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Current Drug Delivery 2022Oxaprozin is labeled as a Class II drug in the biopharmaceutical classification system, and its poor solubility in the entire gastrointestinal tract may be the main...
BACKGROUND
Oxaprozin is labeled as a Class II drug in the biopharmaceutical classification system, and its poor solubility in the entire gastrointestinal tract may be the main reason for its insufficient oral absorption capacity.
OBJECTIVE
The purpose of this study was to develop an oxaprozin formulation to enhance its oral absorption.
METHODS
Oxaprozin-loaded microemulsions were prepared using the titration method and pseudoternary phase diagram. Characterization experiments were performed on microemulsion preparations, including pH, particle size, shape, zeta potential, and stability (thermodynamic, dilution, and differential scanning calorimetry). Then, the in vitro release of the microemulsion and in vivo pharmacokinetics in rats were evaluated.
RESULTS
Several microemulsion formulations were prepared. The optimal formulation was 15% oleoyl macrogolglycerides, 35% Tween 20/isopropanol (Km=2), and 50% distilled water. Its particle size met the requirements, and it had a spherical shape with a negatively charged surface. This microemulsion-loaded drug was applied to in vitro release and in vivo pharmacokinetic experiments at 7.47 mg/mL. In vitro release of the oxaprozin-loaded microemulsion best fit the firstorder model, while the microemulsion preparation had a certain sustained-release effect. In vivo pharmacokinetic experiments indicated that the microemulsion formulation significantly delayed the peak time of the blood concentration and simultaneously prolonged the half-life of drug elimination.
CONCLUSION
The obtained data revealed satisfactory results for this novel microemulsion of oxaprozin, which is very meaningful for clinical trials.
Topics: Administration, Oral; Animals; Emulsions; Oxaprozin; Particle Size; Rats; Solubility
PubMed: 34521326
DOI: 10.2174/1567201818666210914092745 -
Journal of Medicinal Chemistry Nov 2022Severe acute respiratory syndrome-coronavirus-1/2 (SARS-CoV-1/2) macrodomain 3 (Mac3) is critical for replication and transcription of the viral genome and is therefore...
Severe acute respiratory syndrome-coronavirus-1/2 (SARS-CoV-1/2) macrodomain 3 (Mac3) is critical for replication and transcription of the viral genome and is therefore a potential therapeutic target. Here, we solved the crystal structure of SARS-CoV-2 Mac3, which reveals a small-molecule binding pocket. Two low-molecular-weight drugs, oxaprozin and meclomen, induced different patterns of nuclear magnetic resonance (NMR) chemical shift perturbations (CSPs). Meclomen binds to site I of SARS-CoV-2 Mac3 with binding pose determined by NMR CSP and transferred paramagnetic relaxation enhancement, while oxaprozin binds to site II as revealed by the crystal structure. Interestingly, oxaprozin and meclomen both perturb residues in site I of SARS-CoV Mac3. Fluorescence polarization experiments further demonstrated that oxaprozin and meclomen inhibited the binding of DNA-G4s to SARS-CoV-2 Mac3. Our work identified two adjacent ligand-binding sites of SARS-CoV-2 Mac3 that shall facilitate structure-guided fragment linking of these compounds for more potent inhibitors.
Topics: Humans; Binding Sites; Meclofenamic Acid; Oxaprozin; SARS-CoV-2; Viral Nonstructural Proteins; Coronavirus Papain-Like Proteases; COVID-19 Drug Treatment
PubMed: 36356292
DOI: 10.1021/acs.jmedchem.2c01168 -
Journal of Medicinal Chemistry Dec 2023The retinoid X receptors (RXRs) are ligand-activated transcription factors involved in, for example, differentiation and apoptosis regulation. Currently used reference...
The retinoid X receptors (RXRs) are ligand-activated transcription factors involved in, for example, differentiation and apoptosis regulation. Currently used reference RXR agonists suffer from insufficient specificity and poor physicochemical properties, and improved tools are needed to capture the unexplored therapeutic potential of RXR. Endogenous vitamin A-derived RXR ligands and the natural product RXR agonist valerenic acid comprise acrylic acid residues with varying substitution patterns to engage the critical ionic contact with the binding site arginine. To mimic and exploit this natural ligand motif, we probed its structural fusion with synthetic RXR modulator scaffolds, which had profound effects on agonist activity and remarkably boosted potency of an oxaprozin-derived RXR agonist chemotype. Bioisosteric replacement of the acrylic acid to overcome its pan-assay interference compounds (PAINS) character enabled the development of a highly optimized RXR agonist chemical probe.
