Chitosan Nanoparticles for Prolonged Delivery of Timolol Maleate

Timolol maleate-loaded chitosan (CS) nanoparticles were prepared by desolvation method. Experimental variables such as molecular weight of CS and amount of crosslinking agent were varied to study their effect on drug entrapment efficiency, size and release rates of nanoparticles. Chemical stability of timolol maleate (TM) and crosslinking of CS were confirmed by Fourier transform infrared spectroscopy. Differential scanning calorimetric studies were performed on drug-loaded nanoparticles to investigate crystalline nature of the drug after entrapment. Results indicated amorphous dispersion of drug in the polymer matrix. Scanning electron microscopy revealed irregularly shaped particles. Mean particle size of nanoparticles ranged between 118 and 203 nm, while zeta potential ranged between +17 and +22 mV. Entrapment efficiency of nanoparticles ranged between 47.6 and 63.0%. In-vitro release studies were performed in phosphate buffer saline of pH 7.4. A slow release of TM up to 24 h was observed. A 3² full factorial design was employed and second-order regression models were used to study the response (% drug release at 4 h). Release data as analyzed by an empirical relationship suggested that drug release deviated from the Fickian trend.     

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.     

Characterization of in Vitro Transdermal Iontophoretic Delivery of Insulin

Abstract

In-vitro studies were conducted to characterize the transdermal iontophoretic delivery of insulin, thus avoiding potential complications from various biological variations, which may be encountered during in-vivo studies. The proteolytic degradation of insulin in skin homogenates and degradation under the experimental conditions used was investigated. Appropriate adjuvants were incorporated to minimize the potential degradation problems of insulin. ¹²⁵I-Insulin was observed to penetrate into and accumulate in the skin during the iontophoresis period. It was then released gradually from this depot, as a mixture of intact and ¹²⁵-I labelled fragments, into the receptor medium. Drug desorption studies supported the theory of skin depot or reservoir formation. It was found that an electric field could be used to facilitate the desorption of drug from the depot. The post-application flux of insulin (or its fragments) from the skin depot formed during iontophoresis was monitored to study the factors affecting the iontophoretic delivery of insulin. Stripping and delipidization of the skin were noted to increase the skin permeation rate of insulin. The cumulative radioactivity permeated and accumulated in the skin was higher at pH 3.6 than at pH 7.4. The iontophoresis-facilitated transdermal delivery was observed to increase with increasing duration of current application and increasing donor concentration of insulin. Modulation of drug delivery by multiple applications was also found to be feasible.     

Characterization of in Vitro Transdermal Iontophoretic Delivery of Insulin

In-vitro studies were conducted to characterize the transdermal iontophoretic delivery of insulin, thus avoiding potential complications from various biological variations, which may be encountered during in-vivo studies. The proteolytic degradation of insulin in skin homogenates and degradation under the experimental conditions used was investigated. Appropriate adjuvants were incorporated to minimize the potential degradation problems of insulin. ¹²⁵I-Insulin was observed to penetrate into and accumulate in the skin during the iontophoresis period. It was then released gradually from this depot, as a mixture of intact and ¹²⁵-I labelled fragments, into the receptor medium. Drug desorption studies supported the theory of skin depot or reservoir formation. It was found that an electric field could be used to facilitate the desorption of drug from the depot. The post-application flux of insulin (or its fragments) from the skin depot formed during iontophoresis was monitored to study the factors affecting the iontophoretic delivery of insulin. Stripping and delipidization of the skin were noted to increase the skin permeation rate of insulin. The cumulative radioactivity permeated and accumulated in the skin was higher at pH 3.6 than at pH 7.4. The iontophoresis-facilitated transdermal delivery was observed to increase with increasing duration of current application and increasing donor concentration of insulin. Modulation of drug delivery by multiple applications was also found to be feasible.     

