Formulation Development, Optimization and Evaluation of Flurbiprofen Microsponge Tablet for the Treatment of Rheumatoid Arthritis (RA) by using Box- Behnken Design.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic, autoimmune and inflammatory disease that mostly impacts the joints. Chronotherapeutics refers to a treatment method in which in-vivo drug availability is timed to match rhythms of disease in order to optimize therapeutic outcomes and minimize side effects. Flurbiprofen is a non-steroidal anti-inflammatory drug, indicated for the relief of inflammation. OBJECTIVES: The aim of the present study was to develop & optimize the microsponges based of Flurbiprofen tablet for Chronotherapeutics for enhanced therapeutic effect. METHODS: Microsponges were developed by Quasi Emulsion solvent diffusion method. Prepared microsponges were optimized in order to analyze the effects of independent variables like concentration of PVA (X1), Volume of Dichloromethane (X2) & stirring speed (X3) on the Entrapment Efficiency (Y1), Mean particle size (Y2) and Drug release at 8 hr (Y3) using box Behnken design. The optimized formulation was subjected to in vitro study and Comparison with marketed formulation. With release kinetics study. RESULT: The optimized formulation Batch (F-18) Show particle size of 49.12µm, entrapment efficiency of 87.46%, and drug release at 8 h 70.49%, which is under the acceptance criteria, which is more effective compared with Marketed tablet. CONCLUSION: The results showed that, as stirring speed increases, the particle size decreases and entrapment efficiency increases. While volume of dichloromethane increases, particle size decreases. Morphology was found to be porous and spherical. Optimized batch of Flurbiprofen microsponge was further formulated in future for invivo study and clinical trials.

Efficacy and safety of topical NSAIDs combined with physiotherapy for frozen shoulder: a randomized controlled trial.

OBJECTIVE: Frozen shoulder is a prevalent condition among individuals in their middle and later years. Invasive therapy has shown promising results in the treatment of frozen shoulders, but its widespread adoption has been hampered by high costs and the need for advanced medical technology. As a result, patients with frozen shoulders often turn to non-steroidal anti-inflammatory drugs (NSAIDs) for symptomatic relief. However, the oral administration of NSAIDs can lead to troublesome adverse effects on the gastrointestinal, cardiovascular, and urinary systems. In contrast, topical NSAIDs have gained attention for their excellent efficacy and lower adverse effects in various chronic pain conditions. Therefore, our study aimed to investigate the efficacy and safety of topical NSAIDs in improving pain and mobility among patients with frozen shoulders. PATIENTS AND METHODS: A total of 108 patients experiencing moderate to severe pain and mobility impairment due to frozen shoulder were enrolled in this study. The participants were randomly assigned to either the experimental group (n=72) or the control group (n=36). The experimental group received daily treatment with the loxoprofen hydrogel patch (LOX-P) in addition to basic rehabilitation physiotherapy. The control group was treated with flurbiprofen cataplasm (FLU-C) twice a day, along with rehabilitation physiotherapy. The primary endpoint for evaluating the efficacy of the two patches was the Constant-Murley score (CMS). Clinical symptom data, adverse events, and patient satisfaction were also recorded. RESULTS: After 14 days of treatment, the effective rate was 66.67% (n=48) in the experimental group and 41.67% (n=15) in the control group. The overall difference in the effective rates was 25.00% (95% CI=5.20-42.52; p=0.013). The safety profiles of the two topical agents were similar, with only a few adverse events reported. CONCLUSIONS: The loxoprofen hydrogel patch demonstrates a significant ability to alleviate shoulder pain and restore shoulder function in the treatment of frozen shoulder, with minimal adverse reactions. Chictr.org.cn ID: ChiCTR2100052375.

The effect of skin diffusion kinetics of isopropyl ester permeation enhancers on drug permeation: Role of lateral spread and penetration characteristics.

