Effect of O-acylmenthol and salt formation on the skin permeation of diclofenac acid

Purpose: To enhance the transdermal delivery of diclofenac acid (DA) by using O-acylmenthol as a penetration enhancer and complexing with amines, or by a combination of the two methods. Methods: The skin permeability of diclofenac was tested in vitro across rat skin with each of the evaluated permeants in a saturated isopropyl myristate (IPM) donor solution. Results: A 4.5-fold increase in the flux of diclofenac was observed by ion-pair formation with diethylamine; however, the cations with hydroxyl groups had negative effects on the transdermal delivery of diclofenac. 2-isopropyl-5-methylcyclohexyl 2-hydroxypanoate and 2-isopropyl-5-methylcyclohexyl heptanoate produced significant increase in the permeation of diclofenac potassium (D-K); however, both of them were ineffective for the other diclofenac salts, including diclofenac diethylamine (D-DETA), diclofenac ethanolamine (D-EA), diclofenac diethanolamine (D-DEA), diclofenac triethanolamine, and diclofenac N-(hydroxylethyl) piperidine. 2-isopropyl-5-methylcyclohexyl tetradecanoate was effective on the penetration of D-K, D-DETA, D-EA, and D-DEA. Also, it is exciting to note that the combined use of diethylamine with 2-isopropyl-5-methylcyclohexyl tetradecanoate produced a 9.74-fold increase in accumulation amount of diclofenac compared with DA in IPM. Conclusions: The use of ion pair in combination with O-acylmenthol is necessary to further increase the diclofenac flux to provide better compliance for the patients undergoing clinical therapy.     

Percutaneous transport of diclofenac sodium from mixtures of fatty alcohol (or fatty acid) and propylene glycol through the rabbit abdominal skin

Diclofenac sodium is a nonsteroidal anti-inflammatory drug with analgesic, antipyretic, and anti-inflammatory activity. When used in a topical application, diclofenac can diffuse through the skin and into the subcutaneous tissue to effect the anti-inflammatory action. In this study, in vitro evaluations of the percutaneous transport of diclofenac sodium in various bases containing fatty alcohols/propylene glycol or fatty acid/propylene glycol mixtures through the abdominal skin of the rabbit were investigated. Results show that the transdermal flux of diclofenac sodium in the fatty alcohol/propylene glycol bases of the same ratio is affected by the chain length of the fatty alcohol, and its effect is in the order of C10 > C12 > C14 > C18. However, the transdermal flux of diclofenac sodium in the fatty acid/propylene glycol bases of the same ratio is also affected by the chain length of the fatty acid, but no absolute relationship was found. For the same chain length of fatty acid and fatty alcohol used in the formulation base that was otherwise the same, the transdermal flux of diclofenac sodium is higher in the formula containing fatty alcohol than that containing fatty acid.     

Enhanced percutaneous permeability of diclofenac using a new U-type dilutable microemulsion

Enhanced systemic absorption in vivo and percutaneous penetration in vitro was demonstrated after transdermal administration of diclofenac sodium formulated in U-type microemulsion. Diclofenac sodium was solubilized in a typical four-component system consisting of an oil, polyoxyethylene-10EO-oleyl alcohol (Brij 96V) as the surfactant, and 1-hexanol along water dilution line W46 (40 wt % surfactant and 60 wt % oil phase before water titration).Viscosity and small angle X-ray scattering measurements have evidenced bicontinuous structures within water fractions of 0.25 and 0.5 along the dilution line. Self-diffusion NMR studies showed that drug molecules accumulated in the interfacial film and, to some extent, dissolved in the oil. Relative to a commercial macro-emulsion cream (Voltaren® Emulgel®), microemulsions containing paraffin oil or isopropyl myristate increased the in vivo transdermal penetration rate of diclofenac by two order of magnitude, whereas the rat plasma levels were increased by one order of magnitude. The in vitro data obtained from excised rat skin were comparable to the in vivo results, but suffered from discrepancies from the ideal in vivo-in vitro correlation, which might be explained by optimal in vitro conditions of perfusion and hydration. It has also been found that when jojoba oil is formulated as the oil phase in the microemulsion, the penetration rate of the drug decreases significantly. Based on the three-dimensional structure of jojoba oil, the wax is presumed to prevent the drug from being freely diffused into the skin while migrating from the interfacial film into the continuous oil phase.     

