The interaction of the penetration enhancer DDAIP with a phospholipid model membrane.

Differential scanning calorimetry (DSC) was used to investigate the mechanism of action of a proprietary skin penetration enhancer, dodecyl-2-(N,N-dimethylamino)propionate (DDAIP) in dipalmitoylphosphatidylcholine (DPPC) liposomes. Furthermore, the effect of enhancer concentration on lipid thermotropic transitions was investigated. With increasing concentrations of DDAIP (from 5 to 50 mol%), the main transition peak shifted to lower temperatures and became more broad. The pretransition peak also shifted to lower temperatures with increasing concentrations of DDAIP and disappeared completely above an enhancer concentration of 20 mol%. Main transition and pretransition enthalpies of reaction decreased with increasing DDAIP concentration, indicating that enhancer treatment destabilized both rippled gel and liquid crystal phases within the bilayer. At and above a DDAIP concentration of 33.3 mol%, an additional transition was evident, indicating the presence of two phases of enhancer-lipid complex. Results suggest that DDAIP enhances drug transport by interacting with the polar region of the phospholipid bilayer and also by increasing the motional freedom of lipid hydrocarbon chains.

Enhancement of skin permeation of miconazole by phospholipid and dodecyl 2-(N,N-dimethyl amino)propionate (DDAIP).

Miconazole (MCZ) has very low solubility in both water and oil. Permeation rates through shed snakeskin from an aqueous suspension and a mineral oil suspension were 0.5 microg/cm(2)/h and almost none, respectively. When hydrogenated phosphatidylcholine (HPC) was added to mineral oil and heated to 95 degrees C, the solubility of MCZ increased in proportion to the HPC concentration. DSC measurements also indicated an interaction between them. Thus, a gel formed by hydrogenated phospholipid and mineral oil, as vehicle was prepared. The solubility of MCZ in the gel was around 1% and the permeation rate was 1.3 microg/cm(2)/h, which was about 2.5 times that from an aqueous suspension. As an alternative approach, a skin permeation enhancer, dodecyl 2-(N,N-dimethyl amino)propionate (DDAIP) was applied 2 h before a skin permeation study. The permeation from an aqueous suspension became 11 times that of the suspension without DDAIP pretreatment. The concentration of MCZ in the skin increased 8-fold, indicating that the enhancement effect involved high partition of MCZ into the skin. On the other hand, when a gel formulation was used, pretreatment with DDAIP was not as effective as incorporation of DDAIP in the gel formulation. Following pretreatment, permeation was only two times that of the gel without DDAIP pretreatment, and half that of the water suspension with DDAIP pretreatment. This suggested that release from the gel was the rate-limiting step with the gel formulation. When DDAIP was added to the gel, the permeation rate of MCZ was 3.3 microg/cm(2)/h. It was also a release limited type permeation. The gel with DDAIP is potentially a useful formulation, because of relatively high permeation while possibly avoiding overdosing.

Novel approach to improve permeation of ondansetron across shed snake skin as a model membrane.

The purpose of this study was to investigate the feasibility of transdermal drug delivery of ondansetron, an antagonist of the 5-HT3 receptor, used for the treatment of chemotherapy-induced emesis. The permeability of ondansetron from an aqueous suspension through shed snake skin as a model membrane was very low and in order to improve it, several enhancers were tested. Ethanol increased the flux at a concentration of 40% or more. The solubility of ondansetron also increased as the ethanol concentration increased. The permeability coefficient increased after pretreatment of the shed snake skin with Azone, oleic acid or lauryl alcohol. Further improvement of the permeability was observed when ethanol was combined with other enhancers and was maximum for the combination of ethanol and oleic acid. Oleic acid dramatically increased the partition of ondansetron to n-hexane and shed snake skin. Oleic acid may enhance the permeation of ondansetron in two ways: by a direct effect on the stratum corneum or via counterion formation of an ion-pair. The maximum flux obtained from the combination of ethanol and other enhancers seems to be high enough to obtain a therapeutic effect.

Influence of pH on the permeability of p-toluidine and aminopyrine through shed snake skin as a model membrane.

