Controlled Transdermal Occlusive Delivery Device of Primaquine

Abstract

Primaquine an antimalarial drug was studied for its permeation behavior across the human cadaver skin. Ethylene vinyl acetate copolymer (E.V.A. cop) was used for the preparation of drug reservoir. To optimize the drug delivery from the drug reservoir E.V.A. cop of different vinyl acetate mole content (40%, 25%, 18%) was used. To achieve an enhanced skin permeation an occlusive face adhesive type delivery system was fabricated. The prepared systems were characterized for in-vitro studies. The system that delivered the drug in accordance with the theortically calculated required delivery rate was selected for in-vivo performance evaluation. The prepared system functions over an predicted definite time period in an uniform and defined fashion. The drug transdermal application has therapeutic potential.     

Development and Evaluation of Transdermal Salbutamol Delivering Systems

ABSTRACT

The transdermal drug delivery systems based on polymeric pseudolatex and matrix diffusion controlled systems for salbutamol were prepared and compared for in vitro skin permeation profile and in vivo performances. Poly (isobutylene) was used as release controlling polymer in both the systems. In vitro skin permeation was studied using the human cadavar skin in franz diffusion cell. Permeation rate constants for matrix diffusion controlled system and pseudolatices were 10.625 and 13.750 mcg/hr/cm² respectively. The prepared transdermal systems were tested on human volunteers having chronic reversible airways obstruction and compared with oral treatments (Asthaline). The in vivo drug plasma profiles following transdermal and oral treatments reveal that although peak plasma level by oral administration was higher in comparison with the transdermal treatments, troughs and peaks were discernible at dosing times. In the case of transdermal treatments, constant drug plasma and FEV₁ levels were recorded indicating controlled and systemic delivery of drug spaced over 30 hours. Among the prepared transdermal drug delivery systems, pseudolatices demonstrated better drug plasma profile, maintained at relatively higher level and flatter in appearance. The relative performance of the systems was noted to reflect in AUC and FEV₁.     

Polymeric Pseudolatices Dispersion Bearing Isosorbide Dinitrate for Transdermal Application

A pseudolatex based system for transdermal delivery (PL-ISDN-D) of isosorbide dinitrate (ISDN) was developed for its prolonged and controlled systemic availability. To achieve the desired and controlled release rate, different combinations of Eudragit RL-100 and polyvinylpyrrolidone were used in the preparation of pseudolatices polymeric dispersions. These preparations were evaluated for in-vitro release and permeation of the drug across human cadavar skin. The designed systems exhibited linear relationship between drug release (Q) Vs 0.80 function of time (t^0.80).

The product exhibiting required skin permeation (500 mcg/h/ 100 mg) calculated to achieve an effective plasma concentration was selected for the in-vivo performance evaluation. The drug plasma profile was compared with the plasma profile obtained following the administration of conventional oral dose of isosorbide dinitrate.

The study revealed that designed pseudolatex transdermal drug delivery system of isosorbide dinitrate could be used successfully with improved performance.     

Salbutamol Delivering Transdermal Dosage Form Based on Osmo-Regulatory Principle

A transdermal drug delivery system of Salbutamol was developed which released the drug following zero order kinetics. The designed system essentially based on trilaminated matrix concept. The delivery of drug from the system affected by osmotic phenomenon where sodium chloride was used as an osmogent. To establish the desired release rate polyethylene glycol 4000 (PEG 4000) was used as channelising agent in rate controlling membrance of cellulose acetate. The designed systems exhibiting zero-order release rate, were studied for the in-vitro skin permeation. The product which was having skin permeability rate 115 mcg/hr/cm² was selected for the in-vivo evaluation. The forced expiratory volume (FEV₁) and drug plasma concentration were monitored periodically. The study revealed that designed osmoregulatory transdermal drug delivery system of Salbutamol could be used successfully with improved therapeutic response and holds promise for the clinical studies.     

