Repeated applications of a transdermal patch: analytical solution and optimal control of the delivery rate

The integral transform technique was implemented to solve a mathematical model developed for percutaneous drug absorption. The model included repeated application and removal of a patch from the skin. Fick's second law of diffusion was used to study the transport of a medicinal agent through the vehicle and subsequent penetration into the stratum corneum. Eigenmodes and eigenvalues were computed and introduced into an inversion formula to estimate the delivery rate and the amount of drug in the vehicle and the skin. A dynamic programming algorithm calculated the optimal doses necessary to achieve a desired transdermal flux. The analytical method predicted profiles that were in close agreement with published numerical solutions and provided an automated strategy to perform therapeutic drug monitoring and control.     

A two-dimensional mathematical model of non-linear dual-sorption of percutaneous drug absorption

Background  

Certain drugs, for example scopolamine and timolol, show non-linear kinetic behavior during permeation process. This non-linear kinetic behavior is due to two mechanisms; the first mechanism being a simple dissolution producing mobile and freely diffusible molecules and the second being an adsorption process producing non-mobile molecules that do not participate in the diffusion process. When such a drug is applied on the skin surface, the concentration of the drug accumulated in the skin and the amount of the drug eliminated into the blood vessel depend on the value of a parameter, C, the donor concentration. The present paper studies the effect of the parameter value, C, when the region of the contact of the skin with drug, is a line segment on the skin surface. To confirm that dual-sorption process gives an explanation to non-linear kinetic behavior, the characteristic features that are used in one-dimensional models are (1) prolongation of half-life if the plot of flux versus time are straight lines soon after the vehicle removal, (2) the decrease in half-life with increase in donor concentration. This paper introduces another feature as a characteristic to confirm that dual-sorption model gives an explanation to the non-linear kinetic behavior of the drug. This new feature is "the prolongation of half-life is not a necessary feature if the plots of drug flux versus time is a non-linear curve, soon after the vehicle removal".     

Transpapillary Drug Delivery to the Breast

The study was aimed at investigating localized topical drug delivery to the breast via mammary papilla (nipple). 5-fluorouracil (5-FU) and estradiol (EST) were used as model hydrophilic and hydrophobic compounds respectively. Porcine and human nipple were used for in-vitro penetration studies. The removal of keratin plug enhanced the drug transport through the nipple. The drug penetration was significantly higher through the nipple compared to breast skin. The drug’s lipophilicity had a significant influence on drug penetration through nipple. The ducts in the nipple served as a major transport pathway to the underlying breast tissue. Results showed that porcine nipple could be a potential model for human nipple. The topical application of 5-FU on the rat nipple resulted in high drug concentration in the breast and minimal drug levels in plasma and other organs. Overall, the findings from this study demonstrate the feasibility of localized drug delivery to the breast through nipple.     

Low-frequency sonophoresis: a noninvasive method of drug delivery and diagnostics

Transdermal drug delivery offers an attractive alternative to injections and oral medications. However, applications of transdermal drug delivery are limited to only a few drugs as a result of low skin permeability. Application of low-frequency ultrasound enhances skin permeability, a phenomenon referred to as low-frequency sonophoresis. In this method, a short application of ultrasound is used to permeabilize skin for a prolonged period of time. During this period, ultrasonically permeabilized skin may be utilized for drug delivery. In addition, a sample of interstitial fluid or its components may be extracted through permeabilized skin for diagnostic applications. In this paper, we report our in vivo studies that demonstrate the principles of both of these concepts. Detailed studies on drug delivery are performed using inulin and mannitol as model drugs. Studies on diagnostics are performed using glucose as a model analyte. Applications of this technology to drug delivery and diagnostics are discussed.     

