White analytical chemistry-driven stability-indicating concomitant chromatographic estimation of thiocolchicoside and aceclofenac using response surface analysis and red, green, and blue model.

White analytical chemistry is a novel concept for the assessment of analytical methods on basis of its validation efficiency, greenness power, and economical efficiency. White analytical chemistry-driven stability indicating chromatographic method has been developed for the concomitant analysis of thiocolchicoside and aceclofenac. The proposed chromatographic method has been developed using a safe and environmental-friendly organic solvents for the concomitant stability study of thiocolchicoside and aceclofenac. The analytical risk assessment was carried out for the identification of high-risk analytical risk factors and analytical method performance attributes. The mixture design was applied for the design of experiments-based response surface modeling of high-risk analytical risk factors and analytical method performance attributes. The degradation products were isolated and characterized using infrared, nuclear magnetic resonance, and mass spectral data. The proposed method was compared for its validation efficiency, greenness power, and cost-efficiency with published chromatographic methods using the red, green, and blue models. The white score of the proposed and reported method was calculated by averaging the red, green, and blue scores of the methods. The proposed method was found to be robust, green, and economical for the concomitant stability study of thiocolchicoside and aceclofenac.

Eutectic phase transition during tablet manufacture: effect of melting point of eutectic forming drug.

The aim was to investigate eutectic transition during tableting and storage. Mixtures of lidocaine and series of NSAIDs with increasing melting point were used as model systems to guide formulators to scaleup eutectic forming materials gaining enhanced dissolution while avoiding deleterious physical changes. Physical mixtures of NSAIDs with lidocaine were prepared at eutectic forming ratio. These were directly compressed, dry co-ground before compression, or compressed after wet granulation. Dissolution of tablets was compared to corresponding dry co-ground mixture. Thermograms of direct compressed tablet were compared to co-ground mixture and pure compound. Stability of direct compressed tablets was assessed. Tableting initiated eutexia which enhanced dissolution of NSAIDs. Eutexia was associated with tablet softening in case of low melting point ketoprofen and aceclofenac. Wet granulation hastened eutexia developing unacceptable tablet in case ketoprofen and aceclofenac. Tablets prepared by direct compression of physical mixtures underwent gradual eutectic transition upon storage with the magnitude of eutectic transition reducing with increased melting point of NSAIDs. Ketoprofen was physically unstable but aceclofenac degraded chemically as well. Tenoxicam and meloxicam tablets were physically and chemically stable. Direct compression after physical mixing is the best tableting technique, but low melting point drugs should consider different strategy before compression.

Development of a New Voltammetric Method for Aceclofenac Determination on Glassy Carbon Electrode Modified with Hierarchical Nanocomposite.

Aceclofenac (ACL) is an anti-inflammatory drug, which is taken by patients who mainly suffer from rheumatoid conditions. In this work, we propose a new voltammetric method that allows the determination of ACL in pharmaceutics, urine, and plasma. As a working electrode, a glassy carbon electrode (GCE) modified with carbon nanofibers, carbon nanotubes, and NiCo nanoparticles (eCNF/CNT/NiCo-GCE) was used. The mentioned sensors are characterized by good repeatability and sensitivity, and their process of preparation is simple, fast, and cost-effective. Instrumental and method parameters were optimized, and the influence of interferences was investigated. To validate the analytical performance of the method, calibration was conducted. Good linearity was obtained (0.05-1.4 µM, r = 0.998), as well as excellent limit of detection (LOD) and limit of quantification (LOQ) values (0.7 nM and 2.1 nM, respectively). Calculated recoveries that were in the range of 98%-105% indicate that this method is accurate and might be used in routine laboratory practice.

Physicomechanical, stability, and pharmacokinetic evaluation of aceclofenac dimethyl urea cocrystals.