Development and characterization of pseudolatex based transdermal drug delivery system of diclofenac.

A transdermal drug delivery system of diclofenac was developed for prolonged and controlled release of diclofenac. The designed system essentially based on polymeric pseudolatex dispersion. The formulation variables that could effect the formulation stability vis a vis drug release were studied. To achieve the desired release rate, different combination of hydrophilic and hydrophobic polymer were used for the preparation of pseudolatex system. The designed system exhibited linear relationship between drug release (Q) V/s square root of time (t^0.5). The product having skin permeability rate 0.188 mg/h/cm was selected for the in vitro anti-inflammatory activity and in vivo evaluation. The system could maintained a constant and effective plasma level for 24 hours. The effective drug plasma concentration was monitored periodically. The study revealed that designed pseudolatex transdermal drug delivery system of diclofenac could be used successfully with improved performance and hold promise for further studies.     

Improving the topical delivery of zinc phthalocyanine using oleic acid as a penetration enhancer: in vitro permeation and retention

Topical photodynamic therapy with zinc phthalocyanine (ZnPc), second-generation photosensitizer, can be an alternative method for the treatment of skin cancer. However, ZnPc has poor penetration in the skin. This study was aimed at investigating whether the presence of oleic acid (chemical enhancer) in propylene glycol can improve the topical delivery of ZnPc. The topical (to the skin) and transdermal (across the skin) delivery of ZnPc were evaluated in vitro using suine ear skin mounted in Franz diffusion cell. Photosensitizer was quantified by fluorescence emission, which is a sensitive and selective method. At 5 and 10%, oleic acid increased the topical and transdermal delivery significantly. When the concentration of oleic acid was further increased (20-60% w/w), the topical delivery of ZnPc was still elevated, but its transdermal delivery was substantially reduced. It was concluded that oleic acid (in propylene glycol formulations) can promote the topical delivery of ZnPc, with reduced transdermal delivery. This approach can be effective for the treatment of skin cancer by topical photodynamic therapy.     

Aqueous-Lipid Transdermal Formulation of Anti-Inflammatory Agents, Prepared with Hydrogenated Soya Phospholipid

The in vitro transport of various anti-inflammatory agents were examined using rat dorsal skin and shed snake skin as models of the stratum corneum for the evaluation of transdermal formulation. The aqueous-lipid vehicle formulations prepared with hydrogenated soya phospholipid increased the transport of ketoprofen and sodium diclofenac, and an addition of tetradecanol to the formulation increased the transport of both drugs more markedly. The amounts of drug (%) transported during 12 h with rat dorsal skin and during 24 h with shed snake skin was about 50% for ketoprofen and about 30 % for sodium diclofenac. The aqueous-lipid formulation including tetradecanol also increased the transport of indomethacin, but only about 10 %. It is suggested that the small effect of the aqueous-lipid vehicle formulation on indomethacin transport is due to the low solubility of indomethacin in the vehicle.     

Pharmacokinetic profile of a new matrix-type transdermal delivery system: diclofenac diethyl ammonium patch

A transdermal delivery system containing the anti-inflammatory analgesic diclofenac diethyl ammonium in an ethyl hexyl acrylate and vinyl acetate pressure-sensitive adhesive system was developed for percutaneous absorption. These patches were subjected to in vitro permeation and permeation enhancement studies through rat skin using a specially designed diffusion cell. Further, the work deals with percutaneous absorption studies carried out on both animals and human volunteers. The pharmacokinetic parameters calculated from the blood levels of the drug reveal a profile typical of a sustained-release formulation, with the ability to maintain adequate plasma levels for 24 hr (i.e., up to the next application). (Area under the curve [AUC]: 4.356 ± 1.3 mcg/ml.hr in animals and 0.442 ± 0.053 mcg/ml.hr in humans; T_max was 8 hr in both the cases, whereas C_max was 0.288 ± 0.088 mcg/ml in animals and 0.034 ± .008 mcg/ml in human volunteers.) The amount of the drug bioavailable for targeting the sites of action is lower than via the oral route, but the absorbed dose appears to be adequate for therapeutic use, particularly because of the absence of side effects.     

