Controlled Transdermal Mucolytic Delivery System: In Vivo Performance

Abstract

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.     

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.     

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.     

Controlled Transdermal Occlusive Delivery Device of Primaquine

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.     

Adhesive Matrix Type Transdermal Drug Delivery System for Nitroglycerin

The kinetics of release of nitroglycerin from adhesive matrix type patches was studied. At a high drug to adhesive ratio the patch consisted of nitroglycerin in part dispersed as droplets in the adhesive and in part dissolved in the adhesive. This patch showed instant release of a major fraction of nitroglycerin in the patch and thereafter release kinetics similar to that which may be expected for a solution system. The rate of skin permeation of nitroglycerin was influenced by the drug to adhesive ratio; first increasing with increase in drug to adhesive ratio and then showing no significant change at a high drug to adhesive ratio at which the system was apparently an emulsion of nitroglycerin in the adhesive.     

Transdermal Delivery of Propranolol

Three transdermal formulations containing propranolol hydrochloride in a hydrophilic polymer matrix were prepared-one without a rate controlling membrane(H-1), one with a 20μ thick Ethylene Vinyl Acetate(EVA) rate controlling membrane (H-2) and one with a 65μ thick EVA membrane. These patches were evaluated for their in-vitro performance. Cumulative % permeated across excised hairfree rat skin were 79.2% from H-1, 65.53% from H-2 and 53.44% from H-3. Increase in thickness of EVA lead to greater retention of drug in device and a zero order profile was seen with patches H-2 & H-3. Matrix diffusion profile was observed with H-1 patch.     

Transdermal Delivery of Propranolol

Three transdermal formulations containing propranolol hydrochloride in a hydrophilic polymer matrix were prepared-one without a rate controlling membrane(H-1), one with a 20μ thick Ethylene Vinyl Acetate(EVA) rate controlling membrane (H-2) and one with a 65μ thick EVA membrane. These patches were evaluated for their in-vitro performance. Cumulative % permeated across excised hairfree rat skin were 79.2% from H-1, 65.53% from H-2 and 53.44% from H-3. Increase in thickness of EVA lead to greater retention of drug in device and a zero order profile was seen with patches H-2 & H-3. Matrix diffusion profile was observed with H-1 patch.     

Design and Evaluation of a Lorazepam Transdermal Delivery System

The aim of this work was to study the release and the permeation rate of lorazepam, in order to develop a transdermal therapeutic system (TTS) containing that drug. Only a small number of drugs are by themselves able to permeate the skin at a useful rate in order to achieve a therapeutic effect. The lorazepam permeation rate did not reach that value and required a skin permeation enhancer to increase the skin's permeability. Three permeation enhancers (Tween 80, sodium lauryl sulfate, and benzalkonium chloride) were investigated in two different concentrations: 1% and 5% of the amount of lorazepam. The best permeation enhancement results were obtained using benzalkonium chloride in concentration of 5%.     

Design and Evaluation of a Lorazepam Transdermal Delivery System

Abstract

The aim of this work was to study the release and the permeation rate of lorazepam, in order to develop a transdermal therapeutic system (TTS) containing that drug. Only a small number of drugs are by themselves able to permeate the skin at a useful rate in order to achieve a therapeutic effect. The lorazepam permeation rate did not reach that value and required a skin permeation enhancer to increase the skin's permeability. Three permeation enhancers (Tween 80, sodium lauryl sulfate, and benzalkonium chloride) were investigated in two different concentrations: 1% and 5% of the amount of lorazepam. The best permeation enhancement results were obtained using benzalkonium chloride in concentration of 5%.     