Poor physicomechanical properties and limited aqueous solubility restrict the bioavailability of aceclofenac when given orally. To improve its above properties, aceclofenac (ACE) was cocrystallized with dimethyl urea (DMU) in 1:2 molar ratio by dry and solvent assisted grinding. The cocrystals were characterized by ATR-FTIR, DSC, and PXRD, and their surface morphology was studied by SEM. There was enhancement in intrinsic dissolution rate (IDR) (~eight- and ~fivefold in cocrystals prepared by solvent assisted grinding (SAG) and solid state grinding (SSG), respectively, in 0.1 N HCl, pH 1.2) and similarly (~3.42-fold and ~1.20-fold in phosphate buffer, pH 7.4) as compared to pure drug. Additionally, mechanical properties were assessed by tabletability curves. The tensile strength of ACE was < 1 MPa in contrast to the cocrystal tensile strength (3.5 MPa) which was ~1.98 times higher at 6000 psi. The tablet formulation of cocrystal by direct compression displayed enhanced dissolution profile (~36% in 0.1 N HCl, pH 1.2, and ~100% in phosphate buffer, pH 7.4) in comparison to physical mixture (~ 30% and ~ 80%) and ACE (~18% and ~50%) after 60 min, respectively. Stability studies of cocrystal tablets for 3 months indicated a stable formulation. Pharmacokinetic studies were performed by using rabbit model. The AUC0-∞ (37.87±1.3 µgh/ml) and Cmax (6.94±2.94 µg/ml) of the selected cocrystal C1 prepared by SAG were significantly enhanced (p < 0.05) and were ~3.43 and ~1.63-fold higher than that of ACE. In conclusion, new cocrystal of ACE-DMU was successfully prepared with improved tabletability, in vitro and in vivo properties.

The association between nonsteroidal anti-inflammatory drugs and skin cancer: Different responses in American and European populations.

OBJECTIVE: To conduct a comprehensive systematic meta-analysis investigating the association of nonsteroidal anti-inflammatory drugs (NSAIDs) and their subtypes with skin cancer (SC) and its subclasses (basal cell carcinoma BCC; squamous cell carcinoma SCC; melanoma; nonmelanoma skin cancer NMSC) in general, American and European populations. METHODS: PubMed, Embase, the Cochrane Library, the China National Knowledge Infrastructure and ClinicalTrials.gov were searched up to 24 February 2019. Pooled effect sizes and 95% confidence intervals were used to estimate associations. RESULTS: Results based on 26 original studies including 223,619 cases and 1,398,507 controls showed both NSAIDs and nonselective Cyclooxygenase (COX) inhibitors to be statistically significantly associated with a reduced risk of SC, BCC, SCC and NMSC but not with melanoma. Conversely, no association was observed between selective Cyclooxygenase 2 (COX-2) inhibitors and SC or its subclasses. Further subgroup analysis showed that the results analyzed for American populations were almost the same as those for the general population. For European populations, neither NSAIDs nor its subtypes correlated significantly with susceptibility to SC or its subclasses. CONCLUSIONS: The use of NSAIDs might reduce the risk of SC, but many factors including study population, drug subtype, and disease subclass affect the significance of the association.

Effect of lipid and edge activator concentration on development of aceclofenac-loaded transfersomes gel for transdermal application: in vitro and ex vivo skin permeation.

The present investigation focused mainly on the development of aceclofenac (AF) loaded transfersomal gel (AF-TG) to minimize the frequency of oral dosing during the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. AF-loaded transfersomes (AF-TS) were prepared by using the film hydration method. The effect of drug loading, pH of hydration medium, edge activator (EA) and lipid concentration on the properties of the AF-TS were studied and optimized. Optimized AF-TS converted into AF-TG by the addition of carbopol 934. Morphology and compatibility studies of AF-TS were observed with scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). AT-TG formulation was evaluated further for ex vivo skin permeation studies compared with marketed Hifenac 30 g gel. Optimized AF-TS showed vesicle size, PDI, and zeta potential of 111.1 ± 3.2 nm, 0.19 ± 0.02, and -29.6 ± 1.2 mV, respectively. Entrapment efficiency of 74.1 ± 1.8% with pH 5.8 phosphate buffer as a hydration medium and 17.1 ± 0.9 elasticity at 0.15%w/v EA and 1%w/v lipid concentration were observed. SEM and DSC studies revealed the spherical shape and no incompatibilities in the AF-TS formulation. The permeability of the AF from AF-TG was enhanced by 14-folds with similar rheological properties compared with marketed gel. Overall, TG containing AF was superior to marketed AF gel formulation for enhanced skin delivery. Therefore, TS and TG formulation could be considered as an alternative delivery approach for the enhanced transdermal application of AF.