In Vitro Iontophoretic Release of Lithium Chloride and Lidocaine Hydrochloride from Polymer Electrolytes

Ionically conducting polymers, frequently known as polymer electrolytes, are potential candidates as hosts for drugs to be delivered iontophoretically. The iontophoretic delivery of lithium or lidocaine from polymer electrolyte films through a cellophane membrane was examined using different delivery current regimes. Thin, mechanically strong, polymer electrolyte films were fabricated from poly(ethylene oxide) (PEO) with lithium chloride or lidocaine hydrochloride. Experiments showed that iontophoretic transport of both lithium chloride and lidocaine hydrochloride might be achieved from these PEO-based films. Cation transport number determinations give values for PEO-based films of about 0.4 for lithium chloride systems and 0.12 for lidocaine hydrochloride systems. The mechanism of transport from these PEO-based polymer electrolyte films allows the delivery of ionic salts such as lithium chloride and lidocaine hydrochloride to be controlled solely by current, thus providing a system that can deliver precise amounts of drug.     

In Vitro Study of Transdermal Nicotine Delivery: Influence of Rate-Controlling Membranes and Adhesives

The objective of this study was to evaluate the influence of a rate-controlling membrane and adhesive on the in vitro permeation of nicotine. The physicochemical properties of the adhesive, including adhesion and rheology (viscosity), were also detected. Higher permeability of nicotine was observed through a hydrophilic membrane than through a hydrophobic membrane. Natural rubber and silicone were used as the adhesive bases, respectively. The silicone adhesive showed the highest adhesion among all adhesive formulations. To increase the adhesion of natural rubber, a tackifier (polyisoprene) and a secondary tackifier (terpene polymer; Px 1150®) were incorporated into the formulations to achieve acceptable adhesion. The nicotine permeation through silicone adhesive and three natural rubber adhesives with the secondary tackifier (2%, 4%, and 6% Px 1150) was close to that from a commercially available patch (Habitrol®), although the loading amount of nicotine was not the same. A longer lag time during the in vitro permeation study of nicotine was required for the adhesives prepared in our laboratory than for the commercially available patch.     

In Vitro Study of Transdermal Nicotine Delivery: Influence of Rate-Controlling Membranes and Adhesives

The objective of this study was to evaluate the influence of a rate-controlling membrane and adhesive on the in vitro permeation of nicotine. The physicochemical properties of the adhesive, including adhesion and rheology (viscosity), were also detected. Higher permeability of nicotine was observed through a hydrophilic membrane than through a hydrophobic membrane. Natural rubber and silicone were used as the adhesive bases, respectively. The silicone adhesive showed the highest adhesion among all adhesive formulations. To increase the adhesion of natural rubber, a tackifier (polyisoprene) and a secondary tackifier (terpene polymer; Px 1150®) were incorporated into the formulations to achieve acceptable adhesion. The nicotine permeation through silicone adhesive and three natural rubber adhesives with the secondary tackifier (2%, 4%, and 6% Px 1150) was close to that from a commercially available patch (Habitrol®), although the loading amount of nicotine was not the same. A longer lag time during the in vitro permeation study of nicotine was required for the adhesives prepared in our laboratory than for the commercially available patch.     

In Vitro Delivery of Fluocinolone Acetonide in FAPG Base

The effects of oleic acid and lauric acid in a mixture of fatty alcohol and propylene glycol (FAPG base) on the percutaneous absorption of fluocinolone acetonide (FA) were investigated by using nude mouse skin and synthetic membrane in vitro. me mixture of 0.9% sodium chloride and methanol (91) was used as the receptor phase for the diffusion study. The concentration of FA in the receptor phase was determined by HPLC. fie optimal formulation of the FAPG base was obtained with the addition of 5% lauric acid     

Iontophoretic in Vitro Release of Antimycotics from Hydrogels

A new in vitro model for iontophoretic release from hydrogels was developed. It represents a modification of the rotary disk cell developed by Moll/Bender and can be used in a normal dissolution tester. The iontophoretic release from antimycotic hydrogels through an artificial membrane was investigated and different types of antimycotics were tested. The influence of current density, drug concentration and vehicle was determined.     

