Effect of Application Volume of Ethanol-Isopropyl Myristate Mixed Solvent System on Permeation of Zidovudine and Probenecid Through Rat Skin

Permeation of zidovudine (AZT) and probenecid from an ethanol-isopropyl myristate (IPM) mixed system through rat skin was studied in a finite system. Several volume sizes of the ethanol-IPM mixed systems containing AZT and probenecid, both as suspensions, were applied on the skin of the hairless rat using a vertical glass cell, and the fractions of the drugs permeated in 8 hr Q_%,8hr were determined. For the systems containing 40% ethanol, the Q_%,8hr value decreased with the reduction of volume of the system applied, and the decreasing profile was similar to that calculated on the assumption that the permeability of the drug does not change with the volume of the sample applied. On the other hand, in the systems containing 10% or 20% ethanol, the Q_%,8hr value showed a maximum when a specific volume of the sample was applied. Therefore, the effect of sample volume on the Q_%,8hr value was different between the 40% ethanol-IPM system and the 10% or 20% ethanol-IPM system. Following pretreatment of the skin with 0.105 ml/cm² of drug-free 40% ethanol-IPM for 2 hr, several volume sizes of 10% ethanol-IPM systems containing the drugs were applied on the skin to explain why the different profiles were observed in the system containing 10% or 20% ethanol. The results for pretreated skin suggest that the amount of ethanol in the systems with low ethanol concentration and small application volume is too small to exert an effect that enhances permeation of the drugs. In those systems, the integrated effect of ethanol on the skin would be important for the enhancing effect. Total volume, as well as concentration, of an enhancer should be set precisely in designing an efficient transdermal delivery system.     

Skin Permeation of Lidocaine from Crystal Suspended Oily Formulations

ABSTRACT

In vitro permeation of lidocaine (lidocaine base, LID) through excised rat skin was investigated using several LID-suspended oily formulations. The first skin permeation of LID from an LID-suspended oily solution such as liquid paraffin (LP), isopropyl myristate (IPM), polyoxyethylene (2) oleylether (BO-2), and diethyl sebacate (DES) was evaluated and compared with that from polyethylene glycol 400 (PEG400) solution, a hydrophilic base. The obtained permeation rate of LID, J_app, from PEG400, LP, IPM, BO-2, and DES was in the order of DES>BO-2 = IPM>LP>PEG400, and increased with LID solubility in the oily solvents, although LID crystals were dispersed in all solvents. Subsequently, oily formulations that consisted of different ratios of the first oily solvent (IPM, BO-2, or DES) (each 0–20%), the second oily solvent (LP) and an oily mixture of microcrystalline wax/white petrolatum/paraffin (1/5/4) were evaluated. BO-2 groups at a concentration of 5% and 10% had the highest J_app among the oily formulations, although a higher BO-2 resulted in lower skin permeation. In addition, pretreatment with BO-2 increased the skin permeation of LID. These results suggest that the penetration enhancing effect by the system may be related to the skin penetration of BO-2 itself. Finally, mathematical analysis was done to evaluate the effect of BO-2, and it was shown that BO-2 improved the LID solubility in stratum corneum lipids to efficiently enhance the LID permeation through skin.     

Effect of Fatty Acid Diesters on Permeation of Anti-Inflammatory Drugs Through Rat Skin

ABSTRACT

Four fatty acid diesters (diethyl succinate, diethyl adipate, diethyl sebacate, and diisopropyl adipate) were used to study their enhancement effect on the permeation of four non-steroidal anti-inflammatory drugs (NSAIDs: ketoprofen, indomethacin, diclofenac sodium, and ibuprofen) through rat abdominal skin. With the diester pretreatment, drug permeation increased and the lag times decreased. No relationship was observed between the solubilities of the drugs in the diesters and the diester enhancement effects. The enhancement effect decreased with an increase of the drug lipophilicity, but increased with an increase of the lipophilic index of the diester up to about 3.5, after which the enhancement effect decreased or remained constant. Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) was employed to investigate the biophysical changes in the stratum corneum lipids caused by the diesters. The FTIR results showed that treatment of the skin with diesters did not produce a blue shift in the asymmetric and symmetric C–H stretching peak positions. However, all of the above diesters showed a decrease in peak heights and areas for both asymmetric and symmetric C–H stretching absorbances in comparison with water treatment.

