Feasibility studies of dermal delivery of paclitaxel with binary combinations of ethanol and isopropyl myristate: role of solubility, partitioning and lipid bilayer perturbation

In the current investigation, paclitaxel (PCL) delivery into the different layers of skin, vehicle optimization and relationship between vehicle composition and the relative contribution of solubility, partition and diffusion towards drug transport has been outlined. Saturation solubility of PCL was determined in ethanol (EtOH), isopropyl myristate (IPM) and their binary combinations, and partition studies performed to study the probability of skin depot formation. Epidermal and dermal partitioning was carried from PCL saturated vehicles. Skin permeation of PCL was studied using the rat skin. FT-IR has been utilized to study the skin barrier perturbation, and the localization of PCL and isopropyl myristate (IPM) in epidermis. High K(app) value in mineral oil/buffer indicated the tendency of PCL to form a reservoir in skin, and an inverse relationship between PCL solubility in different solvent systems and partitioning into epidermis was found. Maximum K(epidermis) for PCL was observed with IPM, while PCL in EtOH/IPM (1:1) showed high partitioning into dermis. Maximum flux of PCL was observed with EtOH/IPM (1:1). For lipophilic drug like PCL modulation of vehicle seems to be effective approach to increase the permeability across the skin. With a binary combination of EtOH/IPM (1:1) higher concentration of PCL can be delivered to deeper layer of skin whereas with IPM higher concentration of PCL could be localized in the epidermis. While engineering the delivery vehicle selection of solvents should be such that one of them is miscible in both hydrophilic and lipophilic phase like ethanol and another should be lipophilic in nature (IPM in this case) so that an optimum balance between 'push-pull' and 'blending' effect can be achieved.     

Effect of Vehicles on the Maximum Transepidermal Flux of Similar Size Phenolic Compounds

Purpose

In principle, maximum transepidermal fluxes of solutes should be similar for different vehicles, except when the solute or vehicle modifies the skin. Here we estimated maximum flux, stratum corneum solubility, diffusivity and permeability coefficient for a range of similarly sized phenolic compounds with varying lipophilicity from polar and lipophilic vehicles.

Methods

Maximum flux and other skin transport parameters through human epidermis were obtained from lipophilic vehicles (mineral oil (MO) and isopropyl myristate (IPM)) and compared with values from water and propylene glycol (PG)-water solutions. Solvent uptake and changes in stratum corneum infrared spectroscopy and multiphoton microscopy imaging were also investigated.

Results

Maximum fluxes for MO and water were similar but IPM has a higher value for more polar phenols due to a higher diffusivity and PG-water had a higher flux due to higher solubility in the stratum corneum. Whereas maximum flux for various phenols was directly related to solubility in the stratum corneum independent of vehicle, increasing phenol lipophilicity increased and decreased permeability coefficient for aqueous solvents and lipophilic solvents, respectively.

Conclusion

The maximum fluxes for phenols with a similar molecular size and varying lipophilicity were comparable between water and MO vehicles but higher for IPM and PG-water mixtures.     

Transdermal delivery of nicardipine: an approach to in vitro permeation enhancement