In Vitro and In Vivo Adhesion Testing of Mucoadhesive Drug Delivery Systems

Bioadhesive tablets were prepared by physical mixing of polymers and drug, then granulating and compressing into a tablet. The mucoadhesion was evaluated by shear stress measurement, detachment force measurement, and X-ray photography of the rabbit gastrointestinal tract. The strong interaction between the polymer and the mucous lining of the tissue helps increase contact time and permit localization. Polymers like hydroxypropyl methylcellulose K4M (HPMC K4M), hydroxypropyl methylcellulose 100 cps (HPMC 100 cps), carbopol-934, sodium carboxy methylcellulose (Na CMC), guar gum, and polyvinylpyrrolidone (PVP) were tested by shear stress measurement and detachment force measurement methods. HPMC K4M, showing maximum bioadhesion, was used in further studies. Adhesion was maximum between pH 5 and pH 6. Maximum adhesion was observed in the duodenum, followed by the jejunum and ileum. Barium sulfate (BaSO₄) matrix tablets containing polymer and drug were subjected to X-ray studies in rabbits, and it was found that the tablet was mucoadhesive even after 8 hr. Enteric coating did not show any effect on mucoadhesion after passing from the stomach.     

In Vitro and In Vivo Performance of a Multiparticulate Pulsatile Drug Delivery System

ABSTRACT

The objective of this study was to investigate the in vitro and in vivo drug release performance of a rupturable multiparticulate pulsatile system, coated with aqueous polymer dispersion Aquacoat® ECD. Acetaminophen was used as a model drug, because in vivo performance can be monitored by measuring its concentration in saliva. Drug release was typical pulsatile, characterized by lag time, followed by fast drug release. Increasing the coating level of outer membrane lag time was clearly delayed. In vitro the lag time in 0.1 N HCl was longer, compared to phosphate buffer pH 7.4 because of ionisable ingredients present in the formulation (crosscarmelose sodium and sodium dodecyl sulphate). In vitro release was also longer in medium with higher ion concentration (0.9% NaCl solution compared to purified water); but independent of paddle rotation speed (50 vs.100 rpm). Macroscopically observation of the pellets during release experiment confirms that the rupturing of outer membrane was the main trigger for the onset of release. At the end of release outer membrane of all pellets was destructed and the content completely released.

However, pellets with higher coating level and correspondingly longer lag time showed decreased bioavailability of acetaminophen. This phenomenon was described previously and explained by decreased liquid flow in the lower part of intestine. This disadvantage can be considered as a limitation for drugs (like acetaminophen) with high dose and moderate solubility; however, it should not diminish performance of the investigated system in principle.     

In Vitro and Ex Vivo Permeation Studies of Chlorpheniramine Maleate Gels Prepared by Carbomer Derivatives

The antihistaminic chlorpheniramine maleate (CPM) is used for symptomatic relief of hypersensitivity reactions and in pruritic skin disorders. At present, the drug is marketed in tablet, capsule, syrup, cream, and injectable dosage forms. Chlorpheniramine maleate has some side effects when taken orally. Due to its first pass effect, only 25%–45% of the orally administered dose reaches the blood circulation. To bypass these disadvantages, we aimed to investigate percutaneous absorption of CPM from gel formulations prepared with different carbomer derivatives (Carbopol 934, 940, 941, 2984, 980, and 981; main differences are related to presence of a comonomer and cross‐link density). Cellulose membrane was used as the diffusion barrier for all the formulations' drug‐release studies. The release of active substance from carbopol derivatives, which have the least cross‐linking density (Carbopol 941 and 981) was found to be numerically higher than the others. The formulation (F8; 1% Carbopol 941) that exhibited the maximum drug release through the cellulose membrane was further studied for drug release by using polyurethane membrane, excised rat skin, and human skin. The penetration of the active substance through different diffusion barriers was found to be statistically different (p?<?0.05) when compared. Of all the different diffusion barriers, rat skin gave the closest results to human skin. Thus topical application of CPM in the carbomer gel may be of potential use for local activity. The type and concentration of carbomers can affect drug release. The synthetic membranes are useful in assessments of formulations in quality assurance but they do not give definite indication of how a formulation will behave when it is used on skin.     

Transdermal and Buccal Delivery of Methylxanthines Through Human Tissue In Vitro

ABSTRACT

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.     