A Drug-in-Adhesive Matrix Based on Thermoplastic Elastomer: Evaluation of Percutaneous Absorption, Adhesion, and Skin Irritation

A novel drug-in-adhesive matrix was designed and prepared. A thermoplastic elastomer, styrene–isoprene–styrene (SIS) block copolymer, in combination with tackifying resin and plasticizer, was employed to compose the matrix. Capsaicin was selected as the model drug. The drug percutaneous absorption, adhesion properties, and skin irritation were investigated. The results suggested that the diffusion through SIS matrix was the rate-limiting step of capsaicin percutaneous absorption. [SI] content in SIS and SIS proportions put important effects on drug penetration and adhesion properties. The chemical enhancers had strong interactions with the matrix and gave small effect on enhancement of drug skin permeation. The in vivo absorption of samples showed low drug plasma peaks and a steady and constant plasma level for a long period. These results suggested that the possible side effects of drug were attenuated, and the pharmacological effects were enhanced with an extended therapeutic period after application of SIS matrix. The significant differences in pharmacokinetic parameters produced by different formulations demonstrated the influences of SIS copolymer on drug penetrability. Furthermore, the result of skin toxicity test showed that no skin irritation occurred in guinea pig skin after transdermal administration of formulations.Key words: adhesion, in vivo absorption, skin irritation, thermoplastic elastomer, transdermal drug delivery     

Fluorometric documentation of increased cutaneous blood flow after topical application of a PGE2 analog in man

The present study employed fiberoptic fluorometry, a noninvasive means of documenting delivery and removal of fluorescein dye, to evaluate the local circulatory changes elicited by topical application of DHV-PGE2 ME, an investigational PGE2 analog. On Day 1, inactive vehicle was applied to a 5 X 4 cm study site on each thigh of healthy volunteer subjects (n = 12). Symmetrical perfusion was confirmed by similar determinations of dye delivery and removal at each site. On Day 2, DHV-PGE2 ME, 30 or 120 micrograms, was applied to one site while inactive vehicle again was applied to the other. After administration of 120 micrograms in a petrolatum vehicle, fluorometry detected a pronounced increase in nutritive perfusion. There was significant acceleration of dye delivery and removal (p less than 0.05 by ANOVA). Less pronounced changes were noted after the lower dose of DHV-PGE2 ME and when the drug was applied in a triethyl citrate vehicle. The local circulatory changes were not accompanied by systemic effects; there were no changes in vital signs or in fluorometric indices at remote sites.     

Influence of vehicle resistance on transdermal iontophoretic delivery of acetylcholine and sodium nitroprusside in humans.

Iontophoresis is a valuable method of noninvasive drug delivery for assessment of skin microvascular function, but it is important to consider and minimize its potential nonspecific electrical effects on blood flow. The use of sodium chloride (NaCl) instead of water as the iontophoresis vehicle has been reported to reduce these effects because it has a lower electrical resistance. However, this argument may not be valid when an agonist is added to the vehicle because its resistance will be changed. The aim of our study was to determine whether there is a difference in resistance between water and NaCl when used as vehicles for iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP). Four cumulative doses of each drug, dissolved in either water or NaCl, were delivered via iontophoresis to the forearm skin of 14 healthy volunteers. We measured the resulting blood flow responses by using laser-Doppler imaging and the voltage across the electrodes for each delivery as an index of resistance. For ACh and SNP, there were no significant differences between the voltages measured when either water or NaCl was used as the vehicle. However, the blood flow responses to both agonists were significantly lower with NaCl (ACh: 25% lower, P < 0.001; SNP: 15% lower, P = 0.019). The use of NaCl is therefore unlikely to decrease any nonspecific electrical effects, and it may in fact reduce the effective dose of drug delivered. Deionized water is a better iontophoresis vehicle for the assessment of microvascular function in skin when using ACh and SNP.     