Nicardipine hydrochloride (NC-HCl), a calcium channel blocker for the treatment of chronic stable angina and hypertension, seems to be a potential therapeutic transdermal system candidate, mainly due to its low dose, short half-life, and high first-pass metabolism. The objective of the present study was to evaluate its flux and elucidate mechanistic effects of formulation components on transdermal permeation of the drug through the skin. Solubility of NC-HCl in different solvent systems was determined using a validated HPLC method. The solubility of drug in various solvent systems was found to be in decreasing order as propylene glycol (PG)/oleic acid (OA)/dimethyl isosorbide (DMI) (80:10:10 v/v) > PG > PG/OA (90:10 v/v) > polyethylene glycol 300 > ethanol/PG (70:30 w/w) > transcutol > dimethyl isosorbide (DMI) > ethanol > water and buffer 4.7 > 2-propanol. Propylene glycol was then selected as the main vehicle in the development of a transdermal product. As a preliminary step to develop a transdermal delivery system, vehicle effect on the percutaneous absorption of NC-HCl was determined using the excised skin of a hairless guinea pig. Vehicles investigated included pure solvents alone and their selected blends, chosen based on the solubility results. In vitro permeation data were collected at 37 degrees C, using Franz diffusion cells. The skin permeation was then evaluated by measuring the steady state permeation rate (flux) of NC-HCl, lag time, and the permeability constant. The results showed that no individual solvent was capable of promoting NC-HCl penetration. Permeation profiles of the drug through hairless guinea pig skin using saturated solutions of drug were constructed. Among the systems studied, the ternary mixture of PG/OA/DMI and binary mixture of PG/OA showed excellent flux. The flux value of the ternary system was nearly three times higher than the corresponding values obtained for the binary solvent. A similar trend also was observed for the permeation constant, while the values of lag time were reversed. The ternary mixture was then selected as a potential absorption enhancement vehicle for the transdermal delivery of drug. In general, higher fluxes were observed through hairless guinea pig skin as compared with the human stratum corneum. Based on the results obtained from the release study of NC-HCl from saturated solutions of the drug, a novel lecithin organogel (microemulsion-based gel) composed of soybean lecithin, propylene glycol, oleic acid, dimethyl isosorbide, and isopropyl myristate was developed as a possible matrix for transdermal delivery of NC-HCl. In vitro percutaneous penetration studies from this newly developed gel system through giunea pig skin and human stratum corneum revealed that the organogel system has skin-enhancing potential and could be a promising matrix for the transdermal delivery of nicardipine. Furthermore, higher permeation rates were observed when nicardipine free base was incorporated into the gel matrix instead of hydrochloride salt.     

Effect of ethanol/propylene glycol on the in vitro percutaneous absorption of aspirin, biophysical changes and macroscopic barrier properties of the skin.

The effect of the solvent systems ethanol (EtOH), propylene glycol (PG) and combinations thereof was examined on the in vitro percutaneous absorption of the antithrombotic, aspirin, through porcine epidermis. Biophysical changes in the stratum corneum lipids were studied through the use of Fourier transform infrared (FTIR) spectroscopy. Macroscopic barrier properties of the epidermis were examined through the use of in vitro transepidermal water loss (TEWL). The flux of aspirin increased with increasing concentrations of EtOH in the solvent systems. The maximum flux of aspirin was achieved by 80% EtOH in combination with 20% PG beyond which (i.e. 100% EtOH) there was no increase in the flux. FTIR spectroscopic study was enacted in order to determine the biophysical properties of the stratum corneum when the solvents were applied. The FTIR spectra of the stratum corneum treated with 80% EtOH/20% PG showed a maximum decrease in absorbance for the asymmetric and symmetric C&z. sbnd;H peaks, which suggests a greater loss of the lipids in the stratum corneum layers. In vitro TEWL studies allowed an investigation into the macroscopic barrier integrity properties of the stratum corneum. The TEWL results indicated that each of the solvent systems significantly enhanced (P<0.05) in vitro TEWL in comparison to the control. In conclusion, 80% EtOH/20% PG enhanced the percutaneous absorption of aspirin by perturbing the macroscopic barrier integrity of the stratum corneum and through a loss of stratum corneum lipids. Copyright     

Theoretical considerations on the in vivo intestinal permeability determination by means of the single pass and recirculating techniques

The effect of the solvent systems water, ethanol (EtOH), propylene glycol (PG) and their binary combinations was studied on the ex vivo permeation profile of the opioid receptor antagonist, naloxone, through rat skin. Fourier transform-infrared (FT-IR) spectroscopic studies were done to investigate the effect of enhancers on the biophysical properties of the stratum corneum (SC), in order to understand the mechanism of permeation enhancement of naloxone by the solvent systems used. The flux of naloxone was found to increase with increasing concentrations of EtOH, upto 66% in water, and PG upto 50% in water. The maximum flux of 32.85 microg cm(-2) h(-1) was found with 33% PG in EtOH. The FT-IR spectra of SC treated with EtOH showed peak broadening at 2920 cm(-1) at all concentrations of EtOH studied indicating that EtOH increases the translational freedom (mobility) of lipid acyl chains. Theoretical blood levels well above the therapeutic concentration of naloxone can be achieved with the solvent system comprising 33% PG in EtOH and hence, provides flexibility in choice of patch size depending on the addiction status of the patient to be treated.     

