Percutaneous Absorption Of Ketoprofen Research Articles

Characterization of the Percutaneous Absorption of Ketoprofen Using the Franz Skin Finite Dose Model

ABSTRACTObjectives: Ketoprofen is an analgesic, anti-inflammatory agent commonly used in the management of chronic musculoskeletal pain. The aim of this study is to characterize the percutaneous absorption of 2 ketoprofen formulations (ketoprofen 10% in Pluronic Lecithin Organogel (PLO) and ketoprofen 10% in Lipoderm, referred to as phospholipid base), when applied to the human cadaver trunk skin, in vitro, using the Franz skin finite dose model. PLO and phospholipid base are vehicles used to facilitate the delivery of drugs into and through the skin following topical applications.Methods: The percutaneous absorption of ketoprofen was evaluated using human cadaver trunk skin from 3 donors. The skin was cut into small sections and cultured within Franz diffusion cells. A variable finite dose of each formulation was then applied to 3 replicate skin sections per donor and receptor solutions were collected at predetermined time points (0, 4, 8, 12, 24, 32, and 48 hr). After the last receptor sample was collected, skin surfaces were washed and split into epidermis and dermis. Collected samples were analyzed using HPLC.Results: Both PLO and phospholipid base were capable of facilitating the absorption of ketoprofen across human cadaver trunk skin. However, ketoprofen, when in phospholipid base, showed higher mean total absorption (p = 0.022) and faster rate of absorption (p < 0.05 at 2, 6, 10, and 18 hr) than when in PLO.Conclusion: Chronic musculoskeletal pain can be a major burden for most patients, affecting their lifestyle and reducing overall quality of life. When compared to PLO, phospholipid base has the ability to potentially deliver higher concentrations of ketoprofen to underlying soft tissues and at a more rapid rate. With more ketoprofen at the site of injury, the analgesic and anti-inflammatory effects will likely be enhanced, potentially reducing pain and improving quality of life.

Effect of Terpenes on the Skin Permeation of Ketoprofen through Shed Snake Skin

The objective of this work was to investigate the effect of hydrocarbon (a-pinene and limonene) andoxygen containing monoterpenes (carvone and terpineole) at 5%w/v in hydroalcoholic mixtures (50% ethanol)on the permeation of ketoprofen across shed snake skin of Python molurus bivittatus. The amount of KPretained in the skin after 8 h of diffusion was determined. It was found that the percutaneous absorption ofketoprofen was enhanced in the presence of the enhancers. The rank order of enhancement ratio for skinpermeation was found to be a-pinene > limonene > carvone > terpinoele. The enhancers also affected theretention of KP in the skin. The rank order of enhancement ratio for skin retention was the same order with skinpermeation experiment. The results indicated that that lipophilicity is an important structural feature formonoterpenes as skin permeation enhancer for a liphophilic drug, ketoprofen. Key Words: Terpenes; Transdermal delivery; Ketoprofen; Shed snake skin

Promoting mechanism of menthol derivative, 1-O-ethyl-3-buthylcyclohexanol, on the percutaneous absorption of ketoprofen.

Menthol derivatives were synthesized and evaluated for their promoting activity on the percutaneous absorption of ketoprofen and skin irritation in vivo, choosing O-ethylmenthol (MET) as the mother compound. The compound having a C-3 positionned n-butyl group (1-O-ethyl-3-n-buthylcyclohexanol, OEBC) indicated the most promoting activity and caused relatively little skin irritation. In order to understand enhancement mechanism of OEBC an in vitro permeation study of ketoprofen was performed. The time course of the cumulative amounts of drug permeated through the rat skin exhibited a linear relation after an initial lag time. This was analyzed in membrane diffusion model and the diffusion and partition parameters of ketoprofen were estimated. Both parameters were remarkably enhanced when a hydrogel containing a small quantity of OEBC (0.5%) was applied. Furthermore, to clarify the site of action of OEBC, we also investigated in vitro permeation study of ketoprofen employing different skins of state, reversed skin and stratum corneum stripped skin. When OEBC was added to the hydrogels which were applied to the reversed and stripped skins, almost no changes of the flux were observed compared with the control (without OEBC). These results suggested that the site of action of OEBC was stratum corneum. Morphological changes of the stratum corneum surface were microscopically observed with 0-2% OEBC. The spaces between the stratum corneum cells treated with 0.5-2% OEBC became extended and the shape of each cell became clear. This may suggest that the site of action of OEBC was the intercellular of stratum corneum. Furthermore, an electron spin resonance study was performed to investigate the effect of OEBC on the intercellular lipid bilayer fluidity of the stratum corneum and the rotational correlation times were calculated. 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO) and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) were used as the spin label. In use of OEBC, the fluidity of TEMPO labeled the stratum corneum lipid increased as the addition of OEBC. The results suggested that OEBC promote the penetration of drugs by enhancing fluidity of the local lipid bilayers around TEMPO.