Topics: Receptors, Retinoic Acid; Ligands; Acrylates; Retinoid X Receptors
PubMed: 38064686
DOI: 10.1021/acs.jmedchem.3c01435 -
Scientific Reports Jul 2022These days, many efforts have been made to increase and develop the solubility and bioavailability of novel therapeutic medicines. One of the most believable approaches...
These days, many efforts have been made to increase and develop the solubility and bioavailability of novel therapeutic medicines. One of the most believable approaches is the operation of supercritical carbon dioxide fluid (SC-CO). This operation has been used as a unique method in pharmacology due to the brilliant positive points such as colorless nature, cost-effectives, and environmentally friendly. This research project is aimed to mathematically calculate the solubility of Oxaprozin in SC-CO through artificial intelligence. Oxaprozin is a nonsteroidal anti-inflammatory drug which is useful in arthritis disease to improve swelling and pain. Oxaprozin is a type of BCS class II (Biopharmaceutical Classification) drug with low solubility and bioavailability. Here in order to optimize and improve the solubility of Oxaprozin, three ensemble decision tree-based models including random forest (RF), Extremely random trees (ET), and gradient boosting (GB) are considered. 32 data vectors are used for this modeling, moreover, temperature and pressure as inputs, and drug solubility as output. Using the MSE metric, ET, RF, and GB illustrated error rates of 6.29E-09, 9.71E-09, and 3.78E-11. Then, using the R-squared metric, they demonstrated results including 0.999, 0.984, and 0.999, respectively. GB is selected as the best fitted model with the optimal values including 33.15 (K) for the temperature, 380.4 (bar) for the pressure and 0.001242 (mole fraction) as optimized value for the solubility.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Artificial Intelligence; Carbon Dioxide; Oxaprozin; Propionates; Solubility
PubMed: 35907929
DOI: 10.1038/s41598-022-17350-5 -
Organic Letters Jun 2024A metal-free and mild approach for constructing 5-amino-1,2-selenazole skeletons by NBS/KSeCN-mediated -selenocyanation and nucleophilic cyclization of β-enaminones has...
A metal-free and mild approach for constructing 5-amino-1,2-selenazole skeletons by NBS/KSeCN-mediated -selenocyanation and nucleophilic cyclization of β-enaminones has been developed. Various isoselenazole compounds and the isoselenazolyl derivatives of anti-inflammatory medicines, including isosepac, oxaprozin, and ibuprofen, have been obtained with good yields. This efficient, "one-pot", and atomic economy strategy may represent an alternative route for the construction of a 1,2-selenazole framework via the "SeCN" pathway and provide new access to heterocycles containing a Se-N bond.
PubMed: 38842460
DOI: 10.1021/acs.orglett.4c01655 -
Journal of Medicinal Chemistry Apr 2021The retinoid X receptors (RXR) are ligand-activated transcription factors involved in multiple regulatory networks as universal heterodimer partners for nuclear...
The retinoid X receptors (RXR) are ligand-activated transcription factors involved in multiple regulatory networks as universal heterodimer partners for nuclear receptors. Despite their high therapeutic potential in many pathologies, targeting of RXR has only been exploited in cancer treatment as the currently available RXR agonists suffer from exceptional lipophilicity, poor pharmacokinetics (PK), and adverse effects. Aiming to overcome the limitations and to provide improved RXR ligands, we developed a new potent RXR ligand chemotype based on the nonsteroidal anti-inflammatory drug oxaprozin. Systematic structure-activity relationship analysis enabled structural optimization toward low nanomolar potency similar to the well-established rexinoids. Cocrystal structures of the most active derivatives demonstrated orthosteric binding, and profiling revealed superior PK properties compared to current RXR agonists. The optimized compounds were highly selective for RXR activation and induced RXR-regulated gene expression in native cellular and settings suggesting them as excellent chemical tools to further explore the therapeutic potential of RXR.
Topics: Animals; Binding Sites; Cell Survival; Crystallography, X-Ray; Half-Life; Humans; Ligands; Mice; Microsomes; Molecular Dynamics Simulation; Oxaprozin; Protein Isoforms; Pyrazoles; Rats; Retinoid X Receptors; Structure-Activity Relationship
PubMed: 33793232
DOI: 10.1021/acs.jmedchem.1c00235 -
Journal of Inorganic Biochemistry Jun 2023A series of copper(II), nickel(II) and cobalt(II) complexes with the non-steroidal anti-inflammatory drug oxaprozin (Hoxa) have been synthesized and characterized by...