These results suggested that the diesters were more effective for enhancing the penetration of hydrophilic drugs than lipophilic drugs, and the enhancing effect of lipophilic diesters was more effective than that of hydrophilic diesters. The enhancement effects of diesters may be due to their causing lipid extraction in the skin.     

Evaluation of Verapamil Hydrochloride Permeation Through Human Cadaver Skin

Preformulation studies were conducted to determine the feasibility of a transdermal dosage form of verapamil hydrochloride (VPHC1). The apparent partition coefficient (octanol/water or buffer) of VPHC1 in buffers of different Ph values was determined. The saturation solubility of VPHC1 in different buffers and propylene glycol was determined. The target drug flux through the human skin to attain therapeutic concentrations in blood was determined. The maximum flux attainable through the human skin was determined. An attempt was made to increase the flux of the drug using azone as a penetration enhancer. The rate limiting barrier for the permeation of VPHC1 through the skin was determined.     

Enhancing Effects of Fatty Acids on Piroxicam Permeation Through Rat Skins

To increase the skin permeation of piroxicam from the Poloxamer 407 gel, fatty acid was added as a penetration enhancer to the Poloxamer 407 gel containing 1% piroxicam. The enhancing effects of the enhancer on the skin permeation of piroxicam were evaluated using Franz diffusion cells fitted with intact excised rat skins. To elucidate the modes of the action of enhancers, thermal analysis and histological examinations were conducted. Among fatty acids tested, linoleic acid showed the highest enhancing effects, with an enhancement factor (EF) of 1.76. From the thermal analysis results, fatty acids have fluidizing effects on the stratum corneum. The skin pretreated with the Poloxamer 407 gels containing piroxicam including linoleic acid showed a loosely layered stratum corneum and wide intercellular space.     

Transdermal Absorption of Zidovudine from Ethanol-Isopropyl Myristate Mixed System and Influence of Probenecid on It in Rats

Abstract

Transdermal absorption of zidovudine (AZT) from an ethanol-isopropyl myristate (IPM) mixed system was examined in rats. For comparison of bioavailability (BA) after topical applications, 0.25 ml of the ethanol/IPM system containing 40% ethanol and 60 mM AZT was applied as a standard formulation. Values of the area under the plasma concentration-time curves of AZT for 8 hr (AUC_0-8), as indices of BA, following application of various formulations were compared with that of the standard formulation. Then the influence of content of the drug and ethanol, and application volume of the system was evaluated. BA was effectively improved only when the total amount of ethanol applied on the skin was increased. On the other hand, simultaneous transdermal application of AZT and probenecid increased the AU_0-8, of AZT without necessitating the increase in ethanol content in the formulation. In addition, coadministered probenecid improved cerebrospinal fluid/plasma concentration ratio of AZT.     

Transdermal Absorption of Zidovudine from Ethanol-Isopropyl Myristate Mixed System and Influence of Probenecid on It in Rats

Transdermal absorption of zidovudine (AZT) from an ethanol-isopropyl myristate (IPM) mixed system was examined in rats. For comparison of bioavailability (BA) after topical applications, 0.25 ml of the ethanol/IPM system containing 40% ethanol and 60 mM AZT was applied as a standard formulation. Values of the area under the plasma concentration-time curves of AZT for 8 hr (AUC_0-8), as indices of BA, following application of various formulations were compared with that of the standard formulation. Then the influence of content of the drug and ethanol, and application volume of the system was evaluated. BA was effectively improved only when the total amount of ethanol applied on the skin was increased. On the other hand, simultaneous transdermal application of AZT and probenecid increased the AU_0-8, of AZT without necessitating the increase in ethanol content in the formulation. In addition, coadministered probenecid improved cerebrospinal fluid/plasma concentration ratio of AZT.     

Evaluation of the Transdermal Permeation Behavior of Proterguride from Drug in Adhesive Matrix Patches Through Hairless Mouse Skin

