Flurbiprofen Research Articles

Novel drug-drug co-amorphous systems of olaparib with nonsteroidal anti-inflammatory drugs with improved solubility, physical stability, antitumor activity and pharmacokinetics

Olaparib (OLA), the first FDA-approved PARP inhibitor, has been approved successively for monotherapy or maintenance treatment of ovarian, breast and pancreatic cancer. Unfortunately, the poor solubility and bioavailability of OLA have limited its application. In this study, novel drug-drug co-amorphous systems of OLA with five nonsteroidal anti-inflammatory drugs (NSAIDs), including flurbiprofen (FLU), ketoprofen (KET), ibuprofen (IBU), diclofenac (DIC) or indomethacin (IND), were prepared for improving the aqueous solubility of OLA and achieving combination therapy against ovarian cancer. These new co-amorphous products were confirmed by powder X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy. Five co-amorphous systems were more soluble and released faster than the crystalline OLA in pH 6.8 buffer, and OLA-DIC and OLA-IND showed superior physicochemical stability under accelerated storage conditions. The antitumor activities of OLA-FLU, OLA-KET, OLA-IBU and OLA-DIC against OVCAR3 cell line were approximately increased by 3.5, 2.4, 2.7, and 6.0-fold than that of OLA, respectively. Moreover, pharmacokinetic studies of co-amorphous OLA-DIC in rats revealed that the OLA exhibited 6.14-fold improvement in AUC0-t value compared with crystalline OLA. Therefore, our study suggested that OLA-NSAIDs co-amorphous systems showed the great potentials to improve the solubility, dissolution behaviors, and bio-pharmaceutical performance of OLA.

A single, maximal dose of celecoxib, ibuprofen, or flurbiprofen does not reduce the muscle signalling response to plyometric exercise in young healthy adults.

Non-steroidal anti-inflammatory drugs (NSAIDs) possess analgesic and anti-inflammatory properties by inhibiting cyclooxygenase (COX) enzymes. Conflicting evidence exists on whether NSAIDs influence signaling related to muscle adaptations and exercise with some research finding a reduction in muscle protein synthesis signaling via the AKT-mTOR pathway, changes in satellite cell signaling, reductions in muscle protein degradation, and reductions in cell proliferation. In this study, we determined if a single maximal dose of flurbiprofen (FLU), celecoxib (CEL), ibuprofen (IBU), or a placebo (PLA) affects the short-term muscle signaling responses to plyometric exercise. This was a block randomized, double-masked, crossover design, where 12 participants performed four plyometric exercise bouts consisting of 10 sets of 10 plyometric jumps at 40% 1RM. Two hours before exercise, participants consumed a single dose of celecoxib (CEL 200mg), IBU (800mg), FLU (100mg) or PLA with food. Muscle biopsy samples were collected before and 3-h after exercise from the vastus lateralis. Data were analyzed using a repeated measures (RM) ANOVA, ANOVA, or a Friedman test. Significance was considered at p < 0.05. We found no treatment effects on the mRNA expression of PTSG1, PTSG2, MYC, TBP, RPLOP, MYOD1, Pax7, MYOG, Atrogin-1, or MURF1 (all, p > 0.05). We also found no treatment effects on AKT-mTOR signaling or MAPK signaling measured through the phosphorylation status of mTORS2441, mTORS2448, RPS6 235/236, RPS 240/244, 4EBP1, ERK1/2, p38 T180/182 normalized to their respective total abundance (all, p > 0.05). However, we did find a significant difference between MNK1 T197/202 in PLA compared to FLU (p < .05). A single, maximal dose of IBU, CEL, or FLU taken prior to exercise did not affect the signaling of muscle protein synthesis, protein degradation, or ribosome biogenesis three hours after a plyometric training bout.

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.

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.

Nanocomposite Gels Loaded with Flurbiprofen: Characterization and Skin Permeability Assessment in Different Skin Species.

