Conventional Indomethacin Research Articles

Synthesis of novel chitosan-Schiff bases nanoparticles for high efficiency Helicobacter pylori inhibition

Two chitosan Schiff bases were synthesized by condensation of chitosan with 2-(4-formylphenoxy)-N-phenylacetamide and N-(4-bromophenyl)-2-(4-formylphenoxy) acetamide denoted as Cs-SBA and Cs-SBBr, respectively. The molecular structures of the resulting chitosan derivatives were characterized using FTIR and 1HNMR and their thermal properties were investigated by TGA. These derivatives were treated with sodium tripolyphosphate (TPP) to produce Cs Schiff base nanoparticles. The nanoparticles physicochemical properties were determined by FTIR, XRD, TEM, and zeta potential analysis. The antimicrobial action against Helicobacter pylori (H. pylori) was evaluated and the results indicated that the anti-H. pylori activity had minimal inhibitory concentration MIC values of 15.62 ± 0.05 and 3.9 ± 0.03 μg/mL for Cs-SBA and Cs-SBBr nanoparticles (Cs-SBA NPs and Cs-SBBr NPs), respectively. The better biologically active nanoparticles, Cs-SBBr NPs, were tested for their cyclooxygenases (COX-1 and COX-2) inhibitory potential. Cs-SBBr NPs demonstrated COX enzyme inhibition activity against COX-2 (IC50 4.5 ± 0.165 μg/mL) higher than the conventional Indomethacin (IC50 0.08 ± 0.003 μg/mL), and Celecoxib (IC50 0.79 ± 0.029 μg/mL). Additionally, the cytotoxicity test of Cs-SBBr NPs showed cytotoxic effect on Vero cells (CCL-81) with IC50 = 17.95 ± 0.12 μg/mL which is regarded as a safe compound. Therefore, Cs-SBBr NPs may become an alternative to cure H. pylori and prevent gastric cancer.

THU0336 Lower-Dose Solumatrix® Indomethacin Efficacy in Acute Pain: Results from Two Phase 3 Studies

BackgroundIndomethacin is used to treat acute gouty arthritis and other acute pain conditions, but similar to other NSAIDs, is associated with dose-related gastrointestinal, cardiovascular, and renal complications. International health authorities...

Effect of Solid Nanoparticle of Indomethacin on Therapy for Rheumatoid Arthritis in Adjuvant-Induced Arthritis Rat

We designed new oral formulations containing indomethacin (IMC) solid nanoparticles, and investigate their usefulness by evaluating bioavailability and gastrointestinal lesions. The IMC solid nanoparticles were prepared using methylcellulose (MC), 2-hydroxypropyl-β-cyclodextrin (HPβCD), and the bead mill method, and high quality dispersions containing 1.0% IMC nanoparticles were prepared (IMC(nano), particle size: 76 ± 58 nm, means ± S.D.). The fate of serum IMC and the induction of paw edema in adjuvant-induced arthritis (AA) rats receiving low-doses IMC(nano) (0.4 mg/kg) were similar to those following the administration of a therapeutic dose of conventional IMC prepared with MC and HPβCD (conventional IMC, 2 mg/kg), and the bioavailability in 0.4 mg/kg IMC(nano) was 5.3-fold higher in comparison with that in 2 mg/kg conventional IMC. IMC-induced gastrointestinal lesions in AA rats administered IMC(nano) (8 mg/kg), in consideration of bioavailability, were significantly less than for conventional IMC (40 mg/kg). On the other hand, the toxicity caused by conventional IMC and IMC(nano) was similar in Caco-2 cells. It is possible that the oral administration of IMC solid nanoparticles will show increased effectiveness in treating RA without causing IMC-induced gastrointestinal lesions, since the bioavailability is higher than that of conventional IMC. An oral drug delivery system using drug nanoparticles may expand the usage of NSAIDs for therapy in the inflammatory field.