The influence of pH on the permeability of p-toluidine (pKa, 5.3) and aminopyrine (pKa, 5.0) through shed snake skin as a model membrane was studied. The pH was adjusted to several values, and the solubility of the drugs in each donor was measured. Flux rates and permeability coefficients were calculated from the steady-state penetration portions. The flux rates of p-toluidine decreased as the pH value in the donor solution increased. On the other hand, the flux rates of aminopyrine were constant at any pH value. The permeability coefficients of each drug increased as the pH value in the donor solution increased. The partition coefficients (octanol/buffer) of each drug were dependent on the molecular fraction of un-ionized species. From these results, it is suggested that ionized species of p-toluidine transports through shed snake skin, but the ionized species of aminopyrine does not.

Enhanced in vitro percutaneous penetration of salicylate by ion pair formation with alkylamines.

The apparent octanol/water partition coefficient (APC) of salicylate (SA) increased as the concentration of alkylamine (amyl, hexyl, heptyl, octyl and nonylamine) in aqueous phase increased, presumably through intermolecular ion pair formation between the negatively charged SA moiety and the alkylamine cation. The true partition coefficient (TPC) and the formation constant (Kf) of the ion pair were calculated from the partition data. The skin permeability of SA increased as the APC of SA increased, when 20-fold molar excess of alkylamine was added to the donor compartment. Permeability of ion pairs (PAB) from the aqueous phase to a shed snake skin was estimated from the permeability data assuming 1:1 ion pair. The methylene group contribution to the free energy of transfer of ion pairs from water to the shed snake skin was less than the reported value for nonionized drugs. This suggests that the ion pair is more polar by nature than nonionized molecules, even if ionic characteristics are masked to some extent by ion pair formation.

In vitro controlled release kinetics of local anaesthetics from poly(D,L-lactide) and poly(lactide-co-glycolide) microspheres.

Poly(D,L)lactide and polylactide-co-glycolide drug-loaded microspheres were prepared with lipopholic (bupivacaine and etidocaine) and hydrophilic (mepivacine and lidocaine) local anaesthetics. Formulations of drug-loaded microspheres were characterized by the drug content, the in-vitro release kinetics and by the physical state of the drug within the microspheres. Release rates of the local anaesthetics from the microspheres were different and could not be accounted for by the intrinsic dissolution rates of the drugs. The encapsulation efficiency was highly dependent on the lipophilicity of the drugs, reaching the maximum for the lipophilic drugs and the poly(lactide-co-glycolide) polymers. The influence of the molecular weight of the poly(lactide-co-glycolide) polymers on the release rate and on the release mechanism depended on the drug studied and its physical state within the polymeric matrices. Diffusion-controlled release was evidenced in various formulations as a result of the linearity of the release as a function of the square root of time.

Effect of some penetration enhancers on epithelial membrane lipid domains: evidence from fluorescence spectroscopy studies.

The effect of the penetration enhancers Azone, oleic acid, 1-dodecanol, dodecyl N,N-dimethylaminoacetate (DDAA), and dodecyl N,N-dimethylaminoisopropionate (DDAIP) on epithelial membrane lipids was examined using human buccal cell membranes as a model for epithelial lipid bilayer. Buccal epithelial cells (BEC) were labeled with 1,6-diphenyl-1,3,5-hexatriene (DPH), 1-(4-(trimethylammonio)phenyl)-6- phenyl-1,3,5-hexatriene (TMA-DPH), and 8-anilino-1-naphthalene sulphonic acid (ANS) fluorophores to characterize enhancer-induced changes in the hydrophobic core, in the superficial polar head region, and on the exterior surface, respectively, with fluorescence anisotropy and fluorescence lifetimes. All the enhancers studied were found to decrease the BEC membrane lipid packing order in a concentration-dependent and time-dependent manner in the deep bilayer region, as shown by a 37-66% decrease in anisotropy. Oleic acid was also found to disrupt membrane lipids strongly in the polar head region, causing at least a 34% decrease in anisotropy values. Azone and DDAA were shown to alter molecular movement on the surface of the bilayers (24 and 19% decrease in anisotropy, respectively). The results suggest that interaction with membrane lipid domains is an important, but not the only, mode of action for the penetration enhancers studied.

