Effect of Neat Transcutol on Drug Penetration and Permeation
Five studies (5,36,45,46,47) that have characterized drug flux from saturated solutions of neat Transcutol, comparing the results against drug flux from saturated solutions of water. Summarized in Table IV, these studies involved Franz cell experiments using saline as the receptor solution or PBS (pH = 7.4 for lidocaine) except for ondansetron HCl and tenoxicam which were run on side-by-side cells using saline/PEG 400 (60:40) as the receptor. Table IV provides the saturation concentration of the drug (mg/ml) in Transcutol and in water that was dosed, the skin flux values, the enhancement ratio (ER) which is calculated from the drug flux from neat Transcutol divided by the drug flux value obtained from water (control), physical chemical properties of the drug, and details concerning IVPT parameters. Listed in the order of increasing values for flux ER, the results show that the four salts of diclofenac and ondansetron had lower skin flux values when delivered from neat Transcutol compared to water. These publications are discussed below including a concise statement of the conclusions from each study and a critical evaluation of the IVPT methodology.
Minghetti (47) studied four different salts of diclofenac dissolved in four different solvents (W, PG, TRC, and OA), demonstrating that in aqueous solutions, different species of diclofenac exist having different ability to permeate the skin. For each salt studied, the overall permeability was due to the partial contribution of each species, i.e., diclofenac anion, ion pairs, and acidic diclofenac. It was shown that for the saturated water systems, the diethylamine and epolamine salts form ion pairs that have a greater ability to partition into the stratum corneum compared to diclofenac sodium or diclofenac potassium. When dissolved in Transcutol, Minghetti (47) used the solvent effect to explain that Transcutol results in ion pair formation, greater partitioning of the neutralized diclofenac salt into lipid domains of the horny layer, and ultimate dissociation of the ion pairs when diclofenac reaches the aqueous viable epidermis. The researchers did not discuss that flux of the diclofenac salts from Transcutol ranged from 1/100 to 2/3 of the flux values from saturated water. When viewed in light of the Bjorklund (22) study, it would appear that enhanced penetration resulting from a decrease in ionized diclofenac (solvent effect from using neat Transcutol) is overwhelmed by stiffening of the intercellular domain (increased skin barrier) due to stratum corneum dehydration that occurs when dosing with neat Transcutol.
Gwak (46) used IVPT to determine skin flux values and permeability coefficients from saturated solutions of Transcutol and water. Hairless mouse skin was mounted on a side-by-side diffusion cell. As seen in Table IV, ondansetron HCl aqueous saturation concentration of 36 mg/ml was about twice the amount of active found to be soluble in Transcutol. It should be noted that ondansetron is a weak base (pKa = 7.4) that is ionized under acidic conditions. The natural pH of ondansetron HCl solutions is about 4.5 to 4.6 and the solubility is significantly reduced in solutions at, or above, pH equal to 6 (48). Since the calculated (ALOGPS) aqueous solubility of ondansetron HCl is 0.248 mg/ml, it can be assumed that the active in the donor compartment of the side-by-side cell was completely ionized. The Gwak study (46) showed that the flux of ondansetron from neat Transcutol was an order of magnitude lower than from a saturated aqueous solution. Likewise, the apparent permeability coefficient of ondansetron delivered from water was 13.4 × 10−7 cm/s compared to 1.21 × 10−7 cm/s when delivered from neat Transcutol. Since the saturated solutions are at equivalent driving force, any solvent effect benefit from formulating ondansetron in neat Transcutol is overwhelmed by the stratum corneum dehydrating effect of neat Transcutol. Also, since the solubility is dramatically reduced at pH values above 6, ondansetron will not readily partition out of the stratum corneum into the viable epidermis which is at physiological pH.
Bonina (36) studied two model drugs having vastly different physical properties, caffeine and testosterone. Saturated solutions of caffeine and testosterone from seven neat solvents and a blend of PG and propylene glycol dipelargonate (DPPG) were applied to human skin loaded onto Franz cells. The flux values for both model drugs were slightly less from neat Transcutol than from water (ER = 0.88) potentially due to the dehydrating effect of neat Transcutol. One might speculate that the infinite dose of 133 mg donor solution/cm2 of skin may be less capable of dehydrating the skin over 24 h than the 1752 or 4688 mg/cm2 of neat Transcutol listed in Table IV.