Evaluation and structure–activity relationship of synthesized cyclohexanol derivatives on percutaneous absorption of ketoprofen using artificial neural network

The effect of 35 newly synthesized O-ethylmenthol (MET) derivatives on percutaneous absorption of ketoprofen was investigated in rats. In order to understand the relationship between the structure of compounds and promoting activity (structure–activity relationship), an artificial neural network (ANN) was employed. In the in vivo percutaneous absorption study, male Wistar rats, weighing 160–180 g, were used. The apparent penetration rate ( R p) was estimated based on a pharmacokinetic model with a constant rate of penetration through the skin after a lag time. As an index of the promoting activity of each compound, an enhancement factor (Ef), defined as follows, was used: Ef= R p(with enhancer)/ R p(without enhancer). An irritation evoked on rat skin was microscopically judged at the end of the in vivo percutaneous absorption experiment and evaluated as a total irritation score (TIS). Ef and TIS were selected as output variables to determine the ANN structure. Calculated log P, molecular weight, steric energy (SE), van der Waals area, van der Waals volume, dipole moment, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) were used as factors to determine the structural nature of cyclohexanol derivatives. Among these parameters, log P, SE and LUMO significantly affected the prediction of Ef and TIS. The predicted values of Ef and TIS coincided well with in vivo percutaneous absorption experimental values. However, results observed with a linear regression method were poor compared with the ANN approach. The contribution index of log P was ≈50% in the prediction of Ef, suggesting that lipophilicity among physicochemical properties contributes most of the promoting activity of these compounds.

Formula optimization based on artificial neural networks in transdermal drug delivery

The promoting effect of O-ethylmenthol (MET) on the percutaneous absorption of ketoprofen from alcoholic hydrogels was evaluated in rats in vitro and in vivo. Furthermore, a novel simultaneous optimization technique incorporating an artificial neural network (ANN) was applied to a design of a ketoprofen hydrogel containing MET. When a small quantity of MET (0.25–0.5%) was added to the hydrogels, the permeation of ketoprofen increased remarkably, compared with the control. On the other hand, little change in permeation was observed when small amounts of menthol were used (<1%), and at least 2% menthol was required to obtain a promoting efficiency comparable with 0.25% MET. The partitioning of ketoprofen from the hydrogel to the skin was improved by the addition of a small amount of MET, whereas the diffusivity of the drug was enhanced at higher concentration of MET (0.5–1%). For the optimization study, the amount of ethanol and MET were selected as causal factors. A rate of penetration (Rp) and lag time (tL) and total irritation score (TIS) were selected as response variables. A set of causal factors and response variables was used as tutorial data for ANN and fed into a computer. Nonlinear relationships between the causal factors and the response variables were represented well with the response surface predicted by ANN. The optimization of the ketoprofen hydrogel was performed according to the generalized distance function method. The observed results of Rp and TIS, which had a lot of influence on the effectiveness and safety, coincided well the predictions.

Thiomenthol Derivatives as Novel Percutaneous Absorption Enhancers

Thiomenthol derivatives were synthesized and their promoting activity on the percutaneous absorption of ketoprofen from hydrogels was evaluated in rats. The apparent penetration rate (Rp) of ketoprofen absorbed from the hydrogel was estimated by the pharmacokinetic model derived under the assumption of a constant penetration rate through the skin after a lag time. As an index of promoting activity of thiomenthol derivatives, an enhancement factor (Ef) was defined as the ratio of the Rp value with enhancer to the value obtained with the control not containing enhancer. Skin irritancy evoked by these derivatives was investigated microscopically by using a cross-section of the excised skin onto which ketoprofen hydrogel was applied. Total irritation score (TIS) was estimated by summation of each irritation score in several parts of the skin. The physicochemical parameters of thiomenthol derivatives such as a partition coefficient (log P) and a steric energy were calculated and the quantitative relationships between these parameters and the Ef values or TIS values were investigated on the basis of multiple regression analysis. As a result, a parabolic relationship between log P and Ef was noted. A similar relationship was also observed in the case of TIS.