The purpose of present work was to study the effects of permeation enhancers' two kinetic behaviors of simultaneous lateral diffusion and vertical penetration in the skin on its enhancing effect. The skin diffusion kinetics of isopropyl ester permeation enhancers were characterized by the innovative concentric tape peeling study and Raman imaging, which were quantitatively assessed through innovative parameters, namely, lateral-to-vertical penetration amount (CL-V) and lateral-to-vertical penetration distance (DL-V). The enhancement effect of permeation enhancers on drug flurbiprofen (FLU) was assessed by in vitro skin permeation tests, which were confirmed by transdermal water loss and skin resistance study. The relationship between kinetic parameters of permeation enhancers and permeation parameters of FLU was carried out by correlation analysis. The molecular mechanisms of effect of skin diffusion kinetics of permeation enhancers on drug permeation were characterized by molecular docking, modulated-temperature differential scanning calorimetry (MTDSC), Raman spectra, solid-state NMR and molecular dynamic simulation. The results indicated skin diffusion kinetics of short-chain (C8-C12) isopropyl ester permeation enhancers were governed by vertical penetration, while long-chain (C14-C18) ones were characterized by lateral spread. Quadratic correlation between CL-V and enhancement ratio of permeation-retention ratio of FLU (ERQ/R) (R2 = 0.95), DL-V and enhancement ratio of permeation area (ERA) of FLU (R2 = 0.98) indicating that varied skin diffusion kinetics of permeation enhancers directly influenced the barrier function of stratum corneum (SC) and further enhancing drug permeation. In terms of molecular mechanism, long-chain isopropyl ester enhancers had good miscibility with SC, leading to their high CL-V and DL-V, and causing strong interaction strength with SC and resulting in weaker skin barrier function for drug permeation. In summary, in comparison to short-chain isopropyl ester enhancers that relied on penetration, long-chain ones that depended on lateral spread exhibited greater enhancement efficacy, which guided the application of enhancers in transdermal formulations.

Multichiral Mesoporous Silica Screws with Chiral Differential Mucus Penetration and Mucosal Adhesion for Oral Drug Delivery.

In the harsh gastrointestinal tract, helical bacteria with hierarchical chiral architectures possess strong abilities. Taking inspirations from nature, we developed a multichiral mesoporous silica nanoscrew (L/D-MCNS) as an efficient oral drug delivery platform by modifying the structural chiral silica nanoscrew (CNS) with L/D-alanine (L/D-Ala) enantiomers via the sequential application of a chiral template and postmodification strategies. We demonstrated that L-MCNS showed differential biological behaviors and superior advantages in oral adsorption compared to those of CNS, D-MCNS, and DL-MCNS. During the delivery, helical L/D-MCNS presenting distinctive topological structures, including small section area, large rough external surface, and a screw-like body, displayed multiple superiorities in mucus diffusion and mucosal adhesion. Meanwhile, the grafted chiral enantiomers enabled positive or negative chiral recognition with the biosystems. Once racemic flurbiprofen (FP) was encapsulated into the nanopores of L/D-MCNS (FP@L/D-MCNS), L/D-MCNS providing highly cross-linked and mesoscopic chiral nanochannels was beneficial for controlling the drug loading/release kinetics with chiral microenvironment sensitivity. Particularly, we noticed enantioselective absorption of FP in vivo, which could be attributed to the differential biological behaviors of L/D-MCNS. By simple design and regulation of the multilevel chirality of nanocarriers, L/D-MCNS can be employed for efficient oral drug delivery from the perspectives of material science, pharmacy, and bionics.

Supramolecular 3 in 1: A Lubrication and Co-Delivery System for Synergistic Advanced Osteoarthritis Therapy.

The complexity, heterogeneity, and drug resistance of diseases necessitate a shift in therapeutic paradigms from monotherapy to combination therapy, which could augment treatment efficiency. Effective treatment of advanced osteoarthritis (OA) requires addressing three key factors contributing to its deterioration: chronic joint inflammation, lubrication dysfunction, and cartilage-tissue degradation. Herein, we present a supramolecular nanomedicine of multifunctionality via molecular recognition and self-assembly. The employed macrocyclic carrier, zwitterion-modified cavitand (CV-2), not only accurately loads various drugs but also functions as a therapeutic agent with lubricating properties for the treatment of OA. Kartogenin (KGN), a drug for articular cartilage regeneration and protection, and flurbiprofen (FP), an anti-inflammatory agent, were coloaded onto CV-2 assembly, forming a supramolecular nanomedicine KGN&FP@CV-2. The three-in-one combination therapy of KGN&FP@CV-2 addresses the three pathological features for treating OA collectively, and thus provides long-term therapeutic benefits for OA through sustained drug release and intrinsic lubrication in vivo. The multifunctional integration of macrocyclic delivery and therapeutics provides a simple, flexible, and universal platform for the synergistic treatment of diseases involving multiple drugs.