Bayldon (5) investigated the effects of vehicles on the retention and permeation of lidocaine free base after application to sheep skin. The purpose of this study was to determine feasibility of a topical anesthetic veterinary product for use prior to minor surgical procedures. 88.5 μl/cm2 of lidocaine free base saturated solutions were dosed using Franz cells maintained at 32°C with PBS as the receptor solution. The authors emphasize that the clipped felt of sheep skin (the tissue loaded in the Franz cell for this study) had a continuous coat of an emulsion consisting of sweat and sebum. Sheep skin has dramatically more follicles than human skin, with Merino sheep having up to 10,000 follicles per cm2. The study found that non-aqueous (neat) vehicles (100% DMSO, 100% Transcutol, 100% IPM) enhanced penetration of lidocaine free base compared to the aqueous vehicles (0.5% or 1% sodium lauryl sulphate, 50% dimethyl sulfoxide, 50% Transcutol, or 100% water). A saturated solution dose of approximately 88.5 mg/cm2 is considered an infinite dose based upon FDA’s guidance that a finite IVPT dose should be 3–5 mg/cm2 (49). However, this quantity of Transcutol applied to sheep felt that has been processed to assure retention of a layer of sebum/sweat emulsion appears incapable of dehydrating the stratum corneum during IVPT. Thus, for topical application to sheep, the use of neat Transcutol in a clinically relevant dose of 88.5 μl/cm2 will enhance the skin transport of lidocaine.
In an IVPT study published by Gwak (45), the authors emphasized that the permeation fluxes of tenoxicam from saturated solutions in various vehicles were generally low (0.1–1.1 μg/cm2 h) and no individual vehicle possessed the necessary intrinsic activity to dramatically promote permeation. Upon closer examination of the reported permeation rates for water (0.15 ± 0.04 μg tenoxicam/cm2 h) and neat Transcutol (1.13 ± 0.42 μg tenoxicam/cm2 h), it is evident that the latter produced 7.5 times more tenoxicam compared to the saturated water (Table IV). This high ER for tenoxicam delivered from Transcutol could be explained by the inherently high variability in flux measurements of poorly permeating actives, or it could be an example of enhancement due to the solvent effect overwhelming the increased barrier resulting from neat Transcutol dehydrating the stratum corneum. Tenoxicam (45) has the most complex acid-base properties of the drugs considered in this review. At pH values below the pKa1 (4.3), tenoxicam carries a positive charge. At pH values above pKa2 (5.3), tenoxicam carries a negative charge and approaches 5 mg/ml solubility at the physiological pH of the viable epidermis. Based on this acid-base chemistry, neutral tenoxicam dissolved in Transcutol at 4.7 mg/ml should readily partition into the pH = 5 stratum corneum and just as readily partition out of the stratum corneum into the viable epidermis.
A consistent mechanistic picture of how during IVPT experiments neat Transcutol modifies the stratum corneum can be derived from the publications reviewed. If a true infinite dose (in excess of 1 ml/cm2 skin surface area) of neat Transcutol is added to the donor compartment for IVPT, then the stratum corneum dehydrates, stiffening the intercellular lipids and increasing the barrier of the skin. Simultaneously, Transcutol quickly permeates the stratum corneum potentially decreasing the barrier of the skin by decreasing drug charge (solvent effect), increasing the solubility of the active in the stratum corneum, and/or disorganizing the crystalline epidermal lipid structure. Based on the data summarized in Table IV, it is highly likely that the dehydration effect of dosing with neat Transcutol may dominate the competing penetration enhancing effects of dosing with neat Transcutol. This results in saturated water having higher skin flux values than saturated Transcutol.
It should be noted that the decrease in skin flux seen in these publications from neat Transcutol (Table IV) is an infinite dose IVPT artifact rather than a significant insight for developing a commercial topical product. In practice, when applied in vivo, 1 ml of a topical product will spread over 300 cm2 of skin surface area. This thin film of Transcutol will be present on the skin’s surface for less than a minute and will not be able to dehydrate the entire thickness of the stratum corneum. Thus, this mechanistic insight should be used to facilitate interpretation of steady-state IVPT data rather than guide formulation development.
