Enhancement Effects in the Percutaneous Absorption of Alprazolam Through Human Skin in vitro

The enhancement effects of some chemicals on the percutaneous absorption of alprazolam through human skin was investigated in vitro. Linoleic acid, oleic acid, Comperlan F® (linoleic acid diethanolamide), Comperlan KD® (coconut fatty acid diethanolamide) and Ethomeen C12® (bis-(2-hydroxyethyl)cocamine) were evaluated for their enhancing effect either as neat solvents or combined with propylene glycol. The effects of skin pretreatment with the enhancers on the percutaneous absorption of alprazolam from a drug suspension in an aqueous gel were also investigated: skin pretreatment with some enhancers has shown potentially interesting aspects. The determination of alprazolam partitioning into untreated and pretreated horny layer supported the idea that, with oleic and linoleic acid, a contribution to the modification of the diffusional resistance of the skin was given by an increase of the drug solubility in the stratum coraeum.     

Percutaneous Absorption Enhancement by Nonionic Surfactants

The influence of nonionic surfactants (polysorbates) on hydrocortisone penetration through hairless mouse skin in vitro has been determined. Permeation was quite slow from purely aqueous media containing surfactants following finite dose application. However, if the vehicle contained high propylene glycol concentrations (40% or more), inclusion of a surfactant increased permeation rate significantly. Similar effects were noted following application of a large donor volume (infinite dose). Synergism was attributed to enhancement of surfactant absorption by the stratum corneum leading to changes in skin barrier resistance. With vehicles containing a surfactant, penetration was higher after finite dose application due to compositional changes within the vehicle.     

Percutaneous Absorption Enhancement by Nonionic Surfactants

The influence of nonionic surfactants (polysorbates) on hydrocortisone penetration through hairless mouse skin in vitro has been determined. Permeation was quite slow from purely aqueous media containing surfactants following finite dose application. However, if the vehicle contained high propylene glycol concentrations (40% or more), inclusion of a surfactant increased permeation rate significantly. Similar effects were noted following application of a large donor volume (infinite dose). Synergism was attributed to enhancement of surfactant absorption by the stratum corneum leading to changes in skin barrier resistance. With vehicles containing a surfactant, penetration was higher after finite dose application due to compositional changes within the vehicle.     

Percutaneous Absorption Enhancement by Nonionic Surfactants

The influence of nonionic surfactants (polysorbates) on hydrocortisone penetration through hairless mouse skin in vitro has been determined. Permeation was quite slow from purely aqueous media containing surfactants following finite dose application. However, if the vehicle contained high propylene glycol concentrations (40% or more), inclusion of a surfactant increased permeation rate significantly. Similar effects were noted following application of a large donor volume (infinite dose). Synergism was attributed to enhancement of surfactant absorption by the stratum corneum leading to changes in skin barrier resistance. With vehicles containing a surfactant, penetration was higher after finite dose application due to compositional changes within the vehicle.     

Percutaneous Absorption of LHRH Through Porcine Skin: Effect of N-Methyl 2-Pyrrolidone and Isopropyl Myristate

Abstract

The effect of penetration enhancer (PE) on the in vitro permeability of luteinizing hormone-releasing hormone (LHRH) through porcine epidermis was investigated. The permeability coefficient of LHRH significantly increased (p < 0.05) through PE-(e.g., n-methyl 2-pyrrolidone [NMP], and isopropyl myristate [IPM]) treated epidermis in comparison to the control (without PE-pretreated epidermis). The higher permeability coefficient was observed with NMP followed by IPM. This shows that PE such as NMP and IPM can enhance the percutaneous absorption of peptides such as LHRH.     

Enhancement of Percutaneous Absorption of Propranolol Hydrochloride by Iontophoresis

Abstract

Iontophoresis is defined as the migration of ions when an electric current passes through a solution containing ionized species. When applied transdermally, iontophoresis may reduce the barrier porperties of skin and may enhance the transdermal permeation of drugs. This research work was aimed at exploring the factors which influence the effectiveness of iontophoresis facilitated transport of ionized species across the skin, and comparing it with that by passive diffusion. Propranolol hydrochloride was selected as the model drug, and rat abdominal skin as the in-vitro animal model. Pulse dc was applied, at 2.16/3/6/9 mA/cm²; 1:1 or 4:1 duty cycle and 20 KHz frequency for 15/25 minutes. Factors which modify the iontophoretic drug delivery, such as drug concentration, current density, duty-cycle of pulse dc, and duration of iontophoresis, were also evaluated. It was found that iontophoresis causes a significant increase in transdermal permeation of Propranolol hydrochloride in-vitro through rat abdominal skin, as compared to that by passive diffusion.     

