Indomethacin bioavailability

The topic of ocular bioavailability of indomethacin administered in a sub-micrometer emulsion was al.so examined by the research group led by M, J. Alon.so at the University of Santiago de Compo-stela, Spain (32). These workers tested several carriers in vivo in rabbits nanopaiticles, nanocapsules, microparticles, and a submicrometer emulsion. The latter, prepared by the method of Yu et al. (33) with poloxamer 188 and soybean lecithin and containing 0.1% w/v indomethacin, had particles of diameter 0.21 0.02 im. The submicrometer systems (nanoparticles, nanocapsules, and emulsion) increased by more than three-fold the indomethacin concentration in the cornea, aqueous humor, and iris-ciliary body at 0.S and 1.0 h post instillation. Furthermore, an increased indomethacin bioavailability of 300% was observed in comparison with the value obtained for an aqueous commercial solution. Confocal laser scanning microscopy studies indicated (hat the submtcion particles penetrated into the comeal epithelium cells by endocyiosis (he audiors further suggested that the vehicle components (lecithin in the case of emulsions) may act as penetration enhancers or as endocytotic stimulators. 

Although theoretically safe, poorly absorbed antimicrobials could become absorbable in the presence of mucosal inflammatory or ulcerative changes [100], like those occurring in IBD or when invasive bacteria colonize the intestine. To verify whether the presence of intestinal lesions would affect rifaximin absorption, the drug was given to rats with experimentally induced colitis [101]. The indomethacin-induced enteropathy did not affect intestinal absorption of rifaximin. However, under the same experimental conditions, systemic bioavailability of neomycin did increase [101]. 

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]. 

Jambhekar, S., Casella, R., and Maher, T. 2004. The physicochemical characteristics and bioavailability of indomethacin fromp-cyclodextrin, hydroxyethyl-fs-cyclodextrin, and hydroxypropyl-p-cyclodextrin complexeslnt. J. Pharm.270 149-166. 

Calvo, P., et al. 1996. Improved ocular bioavailability of indomethacin by novel ocular drug carriers. J Pharm Pharmacol 48 1147. 

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. 

Calvo, P., Alonso, M. J., Vila-Jato, J. L., and Robinson, J. R. (1996), Improved ocular bioavailability of indomethacin by novel ocular drug carriers,/. Pharm. Pharmacol.,48(11), 1147-1152. 

Several studies have reported on the enhanced bioavailability of cutaneous drugs using o/w and w/o MEs compared to conventional emulsions, gels or solutions, mesophases, micellar and inverse micellar systems, and vesicles [93], Moreover, a diverse range of drug molecules such as ketoprofen, apomorphine, estradiol, lido-caine [94-97], indomethacin and diclofenac [98], prostaglandin Ei [99], aceclofenac... 

When compared to either saline or anionic emulsions, the nanosized cationic emulsions were shown to enhance the ocular bioavailability of indomethacin [108], piroxicam [178], and cyclosporin A [106,179] following one single-drop dose instillation into the rabbit eye (Figure 4). A significant drug reservoir effect was noted in the cornea and conjunctiva even for more than 8 h following the instillation [106],... 

Irradiation of gelatine capsules may not only result in photodegradation of the drug but may also affect the bioavailability of the drug. Irradiated gelatine films showed a decrease of their water vapor transmission. Even though this effect did not occur with indomethacin capsules, long-term irradiation resulted in increased dissolution rates (42). 

Hosny, E.A. Al-Angary, A.A. Bioavailability of sustained release indomethacin suppositories containing polycarbo-phil. Int. J. Pharm. 1995, 113, 209-213. 

In the presence of moisture, calcium salts may be incompatible with amines, amino acids, peptides, and proteins, which may form complexes. Calcium salts will interfere with the bioavailability of tetracycline antibiotics. It is also anticipated that calcium sulfate would be incompatible with indomethacin, aspirin, aspartame, ampicillin, cephalexin, and eryth-romycin " " since these materials are incompatible with other calcium salts. 

One problem with many of the active substances used today is their poor solubility in water and their limited bioavailability. One of the simplest means of improving the bioavailability of an active substance is to improve its dissolution by adding solubilizing agents, such as povidone. It forms water-soluble complexes with many active substances (see Sections 2.2.7 and 2.4.5). With some such substances, it may be sufficient to produce a physical mixture. Fig. 45 shows the improvement in the dissolution rate of reserpine achieved by simply mixing it with an excess of povidone K 30. For the mixture with indomethacin see Section 3.4.3.1. Similar results can be expected with the drugs listed in Section 2.4.5. That this effect also applies to finished preparations can be seen for phenytoin tablets in Fig. 52 [326]. The bioavailability of peroral gidazepam is increased by the addition of povidone too [536]. 

Oral indomethacin has excellent bioavailability. Peak concentrations occur 1 to 2 hours after dosing. Indomethacin is 90% bound to plasma proteins and tissues. The concentration of the drug in the CSF is low, but its concentration in synovial fluid is equal to that in plasma within 5 hours of administration. 

Jambhekar S, Casella R, Maher T, The physicochemical characteristics and bioavailability of indomethacin from y -cyclodextrin, hydroxyethyl-y -cyclodextrin and hydroxypropyl-y -cyclodextrin complexes, Int. J. Pharm. 2004 270 149-166. 

Finally, Skiba et al. report the in vivo application of indomethacin-loaded nanocapsules, prepared from amphiphilic jS-CyD substituted on the secondary face by Ce chains, jS-CyDCe, in a rat model [48]. They compared the rat gastric ulcerative effect of encapsulated indomethacin with that of the indomethacin solution (Indoc-id ). Independently of the administered dose, the ulcerative effect was significantly decreased while the bioavailability of indomethacin was maintained. Gastrointestinal ulcer protection by encapsulation of indomethacin in jS-CyDC nanocapsules was 82% for 5 mg kg and 53% for 10 mg kg administered dose. 

A.S. Chauhan, S. Sridevi, K.B. Chalasani, Dendrimer-mediated transdermal delivery enhanced bioavailability of indomethacin, J. Control. Release 90 (2003) 335-343. 

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