Effect of Transcutol Binary Solvent Blends on Drug Penetration/Permeation
With this understanding of how Transcutol partitions into the lipid filled intercellular spaces of the stratum corneum to retain the high skin permeability of a hydrated stratum corneum at reduced hydration conditions, it becomes apparent that blending Transcutol with molecules having complimentary mechanisms for disrupting epidermal lipid structure could result in synergistic skin penetration enhancement. This combined with Transcutol potentially reducing the charge of certain actives and increasing solubility and/or partition of some drugs into the stratum corneum results in optimized Transcutol blends consistently obtaining the highest enhancement ratios based on IVPT. Studies combining Transcutol with MCT, PG, PGML, PGMC, OA, IPM, propylene glycol laurate (PGL), or sucrose esters including sucrose myristate (SM), sucrose oleate (SO), and sucrose laurate (SL) have shown that Transcutol blends can dramatically increase the skin flux of certain pharmaceutical active ingredients (21,25,41,45,46,50,51,52). Skin flux enhancement ratios of over 50 were obtained for melatonin delivered from a TRC/PGL blend compared to skin flux from neat Transcutol (25). This ability of certain Transcutol blends synergistically enhancing drug penetration rates (for certain actives) is contrasted with the effect of lipophilic enhancer blends with Transcutol such as TRC/MCT for delivery of ivermectin (21) or TRC/IPM combinations studied for UV absorbers (33).
The influence of TRC, W, and PG combinations on clonazepam permeation through artificial membrane and excised rabbit ear skin from Carbopol hydrogels was characterized by Mura et al. (53). Franz cells loaded with rabbit ear skin were dosed at 312.5 mg gel/cm2 over a receptor solution of pH 7.5 PBS containing 25% v/v of PEG 400. The study concluded that Transcutol is a good enhancing carrier for clonazepam, yielding an ER = 3.4 (artificial membranes) or ER = 2.3 (rabbit ear skin) for flux rate as compared with that of the gel base (Fig. 8a). Moreover, when Transcutol was used in combination with PG (10% TRC:50% PG), a further increase in the flux rate was found, up to 6.3 times greater than gel base for the formulation (Fig. 8b). The authors attributed the enhancement of drug permeation to the solubilizing properties of Transcutol combined with its ability to increase drug cutaneous retention and to the penetration and carrier properties of PG across the skin.
The effect of TRC/PGMC and TRC/PGML blends were studied using infinite dosing of excised dorsal skin from hairless mice (6–8 weeks old) for ketorolac tromethamine (41), tenoxicam (45), ondansetron HCl (46), and donepezil HCl (54). Results for ketorolac (dosed at 5 mg/ml as the tromethamine salt) and donepezil (dosed at 1 mg/ml) are shown in Fig. 9. Since these studies did not dose at equivalent thermodynamic driving force, the skin flux values (blue solid lines) should be greatest when dosing (dashed red lines) are nearest drug saturation solubility (green bars) in Fig. 9a–c. This is clearly not the case for ketorolac or donepezil. The greatest skin penetration enhancement for donepezil occurs at 40% TRC and falls between 20 and 60% TRC for ketorolac. For both actives, skin flux is a compromise between the maximal flux caused by the synergistic ratio of TRC/PGMC or TRC/PGML and the loss of thermodynamic driving force for blends with significantly increased drug solubility and a drastic loss of permeation at elevated/neat Transcutol concentrations. It should be noted that more ketorolac was delivered from TRC/PGML mixtures than from the TRC/PGMC blends.
In another IVPT study of ketorolac tromethamine in a pressure sensitive transdermal delivery (Duro-Tak 87-2196R patch) system, Choi (50) tested 38 different combinations of various solvents/enhancers involving PG, MeOH, TRC, PGMC, and fatty acids. Much like the other reports, the combinations consisting of 40:60 ratio of TRC/PGMC or TRC/PGML showed the highest in vitro permeation profiles, in the Sprague-Dawley rat skin model. These formulations were preselected for pharmacokinetic (rat in vivo) experiments that followed and were compared with an orally administered dose. The results confirmed a comparative decrease in Cmax and prolonged Tmax and half-life for the ketorolac in transdermal systems, indicating a prolonged effect with reduced toxicity. Additionally, an excellent relationship was found between in vitro permeation flux and in vivo AUC (systemic delivery).