Development of a Transdermal Delivery Device for Melatonin In Vitro Study

The present study was undertaken to develop a transdermal delivery device for melatonin and to determine the effects of system design on the release of melatonin. Melatonin(MT) diffusion characteristics from 2 solvents through a series of ethylene vinyl acetate membranes with 4.5%, 9%, 19%, 28% vinyl acetate were characterized using vertical Franz® diffusion cells. The solvent used were 40% (v/v) propylene glycol (PG) and 40%(v/v) propylene glycol with 30%(w/v) 2-hydroxypropyl-β-cytrodextrin. The best release rate (Jss = 0.795 μg/h/cm²) was obtained from the 40% PG vehicle through the 28% vinyl acetate membrane. Melatonin diffusion through this membrane with an acrylate pressure sensitive adhesive (PSA) with and without MT loading was also studied. The data revealed an interaction between MT and the PSA in the systems with MT-loaded adhesive. A MT transdermal delivery device was constructed based on the above data. Effect of storage time (1 day, 2 days, and 3 days) on the developed device was also investigated. Steady state flux values of MT did not vary significantly with storage time (p-value = 0.14). The steady state flux was 1.88 ± 0.6 μg/hr/cm²(n = 9). However, storage time did affect the burst effect of MT. Total amount of MT released in the first hour was 137.4 ± 25.7 μg after 3 days, 61.5 ± 8.9 μg after 2 days, and 43.8 ± 20.9 μg after 1 day.     

Development of a Transdermal Delivery Device for Melatonin In Vitro Study

Abstract

The present study was undertaken to develop a transdermal delivery device for melatonin and to determine the effects of system design on the release of melatonin. Melatonin(MT) diffusion characteristics from 2 solvents through a series of ethylene vinyl acetate membranes with 4.5%, 9%, 19%, 28% vinyl acetate were characterized using vertical Franz® diffusion cells. The solvent used were 40% (v/v) propylene glycol (PG) and 40%(v/v) propylene glycol with 30%(w/v) 2-hydroxypropyl-β-cytrodextrin. The best release rate (Jss = 0.795 μg/h/cm²) was obtained from the 40% PG vehicle through the 28% vinyl acetate membrane. Melatonin diffusion through this membrane with an acrylate pressure sensitive adhesive (PSA) with and without MT loading was also studied. The data revealed an interaction between MT and the PSA in the systems with MT-loaded adhesive. A MT transdermal delivery device was constructed based on the above data. Effect of storage time (1 day, 2 days, and 3 days) on the developed device was also investigated. Steady state flux values of MT did not vary significantly with storage time (p-value = 0.14). The steady state flux was 1.88 ± 0.6 μg/hr/cm²(n = 9). However, storage time did affect the burst effect of MT. Total amount of MT released in the first hour was 137.4 ± 25.7 μg after 3 days, 61.5 ± 8.9 μg after 2 days, and 43.8 ± 20.9 μg after 1 day.     

Evaluation of Monolithic Osmotic Tablet System for Nifedipine Delivery In Vitro and In Vivo

Abstract

The aim of this study was to evaluate the monolithic osmotic tablet system (MOTS) containing a solid dispersion with the practically water-insoluble drug nifedipine in vitro and in vivo. In the drug release study in vitro, the release profiles of this system had almost zero-order kinetics. The influences of tablet formulation variables, sizes of the delivery orifice, membrane variables, and values of pH in the dissolution medium on nifedipine release from MOTS have been investigated. The results provided evidence that the tablet core played an important role in MOTS. While orifice sizes and membrane variables affected the nifedipine release rate, MOTS was independent of the dissolution medium. The appropriate orifice size was found to be in the range of 0.5–1.0 mm. The coating membrane incorporating hydrophilic polyethylene glycol (PEG) formed a porous structure. The human pharmacokinetics and relative bioavailability of MOTS containing nifedipine were compared with a commercial Adalat® osmotic tablet system containing an equivalent dose of nifedipine following an oral single dose of 30 mg given to each of 11 healthy volunteers in an open, randomized crossover study in vivo. The relative bioavailability for MOTS was 112%. There was no statistically significant difference in the pharmacokinetic parameters between two dosage forms. It is concluded that the monolithic osmotic tablet controlled release system is feasible for a long-acting preparation as a once-daily treatment.     