The transdermal in vitro permeation behavior of the highly potent dopamine agonist Proterguride was investigated using hairless mouse skin as a model membrane. Drug in adhesive matrix formulations based on different types of pressure-sensitive adhesives (Eudragit® E 100 and Gelva®7883 as acrylates, Oppanol® B 15 SFN as polyisobutylene, and BioPSA® 7-4202 as silicone) with a drug load of 3% by weight were manufactured. All patches were examined for drug crystallization by polarized microscopy immediately after the manufacturing process and after storage for 30 days in sealed aluminium laminate bags at ambient temperature and at 40°C, respectively. Furthermore, the influence of the drug load in acrylate-based formulations onto the steady-state flux of Proterguride was examined. The Eudragit® E 100 system delivered a significantly higher steady-state flux than the systems based on Oppanol® B 15 SFN and also a somewhat higher steady-state flux than the Gelva®-based patch. An addition of 10% by weight of the crystallization inhibitor povidone 25 did not significantly influence the steady-state flux of Proterguride from acrylate matrices. The lipophilic silicone and polyisobutylene adhesives facilitated drug crystallization within the short storage periods at both conditions, probably due to the absence of povidone 25, which was incompatible with these polymers. Varying the drug load in acrylate-based formulations led to a linear increase of the steady-state flux until the steady-state flux of Proterguride leveled off and the patches tended to drug crystallization. It was found that Gelva®-based patches show good physical stability, good skin adhesion, and moderate flux values and, thus, can be evaluated as a basis for a suitable formulation for the transdermal administration of Proterguride.     

Comparison of In Vitro Dissolution and Permeation of Fluconazole from Different Suppository Bases

Fluconazole suppositories were prepared in hydrophilic, lipophilic, and amphiphilic bases. In vitro evaluation was conducted to compare the effect of different bases on the release and permeation of fluconazole. Four types of suppository bases were evaluated: hydrophilic (polyethylene glycol, PEG), lipophilic (cocoa butter, CB; Witepsol W45® WW45), and amphiphilic (Suppocire AP® SAP, a polyglycolized glyceride). The uniformity of dosage units prepared with each base was determined by ultraviolet (UV) spectroscopy. The influence of suppository base on the release of fluconazole was studied using USP dissolution apparatus I. Rate constants for each release pattern were determined and compared using a one-way analysis of variance (ANOVA) on ranks. The order of in vitro dissolution of fluconazole from the bases was as follows: PEG > (SAP = WW45) > CB. Results suggest that in vitro release of fluconazole is greater from a hydrophilic base (PEG). Preliminary permeation studies were conducted on each type of base using Franz diffusion cells. Permeation was studied through the rat rectal membrane, and normal saline was used as the receptor medium. A modified reverse-phase high-performance liquid chromatography (HPLC) method was used and validated for analyzing fluconazole. Flux values (μg/cm²/hr) were calculated and compared using a one-way ANOVA (p <. 001). The order of permeation was as follows: SAP > (PEG = WW45) > CB. The increased permeation characteristics seen with the SAP base are probably due to an alteration of the membrane characteristics due to the surface active properties of the base.     

Effects of Adhesives and Permeation Enhancers on the Skin Permeation of Captopril

To formulate a transdermal drug delivery system of captopril, monolithic adhesive matrix type patches containing 20% captopril, different pressure-sensitive adhesives, and various permeation enhancers were prepared using a labcoater. The effects of the adhesives and permeation enhancers on skin permeation of captopril from the prepared patches were evaluated using Franz diffusion cells fitted with excised rat skins. The permeation rate of the drug through the excised skin was dependent on the type of polyacrylate copolymers studied. Fatty alcohols resulted in a pronounced enhancing effect on the skin permeation of captopril, while dimethyl sulfoxide,N-methyl-2-pyrrolidone, oleic acid, Transcutol, and polysorbate 20 showed no significant enhancing effect. The permeation-enhancing effect of the fatty alcohols reached the maximum at the level of 10%. Based on these results, a captopril patch may be developed with further optimization.     

Development of a Dynamic Skin Permeation System for Long-Term Permeation Studies

Abstract

A dynamic skin permeation system was developed aiming to eliminate the deficiencies observed in the apparatus currently available. It consists of two half-cells in mirror image, each contains a stirring platform to permit a starhead magnet to rotate at a synchronous speed. The solution chamber is equipped with a sampling port, which can be tightly closed with glass stopper. The design characteristics of this new system was calibrated, using the commercially available Franz diffusion cell as the reference. The results clearly suggested that this newly developed skin permeation system shows consistently superior than the Franz diffusion cell in terms of the control of skin surface temperature and the efficiency of solution mixing. To investigate the potential effect of environment, the temperature on the stratum corneum surface was varied, while the dermal solution was maintained at constant body temperature, and its effect on the kinetics of skin permeation was studied. The energy requirements for various steps of skin permeation were determined. The results suggested that the skin permeation system developed in this investigation can be useful for the mechanistic analysis of long-term skin permeation kinetics.     