The Effect of Nanoemulsion as a Carrier of Hydrophilic Compound for Transdermal Delivery

The purpose of the present study was to investigate the effect of nanoemulsions as a carrier vehicle of hydrophilic drug for transdermal delivery. The response surface methodology with a mixture design was used to evaluate the effect of ingredient levels of nanoemulsion formulations including cosurfactant (isopropyl alcohol, 20∼30%), surfactant (mixed of Brij 30 and Brij 35, 20∼30%), and distilled-water (34.5∼50.0%) on properties of the drug-loaded nanoemulsions including physicochemical characters and drug permeability through rat skin. The result showed that the hydrophilic drug in aqueous solution with or without penetration enhancer could not transport across rat skin after 12 h of application. Used nanoemulsions as carrier vehicle, the permeation rate of drug was significantly increased from 0 to 63.23 µg/cm²/h and the lag time was shortened from more than 12 h to about 2.7∼4.0 h. Moreover, the drug-loaded nanoemulsion formulation also showed physicochemical stability after 3 month storage at 25°C and 40°C.     

Physical Characterization of a New Skin Bioadhesive Film

Physical properties (roughness, gloss, mechanical, surface topography and adhesive) of a bioadhesive film for the transdermal delivery of drugs and its interactions with a skin model surface were studied. Roughness is a measurement of the small-scale variations in the height of a physical surface. No significant differences in Ra between the “x” and “y” dimensions for both the skin model and patch were detected, due to uniformity in their production. Scanning electron microscope pictures showed small particles projected from the film. Those particles resulted in increasing roughness and surface area. For the patch, gloss values measured at 20° were 6.0 ± 0.9 and at 60°, 32.2 ± 2.2 gloss units, respectively, indicating a semi-gloss material. Concerning the mechanical properties, the tensile strength of the film resulted four- to sevenfold greater than the peel force from the model skin used, indicating the suitability of the film for skin application. The adhesion to skin model depended on the amount of water used for film application and on the elapsed time between film application and removal. Finally, the model skin that was invented by Charkoudian can be used as an alternative to costly and highly variable human skin substrates since it possesses human topography.     

Fluorometric documentation of increased cutaneous blood flow after topical application of a PGE2 analog in man

The present study employed fiberoptic fluorometry, a noninvasive means of documenting delivery and removal of fluorescein dye, to evaluate the local circulatory changes elicited by topical application of DHV-PGE₂ ME, an investigational PGE₂ analog. On Day 1, inactive vehicle was applied to a 5 × 4 cm study site on each thigh of healthy volunteer subjects (n=12). Symmetrical perfusion was confirmed by similar determinations of dye delivery and removal at each site. On Day 2, DHV-PGE₂ ME, 30 or 120 micrograms, was applied to one site while inactive vehicle again was applied to the other. After administration of 120 micrograms in a petrolatum vehicle, fluorometry detected a pronounced increase in nutritive perfusion. There was significant acceleration of dye delivery and removal (p < 0.05 by ANOVA). Less pronounced changes were noted after the lower dose of DHV-PGE₂ ME and when the drug was applied in a triethyl citrate vehicle. The local circulatory changes were not accompanied by systemic effects; there were no changes in vital signs or in fluorometric indices at remote sites.     

Anti-biofilm properties of a mupirocin spray formulation against Escherichia coli wound infections

Mupirocin ointment is a widely used topical drug for the treatment of bacterial skin infections. However, ointments have some limitations which motivated the development of a film forming spray of mupirocin. Mupirocin spray (2%) was formulated with Eudragit E100 as a film forming agent and tested for its antibacterial and anti-biofilm activities against Escherichia coli, a skin pathogen causing wound and surgical site infections. Treatment with mupirocin spray resulted in significant antibacterial and anti-biofilm activities (inhibition and disruption) with single spray and sub-actual dose concentrations at par with the commercial ointment concentration. The spray formulation was found to be non-toxic to fibroblast cells and greatly resisted removal from the site of application upon washing, in contrast to the ointment which was significantly removed after a single wash. This is the first study to develop and evaluate a spray formulation for mupirocin that forms a stable thin film for sustained release of the drug.     