Comparative in vitro metabolism of phospho-tyrosol-indomethacin by mice, rats and humans

Phospho-tyrosol-indomethacin (PTI; MPI 621), a novel anti-cancer agent, is more potent and safer than conventional indomethacin. Here, we show that PTI was extensively metabolized in vitro and in vivo. PTI was rapidly hydrolyzed by carboxylesterases to generate indomethacin as its major metabolite in the liver microsomes and rats. PTI additionally undergoes cytochromes P450 (CYP)-mediated hydroxylation at its tyrosol moiety and O-demethylation at its indomethacin moiety. Of the five major human CYPs, CYP3A4 and CYP2D6 catalyze the hydroxylation and O-demethylation reactions of PTI, respectively; whereas CYP1A2, 2C9 and 2C19 are inactive towards PTI. In contrast to PTI, indomethacin is primarily O-demethylated by CYP2C9, which prefers acidic substrates. The hydrolyzed and O-demethylated metabolites of PTI are further glucuronidated and sulfated, facilitating drug elimination and detoxification. We observed substantial inter-species differences in the metabolic rates of PTI. Among the liver microsomes from various species, PTI was the most rapidly hydrolyzed, hydroxylated and O-demethylated in mouse, human and rat liver microsomes, respectively. These results reflect the differential expression patterns of carboxylesterase and CYP isoforms among these species. Of the human microsomes from various tissues, PTI underwent more rapid carboxylesterase- and CYP-catalyzed reactions in liver and intestine microsomes than in kidney and lung microsomes. Together, our results establish the metabolic pathways of PTI, reveal significant inter-species differences in its metabolism, and provide insights into the underlying biochemical mechanisms.

Enhancement of Skin Permeation and Anti-Inflammatory Effect of Indomethacin Using Nanoemulsuion

The objective of the present study is to investigate the potential of nanoemulsion formulations for transdermal delivery of indomethacin (IND). Nanoemulsions formulations with different Surfactant: co surfactant ratios (S mix); F1 - F6 (1:1, 2;2, 3:1, 4;1, 1:2 and 3:2) were prepared by the spontaneous emulsification method, and characterized for morphology, droplet size, and rheological characteristics. The ex vivo skin permeation studies were performed using Franz diffusion cell with rabbit skin as permeation membrane. A significant increase in the steady-state flux (Jss), permeability coefficient (Kp), and enhancement ratio (Er) was observed in nanoemulsion formulations compared with the conventional IND gel. The anti-inflammatory effects of nanoemulsion formulations showed a significant increase in percent edema inhibition value after 4 hours. The optimized formulation showed significant increase in the steady-state flux (Jss) and permeability coefficient (Kp). Enhancement ratio (Er) was found to be 8.939 in optimized formulation F1 compared with IND gel. Keywords: Nanoemulsion, Indomethacin, Surfactant:co surfactant mixture, Permeability coefficient, Anti inflammatory effect

Physicochemical Performances of Indomethacin in Cholesteryl Cetyl Carbonate Liquid Crystal as a Transdermal Dosage

A transdermal formulation of indomethacin (IMC) was developed by incorporation into cholesteryl cetyl carbonate (CCC). The liquid crystalline phase properties of the IMC-CCC mixture were detected by polarized light microscopy and differential scanning calorimetry. A low drug loading was obtained (1-5%) similar to that used in conventional topical IMC in a clinical setting. A controlled release of IMC was found over 12h. A low amount of IMC in 1% IMC-CCC permeated the stratum corneum. Further formulation development has been carried out by the addition of lauryl alcohol into 5% IMC-CCC mixture it was found that the permeation of IMC was significantly improved to 45% within 24h.

Enhancement of skin permeation and anti- inflammatory effect of indomethacin using microemulsion

The objective of the present study was to investigate the potential of microemulsion formulations for transdermal delivery of indomethacin (IND). Microemulsion formulations with different surfactant:cosurfactant ratios (Smix); F1-F6 (1:1,2:2, 3:1, 4:1, 1:2, and 3:2) were prepared by the spontaneous emulsification method, and characterized for morphology, droplet size, and rheological characteristics. The ex vivo skin permeation studies were performed using Franz diffusion cell with rabbit skin as a permeation membrane. A significant increase in the steady-state flux (Jss), permeability coefficient (Kp), and enhancement ratio (Er) was observed in microemulsion formulations compared with the conventional IND gel.The anti-inflammatory effects of microemulsion formulations showed a significant increase in percent edema inhibition value after 4 hours. The optimized formulation showed a significant increase in the steady-state flux (Jss) and permeability coefficient (Kp). The enhancement ratio (Er) was found to be 8.939 in optimized formulation F1 compared with IND gel.