Assessment of CYP-Mediated Drug Interactions for Enasidenib Based on a Cocktail Study in Patients with Relapse or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome.

As a selective and potent inhibitor targeting the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib obtained approval from the US Food and Drug Administration (FDA) in 2017 for adult patients with acute myeloid leukemia (AML) with an IDH2 mutation. In vitro investigations demonstrated that enasidenib affects various drug metabolic enzymes and transporters. This current investigation aimed to assess enasidenib on the pharmacokinetics (PKs) of CYP substrates, including dextromethorphan (CYP2D6 probe drug), flurbiprofen (CYP2C9 probe drug), midazolam (CYP3A4 probe drug), omeprazole (CYP2C19 probe drug), and pioglitazone (CYP2C8 probe drug), in patients with AML or myelodysplastic syndrome. Results showed that following the co-administration of enasidenib (100 mg, once daily) for 28 days, the PK parameters AUC(0-∞) and Cmax of dextromethorphan increased by 1.37 (90% confidence interval (CI): 0.96, 1.96) and 1.24 (90% CI: 0.94, 1.65)-fold, respectively, compared to dextromethorphan alone. For flurbiprofen, these parameters increased by 1.14 (90%CI: 1.01, 1.29) and 0.97 (90% CI 0.86, 1.08)-fold, respectively, when compared to flurbiprofen alone. Conversely, midazolam exhibited decreases to 0.57 (90% CI 0.34, 0.97) and 0.77 (90% CI 0.39, 1.53)-fold, respectively, in comparison to midazolam alone. The parameters for omeprazole increased by 1.86 (90% CI: 1.33, 2.60) and 1.47 (0.93, 2.31)-fold, respectively, compared to omeprazole alone, while those for pioglitazone decreased to 0.80 (90% CI: 0.62, 1.03) and 0.87 (90% CI: 0.65, 1.16)-fold, respectively, in comparison to pioglitazone alone. These findings provide valuable insights into dose recommendations concerning drugs acting as substrates of CYP2D6, CYP2C9, CYP3A4, CYP2C19, and CYP2C8 when administered concurrently with enasidenib.

Nonlinear Pharmacokinetics of Topical Flurbiprofen Gel in a Phase I Study Among Chinese Healthy Adults.

INTRODUCTION: PDX-02 (Flurbiprofen sodium) is a topical nonsteroidal anti-inflammatory drug in gel formulation for local analgesia and anti-inflammation. A Phase I clinical trial was conducted to assess the safety, tolerability, and pharmacokinetics of single and multiple doses of PDX-02 gel in Chinese healthy adults. METHODS: The trial comprised three parts: (1) a single-dose ascending study with three dose levels (0.5%, 1% to 2% PDX-02 gel) applied on a 136 cm2 skin area; (2) a multiple-dose study with either 1% or 2% PDX-02 gel applied on a 136 cm2 skin area for 7 consecutive days; and (3) a high dose group with 2% PDX-02 gel on an 816 cm2 skin area and a frequent multiple dose group with 2% PDX-02 gel on a 272 cm2 skin area four times a day for 7 consecutive days. The safety, tolerability and pharmacokinetics of the PDX-02 gel were evaluated in each part. RESULTS: A total of sixty participants completed the trial, with all adverse events recovered and all positive skin reaction being transient and recovered. The overall absorption of topical PDX-02 gel was slow with a mean peak time exceeding 9 h. The elimination rate remained consistent between dose groups. A less-than-dose-proportional nonlinear pharmacokinetics relationship was observed within the studied dose range, and this is likely due to the autoinduction of skin first-pass metabolism. CONCLUSION: The topical PDX-02 gel showed favorable safety and tolerability in both single and multiple dosing studies, with a less-than-dose-proportional nonlinear pharmacokinetics observed.

Flurbiprofen in the subglottic space to prevent postoperative sore throat after cardiac surgery: A randomized double-blind study.