Combination strategies to enhance transdermal permeation of zidovudine (AZT)

The objective of this study was to evaluate the effect of simultaneous application of two penetration enhancers of different chemical classes or a chemical penetration enhancer and current application on permeation of zidovudine (AZT) across rat skin. Ex vivo permeation of AZT using combinations of cineole or menthol in vehicle with either oleic acid/linolenic acid or 0.5 mA/cm2 anodal current application for 6 h was studied. Penetration enhancers were significantly different in enhancing the permeability of AZT across rat skin and are in the decreasing order of activity: linolenic acid > menthol > oleic acid > cineole > vehicle. The combination of cineole and oleic acid synergistically enhanced transdermal flux of AZT in addition to reducing lag time. However, this was not observed for combinations of menthol with oleic or linolenic acid. On the other hand, the simultaneous application of current with menthol and cineole significantly increased cumulative amounts of AZT permeating during the course of current application and reduced the lag time but failed to further increase steady state flux of AZT. These results suggest that a combination of two penetration enhancers of different classes or the simultaneous use of iontophoresis and a penetration enhancer may be advantageous to achieve permeation enhancement with low risk of skin damage.     

Penetration‐Enhancing Effect of Ethanol–Water Solvent System and Ethanolic Solution of Carvone on Transdermal Permeability of Nimodipine from HPMC Gel Across Rat Abdominal Skin

The aim of this investigation was to find the effect of the ethanol–water solvent system and the ethanolic solution of carvone on the permeation of nimodipine across rat abdominal skin in order to select a suitable solvent system and optimal concentration of carvone for the development of membrane‐moderated transdermal therapeutic system of nimodipine. The solubility of nimodipine in water, ethanol, and ethanol–water cosolvent systems, or the selected concentration of carvone [2% (w/w) to 12% (w/w)] in 60:40 (v/v) ethanol–water were determined. The effect of these solvents or cosolvent systems on the transdermal permeation of nimodipine was also studied using in vitro permeability studies across the rat abdominal skin. The cosolvent system containing 60:40 (v/v) of ethanol–water showed highest permeability across the rat abdominal skin. Further, the effect of ethanolic solution [60% (v/v) ethanol–water] of carvone [2% (w/w) to 12% (w/w)] on the in vitro permeation of nimodipine across the rat abdominal skin from 2% (w/w) hydroxypropyl methylcellulose (HPMC) gel was also investigated. The transdermal permeability of nimodipine across rat abdominal skin was enhanced further by the addition of carvone to HPMC gel prepared with 60% (v/v) of ethanol. There was a steady effect on the flux of nimodipine (161.02 ± 4.14 µg/cm²/hr) with an enhancement ratio of 4.56 when carvone was incorporated at a concentration of 10% (w/w) in HPMC gels prepared with 60% (v/v) ethanol. The Fourier transform infrared data indicated that ethanolic solution of carvone increased the transdermal permeability of nimodipine across the rat abdominal skin by partial extraction of lipids in the stratum corneum. The results suggest that 10% (w/w) of carvone in 60% (v/v) ethanol–water, along with HPMC as antinucleating agent may be useful for enhancing the skin permeability of nimodipine from the membrane‐moderated transdermal therapeutic system.     

