Transdermal delivery of tadalafil. I. Effect of vehicles on skin permeation

Transdermal delivery that avoids the presystemic disposition can provide an alternative to oral administration of tadalafil. Accordingly, the aim of this study was to select the best vehicle as the first step in optimization of tadalafil transdermal delivery. The vehicles were used neat or in selected binary combinations and were evaluated for drug solubilization and transdermal delivery. The drug solubility in pure vehicles were ranked as polyethylene glycol (PEG) 400 > propylene glycol (PG) > ethanol > ethyl oleate (EO) > isopropyl myristate (IPM) > water. The solubility in binary systems containing ethanol at 2:1 ratios with EO or IPM was greater than that obtained with pure ethanol, EO, or IPM. This effect could be due to the cosolvency effect. The transdermal drug delivery from pure vehicles was ranked as IPM > EO > ethanol > PG > PEG > water. The delivery from binary mixtures of ethanol with either IPM or EO was higher than that obtained from pure solvents with the delivery increasing with increasing ethanol concentration in the mixtures. The delivery from binary mixtures was synergistic rather than additive. The study thus demonstrated a potential of tadalafil transdermal delivery. Binary combinations of ethanol with either IPM or EO provided the first step forward toward the development of transdermal delivery system for tadalafil.     

Transdermal Delivery of Tadalafil. I. Effect of Vehicles on Skin Permeation

Transdermal delivery that avoids the presystemic disposition can provide an alternative to oral administration of tadalafil. Accordingly, the aim of this study was to select the best vehicle as the first step in optimization of tadalafil transdermal delivery. The vehicles were used neat or in selected binary combinations and were evaluated for drug solubilization and transdermal delivery. The drug solubility in pure vehicles were ranked as polyethylene glycol (PEG) 400 >?propylene glycol (PG) >?ethanol >?ethyl oleate (EO) >?isopropyl myristate (IPM) >?water. The solubility in binary systems containing ethanol at 2:1 ratios with EO or IPM was greater than that obtained with pure ethanol, EO, or IPM. This effect could be due to the cosolvency effect. The transdermal drug delivery from pure vehicles was ranked as IPM >?EO >?ethanol >?PG >?PEG >?water. The delivery from binary mixtures of ethanol with either IPM or EO was higher than that obtained from pure solvents with the delivery increasing with increasing ethanol concentration in the mixtures. The delivery from binary mixtures was synergistic rather than additive. The study thus demonstrated a potential of tadalafil transdermal delivery. Binary combinations of ethanol with either IPM or EO provided the first step forward toward the development of transdermal delivery system for tadalafil.     

Transdermal delivery of physostigmine: effects of enhancers and pressure-sensitive adhesives

The purpose of this study was to investigate the effects of various pressure- sensitive adhesives (PSA) on the percutaneous absorption of physostigmine across hairless mouse skin. In addition, the influences of various vehicles and polyvinylpyrrolidone (PVP) on the percutaneous absorption of physostigmine from PSA matrix across hairless mouse skin were evaluated using a flow-through diffusion cell system at 37°C. Physostigmine showed the highest permeability from silicone adhesive matrix, followed by polyisobutylene (PIB), styrene- isoprene-styrene (SIS), acrylic, and styrene-butadiene-styrene (SBS) matrix. Among acrylic adhesives, the permeability of physostigmine was the highest from grafted acrylic adhesive. Polyvinyl pyrrolidone inhibited the crystallization of physostigmine in the PIB adhesive matrix and enhanced the permeability of physostigmine from the PIB adhesive matrix. When esters of sorbitol and fatty acid, polyethylene glycol (PEG) alkyl esters, and caprylic/capric triglycerides were tested, the more lipophilic was a surfactant, the higher the permeation rate within the same group of surfactants. The enhancement effect of PEG derivatives was lower than that of non-PEG derivatives. Among non-linear fatty acid derivatives, linoleate derivatives showed higher permeability of physostigmine than oleate derivatives. This study showed that several non-ionic surfactants, including PEG-20 evening primrose glyceride, enhanced the permeation of physostigmine across hairless mouse skin better than oleic acid.     