Formulation Design of Indomethacin-Loaded Nanoemulsion For Transdermal Delivery

The aim of the present study was to investigate the potential of nanoemulsion formulations for transdermal delivery of indomethacin (IND). Nanoemulsions formulations with different Surfactant: co surfactant ratios (S mix); F1-F6 (1:1, 2:2, 3:1, 4:1, 1:2 and 3:2) were prepared by the spontaneous emulsification method, and characterized for morphology using transmission electron microscopy (TEM), droplet size, and rheological characteristics. The ex vivo skin permeation studies were performed using Franz diffusion cell with rabbit skin as permeation membrane. A significant increase in the permeability parameters such as steady-state flux (Jss), permeability coefficient (Kp), and enhancement ratio (Er) was observed in nanoemulsion formulations compared with the conventional IND gel. The anti-inflammatory effects of nanoemulsion formulations showed a significant increase in percent inhibition value after 4 hours when compared with conventional IND gel on carrageenan-induced paw edema in rats. Significant increase in permeability parameters was observed in nanoemulsion formulations (P< 0.05). The steady-state flux (Jss) and permeability coefficient (Kp) for optimized nanoemulsion formulation (F1, 1:1 S mix were found to be 22.61±3.45 μg/ cm2/h and 0.22x10− 2 ±0.0003 cm/h, respectively), which were significant compared with conventional IND gel and (P< 0.001). Enhancement ratio (Er) was found to be 8.939 in optimized formulation F1 compared with IND gel. These results suggested that nanoemulsions can be used as potential vehicles for improved transdermal delivery of indomethacin as an approach to eliminate the side effect of the oral dose.

LOCALLY MADE CHITOSAN COVALENTLY LINKED TO INDOMETHACIN: A NOVEL APPROACH TO FORMULATE SUSTAINED RELEASE INDOMETHACIN CAPSULE IN BASRAH

The sustained release capsules are pharmaceutical dosage form used for the treatment of chronic rather than acute diseases and are useful because of its convenience and less side effects. This work describes an attempt to formulate indomethacin sustained release capsule using indomethacin covalently linked to chitosan. Chitosan was prepared by alkaline -N-deacetylation of chitin, which was isolated from the shells of local shrimps. The yield of chitosan was found to be 80%. This polymer was found to be white crystal, odorless and the IR spectroscopy of it was similar to a standard reference. Chitosan has been covalently linked to indomethacin and the ratio of drug to polymer was found to be 5:1. The chemical interaction between the drug and the polymer was proved by IR studies. In vitro release at different pH were performed and the release of indomethacin in the prepared sustained release capsule were tested and compared with conventional indomethacin capsule INDOMIN-25mg, and a commercial sustained release capsule INDO-75-SR. The release of indomethacin in our product was completed within 12 hours, while the conventional INDOMIN capsule and commercial INDO-75-SR capsule released within 2.5 and 5 hours respectively. In conclusion a cheap, locally made chitosan can be used in formulation of sustained release capsules by covalently linked to drugs containing carboxyl group (like indomethacin) or can be modified to have a carboxyl group.

Echocardiographic flow pattern of patent ductus arteriosus: a guide to indomethacin treatment in premature infants

AIMTo compare the efficacy and safety of an indomethacin treatment strategy based on serial echocardiographic measurement of patent ductus arteriosus (PDA) flow pattern with a standard protocol.METHODSNeonates weighing less than...