Effect of neat and binary vehicle systems on the solubility and cutaneous delivery of piperine

Vitiligo is a skin disease characterized by depigmentation disorders due to lack of melanin production. Piperine, an alkaloid extracted from black piper, is active in melanocytes proliferation. To achieve this, the drug has to reach the melanocytes which exist in the deep layer of the epidermis. Higher drug concentration can be obtained after application of optimized formulation to skin. Accordingly, the aim of this work is to investigate the effect of vehicles on skin penetration of piperine as the first step in development of optimized formulation. The tested vehicles include ethanol (Eth), propylene glycol (PG), polyethylene glycol 400 (PEG), and oleic acid (OA) and their combinations. Water was used as the control and skin permeation was monitored using rabbit ear model skin. The highest piperine solubility (48.6?mg/ml) and flux (40.8?μg/cm²?h) was achieved by Eth and the lowest piperine flux (1.17?μg/cm²?h) was reported for PEG. PG and OA showed piperine flux values comparable to that of the control. Among different combination systems, Eth-OA (75:25) binary system had the highest piperine flux (59.3?μg/cm²?h) followed by Eth-OA (50:50) (32.3?μg/cm²?h) and PG-OA (90:10) (22.7?μg/cm²?h). The study thus introduced a vehicle system as the first step in the development of topical formulation of piperine.     

The effect of sorption promoters on percutaneous permeation of a model zwitterion baclofen

In vitro percutaneous penetration of baclofen, a model zwitterion, in the presence of penetration enhancers was investigated to better characterize a porous polar pathway of diffusion across the stratum corneum. The following sorption promoters were studied: DMSO, urea, propylene glycol (PG), sodium lauryl sulphate (SLS), ethanol 95%, Azone, oleic acid (OA) and OA/PG system. No significant increase of penetration or skin accumulation of baclofen was observed when DMSO, urea, PG, Azone or OA were used. The presence of SLS or OA/PG in the vehicle resulted in high penetration rates and uptake of baclofen but this effect was observable only after 30 h and was accompanied with signs of the barrier damage. Ethanol 95% was the only vehicle which promoted baclofen penetration despite its lower solubility in this solvent which is attributed to new pore formation. Penetration rate and skin accumulation of the zwitterion depend on its solubility in the vehicle.     

In Vitro Human Epidermal and Polyethylene Membrane Penetration and Retention of the Sunscreen Benzophenone-3 from a Range of Solvents

Purpose. To study epidermal and polyethylene membrane penetration and retention of the sunscreen benzophenone-3 (BP) from a range of single solvent vehicles and evaluate solvent effects on permeability parameters. Methods. The solubility of BP was measured in a number of solvents. Penetration of BP across human epidermis and high density polyethylene (HDPE) membranes was studied from 50% saturated solutions in each solvent. Results. Maximal BP fluxes from the solvents across the two membranes varied widely. Highest fluxes were observed from 90% ethanol (EtOH) for epidermis and from isopropyl myristate (IPM) and C_12–15 benzoate alcohols (C_12–15 BA) for HDPE membrane. Both the flux and estimated permeability coefficient and skin-vehicle partitioning of BP appeared to be related to the vehicle solubility parameter (_v). The major effects of solvents on BP flux appear to be via changes in BP diffusivity through the membranes. Conclusions. Minimal penetration of sunscreens such as BP is best achieved by choosing vehicles with a _v substantially different to the solubility parameter of the membrane.     

Skin permeation of physostigmine from fatty acids-based formulations: evaluating the choice of solvent

This study was conducted to gain an understanding of the enhancement mechanism of fatty acids in skin permeation of physostigmine (PHY) by using a series of fatty acids and two solvents of opposing lipophilicity (propylene glycol (PG) and mineral oil (MO)). Interaction between fatty acid and drug was proven using NMR and conductivity measurements that showed a dependence on type of solvent used. Permeation flux of physostigmine from mineral oil-based formulations to skin was increased as solubility of physostigmine in mineral oil was enhanced in the presence of fatty acids having a longer chain. Thus, the dominant role of fatty acids in mineral oil was to increase solubility of physostigmine in the formulations that increased the driving force for physostigmine permeation through skin. As for propylene glycol, enhancement caused by fatty acids was attributed to their ability to increase the lipophilicity of formulation and to disrupt the lipid bilayers within the stratum corneum (SC). In conclusion, fatty acids enhancement for drug permeation across the skin was found to be dependent on the solvent used. Among various formulations here, oleic acid in mineral oil yielded fast permeation of PHY with a short lag time, which may be a good vehicle for transdermal delivery of PHY.     