Enhancement of Percutaneous Absorption of Propranolol Hydrochloride by Iontophoresis

Iontophoresis is defined as the migration of ions when an electric current passes through a solution containing ionized species. When applied transdermally, iontophoresis may reduce the barrier porperties of skin and may enhance the transdermal permeation of drugs. This research work was aimed at exploring the factors which influence the effectiveness of iontophoresis facilitated transport of ionized species across the skin, and comparing it with that by passive diffusion. Propranolol hydrochloride was selected as the model drug, and rat abdominal skin as the in-vitro animal model. Pulse dc was applied, at 2.16/3/6/9 mA/cm²; 1:1 or 4:1 duty cycle and 20 KHz frequency for 15/25 minutes. Factors which modify the iontophoretic drug delivery, such as drug concentration, current density, duty-cycle of pulse dc, and duration of iontophoresis, were also evaluated. It was found that iontophoresis causes a significant increase in transdermal permeation of Propranolol hydrochloride in-vitro through rat abdominal skin, as compared to that by passive diffusion.     

Percutaneous Absorption of Piroxicah from Fapg Base Through Rat Skin: Effects of Oleic Acid and Saturated Fatty Acid Added to Fapg Base

Oleic acid (OA) or / and saturated fatty acid (i.e. lauric lyristic, palmitic and stearic acid) decreased the release of piroxican from FAPG (fatty alcohol-propylene glycol) base. The reason would be due to the increase in lipophilicity of the base. The released piroxicam was found to be inversely proportional to the apparent viscosity of the ointments containing OA and saturated fatty acid. However, OA or / and the saturated fatty acids enhanced the in vitro skin permeation and the in vivo percutaneous absorption of piroxican, the enhancing effect was decreased linearly with increasing carbon number of saturated fatty acid from 12 to 18. A useful parameter has been obtained for estimating the properties of the exudation or “bleeding” of the FAPG base. A number of piroxicam FAPG ointments have been selected as an optimal product for less bleeding and more percutaneous absorption of piroxicam than those of controls (containing no oleic acid and saturated fatty acid).     

Percutaneous Absorption of Piroxicah from Fapg Base Through Rat Skin: Effects of Oleic Acid and Saturated Fatty Acid Added to Fapg Base

Abstract

Oleic acid (OA) or / and saturated fatty acid (i.e. lauric lyristic, palmitic and stearic acid) decreased the release of piroxican from FAPG (fatty alcohol-propylene glycol) base. The reason would be due to the increase in lipophilicity of the base. The released piroxicam was found to be inversely proportional to the apparent viscosity of the ointments containing OA and saturated fatty acid. However, OA or / and the saturated fatty acids enhanced the in vitro skin permeation and the in vivo percutaneous absorption of piroxican, the enhancing effect was decreased linearly with increasing carbon number of saturated fatty acid from 12 to 18. A useful parameter has been obtained for estimating the properties of the exudation or “bleeding” of the FAPG base. A number of piroxicam FAPG ointments have been selected as an optimal product for less bleeding and more percutaneous absorption of piroxicam than those of controls (containing no oleic acid and saturated fatty acid).     

Evaluation of Verapamil Hydrochloride Permeation Through Human Cadaver Skin

Preformulation studies were conducted to determine the feasibility of a transdermal dosage form of verapamil hydrochloride (VPHC1). The apparent partition coefficient (octanol/water or buffer) of VPHC1 in buffers of different Ph values was determined. The saturation solubility of VPHC1 in different buffers and propylene glycol was determined. The target drug flux through the human skin to attain therapeutic concentrations in blood was determined. The maximum flux attainable through the human skin was determined. An attempt was made to increase the flux of the drug using azone as a penetration enhancer. The rate limiting barrier for the permeation of VPHC1 through the skin was determined.     