STUDY OBJECTIVE: Postoperative sore throat (POST) and hoarseness are common complications of tracheal intubation. This study aims to evaluate the efficacy of flurbiprofen administered through the subglottic port of tracheal tubes to prevent POST after cardiac surgery. DESIGN: Single-center, prospective, randomized, double-blind, placebo-controlled trial. SETTING: Tertiary Care Referral University Hospital (Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome). PATIENTS: Included 71 patients undergoing for elective cardiac surgery. Inclusion criteria were (a) age between 50 and 75 years, (b) NYHA class I or II, (c) surgery for myocardial revascularization or valve repair or replacement under cardiopulmonary bypass. INTERVENTION: Patients were double blind randomized to receive flurbiprofen or saline in the subglottic port of the endotracheal tube (groups F and P). The solution was injected ten minutes after tracheal tube placement, ten minutes after ICU admission and ten minutes before tracheal tube removal. MEASUREMENTS: The primary outcome was to assess the effect of topical flurbiprofen administered through the subglottic port of the tracheal tube to prevent post-operative sore throat (POST). The secondary outcomes were the presence of hoarseness safety and patient's subjective satisfaction with their recovery. We did not report any exploratory outcomes. MAIN RESULTS: We analyzed 68 patients, 34 patients in each group. In group F, two patients complained of POST and hoarseness (5.9%), while all controls did. The two groups significantly differed in the severity scores (VAS and TPS for sore throat and HOAR for hoarseness) at all time points. In group P, patients reported mild to moderate symptoms that significantly improved or disappeared 36 h after tracheal tube removal. According to the multivariable model, hoarseness affected women less than men, in the control group (p = 0.002). None of the patients in either group reported any adverse effects. CONCLUSIONS: Repeated administration of flurbiprofen through the subglottic port of tracheal tubes reduced the incidence of sore throat and hoarseness after cardiac surgery without evidence of complications.

NSAIDs do not prevent exercise-induced performance deficits or alleviate muscle soreness: A placebo-controlled randomized, double-blinded, cross-over study.

Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently consumed by athletes to manage muscle soreness, expedite recovery, or improve performance. Despite the prevalence of NSAID use, their effects on muscle soreness and performance, particularly when administered prophylactically, remain unclear. This randomized, double-blind, counter-balanced, crossover study examined the effect of consuming a single dose of each of three NSAIDs (celecoxib, 200 mg; ibuprofen, 800 mg; flurbiprofen, 100 mg) or placebo 2 h before on muscle soreness and performance following an acute plyometric training session. Twelve healthy adults, aged 18-42 years, completed a standardized plyometric exercise session consisting of 10 sets of 10 repetitions at 40 % 1-repetition maximum (1RM) on a leg press device. During exercise, total work, rating of perceived exertion, and heart rate were measured. Maximum voluntary contraction force (MVC), vertical jump height, and muscle soreness were measured before exercise and 4-h and 24-h post-exercise. We found no significant differences in total work, heart rate, or rating of perceived exertion between treatments. Additionally, no significant differences in muscle soreness or vertical jump were observed between treatments. Ibuprofen and flurbiprofen did not prevent decrements in MVC, but celecoxib attenuated decreases in MVC 4-h post exercise (p < 0.05). This study suggests that athletes may not benefit from prophylactic ibuprofen or flurbiprofen treatment to prevent discomfort or performance decrements associated with exercise, but celecoxib may mitigate short-term performance decrements.

Comparison of postoperative analgesia in children following ropivacaine and lidocaine surgical field infiltration with epinephrine for cleft palate repair: A double-blinded, randomized controlled trial.

STUDY OBJECTIVE: The study aimed to evaluate the efficacy of ropivacaine in providing postoperative analgesia for children undergoing cleft palate repair. METHODS: A double-blinded, randomized controlled trial was conducted on sixty-four children scheduled for cleft palate repair. The patients received either local infiltration with 1% lidocaine or 0.2% ropivacaine before incision. The primary outcome was the postoperative average pain score, and secondary outcomes included pain scores at various time points, consumption of flurbiprofen and hydromorphone, effectiveness of nurse-controlled analgesia pump, and incidence of bradycardia, vomiting, and respiratory depression. MAIN RESULTS: The results showed that the postoperative average pain score was significantly lower in the ropivacaine group compared to the lidocaine group (1.27±0.28 vs. 1.75±0.29, P<0.001). Pain scores at multiple postoperative time points were also lower in the ropivac:aine group. Additionally, consumption of flurbiprofen and hydromorphone was lower, and ineffective compressions of the nurse-controlled analgesia pump were reduced in the ropivacaine group. The incidence of vomiting, bradycardia, and respiratory depression did not show significant differences between the two groups. CONCLUSION: Local infiltration with ropivacaine effectively provided postoperative analgesia for children undergoing cleft palate repair without major side effects. It was found to be superior to lidocaine in reducing the need for additional rescue analgesia.