Transdermal delivery of ondansetron hydrochloride: effects of vehicles and penetration enhancers

The effects of vehicles and penetration enhancers on the in vitro permeation of ondansetron hydrochloride (OS) across dorsal hairless mouse skins were investigated. Various types of vehicles, including ester, alcohol, and ether and their mixtures were used, and then a series of fatty acids and fatty alcohols were employed as enhancers. Among pure vehicles used, water and ethanol showed high permeation fluxes, which were 48.2 ± 23.7 and 41.9 ± 17.9 µg/cm² per h, respectively. Even though propylene glycol monocaprylate (PGMC) alone did not show a high permeation rate, the skin permeability of OS was increased by the addition of diethylene glycol monoethyl ether (DGME); the highest flux was achieved at 40% of DGME. Also, the combination of PGMC and ethanol (80:20) or PGMC and propylene glycol (PG) (60:40) increased the permeation flux by six- and two-fold, respectively, compared to PGMC alone. The synergistic enhancement was also obtained by using PG-oleyl alcohol (OAl) cosolvent. The greatest flux was attained by the addition of unsaturated fatty acids at 3% concentration to PG. The enhancement factors with the addition of oleic acid or linoleic acid to PG were about 1250 and 450, respectively. But saturated fatty acids failed to show a significant enhancing effect. When the PGMC-DGME (60:40) cosolvent system was used as a vehicle, all fatty acids, including unsaturated fatty acids, failed to show significant enhancing effects. The results indicate that the combinations of oleic acid, linoleic acid, or oleyl alcohol with PG, or PGMC-DGME (60:40) cosolvent could be used for the design of the OS transdermal system.     

Transdermal delivery of ketorolac tromethamine: effects of vehicles and penetration enhancers

The effects of vehicles and penetration enhancers on the in vitro permeation of ketorolac tromethamine (KT) across excised hairless mouse skins were investigated. Among pure vehicles examined, propylene glycol monolaurate (PGML) showed the highest permeation flux, which was 94.3 ± 17.3 µg/cm²/h. Even though propylene glycol monocaprylate (PGMC) alone did not show high permeation rate, the skin permeability of KT was markedly increased by the addition of diethylene glycol monoethyl ether (DGME); the enhancement factors were 19.0 and 17.1 at 20% and 40% of DGME, respectively. When DGME was added to PGML, the permeation fluxes were almost two times at 20-60% of DGME compared to PGML alone. In the cosolvent system consisting of propylene glycol (PG)-oleyl alcohol, the permeation rate increased as the ratio of PG increased. In the study to investigate the effect of drug concentration on the permeation rate of KT, the permeation rates increased as the drug concentration increased in all vehicles used, and the dramatic increase in permeation rate was obtained when the drug concentration was higher than its solubility. For the effects of fatty acids on the permeation of KT, five fatty acids were added to PG at concentrations of 1%-, 3%-, 5%- and 10%-caprylic acid, capric acid, lauric acid, oleic acid, and linoleic acid. The enhancing effects of fatty acids were different, depending on the concentration as well as the sort of fatty acids. The highest enhancing effect was attained with 10% caprylic acid in PG; the permeation flux was 113.6 ± 17.5 µg/cm²/h. The lag time of KT was reduced as the concentration of fatty acids increased except for caprylic acid.     