Inhibitory effect of toluene on tumor promotion in mouse skin

In the two-stage mouse model for skin tumorigenesis with phorbol-12-myristate-13-acetate (PMA) as promoter, topical application of 40 microliters of toluene 2X/week at the initiation/promotion site (the back) reduced the average number of tumors/mouse (ANT/M) to approximately one-fourth that of controls. Control procedure involved initiation of C3H mice with benzo[a]pyrene (BaP) and CD-1 mice with 7,12-dimethylbenz[a]anthracene (DMBA) followed by promotion with from 1 to 5 micrograms PMA in 40 microliters acetone 2X/week. Forty microliters of toluene 2X/week per se was a weak promoter (6-13% of control ANT/M), and produced mild skin irritation at the application site but behavior and body weights were normal. The toluene inhibition of tumorigenesis was not a direct chemical action on PMA since similar effects occurred whether toluene was the vehicle for PMA or whether it was applied up to 1 day before PMA (i.e., prepromotion). Prepromotion with acetone had no effect on tumorigenesis, substantiating its use as control vehicle and suggesting that the toluene inhibition was a specific tissue reaction. The inhibitory effect appeared to be on PMA promotion rather than on initiation since toluene and acetone produced similar numbers of tumors when used as the vehicle for BaP or DMBA in two-stage or BaP in single-stage trials. The inhibition was not permanent since tumorigenesis returned to control rates 2-3 weeks after prepromotion with toluene ceased but promotion with PMA in acetone continued. Toluene may be unique among reported promotion inhibitors in that it is a widely used commercial chemical which sometimes serves as a vehicle in cancer-screening trials. Since its metabolism is reasonably well defined, it may be of value in exploring further the process of tumor promotion.     

Phosphatidyl choline-based colloidal systems for dermal and transdermal drug delivery

In this study we have prepared various phosphatidyl choline based colloidal systems, namely liposomes, transfersomes, microemulsions and micelles, using similar excipients and compared their ability to deliver drugs into and through the skin under occlusive and non-occlusive conditions. Hydrophilic propranolol hydrochloride (PHCl) and lipophilic propranolol base (PB) were used as model drugs. All tested parameters, that is formulation composition, drug characteristics and testing conditions, influenced skin permeability and skin retention. A trend was observed showing that the skin permeation as well as skin retention decreases with the amount of phosphatidyl choline in the formulations for both tested model drugs (micelles > transfersomes > liposomes > microemulsion). The lipophilic model drug had higher skin permeability especially when incorporated into the systems containing mainly hydrophilic excipients. Skin retention, however, was not affected by the drug hydrophilicity to the same extent as skin permeability. Occlusion increased both skin retention and skin permeation for both model drugs.     

Sustained Anti-inflammatory Effect of Resveratrol-Phospholipid Complex Embedded Polymeric Patch

Resveratrol-phospholipid complex (Phytosome®) (RSVP) was found better aqueous soluble and permeable than free resveratrol (RSV). RSVPs were incorporated in polymeric patch prepared by solvent casting method using Eudragit RL 100, PVP K30, and PEG 400 for application on dermal sites for sustained treating of inflammation. Prepared patches were evaluated for various physicochemical properties, surface morphology by SEM, TEM, and compatibility of patch components by FT-IR and DSC studies. Optimized formulation (F9) gave 95.79?±?3.02% drug release and 51.36% (4.28?±?0.48 mg/cm²) skin permeation after 24 h. Skin extract when examined for drug accumulation showed 38.31?±?2.42% drug content. FE-SEM images of the patch taken after drug release and skin permeation studies showed that RSVPs in polymeric patch are stable and retain their structure after 24 h long exposure to physiologic environment. Sustained anti-inflammatory effect was established in carrageenan-induced paw edema model in which test formulation gave 84.10% inhibition of inflammation at 24 h as compared to 39.58% for standard diclofenac sodium gel. The CLSM study confirmed the localization of RSVPs for a longer period, thus enabling drug targeting to the dermis for sustained effect. Skin irritation test on rabbit revealed that the patches are safe for skin application. Histological observations suggested that after exposure to the permeants, the SC integrity had not altered and no evidence of presence of inflammatory cells found. RSVP (Phytosome®) containing patches abled to give sustained therapeutic effect that may be useful in treating acute and chronic inflammation.     