Contribution of prophylactic administration of flurbiprofen for mesenteric traction syndrome to postoperative leakage or bleeding in gastrointestinal surgery: a retrospective observational study.

PURPOSE: Mesenteric traction syndrome (MTS) sometimes occurs during abdominal surgery. Prophylactic administration of flurbiprofen, a non-steroidal anti-inflammatory drug, prevents the development of MTS. However, administration of non-steroidal anti-inflammatory drugs for postoperative pain increases the incidence of postoperative bleeding. Our aim was to examine the effect of prophylactic flurbiprofen administration on postoperative leakage or bleeding after gastrointestinal surgery. METHODS: A retrospective observational study on patients who underwent open or laparoscopic abdominal surgery was conducted. Perioperative, anesthesia and medical records were reviewed. Patients who did (Flurbio-Group) or did not receive (Control-Group) prophylactic flurbiprofen administration were compared. Then, the Flurbio-Group and Control-Group were each divided into two groups according to whether the patients did or did not develop MTS (Flurbio-MTS-Group and Flurbio-no-MTS-Group, respectively, Control-MTS-Group and Control-no-MTS-Group, respectively). RESULTS: This study included 188 patients (Flurbio-MTS-Group, 1 patient; Flurbio-no-MTS-Group, 31 patients; Control-MTS-Group, 59 patients; Control-no-MTS-Group, 97 patients). Seventeen patients developed postoperative leakage or bleeding. Eleven Flurbio-MTS-Group patients (18.6%), 4 Flurbio-no-MTS-Group patients (12.9%, 4/31), and only 2 Control-no-MTS-Group patients (2%, 2/97) developed postoperative leakage or bleeding. Multivariate logistic regression analysis demonstrated that there was a qualitative interaction effect between prophylactic administration of flurbiprofen and the development of MTS on postoperative leakage or bleeding. CONCLUSION: Prophylactic flurbiprofen administration increased the risk of postoperative leakage or bleeding among patients who did not develop MTS.

γ-Cyclodextrin-based polypseudorotaxane hydrogels for ophthalmic delivery of flurbiprofen to treat anterior uveitis.

Anterior uveitis is a sight-threatening inflammation inside the eyes. Conventional eye drops for anti-inflammatory therapy need to be administered frequently owing to the rapid elimination and corneal barrier. To address these issues, polypseudorotaxane hydrogels were developed by mixing Soluplus micelles (99.4 nm) and cyclodextrins solution. The optimized hydrogels exhibited shear-thinning and sustained release properties. The hydrogels exhibited higher transcorneal permeability coefficient (Papp, 1.84 folds) than that of drug solutions. Moreover, animal study indicated that the hydrogels significantly increased the precorneal retention (AUC, 21.2 folds) and intraocular bioavailability of flurbiprofen (AUCAqueous humor, 17.8 folds) in comparison with drug solutions. Importantly, the hydrogels obviously boosted anti-inflammatory efficacy in rabbit model of endotoxin-induced uveitis at a reduced administration frequency. Additionally, the safety of hydrogels was confirmed by cytotoxicity and ocular irritation studies. In all, the present study demonstrates a friendly non-invasive strategy based on γ-CD-based polypseudorotaxane hydrogels for ocular drug delivery.

Application effect of dexmedetomidine combined with flurbiprofen axetil and flurbiprofen axetil monotherapy in radical operation of lung cancer and evaluation of the immune function.

