Iontophoretic Transdermal Delivery of Ketoprofen. Effect of Iontophoresis on Drug Transfer from Skin to Cutaneous Blood.

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Transdermal drug absorption includes several sequential processes, as follows: (1) drug absorption into the skin; (2) transfer from skin to cutaneous vein; (3) transport to systemic circulation by blood flow. In systemic therapy, it is necessary to transfer drug molecules from skin (application site) to cutaneous blood flow and to transport to the target organ through systemic circulation. [2][3][4][5][6][7] On the other hand, local therapy needs to accumulate drug molecules at the local site (skin, muscle and joint, etc.), but not to eliminate into the blood flow.2-7) Therefore, the evaluation of drug transfer properties into local blood flow would be expected to predict the systemic and local therapeutic effects.Previously, we have developed a method to investigate transdermal absorption processes in vivo, whereby the drug concentrations in skin, cutaneous vein and systemic vein are measured after iontophoretic delivery of drugs to rats. 8) Further, kinetic analysis of drug transfer from skin to cutaneous vein has been established by modifying a physiological pharmacokinetic model. 9) In the previous study, we investigated the effect of drug lipophilicity on the iontophoretic transdermal absorption of non-steroidal anti-inflammatory drugs (NSAIDs) such as salicylic acid, ketoprofen, naproxen and indomethacin.10) The transfer properties of these NSAIDs from skin to cutaneous vein decreased with an increase in their lipophilicity.The NSAIDs examined previously are acidic drugs with a carboxyl group. In the present study, b-blockers were selected as basic drugs having an amino group and included atenolol (AT), pindolol (PD), metoprolol (MP), acebutolol (AB), oxprenolol (OX) and propranolol (PP). The chemical structures and physicochemical properties are listed in Table 1. 11-13) These b-blockers are adequate for evaluating the effect of lipophilicity on transdermal absorption properties, because the molecular weights are of narrow range. As an indication of drug lipophilicity, we used the logarithm of n-octanol/buffer partition coefficient (Log P), which varied from Ϫ0.11 to 1.49 (pH 7.4, 37°C).12) The difference in the lipophilicity is a consequence of the difference in the aromatic substituents of the b-blockers.Beta-blockers are used in the treatment of hypertension, angina pectoris and cardiac arrhythmia.14) Because of their short elimination half-life (from several to less than 6 h), 15) sustained release formulations for oral administration have been developed to prolong the therapeutic effects.16-21) However, the oral absorption of b-blockers is influenced by hepatic first-pass metabolism. 15,22) Thus, the development of transdermal delivery systems may be expected to achieve good maintenance of optimal blood levels and the avoidance of first-pass effects. Anodal Iontophoresis Anodal iontophoresis was performed as described previously. 10) Briefly, male SpragueDawley rats (8-10 weeks old, Charles River Japan) were anesthetized with ether throughout the experiment, and their body temperature was maintained...

“…9,10) Briefly, the rate of local drug transfer from skin to cutaneous vein (R SC ) can be obtained from the arterio-venous blood concentration difference in the skin:…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Effect of Lipophilicity on in Vivo Iontophoretic Delivery. II. .BETA.-Blockers.

Tashiro

Sami

Shichibe

et al. 2001

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“…Therefore, it is necessary to develop enhancement techniques to assist the skin penetration of KET, and extensive research has been done to find both topical and transdermal KET formulations. 1,[4][5][6] To improve the delivery of KET through the skin, several techniques have been employed as follows: liposomes, 7) gels, 8,9) ointments, creams, 10) patches 11,12) incorporating various permeation enhancers, micro-needle treatment, 13) iontophoresis 14,15) and therapeutic frequency sonophoresis (1 MHz). 16,17) Recently, strategies using nanoparticles have been developed and investigated as nanomedicines.…”

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Pharmacokinetics and Antiinflammatory Effect of a Novel Gel System Containing Ketoprofen Solid Nanoparticles

