Indomethacin formulations

P. Albin, A. Markus, Z. Pelah, Z. Ben-Zvi, Slow release indomethacin formulation based on polysaccharides evaluation in vitro and in vivo in dogs, J.Control. Release, 29,25-39,1994. T.W Wong, S. Wahab, and Y. Anthony, Effects of microwave on drug release property of poly(methyl vinyl ether-co-maleic acid) matrix. Drug Dev. Ind. Pharm., 33 (7), 737-746, 2007. 

Dendrimer micelles of this type have been formulated as drug delivery vehicles. Dendrimers with a hydrophobic interior have been used to entrap a hydrophobic drug such as indomethacin. This is retained because of the hydrophilic periphery containing ethylene glycol functional groups, and is released slowly because of the collapsed configuration of the interior, through which molecular diffusion is obstructed. 

The interaction between drug compounds and excipients, as these influence drug dissolution, can be successfully studied by means of reflectance spectroscopy. In one study concerning probucol and indomethacin, it was deduced that hydrogen bonding and van der Waals forces determined the physisorption between the active and the excipients in several model formulations [36]. Chemisorption forces were found to play only minor roles in these interactions. These studies indicated that surface catalytic effects could be important during the selection of formulation excipients. 

Calvo et al. [63] studied ehitosan (CS)- and poly-L-lysine (PLL)-eoated poly-e-caprolactone (PECL) nanocapsules for oeular application. In comparison with commercial eye drops, the systems investigated (uncoated, PLL-coated, and CS-coated nanocapsules) significantly increased the eoneentrations of indomethacin in the cornea and aqueous humor of rabbit eyes. The ehitosan-eoated formulation doubled the ocular bioavailability of indomethacin over the uncoated partieles, whereas the PLL coating was ineffective. The authors eoneluded that the speeifie nature of CS was responsible for the enhaneed indomethaein uptake and not the positive surfaee eharge. Both the PLL- and CS-eoated nanoeapsules displayed good oeular toleranee [63]. 

Ketorolac (Toradol), an NSAID chemically related to indomethacin and tolmetin, is mainly used as an analgesic, not for the treatment of inflammatory disease. It is available in oral, parenteral, and topical formulations. 

The combination of solid-state ATR-IR and solid-state NMR data supported the conclusion that the presence of crystalline material was responsible for changes in the dissolution profiles of the different lots. The results appear consistent with historical examples of changes in API physical form of solid, high molecular weight, polyethylene glycol dispersion formulations of amorphous indomethacin and griseofulvin (92-95). 

Given the insolubility of indomethacin, a number of formulation approaches have been taken to improve the physical properties of this nonsteroidal anti-inflammatory drug substance. A 1 1 cocrystal was successfully prepared with saccharin using both solid-state dry grinding and... 

Oral ibuprofen is often prescribed in lower doses (< 2400 mg/d), at which it has analgesic but not anti-inflammatory efficacy. It is available over the counter in low-dose forms under several trade names. A topical cream preparation appears to be absorbed into fascia and muscle an (S)( ) formulation has been tested. Ibuprofen cream was more effective than placebo cream for the treatment of primary knee osteoarthritis. A liquid gel preparation of ibuprofen 400 mg provided faster relief and superior overall efficacy in postsurgical dental pain. In comparison with indomethacin, ibuprofen decreases urine output less and also causes less fluid retention than indomethacin. Ibuprofen has been shown to be effective in closing patent ductus arteriosus in preterm infants, with much the same efficacy and safety as indomethacin. Oral ibuprofen is as effective as intravenous administration in this condition. 

The half-life at room temperature is about 200 hours in pH 8.0 buffer and about 90 minutes in pH 10.0 solutions(36). In a patent specification, Sumitomo Chemical Co. Ltd. reports stability conditions for seven different injectable formulations of indomethacin(38). Several of these formulations were stable after four months storage at 50°C. 

Formulations of indomethacin as the free-acid and as the sodiui salt are available in various parts of the world. They include ... 

In aqueous methanol, indomethacin exhibits a half-wave potential (E.,-) at the droning mercury electrode which is dependent upon pH. In 0.1M methanolic lithium chloride, indomethacin has two waves between -1.4v and -1.6v (vs. S.C.E.). The first step height is diffusion controlled and corresponds to a two electron reduction of the amide carbonyl. The second wave is believed to be a kinetic wave. The method as described is specific for nonhydrolyzed indomethacin and is suitable for analysis of capsules, suppositories and suspensions with precision of +1.2%, +0.7% and +1.2% for the respective formulations(43). 

