Percutaneous Absorption Of Indomethacin Research Articles

Mechanistic investigation and reversible effect of 2-isopropyl-5-methylcyclohexyl heptanoate on the in vitro percutaneous absorption of indomethacin

In the present study, the enhancing effect of 2-isopropyl-5-methylcyclohexyl heptanoate (M-HEP) on the percutaneous absorption of indomethacin (IM) was evaluated by the in vitro penetration experiments using the rat abdominal skin as a barrier. Partition experiment, attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectrum and transepidermal water loss (TEWL), was employed to investigate the possible mechanisms of the action of M-HEP. Furthermore, the reversible effect of M-HEP on excised rat skin was also evaluated through in vitro permeation as a preliminary indicator of safety. The result of in vitro permeation experiment indicated that, 10% (w/w) M-HEP in combination with isopropyl palmitate (IPP) significantly increased (p < 0.05), the cumulative amount of IM in comparison with the control group (IPP only). The partition coefficient of IM between the stratum corneum (SC) and enhancer solution was also greater than that between the SC and IPP. A blue shift in the ATR-FTIR spectra of SC after treatment with M-HEP solution was observed at the CH2 band, which indicating that M-HEP disrupted the intercellular lipid structure of the SC. In addition, both M-HEP/IPP and L-menthol (MT)/IPP improved the TEWL value of rat abdominal skin. After removal of M-HEP, the skin barrier function would be restored in 8 h. In conclusion, M-HEP could reversibly enhance the percutaneous absorption of IM by increasing the partitioning of IM into the SC from enhancer solution and disturbing the organized structure of SC lipids and the reversibility of M-HEP was better than MT.

ChemInform Abstract: Transdermal Delivery of Drugs and Enhancement of Percutaneous Absorption

This paper describes 1) the drug delivery through the skin to produce systemic effects, 2) the enhancement of percutaneous absorption by absorption enhancers, heating and complex formation, 3) the mechanism for the enhancement effect by enhancers, 4) the percutaneous absorption of peptides, and 5) the pharmacokinetic analysis for percutaneous absorption. 1,3-Dinitroglycerin, indomethacin (IND) and many drugs were efficiently absorbed via rat and rabbit skins in the presence of some enhancers, and using a microporous membrane therapeutic plasma concentrations were maintained for a long time. Enhancement of percutaneous absorption by the complex formation with fatty acid was observed for propranolol (PL) in vitro and in vivo. Heating at 42-45 degrees C also enhanced the percutaneous absorption dramatically, with decreased activation energies. The following mechanisms for the enhancement effect by enhancers were found: a) an increase in the fluidity of the stratum corneum lipids and reduction in the diffusional resistance to permeants, b) the removal of intercellular lipids and dilation between adherent cornified cells, c) an increase in the thermodynamic activity of drugs in vehicles, d) the exfoliation of stratum corneum cell membranes, the dissociation of adherent cornified cells and elimination of the barrier function. Peptides such as enkephalin, elcatonin and insulin were effectively absorbed through the skin in the presence of some enhancers and specific inhibitors, with no proteolytic degradation. The pharmacokinetic model with two parallel absorption processes, lipidic and aqueous pore transport pathways, in skin could adequately describe the percutaneous absorption of IND, PL and valproic acid. With peptides, a kinetic model including zero-order input rate, first-order permeation rate and first-order degradation rate was able to describe well the steady-state flux of peptides.

Percutaneous absorption of indomethacin from pluronic F127 gels in rats.

Thermally reversible gels of the poly(oxyethylene)-poly (oxypropylene)-(polyoxyethylene) triblock copolymer, Pluronic F127, were evaluated as vehicles for the percutaneous administration of drugs using indomethacin as a model drug. In-vivo percutaneous absorption studies using a rat model suggest that a 20% w/w aqueous gel of Pluronic F127 may be of practical use as a base for topical administration of the drug. The addition of isopropyl myristate or (+)-limonene to the gel formulation significantly improved percutaneous absorption, particularly when the gel was applied using an occlusive dressing technique.