[Assessment of the safety, tolerability and effectiveness of first Russian generic aceclofenac in patients with undifferentiated peripheral inflammatory arthritis].

AIM: To evaluate the effectiveness and tolerability of the drug in patients with undifferentiated peripheral inflammatory arthritis (UPIA). MATERIALS AND METHODS: We observed 60 patients (39 women and 21 men) met G. Hazlewood et al., UPIA criteria, 2011. Patients were divided into 3 groups: with monoarthritis, oligoarthritis and polyarthritis. They took aceclofenac 100 mg twice day for 3 weeks. RESULTS: We noted significant decreasing in pain level according to visual analogue scale: in patients with monoarthritis by 69.3 mm (p0.001); in oligoarthritis group by 47.5 mm (p0.001), in patients with polyarthritis by 30 mm (p0.001). The life quality by the EQ-5D-5L index was improved too in all groups from 0.616 to 0.829 (p0.001). The satisfaction with the therapy was: in monoarthritis patients (80% of patients and 93% of doctors noted good results), in oligoarthritis group (53% and 39% accordingly) and polyarthritis (74% and 64% respectively). We suppose the difference was due to the fact that mono- and oligoarthritis patients suffered from initial forms of seronegative spondylarthropathy, in which the effectiveness of NSAIDs is traditionally higher; polyarthritis patients probably had debut of rheumatoid arthritis. Adverse events of therapy were mild. We noted gastrointestinal tract symptoms (dyspepsia) and increased ALT in 10 patients and increased blood pressure in 1 patient. The symptoms did not require discontinuation of therapy. Сonclusion. Post-registration observational study of first Russian generic aceclofenac (Alental, Vertex, Russia) was conducted. In UPIA patients aceclofenac therapy was most effective in mono- and oligoarthritis patients. The first Russian generic aceclofenac (Alental, Vertex, Russia) has good efficacy, tolerability and safety and can be recommended for arthritis treatment.

In situ composite ion-triggered gellan gum gel incorporating amino methacrylate copolymer microparticles: a therapeutic modality for buccal applicability.

The aim of the current investigation is to delineate the buccal applicability of an in situ composite gel containing aceclofenac (AC) amino methacrylate copolymer microparticles (MPs), surmounting limitations of oral existing conventional therapy. AC Eudragit RL100 MPs were fabricated and statistically optimized using 2241 factorial design. Better buccal applicability and enhanced localization were achieved by combining the optimum MPs with in situ ion-activated gellan gum gel. The crosslinking and gelation of in situ gel were investigated by morphological and solid state characterizations. Suitability for buccal delivery and in vivo therapeutic efficacy in inflammation model of rats were also assessed. Results showed that the best performing formula displayed particle size (PS) of 51.00 µm and high entrapment efficiency (EE%) of 94.73%. MPs were successfully entrapped inside the gel network of the composite system. Gelation tendency, pH, shear-thinning properties and mucoadhesivity of the prepared in situ composite gel guaranteed its buccal suitability. Sustained AC release features and promising in vitro anti-arthritic response were also demonstrated. Moreover, consistent and prolonged in vivo anti-inflammatory effect was achieved, relative to standard AC. Taken together; this study proves the potential of in situ composite gel as an appropriate therapeutic proposal for AC buccal delivery.

Aceclofenac-Galactose Conjugate: Design, Synthesis, Characterization, and Pharmacological and Toxicological Evaluations.

Aceclofenac is a popular analgesic, antipyretic, and nonsteroidal anti-inflammatory drug (NSAID) used for prolonged treatment (at least three months) in musculoskeletal disorders. It is characterized by several limitations such as poor water solubility and low oral bioavailability. The main side-effect of aceclofenac, as well as all NSAIDs, is the gastrotoxicity; among other adverse effects, there is the risk of bleeding since aceclofenac reversibly inhibits platelet aggregation. With the aim to reduce these drawbacks, we have designed, synthesized, and characterized, both in vitro and in vivo, an orally administrable pro-drug of aceclofenac (ACEgal). ACEgal was obtained by conjugating carboxyl group with the 6-OH group of d-galactose; its structure was confirmed by X-ray powder diffractometry. The pro-drug was shown to be stable at 37 °C in simulated gastric fluid (SGF-without pepsin, pH = 1.2) and moderately stable in phosphate buffered saline (PBS, pH = 7.4). However, it hydrolyzed in human serum with a half-life ( t1/2) of 36 min, producing aceclofenac. Furthermore, if compared to its parent drug, ACEgal was four-times more soluble in SGF. To predict human intestinal absorption, cell permeability in a Caco-2 model of aceclofenac and ACEgal was determined. Anti-inflammatory, analgesic, and ulcerogenic activities have been investigated in vivo. In addition, oxidative stress parameters (thiobarbituric acid reactive substances, TBARS, and glutathione, GSH) and platelet antiaggregatory activity both of parent drug and pro-drug were evaluated. Results clearly showed that the conjugation of aceclofenac to a galactose molecule improves physicochemical, toxicological (at gastric and blood level), and pharmacological profile of aceclofenac itself without changing intestinal permeability and antiplatelet activity (in spite the new sugar moiety).