Figure 10 presents the permeation enhancement (flux ER) data for similar TRC/PGMC and TRC/PGML blends saturated with either tenoxicam (45) or ondansetron HCl (46). Enhancement ratio was calculated as drug flux (μg/cm2 h) from the formulation divided by its flux from 100% TRC. Overall, the TRC/PG fatty ester ratio of 40:60 provided the maximum skin flux for both actives. More tenoxicam was delivered from TRC/PGML (ER = 20) than from TRC/PGMC (ER = 13.5). Tenoxicam was soluble up to 4.74 mg/ml in Transcutol, 1.27 mg/ml in PGMC, and 0.59 mg/ml in PGML. As for ondansetron, the highest ER ratio of 6.4 was obtained. Ondansetron solubility was higher in the TRC/PGMC blends, ranging from 18.1 mg/ml Transcutol to 1.0 mg/ml PGMC.
Since a decreased lag time occurred for the maximum ondansetron flux (ER = 6.4) a mechanistic narrative can be proposed. Transcutol disrupts structure in the region of the ceramide head group which allows the PG fatty ester greater penetration into the bilayer structured epidermal lipids. TRC/PGML blends appear to enhance penetration better than TRC/PGMC blends. Speculation concerning how and where the PG fatty ester disorders the structured epidermal lipids cannot be made based solely on IVPT results.
Binary mixtures of TRC/PGL and TRC/IPM were studied for permeation of melatonin across hairless mouse skin by Gwak (25). Solubility of melatonin increased with increasing ratio of Transcutol in the PGL or IPM. Flux enhancement ratios however varied significantly, the lowest observed for neat Transcutol and the highest synergistic effect with the 20:80 mixture of TRC/PGL (Fig. 11). It is worth noting that the experiments were run in triplicate and the largest standard deviation of the data set pertained to the 20:80 TRC/PGL mixture. Thus, the enhancement ratio of 56.6 (21.5 ± 7.34 μg/cm2 h) should not be viewed as rigorously quantitative, but the observation that TRC/PGL blends result in synergistic skin penetration enhancement for certain pharmaceutical active ingredients is consistent in the scientific literature. In contrast, when Transcutol was blended with IPM (25), melatonin skin permeation increased by a factor of 23.9 (at 20:80 ratio of TRC/IPM), dropping gradually at higher Transcutol ratios.
When saturated carbenoxolone solutions were dosed (Franz cell, 885 mg/cm2) on heat separated human skin (51), the 50:50 TRC/PGL solvent blend produced a drug flux of 1.55 μg/cm2 h compared to 0.76 μg carbenoxolone/cm2 h skin flux for a 50:50 TRC/IPM (Fig. 12). The highest carbenoxolone skin flux obtained in this study was 1.64 μg/cm2 h which required the blend of three excipients TRC/PGL/IPM (50:25:25). This additional example of Transcutol combined with IPM not synergistically enhancing skin penetration can be contrasted with results of another study involving clebopride (55) where increasing concentration of Transcutol in the TRC/IPM binary blends resulted in increased drug flux across the rat skin. As shown in Fig. 13, flux rates as high as 44 and 46 μg/cm2 h were obtained, representing 80- and 90-fold enhancement ratios respectively compared to that obtained from a 100% IPM control formulation (0.58 μg/cm2 h). Fig. 13 also shows the lag times observed for each of the binary mixtures studied, increasing from 5 h (100% IPM formulation) to 15 h from the 100% Transcutol formulation. A 15-h lag time in a 24-h infinite dose IVPT indicates that lipids are being extracted from the skin into the donor phase to cause a sudden loss of the skin barrier. Thus, the 80-fold increase in clebopride skin penetration for a 40:60 blend of TRC/IPM compared to IPM alone (as control) must be viewed in terms of the experimental design.
Godwin (33) examined the effect of TRC/IPM mixtures on the skin accumulation as well as skin permeation of UV absorbers oxybenzone (log P = 3.8) and octyl-4-methoxy cinnamate (cinnamate, log P = 5.8). These experiments used Franz cells loaded with hairless mouse skin, dosed at 312.5 mg/cm2 (6% w/w) UV absorber dissolved in IPM or TRC/IPM blends. Per the results summarized in Fig. 14a, the increases in skin accumulation were statistically significant for both UV absorbers at Transcutol concentrations of 18, 25, and 50%, with oxybenzone having twice the skin accumulation compared to cinnamate. The flux values (Fig. 14b) were also higher for oxybenzone than with cinnamate and this without statistical significance. The researchers concluded that inclusion of Transcutol led to increased skin accumulation of oxybenzone and cinnamate without a concomitant increase in transdermal permeation.