Crude drug (zingiberaceae) enhancement of percutaneous absorption of indomethacin: in vitro and in vivo permeation.

To improve drug permeation through skin, extracts of crude drugs were evaluated using in vitro and in vivo penetration techniques with rabbit skin as a model membrane. The acetone extract of Amomum cardamomum (ae-AC) and Elettaria cardamomum (ae-EC) had the best effect in enhancing the penetration of Indomethacin (IDM). The flux of IDM for the formulation containing ae-AC from pH 7.4 buffer-alcohol donor solution was 3.6 times higher than that from the 50% alcohol donor solution. In order to confirm enhancer/skin interaction, a microscopic study was carried out in order to determine the presence of physical evidence in the skin caused by enhancers. A pharmacokinetic model of percutaneous absorption of IDM after topical administration was employed on the assumption of a zero-order penetration rate through the stratum corneum followed by absorption into the blood by a first-order process. Good correlation was observed between the experimental data point and simulated plasma concentration. From the results of the study, the in vitro permeability coefficient correlates with the in vivo penetration rate through the stratum corneum.

Effect of d-limonene on the amounts of ethanol and indomethacin penetrated from aqueous gel ointments to rat skin.

The amounts of d-limonene, ethanol and indomethacin (IMC) which were transferred from aqueous gel ointments to the skin were determined in rats. The concentration of IMC in the skin correlated well with the plasma concentration of IMC percutaneously absorbed from the gel ointment. The increase of d-limonene concentration in the gel ointments was directly proportional to the accumulation of ethanol in the skin. The amount of ethanol in the skin was closely associated with the percutaneous absorption of IMC. As a possible mechanism for enhancement action of d-limonene and ethanol, it was considered that, at first, d-limonene penetrates into the skin under coexistence with ethanol and may change the barrier structure of the stratum corneum. The transfer of ethanol to the skin is thereby enhanced under the coexistence of d-limonene in the skin. Thus, the permeation of IMC can be promoted due to its affinity with ethanol.

Percutaneous Absorption of Indomethacin from Transparent Oil/Water Gels in Rabbits

The percutaneous absorption of indomethacin from transparent oil in water gels (TOW gels) has been studied in rabbits and compared with absorption from a hydrophilic gel and from a spray formulation. The area under the curve and the Cmax values in plasma were significantly higher for the TOW gels in comparison with the other formulations after single application. The pH of the aqueous phase of the TOW gels did not significantly influence the bioavailability. After multiple application the TOW gels induced a larger increase in AUC (vs first application) in comparison with the other formulations. None of the formulations without drug damaged the skin after multiple application. For indomethacin formulations skin damage was more pronounced with the hydrophilic gel than for the TOW gels and spray formulation.

The effects of pH and chemical enhancers on the percutaneous absorption of indomethacin

AbstractThe absorption of indomethacin through excised hairless mouse skin from aqueous solution was determined at different pH values. We found that the rate of its absorption increased with decreasing pH. Its distribution coefficient in octanol-phosphate buffer was also pH dependent. Furthermore, the change of permeability coefficient with pH correlated well with the distribution coefficient by a two-degree polynominal equation. The individual incorporation of five chemical enhancers into a polymeric patch at optimal pH resulted in an increase or decrease in the in vitro absorption rate and in the amount absorbed during the first 24 hours depending on the enhancer and its concentration used. Both sodium cholate at 4 and 6 %, and sodium lauryl sulfate at 4 % increased the absorption rate about four to seven times compared to the control. The in vivo absorption using rabbits from patch containing 6% sodium cholate also showed an increase in rate and the AUC compared to that from the control; however, the ...

Percutaneous absorption of indomethacin from mixtures of fatty alcohol and propylene glycol (FAPG bases) through rat skin: Effects of oleic acid added to FAPG base.