Permeation of Naproxen from Saturated Solutions and Commercial Formulations Through Synthetic Membranes

Abstract

The release of naproxen through synthetic membranes, mounted in modified Franz-type diffusion cells, was evaluated, either from saturated solutions or from commercially available topical formulations containing 10% naproxen. The results obtained showed that the porous type synthetic membranes chosen (cellulose acetate and polyethersulphone) can be used for assessing product performance in quality control procedures. The formulations interacted with the solid membranes (silicone and EVA) to change their diffusional characteristics. However, transfer in the membrane, and not the formulation was rate controlling. These membranes could not therefore be used in assessing product release performance for quality control.     

Development of a Dynamic Skin Permeation System for Long-Term Permeation Studies

A dynamic skin permeation system was developed aiming to eliminate the deficiencies observed in the apparatus currently available. It consists of two half-cells in mirror image, each contains a stirring platform to permit a starhead magnet to rotate at a synchronous speed. The solution chamber is equipped with a sampling port, which can be tightly closed with glass stopper. The design characteristics of this new system was calibrated, using the commercially available Franz diffusion cell as the reference. The results clearly suggested that this newly developed skin permeation system shows consistently superior than the Franz diffusion cell in terms of the control of skin surface temperature and the efficiency of solution mixing. To investigate the potential effect of environment, the temperature on the stratum corneum surface was varied, while the dermal solution was maintained at constant body temperature, and its effect on the kinetics of skin permeation was studied. The energy requirements for various steps of skin permeation were determined. The results suggested that the skin permeation system developed in this investigation can be useful for the mechanistic analysis of long-term skin permeation kinetics.     

Synthesis and Skin Permeation Study of Lidocaine Organic Salts

Four organic quarternary ammonium salts of lidocaine, lidocaine adipate, lidocaine maleate, lidocaine malonate and lidocaine tosylate were prepared in this study. These compounds were regarded as prodrugs of lidocaine and were expected to enhance skin permeability by ion-pair approach. In vitro permeation study through pig skin and determination of partition coefficients were carried out. The skin permeation of lidocaine adipate and lidocaine malonate after 12 hours of application was significantly higher than lidocaine hydrochloride but was not significantly different from lidocaine (α < 0.05). The increase in permeation of organic salts from lidocaine hydrochloride and the different profile of permeation from lidocaine may be the result of prodrug structure contributing ion-pair transportation beside normal route of transportation.     

Effect of Penetration Enhancers on the in Vitro Transport of Ephedrine Through Rat Skin and Human Epidermis from Matrix Based Transdermal Formulations

The potential of skin as a site for administration of systemically active Ephedrine HCl (EH) has been recognised. The effect of penetration enhancers, i.e., Dimethyl sulfoxide (DMSO), Dimethyl acetamide (DMA), Dimethyl formamide (DMF) and Azone on the in-vitro transport of EH from matrix based transdermal formulations through full thickness rat skin and human epidermis was investigated. The highest flux with minimum time lag through rat skin and human epidermis was observed from the batch containing Azone as penetration enhancer.     

Effect of Penetration Enhancers on the in Vitro Transport of Ephedrine Through Rat Skin and Human Epidermis from Matrix Based Transdermal Formulations

Abstract

The potential of skin as a site for administration of systemically active Ephedrine HCl (EH) has been recognised. The effect of penetration enhancers, i.e., Dimethyl sulfoxide (DMSO), Dimethyl acetamide (DMA), Dimethyl formamide (DMF) and Azone on the in-vitro transport of EH from matrix based transdermal formulations through full thickness rat skin and human epidermis was investigated. The highest flux with minimum time lag through rat skin and human epidermis was observed from the batch containing Azone as penetration enhancer.     