The effect of Transcutol concentration on active flux was evident in the work of Yazdanian and yet certain conclusions drawn from that work need closer examination. In Yazdanian (21), the authors were developing a veterinary topical ivermectin product for cattle. As part of the study they prepared ivermectin solutions (14 mg/ml) in Miglyol 812 (MCT) and Transcutol blends of 90/10, 70/30, 50/50, and 0/100 (neat Transcutol). They traced tritiated ivermectin as it crossed excised bovine skin (Hostein, dermatomed to 4.5 ± 0.2 mm) and measured the appearance of Transcutol in the receptor solution (gas chromatography). The distribution profiles of ivermectin as a function of skin depth and solvent composition are summarized in Fig. 15a. As shown, the amount of ivermectin present in the skin was significantly greater, with most of the ivermectin localized in the upper layers of the skin. The authors reported that ivermectin permeation was accompanied by the formation of cutaneous depots of ivermectin; that partitioning of ivermectin into the skin was far greater in the presence of Transcutol in saturated solutions; that ivermectin “was permeating with Transcutol, in which it is very soluble.” It was also noted that there were no significant statistical differences in the flux of Transcutol as the concentration of Transcutol in the donor phase was increased. This was in contrast to what was expected on the basis of thermodynamic activity. A closer examination of the data (Fig. 15b, c), however, reveals that overall, ivermectin solubility as well as skin permeation parameters (flux and Kp) increased significantly with the increasing concentration of Transcutol. Since this IVPT study (21) was completed in support of a veterinary product, it is important to note that the Franz cell study (dosed at 282 mg/cm2 using a receptor solution of 25% glycerol in water) held the skin temperature at 39°C to match the skin temperature of living cattle. No quantitative correlation between bovine and human skin transport should be inferred from this study; however, the observation of how flux and permeability coefficient trend with increasing Transcutol concentration is noteworthy.
Rieg-Falson (56) blended Transcutol with Labrafac Hydro, a liquid non-ionic surfactant consisting of caprylic/capric triglyceride PEG-4 esters (LABH). The liquid mixtures of TRC/LABH were saturated with radiolabeled morphine free base or radiolabeled morphine HCl and then these formulations were gelled with 10% Ethocel 20. They mounted hairless mouse abdominal skin on a diffusion cell, dosed at 394 mg/cm2, and followed skin permeation for 96 h. In general, solubility for both the free base and hydrochloride salt of morphine increased with increasing Transcutol concentrations, with morphine HCl being about 60-fold less soluble in the formulations than the free base (Fig. 16a). The morphine flux values (56) were very similar to those reported by Yazdanian (21) for ivermectin. As shown (Fig. 16b), skin flux increased with increasing concentrations of Transcutol until plateauing at ~ 30% Transcutol. The flux of both actives from neat Transcutol dramatically decreased, likely due to neat Transcutol dehydrating the stratum corneum and increasing the barrier properties of the skin. Since all of the formulations were at equivalent, maximum thermodynamic driving force, the marked difference in the flux values between the morphine free base and the morphine HCL may be attributed to the lower permeability of the latter, i.e., the HCL salt being in ionized form. Noteworthy is the proximity of the nearly equal flux values at 50:50 TRC/LABH for both species of the morphine, indicating the possibility of a solvent effect being responsible for reducing the morphine HCl charge.
In a human volunteer study (39) MCT gelled with 7.5% polypropylene was the control formulation for delivering methyl nicotinate. Increased blood flow induced by this active that rapidly crosses the stratum corneum was measured using laser Doppler flowmetry. 0.25 ml of the gelled, non-aqueous test articles were applied to the forearm of volunteers using a Hilltop (occlusive) chamber. Addition of 10% Transcutol resulted in a statistically significant enhancement factor of 4.6 ± 2.7 for 10% Transcutol formulation compared to the control formulation at 0.5-h application time. It should be noted that the relative bioavailability enhancement factor calculated by these researchers is very different than the simple ER values used throughout this review. The researchers also studied the test article application sites using ATR-FTIR spectroscopy. The ATR-FTIR band intensity indicated that the MCT/TRC blend appeared to retain more water in the stratum corneum compared to control, but that neither significant disorder of the bilayer structured intercellular lipids nor significant protein configuration changes occurred when Transcutol was added.