Gastric mucosal damage induced by nonsalicylate nonsteroidal antiinflammatory drugs in rats is mediated systemically

The gastric toxicities of an enteric-coated formulation and conventional indomethacin were compared in rats. Both formulations were equally damaging to the mucosa, suggesting that topical damage was not the major route of injury. The importance of systemically mediated damage was further determined by gastrotoxicity dose-response curves and pyloric ligation experiments in which indomethacin was administered either orally or parenterally, or into stomach or duodenum with the pylorus occluded. Gastric damage was significantly higher in those groups that had received the drug parenterally or intraduodenally. The extent of deeper mucosal damage, assessed histologically, was greater in parenterally dosed rats. In further experiments, oral and parenteral routes of administration of two other nonsalicylate NSAIDs, naproxen and sodium diclofenac, were found to be equally damaging to the mucosa. Our results show that indomethacin-induced gastric damage, unlike aspirin injury, is mediated mainly systemically. Enteric-coating may not be a useful strategy in reducing gastric injury by nonsalicylate, nonsteroidal antiinflammatory drugs.

Bioavailability of indomethacin from a modified release system containing indomethacin as the lysine salt.

The bioavailability of a new controlled release formulation of indomethacin lysine salt in tablets was tested in 6 healthy humans against a conventional indomethacin lysinate formulation in capsules. Both contained 100 mg of the drug, i.e. 70 mg indomethacin. Peak plasma levels were lower and more lasting and the AUC was higher with the new controlled release formulation. The latter on average produced active plasma levels for 12 h, and so it can be recommended for twice daily administration.

Pharmacokinetic overview of indomethacin and sustained-release indomethacin

Indomethacin has a moderately short half-life, usually requiring dosing twice a day or three times a day. A more convenient once or twice daily regimen is made possible with a sustained-release formulation. Following multiple-dose administration of either sustained-release indomethacin (Indocin SR) or conventional indomethacin, drug accumulation is low. Clinical studies indicate comparable safety and efficacy profiles between the two preparations. Pharmacokinetic information on both dosage forms is reviewed.

Sustained-release indomethacin in the comprehensive management of osteoarthritis

Osteoarthritis, although primarily a degenerative joint disease, may be associated with significant secondary inflammation. Hydrolytic enzymes result in primary cartilage degradation; secondary inflammation occurs in response to degenerative cartilage breakdown products and crystal deposition. Humoral and cell-mediated immune responses have been described. Analgesic and anti-inflammatory agents play a major role in symptomatic relief. Anti-inflammatory activity of the nonsteroidal anti-inflammatory drugs has been ascribed to prostaglandin synthesis inhibition; recent studies suggest additional effects based on inhibition of neutrophil aggregation, superoxide radical generation, and lysosomal enzyme release. Indomethacin, the first of the newer nonsteroidal anti-inflammatory drugs, has a long history of use and patient acceptance. Sustained-release indomethacin (Indocin SR), a 75 mg formulation equivalent to three consecutive doses of conventional indomethacin, adds ease of administration and potential for improved compliance. Nonsteroidal anti-inflammatory drugs, used in conjunction with other therapeutic approaches, provide the opportunity for response that can be gratifying for both patients and physicians.

Indomethacin and indomethacin sustained release—A comparison of their pharmacokinetic profiles

The data reviewed here show that INDOCIN ® SR (Indomethacin, MSD) exhibits good sus- tained-release characteristics. It produces more sustained plasma levels and shows no evidence of dose-dumping. Bioavailability is equivalent to that of three consecutive doses of conventional indomethacin capsules. Results of several controlled clinical studies 31–33 are consistent with the pharmacokinetic observations. It is generally believed that an ideal sustained-release product should release its active ingredient in a zero-order fashion similarly to a continuous constant-rate intravenous infusion. Under these conditions, the absorption rate and the resultant plasma levels would appear flat and constant for a specified time interval. Because of the sporadic nature of the enterohepatic recirculation, such an ideal goal cannot be achieved with indomethacin. Nevertheless, clinical data suggest that INDOCIN SR when administered once or twice daily, is comparable to conventional capsules in tolerability and efficacy. 31–33