A series of copper(II), nickel(II) and cobalt(II) complexes with the non-steroidal anti-inflammatory drug oxaprozin (Hoxa) have been synthesized and characterized by diverse techniques. The crystal structures of two copper(II) complexes, namely the dinuclear complex [Cu(oxa)(DMF)] (1) and the polymeric complex {[Cu(oxa)]·2MeOH·0.5MeOH} (12) were determined by single-crystal X-ray diffraction studies. In order to evaluate in vitro the antioxidant activity of the resultant complexes, their scavenging ability towards 1,1-diphenyl-picrylhydrazyl (DPPH), hydroxyl and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals was investigated revealing their high effectiveness against these radicals. The binding of the complexes to bovine serum albumin and human serum albumin was examined and the corresponding determined albumin-binding constants showed a tight and reversible interaction. The interaction of the complexes with calf-thymus DNA was monitored by diverse techniques including UV-vis spectroscopy, cyclic voltammetry, DNA-viscosity measurements and competitive studies with ethidium bromide. Intercalation may be proposed as the most possible DNA-interaction mode of the complexes.
Topics: Humans; Oxaprozin; Copper; Coordination Complexes; Anti-Inflammatory Agents, Non-Steroidal; Serum Albumin, Bovine; DNA; Crystallography, X-Ray
PubMed: 36966675
DOI: 10.1016/j.jinorgbio.2023.112196 -
Drug Delivery and Translational Research Feb 2020The potential for physicochemical driving forces facilitating topical transport of the lipid-soluble drug oxaprozin (OXA) was investigated using surface-enhanced Raman...
The potential for physicochemical driving forces facilitating topical transport of the lipid-soluble drug oxaprozin (OXA) was investigated using surface-enhanced Raman spectroscopy (SERS) in this study. Azone, iontophoresis (IP), and sonophoresis (SP) were combined and performed on mouse skin for the OXA transdermal penetration, and the synergistic effect was analyzed using Raman spectroscopy. The data of characteristic peak intensity were processed with overlapping peak resolving and standard normalization. The results showed that Azone promoted the transdermal penetration of OXA (5.9-fold greater than the OXA concentration of normal penetration); SP enhanced OXA transdermal penetration (5.5-fold); IP enhanced OXA transdermal penetration (4.2-fold); the combined application of Azone and SP (Azone+SP) and SP+IP can improve the enhancement coefficient of OXA transdermal penetration (8.4-fold and 6.1-fold, > 5.9, > 5.5, > 4.2), and their combined application has a synergistic effect; Azone+IP does not have a synergistic effect while the enhancement coefficient of Azone+IP (5.3-fold, < 5.9) and Azone+SP+IP (7.2-fold, < 8.4) was slightly reduced. As for the drug OXA, Azone+SP is an effective method of transdermal penetration.
Topics: Administration, Cutaneous; Animals; Azepines; Iontophoresis; Male; Mice; Oxaprozin; Permeability; Skin Absorption; Spectrum Analysis, Raman; Ultrasonography
PubMed: 31407271
DOI: 10.1007/s13346-019-00664-9 -
Clinical and Experimental Nephrology Mar 2020Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by inhibiting the urate transporter 1. The results of nonclinical... (Clinical Trial)
Clinical Trial
BACKGROUND
Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by inhibiting the urate transporter 1. The results of nonclinical studies indicated the possibility that the concomitant use of the non-steroidal anti-inflammatory drug oxaprozin affects the pharmacokinetics of dotinurad. We evaluated drug-drug interactions with respect to the pharmacokinetics and safety of dotinurad when co-administered with oxaprozin.
METHODS
This was an open-label, two-period, add-on study in healthy adult males. For a single dose of 4 mg of dotinurad with and without oxaprozin, we compared its pharmacokinetic parameters and evaluated safety.
RESULTS
This study enrolled 12 subjects, 11 of whom completed the study. The geometric mean ratio (90% confidence interval [CI]) of the urinary excretion rate of glucuronate conjugates of dotinurad after co-administration with oxaprozin compared to administration of dotinurad alone was 0.657 (0.624-0.692), while the geometric mean ratios (90% CIs) of the maximum plasma concentration and area under the plasma concentration-time curve from time zero to infinity (AUC) were 0.982 (0.945-1.021) and 1.165 (1.114-1.219), respectively. During the study, two adverse events occurred after administration of dotinurad alone and one occurred after administration of oxaprozin alone.
CONCLUSIONS
In comparison with administration of dotinurad alone, co-administration with oxaprozin was associated with a 34.3% decrease in the urinary excretion rate of the glucuronate conjugates of dotinurad, and a 16.5% increase in AUC of dotinurad. However, no clinically meaningful drug-drug interactions were observed. Administration of dotinurad alone was similar safety to co-administration with oxaprozin.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03350386.
Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Benzothiazoles; Drug Interactions; Glucuronides; Humans; Japan; Male; Oxaprozin; Sulfates; Uricosuric Agents
PubMed: 32076889
DOI: 10.1007/s10157-020-01855-2