The development of Cutina lipogels and gel microemulsion for topical administration of fluconazole

The influence of the vehicle on the release and permeation of fluconazole, a topical antifungal drug dissolved in Jojoba oil was evaluated. Series of Cutina lipogels (Cutina CPA [cetyl palmitate], CBS [mixture of glyceryl stearate, cetearyl alcohol, cetyl palmitate, and cocoglycerides], MD [glyceryl stearate], and GMS [glyceryl monostearate]) in different concentrations as well as gel microemulsion were prepared. In-vitro drug release in Sorensens citrate buffer (pH 5.5) and permeation through the excised skin of hairless mice, using a modified Franz diffusion cell, were performed. The rheological behavior and the apparent viscosity values for different gel bases were measured before and after storage under freezing conditions at −4 °C and were taken as measures for stability of network structure.Candida albicans was used as a model fungus to evaluate the antifungal activity of the best formula achieved. The results of in vitro drug release and its percutaneous absorption showed that the highest values from gel microemulsion were assured. The rheological behavior of the prepared systems showed pseudoplastic (shear-thinning) flow indicating structural breakdown of the existing intermolecular interactions between polymeric chains. Moreover, the stability study revealed no significant difference between viscosity before and after storage for different formulae except for CPA Cutina lipogel (using analysis of variance [ANOVA] test at level of significance .05). The antifungal activity of fluconazole showed the widest zone of inhibition with gel microemulsion. The gel microemulsion is an excellent vehicle for fluconazole topical drug delivery.     

Preparation,Characterization, and <Emphasis Type="Italic">In Vitro</Emphasis> Permeation Study of Terbinafine HCl in Poloxamer 407<Emphasis Type="Bold">-</Emphasis>Based Thermogelling Formulation for Topical Application

Upon topical administration, a high penetration rate of antifungal drug into the infected site is desirable to reduce treatment length and systemic side effects which occur especially after a prolonged peroral administration. Thermogelling formulations composed of poloxamer 407, medium chain triglycerides, isopropyl alcohol, dimethyl isosorbide, and water for topical application were developed, and a lipophilic drug terbinafine HCl (TBF) was incorporated. Previously, a remarkable high permeation rate of a hydrophilic drug 5-aminolevulinic acid from this vehicle was evident compared to different creams from German Pharmacopoeia. By varying the composition of vehicle constituents, a broad range of consistencies and appearances was obtained. Up to 4% TBF could be solubilized in the vehicle. TBF fluxes at steady state across human stratum corneum from these formulations were higher than those from the German Pharmacopoeia Basiscreme Deutscher Arzneimittel Codex and a marketed product at similar concentration of 1%. TBF fluxes increased along with a higher content of TBF in the formulation. The amount of TBF retained in stratum corneum was higher compared to those from both standards of comparison (p < 0.01). The thermodynamic activity of TBF in the thermogelling formulation was lower compared to those in other formulations. Therefore, the nature of the vehicle and its interaction with TBF are suggested to play a significant role in explaining higher fluxes along with higher TBF content. Differential scanning calorimetry measurements revealed comparable T2 and T3 endothermic shifts from all examined formulations suggesting equal influences to the skin lipids.     

Pinealectomy-induced elevation of collagen content in the intact skin is suppressed by melatonin application

The pineal gland is involved in wound repair and collagen deposition in sponge-induced granulomas. The aim of this investigation was to discover whether the pineal gland was able to regulate collagen accumulation in the intact skin. Wistar rats were divided into five groups: control, sham-operated with vehicle application, sham-operated with melatonin injections (30 micrograms/100 g body wt), pinealectomized with vehicle, and pinealectomized with melatonin supplementation. After 8 weeks, the collagen content was estimated as hydroxyproline concentration in the dry tissue of the skin. The results showed that melatonin markedly (p < 0.001) reduced collagen accumulation in the skin. Pinealectomy enhanced collagen deposition in the skin (p < 0.02) and melatonin application reduced the pinealectomy-induced elevation of collagen content (p < 0.001). Results clearly indicate that collagen accumulation in the intact skin is under the control of the pineal gland, and that melatonin, the pineal hormone, is responsible for this control.     