Contributions of Drug Solubilization,Partitioning, Barrier Disruption,and Solvent Permeation to the Enhancement of Skin Permeation of Various Compounds with Fatty Acids and Amines

The contributions of several proposed mechanisms by which fatty acids and amines might increase skin permeation rates were assessed. Permeation rates of model diffusants with diverse physicochemical properties (naloxone, testosterone, benzoic acid, indomethacin, fluorouracil, and methotrexate) through human skin were measured in vitro. The enhancers evaluated were capric acid, lauric acid, neodecanoic acid, and dodecylamine. Increased drug solubility in the vehicle, propylene glycol (PG), in some cases accounted for the increases in flux in the presence of adjuvants, since permeability coefficients were unchanged. Partition coefficients of some drugs into isopropyl myristate or toluene were increased by the adjuvants, but this did not occur for combinations of an acid with a base (adjuvant-drug or drug-adjuvant). Increases in flux not accounted for by increases in drug solubility or partitioning were assumed to involve disruption of the barrier function of skin (increased skin diffusivity). All fatty acids increased skin diffusivity of naloxone, testosterone, indomethacin, and fluorouracil but not of methotrexate or benzoic acid. Dodecylamine increased skin diffusivity only for fluorouracil. Capric acid and dodecylamine, but not lauric acid or neodecanoic acid, increased the skin permeation rate of PG, suggesting that enhanced solvent penetration could also be involved as a mechanism for increased skin permeation of the drug. However, the increase in PG flux due to dodecylamine was nullified when methotrexate was added to the vehicle, possibly because of a dodecylamine/methotrexate interaction. These studies demonstrate that drug solubilization in the vehicle, increased partitioning, increased solvent penetration, and barrier disruption each can contribute to increased skin permeation rates in the presence of fatty acids and amines. The relative contributions of the mechanisms vary with the drug, the adjuvant, and the vehicle.     

Transdermal delivery of antiparkinsonian agent, benztropine. I. Effect of vehicles on skin permeation

The influence of pH and various lipophilic and hydrophilic vehicles on the epidermal permeation of benztropine (BZ) free base and its mesylate salt were studied in vitro using the hairless mouse (HLM) and human cadaver (HC) skin membranes. The pH-partition behavior of BZ base (pK(a)=10) was examined using n-octanol and Britton-Robinson buffers over the pH range of 5-12. Unexpectedly, the ionized species of BZ yielded a high partition coefficient (log K(octanol/water)=2. 14), which was reflected by its relatively high skin permeability (P=1.6x10(-2)cm h(-1)). BZ base delivered from a lipophilic vehicle with a solubility parameter range of 7.1-10.3 (cal cm(3))(1/2) exhibited a significantly enhanced rate of permeation as compared to that attained from a hydrophilic vehicle of solubility parameter range between 12.5-23.4 (cal cm(3))(1/2). Among the neat solvents examined, a lipophilic carrier, isopropyl myristate (IPM) provided the most enhancing effect on the permeation of BZ base. In addition, the neat IPM carrier offered the maximum BZ base flux of 150 microg per cm(2) h(-1) across HC skin, which was approximately 16 times greater than the target delivery rate of BZ from a 10-cm(2) device. In comparison, BZ base exhibited a 2-60 times greater flux than BZ mesylate when delivered from the neat solvents. However, interestingly enough, the binary cosolvents consisting of IPM and short-chain alkanols such as ethanol (EtOH), isopropanol (iPrOH), and tertiary butanol (tBtOH), in particular a 2:8 combination, produced a marked synergistic enhancement of BZ flux from the mesylate salt, whereas a retarding effect was noticed for the permeation of BZ base. The enhancement potency for the BZ mesylate permeation increased linearly with the carbon number of the branched alcohols present in the binary mixtures. A tBtOH-IPM (2:8) combination produced the highest BZ flux from the mesylate salt, i.e. , 2016 mg per cm(2) h(-1), which was 100-fold greater than from water and 44-540-fold greater than the individual neat solvents, respectively. The observed permeation enhancement of BZ mesylate by the alkanol-IPM mixtures was probably as a result of a combination of decreasing barrier ability of the stratum corneum by the binary vehicles and moderately partitioning BZ mesylate through the viable epidermis/dermis.     