Controlled Transdermal Mucolytic Delivery System

Bromhexine a mucolytic agent was studied to explore for dermal route of administration. The formulations were based on commercial eudragit polymers and polyvinyl pyrrolidone.

Two systems i.e., Matrix and Pseudolatex were studied for their comparative performance evaluation in in vitro. The various combinations of hydrophobic (Eudragit RL-100) and hydrophilic (PVP 40,000) polymers were used to prepare the both matrix and pseudolatex topical systems. The prepared systems were studied for in vitro diffusion using a Franz diffusion cell. Study revealed that the relative concentration of hydrophobic to hydrophilic polymers determines the drug diffusion and across the skin permeation of the drug. Both the systems were noted to be stable, however, the drug release and across the skin permeability of drug from pseudolatex system recorded to be better and uniform. Preliminary studies on bromhexine are indicative of its potentiality for transdermal preparation and establish the need for in vivo evaluation.     

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 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.     

Controlled Transdermal Mucolytic Delivery System: In Vivo Performance

A multicomponent transdermal bromhexine delivering system was developed. The drug permeation across the human cadavar skin from either sexes was determined and found to be dependent on age, sex and site of skin. The system that could control the the delivery of the drug to allow it to permeate across the skin at a rate that is required to achieve the therapeutic concentration was selected and chosen for in vivo performance evaluation. Prior to in human volunteers availability testing the designed system was evaluated in rabbits and the system exhibiting desirable performance was redesigned for evaluation in human volunteers.T.P.S_o system delivering 1.991±0.116 mg bromhexine/cm² hr with a 453 μg/cm² priming dose was tested in human volunteers and found to maintain bromhexine blood level at or around peak plasma level for 20-24 hrs. The study reveals that bromhexine holds potential for transdermal delivery with a need of further clinical and pharmacodynamic studies.     

Mechanism of Transdermal Controlled Nitroglycerin Administration (III) Control of Skin Permeation Rate and Optimization

A mathematical model was developed to correlate the drug permeation rate through the skin with the drug release rate from a matrix-type drug delivery system. Experiments were carried out using hairless mouse abdominal skin mounted on a recently-developed and hydrodynamically well-calibrated Keshary-Chien skin permeation system. A matrix-type drug delivery system was designed to contain different loading doses of nitroglycerin and to study the effect of drug loading variation on the rate of drug release, the rate of skin permeation and the equilibrium concentration of nitroglycerin in the skin.

Results indicated that the stratum corneum plays a significant rate-limiting role in the skin permeation of nitroglycerin across the intact skin, yielding a constant skin permeation profile. The permeation rate across the intact skin was observed to increase with the increase in the drug release flux initially and then levelled off in a hyperbolic fashion. Various constants were obtained from the reciprocal plot of skin permeation rate vs. drug release flux. These constants could be used for the prediction of the skin permeation rate. A very good correlation between the predicted and the observed values of skin permeation rates was observed.

After the stratum corneum was removed by stripping technique, the mechanism and the rate of skin permeation became dominated by the mechanism and the release rate of the delivery system.

A linear correlation was observed between the drug permeation rate through the skin and the equilibrium concentration of drug in the skin. This correlation was observed in both intact and viable skins.     

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.     

Transdermal Nicotine Delivery Systems: Multi-institutional Cooperative Bioequivalence Studies

