was spray-dried and fluid-bed granulated together with Avicel using Ca-silicate or HP- ß-CD as a solid carrier, producing four different solid SNEDDS and SEGS formulations. Unlike the Ca-silicate-based systems, spherical shape and aggregated particles were shown in HP-ß-CD-based solid SNEDDS and SEGS, respectively. Molecular interaction was detected between Ca-silicate and the drug; though, none was shown between HP-ß-CD and the drug. Each system prepared with either carrier gave no significant differences in micromeritic properties, crystallinity, droplet morphology, size, dissolution and oral bioavailability in rats. However, the HP-ß-CD-based system more significantly improved the drug solubility than did the Ca-silicate-based system. Therefore, both carriers hardly affected the properties of both solid SNEDDS and SEGS; though, there were differences in the aspect of appearance, molecular interaction and solubility.

Prediction of medication-related osteonecrosis of the jaws using machine learning methods from estrogen receptor 1 polymorphisms and clinical information.

Objective: The purpose of this study was to evaluate the effect of estrogen receptor 1 (ESR1) polymorphisms on the development of medication-related osteonecrosis of the jaws (MRONJ) in women with osteoporosis. Methods: A total of 125 patients taking bisphosphonates was evaluated the relationship between MRONJ occurrence and single nucleotide polymorphisms (SNPs) of ESR1. Clinical information was collected, including current age, treatment duration, and comorbidity. Univariate and Multivariable regression analyzes were performed to evaluate the independent predictive factors for MRONJ occurrence. Predictive models were constructed using machine learning methods such as Lasso regression, Random forest (RF), and Support vector machine (SVM). The area under the receiver-operating curve (AUROC) was used to evaluate the performance of a binary classifier. Result: Two SNPs of ESR1 (rs4870056 and rs78177662) were significantly associated with MRONJ development. Patients with variant allele (A) of rs4870056 showed 2.45 times (95% CI, 1.03-5.87) the odds of MRONJ occurrence compared to those with wild-type homozygote (GG) after adjusting covariates. Additionally, carriers with variant allele (T) of rs78177662 had higher odds than those with wild-type homozygote (CC) (adjusted odds ratio (aOR), 2.64, 95% CI, 1.00-6.94). Among demographic variables, age ≥ 72 years (aOR, 3.98, 95% CI, 1.60-9.87) and bisphosphonate exposure ≥48 months (aOR, 3.16, 95% CI, 1.26-7.93) were also significant risk factors for MRONJ occurrence. AUROC values of machine learning methods ranged between 0.756-0.806 in the study. Conclusion: Our study showed that the MRONJ occurrence was associated with ESR1 polymorphisms in osteoporotic women.

Nutrition Therapy by Nutrition Support Team: A Comparison of Multi-Chamber Bag and Customized Parenteral Nutrition in Hospitalized Patients.

This study aimed to investigate the activity of a nutrition support team (NST) and the trends of multi-chamber bag (MCB) and customized parenteral nutrition (PN) with NST consultations in South Korea. Data were obtained from the National Inpatient Sample Cohort between 2015 and 2020. Three datasets were constructed for NST consultation, MCB-PN product prescriptions, and aseptic preparation of total PN. The intersections of the NST consultation and each PN dataset were compiled into MCB-PN with NST or customized PN with a NST sub-dataset, respectively. Using personal identifiers, the patients' characteristics were evaluated in the NST cohort. A total of 91,384 reimbursements and 70,665 patients were included. The NST activity had increased by more than 50% over 6 years. Approximately 70% and 11%, respectively, of the NST cohort were classified into two subgroups: MCB-PN with NST (M-NST) and customized PN with NST (C-NST). M-NST had many elderly patients with cancer and showed a higher in-hospital mortality than C-NST (12.6% vs. 9.5%). C-NST included a larger number of patients under the age of 5 years, and the hospitalization period was more extended than M-NST (26.2 vs. 21.2 days). The present study showed that NST activities and the proportion of PN with NST consultation are gradually increasing in South Korea.

Hydroxypropyl-ß-cyclodextrin-based solid dispersed granules: A prospective alternative to conventional solid dispersion.

The purpose of the present study was to develop hydroxypropyl-ß-cyclodextrin (HP-ß-CD)-based solid dispersed granules as a superior system to solid dispersion. The solid dispersed granules and solid dispersion were compared in terms of powder property improvement, solubility increment and oral bioavailability enhancement of poorly water-soluble dexibuprofen. Solid dispersion (drug/HP-ß-CD/Tween80 = 1:7:0.1, weight ratio) and solid dispersed granules (drug/HP-ß-CD/Tween80/Microcrystalline cellulose = 1:7:0.1:4) were fabricated using a spray-dryer and fluid bed granulator, respectively. The HP-ß-CD-based solid dispersed granules significantly improved solubility, dissolution profile and oral bioavailability of dexibuprofen compared to pure drug powder. Moreover, the solid dispersed granules maximised the oral bioavailability of dexibuprofen to the same extent as the solid dispersion. However, considerable improvements of powder and tablet properties were observed in solid dispersed granules as compared with solid dispersion. Therefore, HP-ß-CD-based solid dispersed granules would be a prospective alternative to solid dispersion.

Comparison of Three Different Aqueous Microenvironments for Enhancing Oral Bioavailability of Sildenafil: Solid Self-Nanoemulsifying Drug Delivery System, Amorphous Microspheres and Crystalline Microspheres.

BACKGROUND: The purpose of this study was to screen various drug delivery systems for improving the aqueous solubility and oral bioavailability of sildenafil. Three representative techniques, solid self-nanoemulsifying drug delivery systems (SNEDDS), amorphous microspheres and crystalline microspheres, were compared. METHODS: Both microspheres systems contained sildenafil:Labrasol:PVP at a weight ratio of 1:1:6. The amorphous microspheres were manufactured using ethanol, while crystalline microspheres were generated using distilled water. Liquid SNEDDS was composed of sildenafil:Labrasol:Transcutol HP:Captex 300 in the ratio of 1:70:15:15 (w:w:w:w). The solidification process in SNEDDS was performed using HDK N20 Pharma as a solid carrier. RESULTS: The amorphous microspheres appeared spherical with significantly decreased particle size compared to the drug powder. The crystalline microspheres exhibited a rough surface with no major particle-size difference compared with sildenafil powder, indicating that the hydrophilic excipients adhered to the sildenafil crystal. Solid SNEDDS presented a smooth surface, assuming that the oily liquid was adsorbed to the porous solid carrier. According to the physicochemical evaluation, the crystalline state maintained in crystalline microspheres, whereas the crystal state changed to amorphous state in other formulations. Amorphous microspheres, crystalline microspheres and solid SNEDDS produced about 79, 55, 82-fold increased solubility, compared to drug powder. Moreover, the prepared formulations provided a higher dissolution rate (%) and plasma concentration than did the drug powder (performance order; solid SNEDDS ≥ amorphous microspheres ≥ crystalline microspheres > drug powder). Among the formulations, solid SNEDDS demonstrated the highest improvement in oral bioavailability (AUC; 1508.78 ± 343.95 h·ng/mL). CONCLUSION: Therefore, solid SNEDDS could be recommended as an oral dosage form for enhancing the oral bioavailability of sildenafil.

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.