-
Advanced Drug Delivery Reviews Feb 2013It is now widely accepted that vehicle and formulation components influence the rate and extent of passive chemical absorption through skin. Significant progress, over... (Review)
Review
It is now widely accepted that vehicle and formulation components influence the rate and extent of passive chemical absorption through skin. Significant progress, over the last decades, has been made in predicting dermal absorption from a single vehicle; however the effect of a complex, realistic mixture has not received its due attention. Recent studies have aimed to bridge this gap by extending the use of quantitative structure-permeation relationship (QSPR) models based on linear free energy relationships (LFER) to predict dermal absorption from complex mixtures with the inclusion of significant molecular descriptors such as a mixture factor that accounts for the physicochemical properties of the vehicle/mixture components. These models have been compiled and statistically validated using the data generated from in vitro or ex vivo experimental techniques. This review highlights the progress made in predicting skin permeability from complex vehicles.
Topics: Animals; Drug Delivery Systems; Humans; Linear Energy Transfer; Models, Theoretical; Permeability; Pharmaceutical Preparations; Pharmaceutical Vehicles; Quantitative Structure-Activity Relationship; Skin; Skin Absorption
PubMed: 22342772
DOI: 10.1016/j.addr.2012.01.019 -
Journal of Pharmaceutical Sciences Feb 1990A novel method to differentiate basic vehicle models for topically applied drugs is proposed. In this method, the rate of drug release as a function of time, obtained by...
A novel method to differentiate basic vehicle models for topically applied drugs is proposed. In this method, the rate of drug release as a function of time, obtained by using a flow-through cell, is plotted on both semilogarithmic and logarithmic scales. In the Solution Case, where all of the drug is dissolved in the vehicle, the profiles become linear on the semilogarithmic scale. However, in the Suspension Case, where the initial drug amount per vehicle volume is greater than the solubility of the drug and the vehicle contains finely dispersed drug, the profiles are linear on the logarithmic scale with a slope of -0.5. They abruptly depart from this pattern upon depletion of the suspended phase. The different attributes of the profiles for the drug release rate-time curves in these two cases can be visualized more clearly when vehicle thickness and drug concentration are varied. The theoretical principles are illustrated in profiles for the drug release-rate time plots of therapeutic patches containing the beta blocker timolol. This was formulated at different concentrations in an acryl copolymer with varied thickness. The release profiles were best fitted to the Solution Case treatment of the data.
Topics: Administration, Topical; Delayed-Action Preparations; Diffusion; Half-Life; Membranes, Artificial; Models, Biological; Ointments; Pharmaceutical Vehicles; Polymers; Timolol
PubMed: 2324968
DOI: 10.1002/jps.2600790220 -
International Journal of Cosmetic... Dec 2012Previous work from this group has focused on the molecular mechanism of alcohol interaction with model membranes, by conducting thermodynamic and kinetic analyses of...
Previous work from this group has focused on the molecular mechanism of alcohol interaction with model membranes, by conducting thermodynamic and kinetic analyses of alcohol uptake, membrane partitioning and transport studies of a model compound (i.e. methyl paraben) in silicone membranes. In this article, similar membrane transport and partitioning studies were conducted in silicone membranes to further extend the proposed model of alcohol interactions with silicone membranes to include other vehicles more commonly used in dermal formulations, that is, isopropyl myristate (IPM), dimethyl isosorbide (DMI), polyethylene glycol (PEG) 200, PEG 400 and Transcutol P® (TC). More importantly, membrane partitioning studies were conducted using human SC to evaluate the application of the proposed model of solvent-enhanced permeation in simple model membranes for the more complex biological tissue. The findings support a model of vehicle interactions with model membranes and skin where high solvent uptake promotes drug partitioning (i.e. K) by enabling the solute to exist within the solvent fraction/solvent-rich areas inside the membrane or skin in a concentration equivalent to that in the bulk solvent/vehicle. High solvent sorption may also ultimately impact on the membrane diffusional characteristics, and thus the diffusion coefficient of the solute across the membrane. The implications for skin transport are that increased partitioning of a drug into the SC may be achieved by (i) selecting vehicles that are highly taken up by the skin and also (ii) by having a relatively high concentration (i.e. molar fraction) of the drug in the vehicle. It follows that, in cases where significant co-transport of the solvent into and across the skin may occur, its depletion from the formulation and ultimately from the skin may lead to drug crystallization, thus affecting dermal absorption.