Nanocomposite gels consist of nanoparticles dispersed in a gel matrix. The main aim of this work was to develop nanocomposite gels for topical delivery of Flurbiprofen (FB) for humans and farm animals. Nanocomposite gels were prepared stemming from nanoparticles (NPs) freeze-dried with two different cryoprotectants, D-(+)-trehalose (NPs-TRE) and polyethylene glycol 3350 (NPs-PEG), sterilized by gamma (γ) irradiation, and gelled with Sepigel® 305. Nanocomposite gels with FB-NPs-TRE and FB-NPs-PEG were physiochemically characterized in terms of appearance, pH, morphological studies, porosity, swelling, degradation, extensibility, and rheological behavior. The drug release profile and kinetics were assessed, as well as, the ex vivo permeation of FB was assessed in human, porcine and bovine skin. In vivo studies in healthy human volunteers were tested without FB to assess the tolerance of the gels with nanoparticles. Physicochemical studies demonstrated the suitability of the gel formulations. The ex vivo skin permeation capacity of FB-NPs nanocomposite gels with different cryoprotectants allowed us to conclude that these formulations are suitable topical delivery systems for human and veterinary medicine. However, there were statistically significant differences in the permeation of each formulation depending on the skin. Results suggested that FB-NPs-PEG nanocomposite gel was most suitable for human and porcine skin, and the FB-NPs-TRE nanocomposite gel was most suitable for bovine skin.

Advancing ophthalmic delivery of flurbiprofen via synergistic chiral resolution and ion-pairing strategies

Flurbiprofen (FB), a nonsteroidal anti-inflammatory drug, is widely employed in treating ocular inflammation owing to its remarkable anti-inflammatory effects. However, the racemic nature of its commercially available formulation (Ocufen®) limits the full potential of its therapeutic activity, as the (S)-enantiomer is responsible for the desired anti-inflammatory effects. Additionally, the limited corneal permeability of FB significantly restricts its bioavailability. In this study, we successfully separated the chiral isomers of FB to obtain the highly active (S)-FB. Subsequently, utilizing ion-pairing technology, we coupled (S)-FB with various counter-ions, such as sodium, diethylamine, trimethamine (TMA), and l-arginine, to enhance its ocular bioavailability. A comprehensive evaluation encompassed balanced solubility, octanol-water partition coefficient, corneal permeability, ocular pharmacokinetics, tissue distribution, and in vivo ocular anti-inflammatory activity of each chiral isomer salt. Among the various formulations, S-FBTMA exhibited superior water solubility (about 1–12 mg/ml), lipid solubility (1< lg Pow < 3) and corneal permeability. In comparison to Ocufen®, S-FBTMA demonstrated significantly higher in vivo anti-inflammatory activity and lower ocular irritability (such as conjunctival congestion and tingling). The findings from this research highlight the potential of chiral separation and ion-pair enhanced permeation techniques in providing pharmaceutical enterprises focused on drug development with a valuable avenue for improving therapeutic outcomes.

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.

Launaea fragilis extract attenuated arthritis in rats through modulation of IL-1β, TNF-α, IL-6, NF-κB, COX-2, IL-4, and IL-10.

Launaea fragilis (Asso) Pau is a Cholistan desert medicinal plant. Launaea species are used as traditional remedies against various inflammatory conditions. The current research was designed to evaluate the anti-nociceptive, anti-inflammatory, and anti-arthritic potential of ethanolic extract of L. fragilis (Et-LF). The plant extract was prepared by triple maceration. GC-MS screening explored the presence of various bioactive phytoconstituents including n-tetracosanol-1, 1-heptacosanol, and n-hexadecanoic acid. DPPH assay demonstrated the antioxidant potential of Et-LF. Safety profile data indicated that Et-LF was safe up to the oral dose of 5000mg/kg in female rats. Anti-nociceptive activity of Et-LF was assessed in hot plate method and acetic acid-induced writhing model and the results suggested that Et-LF had significant analgesic effects in both animal models. Carrageenan, histamine, and serotonin-induced edema models were used to estimate the anti-inflammatory effects of Et-LF and were found to prevent paw edema development dose dependently. The anti-arthritic effect of Et-LF was estimated in CFA-induced arthritic rat model. Treatment with Et-LF 125, 250, 500 and flurbiprofen (FP) 10mg/kg/day significantly attenuated the paw edema, reversed the reduced body weight, and restored the altered hematological parameters in arthritic rats. Gene expression studies revealed the significant downregulation of IL-1β, TNF-α, IL-6, NF‑κB, and COX-2, and upregulation of IL-4 and IL-10 in arthritic rats treated with various doses of plant extract. Histological evaluation of ankle joints showed that Et-LF mitigated pannus formation, infiltration of inflammatory cells, and fibrous connective tissue formation in the diseased rats. Thereof, it may be concluded that the recent study demonstrated the anti-nociceptive, anti-inflammatory, and anti-arthritic effects ascribed to the signifying presence of phytoconstituents in L. fragilis.