Effect of chemical interactions in pentachlorophenol mixtures on skin and membrane transport.

Pentachlorophenol (PCP) has been widely used as a pesticide, and topical exposure to a chemical mixture can alter its dermal absorption. The purpose of this study was to evaluate the influence of single and binary solvent systems (ethanol, EtOH, and water), a surfactant (6% sodium lauryl sulfate, SLS), and a rubifacient/vasodilator (1.28% methyl nicotinate, MNA) on PCP membrane transport, and to correlate these effects with physiochemical characteristics of the PCP mixtures. Partitioning, diffusion, and absorption parameters of (14)C-PCP at low (4 microg/cm(2)) and high (40 microg/cm(2)) doses were assessed in porcine skin and silastic membranes in vitro. In these 8-h, flow-through diffusion studies, PCP was dosed with the following vehicles: 100% EtOH, 100% water, 40% EtOH + 60% water, 40% EtOH + 60% water + SLS, 40% EtOH + 60% water + MNA, and 40% EtOH + 60% water + SLS + MNA. PCP absorption ranged from 1.55-15.62% for the high dose and 0.43-7.20% for the low dose. PCP absorption, flux, and apparent permeability were influenced by PCP solubility, and PCP apparent permeability was correlated with log PC (r2 = 0.66). Although PCP was very soluble in pure ethanol (100%), this vehicle evaporated very rapidly, and PCP absorption in ethanol was the lowest with this vehicle when compared to pure water (100%) or aqueous ethanol mixtures in general. MNA had no significant effect on membrane absorption or relative permeability R(P) in aqueous ethanol solutions, but the presence of the surfactant, SLS, significantly reduced PCP absorption and R(P) in both membrane systems. In conclusion, these studies demonstrated that modification in mixture composition with either a solvent and/or a surfactant can influence PCP diffusion in skin. Physicochemical interactions between these mixture components on the skin surface and stratum corneum contributed significantly to PCP transport, and these interactions were identified by simultaneously assessing chemical diffusion in biological and inert membrane systems.     

Oxide terpenes as human skin penetration enhancers of haloperidol from ethanol and propylene glycol and their modes of action on stratum corneum

In this study, two terpenes with the same functional group; limonene oxide and pinene oxide were used at 5% w/v concentration in 50% v/v ethanol and 100% v/v propylene glycol (PG) to enhance the in vitro permeation of haloperidol (HP) through the human epidermis (or stratum corneum, SC). The enhancement mechanism of terpenes from both solvents was elucidated with HP-SC binding studies, Fourier transform infrared spectroscopy and differential scanning calorimetry. The enhancement activity of these terpenes was higher in 50% v/v ethanol than in 100% v/v PG. These terpenes in 50% v/v ethanol were predicted to provide the required therapeutic plasma concentration and daily-permeated amounts of the drug. Limonene oxide showed higher enhancement in both solvents, which was attributed to its less bulky structure. The terpenes in both solvents did not increase the partition of HP. Instrumental studies showed that these terpenes in 50% v/v ethanol extracted the SC lipids, disrupted the bilayer packing and partially fluidised the lipids. Limonene oxide in 100% v/v PG possibly disrupted the lipid bilayer, whilst leaving the overall bilayer structure intact and pinene oxide in the same vehicle fluidised the lipids within the ordered environment. This study showed that the mode of interactions of terpenes with SC were different in two solvent systems.     