Recovery of Skin Barrier After Stratum Corneum Removal by Microdermabrasion

Microdermabrasion is widely used as a non-invasive cosmetic technique that has recently been adapted to selectively remove stratum corneum to increase skin permeability for transdermal drug delivery. This study measured the kinetics of skin barrier recovery after stratum corneum removal using microdermabrasion in hairless guinea pigs. The skin was abraded at two sites on each animal, one of which was allowed to recover under occlusion while the other remained non-occluded. Histological measurements showed that skin barrier properties to sulforhodamine B largely recovered within 12 h, and the stratum corneum appeared largely reformed within 24 h for both occluded and non-occluded skin. Skin electrical resistance measurements showed significant recovery of the skin barrier within 24 h. We conclude that transdermal drug delivery may occur for up to 12 h after microdermabrasion in guinea pigs; however, humans will probably have a longer recovery time due to expected slower skin healing rates.     

Development and evaluation of topical formulation containing solid lipid nanoparticles of vitamin A

The purpose of this research was to investigate novel particulate carrier system such as solid lipid nanoparticles (SLN) for topical application of vitamin A palmitate and to study its beneficial effects on skin. Topical gels enriched with SLN of vitamin A were prepared. The solid lipid nanoparticulate dispersion was prepared using high-pressure homogenization technique and was incorporated into polymeric gels of Carbopol, Pemulen, Lutrol, and Xanthan gum for convenient application. The nanoparticulate dispersion and its gels were evaluated for various parameters such as particle size, in vitro drug release, in vitro penetration, in vivo skin hydration, and skin irritation. The solid lipid nanoparticulate dispersion showed mean particle size of 350 nm. Differential scanning calorimetry studies revealed no drugexcipient incompatibility. In vitro release profile of vitamin A palmitate from nanoparticulate dispersion and its gel showed prolonged drug release up to 24 hours, which could be owing to embedment of drug in the solid lipid core. In vitro penetration studies showed almost 2 times higher drug concentration in the skin with lipid nanoparticle-enriched gel as compared with conventional gel, thus indicating better localization of the drug in the skin. In vivo skin hydration studies in albino rats revealed increase in the thickness of the stratum corneum with improved skin hydration. The developed formulation was nonirritant to the skin with no erythema or edema and had primary irritation index of 0.00. Thus it can be concluded that SLN represents a promising particulate carrier having controlled drug release, improved skin hydration, and potential to localize the drug in the skin with no skin irritation.     

Coenzyme Q10-Loaded Fish Oil-Based Bigel System: Probing the Delivery Across Porcine Skin and Possible Interaction with Fish Oil Fatty Acids

Coenzyme Q10 (CoQ10) is a vitamin-like oil-soluble molecule that has anti-oxidant and anti-ageing effects. To determine the most optimal CoQ10 delivery vehicle, CoQ10 was solubilised in both water and fish oil, and formulated into hydrogel, oleogel and bigel. Permeability of CoQ10 from each formulation across porcine ear skin was then evaluated. Furthermore, the effects of the omega-3 fatty eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids from fish oil on skin permeation were investigated by means of nuclear magnetic resonance (NMR) and computerised molecular modelling docking experiments. The highest drug permeation was achieved with the bigel formulation that proved to be the most effective vehicle in delivering CoQ10 across the skin membrane due to a combination of its adhesive, viscous and lipophilic properties. Furthermore, the interactions between CoQ10 and fatty acids revealed by NMR and molecular modelling experiments likely accounted for skin permeability of CoQ10. NMR data showed dose-dependent changes in proton chemical shifts in EPA and DHA. Molecular modelling revealed complex formation and large binding energies between fatty acids and CoQ10. This study advances the knowledge about bigels as drug delivery vehicles and highlights the use of NMR and molecular docking studies for the prediction of the influence of drug–excipient relationships at the molecular level.