Aqueous-Lipid Transdermal Formulation of Anti-Inflammatory Agents,Prepared with Hydrogenated Soya Phospholipid

Abstract

The in vitro transport of various anti-inflammatory agents were examined using rat dorsal skin and shed snake skin as models of the stratum corneum for the evaluation of transdermal formulation. The aqueous-lipid vehicle formulations prepared with hydrogenated soya phospholipid increased the transport of ketoprofen and sodium diclofenac, and an addition of tetradecanol to the formulation increased the transport of both drugs more markedly. The amounts of drug (%) transported during 12 h with rat dorsal skin and during 24 h with shed snake skin was about 50% for ketoprofen and about 30 % for sodium diclofenac. The aqueous-lipid formulation including tetradecanol also increased the transport of indomethacin, but only about 10 %. It is suggested that the small effect of the aqueous-lipid vehicle formulation on indomethacin transport is due to the low solubility of indomethacin in the vehicle.     

Topical oleo-hydrogel preparation of ketoprofen with enhanced skin permeability.

In an attempt to improve the skin penetration of ketoprofen, various transdermal formulations were prepared, and their in vitro skin permeability and in vivo percutaneous absorption were evaluated. In vitro permeation studies were performed using a modified Franz cell diffusion system in which permeation parameters such as cumulative amount at 8 hr Q8hr, steady-state flux Jss, or lag time tL were determined. In the in vivo percutaneous absorption study using the hairless mouse, maximum concentration Cmax and area under the curve at 24 hr AUC24h were measured. The optimal transdermal formulation (oleo-hydrogel formulation) of ketoprofen showed a Q8hr value of 227.20 micrograms/cm2, a Jss value of 29.61 micrograms/cm2/hr, and a tL value of 0.46 hr. The Q8hr and Jss values were about 10-fold (p < .01) higher than those (Q8hr = 19.61 micrograms/cm2; Jss = 2.66 micrograms/cm2/hr) from the K-gel and about 3.5-fold (p < .01) than those (Q8hr = 60.00 micrograms/cm2; Jss = 7.99 micrograms/cm2/hr) of the K-plaster. In the in vivo percutaneous absorption, the Cmax (6.82 micrograms/ml) and AUC24h (55.74 micrograms.hr/ml) values of the optimal formulation were significantly (p < .01) higher than those of K-gel and K-plaster. The relative bioavailability of the oleo-hydrogel following transdermal administration in reference to oral administration was about 37%, and the Cmax value (4.73 micrograms/cm2) in the hypodermis following topical administration was much higher than those from the conventional products (Cmax of K-gel and K-plaster were 0.92 +/- 0.19 microgram/cm2 and 1.27 +/- 0.37 microgram/cm2, respectively). These data demonstrate that the oleo-hydrogel formulation of ketoprofen was more beneficial than conventional products (K-gel and K-plaster) in enhancing transdermal permeation and skin absorption of ketoprofen. Furthermore, there was a good correlation between in vitro permeation parameters and in vivo percutaneous absorption parameters.     

Pharmacokinetic Profile of a New Matrix-Type Transdermal Delivery System: Diclofenac Diethyl Ammonium Patch

A transdermal delivery system containing the anti-inflammatory analgesic diclofenac diethyl ammonium in an ethyl hexyl acrylate and vinyl acetate pressure-sensitive adhesive system was developed for percutaneous absorption. These patches were subjected to in vitro permeation and permeation enhancement studies through rat skin using a specially designed diffusion cell. Further, the work deals with percutaneous absorption studies carried out on both animals and human volunteers. The pharmacokinetic parameters calculated from the blood levels of the drug reveal a profile typical of a sustained-release formulation, with the ability to maintain adequate plasma levels for 24 hr (i.e., up to the next application). (Area under the curve [AUC]: 4.356 ± 1.3 mcg/ml.hr in animals and 0.442 ± 0.053 mcg/ml.hr in humans; T_max was 8 hr in both the cases, whereas C_max was 0.288 ± 0.088 mcg/ml in animals and 0.034 ±. 008 mcg/ml in human volunteers.) The amount of the drug bioavailable for targeting the sites of action is lower than via the oral route, but the absorbed dose appears to be adequate for therapeutic use, particularly because of the absence of side effects.     