Enhancement of percutaneous absorption of ketoprofen: effect of vehicles and adhesive matrix

The effects of various vehicles on percutaneous absorption of ketoprofen in a solution formulation and in a pressure-sensitive adhesive (PSA) matrix were evaluated. The permeation rate of ketoprofen across hairless mouse skin was evaluated using a flow-through diffusion cell system at 37°C. The solubility of ketoprofen was determined using the equilibrium solubility method. Among tested vehicles, octanol, ethanol, and propylene glycol (PG)/oleyl alcohol (OA) mixture showed the highest flux of 30 μg/cm 2 per h from 5 mg/ml solution. However, it was not possible to demonstrate any correlation between the solubility of ketoprofen and its permeation rate, indicating change in the barrier property of the skin and/or carrier mechanism by vehicles used. When the effects of various vehicles on the percutaneous absorption of ketoprofen from acrylic PSA matrix were evaluated, oleic acid showed a slightly higher flux of 2 μg/cm 2 per h than all other solvents tested. As the concentration of ketoprofen in acrylic PSA matrix increased from 6.3 to 16.7%, the permeation rate also increased almost linearly. The permeation rate of ketoprofen from polyisobutylene (PIB)-type PSA matrix was more than three times higher than that from acrylic PSA matrix.

Promoting effect of O-ethylmenthol on the percutaneous absorption of ketoprofen

The promoting effect of O-ethylmenthol (MET) on the percutaneous absorption of ketoprofen from alcoholic hydrogels was evaluated in rats in vitro and in vivo. Further, the anti-inflammatory action of ketoprofen hydrogels was evaluated with a rat paw edema test. The time course of the cumulative amounts of drug permeated through the rat skin in vitro exhibited a linear relation after an initial time lag. This was analyzed in a membrane diffusion model and the diffusion and partition parameters of ketoprofen were estimated. Both parameters were remarkably enhanced when a hydrogel containing a small quantity of MET (0.5%) was applied. However, at least 2% menthol was required to obtain the same activity as 0.25% MET. A pharmacokinetic model, which was derived on the assumption of a constant penetration rate ( R p) after a lag time, was employed to evaluate in vivo percutaneous absorption of ketoprofen from hydrogels containing MET. Further, the area under the plasma concentration-time curve (AUC 0–8 h) was estimated. Similarly to the results observed in vitro, R p and AUC 0–8 h values were increased significantly by the administration of hydrogels containing a small amount of MET (0.25–0.5%). In order to obtain the significant inhibitory action of ketoprofen on the rat paw edema induced by carrageenan, at least 1% menthol was required in the hydrogel formulation. On the other hand, a small amount of MET (0.25–0.5%) was enough to bring about significant inhibitory action of ketoprofen. Distinguishable changes of the skin surface were microscopically observed with 0.5–2% MET, i.e. the spaces between the stratum corneum cells became extended and the shape of each cell became clear, whereas the morphological changes caused by menthol were relatively weak. Both MET and menthol may change the dense barrier structure of the stratum corneum of skin; however, the efficiency of MET is significantly greater than that of menthol.