Topics: Chromatography, High Pressure Liquid; Gas Chromatography-Mass Spectrometry; Humans; Membranes, Artificial; Parabens; Pharmaceutical Vehicles; Silicones; Skin Absorption
PubMed: 22928552
DOI: 10.1111/j.1468-2494.2012.00753.x -
Journal of Pharmaceutical Sciences Apr 1992The fluxes of representative hydrophilic (propranolol hydrochloride) and lipophilic (diazepam or indomethacin) drugs, administered as ethanolic solutions containing...
The fluxes of representative hydrophilic (propranolol hydrochloride) and lipophilic (diazepam or indomethacin) drugs, administered as ethanolic solutions containing putative penetration enhancers (n-nonane, 1-nonanol, and 1-decanol), were measured across hairless mouse skin in vitro. Propranolol transport was augmented significantly by the presence of 4% (v/v) alkane or alkanol in the vehicle; diazepam and indomethacin, on the other hand, were enhanced only by n-nonane. Experiments with saturated solutions of the drugs as the donor phase revealed that the actions of the enhancers were taking place in the skin and were not a result of an alteration of solute thermodynamic activity in the vehicle. In separate runs, the impact of n-nonane and 1-nonanol on the percutaneous penetration of ethanol was determined. Temporal effects identical to those on the flux of propranolol were observed. A further measurement revealed that the penetration of 1-decanol, when administered as a 4% (v/v) solution in ethanol, followed a profile similar to that of the solvent (which, in turn, was comparable with that of the independently assessed propranolol hydrochloride). Thus, considerable linkage exists between the transport of a hydrophilic drug and the major vehicle component in the presence of n-nonane and 1-nonanol. The lipophilic drugs, conversely, were promoted only by n-nonane and only after most of the ethanol had been absorbed. The results show that an apparent synergy of transport between a putative enhancer and a cosolvent may not always lead to augmented drug flux. Study of the transport of all key formulation components is recommended, therefore, to optimize vehicles for transdermal drug delivery.
Topics: Alkanes; Animals; Chemistry, Pharmaceutical; Diazepam; Drug Synergism; Ethanol; Fatty Alcohols; In Vitro Techniques; Mice; Pharmaceutical Vehicles; Propranolol; Skin Absorption; Tritium
PubMed: 1501066
DOI: 10.1002/jps.2600810406 -
Journal of Pharmaceutical Sciences May 1988Solid dispersions of a poorly water-soluble drug [REV 5901; alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; 1] in an amphiphilic vehicle [Gelucire 44/14; 2] and in...
Solid dispersions of a poorly water-soluble drug [REV 5901; alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; 1] in an amphiphilic vehicle [Gelucire 44/14; 2] and in polyethylene glycol (PEG) 1000, PEG 1450, and PEG 8000 were prepared. The vehicle 2 was a mixture of hydrogenated fatty acid esters with a mp of 44 degrees C, and had a HLB value of 14. Compound 1 was dissolved or dispersed in molten vehicles at elevated temperatures. The pulverization and compression of solid dispersions were avoided by encapsulating the hot solutions directly into hard gelatin capsules. At room temperature, the dispersions solidified forming plugs inside the capsules. On storage, greater than 180 mg of 1 remained dissolved per gram of vehicle, while the excess drug formed fine crystals (less than 20 micron). When mixed with water, the dissolved drug separated as a metastable liquid. Due to the surfactant property of 2, the oily form of 1 that separated from this vehicle formed an emulsified system with a globular size of less than 1 micron, while greater than 80% of 1 that separated from the other three formulations coalesced to form large oily masses. As a result of the large difference in surface area, the dissolution rate of 1 in simulated gastric fluid from capsules containing 2 was much higher than that of a PEG-based formulation. The bioavailability (AUC) of 1 in dogs from capsules containing 2 was also higher than that from PEG 1000-based capsules.