Improvement of biomedical properties of PEO-treated titanium with flurbiprofen and exosome conjugation

Exosome (EXO)-based drug delivery systems have attained a desirable position among scientific researchers and in biomedical applications. In this study, an exosomal coating comprising the anti-inflammatory drug flurbiprofen (FLB) was applied on a commercially pure titanium (cp-Ti) substrate that had undergone surface treatment using plasma electrolytic oxidation (PEO) process. The samples were characterized through field emission scanning electron microscopy (FESEM), energy dispersive spectroscopy (EDS), X-ray diffraction (XRD), atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FTIR), and water contact angle (WCA) measurement. The results indicated that FLB was loaded onto the EXO and the formation of FLB.EXO was confirmed by FTIR, XRD, AFM and FESEM. Furthermore, FLB.EXO system was treated on PEO-treated substrates and FLB.EXO@PEO system demonstrated a considerable degree of roughness (Ra= 51.16 nm) and exceptional WCA (37.2 ± 0.7 ̊) in comparison to the other samples. The cellular inquiries were assessed through examination of the morphology of bone marrow mesenchymal stem cells (BMMSc) and the MTT assay. The cytotoxicity assessment showed that the FLB.EXO@PEO improved BMMSCs attachment without toxicity. The antibacterial efficacy was determined by means of bacterial adhesion testing against both gram-positive Staphylococcus aureus (S. aureus) and gram-negative Escherichia coli (E. coli) bacterial strains. FLB.EXO@PEO sample also revealed an excellent antibacterial rate of ∼ 86 % against S. aureus and ∼ 55 % against E. coli. Additionally, in vitro drug release evaluations indicated that sustained drug release was occurred and FLB released from FLB.EXO@PEO during 191 h that was lower than release time in FLB.EXO (120 h). Moreover, the prolonged release was confirmed by constant release rate in both of systems of FLB.EXO and FLB.EXO@PEO after 191 h and 167 h, respectively. The release kinetic of FLB.EXO and FLB.EXO@PEO followed the zero order and first-order model, respectively. Overall, the results indicate that the designed sustained release system have a high potential for development of advanced biomedical implants.

NSAIDs do not influence exercise effects on muscle size in rats or muscle protein synthesis signaling in humans

BACKGROUND: The aim of this project was to determine the impact of non-steroidal anti-inflammatory drugs (NSAIDs) on skeletal muscle adaptations to exercise. NSAIDs possess analgesic and anti‐inflammatory properties that occur by blocking cyclooxygenase (COX) enzymes, thereby inhibiting the production of prostaglandins. In the first study, we determined if low-dose chronic NSAID use affects muscle size in rodents exercising for six weeks. In the second study, we determined if a single high dose of NSAIDs effects the muscle protein synthetic signaling response to a bout of plyometric exercise. Our hypotheses were that NSAIDs would reduce both muscle size and muscle protein synthesis (MPS) signaling. METHODS: Study 1: 9-wk-old male Wistar rats (n=80) were randomized to placebo (PLA), naproxen (NAP), ibuprofen (IBU), or flurbiprofen (FLU) with or without exercise (EX) for six weeks. Exercise consisted of treadmill running at 25 m/min, for 30 minutes per day, five days per week. Soleus muscle was stained for myosin heavy chain (MHC) I or MHC IIA then analyzed for cross sectional area (CSA) and fiber type percentage. Rodent data were analyzed using a one-way ANOVA. Study 2: In a randomized, counter-balanced order, 12 participants (2 females, 10 males), performed four independent plyometric exercise bouts consisting of 10 sets of 10 plyometric jumps at 40% of their 1RM, separated by a minimum of one week. Prior to each session, participants consumed a single dose of celecoxib (CEL 200 mg), IBU (800 mg), FLU (100 mg) or PLA. Muscle biopsies were collected before (PRE) and 3-hours post (POST) exercise. Muscle was analyzed via immunoblot for the following: phospho(p)-AKT(S473), total AKT, p-mTOR (S448), total mTOR, p-S6 (S235/236), total S6, p-4EBP1, and total 4EBP1. Fold changes were calculated from PRE to POST. Data were analyzed using a repeated measures ANOVA. All data are presented as mean ± SD. RESULTS: Study 1: There was no significant difference (p&lt;0.05) in muscle CSA (PLA: 4060±517; PLA+EX: 3965±605; IBU: 3720±804; IBU+EX:4129±477; FLU: 3743±671; FLU+EX: 3649±541; NAP: 4157±1011; NAP+EX: 4123±586) or MHC IIA percentage (PLA: 10±7; PLA+EX: 10±5; IBU: 7±5; IBU+EX:9±3; FLU: 11±4; FLU+EX: 11±6; NAP: 11±4; NAP+EX: 12±3) between groups. Study 2: There was no significant difference (p&lt;0.05) in fold-change between groups for p-AKT/total AKT (PLA: 1.23±0.4; IBU: 1.13±0.3; CEL: 1.26±0.4; FLU: 1.31±0.4), p-mTOR/total mTOR (PLA: 1.21±0.2; IBU: 1.21±0.3; CEL:1.34±0.2; FLU: 1.49±0.3), p-S6/total S6 (PLA: 11.48±10.6; IBU: 10.9±6.8; CEL: 6.01±2.98; FLU: 25.25±19.38), or p-4EBP1/total 4EBP1 (PLA: 1.71± 1.35; IBU: 1.23±0.98; CEL: 1.07 ±0.64; FLU: 2.03±1.49). CONCLUSION: Chronic low-dose NSAID consumption does not influence muscle size or MHC in exercising rodents. Similarly, an acute high dose of an NSAID does not affect the MPS signaling response in exercising humans. Funding was provided by the Military Operational Medicine Research Program. The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as offcial or as reflecting the views of the Army or the Department of Defense. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Development and Characterization of Thermosensitive and Bioadhesive Ophthalmic Formulations Containing Flurbiprofen Solid Dispersions.