PURPOSE: To explore the effect of dexmedetomidine combined with flurbiprofen axetil on postoperative analgesia and immune function in patients with lung cancer after radical operation. METHODS: 60 lung cancer patients undergoing open chest radical surgery were selected and randomly divided into D & F Group (dexmedetomidine combined with flurbiprofen axetil) and F Group (flurbiprofen axetil), with 30 cases in each group. Before induction of general anesthesia, Group F was administered intravenous flurbiprofen axetil, and in D & F group, dexmedetomidine and erfuorbiprofen axetil were injected. RESULTS: At T2 (intubation) and T3 (extubation), map and HR in D & F group were significantly lower than those in F group (p<0.05). The extubation quality score of D & F group was significantly lower than that of F group (p<0.05). At 6 h and 12 h after operation, visual analogue scale (VAS) score and Bruggrmann comfort scale (BCS) score of D & F group were significantly lower than that of F group (p<0.05). The dosage of sufentanil and the times of pressing analgesia pump in group D & F were significantly less than those in group F (p<0.05). NK cells, CD3 + T cells and CD4 + / CD8 + in the D & F group were significantly higher than those in F group at 12h, 24h, 48 h and 1 week after operation (p<0.05). CONCLUSIONS: Flurbiprofen axetil can improve postoperative pain, but combined with dexmedetomidine better effect, postoperative comfort and immune function of patients were significantly improved.

The association of topical flurbiprofen with the incidence of postoperative glaucoma after phacoemulsification in dogs.

OBJECTIVE: To investigate the relationship between topical administration of flurbiprofen plus corticosteroids versus corticosteroids alone following phacoemulsification and the development of postoperative glaucoma in dogs. ANIMAL STUDIED: Thirty-eight/eighty-three (45.8%) eyes were prescribed topical flurbiprofen plus corticosteroids immediately postop while 45/83 (54.2%) eyes received topical corticosteroids alone. PROCEDURES: Logistic regression models were performed to analyze the relationship between topical flurbiprofen and development of glaucoma and to predict potential risk factors for postoperative glaucoma occurrence. RESULTS: Eighty-three eyes (65 dogs) were included. The mean age at surgery was 8.2 years, with even gender distribution. Increasing age at the time of surgery significantly increased the probability of postoperative glaucoma occurrence (odds ratio [OR] = 1.344, 95% confidence interval [CI] 1.093-1.652; p = 0.005). Glaucoma occurred in 17/83 (20.5%) eyes; of these, 15/38 (39.5%) and 2/45 (4.4%) eyes were prescribed topical flurbiprofen plus corticosteroids and topical corticosteroids alone, respectively. Immediate postoperative use of topical flurbiprofen was significantly associated with an increased probability of postoperative glaucoma occurrence (OR = 19.183 [95% CI 3.367-109.286], p = 0.001). CONCLUSIONS: Immediate postoperative use of topical flurbiprofen was a potential predisposing risk factor for the development of glaucoma following phacoemulsification. Restriction of postoperative use of topical flurbiprofen might decrease the possibility of postoperative glaucoma development in dogs.

Effectiveness of analgesia with hydromorphone hydrochloride for postoperative pain following surgical repair of structural congenital malformations in children: a randomized controlled trial.

BACKGROUND: Effective postoperative analgesia is needed to prevent the negative effects of postoperative pain on patient outcomes. To compare the effectiveness of hydromorphone hydrochloride and sufentanil, combined with flurbiprofen axetil, for postoperative analgesia in pediatric patients. METHODS: This prospective randomized controlled trial included 222 pediatric patients scheduled for repair of a structural congenital malformation under general anesthesia. Patients were randomized into 3 groups: hydromorphone hydrochloride 0.1 mg/kg (H1), hydromorphone hydrochloride 0.2 mg/kg; (H2) or sufentanil 1.5 µg/kg (S). Analgesics were diluted in 0.9% saline to 100 ml and infused continuously at a basic flow rate of 2 mL per h. The primary outcome measure was the Face, Legs, Activity, Cry, and Consolability (FLACC) pain score. Secondary outcomes included heart rate (HR), respiration rate (RR), SpO2, Ramsay sedation scores, scores on the Paediatric Anaesthesia Emergence Delirium (PAED) scale, adverse reactions, parent satisfaction with analgesia. RESULTS: The FLACC score was significantly lower in H1 and H2 groups compared to S. The Ramsay sedation score was significantly higher in H1 and H2 groups compared to S. Recovery time was shorter in H1 group compared to patients H2 group or S group. There were no significant differences in the PAED scale, HR, RR, SpO2, adverse reactions, satisfaction of parents with analgesia, or length and cost of hospital stay. CONCLUSIONS: Hydromorphone hydrochloride is a more effective analgesic than sufentanil for postoperative pain in pediatric patients following surgical repair of a structural congenital malformation, however, hydromorphone hydrochloride and sufentanil had similar safety profiles in this patient population. TRIAL REGISTRATION: Chinese Clinical Trial Register ChiCTR-INR-17013935). Clinical trial registry URL: Date of registration: December 14, 2017.