Liquid chromatography-tandem MS/MS method for simultaneous quantification of paracetamol, chlorzoxazone and aceclofenac in human plasma: An application to a clinical pharmacokinetic study.

A facile, fast and specific method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the simultaneous quantitation of paracetamol, chlorzoxazone and aceclofenac in human plasma was developed and validated. Sample preparation was achieved by liquid-liquid extraction. The analysis was performed on a reversed-phase C18 HPLC column (5 µm, 4.6 × 50 mm) using acetonitrile-10 mM ammonium formate pH 3.0 (65:35, v/v) as the mobile phase where atrovastatin was used as an internal standard. A very small injection volume (3 µL) was applied and the run time was 2.0 min. The detection was carried out by electrospray positive and negative ionization mass spectrometry in the multiple-reaction monitoring mode. The developed method was capable of determining the analytes over the concentration ranges of 0.03-30.0, 0.015-15.00 and 0.15-15.00 µg/mL for paracetamol, chlorzoxazone and aceclofenac, respectively. Intraday and interday precisions (as coefficient of variation) were found to be ≤12.3% with an accuracy (as relative error) of ±5.0%. The method was successfully applied to a pharmacokinetic study of the three analytes after being orally administered to six healthy volunteers.

Factors affecting the results of analgesic therapy. Results of the Russian multicentre study of NOTE (NSAID: Open-label Trial of Efficacy).

AIM: To identify factors affecting the effectiveness of NSAIDs in patients with OA and LBP. MATERIALS AND METHODS: An observational study was conducted to evaluate the effectiveness of a 2-week course of NSAIDs in OA and LBP in real clinical practice. The study group consisted of 3604 patients with OA and LBP (60.6% women and 39.4% men, mean age 55.0±13.4 years). According to the study design, aceclofenac (Airtal) and other NSAIDs used in the ratio 1:1. The main criterion of effectiveness was the frequency of complete pain relief after 2 weeks of therapy. In addition, the decrease of pain and general health were determined on a 10-point numerical rating scale (NRS). We compared the frequency of complete pain relief in patients who had and did not have the studied factors. The value of the studied factors was determined using OR (95% CI). RESULTS: Most patients received aceclofenac (54.9%), as well as diclofenac (2.0%), ketoprofen (1.9%), lornoxicam (2.2%), meloxicam (13.7%), naproxen (2.1%), nimesulide (5.8%), celecoxib (5.9%), ethicoxib (7.1%) and other NSAIDs (4.4%); 56.2% of patients received muscle relaxants, mainly tolperisone (74.7%), vitamin B (10.4%), and proton pump inhibitors (42.8%). Complete pain relief was achieved in 54.8% of patients. The pain decrease and general health improvement were (for NRS) 63.9±13.4% and 61.7±14.8%, respectively. The efficacy of aceclofenac was slightly higher than in the whole group: complete pain relief was in 59.9% of patients. Adverse events in aceclofenac use were observed in 2.3% of patients, other NSAIDs-from 2.4 to 14.1%. The frequency of complete pain relief was higher in men: OR 1,239 (95% CI 1.08-1.418; p=0.002), who had the first episode of pain - OR 3.341 (95% CI 2.873-3.875; p=0.000), a good" response " to NSAIDs in history - OR 1.656 (95% CI 1.385-1.980; p=0.000) and received NSAIDs in combination with muscle relaxants - OR 1.218 (95% CI 1.067-1.390; p=0.004). The effect of therapy is lower in patients 65 years and older-OR 0,378 (95% CI 0.324-0.442; p=0,000), with body mass index >30 kg/m² - OR 0.619 (95% CI 0.529-0.723; p=0.000), with severe pain (≥7 points NRS) - OR 0.662 (95% CI 0.580-0.756; p=0.002), with pain at rest, - OR 0.515 (95% CI 0.450-0,589; p=0.000), pain at night - OR 0.581 (95% CI 0.501-0.672; p=0.000) and the presence of stiffness - OR 0.501 (95% CI 0.438-0,573; p=0.000). Treatment results are significantly worse in the cases of combination of LBP and joint pain, as well as pain in the trochanter major and pes anserinus area (p<0.001). CONCLUSION: NSAIDs are the first-line medications for the pain treatment in LBP and OA. Aceclofenac is effective and safe in this conditions. When carrying out analgesic therapy should take into account factors that affect the effectiveness of treatment: old age, overweight, insufficient effect of NSAIDs in history, severe pain, signs of "inflammatory" pain, multiple sources of pain.