Chemical Enhancers for the Absorption of Substances Through the Skin: Laurocapram and Its Derivatives

ABSTRACT

Absorption enhancers are substances used for temporarily increasing a membrane's permeability (e.g., the skin and mucosa), either by interacting with its components (lipids or proteins) or by increasing the membrane/vehicle partition coefficient. This article presents the results of biophysical and permeability studies performed with Laurocapram and its analogues. As shown, Laurocapram and its analogues present different enhancing efficacies, for most of both hydrophilic and lipophilic substances. The enhancing effect of Laurocapram (Azone®) is attributed to different mechanisms, such as insertion of its dodecyl group into the intercellular lipidic bilayer, increase of the motion of the alkylic chains of lipids, and fluidization of the hydrophobic regions of the lamellate structure. Toxicological studies reveal a low toxicity for Laurocapram, and for some derivatives, a relationship exists between toxicity and the number of carbons in the alkylic chain. Very important, when applied to human skin, Laurocapram shows a minimal absorption, being quickly eliminated from circulation. However, although Laurocapram and its derivatives have been shown to provide enhancement, they have not been widely accepted because of their suspected pharmacological activity or questions about their safety.     

Effects of the Administration of Ketoprofen gel on the Percutaneous Absorption of Ketoprofen in Rabbits

The effects of the administration for a commercial keto-profen gel on the percutaneous absorption of ketoprofen (through rabbit abdominal skin) were investigated. The AUC (area under the curve) value of absorbed ketoprofen for single topical administration of 6 g of ketoprofen gel applied with ODT (occlusive dressing technique) was found to be about 6 -fold greater than that of repeated administration of 1.5 g of ketoprofen gel applied with ODT at 6 h interval in a day. It was about 14-fold greater than that of repeated administration of 1.5 g of ketoprofen gel applied without ODT at 6 h interval in a day. The experiment of volatilation of ketoprofen gels and the in vitro release test of ketoprofen gel applied with ODT and without ODT had been, in addition, respectively approached. The volatilation of solvent in the gel, as a result of this, may clearly be the primary factor for inducing a sharp descending of the plasma ketoprofen level following the Cmax (maximun concentration) in the in vivo percutaneous absorption of ketoprofen gel: this factor also results in a lower plasma ketoprofen level for the gel applied without ODT than that with ODT.     

Effect of Penetration Enhancers on Transdermal Absorption of Insulin Across Human Cadaver Skin

The transdermal diffusion of insulin, a model polypeptide drug, across the human cadaver skin (HCS) was evaluated in vitro, in presence of penetration enhancing solvents, anionic surfactants, biosurfactants, a natural moisturizing agent and combinations thereof. Also, an attempt was made to relate the enhanced penetration to physical parameters like distribution coefficient, surface tension and viscosity. The results of the permeation experiments indicate that the permeation enhancers used in the present investigation significantly enhance the amount of drug entering into the HCS and the amount reaching to the skin. A synergistic effect on permeation enhancement was observed in cases where combination of permeation enhancers were selectively used. Reasons for this synergism were critically examined and established.     

Effect of Penetration Enhancers on Transdermal Absorption of Insulin Across Human Cadaver Skin

The transdermal diffusion of insulin, a model polypeptide drug, across the human cadaver skin (HCS) was evaluated in vitro, in presence of penetration enhancing solvents, anionic surfactants, biosurfactants, a natural moisturizing agent and combinations thereof. Also, an attempt was made to relate the enhanced penetration to physical parameters like distribution coefficient, surface tension and viscosity. The results of the permeation experiments indicate that the permeation enhancers used in the present investigation significantly enhance the amount of drug entering into the HCS and the amount reaching to the skin. A synergistic effect on permeation enhancement was observed in cases where combination of permeation enhancers were selectively used. Reasons for this synergism were critically examined and established.     

Percutaneous Absorption of Salicylic Acid in Rabbits

The pharmacokinetic parameters defining the percutaneous absorption of salicylic acid in rabbits have been investigated. A one compartment open model with apparent first order absorption was found to describe adequately the blood level data.     