In this study, we aimed to develop thermosensitive and bioadhesive in situ gelling systems containing solid dispersions of flurbiprofen (FB-SDs) using poloxamer 407 (P407) and 188 (P188) for ophthalmic delivery. FB-SDs were prepared with the melt method using P407, characterized by solubility, stability, SEM, DSC, TGA, and XRD analyses. Various formulations of poloxamer mixtures and FB-SDs were prepared using the cold method and P407/P188 (15/26.5%), which gels between 32 and 35 °C, was selected to develop an ophthalmic in situ gelling system. Bioadhesive polymers Carbopol 934P (CP) or carboxymethyl cellulose (CMC) were added in three concentrations (0.2, 0.4, and 0.6% (w/w)). Gelation temperature and time, mechanical properties, flow properties, and viscosity values were determined. The in vitro release rate, release kinetics, and the release mechanism of flurbiprofen (FB) from the ophthalmic formulations were analyzed. The results showed that FB-SDs' solubility in water increased 332-fold compared with FB. The oscillation study results indicated that increasing bioadhesive polymer concentrations decreased gelation temperature and time, and formulations containing CP gel at lower temperatures and in a shorter time. All formulations except F3 and F4 showed Newtonion flow under non-physiological conditions, while all formulations exhibited non-Newtonion pseudoplastic flow under physiological conditions. Viscosity values increased with an increase in bioadhesive polymer concertation at physiological conditions. Texture profile analysis (TPA) showed that CP-containing formulations had higher hardness, compressibility, and adhesiveness, and the gel structure of formulation F4, containing 0.6% CP, exhibited the greatest hardness, compressibility, and adhesiveness. In vitro drug release studies indicated that CP and CMC had no effect below 0.6% concentration. Kinetic evaluation favored first-order and Hixson-Crowell kinetic models. Release mechanism analysis showed that the n values of the formulations were greater than 1 except for formulation F5, suggesting that FB might be released from the ophthalmic formulations by super case II type diffusion. When all the results of this study are evaluated, the in situ gelling formulations prepared with FB-SDs that contained P407/P188 (15/26.5%) and 0.2% CP or 0.2% CMC or 0.4 CMC% (F2, F5, and F6, respectively) could be promising formulations to prolong precorneal residence time and improve ocular bioavailability of FB.