Interestingly, the relative optimization of drug flux at 50:50 blends with Transcutol is a recurring theme in a number of other studies (56,57,58). Koprda (18) studied permeation in the rat skin of dicarbine (stobadine HCl) from TRC/W solutions at 1:1 and 2:1 ratio, with and without azone. The results summarized in Fig. 17 show that drug permeation increased with the addition of 1% and 5% azone and that the drug permeation was effectively higher from the 50:50 (TRC/W) than with the 66:33 (TRC/W) mixture, even if 1% azone was added. However, addition of 5% azone to the 2:1 TRC/W combination increased the flux dramatically by 16 times. The enhancing effect of azone has been attributed to direct interactions with the stratum corneum lipids and lowering their melt transition temperature, thus creating a more fluid environment amenable to permeant diffusion. The ability of Transcutol to preferentially partition into more polar environments and disturb the packing in the interfacial head group layer of the intercellular lipids works synergistically with azone’s ability to melt the natural orthorhombic structure of the hydrocarbon chain packing of the intercellular lipids. This synergism between Transcutol and azone appears to be greatest at a specific ratio of Transcutol, water and azone. In addition to Transcutol facilitating azone fluidizing of the intercellular lipids, Transcutol is likely enhancing the solubility of dicarbine in the skin (22,28,43).
Addition of OA to TRC can produce an additive enhancing effect on the delivery of water soluble actives like theophylline (57) and caffeine (58). Excised hairless mouse skin mounted on side-by-side diffusion was used for both actives. In the theophylline study, Touitou (57) added a blend of 20% TRC and 10% OA to three bases, namely a carbomer gel consisting of 60% EtOH, a petrolatum and polysorbate 80 (PS 80)-based cream, and a hydrophilic PEG 400/PEG 4000 ointment base. The concentration of the tritiated theophylline in the formulation was at 10 mg/g. Fig. 18 summarizes the permeation rate of theophylline from each of these formulation bases where the TRC/OA/PEG base (2:1:7) combination produced the highest flux (11.1 mg/cm2 h) representing an enhancement ratio of 260 vs. control (0.0428 mg/cm2 h) and flux ER of 1.6 against the PG/OA/PEG base (6.99 mg/cm2 h) combination.
In a later study (58), this same skin penetration enhancing 2:1:7 combination of TRC/OA/PEG base was tested for delivery of 3% caffeine. The findings for caffeine were similar in that the best additive combination effect was associated with the TRC/OA blend as enhancer. This latter study however took additional steps to examine the effect of hydration (water in the formulation) (Fig. 19) with results that highlighted the importance of water in the enhancement or formulation optimization.
It should be noted that OA, especially at high concentrations, can disrupt the lipid domains within the stratum corneum by forming pools in the intercellular space to create “pores.” These pores provide less resistance for polar molecules resulting in skin penetration enhancement. Non-polar molecules have also been shown to be enhanced when OA pools in the intercellular space of the lipid domain. The original research characterizing this phenomenon was concisely reviewed by Benson (23) .
This next example involving the highly lipophilic tetrahydrocannabinol (THC) helps compare the penetration properties of Transcutol against OA in different carrier systems. To assess whether drug carriers could influence the drug pathway through the skin, Fabin (59) incorporated THC or OA as permeant into three enhancer systems: neat TRC, PEG 400, and a 7:3 blend of PG/EtOH. Formulations with 0.8 g THC (50 μCi drug) were applied to 3.2 cm2 surface area of rat skin in vivo. Samples of the skin were then analyzed ex vivo at 2 and 24 h after application, using quantitative autoradiography to visualize and measure the trace levels of tritiated THC penetrating the different layers of the skin. The highest penetration for THC was observed with the Transcutol formulation after 2 h of application, with no significant difference between the THC and OA concentrations accumulating in the skin layers. Increasing the study duration to 24 h however helped emphasize the preference of THC or OA to choose the penetration route, demonstrated by a much greater skin penetration, as well as a different localization for both but THC having a significantly higher overall distribution than OA. The penetration results from the three enhancer systems for THC are summarized in Fig. 20, showing that the concentrations delivered from neat Transcutol were significantly higher compared to PEG 400 or the PG/EtOH mixture. Comparing the 24 h data to those obtained at 2 h of application, the authors noted that the skin distribution profile of THC and OA had changed over time with the PG/EtOH (7:3) formulation, whereas it was unchanged from the neat Transcutol formulation. This indicated that Transcutol, unlike OA, does not change the skin barrier/permeability over time.