The effect of component of microemulsion for transdermal delivery of nicardipine hydrochloride

Purpose: Nicardipine hydrochloride has been used widely for the treatment of angina pectoris and hypertension. Because of its extensive first pass metabolism after oral administration, the transdermal administration of nicardipine microemulsions was developed in this study. Methods: Microemulsions consisted of isopropyl myristate (IPM), surfactant mixture of Tween 80/Span 80 and/or Tween 80/Span 20, co-surfactant (ethanol) and aqueous phase. Pseudo-ternary phase diagrams were constructed using water titration method. The effect of component of microemulsion on the percutaneous absorption of drug was evaluated by in vitro permeation study. Results: The area of microemulsion isotropic region in the presence of ethanol was comparably larger in the absence of ethanol. The mean droplet size of nicardipine microemulsions ranged from 70 to 123 nm. With addition of ethanol, the droplet size became smaller. The permeation rate and extent of nicardipine microemulsion transport across rat skin was affected by the components of microemulsion. Nicardipine microemulsion had higher flux at surfactant mixture with lower hyrophile-lipophile balance (HLB) value and Tween content. Conclusions: The microemulsion consisted of 52% IPM, 35% surfactant mixture and 13% water had higher permeation rate through rat skin above 122.53±1.87 μg/cm2/h and was expected to develop a transdermal delivery system.     

Two steps modification for improvement of cyclobenzaprine transdermal delivery: releasing from patch and penetrating through skin

The aim of this study was to improve the transdermal delivery of cyclobenzaprine (CBZ) from drug-in-adhesive patch which showed less side effects and better compliance. CBZ base was prepared and then characterized using differential scanning calorimetry (DSC). The interaction between CBZ and pressure-sensitive adhesive (PSA) was determined by Fourier Transform Infrared Spectroscopy (FT-IR). The influences of PSAs, penetration enhancers, patch thickness and drug content on the transdermal delivery of CBZ were studied thoroughly in vitro. Both CBZ releasing from patch and penetrating through the skin showed very great effect on the transdermal delivery of CBZ. The percentage of drug released from patch was increased with the decreasing of patch thickness, and so did the permeation percentage. The stratum corneum (SC) contributed approximately 57% resistance of total skin permeation resistance, and Span 20 increased the transdermal permeation by approximately 1.59-fold. The pharmacokinetic parameters were obtained through in vivo experiments of the optimized formulation using rabbit. Furthermore, the in vitro skin permeation results of CBZ patch correlated well with the in vivo absorption results in rabbit.     

Percutaneous absorption of captopril from hydrophilic cellulose derivatives through excised rabbit skin and human skin

The purpose of this investigation was to evaluate the influence of percutaneous absorption of captopril from hydrophilic cellulose derivatives gel bases (carboxymethylcellulose sodium [CMC], hydroxypropylcellulose [HPC] and hydroxylpropylmethylcellulose [HPMC]. The effects of various types and concentrations of penetration enhancers on captopril percutaneous absorption from HPC gel through rabbit skin were evaluated and selected to obtain some optimal formulations for penetration study through human chest skin. Then the required flux (1488 microg/hr) for captopril transdermal drug delivery system to maintain the therapeutic minimum effective concentration through human skin was used to evaluate the development of the optimal formulations. The results indicated that the minimum administered areas for therapeutic minimum effective concentration of captopril (cap) gel containing decanol (dec) were 10.4 cm2 (5% cap, 7% dec) and 7.6 cm2 (7% cap, 7% dec). These areas were within acceptable range, so these formulations can possibly be developed for a transdermal drug delivery system.     