Rapid identification of potential nonsteroidal anti-inflammatory drug overdose-induced liver toxicity and prediction of follow-up exposure: Integrating bioanalytical and population pharmacokinetic assay.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs that can cause liver toxicity. The aim of this study was to integrate bioanalytical and population pharmacokinetic (PopPK) assay to rapidly screen and quantify the concentrations of NSAIDs in plasma and monitor clinical safety. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous quantification of acetaminophen (APAP), flurbiprofen (FLB), aspirin (ASP), and ibuprofen (IBP), four commonly used NSAIDs. The PopPK model of the signature toxicant was analyzed based on the published literature. The LC-MS/MS method was successfully validated and applied to determine NSAID concentrations in patient plasma samples. APAP, ASP, and IBP data were best fitted using a one-compartment model, and FLB data were best fitted using a two-compartment model. Bootstrapping and visual predictive checks suggested that a robust and reliable pharmacokinetic model was developed. A fast, simple, and sensitive LC-MS/MS method was developed and validated for determining APAP, FLB, ASP, and IBP in human plasma. Combined with the PopPK model, this method was applied to rapidly analyze the concentrations of NSAIDs in clinical samples from patients presenting to the emergency department with acute liver dysfunction and monitored NSAIDs clinical safety.

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

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. 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. 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 9h. 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. 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.

The Development and Characterization of Novel Ionic Liquids Based on Mono- and Dicarboxylates with Meglumine for Drug Solubilizers and Skin Permeation Enhancers.

In this study, we synthesized a family of novel ionic liquids (ILs) with meglumine (MGM) as cations and tartaric acid (TA), azelaic acid (AA), geranic acid (GA), and capric acid (CPA) as anions, using pharmaceutical additives via simple acid-base neutralization reactions. The successful synthesis was validated by attenuated total reflection-Fourier transform infrared (ATR-FTIR) and powder X-ray diffraction (PXRD). Thermal analysis using differential scanning calorimetry confirmed the glass transition temperature of MGM-ILs to be within the range of -43.4 °C--13.8 °C. We investigated the solubilization of 15 drugs with varying pKa and partition coefficient (log P) values using these ILs and performed a comparative analysis. Furthermore, we present MGM-IL as a new skin permeation enhancer for the drug model flurbiprofen (FRP). We confirmed that AA/MGM-IL improves the skin permeation of FRP through hairless mouse skin. Moreover, AA/MGM-IL enhanced drug skin permeability by affecting keratin rather than stratum corneum lipids, as confirmed by ATR-FTIR. To conclude, MGM-ILs exhibited potential as drug solubilizer and skin permeation enhancers of drugs.

In Vitro and Biological Evaluation of Oral Fast-Disintegrating Films Containing Ranitidine HCl and Syloid® 244FP-Based Ternary Solid Dispersion of Flurbiprofen.

Flurbiprofen (FBP), a nonsteroidal anti-inflammatory drug (NSAID), is commonly used to treat the pain of rheumatoid arthritis, but in prolonged use it causes gastric irritation and ulcer. To avoid these adverse events of NSAIDs, the simultaneous administration of H2 receptor antagonists such as ranitidine hydrochloride (RHCl) is obligatory. Here, we developed composite oral fast-disintegrating films (ODFs) containing FBP along with RHCl to provide a gastroprotective effect as well as to enhance the solubility and bioavailability of FBP. The ternary solid dispersion (TSD) of FBP was fabricated with Syloid® 244FP and poloxamer® 188 using the solvent evaporation technique. The synthesized FBP-TSD (coded as TSD) was loaded alone (S1) and in combination with plain RHCl (S2) in the composite ODFs based on hydroxypropyl methyl cellulose E5 (HPMC E5). The synthesized composite ODFs were evaluated by in vitro (thickness, folding endurance, tensile strength, disintegration, SEM, FTIR, XRD and release study) and in vivo (analgesic, anti-inflammatory activity, pro-inflammatory cytokines and gastroprotective assay) studies. The in vitro characterization revealed that TSD preserved its integrity and was effectively loaded in S1 and S2 with optimal compatibility. The films were durable and flexible with a disintegration time ≈15 s. The release profile at pH 6.8 showed that the solid dispersion of FBP improved the drug solubility and release when compared with pure FBP. After in vitro studies, it was observed that the analgesic and anti-inflammatory activity of S2 was higher than that of pure FBP and other synthesized formulations (TSD and S1). Similarly, the level of cytokines (TNF-α and IL-6) was also markedly reduced by S2. Furthermore, a gastroprotective assay confirmed that S2 has a higher safety profile in comparison to pure FBP and other synthesized formulations (TSD and S1). Thus, composite ODF (S2) can effectively enhance the FBP solubility and its therapeutic efficacy, along with its gastroprotective effect.