Drug Transport from Transcutol and Sucrose Ester Mixtures
In a study involving healthy human volunteers, Ayala Bravo (60) used FTIR and TEWL measurements to assess the effect of TRC, SO, SL, and their combinations on the penetration depth of a model drug, 4-hydroxybenzonitrile (4-HB). The model penetrant was selected on the basis of its intense C≡N stretching absorbance at 2230 cm−1, permitting it to be monitored by ATR-FTIR spectroscopy. Drug penetration distances were measured after a pretreatment (1-h application) with various TRC/sucrose ester combinations. Whereas the distribution of 4-HB for the control formulation suggested that the active is able to distribute itself in the stratum corneum independent of enhancers, the extent of its penetration was clearly influenced by the addition of the enhancer/combinations (Fig. 21). The penetration distance of 4-HB from neat Transcutol was similar to the aqueous solutions of sucrose esters, SO/W (10:90) and SL/W (2:98). Referring to a prior study where no modification of stratum corneum lipids had been observed for sucrose ester aqueous solutions, the authors pointed to a distinct lipid fluidization in the presence of SL-TRC and suggested that the SL absorption in the stratum corneum was facilitated by TRC.
In developing ibuprofen transdermal gel formulations, Csizmazia (61) dissolved 5% ibuprofen in PEG 400 (20%), followed by adding the solution to Carbopol 971 hydrogel to serve as control formulation. Similarly, hydrogels consisting of 2.64% SL or 10% TRC were prepared and tested on excised human skin. Per the IVPT results, the skin permeation of ibuprofen increased from the SL formulation by over 2-fold, whereas the permeation from the neat TRC formulation was about half that from the control formulation. In the same study, the FTIR analysis of 3 to 18 strips taken from the treated skin samples confirmed a higher amount of ibuprofen for the Transcutol formulation compared to the control (Fig. 22). The authors did not elaborate if the three formulations had equivalent solubility/thermodynamic forces. However, the study concluded that Transcutol is an effective diffusion enhancer while the sucrose ester is a permeation promoter for ibuprofen.
Ibuprofen penetration and permeation studies by Balazs (62) and Cazares-Delgadillo (63) also involved combinations of Transcutol with sucrose esters. Balazs (62) prepared formulations PEG 400 aqueous carbomer gels consisting 10% TRC and 2.64% SL or SM mixtures. Heat-separated human epidermis was loaded in a Franz cell and dosed at 170 mg/cm2 with a dissolved 5% ibuprofen PEG 400 aqueous carbomer gel. The gel consisting of TRC/SL produced an enhancement ratio of 0.80 for skin flux and 0.95 for skin concentration against the gel without enhancer. This compares to the more effective blend of TRC/SM which had an enhancement ratio of 1.7 for skin flux and 1.7 for skin concentration.
The effect of SL or SO combined with TRC on the percutaneous penetration of lidocaine as a function of ionization was determined by Cazares-Delgadillo (63). In this study pig ear skin was loaded in a Franz cell (0.8 cm2) and pretreated for 1 h with 100 μl of the formulation, i.e., 2% SL in TRC or 2% SO in TRC. The pretreatment solution was removed with a cotton swab followed by application of 300 μl of a saturated lidocaine hydrochloride solution in phosphate buffer at pH 5.0 (unionized fraction = 0.00), pH 7.0 (unionized fraction = 0.11), and pH 9.0 (unionized fraction = 0.93). The diffusion of lidocaine was significantly improved when the skin was pretreated with both TRC/SL and the TRC/SO (98:2) formulations. However, the effect of each ester on the penetration of the ionized and unionized forms was quite distinct: SL favored the diffusion of the ionized species (pH 5.0 ER = 11.9 and pH 7.0 ER = 10.8) but reduced the passage of the uncharged base (pH 9.0 ER = 0.6). In contrast, SO enhanced the permeation of both the ionized and unionized species of lidocaine (pH 5.0 ER = 3.8, pH 7.0 ER = 3.4, and pH 9.0 ER = 2.7).