Elevation of plasma levels of L-dopa in transdermal administration of L-dopa-butylester in rats

To increase delivery of L-dopa in its transdermal absorption, a new lipophilic derivative of L-dopa, L-dopa-butylester, was synthesized. An in-vitro study employing two-chamber diffusion cells, in which the excised rat abdominal skin was mounted, revealed that, in the presence of L-menthol and ethanol, L-dopa-butylester penetrated in its original form more effectively than L-dopa. L-Dopa-butylester sheets were made by immersing wiper sheets in methanol containing the compound, and then evaporating the methanol. An extraction study of the compound from the sheets revealed that its stability was maintained for at least 12 weeks. In an in-vivo cutaneous absorption study, an L-dopa-butylester sheet was attached to the shaved rat abdominal skin. A hydrogel containing L-menthol and ethanol was spread on vinyl tape, and this sheet was placed over it. In plasma, the L-dopa level rose linearly between 30 and 180 min after the cutaneous application; L-dopa-butylester was not detected. The L-dopa level was higher than that in which L-dopa was applied. These findings indicated that the lipophilic nature of L-dopa-butylester further increased its penetration through the skin, and that L-dopa-butylester that was taken up into the general circulation system was rapidly converted to L-dopa by hydrolysis in the body.     

Comparison of the transdermal absorption of nimesulide from three commercially available gel formulations

Nimesulide is a non-steroidal anti-inflammatory drug (NSAID) applied topically for a variety of conditions characterized by pain and inflammation. One of the aims of this study was to compare the permeation profile of nimesulide from the commercially available transdermal gel formulations across dermatomed porcine and human skin. The in vitro transdermal absorption of nimesulide formulations across porcine skin and human skin was studiedfor 24 hr using a continuous flow-through diffusion cell. The three commercial gels used in this study were Nimulid, Nise Gel, and Orthobid. All gels contained 1% (w/w) nimesulide. An infinite dose of nimesulide gel (about 300mg) was applied on the skin over 0.636 cm2 surface area. The rank order for the drug permeation from these formulations using porcine skin was: Nimulid > Orthobid > Nise Gel. The rank order of the permeation across human skin was: Nimulid> Nise Gel> Orthobid. The permeation profiles followed zero-order kinetics without any significant lag time. The steady-state flux of nimesulide from Nimulid was significantly higher than that of Nise Gel and Orthobid in both porcine and human skin (p <.05). However, there were no significant differences in the delivery of nimesulide (24 hr) from Nise Gel and Orthobid across both human and porcine skins. The results suggest that the Nimulid gel may have a greater bioavailability of nimesulide compared to the other gels. In addition, permeation profiles of the various gels across porcine skin did show a positive profile behavior to human skin. However, the in vitro drug release of nimesulide gels across a synthetic membrane did not correlate with skin permeation profiles.     

Microneedle assisted iontophoretic transdermal delivery of prochlorperazine edisylate

This paper investigates the microneedle (MN) mediated in vitro transdermal iontophoretic delivery of prochlorperazine edisylate (PE) across dermatomed human skin. The Dermaroller? induced microchannels were visualized using methylene blue staining and scanning electron microscopy. In vitro skin permeation studies were performed using vertical static Franz diffusion cells. Iontophoretic protocols involved application of direct current at a density of 0.4 mA/cm(2) using Ag as an anode and Ag/AgCl as a cathode. The effect of PE concentration (20, 50 and 100 mg/mL), number of passes of microneedles (0, 5, 10 and 20) on both iontophoretic and passive delivery of PE was studied. The Dermarollertm was found to successfully breach the skin barrier and a linear relationship (r(2) = 0.99) was observed between the number of passes of the Dermaroller? and the number of microchannels created. Passive transdermal flux of PE (0.060 ± 0.003 μg/cm(2)/h) at 50 mg/mL donor PE concentration) was low and increased (4.15 ± 0.57 μg/cm(2)/h) with the application of direct current. Application of iontophoresis in conjunction with microneedle pre-treatment resulted in enhanced flux (4.90 ± 0.39 μg/cm(2)/h at 50 mg/mL donor PE concentration) of PE. The projected transdermal PE flux indicates that a 9 cm(2) patch could deliver PE in a sufficient amount to maintain therapeutic levels of the drug. In conclusion, microneedles when used in conjunction with iontophoresis significantly enhanced the transdermal delivery of PE and it may be feasible to develop an iontophoretic transdermal patch that could be integrated with MN.     