Ethylenediamine Salt Enhances the Solubility and Dissolution of Flurbiprofen.

Drugs that are poorly soluble in water are difficult to absorb orally, resulting in low bioavailability. Flurbiprofen (FLU) is an arylpropionic acid nonsteroidal anti-inflammatory drug belonging to BCS class II, with low water solubility. In this study, a novel flurbiprofen-ethylenediamine salt (FLU-EDA) was successfully prepared via solvent crystallization. Its crystal structure was determined via single-crystal X-ray diffraction (SXRD). Further, the physicochemical properties of FLU-EDA salt were characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FT-IR). The solubility and intrinsic dissolution rate (IDR) of FLU-EDA salt in water were investigated. The results showed that compared with FLU, the solubility and IDR of FLU-EDA salt increased by 57-fold and 32-fold, respectively. This indicates that FLU-EDA salt can significantly enhance the solubility and dissolution rate of flurbiprofen in water. This study provides basic data and theory for the development of new formulations of flurbiprofen.

Chiral resolution of (±)-flurbiprofen using molecularly imprinted hydrazidine-modified cellulose microparticles

Flurbiprofen (FP) is one of the non-steroidal anti-inflammatory drugs (NSAIDs) commonly used to treat arthritic conditions. FP has two enantiomers: S-FP and R-FP. S-FP has potent anti-inflammatory effects, while R-FP has nearly no such effects. Herein, molecularly imprinted microparticles produced from hydrazidine-cellulose (CHD) biopolymer for the preferential uptake of S-FP and chiral resolution of (±)-FP were developed. First, cyanoethylcellulose (CECN) was synthesized, and the -CN units were transformed into hydrazidine groups. The developed CHD was subsequently shaped into microparticles and ionically interacted with the S-FP enantiomer. The particles were then imprinted after being cross-linked with glutaraldehyde, and then the S-FP was removed to provide the S-FP enantio-selective sorbent (S-FPCHD). After characterization, the optimal removal settings for the S- and R-FP enantiomers were determined. The results indicated a capacity of 125 mg/g under the optimum pH range of 5–7. Also, S-FPCHD displayed a noticeable affinity toward S-FP with a 12-fold increase compared to the R-FP enantiomer. The chiral resolution of the (±)-FP was successfully attempted using separation columns, and the outlet sample of the loading solution displayed an enantiomeric excess (ee) of 93 % related to the R-FP, while the eluent solution displayed an ee value of 95 % related to the S-FP.

Design, development, and evaluation of spray dried flurbiprofen loaded sustained release polymeric nanoparticles using QBD approach to manage inflammation

Spray-dried Flurbiprofen (FLB) loaded polymeric nanoformulation using Eudragit L 100 and Ethylcellulose. They were optimized and evaluated. This study determined drug release (%) and encapsulation efficiency (%) by developing a nanoparticulate system using the design of experiment (DoE) approach. FLB is slightly soluble in water; it dissolves slowly and has a low oral bioavailability. FLB-loaded polymeric nanoparticles were produced by solvent evaporation and Spray drying technology. In this research, nanoparticle formulation was prepared by screening and optimization by approaching two different statistical methods (Plackett-Burman and Central composite Designs). The polymeric nanoparticles were evaluated for various characteristics, including drug release, percentage of encapsulation efficiency, X-ray diffraction (X-RD), surface morphology, and Fourier transform infrared (FTIR) spectroscopy. Based on the X-RD analysis, it was found that the drug was successfully incorporated into the polymeric nanoparticles. As a result of nanoparticles containing FLB, % Drug release values were found to be nearly 85-90% increased while % EE was observed in the range of 79-89%. An excellent sustained release, i.e., 14 h, is possible by combining Ethylcellulose (EC) and Eudragit L 100 (ED-100) polymers. The results are beneficial in identifying the ideal formulation parameters for effective encapsulation. Abbreviations: FLB: Flurbiprofen; API: Active pharmaceutical ingredient; DR: Drug release; EE: Encapsulation efficiency; DoE: Design of experiment; X-RD: X-ray diffraction; FTIR: Fourier transform infrared spectroscopy.; PVA: Polyvinyl alcohol; EC: Ethylcellulose; EUGD: Eudragit L 100; NPs: Nanoparticles; PBD: Placket- Burman Design; CCD: Central Composite Design; CMV: Critical method variables; GIT: Gastrointestinal track; SLN: Solid lipid nanoparticles; NLC: Nanostructured lipid carriers; NSAID: Nonsteroidal anti-inflammatory drug; BCS: Biopharmaceutical classification system; PS: Particle size; PDI: Polydispersity Index; ZP: Zeta potential; FE-SEM: Field emission scanning electron microscopy; 2D: 2 Dimensional; 3D: 3 Dimensional