Improved oral delivery of valsartan from maltodextrin based proniosome powders

Proniosome powders proved to be the potential carriers for efficient oral delivery of lipophilic or amphiphilic drugs. Henceforth, an attempt was made to improve the oral delivery of valsartan by loading into maltodextrin based proniosome powders. The proniosome powders were prepared by varying the ratio of span 60 and cholesterol and evaluated for micromeritic properties and the results indicate acceptable flow properties. The formulation containing equimolar ratio of span 60 and cholesterol showed smaller vesicle size, high surface charge and entrapment efficiency. The formation of niosomes and surface morphology of optimized proniosome formulation was studied by optical and scanning electron microscopy, respectively. FT-IR, differential scanning calorimetry, and powder X-ray diffraction studies performed to understand the solid state properties of the drug reveal the absence of chemical interaction, drug transformation from crystalline to amorphous and molecular state. The in vitro dissolution study carried out in both simulated gastric and intestinal fluid demonstrate improved dissolution characteristics compared to pure drug. The augment in permeation enhancement from proniosome formulation across rat intestine suggest the potential of proniosome carriers for improved oral delivery of valsartan.     

Transdermal drug delivery system of haloperidol to overcome self-induced extrapyramidal syndrome

Haloperidol (HAL), an antipsychotic, is associated with side effects of drug-induced extrapyramidal syndrome (EPS) in conventional monotherapy. Controlled released transdermal dosage form (TDDS) of the drug was designed for maintenance therapy. Matrix-diffusion type transdermal film of HAL was designed with Eudragit NE 30D copolymer without permeation enhancer in different combinations. For the feasibility studies, all standard evaluations were performed, and their results pointed toward the suitability of TDDS. The drug release and permeation studies in Franz diffusion cell in 20% PEG-normal saline followed the Higuchi equation with optimum correlation coefficient. The neuroleptic efficacy was confirmed by maximum graded response in a rotarod apparatus. The neuroleptic-induced catatonia (EPS) in albino rats was minimum with a score of zero over a 72-hr study. The pharmacokinetic parameters in rabbit model showed a very significant prolongation of action up to 72 hr with steady-state plasma concentration (cp_ss) of 11.58 ng/mL. Thus, the HAL-loaded TDDS improved the therapeutic profile by preventing the neuroleptic-induced EPS and might be a better alternative during its long period of psychiatric treatment over conventional dosage form.     

Transdermal and buccal delivery of methylxanthines through human tissue in vitro

We examined the in vitro permeation of central nervous stimulants—caffeine, theophylline, and theobromine across human skin with the aid of six chemical enhancers. It was found that oleic acid was the most potent enhancer for all three methylxanthines. Further optimization studies with different solvents showed that caffeine transport could be enhanced to give flux values up to 585 μg/cm².hr^-1. Theobromine and theophylline delivery rates proved insufficient. An additional study involving a buccal tissue equivalent showed that this membrane was more permeable than skin for all model actives tested and would offer an alternate way of delivery.     

Transdermal delivery of alprazolam from a monolithic patch: formulation based on in vitro characterization

Alprazolam, a benzodiazepine widely used for the treatment of psychiatric disorders, has been aimed to be formulated in a transdermal delivery system (TDS) prototype. A series of TDS prototypes dosed in all cases at 0.35 mg·cm^?2 of alprazolam were prepared as a monolithic drug in adhesive matrix using acrylic pressure-sensitive adhesives (PSA) of acrylate vinyl acetate (Duro-tack^®). The effects of several permeation enhancers as azone, transcutol, propylene glycol, dodecyl alcohol, decyl alcohol, diethanolamine, N-methyl pyrrolidone and lauric acid were studied. Prototypes have been characterized based on adhesion parameters (peel adhesion and shear adhesion), in vitro human skin permeation and in vitro drug release according to European Pharmacopoeia for the selected prototype. Best results show that a combination of permeation enhancers from different chemical groups is able to provide almost a 33 fold increase in the transdermal alprazolam flux of an aqueous saturated dispersion (from 0.054?±?0.019 to 1.76?±?0.21 μg h.cm^?2). Based on these in vitro flux data, a predictive simulation of the achievable plasmatic levels was performed assuming a constant systemic infusion of drug. In summary, it is possible to obtain a prototype of a TDS of alprazolam with adequate adhesive properties (peel adhesion and shear adhesion) and able to predict sustained therapeutic plasmatic levels.     