Topics: Administration, Oral; Animals; Biological Availability; Capsules; Chemical Phenomena; Chemistry, Physical; Dogs; Hydroxyquinolines; Male; Particle Size; Pharmaceutical Vehicles; Polyethylene Glycols; Quinolines; Solubility
PubMed: 3411464
DOI: 10.1002/jps.2600770512 -
Dermatology (Basel, Switzerland) 2005Topical treatment of the skin is as old as the evolution of man. Instinctively, we try to treat a skin injury or irritation with cooling or soothing substances. Even... (Review)
Review
Topical treatment of the skin is as old as the evolution of man. Instinctively, we try to treat a skin injury or irritation with cooling or soothing substances. Even animals lick their wounds, trusting instinctively in the healing power of saliva. When did this archaic pattern of treatment take the gigantic leap from folk medicine to modern drug therapy? This text illustrates the evolution of topical dermatological vehicles, their application (guidelines) and future use. In particular, a phenomenon that has so far been ignored in product development and clinical testing is the vehicle metamorphosis. In clinical and experimental situations, most dermatological vehicles undergo considerable changes after they have been removed from the primary container and are applied to the skin. Subsequently, the initial structural matrix, and the quantitative composition of the vehicle, will most likely change during and after the mechanical shear associated with application of the product and/or evaporation of ingredients. This natural, but highly dynamic process will generate mini-environments for the active moiety that are difficult to predict and that are crucial to the fate of the active moiety. Despite the reasonable wishes of formulators, clinicians, patients and customers, there are still no universal vehicles. Each drug, at each concentration, requires a different vehicle for optimized therapy. Stability and compatibility of excipients and active moiety are crucial for any commercially available pharmaceutical or cosmetic formulation, together with local and systemic safety of all components. Nonetheless, more diverse and molecularly complex classes of new dermatological vehicles are continuously being researched and refined. The scientific progress has been remarkable when one considers the simple emulsion mixtures that were commonplace in dermatological therapy and still persist to this day in commercial products. It is to be hoped that the result of these research endeavors will be the emergence of more innovative topical formulations, applying engineered bioavailability control systems, with broader applications in topical therapeutic and cosmetic vehicles.
Topics: Administration, Cutaneous; Dermatologic Agents; Humans; Pharmaceutical Vehicles; Skin Diseases
PubMed: 15724099
DOI: 10.1159/000082572 -
Journal of Drugs in Dermatology : JDD Feb 2019Topical delivery of therapeutic agents for skin diseases is a major advantage in dermatology. However, the efficacy and tolerability of topically applied therapies is... (Review)
Review
The Clinical Relevance and Therapeutic Benefit of Established Active Ingredients Incorporated into Advanced Foam Vehicles: Vehicle Characteristics Can Influence and Improve Patient Outcomes.
Topical delivery of therapeutic agents for skin diseases is a major advantage in dermatology. However, the efficacy and tolerability of topically applied therapies is dependent on several characteristics, including percutaneous penetration and permeation of active ingredient and lack of side effects, especially local tolerability reactions. Importantly, the ultimate performance of a topical product includes collectively the effects of the active ingredient and the impact that specific additives have on vehicle characteristics, such as penetration, permeation, epidermal barrier properties, relative irritancy, allergenicity potential, and patient acceptance/preference of the vehicle formulation used. Foam vehicles have evolved over time with the emergence of a menu of alcohol-based and aqueous-based variations that provide various advantages depending on clinical circumstances and the disease being treated. Aqueous-based foams have gained widespread acceptance and preference, especially due to favorable skin tolerability and the cosmetic elegance of the products. In this manuscript, data are presented supporting the efficacy, tolerability, and safety, of specific aqueous-based foam vehicles for calcipotriene used to treat plaque psoriasis, and for tazarotene used to treat acne vulgaris. Discussions include both vehicle-based properties that are relevant to clinical practice, and outcomes from the large-scale pivotal clinical trials that review efficacy and safety results and patient reported outcomes. The latter also discusses several practical subject assessments about use of the foam vehicle. J Drugs Dermatol. 2019;18(2 Suppl):s100-107.
Topics: Administration, Cutaneous; Dermatologic Agents; Drug Delivery Systems; Drug Liberation; Humans; Pharmaceutical Vehicles; Skin Absorption; Skin Diseases; Treatment Outcome; Water
PubMed: 30811153
DOI: No ID Found -
Lasers in Medical Science Apr 2017Ablative fractional laser (AFXL) is an emerging method that enhances topical drug delivery. Penetrating the skin in microscopic, vertical channels, termed microscopic...
Ablative fractional laser (AFXL) is an emerging method that enhances topical drug delivery. Penetrating the skin in microscopic, vertical channels, termed microscopic treatment zones (MTZs), the fractional technique circumvents the skin barrier and allows increased uptake of topically applied drugs. This study aims to elucidate the impact of vehicle type on the filling of MTZs from application of liquid, gel, and cream vehicles. Ex vivo pig skin was exposed to 10,600 nm fractional CO laser at 5% density, 120 μm beam diameter, and fluences of 40 and 80 mJ/microbeam (mJ/mb). Six repetitions were performed for each of six interventions (2 fluences and 3 vehicle types, n = 36). MTZ dimensions and filling by vehicle type were evaluated by optical coherence tomography, using blue tissue dye as a contrast-enhancing agent. Outcome measure was degree of MTZ filling assessed as percentages of empty, partially filled, and completely filled MTZs (108-127 MTZs/intervention analyzed) and evaluated statistically using Kruskal-Wallis and Dunn's tests. MTZs reached mid-dermal levels of 225 μm (40 mJ/mb) and 375 μm (80 mJ/mb) penetration depths (p < 0.0001). Filling of MTZs depended on type of applied vehicle. At 80 mJ/mb, liquid (67% completely filled, p < 0.01) and gel (60%, p < 0.05) formulations filled MTZs significantly better than cream formulation (31%). At 40 mJ/mb, liquid and gel formulations filled 90% (p < 0.05) and 77% (p > 0.05) of MTZs completely versus 55% for cream formulation. Thus, filling was overall greater for more superficial MTZs. In conclusion, vehicle type affects filling of MTZs, which may be of importance for AFXL-assisted drug delivery.