Percutaneous absorption of ketoprofen. I. In vitro release and percutaneous absorption of ketoprofen from different ointment bases

Ketoprofen (KP) is a potent non-steroidal anti-inflammatory drug which is used for the treatment of rheumatoid arthritis. The oral administration of KP can cause gastric irritation and renal adverse effects. Topical application of the drug can bypass gastrointestinal disturbances and provide relatively consistent drug levels at the site of action. Since the efficacy of an ointment depends on the type of ointment base and the concentration of the drug, four different bases (white petrolatum, cold cream, hydrophilic ointment and Carbopol 940 gel) were used at 1, 3, 5, 7 and 10% concentrations of KP to evaluate the effect of ointment base and concentration. The general rank order of the drug release was found to be: Carbopol gel > hydrophilic ointment > cold cream > white petrolatum. There was a positive correlation between the concentration of KP and release rate for all bases except Carbopol gel. The in vivo percutaneous absorption of KP from different ointment bases at 3% concentration was studied by carrageenan-induced paw edema in mice. The rank order of the percent edema inhibition was as follows: Carbopol gel ≥ hydrophilic ointment > cold cream > white petrolatum. There was a good correlation between the in vitro and in vivo results.

ケトプロフェンの経皮吸収に及ぼす入浴および貼付タイミングの影響

ケトプロフェンの経皮吸収に及ぼす入浴および貼付タイミングの影響

Combined effect of d-limonene and temperature on the skin permeation of ketoprofen

The effect of temperature on the enhancement action of d-limonene on percutaneous absorption of ketoprofen (KPF) was investigated in rats in vivo and in vitro. The apparent penetration rate ( R p ) of KPF absorbed from alcoholic hydrogels in rats was estimated based on a pharmacokinetic model, which was derived on the assumption of a constant penetration rate through the skin. The R p value increased sigmoidally with increase in the temperature applied, i.e., the R p value was almost constant at the lower temperatures, however, it increased abruptly at the critical temperature ( T c ) of applied heat. The T c value was significantly lowered by increasing the content of d-limonene in the hydrogel. The steady-state permeability coefficients ( P) of KPF through the skin was determined by employing two-chamber diffusion cells in which the excised rat abdominal skin was mounted. The combined effect of d-limonene and temperature on the P value was also clarified. The Arrhenius plots of P values showed a linear relationship when the skin was pretreated with 30% ethanol without d-limonene. The activation energy of permeation of KPF through the skin was estimated to be 6.49 kJ/mol. When the skin was pretreated with 1.5% d-limonene in 30% ethanol, the Arrhenius plots of P exhibited a convex curvature. Morphological changes of the skin surface were also observed microscopically. The application of heat, along with the synergistic effect of d-limonene, may effectively change the dense barrier structure of the stratum corneum.

Effects of the Administration of Ketoprofen gel on the Percutaneous Absorption of Ketoprofen in Rabbits

AbstractThe effects of the administration for a commercial keto-profen gel on the percutaneous absorption of ketoprofen (through rabbit abdominal skin) were investigated. The AUC (area under the curve) value of absorbed ketoprofen for single topical administration of 6 g of ketoprofen gel applied with ODT (occlusive dressing technique) was found to be about 6 -fold greater than that of repeated administration of 1.5 g of ketoprofen gel applied with ODT at 6 h interval in a day. It was about 14-fold greater than that of repeated administration of 1.5 g of ketoprofen gel applied without ODT at 6 h interval in a day. The experiment of volatilation of ketoprofen gels and the in vitro release test of ketoprofen gel applied with ODT and without ODT had been, in addition, respectively approached. The volatilation of solvent in the gel, as a result of this, may clearly be the primary factor for inducing a sharp descending of the plasma ketoprofen level following the Cmax (maximun concentration) in the in vivo per...

Percutaneous absorption of ketoprofen from acrylic gel patches containing d-limonene and ethanol as absorption enhancers.

The percutaneous absorption of ketoprofen (KPF) from gel patches containing d-limonene and ethanol was investigated in rats. Plasma levels of KPF varied with the kind of polymers which constitute the gel patch, and the highest level was observed when the copolymer of ethylacrylate (EA) and diethyleneglycolmethacrylate (DEGMA) was used as a vehicle. The amount of KPF permeating through the rat skin from the gel patch was well correlated with that of ethanol. Permeations were enhanced with increase in the amount of d-limonene distributed from the vehicle to the skin tissue. The amount of d-limonene accumulated in the skin varied greatly with the kind of polymers; the highest accumulation was observed with the EA-DEGMA copolymer, and decreased with increasing affinity of d-limonene to the polymers. The reason EA-DEGMA copolymer showed the highest percutaneous absorption of KPF from gel patches containing d-limonene may be the hydrophilic nature of this polymer which showed the lowest affinity to d-limonene.