Transdermal iontophoresis of insulin: IV. Influence of chemical enhancers

Transdermal iontophoresis per se may not be able to achieve significant permeation of large peptides like insulin, thereby necessitating the use of combination strategies involving chemical enhancers and iontophoresis. The study investigated effect of pre-treatment with commonly used vehicles such as ethanol (EtOH), propylene glycol (PG), water and their binary combinations, dimethyl acetamide (DMA), 10% dimethyl acetamide in water, ethyl acetate (EtAc) and isopropyl myristate (IPM) on insulin iontophoresis. Solvents, which acted on the lipid bilayer, were able to produce a synergistic enhancement with iontophoresis. The binary solvent systems produced either additive or no effect, when combined with iontophoresis. FT-IR studies showed that EtOH, DMA, EtAc caused lipid extraction and the former two also caused changes in skin proteins, whereas IPM caused increase in lipid fluidity. TGA studies showed that EtOH and PG caused dehydration of skin. Skin barrier property was severely compromised with DMA, followed by EtOH and EtAc, while IPM and PG had relatively minimum skin barrier altering potential. Thus, this study demonstrates the possibility of achieving higher permeation of large peptides like insulin by combining iontophoresis with chemical enhancers that act on the intercellular lipids.     

Permeation enhancement of ketoprofen using a supersaturated system with antinucleant polymers

Permeation enhancement of ketoprofen (KP) from supersaturated systems and the effects of antinucleant polymers on both stability and permeation of supersaturated KP were investigated using silicone membrane as a skin model. The supersaturation was prepared by the cosolvent technique with water and propylene glycol (PG). Saturated solubility of KP in water/PG cosolvent increased markedly with an increase in PG percentage. The time-profiles of the cumulative amount of released KP from supersaturated solutions through the membrane increased linearly, and this KP flux had a significant correlation with the degree of saturation (DS) in 80 : 20, 60 : 40, 50 : 50, and 40 : 60 (v/v) water/PG cosolvent systems. The influence of 1% solutions of antinucleant polymers, hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), and sodium carboxymethylcellulose (SCMC) on the DS and the stability of supersaturated KP was examined in 60 : 40 (v/v) water/PG cosolvent. The remaining DS for 24 h after mixing the solvents increased in the presence of HPMC and SCMC but not PVP. In the presence of SCMC, the physical stability of supersaturated KP was higher, however, the KP flux was lower than that in the control and in the presence of the other polymers. In conclusion, the supersaturation system can be applied to achieve higher transmembrane permeation of KP, and appropriate antinucleant polymers such as HPMC can optimize the physical stability and permeability of KP.     

Cosolvency of Dimethyl Isosorbide for Steroid Solubility

Dimethyl isosorbide (DMI), which is currently under investigation for its potential use as a pharmaceutical vehicle and drug permeation enhancer, is a water-miscible liquid with relatively low viscosity. The solubilization behavior of DMI as a cosolvent for nonpolar drugs was characterized via dielectric constant measurements of binary solvent systems containing DMI and either water, propylene glycol (PG), or polyethylene glycol (PEG). Evidence from the dielectric constant profiles and NMR studies suggest that DMI undergoes complexation with water and PG, but not with PEG, through hydrogen bonding interactions. The solvent complexation exhibited a major effect on the solubilities of prednisone, dexamethasone, and prednisolone in the mixed solvent systems. Maximum solubility of each drug was found to occur near a DMI/water or DMI/PG concentration ratio of 1:2. In the DMI–PEG mixed system, while there is no apparent interaction between DMI and PEG molecules, the solubility of prednisone was found to increase with decreasing dielectric constant.     

Effect of propylene glycol on ibuprofen absorption into human skin in vivo

The objective was to assess the impact of propylene glycol (PG), a common cosolvent in topical formulations, on the penetration of ibuprofen into human skin in vivo. Drug uptake into the stratum corneum (SC), following application of saturated formulations containing from 0 to 100% v/v PG, was assessed by tape-stripping. Dermatopharmacokinetic parameters, characterizing drug amount in and diffusivity through the SC, were derived. The solubility behavior of ibuprofen in PG-water mixtures was carefully evaluated, as were a number of other physical properties. Ibuprofen delivery depended on the level of PG in the vehicle, despite all formulations containing the drug at equal thermodynamic activity. PG appeared to alter the solubility of ibuprofen in the SC (presumably via its own uptake into the membrane), the effect becoming more important as the volume fraction of cosolvent in the formulation increased. In summary, tape-stripping experiments, with careful interpretation, can reveal details of a drug's bioavailability in the skin following topical application and may be used to probe the mechanism(s) by which certain excipients influence local drug delivery.