Evaluation of diclofenac prodrugs for enhancing transdermal delivery

Objective: The purpose of this study was to evaluate the approach of using diclofenac acid (DA) prodrugs for enhancing transdermal delivery.

Methods: Methanol diclofenac ester (MD), ethylene glycol diclofenac ester (ED), glycerol diclofenac ester (GD) and 1,3-propylene glycol diclofenac ester (PD) were synthesized and evaluated for their physicochemical properties such as solubilities, octanol/water partition coefficients, stratum corneum/water partition coefficients, hydrolysis rates and bioconversion rates. In vitro fluxes across human epidermal membrane (HEM) in the Franz diffusion cell were determined on DA-, MD-, ED-, GD- and PD-saturated aqueous solutions.

Results: The formation of GD and ED led to the prodrugs with higher aqueous solubilities and lower partition coefficients than those of the parent drug. Prodrugs with improved aqueous solubility showed better fluxes across HEM in aqueous solution than that of the parent drug, with GD showing the highest aqueous solubility and also the highest flux. There is a linear relationship between the aqueous solubility and flux for DA, ED and PD, but GD and MD deviated from the linear line.

Conclusion: Diclofenac prodrugs with improved hydrophilicity than the parent drug could be utilized for enhancing transdermal diclofenac delivery.     

Transdermal absorption of L-dopa from a new system composed of two separate layers of L-dopa and hydrogel in rats

To maintain the stability of L-dopa in hydrogel, a new system composed of two separate layers of L-dopa and hydrogel was developed. L-Dopa sheets were made by immersing L-dopa solution into wiper sheets and by lyophilizing them. Examination for stability of L-dopa in the L-dopa sheet revealed that its stability was maintained for at least 12 weeks, providing the sheet was kept at room temperature in a dark box. In a cutaneous absorption study of L-dopa in rats, an L-dopa sheet was attached to the shaved abdominal skin. A hydrogel composed of cutaneous absorption enhancers, water and ethanol, was spread on vinyl tape (hydrogel sheet), and this sheet was placed over the L-dopa sheet. L-Dopa that was administered transdermally effectively penetrated through the skin: The plasma level of L-dopa peaked at 30 min and remained high between 60 and 180 min after the cutaneous application. Our system, composed of two separated layers of L-dopa and hydrogel, enabled the stability of L-dopa to be maintained without losing transdermal absorption of L-dopa.     

Effect of Various Physical/Chemical Properties on the Transdermal Delivery of Cyclosporin Through Topical Application

The pulpose of this study was to evaluate the effect of (A) skin stripping (B) trans-dermal enhancer and (C) iontophoresis, on the in vitro transdermal delivery of cyclosporin. An in vitro transdermal study through hairless mouse skin using a selected cyclosporin topical formulation was also conducted. Results show that the permeation coeflcient of cyclosporin was increased as the skins were stripped more times. Among the transdermal enhancers, azone, salicyclic acid, dimethyl sulfoxide, sodium lauryl sulfate and Tween 20; azone, and dimethyl sulfoxide were found to significantly increase the cyclosporin delivery; while salicylic acid, sodium lauryl sulfate and Tween 20 had no apparent effects. In further studies to define the optimum concentration of the above enhancers, the greatest effect was determined to be 1% for azone and 5% for dimethyl sulf oxide. Constant voltage iontophoresis was proven to be effective in enhancing the cyclosporin transdermal delivery. Data show that an increase in the permeability was observed when the voltage was increased from 1 to 7 V. The results of in vivo topical application of a selected cyclosporin formulation to hairless muse skin indicate that both blood and skin concentration reached maximum at about 36 hr after application, and that the cyclosporin concentration in the skin was constantly higher (10 times at the peak maximum) than its corresponding blood concentration at the same time intervals