Permeation and Sorption of Water and Gases Through EVA Copolymers Films

The transport of water and gases (pure oxygen and carbon dioxide) through poly(ethylene-co-vinyl acetate) (EVA) films of different VA contents and through a low density polyethylene LDPE (used as reference with 0 wt.% VA), was analysed by permeation and sorption measurements. In the case of water, for EVA of 70 wt.% VA, a plasticization effect on the material was observed. For EVA of 19 wt.% VA, there was no plasticization, while for EVA of 4.5 wt.% VA and for LDPE, the water diffusion coefficient decreases with increasing water. An empirical law was then found to account for the reduction of the water diffusivity. A negative plasticization effect was attributed to the formation of water clusters in these rather non polar polymers. This latter result was confirmed by sorption measurements and infra-red spectroscopy. The increase in water sorption extent with the VA content leads to a steady increase in the water permeability in the EVA copolymers. In the case of gas permeation, both for O₂ and CO₂ and whatever the VA content of the copolymer used, the experimental curves are characterized by a constant diffusion coefficient. This is confirmed by sorption experiments. In terms of gas permeability, EVA copolymers are characterized by low coefficients especially for oxygen. In the EVA rubbery copolymers, The O₂ solubility coefficient does not increase with the VA content due to the lack of polar interactions, while the CO₂ one increases due to the overall interactions between CO₂ induced dipoles and the polar the VA carbonyl groups. For these copolymers, the H₂O/CO₂ and H₂O/O₂ selectivities are very high. The experimental values of the selectivities indicate that these EVA copolymers appear as good candidates for applications using high perm-selectivity properties. Electronic Publication     

Percutaneous Absorption of Piroxicah from Fapg Base Through Rat Skin: Effects of Oleic Acid and Saturated Fatty Acid Added to Fapg Base

Abstract

Oleic acid (OA) or / and saturated fatty acid (i.e. lauric lyristic, palmitic and stearic acid) decreased the release of piroxican from FAPG (fatty alcohol-propylene glycol) base. The reason would be due to the increase in lipophilicity of the base. The released piroxicam was found to be inversely proportional to the apparent viscosity of the ointments containing OA and saturated fatty acid. However, OA or / and the saturated fatty acids enhanced the in vitro skin permeation and the in vivo percutaneous absorption of piroxican, the enhancing effect was decreased linearly with increasing carbon number of saturated fatty acid from 12 to 18. A useful parameter has been obtained for estimating the properties of the exudation or “bleeding” of the FAPG base. A number of piroxicam FAPG ointments have been selected as an optimal product for less bleeding and more percutaneous absorption of piroxicam than those of controls (containing no oleic acid and saturated fatty acid).     

Percutaneous Absorption of Piroxicah from Fapg Base Through Rat Skin: Effects of Oleic Acid and Saturated Fatty Acid Added to Fapg Base

Oleic acid (OA) or / and saturated fatty acid (i.e. lauric lyristic, palmitic and stearic acid) decreased the release of piroxican from FAPG (fatty alcohol-propylene glycol) base. The reason would be due to the increase in lipophilicity of the base. The released piroxicam was found to be inversely proportional to the apparent viscosity of the ointments containing OA and saturated fatty acid. However, OA or / and the saturated fatty acids enhanced the in vitro skin permeation and the in vivo percutaneous absorption of piroxican, the enhancing effect was decreased linearly with increasing carbon number of saturated fatty acid from 12 to 18. A useful parameter has been obtained for estimating the properties of the exudation or “bleeding” of the FAPG base. A number of piroxicam FAPG ointments have been selected as an optimal product for less bleeding and more percutaneous absorption of piroxicam than those of controls (containing no oleic acid and saturated fatty acid).     

In-Vitro Release Studies of Chlorpheniramine Maleate from Topical Bases Using Cellulose Membrane and Hairless Mouse Skin

Abstract

In-vitro release of chlorpheniramine maleate from various dermatological bases including a polymeric gel base, the modified hydrophilic base and the modified hydrophilic petrolatum base, was studied. The additive ingredients known to enhance the drug release from the topical bases were also evaluated at different concentration levels. These included urea, ethanol and dimethylsulfoxide (DMSO). The rank order of drug release through the cellulose membrane was observed to be: the gel base > the modified hydrophilic base > the modified hydrophilic petrolatum base. In general, the presence of the additives adversely affected the drug release except for the (DMSO) and ethanol in certain cases.

The formulations with optimum in-vitro release profiles of the drug through the cellulose membrane, were selected for further studies of the drug release using hairless mouse skin as the diffusion barrier. Here again, the gel formulation gave the best in-vitro release of the drug, and the data correlated well with the results previously obtained from the cellulose membrane.

The in-vitro data were treated with various kinetic principles to determine the relevant parameters, such as the steady state flux, the diffusion coefficient and the permeability coefficient. Using these information, the formulations were evaluated for their suitability for delivering chlorpheniramine maleate via the diadermatic dosage form.