Enhanced Dermal Delivery of Flurbiprofen Nanosuspension Based Gel: Development and Ex Vivo Permeation, Pharmacokinetic Evaluations.

PURPOSE: The objective of this study was to optimize the Flurbiprofen (FB) nanosuspension (NS) based gel and to investigate the in vitro release, ex vivo permeation, the plasma concentration-time profile and pharmacokinetic parameters. METHODS: FB-NSs were developed using the wet milling process with the Design of Experiment (DoE) approach. The optimum FB-NS was characterized on the basis of SEM, DSC, XRPD, solubility and permeation studies. The dermal gel was prepared by incorporating FB-NS into HPMC gel. Then the in-vitro release, ex vivo permeation studies were performed, and pharmacokinetic studies were evaluated on rats. RESULTS: The particle size, polydispersity index and zeta potential values of optimum NS were determined as 237.7 ± 6.8 nm, 0.133 ± 0.030 and - 30.4 ± 0.7 mV, respectively. By means of the surfactant content and nanosized particles of the nanosuspension, the solubility of FB was increased about 7-fold. The percentage permeated amount of FB from FB-NS gel (8.40%) was also found to be higher than the physical mixture (5.25%) and coarse suspension (reference) (2.08%) gels. The pharmacokinetic studies showed that the Cmax of FB-NS gel was 2.5 times higher than the reference gel, while AUC0-24 was 2.96 times higher. CONCLUSION: FB-NSs were successfully prepared with a wet milling method and optimized with the DoE approach. The optimized FB nanosuspension gel provided better permeation and pharmacokinetic performance compared to FB coarse suspension gel.

Napabucasin Drug-Drug Interaction Potential, Safety, Tolerability, and Pharmacokinetics Following Oral Dosing in Healthy Adult Volunteers.

Napabucasin is an orally administered reactive oxygen species generator that is bioactivated by the intracellular antioxidant nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1. Napabucasin induces cell death in cancer cells, including cancer stem cells. This phase 1 study (NCT03411122) evaluated napabucasin drug-drug interaction potential for 7 cytochrome P450 (CYP) enzymes and the breast cancer resistance protein transporter/organic anion transporter 3. Healthy volunteers who tolerated napabucasin during period 1 received probe drugs during period 2, and in period 3 received napabucasin (240 mg twice daily; days 1-11) plus a phenotyping cocktail containing omeprazole (CYP2C19), caffeine (CYP1A2), flurbiprofen (CYP2C9), bupropion (CYP2B6), dextromethorphan (CYP2D6), midazolam (CYP3A) (all oral; day 6), intravenous midazolam (day 7), repaglinide (CYP2C8; day 8), and rosuvastatin (breast cancer resistance protein/organic anion transporter 3; day 9). Drug-drug interaction potential was evaluated in 17 of 30 enrolled volunteers. Napabucasin coadministration increased the area under the plasma concentration-time curve from time 0 extrapolated to infinity (geometric mean ratio [90% confidence interval]) of caffeine (124% [109.0%-141.4%]), intravenous midazolam (118% [94.4%-147.3%]), repaglinide (127% [104.7%-153.3%]), and rosuvastatin (213% [42.5%-1068.3%]) and decreased the area under the plasma concentration-time curve from time 0 extrapolated to infinity of dextromethorphan (71% [47.1%-108.3%]), bupropion (79% [64.6%-97.0%]), and hydroxybupropion (45% [15.7%-129.6%]). No serious adverse events/deaths were reported. Generally, napabucasin is not expected to induce/inhibit drug clearance to a clinically meaningful degree.

Muscle Tissue as a Surrogate for In Vitro Drug Release Testing of Parenteral Depot Microspheres.