Nicotine transdermal delivery systems (nicotine-TDSs) have been evaluated clinically and found to provide effective assistance to smokers in smoking cessation with minimal occurrence of withdrawal symptoms. However, substantial skin reactions have been reported with the four nicotine-TDSs marketed recently. To reduce the skin reactions, a new type of nicotine-TDS has been recently developed. In vitro skin permeation studies demonstrated that this nicotine-TDS yields a constant skin permeation profile with a rate of permeation across the human cadaver skin comparable to the steady-state permeation rates attained by Habitrol™ and Nicoderm® systems. Clinical studies completed in two ethnic groups have demonstrated that this newly-developed nicotine-TDS is clinically effective and has yielded minimal skin irritation. As part of technical transfer program, a clinical study was initiated in 18 non-obese non-smoking Taiwanese, using Latin-square design, to compare the systemic bioavailability and pharmacokinetic profile of nicotine delivered transdermally from the nicotine-TDSs fabricated at technology licensee (Sintong nicotine-TDS) in comparison with that from the technology developer (TBS nicotine-TDS), using one marketed nicotine-TDS (Habitrol™ system) as the reference product. In vitro release and skin permeation studies of nicotine from the nicotine-TDSs manufactured at both licensor and licensee were found similar in kinetic profiles and comparable in rates. Since the patch size of these nicotine-TDSs studied was smaller than the marketed product used (10 cm² for both Sintong and TBS nicotine-TDSs, versus 20 cm² for Habitrol™ system), the daily doses of nicotine delivered to the volunteers are equivalent between Sintong and TBS nicotine-TDSs [9.58 (± 2.23) vs. 8.76 (± 1.88) mg/day/patch] but are lower than that from Habitrol™ system [15.13 (± 4.05) mg/day/patch]. Thus, for the statistical analysis of the pharmacokinetic parameters obtained need to be corrected for the difference in patch size and daily nicotine dose delivered. The results of statistical analysis suggested that Sintong and TBS nicotine-TDSs are bioequivalent to Habitrol™ system.     

Mechanism of Transdermal Controlled Nitroglycerin Administration (III) Control of Skin Permeation Rate and Optimization

Abstract

A mathematical model was developed to correlate the drug permeation rate through the skin with the drug release rate from a matrix-type drug delivery system. Experiments were carried out using hairless mouse abdominal skin mounted on a recently-developed and hydrodynamically well-calibrated Keshary-Chien skin permeation system. A matrix-type drug delivery system was designed to contain different loading doses of nitroglycerin and to study the effect of drug loading variation on the rate of drug release, the rate of skin permeation and the equilibrium concentration of nitroglycerin in the skin.

Results indicated that the stratum corneum plays a significant rate-limiting role in the skin permeation of nitroglycerin across the intact skin, yielding a constant skin permeation profile. The permeation rate across the intact skin was observed to increase with the increase in the drug release flux initially and then levelled off in a hyperbolic fashion. Various constants were obtained from the reciprocal plot of skin permeation rate vs. drug release flux. These constants could be used for the prediction of the skin permeation rate. A very good correlation between the predicted and the observed values of skin permeation rates was observed.

After the stratum corneum was removed by stripping technique, the mechanism and the rate of skin permeation became dominated by the mechanism and the release rate of the delivery system.

A linear correlation was observed between the drug permeation rate through the skin and the equilibrium concentration of drug in the skin. This correlation was observed in both intact and viable skins.     

Enhanced percutaneous permeability of nicardipine hydrochloride by carvone across the rat abdominal skin

The purpose of this study was to investigate the effect of carvone on the permeation of nicardipine hydrochloride across the excised rat abdominal epidermis from 2% w/w hydroxypropyl cellulose (HPC) gel system. The HPC gel formulations containing nicardipine hydrochloride (1% w/w) and selected concentrations of carvone (0 to 12% w/w) were prepared, and evaluated for drug content, stability of the drug, and in vitro permeation of the drug through excised rat abdominal epidermis. The HPC gel was found to contain 99.98 to 101.6% of nicardipine hydrochloride, and the drug was found to be stable in the HPC gels. The permeation flux of nicardipine hydrochloride across rat epidermis was increased markedly by the addition of carvone to the HPC gels. A maximum flux of nicardipine hydrochloride (243.95.70 ± 1.90 µg/cm²/hr) was observed with an enhancement ratio of 7.9 when carvone was incorporated at a concentration of 12% w/w in the HPC reservoir system. The differential scanning calorimetry and Fourier transform-infrared data indicated that carvone increased the permeability of nicardipine hydrochloride across the rat epidermis by partial extraction of lipids in the stratum corneum. The results suggest that carvone may be useful for enhancing the skin permeability of nicardipine hydrochloride from transdermal therapeutic system containing HPC gel as a reservoir.     