缬沙坦原料颗粒形貌对缬沙坦氨氯地平片溶出的影响

为了找寻2批缬沙坦原料制备的缬沙坦氨氯地平片溶出存在显著差异的原因,以p H=4. 5的磷酸盐缓冲液作为溶出介质,测定缬沙坦氨氯地平片的溶出;以粉末X射线衍射测定缬沙坦原料晶型,以激光粒度法测定缬沙坦原料粒径,以光学显微镜观察缬沙坦原料及其在预混料中粒子的形貌,对比批间差异,探究导致溶出差异的原因。结果显示:2批缬沙坦原料晶型均为无定形;在质量分数为1%的十二烷基硫酸钠(SDS)和液体石蜡中测定的粒径相同;但2批缬沙坦原料在粉末形态、预混料中的颗粒形貌存在明显差异,缬沙坦原料颗粒形貌分别为树枝状和球团状。在晶型和粒径相同的情况下,原料颗粒形貌可能影响制剂的溶出,球团状原料在片剂制备过程中物料间接触面小,难以粘结成大团块,片剂崩解后溶出较快;树枝状原料则相反。并且当原料的晶型和粒径相同时,仅采用粒径数据无法区分原料的批间差异,应增加对原料颗粒形貌的控制。     

Transdermal delivery of alprazolam from a monolithic patch: formulation based on in vitro characterization

Alprazolam, a benzodiazepine widely used for the treatment of psychiatric disorders, has been aimed to be formulated in a transdermal delivery system (TDS) prototype. A series of TDS prototypes dosed in all cases at 0.35 mg·cm(-2) of alprazolam were prepared as a monolithic drug in adhesive matrix using acrylic pressure-sensitive adhesives (PSA) of acrylate vinyl acetate (Duro-tack(?)). The effects of several permeation enhancers as azone, transcutol, propylene glycol, dodecyl alcohol, decyl alcohol, diethanolamine, N-methyl pyrrolidone and lauric acid were studied. Prototypes have been characterized based on adhesion parameters (peel adhesion and shear adhesion), in vitro human skin permeation and in vitro drug release according to European Pharmacopoeia for the selected prototype. Best results show that a combination of permeation enhancers from different chemical groups is able to provide almost a 33 fold increase in the transdermal alprazolam flux of an aqueous saturated dispersion (from 0.054?±?0.019 to 1.76?±?0.21 μg h.cm(-2)). Based on these in vitro flux data, a predictive simulation of the achievable plasmatic levels was performed assuming a constant systemic infusion of drug. In summary, it is possible to obtain a prototype of a TDS of alprazolam with adequate adhesive properties (peel adhesion and shear adhesion) and able to predict sustained therapeutic plasmatic levels.     

Development and optimization of press coated tablets of release engineered valsartan for pulsatile delivery

The present work is aimed to develop and optimize pulsatile delivery during dissolution of an improved formulation of valsartan to coordinate the drug release with circadian rhythm. Preliminary studies suggested that β cyclodextrin could improve the solubility of valsartan and showed A_L type solubility curve. A 1:1 stoichiometric ratio of valsartan to β cyclodextrin was revealed from phase solubility studies and Job’s plot. The prepared complex showed significantly better dissolution efficiency (p?<?0.05) compared to pure drug, which could be due to the formation of inclusion complex as revealed from FTIR and DSC studies. Continuous dissolution-absorption studies revealed that absorption of drug from valsartan β cyclodextrin complex was significantly higher (p?2 full factorial design was used to measure the response of HPMC K4M and EC on lag time and time taken for 90% drug release (T90). The optimized batch prepared according to the levels obtained from the desirability function had a lag time of 6?h and consisted of HPMC K4M:ethylcellulose in a 1:1.5 ratio with 180?mg of coating and revealed a close agreement between observed and predicted value (R^2?=?0.9694).     