The effects of oleic acid (OA) added to mixtures of fatty alcohol and propylene glycol (FAPG bases) on the percutaneous absorption of indomethacin (ID) were investigated by using the abdominal skin of rats in vivo. The percutaneous absorption of propylene glycol (PG) from FAPG base was simultaneously examined. The percutaneous absorption of ID from FAPG bases in the absence of OA was poor as compared with that from FAPG bases containing OA. It was observed that when OA was added to the vehicles in the range of 5 to 30%, the percutaneous absorption of ID from the vehicles was increased. In particular, the maximal enhancement of percutaneous absorption of ID was achieved at 5% OA. However, the enhancing effect of percutaneous absorption of ID diminished when the OA content in the vehicle exceeded 50%. PG was readily absorbed through the rat skin from FAPG bases and its percutaneous absorption profiles were similar to those of ID. It can be presumed that PG and ID penetrate together through the skin. In addition, it was confirmed that the percutaneous absorption of ID and PG from FAPG bases was not affected by the viscosity of the vehicle. If FAPG base is to be used as a vehicle for the purpose of percutaneous absorption of ID, OA is considered to be a useful additive.

Enhancing effects of myristyl lactate and lauryl lactate on percutaneous absorption of indomethacin in rats.

The enhancing effects of myristyl lactate (ML) and lauryl lactate (LL) on the percutaneous absorption of indomethacin (ID) from test solutions in propylene glycol (PG) were investigated in rats. ID absorption was observed to be markedly enhanced by the addition of ML or LL to PG as compared with the control (PG alone). The marked enhancing effects were observed at concentrations greater than 3% ML and 3% LL in PG. In particular, the maximal enhancement of percutaneous absorption of ID was achieved at 5% ML and LL. To elucidate the mode of action of ML as an enhancer, the percutaneous absorption of ID through the skin pretreated with ML alone was investigated. It was suggested that ML acts on the stratum corneum to produce its effect.

Enhancing effect of cetyl lactate on the percutaneous absorption of indomethacin in rats.

The enhancing effect of cetyl lactate (CL) on the percutaneous absorption of indomethacin (ID) from test solutions in propylene glycol (PG) was investigated by using the abdominal skin of rats in vivo. The percutaneous absorption rate of ID from 1 or 3% CL-PG test solution through the intact skin of rats was observed to be faster than that from the control solution (without CL). The bioavailability of ID was about 0.04% for the control solution, 2.2% for 1% CL-PG and 6.8% for 3% CL-PG test solutions. These results suggest that CL functions as an enhancer for the percutaneous absorption of ID. Furthermore, marked enhancing effects on percutaneous absorption of ID were obtained at a concentration greater than 1% CL in PG. In order to elucidate the mode of action of CL as an absorption enhancer, the percutaneous absorption of ID from the control solution and 3% CL-PG test solution through damaged skin from which the stratum corneum had been stripped was additionally investigated. It was confirmed that CL acts on the stratum corneum to produce its effect.

Effect of several penetration enhancers on the percutaneous absorption of indomethacin in hairless rats.

In order to measure the effect of several penetration enhancers on the percutaneous absorption of drugs and to classify the enhancers into several categories in terms of the mode and mechanism of action, in vitro permeation experiments with a model drug, indomethacin, from aquenous, ethanolic and binary solvent systems were carried out by using excised hairless rat abdominal skin and a 2-chamber diffusion cell at 37°C. Among the enhancers used in the present experiments, Azone, dimethyl sulfoxide (DMSO), isopropylmyristate, diethylsebacate, diethylmethylbenzamide, methylpyrrolidone and salicyclic acid enhanced the skin permeation of indomethacin, whereas urea, pyrrolidonecarboxylic acid and sodium hyaluronate did not as compared with the same solvent system without enhancer. These results suggest that the lipophilicity of enhancers may be an important factor for the penetration-enhancing effect on the skin permeation of indomethacin. It is also suggested that the effect of methylpyrrolidone is dependent upon the kind of solvent system; higher water content resulted in a lower effect.Further experiments to clarify the mechanism of action were done with pyrrolidones and salicylates, since it has already been reported that other enhancers such as Azone and DMSO might mainly affect the lipid in skin. Pyrrolidones had an in vitro moisturizing effect on keratin tablets and an in vivo skin-moisturizing effect. They affected the dissolution of keratin powder. On the other hand, salicylates dissloved and softened keratin powder, but they had no effect on the skin moisturizing. These results suggest that pyrrolidones and salicylates affect the keratin cells in the stratum corneum to enhance skin permeability, although the mechanism of action is different between the two groups.