Evaluation and Controlled Release Characteristics of Modified Xanthan Films for Transdermal Delivery of Atenolol

ABSTRACT

The present study was performed to evaluate the possibility of using modified xanthan films as a matrix system for transdermal delivery of atenolol (ATL), which is an antihypertensive drug. Acrylamide was grafted onto xanthan gum (XG) by free radical polymerization using ceric ion as an initiator. Fourier transform infrared spectroscopy and differential scanning calorimetry indicated the formation of the graft copolymer. The obtained graft copolymer was loaded with ATL and films were fabricated by solution casting method for transdermal application. Various formulations were prepared by varying the grafting ratio, drug loading, and different penetration enhancers. The formulations prepared were characterized for weight, thickness uniformity, water vapor transmission rate, and uniformity in drug content of the matrix. All the thin films were slightly opaque, smooth, flexible, and permeable to water vapor, indicating their permeability characteristics suitable for transdermal studies. Fourier transform infrared spectroscopy and differential scanning calorimetry studies indicated no significant interactions between drug and polymer. Drug is distributed uniformly in the matrix but showed a slight amorphous nature. Drug-loaded films were analyzed by X-ray diffraction to understand the drug polymorphism inside the films. Scanning electron microscopic studies of the placebo and drug-loaded films demonstrated a remarkable change in their surface morphology. The skin irritation tests were performed in mice and these results suggested that both placebo and drug-loaded films produced negligible erythema and edema compared to formalin (0.8% v/v) as the standard irritant. The in vitro drug release studies were performed in phosphate buffer saline using a Keshary-Chien diffusion cell. Different formulations were prepared and variations in drug release profiles were observed. Release data were analyzed by using the Ritger and Peppas equation to understand the mechanism of drug release as well as the estimation of n values, which ranged between 0.41 and 0.53, suggesting a Fickian diffusion trend.     

Transdermal Contraceptive Delivery System: Preclinical Development and Clinical Assessment

Abstract

An once-a-week transdermal (monophasic) contraceptive delivery system (TCDS), intended to be marketed in Asian countries, was developed at the Controlled Drug-Delivery Research Center, Rutgers, College of Pharmacy under the sponsorship of Sintong Chemical Industrial Co. Ltd. in Taiwan. This TCDS was designed to simultaneously deliver a low dose combination of levonorgestrel (LNG) and 17B-estradiol (E2) through the skin for the fertility regulation in female. In-vitro permeation study using human cadaver skin shows that 60.0 ± 9.42 mcg/day/10 cm² of LNG and 28.8 ± 4.96 mcg/day/10 cm² of E2 can be delivered from this system. The result of the one-week dermal toxicity study on 6 rabbits indicated the minimal potential of this TCDS to cause skin irritation. Histopathological examination revealed that this system causes only mild to moderate inflammation to the test animal which also showed no significant body weight change and sign of toxicity.

A phase I bioavailability-dose proportionality clinical study which consists of pre-treatment, treatment and post-treatment cycles was conducted on Fertile Chinese women. During the pre-treatment cycle, the 48 recruited subjects were given placebo patches to study the wearability (including skin irritation and adhesion tests). During the treatment cycle, each of the 8 subjects in Groups A, B and C received weekly application of 1, 2 or 3 pieces of 10 cm² TCDS patches, respectively, while each subject in Group D received one Chinese-made oral contraceptive pill (each pill contains 150 mcg of LNG and 35 mcg of ethynyl estradiol) per day as reference.

The TCDS patches were found to be very well accepted by the subjects as indicated by the results of the wearability study (PDII is less than 1.0 and mean survival rate of the patches = 99.5%). Residual assay of the used patches indicated that this TCDS has delivered LNG and E2 at the rate of about 5.0 mcg/cm².day and 4.0 mcg/cm². day, respectively, during the treatment cycle of the study. Radioimmunoassay of serum samples revealed that therapeutically effective serum concentration of LNG was achieved. Serum profiles of progesterone, LH and FSH also indicated that ovulation inhibition occurred in the majority of the all 3 groups of subjects receiving TCDS patches. The post-treatment hormonal profiles also indicated that upon the termination of the administration of TCDS patches, the majority of the subjects return to their normal state of menstrual cycle. It was also reported that none of the subjects participated in this phase I study became pregnant.

Due to the success of this phase I study, a pilot phase II study has been initiated which involves more than 100 study subjects. Up to the first week of September, 1993, 112 subjects have completed 3 cycles of study with a total of 342 woman-month. During this pilot phase II study, the participated subjects were found to be sexually active and none of the subject has been reported to become pregnant so far.     