Synthesis and enhancing effect of dodecyl 2-(N,N-dimethylamino)propionate on the transepidermal delivery of indomethacin, clonidine, and hydrocortisone.

The biodegradable transdermal penetration enhancer, dodecyl 2-(N,N-dimethylamino)propionate (II; DDAIP), was prepared by reacting dodecyl 2-bromopropionate (I), obtained by reaction of n-dodecanol with 2-bromopropionyl halogenide, with dimethylamine. The penetration enhancing effects of DDAIP on the transport of indomethacin, clonidine, and hydrocortisone across shed snake skin (Elaphe obsoleta) were evaluated. Azone and lauryl alcohol, a possible decomposition product of DDAIP, were used as standard enhancers for comparison. In terms of flux, DDAIP showed 4.7 and 7.5 times the promoting effect for indomethacin compared to azone and lauryl alcohol, respectively. With clonidine this effect was 1.7 and 3.1 times, whereas with hydrocortisone it was 2.4 and 2.8 times higher, respectively. In vitro biodegradability of DDAIP was demonstrated in the presence of porcine esterase. The results indicate that DDAIP increases markedly the transepidermal delivery of several types of drug substances.

Percutaneous permeation of basic compounds through shed snake skin as a model membrane.

Relationships between the in-vitro permeability of basic compounds through shed snake skin as a suitable model membrane for human stratum corneum and their physiochemical properties were investigated. Compounds with low pKa values were selected to compare the permeabilities of non-ionized forms of the compounds. Steady-state penetration was achieved immediately without a lag time for all compounds. Flux rate and permeability coefficient were calculated from the steady-state penetration data and relationships between these parameters and the physicochemical properties were investigated. The results showed that permeability may be controlled by the lipophilicity and the molecular size of the compounds. Equations were developed to predict the permeability from the molecular weights and the partition coefficients of basic compounds.

Effects of transdermal penetration enhancers on the permeability of shed snakeskin.

The effects of Azone and lauryl alcohol on the permeability of shed snakeskin were examined. Permeability of a variety of compounds through shed snakeskin was increased after Azone or lauryl alcohol pretreatment but the magnitude of the enhancement varied depending on the lipophilicity and the molecular size of the permeant. It was found that the shed snakeskin became more permeable after Azone or lauryl alcohol pretreatment, with a greater permeability increase for more hydrophilic and larger-molecular size permeants. As has been shown for untreated shed snakeskins, both the lipophilicity and the molecular size of the permeants are important in skin penetration and in determining the effects of transdermal penetration enhancers.

Dodecyl N,N-dimethylamino acetate and azone enhance drug penetration across human, snake, and rabbit skin.

The effectiveness of the penetration enhancers, dodecyl N,N-dimethylamino acetate (DDAA) and Azone, on pretreated human epidermis for the permeation of model drugs, indomethacin, 5-fluorouracil, and propranolol-HCl, was studied in in vitro diffusion cells. Snakeskin (Elaphe obsoleta) and rabbit pinna skin were compared as possible models for human skin. The drug concentrations were analyzed by HPLC. With all skins and all model drugs, DDAA increased drug permeability at least as well as Azone, and in most cases it was a more effective permeation enhancer. The relative permeation improvements in human skin, snakeskin, and rabbit skin were 10- to 20-, 5- to 50-, and 20- to 120-fold, respectively. Tritiated water served as an indicator of skin condition. Its penetration in the skin samples was independent of the drugs used, and both penetration enhancers significantly increased the flux of tritiated water through all skins. Thus, DDAA and Azone significantly increased the permeation of lipophilic and hydrophilic model compounds. Rabbit pinna skin was a poor model for human skin in vitro, while snakeskin was much closer to human skin in terms of transdermal permeability. In most cases drug permeability decreased in the order rabbit much greater than human greater than or less than snake.