Functionalized Lipid-Polymer Hybrid Nanoparticles Mediated Codelivery of Methotrexate and Aceclofenac: A Synergistic Effect in Breast Cancer with Improved Pharmacokinetics Attributes.

The present study was aimed to coencapsulate methotrexate (MTX) and aceclofenac (ACL) in fucose anchored lipid-polymer hybrid nanoparticles (Fu-LPHNPs) to achieve target specific and controlled delivery for developing therapeutic interventions against breast cancer. The effective combination therapy requires coadministration of drugs to achieve synergistic effect on tumor with minimum adverse effects. Present study investigates the potential of codelivery of MTX and ACL through LPHNPs in MCF-7 and triple negative breast cancer cells (MDA-MB-231). We obtained LPHNPs in the nanosize range (<150 nm) with better particle size distribution (<0.3). The entrapment and loading efficiency of MTX and ACL was calculated as 85-90% and 10-12%, respectively. The coumarin-6 LPHNP formulations showed rapid internalization within 2 h incubation with MCF-7 and MDA-MB-231 cells. With 8-10 times, greater bioavailability of drug-loaded LPHNPs than free MTX and ACL was obtained. Also, antitumor efficacy of MTX- and ACL-loaded LPHNPs was determined on DMBA-induced experimental breast cancer mouse model. This model showed better control over tumor growth with MTX- and ACL-loaded LPHNPs than the combination of MTX and ACL or MTX alone. ACL-loaded LPHNPs showed prophylactic and anticancer activity in DMBA-induced mouse model at higher dose (10 mg/kg). ACL-LPHNPs confer synergistic anticancer effect when administered in combination with MTX. In conclusion, ACL enhances the therapeutic and anticancer efficacy of MTX, when coencapsulated into fucose-anchored LPHNPs, as confirmed by cell viability and serum angiogenesis (IL-6, TNF-α, IL-1ß, COX2, and MMP1) at both transcript and proteome level.

Synthesis and Pharmacological Evaluation of Acrylate-Based Gastrosparing NSAID Prodrugs.

Dexibuprofen and aceclofenac are well-known NSAID molecules, their oral use leads to gastrointestinal (GI) toxicity. To circumvent that GI toxicity, the prodrug approach is a better alternative. Hence, this research was undertaken to synthesize prodrugs of dexibuprofen and aceclofenac using acrylic polymers with degradable ester bonds. Dexibuprofen was linked to 2-hydroxypropyl methacrylate by an activated ester technique. The resulting material was copolymerized with 2-hydroxyethyl methacrylate and methyl methacrylate (in 1:3 mole ratios) by the free radical polymerization method, utilizing azoisobutyronitrile at 65-70°C. Similarly aceclofenac was also processed. The resulting prodrugs were characterized by IR, NMR, and elemental analysis. The synthesized prodrugs possess optimal physicochemical characteristics such as the intended molecular weight, lipophilicity, partition coefficient, and protein binding. The drug release on hydrolysis was studied in various fluids such as SGF (pH 1.2), SIF (pH 7.4), and SCF (pH 6.8), to establish the drug release kinetics. Pharmacological evaluation exhibited anti-inflammatory activity with remarkable reduction in ulcerogenicity compared to the parent drug. Under the conditions used, the prodrugs showed no antigenicity in Wistar rats. Thus, it was concluded that acrylic-based prodrugs were efficient in drug localization in the stomach, without gastric problems.