Transdermal Dual-Controlled Delivery of Testosterone and Estradiol: (I) Impact of system Design

A multilaminate-type transdermal drug delivery (m-TDD) system was designed with the objective of delivering testosterone and estradiol simultaneously but at different daily dosage rates. To achieve such a dual-controlled transdermal delivery, skin permeation enhancer and permselective membrane were incorporated into the system. The results demonstrated that skin permeation enhancer, which is incorporated into the testosterone reservoir layer, and permselective membrane, which is added onto the drugreleasing surface of estradiol reservoir layer, can both alter the overall rate of skin permeation for both drugs. The skin permeation enhancer was observed to enhance the skin permeation rate of testosterone, while the permselective membrane was shown to reduce the skin permeation rate of estradiol. The addition of permselective membrane was observed to modify the release kinetics of estradiol from the matrix diffusion-controlled drug delivery to membrane permeation-controlled drug delivery. Other factors which may affect the deliver rate of drug, e.g., the thickness of permselective membrane and loading dose of drugs, were also studied. Furthermore, evaluation of physical stability of this mTDD system demonstrated that the inter-layer migration of drugs is at minimum.     

Transdermal Dual-Controlled Delivery of Testosterone and Estradiol: (I) Impact of system Design

Abstract

A multilaminate-type transdermal drug delivery (m-TDD) system was designed with the objective of delivering testosterone and estradiol simultaneously but at different daily dosage rates. To achieve such a dual-controlled transdermal delivery, skin permeation enhancer and permselective membrane were incorporated into the system. The results demonstrated that skin permeation enhancer, which is incorporated into the testosterone reservoir layer, and permselective membrane, which is added onto the drugreleasing surface of estradiol reservoir layer, can both alter the overall rate of skin permeation for both drugs. The skin permeation enhancer was observed to enhance the skin permeation rate of testosterone, while the permselective membrane was shown to reduce the skin permeation rate of estradiol. The addition of permselective membrane was observed to modify the release kinetics of estradiol from the matrix diffusion-controlled drug delivery to membrane permeation-controlled drug delivery. Other factors which may affect the deliver rate of drug, e.g., the thickness of permselective membrane and loading dose of drugs, were also studied. Furthermore, evaluation of physical stability of this mTDD system demonstrated that the inter-layer migration of drugs is at minimum.     

Transdermal delivery of propranolol using mixed grades of Eudragit: design and in vitro and in vivo evaluation

A matrix-dispersion-type transdermal drug delivery system of propranol was developed using different ratios of mixed polymeric grades of Eudragit. Formulations were evaluated for in vitro dissolution characteristics using a Cygnus' sandwich patch holder. Selected formulations followed zero-order release kinetics. In vivo evaluation was carried out on healthy human volunteers following a balanced incomplete block design (BIBD). In vitro dissolution rate constant k and pharmacokinetic parameters generated from plasma and urine were evaluated statistically. Statistically excellent correlation was found between percentages of drug absorbed from patch versus C_max, AUC_0-24, and AUC_0-∞. A highly significant difference was observed when C_max and AUC_0- generated from plasma and urine data were compared, but when k_e, t_1/2e, k_a, t_1/2awere compared, the difference was not significant. Urinary excretion data are suggested as a simpler alternative to blood-level data in studying the kinetics of absorption and deriving the absorption parameter.     

Influence of drug lipophilicity on terpenes as transdermal penetration enhancers.