Topics: Administration, Cutaneous; Animals; Drug Carriers; Humans; Image Processing, Computer-Assisted; Laser Therapy; Lasers, Gas; Skin; Sus scrofa; Tomography, Optical Coherence
PubMed: 28213875
DOI: 10.1007/s10103-017-2168-z -
International Journal of Pharmaceutics Jan 2007The low density lipoprotein (LDL) receptor has been shown to be upregulated in GBM tumor cells and is therefore a potential molecular target for the delivery of...
The low density lipoprotein (LDL) receptor has been shown to be upregulated in GBM tumor cells and is therefore a potential molecular target for the delivery of therapeutic agents. A synthetic nano-LDL (nLDL) particle was developed and tested to determine its utility as a drug delivery vehicle targeted to GBM tumors. nLDL particles were constructed by combining a synthetic peptide containing a lipid binding motif and the LDL receptor (LDLR) binding domain of apolipoprotein B-100 with a lipid emulsion consisting of phosphatidyl choline, triolein, and cholesteryl oleate. Composition analysis, fast protein liquid chromatography, and electron microscopy revealed that nLDL was highly reproducible and intermediate in size between high density lipoprotein and LDL particles (10.5+/-2.8 nm diameter). The binding and uptake of fluorescently labeled nLDL particles was assessed using fluorescence microscopy. Uptake of nLDL was time dependent, exhibiting saturation at approximately 3 h, and concentration dependent, exhibiting saturation at concentrations greater than 5 microM peptide. Using Lysotracker as a cellular marker, nLDL co-localized with lysosomes. nLDL binding was eliminated by blocking LDLRs with suramin and nLDL inhibited binding of plasma LDL to LDLRs. Collectively these data strongly suggest that the synthetic nano-LDLs described here are taken up by LDLR and can serve as a drug delivery vehicle for targeting GBM tumors via the LDLR.
Topics: Amino Acids; Brain Neoplasms; Cell Line, Tumor; Drug Delivery Systems; Emulsions; Fluorescent Dyes; Glioblastoma; Humans; Lipoproteins, LDL; Microscopy, Confocal; Microscopy, Fluorescence; Nanoparticles; Particle Size; Peptides; Pharmaceutical Vehicles; Protein Binding; Temperature
PubMed: 16959446
DOI: 10.1016/j.ijpharm.2006.07.046 -
The Journal of Investigative Dermatology Aug 1986The solubilities of theophylline in, and fluxes through skin from, isopropyl myristate, octanol, dimethylformamide, propylene glycol, ethylene glycol, and formamide have...
The solubilities of theophylline in, and fluxes through skin from, isopropyl myristate, octanol, dimethylformamide, propylene glycol, ethylene glycol, and formamide have been determined experimentally. Values for experimental permeability coefficients (Kp) corresponding to the respective fluxes were determined from, flux/solubility = Kp, which were then compared with values for the respective theoretical partition coefficients (PC) calculated from the known solubility parameters for the vehicles (delta v), theophylline (delta i) and skin (delta s). There was a good correlation for theoretical log PC - 2.52 = experimental log Kp for vehicles exhibiting solubility parameters in the range of delta v = 12-18 (cal/cm3)1/2. This allows relative fluxes to be determined from calculated theoretical partition coefficients and experimentally determined solubilities in that range. For vehicles or mixtures of vehicles exhibiting solubility parameters in the range of delta v = 8-12 (cal/cm3)1/2 large increases in fluxes and permeability coefficients, compared with those predicted from the results in the delta v = 12-18 (cal/cm3)1/2 range, were observed because of vehicle effects on the skin caused by the similarity in solubility parameters of those vehicles to that of skin. Qualitatively, fluxes and permeability coefficients were found to be inversely dependent on drug solubility in the vehicles with a minimum that corresponded approximately to the point where delta i = delta v.
Topics: Administration, Topical; Animals; Chemical Phenomena; Chemistry, Physical; Diffusion; Female; Mathematics; Mice; Mice, Hairless; Models, Biological; Pharmaceutical Vehicles; Skin Absorption; Solubility; Theophylline
PubMed: 3734472
DOI: 10.1111/1523-1747.ep12696635