[Evaluation of the efficacy of pregabalin in the therapy of chronic pain in patients with knee osteoarthritis]. / Otsenka éffektivnosti pregabalina v terapii khronicheskoi boli u patsientov s osteoartrozom kolennykh sustavov.

AIM: To evaluate the efficacy of pregabalin in the therapy of chronic pain in patients with knee osteoarthritis (KOA). SUBJECTS AND METHODS: The study enrolled 60 patients with KOA and neuropathic pain component (NPC) (Douleur Neuropathique en 4 questions (DN4) questionnaire scores, >4) who were randomized into two groups to receive aceclofenac or aceclofenac + pregabalin for 5 weeks. All the patients underwent clinical and neurological examinations, assessment of the functional WOMAC index, pain intensity at rest and during movement, and diagnosis of neuropathic pain (NP) (DN4 and Pain DETECT questionnaires). RESULTS: Both groups were observed to have positive changes in the studied parameters; however, combination therapy using an anticonvulsant drug (pregabalin) showed a more pronounced positive effect against not only NPC, but also the functional activity (WOMAC) and severity of pain (visual analogue scale). CONCLUSION: Combination therapy using pregabalin in KOA patients having the signs of NP is more effective than monotherapy with nonsteroidal anti-inflammatory drugs (aceclofenac).

[Therapy for acute/subacute musculoskeletal pain: results of the ATUSA (Analgesic Treatment Using a Systemic Algorithm) observational study]. / Terapiia ostroi/podostroi skeletno-myshechnoi boli: rezul'taty nabliudatel'nogo issledovaniia ALISA (Anal'geticheskoe Lechenie s Ispol'zovaniem Sistemnogo Algoritma).

AIM: To evaluate the efficiency of therapy for acute/subacute musculoskeletal pain (MSP) by applying an individualized pathogenetic approach (an algorithm) elaborated on the basis of Russian experts' recommendations. SUBJECTS AND METHODS: A total of 262 physicians treating patients with rheumatic diseases participated in the ATUSA (Analgesic Treatment Using a Systemic Algorithm) program. The study enrolled 3,304 patients (54.3% women, 45.7% men; mean age, 48.6±14.3 years) with osteoarthritis, nonspecific back pain (NBP), and rheumatic diseases of periarticular soft tissues, who had experienced MSP. Treatment was performed in accordance with the following algorithm: the first prescribed medication was nonsteroidal anti-inflammatory drugs (NSAIDs) (aceclofenac): paracetamol and/or tramadol and a topical NSAID in case of contraindications and muscle relaxants in case of indications. The results of treatment were assessed after 7, 14, and 28 days. The treatment was corrected during each visit; the NSAID was, if necessary, changed; corticosteroids were locally injected; antidepressants or anticonvulsant drugs were used. The investigators assessed dynamic changes in pain using a 0-10 paint intensity numeric rating scale (NRS), the number of patients, in whom MSP was completely relieved, and satisfaction with treatment. RESULTS: The first prescribed medication was oral NSAIDs in 97.5% of the patients and those in combination with a muscle relaxant in 67.6%. By visit 4, MSP decreased from 6.9±1.5 to 2.2±1.3 NRS scores. After 28 days, only 16.2% of patients continued to need analgesics. 88.4% of the patients rated treatment results as good or excellent. NSAID switching was required in 8.1% of cases; local glucocorticosteroid injections were needed in 1.9%; there was a need for the use of an antidepressant or anticonvulsant in 1.5% and for hospitalization in 0.25%. Adverse events were observed in 2.2% of patients. The efficiency of treatment (complete pain relief after 28 days) was influenced by the following factors: NRS diagnosis (OR, 2.24; 95% CI, 1.67 to 3.11), age ≥65 years (OR, 0.72; 95% CI, 0.52 to 0.98), moderate pain (NRS scores of ≤7) at the beginning of the study (OR, 2.63; 95% CI, 1.99 to 3.48), mild/moderate pain (NRS scores of <4) after 7 days of therapy (OR, 2.5; 95% CI, 1.89 to 3.33), and the use of muscle relaxants (OR, 1.77; 95% CI, 1.23 to 2.96) (p<0.05 for all comparisons). CONCLUSION: The comprehensive pathogenetic approach used in analgesic therapy provides an effective and relatively safe relief of MSP in most patients with NBP and osteoarthritis.