Simple Gel Formulations with 1–50% Transcutol
For the 12 pharmaceutical actives listed in Table V (enhancement of skin flux) and Table VI (enhancement of skin retention), adding 1–50% Transcutol to a simple gel formulation resulted in ER values of 1–4.8 for skin flux and ER values of up to 3.4 for skin retention. For the studies that varied the amount of Transcutol in the formulation, the ER generally increased with increasing amounts of Transcutol. Addition of up to 50% Transcutol to a simple gel formulation resulted in enhanced skin penetration, presumably by partitioning into the skin and allowing the epidermal lipid domain to retain the high skin permeability of a hydrated stratum corneum and depending on the active potentially decreasing drug charge (solvent effect) or increasing solubility/partitioning of the active in the stratum corneum.
The Intracutaneous Depot
Starting in 1988, Ritschel and his group (1,19,34,35,40,67,70,71) published a series of papers showing that Transcutol in certain topical preparations could form an “intracutaneous depot”: for griseofulvin (19), coumarin (70), meperidine (71), papaverine (72), and clobetasol 17-propionate (67).
In the frequently cited 1991 publication (34), a 0.09% hydrocortisone gel consisting of 50% Transcutol, 12.00% PG, 10.00% Cab-O-Sil, and triethanolamine buffer pH 8.0 q.s. ad to 100% was prepared. Sprague-Dawley rats were dosed daily by applying 1 g of gel into a flexible Teflon ring (4.24 cm2). The dosing area was then closed with a polyethylene membrane and secured with bandage around the body of the rat. The skin under the dosing area was excised and prepared for autoradiography and morphological (both light and electron microscopy) study. Ritschel (34) proposed the following mechanism for forming the intracutaneous depot. “The major barrier for the absorption of drugs through the skin is the stratum corneum….The intercellular space volume is relatively small (1–10%) and may be a major pathway for permeation but at the same time the intercellular lipids are important in controlling the percutaneous absorption. The swelling of intercellular spaces, and the accumulation of foreign material outside the cell membrane is seen in the presence of Transcutol (evident from electron micrographs). It appears that Transcutol may incorporate into the multiple bilayer due to its polar and non-polar nature and thereby swell the intercellular lipids without altering the multiple bilayer structure. These swollen lipids may hold hydrocortisone and thereby form an intracutaneous depot in the presence of Transcutol, since hydrocortisone has high affinity for Transcutol.”
The aforementioned gel formulation (50% TRC:12% PG:10% Cab-O-Sil) was evaluated by Panchagnula (40) for delivery of hydrocortisone and dexamethasone in vitro and in vivo. The amount of steroid permeating across the rat skin (in vitro) was significantly less compared to the control formulation (without Transcutol). This was concurrent with a 3-fold increase in the skin concentration of hydrocortisone with the Transcutol formulation. The subsequent in vivo rat experiments involving radiolabeled hydrocortisone, obtained by measuring the total radioactivity in the blood for up to 96 h corroborated with the in vitro results. After a single dose administration, the amount of hydrocortisone measured in the plasma was 6.06 ± 1.27 d min−1 ml−1 h for the Transcutol formulation compared with 2.52 ± 0.43 × 106 d min−1 ml−1 h for the control formulation, indicating a 58% reduction in body burden (Fig. 23).
After review of the Transcutol literature in light of the work by Ritschel and colleagues, formation of the intracutaneous depot occurs for a subset of actives that after being dissolved in Transcutol have significantly greater solubility in the stratum corneum. These drugs also have low water solubility (such as clobetasol 17-propionate at 0.004 mg/ml, griseofulvin at 0.008 mg/ml), papaverine at 0.013 mg/ml, dexamethasone at 0.089 mg/ml, or hydrocortisone at 0.32 mg/ml) or large octanol-water partition coefficients (such as meperidine having a log P = 2.7, clobetasol 17-propionate having a log P = 3.5, or papaverine having a log P = 4.2) and will not readily partition out of the stratum corneum into the viable epidermis. For this subset of drugs, certain in vitro techniques result in remarkably high concentrations of active being measured in the skin. Thus, the intracutaneous depot could also be termed Transcutol-enhanced stratum corneum reservoir function (73) .