Percutaneous absorption of indomethacin from mixtures of fatty alcohol and propylene glycol (FAPG bases) through rat skin: effects of fatty acid to FAPG base.

The effects of oleic acid (OA) added to mixtures of fatty alcohol and propylene glycol (FAPG bases) on the percutaneous absorption of indomethacin (ID) were investigated by using the abdominal skin of rats in vivo. The percutaneous absorption of propylene glycol (PG) from FAPG base was simultaneously examined. The percutaneous absorption of ID from FAPG bases in the absence of OA was poor as compared with that from FAPG bases containing OA. It was observed that when OA was added to the vehicles in the range of 5 to 30%, the percutaneous absorption of ID from the vehicles was increased. In particular, the maximal enhancement of percutaneous absorption of ID was achieved at 5% OA. However, the enhancing effect of percutaneous absorption of ID diminished when the OA content in the vehicle exceeded 50%. PG was readily absorbed through the rat skin from FAPG bases and its percutaneous absorption profiles were similar to those of ID. It can be presumed that PG and ID penetrate together through the skin. In addition, it was confirmed that the percutaneous absorption of ID and PG from FAPG bases was not affected by the viscosity of the vehicle. If FAPG base is to be used as a vehicle for the purpose of percutaneous absorption of ID, OA is considered to be a useful additive.

Effect of polysorbates on percutaneous absorption of indomethacin from ointment in rabbits.

Four kinds of polysorbates were incorporated into an absorption ointment base containing indomethacin. Percutaneous absorption was determined from plasma indomethacin levels in rabbits at regular interval for 14 hours following application of the ointment. Percutaneous absorption of indomethacin was decreased significantly when polysorbate 20 and 40 were added to the ointment. Four different concentrations of polysorbate 80 were studied: 2.3%, 4.62%; 6.93% and 15% (w/w). The lowest polysorbate 80 concentration (2.3%) did not produce any significant change in the percutaneous absorption of indomethacin. However, a decrease in drug absorption was observed after the addition of higher concentrations of polysorbate 80 at 6.93% or 15%. The absorption ointment base has poor drug-releasing effect, poor percutaneous absorption and promotes scarce reservation in the skin for indomethacin. This is due to the formation of many inclusion compounds of indomethacin with numerous micelles produced by the high concentration of polysorbate in the aqueous phase of the ointment.

Stability, anti-inflammatory effect and percutaneous absorption of indomethacin in absorption ointment formulations

Both the topical and percutaneous anti-inflammatory activities of absorption ointment formulations containing indomethacin were investigated in rabbits. Indomethacin absorption ointment significantly inhibited the formation of granuloma and decreased edema on the dorsal skin induced by a subcutaneous injection of carrageenin. The determination of indomethacin and its hydrolysis products such as p-chlorobenzoic acid and 5-methoxy-2-methyl-3-indole acetic acid from an ointment was proposed by using reversed-phase HPLC and UV detection. The apparent first-order rate constant can be obtained accurately and easily by using the Weibull probability paper, and was used to predict the stability of indomethacin in an ointment. The stability increased in proportion to the concentration of polysorbate 20 or polysorbate 80. However, a marked decrease in the percutaneous absorption of indomethacin occurred with the absorption ointment base containing a concentration of 4.62% polysorbate 20. But the additional concentration of polysorbate 80 below 4.62% did not produce any significant change in percutaneous absorption of indomethacin.