Percutaneous Absorption of Capsaicin and Its Derivatives

Nonivamide (NVA), sodium nonivamide acetate (SNA) and sodium nonivamide propionate (SNP) are analogues of Capsaicin (CAP). The structure and pungent property of NVA are similar to CAP. The solubilities of SNA in different pH value buffer solution were higher than that of NVA and CAP. For the NVA and SNA, the n-octanol/buffer partition coefficients decreased with increasing pH value. The fluxes of CAP and its analogues were determined using excised rat skin and the effect of pH was also investigated. The flux of NVA and SNA mixture was higher than individually NVA or SNA, and the ratio of 70:30 was a better choice. Sodium lauryl sulfate (SLS), an anionic surfactant, had significant effect on SNA skin permeation.     

Percutaneous Absorption of Metopimazine and Effect of Cyclodextrins

Metopimazine (MPZ) is used to prevent emesis during chemotherapies. A transdermal delivery system of MPZ may present a great advantage in patients to improve compliance. Hydroxypropyl β cyclodextrin (HPβCD) and partially methylated β cyclodextrin (PMβCD) were tested to enhance the percutaneous absorption of MPZ through pig skin using Franz's cells. The MPZ hydrochloride flux was low with 0.176 ± 0.054 μg/h/cm² and no flux was detected with a suspension of MPZ (base). The used characterization analyses demonstrated the formation of an inclusion complex with cyclodextrin and this complex improved percutaneous absorption of MPZ. Flux was increased to 0.240 ± 0.032 μg/h/cm² and 0.566 ± 0.057 μg/h/cm² for HPβCD and PMβCD, respectively, with a concentration of 20%. This study has shown that HPβCD and PMβCD improved the percutaneous penetration of MPZ. Cyclodextrin complexes increased MPZ bioavailability at the skin surface and PMβCD was also able to extract cutaneous fatty acids.     

Effect of Penetration Enhancers on the in Vitro Transport of Ephedrine Through Rat Skin and Human Epidermis from Matrix Based Transdermal Formulations

The potential of skin as a site for administration of systemically active Ephedrine HCl (EH) has been recognised. The effect of penetration enhancers, i.e., Dimethyl sulfoxide (DMSO), Dimethyl acetamide (DMA), Dimethyl formamide (DMF) and Azone on the in-vitro transport of EH from matrix based transdermal formulations through full thickness rat skin and human epidermis was investigated. The highest flux with minimum time lag through rat skin and human epidermis was observed from the batch containing Azone as penetration enhancer.     

Effect of Penetration Enhancers on the in Vitro Transport of Ephedrine Through Rat Skin and Human Epidermis from Matrix Based Transdermal Formulations

Abstract

The potential of skin as a site for administration of systemically active Ephedrine HCl (EH) has been recognised. The effect of penetration enhancers, i.e., Dimethyl sulfoxide (DMSO), Dimethyl acetamide (DMA), Dimethyl formamide (DMF) and Azone on the in-vitro transport of EH from matrix based transdermal formulations through full thickness rat skin and human epidermis was investigated. The highest flux with minimum time lag through rat skin and human epidermis was observed from the batch containing Azone as penetration enhancer.     

Human Insulin Absorption from the Intestine in Diabetic Rats

Abstract

The ability of human insulin to produce hypoglycemia in streptozocin-diabetic rats (average weight 500 g) was investigated. A simple solution of human insulin (insulin in hypotonic buffer solution) was administered intraduodenally. Rats received a dose of insulin of either 200 U/kg, 400 U/kg, or 600 U/kg. The hypoglycemic response was most significant when 600 U/kg solution of insulin was administered. The 200 U/kg dose was of two forms; one form was a solution of insulin with a concentration of 25 U/ml, 4 ml, and the other was a solution of insulin with a concentration of 50 U/ml, 2 ml. The dose of 25 U/ml, 4 ml produced a more significant hypoglycemic response than that of 50 U/ml, 2 ml. Carrier-insulin systems were also introduced intraduodenally in streptozocin-diabetic rats. The results indicate that the carrier systems without insulin had glucogenic effect. Despite this glucogenic effect, carrier-insulin systems at 200 U/kg dose were as effective as that of 600 U/kg of insulin solution. We conclude that insulin absorption from the intestine can cause a significant hypoglycemic state if given in a large enough dose, even without the presence of other absorption enhancers in the dosage form.