A pH-triggered delayed-release chronotherapeutic drug delivery system of aceclofenac for effective management of early morning symptoms of rheumatoid arthritis.

CONTEXT: Rheumatoid arthritis (RA) is differentiated as an early morning exacerbation of the core arthritis condition associated with increase in pain and stiffness in joints and necessitate for medication. OBJECTIVE: The aim of the present work was to develop and optimise a pH-triggered delayed-release colon-specific aceclofenac microspheres and to accomplish chronotherapy of RA. METHODS: A 3-factor, 3-level Box-Behnken design (BBD) was used to optimise selected variables. Developed formulation was evaluated for in vivo delayed response and anti-arthritis activity in rats. RESULTS: The particle size and encapsulation efficacy of these microspheres were 117.36 ± 10.54 µm and 85.06 ± 5.85%, respectively. Optimised formulation was analysed by SEM, DSC, X-RPD and FTIR. The in vivo evaluation revealed delayed anti-inflammatory activity in carrageenan-induced rats and anti-arthritic activity in freund's adjuvant-induced arthritis rats. CONCLUSION: The optimised aceclofenac microspheres formulation is potential for the chronotherapy of early morning symptoms of RA.

A novel approach to formulation factor of aceclofenac eye drops efficiency evaluation based on physicochemical characteristics of in vitro and in vivo permeation.

The purpose of the present study was to evaluate aceclofenac eye drop through excised goat cornea. Raising pH of the formulation from 6.0 to 8.0, effect of different preservatives or effect of viscosity enhancer decreases apparent permeability coefficient. Topical ophthalmic NSAID are used to treat ocular surface and anterior segment inflammation as well as post operative management of pain and inflammation. Aceclofenac's unique chemical structure makes it both a potent anti inflammatory drug and lipophilic molecule that penetrates ocular tissue, ensuring relief of pain in cataract and refractive surgery and corneal abrasion. The octanol/water partition coefficient of aceclofenac drug is 1.86 ± 0.75. Permeation characteristics of the drug were evaluated by putting 1 ml formulation on freshly excised goat cornea fixed between donor and receptor compartments of an all-glass modified Franz diffusion cell and measuring the drug permeated in the receptor by spectrophotometry at 275 nm, after 120 min. The results suggest that aceclofenac ophthalmic solution (pH 7) containing BAC provides increased in vitro ocular availability through goat corneas. The combination of methyl paraben and propyl paraben MP-PP preservative in aceclofenac ophthalmic eye drop 0.1% formulated in phosphate buffer increases transcorneal permeation. The developed formulations were evaluated for their pharmacodynamics in albino rabbits, by measuring in-vivo study and were compared to a marketed voltrane ophthalmic solution.

Delivery of nano-emulgel carrier: optimization, evaluation and in vivo anti-inflammation estimations for osteoarthritis.

Aim: Optimization and evaluation of Aceclofenac nanoemulgel for treatment for rheumatoid arthritis and reduction of GI irritation and enhancement of bioavaibility. Materials & methods: Different batches of emulgel and selected batch was proceeded for characterization like particle size, scanning electron microscopy, drug ingredient, in vitro release, Fourier transform infrared and x-ray diffraction in vitro inflammation and gel evaluation such as (spreadability, swelling index), ex vitro permeation, skin irritation and in vivo anti-inflammatory. Result: Emulgel showed nanometri size sustained release (79.96% in 6 h), compatibility and anti-inflammatory activity compared with pure drug. Concluded that emulgels had better (nearly twice as good) anti-inflammatory action as the commercial product. Conclusion: Compared with the commercial gel, the emulgel's anti-inflammatory effect had a quicker onset and a longer duration of action.