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 of a Skin Permeation cell to Simulate Clinical Study of Iontophoretic Transdermal Delivery

A new single-compartment iontophoretic skin permeation cell was developed to simulate the clinical application of iontophoretic devices. The stability and permeation kinetics of LHRH, the model peptide, were investigated in this new permeation cell (cell design A) using two analytical methods and compared with a commonly used skin permeation cell (cell design B). A polyacrylamide-based hydrogel device was fabricated as the drug reservoir for the iontophoretic transdermal delivery of LHRH. The skin permeation profiles of LHRH were found identical for both permeation cells when assayed by radioactivity measurement. However, cell design A gave a skin permeation profile that was substantially higher than that obtained in cell design B when assayed by HPLC. This is because the electrochemical degradation of LHRH occurred in the receptor compartment of the Valia-Chien permeation cell (cell design B). This degradation could be overcome by using the new single-compartment iontophoretic permeation cell.     

Effects of Adhesives and Permeation Enhancers on the Skin Permeation of Captopril

To formulate a transdermal drug delivery system of captopril, monolithic adhesive matrix type patches containing 20% captopril, different pressure-sensitive adhesives, and various permeation enhancers were prepared using a labcoater. The effects of the adhesives and permeation enhancers on skin permeation of captopril from the prepared patches were evaluated using Franz diffusion cells fitted with excised rat skins. The permeation rate of the drug through the excised skin was dependent on the type of polyacrylate copolymers studied. Fatty alcohols resulted in a pronounced enhancing effect on the skin permeation of captopril, while dimethyl sulfoxide,N-methyl-2-pyrrolidone, oleic acid, Transcutol, and polysorbate 20 showed no significant enhancing effect. The permeation-enhancing effect of the fatty alcohols reached the maximum at the level of 10%. Based on these results, a captopril patch may be developed with further optimization.     

Pharmacokinetic profile of a new matrix-type transdermal delivery system: diclofenac diethyl ammonium patch

A transdermal delivery system containing the anti-inflammatory analgesic diclofenac diethyl ammonium in an ethyl hexyl acrylate and vinyl acetate pressure-sensitive adhesive system was developed for percutaneous absorption. These patches were subjected to in vitro permeation and permeation enhancement studies through rat skin using a specially designed diffusion cell. Further, the work deals with percutaneous absorption studies carried out on both animals and human volunteers. The pharmacokinetic parameters calculated from the blood levels of the drug reveal a profile typical of a sustained-release formulation, with the ability to maintain adequate plasma levels for 24 hr (i.e., up to the next application). (Area under the curve [AUC]: 4.356 ± 1.3 mcg/ml.hr in animals and 0.442 ± 0.053 mcg/ml.hr in humans; T_max was 8 hr in both the cases, whereas C_max was 0.288 ± 0.088 mcg/ml in animals and 0.034 ± .008 mcg/ml in human volunteers.) The amount of the drug bioavailable for targeting the sites of action is lower than via the oral route, but the absorbed dose appears to be adequate for therapeutic use, particularly because of the absence of side effects.     

Comparison of Skin Permeation of Dideoxynucleoside-Type Anti-HIV Drugs: Alone Versus Combination