Emulsions have been used for centuries for the oral administration of medical oils and vitamins and as dermatological vehicles. Recently, their application has been extended as drug carriers in the delivery and targeting of ophthalmic drags. An indomethacin emulsion has been reported to increase ocular bioavailability and efficacy compared to commercially available formulation in rabbits. 0.4% indomethacin emulsion showed 2.2 fold increase in the area under the anterior aqueous drag concentration/time curve compared to a 1% indomethacin suspension. The emulsion formulation also reduced ocular surface irritation caused by indomethacin Similar advantages have been shown for a pilocarpine emulsion which produced a prolonged therapeutic effect in comparison with pilocarpine hydrochloride eyedrops in man. It can be administered only twice a day, rather than four times daily for conventional formulation. 

Rainsford et al. (2003) described gastrointestinal mucosal injury following repeated daily oral administration of conventional formulations of indomethacin and other non-steroidal anti-inflammatory drags to Landrace pigs as a model for human gastrointestinal... 

Flurbiprofen, 100 mg three times daily, is a well-established first-line NSAID providing there is no evidence of vascular closure or scleral destruction on biomicroscopy. Flurbiprofen should provide pain relief within 2 days and improvement in clinical signs within 1 week. Indomethacin SR fiarmulation, 75 mg twice daily, is a well-established second-choice drug when flurbiprofen is not effective but has also been used as first line. NSAIDs that have shown efficacy and are now available in over-the-counter formulations include naproxen, 500 mg twice daily, and ibuprofen, 600 mg four times daily. If a simplified dosing schedule is a consideration, then pirox-icam, 20 mg/day, may be considered. Once effective control is established, a lower maintenance dose may suffice until the scleritis enters remission. To reduce the risk of gastrointestinal side effects, patients should be instructed to take NSAIDs with food or antacids. 

Other drugs studied by Moore et al. include chlorine containing photosensitizers (178), the effect of surfactants on photosensitizers (179), photosensitization by malarial drugs (180), nalidic and oxolinic acids (181), 6-mercaptopurine (182), azathioprine and nitroimidazole (183), 7-methylbenz[c]acridine and related products (184), naproxen, ben-oxaprofen and indomethacin (185), mefloquine (186), sulfamethoxazole and trimethoprim (187), benzydamine (188), photodecomposition of hydrochlorthiazide (189), tetracycline (190), frusemide (191), 6-mercaptopurine (192), 7-methylbenz[c]acridine (193), metronidazole, misonidazole and azathioprine (194), misonidazole and metronidazole (195), benzydamine (196), components in drug formulations (197) and sulfamethoxazole (198,199). 

Amorphous materials typically have a higher rate of dissolution and a higher kinetic solubility that their crystalline counterparts (Fig. 1). These characteristics can be exploited to enhance the rate and extent of absorption of poorly water-soluble APIs from the gastrointestinal tract. Such formulation approaches have been described for many APIs including indomethacin, griseofulvin, and several barbiturates. ... 

An IVIVC correlation was tried on indomethacin suppositories containing either suppocire (lipophilic) or poly ethylene glycol(PEG hydrophilic) as the main excipient. For both formulations, in vitro dissolution was performed with USP IV apparatus and a correlation was attempted, the results of the intrinsic validation are presented in Fig. 12 and show good predictability of the plasma concentrations in both cases. 

Bobrove AM, Calin A. Efficacy and tolerance of a novel precision-dose formulation of indomethacin double-blind trials in rheumatoid arthritis and osteoarthritis. Curr Med Res Opin 1983 8(Suppl 2) 55-61. 

Dibasic calcium phosphate dihydrate should not be used to formulate tetracycline antibiotics.Dibasic calcium phosphate dihydrate has been reported to be incompatible with indomethacin aspirin,aspartame, ampicillin, cephalexin,and erythromycin. The surface of dibasic calcium phosphate dihydrate is alkaline and consequently it should not be used with drugs that are sensitive to alkaline pH. 

Ford JL, Rubinstein MH. Formulation and ageing of tablets prepared from indomethacin-polyethylene glycol 6000 solid dispersions. Pharm Acta Helv 1980 55 1-7. 

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