Despite the importance of drug release testing of parenteral depot formulations, the current in vitro methods still require ameliorations in biorelevance. We have investigated here the use of muscle tissue components to better mimic the intramuscular administration. For convenient handling, muscle tissue was used in form of a freeze-dried powder, and a reproducible process of incorporation of tested microspheres to an assembly of muscle tissue of standardized dimensions was successfully developed. Microspheres were prepared from various grades of poly(lactic-co-glycolic acid) (PLGA) or ethyl cellulose, entrapping flurbiprofen, lidocaine, or risperidone. The deposition of microspheres in the muscle tissue or addition of only isolated lipids into the medium accelerated the release rate of all model drugs from microspheres prepared from ester-terminated PLGA grades and ethyl cellulose, however, not from the acid-terminated PLGA grades. The addition of lipids into the release medium increased the solubility of all model drugs; nonetheless, also interactions of the lipids with the polymer matrix (ad- and absorption) might be responsible for the faster drug release. As the in vivo drug release from implants is also often faster than in simple buffers in vitro, these findings suggest that interactions with the tissue lipids may play an important role in these still unexplained observations.

Sustained-release hot melt extrudates of the weak acid TMP-001: A case study using PBB modelling.

Over the last 30 years, hot melt extrusion has become a leading technology in the manufacture of amorphous drug delivery systems. Mostly applied as an 'enabling formulation' for poorly soluble compounds, application in the design of sustained-release formulations increasingly attracts the attention of the pharmaceutical industry. The drug candidate TMP-001 is currently under evaluation for the early treatment of Multiple Sclerosis. Although this weak acid falls into class II of the Biopharmaceutics Classification System, the compound exhibits high solubility in the upper intestine resulting in high peroral bioavailability. In the present studies, four different formulation prototypes varying in their sustained-release behavior were developed, using L-arginine as a pore-forming agent in concentrations ranging between 0 and 20%. Initially, biorelevant release testing was applied to assess the dissolution behavior of the prototypes. For these formulations, a total drug release of 44.7%, 64.6%, 75%, and 90.5% was achieved in FaSSIF-v2 after 24 h. Two candidates were selected for further characterization considering the crystal structure and the physical stability of the amorphous state of TMP-001 in the formulations together with the release behavior in Level II biorelevant media. Our findings indicate L-arginine as a valuable excipient in the formulation of hot melt extrudates, as its presence led to a considerable stabilization of the amorphous state and favorably impacted the milling process and release behavior of TMP-001. To properly evaluate the proposed formulations and the importance of colonic dissolution and absorption on the overall bioavailability, a physiologically-based biopharmaceutics model was used.

Effects of Oxycodone Combined With Flurbiprofen Axetil on Postoperative Analgesia and Immune Function in Patients Undergoing Radical Resection of Colorectal Cancer.

The influence of surgery and anesthesia on immune function during the perioperative period should not be neglected. In this study, we evaluated the effects of oxycodone combined with flurbiprofen axetil on postoperative analgesia and immune function in patients undergoing radical resection of colorectal cancer (CRC). One hundred and thirty-three were randomized into the oxycodone combined with flurbiprofen axetil (OF) group or the sufentanil combined with flurbiprofen axetil (SF) group. Patients in the OF group were prescribed oxycodone hydrochloride 0.1 mg/kg combined with flurbiprofen axetil 3 mg/kg for postoperative analgesia, whereas the SF group received sufentanil 0.1 µg/kg combined with flurbiprofen axetil 3 mg/kg. The primary outcome was visual analog scale (VAS) score. Secondary outcomes included the quantities of CD4+ , CD8+ , and natural killer (NK) T cells, tumor necrosis factor (TNF)-α level, and interleukin (IL)-6 in peripheral blood, the consumption of analgesics, and the incidence of adverse reactions, and so forth. The VAS scores at rest were similar in both group. However, the VAS scores at cough in the OF group at 8, 12, and 24 hours postsurgery were lower than those in the SF group. Compared with the SF group, the count of CD4+ T cells and ratio of CD4+ /CD8+ were higher in the OF group at 12, 24, 48, and 72 hours postsurgery, although the count of CD8+ and NK T cells was higher than that in the SF group at 48 and 72 hours postsurgery. In addition, the serum level of TNF-α and IL-6 at 12, 24, 48, and 72 hours postsurgery in the OF group was lower than that in the SF group. In addition, the incidence of postoperative nausea, postoperative vomiting, and pruritus was lower, the time to first flatus and bowel movement was earlier in the OF group. Oxycodone combined with flurbiprofen axetil applied for patient-controlled intravenous analgesia could effectively reduce pain intensity, particularly for visceral pain, and help to reverse the status of immunosuppression during radical resection of CRC.