The Effects of Formulation Variables on Iontophoretic Transdermal Delivery of Leuprolide to Humans

Abstract

Feasibility of applying iontophoresis to facilitate the transdermal permeation of leuprolide acetate was investigated. Because of the complexity of the factors involved in the process of iontophoresis, theoretical predictions of the combination effects from formulation variables are difficult. This study incorporated the formulation variables, drug levels and buffer concentrations, in a device prepared by Drug Delivery System, Inc., to assess the feasibility for leuprolide delivery.

Steady state serum leuprolide concentrations were achieved within 30 minutes of patch application, and were maintained for the duration of the study period. An increase in LH levels was observed for each formulation. The serum leuprolide concentrations were higher with lower drug concentration and more dilute buffer solutions. Increasing drug concentration in the patch appeared to inhibit delivery of leuprolide. A mean steady state serum concentration, 0.8 ng/ml, was achieved by a formulation composed of 10 mg/ml leuprolide acetate and 0.05 M acetate buffer at pH 5.0. Competitive reaction of ions possibly involved in the delivery mechanism will be discussed.     

The Effects of Formulation Variables on Iontophoretic Transdermal Delivery of Leuprolide to Humans

Feasibility of applying iontophoresis to facilitate the transdermal permeation of leuprolide acetate was investigated. Because of the complexity of the factors involved in the process of iontophoresis, theoretical predictions of the combination effects from formulation variables are difficult. This study incorporated the formulation variables, drug levels and buffer concentrations, in a device prepared by Drug Delivery System, Inc., to assess the feasibility for leuprolide delivery.

Steady state serum leuprolide concentrations were achieved within 30 minutes of patch application, and were maintained for the duration of the study period. An increase in LH levels was observed for each formulation. The serum leuprolide concentrations were higher with lower drug concentration and more dilute buffer solutions. Increasing drug concentration in the patch appeared to inhibit delivery of leuprolide. A mean steady state serum concentration, 0.8 ng/ml, was achieved by a formulation composed of 10 mg/ml leuprolide acetate and 0.05 M acetate buffer at pH 5.0. Competitive reaction of ions possibly involved in the delivery mechanism will be discussed.     

Transdermal Iontophoretic Delivery of Thyrotropin-Releasing Hormone Across Excised Rabbit Pinna Skin

Abstract

Enhanced transport of a model peptide drug thyrotropin-releasing hormone (TRH), a tripeptide of molar mass 362 g and a pK_a 6.2, through excised rabbit pinna skin was achieved by means of iontophoresis with continuous current or monophase periodically pulsed current. The resulting flux in the steady state was proportional to the applied current density. In the transdermal iontophoretic delivery of TRH, the pulsed iontophoretic flux exceeded that obtained with a continuous current. At a low ionic strength, an increased degree of protonation in TRH increased the rate of permeation. The flux of TRH in a buffer at pH 4 is greater than that at pH 8 when the ionic strength is 0.1 M. At a greater ionic strength, the trend is reversed. The enhanced flux of unprotonated TRH during transdermal iontophoresis is attributed largely to electro-osmotic volume flow. An increased rate of permeation of TRH crossing the skin is achieved at low ionic strength, moderate pH, and a large duly cycle of current; the frequency of pulsed current had no significant influence on the rate of transdermal iontophoretic delivery of TRH.     

Transdermal Iontophoretic Delivery of Thyrotropin-Releasing Hormone Across Excised Rabbit Pinna Skin

Enhanced transport of a model peptide drug thyrotropin-releasing hormone (TRH), a tripeptide of molar mass 362 g and a pK_a 6.2, through excised rabbit pinna skin was achieved by means of iontophoresis with continuous current or monophase periodically pulsed current. The resulting flux in the steady state was proportional to the applied current density. In the transdermal iontophoretic delivery of TRH, the pulsed iontophoretic flux exceeded that obtained with a continuous current. At a low ionic strength, an increased degree of protonation in TRH increased the rate of permeation. The flux of TRH in a buffer at pH 4 is greater than that at pH 8 when the ionic strength is 0.1 M. At a greater ionic strength, the trend is reversed. The enhanced flux of unprotonated TRH during transdermal iontophoresis is attributed largely to electro-osmotic volume flow. An increased rate of permeation of TRH crossing the skin is achieved at low ionic strength, moderate pH, and a large duly cycle of current; the frequency of pulsed current had no significant influence on the rate of transdermal iontophoretic delivery of TRH.