The effects of vehicles and skin permeation enhancer on the skin permeation of dideoxynucleoside-type anti-HN drugs, Zalcitabine (DDC), Didanosine (DDI), and Zidovudine (AZT), alone and in combination, were compared using hairless rat and human cadaver skins. Each drug alone or a combination of three drugs was added to various compositions of ethanol/water or ethanol/tricaprylin cosolvent system to saturation, and in vitro skin permeation studies were conducted using Valia-Chien skin permeation cells. In both ethanol/water and ethanol/tricaprylin systems, the hairless rat skin permeation rates achieved by each drug alone and three drugs in combination were not significantly different. Addition of oleic acid [1.0% (v/v) for each drug alone and 5.0% (v/v) for drug combination] in ethanol/tricaprylin (50:50) could not significantly enhance the skin permeation of these drugs. In hairless rat skin permeation of each drug alone, the permeation rates of all three drugs were dramatically enhanced with the addition of oleic acid in ethanol/water (60:40) cosolvent system and reached plateau level with oleic acid as low as 0.3% (v/v). However, in the case of drug combination, the enhancement of skin permeation rates of these drugs with the addition of oleic acid in ethanol/water (80:20) cosolvent system was not as high as that observed for each drug alone, and plateau level was not observed even at 5.0% (v/v) of oleic acid. Human cadaver skin permeation rates of each drug alone saturated in ethanol/ water (60:40) cosolvent system containing 1.0% (v/v) of oleic acid were 3-4 times lower than those of hairless rat skin. However, in skin permeation of three drugs in combination, saturated in ethanol/water (80:20) cosolvent system containing 5.0% (v/v) of oleic acid, human cadaver skin permeation rates of DDC and DDI were slightly lower than those of hairless rat skin, and there was no significant difference between the two skins for AZT. These results show that mutual skin permeation-enhancing effects of oleic acid and an ethanol/water cosolvent system Made the transdermal delivery of anti-HIV drugs, alone and in combination, feasible.     

Improved Stability of Lipid Coated Vitamin a in Animal Feed Additives

ABSTRACT

Lipids have been studied as methods of encapsulation, permeation enhancers, and as drug delivery systems. A lipid coating containing lecithin, cholesterol and functionalized stearyls was utilized in this study to inhibit the mineral catalyzed Vitamin A degradation in a dry flowable animal feed additive. Results indicate much improved stability.     

Comparison of Skin Permeation of Dideoxynucleoside-Type Anti-HIV Drugs: Alone Versus Combination

Abstract

The effects of vehicles and skin permeation enhancer on the skin permeation of dideoxynucleoside-type anti-HN drugs, Zalcitabine (DDC), Didanosine (DDI), and Zidovudine (AZT), alone and in combination, were compared using hairless rat and human cadaver skins. Each drug alone or a combination of three drugs was added to various compositions of ethanol/water or ethanol/tricaprylin cosolvent system to saturation, and in vitro skin permeation studies were conducted using Valia-Chien skin permeation cells. In both ethanol/water and ethanol/tricaprylin systems, the hairless rat skin permeation rates achieved by each drug alone and three drugs in combination were not significantly different. Addition of oleic acid [1.0% (v/v) for each drug alone and 5.0% (v/v) for drug combination] in ethanol/tricaprylin (50:50) could not significantly enhance the skin permeation of these drugs. In hairless rat skin permeation of each drug alone, the permeation rates of all three drugs were dramatically enhanced with the addition of oleic acid in ethanol/water (60:40) cosolvent system and reached plateau level with oleic acid as low as 0.3% (v/v). However, in the case of drug combination, the enhancement of skin permeation rates of these drugs with the addition of oleic acid in ethanol/water (80:20) cosolvent system was not as high as that observed for each drug alone, and plateau level was not observed even at 5.0% (v/v) of oleic acid. Human cadaver skin permeation rates of each drug alone saturated in ethanol/ water (60:40) cosolvent system containing 1.0% (v/v) of oleic acid were 3-4 times lower than those of hairless rat skin. However, in skin permeation of three drugs in combination, saturated in ethanol/water (80:20) cosolvent system containing 5.0% (v/v) of oleic acid, human cadaver skin permeation rates of DDC and DDI were slightly lower than those of hairless rat skin, and there was no significant difference between the two skins for AZT. These results show that mutual skin permeation-enhancing effects of oleic acid and an ethanol/water cosolvent system Made the transdermal delivery of anti-HIV drugs, alone and in combination, feasible.