Percutaneous absorption-enhancing effects on the skin of hairless mice of 11 monoterpenes [1, (+)-limonene; 2, (-)-menthone; 3, (+)-terpinen-4-ol; 4, alpha-terpineol; 5, 1,8-cineole; 6, (+)-carvone; 7, (-)-verbenone; 8, (-)-fenchone; 9, p-cymene; 10, (+)-neomenthol; and 11, geraniol] were investigated using three different model drugs (caffeine, hydrocortisone, triamcinolone acetonide [TA]) with varying lipophilicities. Terpenes were applied at 0.4 M in propylene glycol (PG) to mouse skin. The model drugs were applied as suspensions in PG 1 hr following enhancer pretreatment. The combination of terpenes in PG provided significant enhancement of the permeation of caffeine through mouse skin. The most active compounds 10 and 11 increased permeation by between 13-fold and 16-fold. The terpenes also enhanced the delivery of hydrocortisone, but not to as great an extent. The most active compounds 3 and 4 increased permeation between 3.9-fold and 5-fold. The compounds examined did not significantly increase the delivery of TA. The most active compound 4 only increased delivery 2.5-fold, while the next most active compound 6 only increased delivery 1.7-fold. Overall, these results indicate that the combination of terpenes with PG can significantly increase the transdermal penetration of the hydrophilic drug caffeine and the polar steroid hydrocortisone.     

Effect of Penetration Enhancers on Transdermal Delivery of Timolol Maleate

In vitro skin permeation of Timolol maleate through human cadaver skin was studied using Franz diffusion cell. The results indicate that the drug penetrates poorly through human cadaver skin. However, skin penetration enhancers such as dimethyl sulfoxide (DMSO), oleic acid (OA) and lauryl chloride (LC) enhanced the permeability of Timolol maleate (TM) through human cadaver skin. The permeation enhancement of drug was maximum by lauryl chloride amongst the three enhancers. Moreover, lauryl chloride increases the permeation of drug through skin with increase in the time of application and concentration on skin. The change in lag time was also observed.     

Mucoadhesive delivery systems. I. Evaluation of mucoadhesive polymers for buccal tablet formulation

Different types of mucoadhesive polymers, intended for buccal tablet formulation, were investigated for their comparative mucoadhesive force, swelling behavior, residence time and surface pH. The selected polymers were carbopols (CP934, and CP940), polycarbophil (PC), sodium carboxymethyl cellulose (SCMC) and pectin representing the anionic type, while chitosan (Ch) as cationic polymer and hydroxypropylmethyl cellulose (HPMC) as a non-ionic polymer. Results revealed that polyacrylic acid derivatives (PAA) showed the highest bioadhesion force, prolonged residence time and high surface acidity. SCMC and chitosan ensured promising bioadhesive characteristics, whilst HPMC and pectin exhibited weaker bioadhesion. Different polymer combinations as well as formulations were evaluated to improve the mucoadhesive performance of the tablets. Bioadhesive tablet formulations containing either 5% CP934, 65% HPMC and 30% spray-dried lactose or 2% PC, 68% HPMC and 30% mannitol showed optimum mucoadhesion and suitable residence time. SCMC, when formulated individually, exhibited promising bioadhesion, acceptable swelling, convenient residence time and surface pH. In-vivo trials of these formulations proved non-irritative and prolonged residence of the mucoadhesive tablets on human buccal mucosa for 8 to 13 h.     

Mechanisms of Transdermal Controlled Nitroglycerin Administration (I): Development of a Finite-Dosing Skin Permeation System

A new finite-dosing cell for in vitro skin permeation studies was recently developed to overcome the deficiencies observed in the commercially available Franz diffusion cell and to accomplish the solution hydrodynamics and temperature control required in studying the rate profiles of skin permeation.

Results of comparative studies indicated that the improved diffusion cell, named Keshary-Chien diffusion cell, can achieve and maintain the target body temperature on the skin surface and in the receptor solution, which cannot be accomplished by the Franz diffusion cell. Solution mixing efficiency was substantially improved, so the drug distribution and concentration homogeneity could be achieved in the Keshary-Chien diffusion cell within a duration four times shorter than in the Franz diffusion cell; and a 3-fold reduction in the thickness of the hydrodynamic boundary layer was achieved, so the effect of mass transfer in the hydrodynamic boundary layer on the skin permeation rate profiles was minimized.