Dual cross-linked gellan gum/gelatin-based multifunctional nanocomposite hydrogel scaffold for full-thickness wound healing

Biological macromolecules are excellent materials for wound dressing owing to their similar structure to the extracellular matrix and adjustable physicochemical properties. This research focuses on fabricating biological macromolecule-based hydrogel with desirable antibacterial, antioxidant, controlled drug release, cytocompatibility, and wound healing properties. Herein, different concentrations of nanoceria (NC) and flurbiprofen (FLU) drug-loaded gellan gum/gelatin (GG/Ge) based dual crosslinked (Ionic and EDC/NHS coupling) hydrogels were engineered.All fabricated hydrogels were hydrophilic, biodegradable, good strength, porous, antioxidant, hemocompatible and cytocompatible. Among all, hydrogel loaded with 500 μg/ml NC (GG/Ge/NC@FLU) exhibited desirable antioxidant, antibacterial (killed Staphylococcus aureus and Escherichia coli within 12 h), hemocompatible, cytocompatible, supports oxidative-stressed L929 cell growth and acted as a controlled release matrix for FLU, following Fickian diffusion, Peppas Sahlin and Korsmeyer-Peppas drug release models.Furthermore, nanocomposite hydrogel (GG/Ge/NC@FLU)-treated wounds of rats on day 14 demonstrated significantly higher collagen synthesis, nearly 100 % wound contractions, and efficiently decreased the expression of TNF-α and IL-1 while increasing the production of IL-10 and TNF-ß3, indicating antiinflammatory activity, and effectively reduced the expression of VEGF gene indicating effective angiogenesis than all other controls. In conclusion, the fabricated multifunctional GG/Ge/NC@FLU nanocomposite hydrogel shows promising potential for effectively treating full-thickness wound healing in a rat model.

In Vitro and In Vivo Evaluation of Composite Oral Fast Disintegrating Film: An Innovative Strategy for the Codelivery of Ranitidine HCl and Flurbiprofen.

Here, we evaluate the feasibility of co-loading plain ranitidine hydrochloride (RHCl) and microencapsulated flurbiprofen (FBP) in a Lycoat® RS780-based oral fast disintegrating film (ODF). These films were developed by the solvent casting method to minimize the adverse effects of FBP and reduce the dosage form burden on patients. Optimized FBP microparticles (M3) with an average size of 21.2 ± 9.2 µm were loaded alone (F1) and in combination with plain RHCl (F2) in the composite ODF. All films were evaluated physicomechanically and physicochemically. These films were resilient, flexible, and disintegrated within thirty seconds. SEM images showed intact FBP microparticles in both formulations and, moreover, did not observe an interaction between the drug and film components. Microencapsulated FBP was released in a controlled manner over 48 h from the proposed formulations, while RHCl was released within 5 min from F2. After in vitro evaluation, formulations were also tested for in vivo anti-inflammatory activity, cytokine (TNF-α and IL-6) levels, and gastroprotective effects in rats. The anti-inflammatory activity and gastroprotective effect of F2 were markedly higher than pure FBP and other synthesized formulations (M3 and F1). The average score of gastric lesions was in the order of pure FBP (15.5 ± 1.32) > M3 (8 ± 2) > F1 (1 ± 0.5) > F2 (0.5 ± 0) > control (0). Additionally, F2 showed a sustained anti-inflammatory effect up to 10 h in the rat paw edema model. Furthermore, F2 also markedly reduced TNF-α and IL-6 levels. Conclusively, the Lycoat® RS780-based composite film could be a promising carrier for the co-loading of microencapsulated FBP with RHCl. In the future, an optimized formulation (F2) could be capable of countering the issues related to multiple drug administration in geriatric patients and evading the gastric irritation associated with FBP.