A non-steroidal anti-inflammatory drug (NSAID) aceclofenac is used as the treatment for rheumatoid arthritis. It is generally taken orally. However, there are a few issues with it being taken this way. The main ones are: some of the drug reacts too early in the body, meaning only a small amount of it reaches the parts of the body where it is needed; it can irritate the digestive system; and it does not dissolve very well in water, which also makes it harder to reach the parts of the body where it is needed. The authors of this study created a new type of gel for people to rub into their skin, instead of taking a pill. They hoped that this would allow the drug to be absorbed more directly into the parts of the body where it was needed, without irritating the digestive system. They tested the gel to see how well it contained and released the drug, how well it absorbed into the skin, and whether it irritated the skin. They found that the gel contained and released the drug more effectively than similar gels which are already available and caused less irritation to the skin.

QbD-assisted optimisation of liposomes in chitosan gel for dermal delivery of aceclofenac as synergistic approach to combat pain and inflammation.

Aceclofenac (ACE) is a drug that was precisely devised to circumvent the shortcomings associated with diclofenac. However, ACE too corresponds to nonsteroidal anti-inflammatory drug (NSAID)-related adverse effects, but with a lower amplitude. The present investigation seeks to develop liposomes loaded with ACE adopting a central composite design (CCD) and formulate a chitosan-based hydrogel for synergistic anti-inflammatory efficacy and improved ACE dermal administration. On the basis of preliminary vesicle size, Poly Dispersity Index (PDI), and drug entrapment, the composition of lipid, cholesterol, and vitamin E TPGS were chosen as independent variables. The formulation composition met the specifications for an optimum liposomal formulation, with total lipid concentration (13.5% w/w), cholesterol concentration (10% w/w), and surfactant concentration (2% w/w). With particle size and PDI of 174.22 ± 5.46 nm and 0.285 ± 0.01 respectively, the optimised formulation achieved an entrapment effectiveness of 92.08 ± 3.56%. Based on the CCD design, the optimised formulation Acec-Lipo opt was chosen and was subsequently transformed to a chitosan-based gel formulation for in vitro drug release, penetration through the skin, in vivo analgesic therapeutic activity, and skin irritation testing. % age oedema inhibition was found to be greatest with the Acec-Lipo opt gel formulation, followed by Acec gel. These results reinforce the notion that the inclusion of chitosan resulted in a synergistic effect despite the same strength of the drug. The findings suggested that Acec-Lipo incorporated in chitosan gel for skin targeting might be an effective formulation for topical ACE administration in clinical subjects.

Co-Delivery of Aceclofenac and Methotrexate Nanoparticles Presents an Effective Treatment for Rheumatoid Arthritis.

Background: Rheumatoid arthritis (RA) is a common acute inflammatory autoimmune connective tissue arthropathy. The genetic studies, tissue analyses, experimental animal models, and clinical investigations have confirmed that stromal tissue damage and pathology driven by RA mounts the chronic inflammation and dysregulated immune events. Methods: We developed methotrexate (MTX)-loaded lipid-polymer hybrid nanoparticles (MTX-LPHNPs) and aceclofenac (ACE)-loaded nanostructured lipid carriers (ACE-NLCs) for the efficient co-delivery of MTX and ACE via intravenous and transdermal routes, respectively. Bio-assays were performed using ex-vivo skin permeation and transport, macrophage model of inflammation (MMI) (LPS-stimulated THP-1 macrophages), Wistar rats with experimental RA (induction of arthritis with Complete Freund's adjuvant; CFA and BCG), and programmed death of RA affected cells. In addition, gene transcription profiling and serum estimation of inflammatory, signaling, and cell death markers were performed on the blood samples collected from patients with RA. Results: Higher permeation of ACE-NLCs/CE across skin layers confirming the greater "therapeutic index" of ACE. The systemic delivery of MTX-loaded LPHNPs via the parenteral (intravenous) route is shown to modulate the RA-induced inflammation and other immune events. The regulated immunological and signaling pathway(s) influence the immunological axis to program the death of inflamed cells in the MMI and the animals with the experimental RA. Our data suggested the CD40-mediated and Akt1 controlled cell death along with the inhibited autophagy in vitro. Moreover, the ex vivo gene transcription profiling in drug-treated PBMCs and serum analysis of immune/signalling markers confirmed the therapeutic role co-delivery of drug nanoparticles to treat RA. The animals with experimental RA receiving drug treatment were shown to regain the structure of paw bones and joints similar to the control and were comparable with the market formulations. Conclusion: Our findings confirmed the use of co-delivery of drug nanoformulations as the "combination drug regimen" to treat RA.