Nagai

Iwamae

Tanimoto

et al. 2015

We previously reported that dermal application using nanoparticles improves skin penetration. In this study, we prepared novel topical formulations containing ketoprofen (KET) solid nanoparticles (KET nano gel ointment) and investigated the antiinflammatory effect of the KET nanoparticle formulations on rheumatoid arthritis using adjuvant-induced arthritis (AA) rats. The KET nano gel ointment was prepared using a bead mill method and additives including methylcellulose and Carbopol 934; the mean particle size of the KET nanoparticles was 83 nm. In the in vitro skin penetration experiment, the penetration rate (J c ) and penetration coefficient through the skin (K p ) values of the KET nano gel ointment were significantly higher than those of gel ointment containing KET microparticles (KET micro gel ointment; mean particle size 7.7 µm). On the other hand, in the in vivo percutaneous absorption experiment, the apparent absorption rate constant (k a ) and the areas under the KET concentration-time curve values in the skin of rats receiving the KET nano gel ointment were significantly higher than those of rats receiving the KET micro gel ointment, and the amounts of KET in the skin tissues of rats receiving the KET nano gel ointment were also significantly higher than those of rats receiving the KET micro gel ointment. In addition, the application of the KET nano gel ointment attenuated the enhancement of paw edema of the hind feet of AA rats more than the application of the KET micro gel ointment. Our findings suggest that a topical drug delivery system using nanoparticles could lead to expansion in the therapeutic use of KET.Key words nanoparticle; ketoprofen; gel ointment; drug delivery; adjuvant-induced arthritis Ketoprofen (KET) is a reversible inhibitor of cyclooxygenases 1 and 2 whose action leads to a reduction in the formation of prostaglandin precursors. 1) Thus, KET acts as an antiinflammatory agent, and is used in the treatment of rheumatoid arthritis (RA) and osteoarthritis. However, its usefulness is limited due to its low water solubility and the fact that oral administration of KET tends to cause gastrointestinal lesions in 10-30% of patients. These gastrointestinal lesions lead to an interruption of drug therapy in about 5-15% patients. 2,3)Topical and transdermal delivery routes of drug administration reduce the incidence of gastrointestinal lesions and improve patient compliance. Furthermore, the transdermal route of application avoids hepatic first pass metabolism, meaning that therapeutic serum drug concentrations can be applied with a reduced risk of nephrotoxicity and drug-drug interactions.2) However, the transdermal route of application is limited by the barrier properties of the skin. Therefore, it is necessary to develop enhancement techniques to assist the skin penetration of KET, and extensive research has been done to find both topical and transdermal KET formulations.

“…However, the percutaneous absorption of drugs with a high molecular weight and hydrophilic properties is not sufficient due to the barrier function of the skin. To enhance the absorption, several investigations using vehicles, 1,2) chemical enhancers, [3][4][5][6] iontophoresis, [7][8][9] electroporation 10,11) and phonophoresis 12,13) have been performed. We have focused on iontophoresis in terms of the enhancement of the amount of drug delivered by current with low skin irritation.…”

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Evaluation of Skin Barrier Function Using Direct Current III: Effects of Electrode Distance, Boundary Length and Shape

Kanebako¹,

Inagi²,

Takayama

2003

Transdermal drug delivery can avoid first-pass metabolism, which is the greatest disadvantage of oral administration. However, the percutaneous absorption of drugs with a high molecular weight and hydrophilic properties is not sufficient due to the barrier function of the skin. To enhance the absorption, several investigations using vehicles, 1,2) chemical enhancers, [3][4][5][6] iontophoresis, 7-9) electroporation 10,11) and phonophoresis 12,13) have been performed. We have focused on iontophoresis in terms of the enhancement of the amount of drug delivered by current with low skin irritation. In a previous study, we predicted that the amount of drug that migrated in the skin was determined by a synergistic effect of both current application and enhanced passive diffusion due to the reduction in barrier function.14)The prediction was proved by the measurement of the distribution using indomethacin as a model drug. 15) In these studies, the accumulation of drug in the stratum corneum contributed to enhanced passive diffusion due to the reduction in barrier function. On the other hand, the accumulation from dermis to upper dermis was attributed to a passage of current. Further, a novel method for analyzing the reduction in barrier function under constant voltage was proposed.16) With this method, the barrier function was defined as resistance, which represented the sum of exponential functions of surface and skin resistance. In addition, the evaluation was carried out using the initial value and rate constant of the surface resistance. Using this method, effects of conductivity in the adhesive pad, voltage, the distance between electrodes and electrode area on the barrier function were evaluated. Furthermore, the influence of a pulsed direct current, which could prevent skin polarization and irritation was investigated. 17)The reduction in barrier function brought about by the application of sine and rectangular waveforms with a 75% duty cycle was almost the same as that caused by the application of direct current. Considering the skin polarization, the pulsed currents were more suitable.In the evaluation of changing electrode area, 16) although the initial value of surface resistance increased with increasing electrode area, no change of rate constant was observed. The rate constant showed the damping of the surface resistance, i.e., the barrier function. These phenomena contributed to the higher current density in the portion adjacent to the other electrode. Therefore, we investigated the electrode disposition and shape considering the reduction in barrier function as well as effective delivery of drugs into the skin. Similar results were reported by Haga et al. 18) They prepared electrodes with different boundary lengths using a photoeching technique, and then observed the skin distribution of 6-carboxyfluorescein (6-CF) under constant voltage. In that paper, the topical distribution of 6-CF in the skin was recognized in both boundary portions, i.e., the portion adjacent to the other electrode. They suggested ...