In vitro percutaneous transport of sodium diclofenac and diclofenac from oleaginous vehicle.

The penetration enhancement of sodium diclofenac and diclofenac by alcohols with various alkyl chains (C8 to C14) was evaluated by the steady state flux of diclofenac through rat abdominal skin. Decanol showed the greatest effect in this series. A more remarkable enhancing effect of the alcohols was observed in sodium diclofenac than in diclofenac. Diclofenac can penetrate through the ethylene-vinyl acetate membrane as a lipoid model membrane, but sodium diclofenac can not. Decanol enhanced the penetration of phenol red being dependent on its concentration in the vehicle. Therefore, decanol may interact with lipoid components of the skin and increase the aqueous pathway in the skin. These results indicate that sodium diclofenac and diclofenac may be penetrated through partially different pathways.

In vitro transport of sodium diclofenac across rat abdominal skin: effect of selection of oleaginous component and the addition of alcohols to the vehicle.

The in vitro percutaneous transport of sodium diclofenac from various oil vehicles was examined using rat abdominal skin as a model skin membrane. The overall transport of diclofenac through the skin from the oleaginous vehicles was very poor because of a poor solubility of sodium diclofenac in nonpolar oils. To increase the solubility and the permeability of sodium diclofenac, ethanol and n-octanol were added to each oil (designated as the formulated vehicles). The addition of ethanol and n-octanol to the nonpolar vehicles resulted in an extreme increase in drug solubility in each vehicle, with a remarkable increase in the permeation of diclofenac. The effects of oil components in the formulated vehicle on the permeation of diclofenac across the skin were in the following order: squalane greater than or equal to squalene greater than liquid paraffin greater than middle chain triglyceride greater than olive oil greater than castor oil. In order to clarify the reason for the differences in permeation of diclofenac from these formulated vehicles, the release of diclofenac and n-octanol from these vehicles in vitro was studied. The release rates of n-octanol from the formulated vehicles were in the following order: liquid paraffin greater than squalene greater than or equal to squalane greater than middle chain triglyceride greater than or equal to olive oil greater than castor oil. On the other hand, a linear correlation was observed between the initial release rate of diclofenac from the formulated vehicle and the in vitro permeation of diclofenac through the vehicle to the skin.(ABSTRACT TRUNCATED AT 250 WORDS)

A method to predict the percutaneous permeability of various compounds: shed snake skin as a model membrane.

Penetration of various compounds through shed snake skin was measured in vitro to examine the effect of lipophilicity and molecular size of a compound on permeability through this model membrane. The permeabilities were found to be controlled by the lipophilicity and the molecular size of the permeant. The smaller and the more lipophilic the compound, the greater the permeability. Equations have been developed to predict the permeability from the molecular weight and the distribution coefficient of a compound. Further, the lipophilicity of shed snake skin is similar to that of human skin and the response of shed snake skin to the molecular size of a permeant is more similar to human skin than to hairless mouse skin. Considering the similarities between shed snake skin and human stratum corneum in terms of structure, composition, and permeability characteristics, the same considerations may apply to permeability through human stratum corneum.

Use of shed snake skin as a model membrane for in vitro percutaneous penetration studies: comparison with human skin.

The potential usefulness of shed snake skin as a model membrane for transdermal research was examined. There are similarities between shed snake skin and human stratum corneum in terms of structure, composition, lipid content, water permeability, etc. The permeability of various compounds and the contribution of several functional groups to the permeability were also found to be similar between shed snake skin and human skin. Moreover, the permeability of compounds through shed snake skin was increased by Azone, one of the most extensively studied transdermal penetration enhancers. Considering the similarities between shed snake skin and human skin, ease of storage and handling, and low cost, shed snake skin may offer a good model membrane for transdermal research.

Combined effect of alcohol and urea on the in vitro transport of indomethacin across rat dorsal skin.