Application of fatty alcohols to pharmaceutical dosage form. III. Percutaneous absorption of indomethacin from fatty alcohol and propylene glycol (FAPG) bases consisting of a mixture of fatty alcohol and propylene glycol

Application of fatty alcohols to pharmaceutical dosage form. III. Percutaneous absorption of indomethacin from fatty alcohol and propylene glycol (FAPG) bases consisting of a mixture of fatty alcohol and propylene glycol

Cutaneous absorption of indomethacin from two topical preparations in volunteers.

The percutaneous absorption of indomethacin in 0.5 % or 1 % solution or 1 % gel at a dose of 50 mg or 100 mg indomethacin was compared in a randomized complete block design in seven healthy volunteers. The formulations were applied over an area of 12 dm(2) under an 8 h occlusion dressing. In addition, in the same volunteers the plasma concentration curves were determined after a single oral dose of 50 mg indomethacin. Indomethacin and some of its metabolites were determined with modified, existing assays using HPLC-fluorescence or gas chromatography-mass spectrometry. On the basis of a newly developed method, it was possible to separate and quantify O-desmethylindomethacin and N-deschlorobenzoyl-O-desmethylin-domethacin. After cutaneous administration of the two drug formulations, peak indomethacin plasma concentration of 95 ng/ml and 130 ng/ml were found between 4 and 8 h; the cutaneous bioavailability was approximately 20 % of the oral dose, as judged by comparing the areas under the plasma concentration time curves (AUC) and the amount of metabolites excreted into the urine. Percutaneous absorption did not change the metabolic pattern in the urine that is obtained after oral administration.

Percutaneous absorption and anti-inflammatory activity of indomethacin in ointment.

A jelly-type ointment containing 1% indomethacin, ID gel, was prepared, and the anti-infla-mmatory effects and percutaneous absorption of ID gel were studied. ID gel inhibited carrageenin-induced paw edema concentration-dependently by topical application and showed significant effect at concentratin over 1%. ID gel inhibited inflammation only in the applied foot, but did not influence the edema of non-applied foot in car-rrageenin-induced edema experiments. It was shown that percutaneous absorption of indomethacin was markedly more into the exudate and muscle of the applied foot than those of non-applied foot and systemic blood. ID gel showed also anti-inflam-matory erects on adjuvant arthritis in rats and ultraviolet-induced erythema in guinea pigs.

Changes in site and size of application of indomethacin onitment and percutaneous absorptions in rabbits

The percutaneous absorption of indomethacin from ointment applied to the skin surface was influenced by the anatomical site of skin and the size of the application area. Dorsal sites led to higher levels than abdominal sites which in turn led to the higher levels than application to the thigh areas. The absorption increased in direct proportion to the size of the application area in the abdomen. The effects of different pH values of indomethacin solution in the onintment on the percutaneous absorption were examined. At a lower pH (7.07), there was good absorption.

Percutaneous absorption of indomethacin from ointment bases in rabbits

A pharmacokinetic model was developed to test certain concepts regarding the percutaneous absorption of indomethacin from topical ointment bases. Both the drug from the ointment bases and absorption from the skin followed first-order kinetics, with the exception of the initial period (lag time). The ointment bases selected for study were solution-type and suspension-type ointment bases. Indomethacin was most effectively absorbed from absorption ointment bases. The effect of additives on the percutaneous absorption was also investigated using absorption ointment bases. The optimal effect with additives in the ointment bases was finally attained with the addition of 0.5% urea.

Percutaneous absorption and anti-inflammatory activity of indomethacin in ointment

A jelly-type ointment containing 1% indomethacin, ID gel, was prepared, and the anti-infla-mmatory effects and percutaneous absorption of ID gel were studied. ID gel inhibited carrageenin-induced paw edema concentration-dependently by topical application and showed significant effect at concentratin over 1%. ID gel inhibited inflammation only in the applied foot, but did not influence the edema of non-applied foot in car-rrageenin-induced edema experiments. It was shown that percutaneous absorption of indomethacin was markedly more into the exudate and muscle of the applied foot than those of non-applied foot and systemic blood. ID gel showed also anti-inflam-matory erects on adjuvant arthritis in rats and ultraviolet-induced erythema in guinea pigs.