Transdermal Contraceptive Delivery System: Preclinical Development and Clinical Assessment

An once-a-week transdermal (monophasic) contraceptive delivery system (TCDS), intended to be marketed in Asian countries, was developed at the Controlled Drug-Delivery Research Center, Rutgers, College of Pharmacy under the sponsorship of Sintong Chemical Industrial Co. Ltd. in Taiwan. This TCDS was designed to simultaneously deliver a low dose combination of levonorgestrel (LNG) and 17B-estradiol (E2) through the skin for the fertility regulation in female. In-vitro permeation study using human cadaver skin shows that 60.0 ± 9.42 mcg/day/10 cm² of LNG and 28.8 ± 4.96 mcg/day/10 cm² of E2 can be delivered from this system. The result of the one-week dermal toxicity study on 6 rabbits indicated the minimal potential of this TCDS to cause skin irritation. Histopathological examination revealed that this system causes only mild to moderate inflammation to the test animal which also showed no significant body weight change and sign of toxicity.

A phase I bioavailability-dose proportionality clinical study which consists of pre-treatment, treatment and post-treatment cycles was conducted on Fertile Chinese women. During the pre-treatment cycle, the 48 recruited subjects were given placebo patches to study the wearability (including skin irritation and adhesion tests). During the treatment cycle, each of the 8 subjects in Groups A, B and C received weekly application of 1, 2 or 3 pieces of 10 cm² TCDS patches, respectively, while each subject in Group D received one Chinese-made oral contraceptive pill (each pill contains 150 mcg of LNG and 35 mcg of ethynyl estradiol) per day as reference.

The TCDS patches were found to be very well accepted by the subjects as indicated by the results of the wearability study (PDII is less than 1.0 and mean survival rate of the patches = 99.5%). Residual assay of the used patches indicated that this TCDS has delivered LNG and E2 at the rate of about 5.0 mcg/cm².day and 4.0 mcg/cm². day, respectively, during the treatment cycle of the study. Radioimmunoassay of serum samples revealed that therapeutically effective serum concentration of LNG was achieved. Serum profiles of progesterone, LH and FSH also indicated that ovulation inhibition occurred in the majority of the all 3 groups of subjects receiving TCDS patches. The post-treatment hormonal profiles also indicated that upon the termination of the administration of TCDS patches, the majority of the subjects return to their normal state of menstrual cycle. It was also reported that none of the subjects participated in this phase I study became pregnant.

Due to the success of this phase I study, a pilot phase II study has been initiated which involves more than 100 study subjects. Up to the first week of September, 1993, 112 subjects have completed 3 cycles of study with a total of 342 woman-month. During this pilot phase II study, the participated subjects were found to be sexually active and none of the subject has been reported to become pregnant so far.     

Transdermal Drug Delivery System of Haloperidol to Overcome Self-Induced Extrapyramidal Syndrome

Abstract

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.     

Permeation Enhancers for Transdermal Drug Delivery

The transdermal route has been recognized as one of the highly potential routes of systemic drug delivery and provides the advantage of avoidance of the first-pass effect, ease of use and withdrawal (in case of side effects), and better patient compliance. However, the major limitation of this route is the difficulty of permeation of drug through the skin. Studies have been carried out to find safe and suitable permeation enhancers to promote the percutaneous absorption of a number of drugs. The present review includes the classification of permeation enhancers and their mechanism of action; thus, it will help in the selection of a suitable enhancer(s) for improving the transdermal permeation of poorly absorbed drugs.     

Iontophoretically Induced Transdermal Delivery of Salbutamol

Abstract

Passive and iontophoretically assisted transport of salbutamol from a hydrogel matrix has been studied in vitro across a model membrane and in vivo and in vitro across human stratum corneum.

in vitro experiments were conducted in specially designed glass diffusion cells and initial experiments using cellophane membranes showed that the passive release of salbutamol from the hydrogel across the membrane was matrix-controlled and that this transport could be significantly enhanced by the application of an iontophoretic current Passive diffusion of salbutamol from a gel matrix containing the sulphate through stratum corneum membranes, was found to be negligible over a 24 hour period, but significant transport could be induced using current densities in the range 0.04-0.4mA cm^-2. The quantity of drug transported increased linearly with time, and was proportional to the current density used.

Preliminary in vivo trials in two subjects showed significant electrically assisted systemic delivery of the drug using iontophoretic currents of 0.1 - 0.2mA over a 4 hour period.