An aqueous gel, prepared with hydrogenated soya phospholipid, increased the in vitro transport of indomethacin across rat dorsal skin. The addition of various alkanols further accelerated the transport, with an increasing effect as the chain length of the alkanol increased. The addition of urea alone did not significantly affect the transport of indomethacin. However, the addition of urea markedly accelerated the transport of indomethacin when included in an aqueous gel containing an alkanol such as 1-octanol, 1-decanol, or 1-dodecanol. Thus, it appears that a combination of urea and these alkanols strongly enhances the transdermal absorption of indomethacin. Urea appears to accelerate enhanced drug transport into the stratum corneum by a mechanism involving the transport of urea enhanced by these alkanols.

Facilitated transport of basic and acidic drugs in solutions through snakeskin by a new enhancer--dodecyl N,N-dimethylamino acetate.

The permeation characteristics of two model drugs, clonidine (basic) and indomethacin (acidic), were studied by determining their penetration fluxes through hydrated shed snakeskins (Elaphe obsoleta) at 32 degrees C. The drugs were formulated in buffers of different pH's, ranging from 3 to 7. The total penetration fluxes at pH 7.0 for both compounds using skins pretreated with dodecyl N,N-dimethylamino acetate were at least 11 times higher than those of the control runs without enhancer treatment. Equations were derived to calculate the permeability coefficients (Ki) and fluxes (Ji) for the ionized and the nonionized species to allow for comparison of their penetration ability through the model membrane. The permeability coefficient of clonidine is 2.50 x 10(-3) cm/hr for the nonionized form and 2.41 x 10(-4) cm/hr for the protonated form. This result indicates that the nonionized form penetrates the skins better than the ionized form. Both permeability coefficient values are 11 times larger than the corresponding values obtained from the control skins. The total flux of clonidine is dependent on its initial concentration in the donor cell but is independent of the ionic strength of the solution formulations. The penetration characteristics of indomethacin are similar to those of clonidine, with a higher permeability coefficient of the nonionized form (3.90 x 10(-3) cm/hr) than of the ionized form (7.97 x 10(-4) cm/hr) using pretreated skins. While the enhancer shows 24 times penetration enhancement of the ionized form of indomethacin, it does not enhance the penetration of the nonionized species.

New alkyl N,N-dialkyl-substituted amino acetates as transdermal penetration enhancers.

New alcohol derivatives of N,N-disubstituted amino acids with a low toxicity have been synthesized and evaluated for their transdermal penetration enhancing effects on the transport of indomethacin from petrolatum ointments across shed skin of black rat snake (Elaphe obsoleta). The derivatives show excellent penetration enhancement of indomethacin, as high as 3.8 times that of Azone, with decyl N,N-dimethylamino acetate as the lead compound in the series. The release of indomethacin from an ointment containing 1% indomethacin, 5% dodecyl N,N-dimethylamino acetate, and 94% petrolatum was 3.15 micrograms/min1/2/cm2. Saturation studies performed by incorporating varying concentrations of indomethacin, from 0.1 to 10%, into the ointments and determination of the fluxes of indomethacin demonstrated that the saturated concentration of indomethacin in petrolatum base was approximately 1%. Penetration fluxes of indomethacin (1%) through snake skin increased linearly as the concentration of dodecyl N,N-dimethylamino acetate increased from 2.5 to 15%. Experiments involving the pretreatment of the snake skins with dodecyl N,N-dimethylamino acetate indicated that pretreatment of the skin increased the skin permeability significantly. Electron micrograph studies on the snake skin treated with dodecyl N,N-dimethylamino acetate show clearly that the enhancer interacted with both the lipid-rich layer (mesos phase) and the keratin-rich layers (both alpha and beta phases).

Unsaturated cyclic ureas as new nontoxic biodegradable transdermal penetration enhancers I: Synthesis.

A new concept was implemented to reduce the toxicity of some new biodegradable transdermal penetration enhancers. These enhancers consist of 1-alkyl-4-imidazolin-2-one and a long-chain alkyl ester group at the N-3 position. The synthesis involves N-alkylation of the parent compound with soft alkylating agents which were prepared in high yields by an improved method. A phase transfer catalysis technique using KOH as the base, tetrabutylammonium bromide as the catalyst, and toluene as the solvent was found to be most effective in the N-alkylation step.