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.     

Release of Tolmetin from Carbomw Gel Systems

Abstract

Gel-formulations containing a nonsteroidal anti-inflammatory drug, tolmetin, were prepared using three different carbomers namely, Carbopol? 934, 940 and 941. Effects of cosolvent composition, carbomer type, carbomer concentration and drug concentration on drug release from the gels were analyzed by factorial design. Gels with high aqueous content yielded significantly higher tolmetin release rates than gels with lower aqueous content. Although no significant differences in drug release characteristics were observed between the three carbomer gels, there was a trend in the release profiles; fastest drug release was observed from Carbopol? 941 gels and the slowest drug release was observed from Carbopol? 940 gels. Increasing the carbomer concentration from 1% w/w to 2% w/w had no significant effect on drug release from gel formulations prepared with all the three different types of carbomers. However, increasing the tolmetin concentration in the gels from 1% w/w to 4% w/w resulted in a dramatic increase in drug release. An investigation of the mechanism of drug release from the gels revealed that tolmetin release was diffusion controlled, except at the outset.     

Release of Tolmetin from Carbomw Gel Systems

Gel-formulations containing a nonsteroidal anti-inflammatory drug, tolmetin, were prepared using three different carbomers namely, Carbopol™ 934, 940 and 941. Effects of cosolvent composition, carbomer type, carbomer concentration and drug concentration on drug release from the gels were analyzed by factorial design. Gels with high aqueous content yielded significantly higher tolmetin release rates than gels with lower aqueous content. Although no significant differences in drug release characteristics were observed between the three carbomer gels, there was a trend in the release profiles; fastest drug release was observed from Carbopol™ 941 gels and the slowest drug release was observed from Carbopol™ 940 gels. Increasing the carbomer concentration from 1% w/w to 2% w/w had no significant effect on drug release from gel formulations prepared with all the three different types of carbomers. However, increasing the tolmetin concentration in the gels from 1% w/w to 4% w/w resulted in a dramatic increase in drug release. An investigation of the mechanism of drug release from the gels revealed that tolmetin release was diffusion controlled, except at the outset.     

Studies on Drug Release Kinetics from Carbomer Matrices

The objective of this study is to gain a mechanistic understanding of drug release kinetics from directly compressed tablets containing Carbopol 934P and 974P resins. Carbopol resins belong to a family of carbomers which are synthetic, high molecular weight, non-linear polymers of acrylic acid, crosslinked with polyalkenyl polyether. They are currently being used as polymeric matrices for controlling drug release in pharmaceutical tablets. This investigation focuses on the influence of the type of drug and the pH of the dissolution media, along with other factors on the drug release kinetics from carbomer matrices. Directly compressed tablets were prepared using a Stokes single station laboratory press and blends of polymers and lactose with drugs like theophylline, norephedrine HCI, and chlorpheniramine maleate. In vitro. drug release studies from the tablets were performed according to USP method II. Drug release rates were obtained by plotting the fraction released versus time and data fitted to the equation:     

Studies on Drug Release Kinetics from Carbomer Matrices

The objective of this study is to gain a mechanistic understanding of drug release kinetics from directly compressed tablets containing Carbopol 934P and 974P resins. Carbopol resins belong to a family of carbomers which are synthetic, high molecular weight, non-linear polymers of acrylic acid, crosslinked with polyalkenyl polyether. They are currently being used as polymeric matrices for controlling drug release in pharmaceutical tablets. This investigation focuses on the influence of the type of drug and the pH of the dissolution media, along with other factors on the drug release kinetics from carbomer matrices. Directly compressed tablets were prepared using a Stokes single station laboratory press and blends of polymers and lactose with drugs like theophylline, norephedrine HCI, and chlorpheniramine maleate. In vitro. drug release studies from the tablets were performed according to USP method II. Drug release rates were obtained by plotting the fraction released versus time and data fitted to the equation:     

In-Vitro Release Studies of Chlorpheniramine Maleate from Topical Bases Using Cellulose Membrane and Hairless Mouse Skin

Abstract

In-vitro release of chlorpheniramine maleate from various dermatological bases including a polymeric gel base, the modified hydrophilic base and the modified hydrophilic petrolatum base, was studied. The additive ingredients known to enhance the drug release from the topical bases were also evaluated at different concentration levels. These included urea, ethanol and dimethylsulfoxide (DMSO). The rank order of drug release through the cellulose membrane was observed to be: the gel base > the modified hydrophilic base > the modified hydrophilic petrolatum base. In general, the presence of the additives adversely affected the drug release except for the (DMSO) and ethanol in certain cases.

The formulations with optimum in-vitro release profiles of the drug through the cellulose membrane, were selected for further studies of the drug release using hairless mouse skin as the diffusion barrier. Here again, the gel formulation gave the best in-vitro release of the drug, and the data correlated well with the results previously obtained from the cellulose membrane.

The in-vitro data were treated with various kinetic principles to determine the relevant parameters, such as the steady state flux, the diffusion coefficient and the permeability coefficient. Using these information, the formulations were evaluated for their suitability for delivering chlorpheniramine maleate via the diadermatic dosage form.     

In-vitro release studies op chlorpheniramine maleate from topical bases using cellulose membrane and hairless mouse skin

Abstract

In-vitro release of chlorpheniramine maleate from various topical bases was studied using cellulose membrane and hairless mouse skin as the diffusion barriers. These included a polymer gel base, a modified hydrophilic ointment base and a modified petrolatum base. The effects of the additive ingredients, such as, urea, ethanol and dimethylsulfoxide (DMSO) on the drug release were also investigated. The rank order of drug release through the cellulose membrane was observed to be: the gel base > the modified hydrophilic ointment base > the modified hydrophilic petrolatum base. In general, the presence of additives adversely affected the drug release except for the (DMSO) and ethanol in certain cases.

The samples with maximum drug release through the cellulose membrane were further studied for the drug release using hairless mouse skin as the diffusion barrier. Here again, the gel base gave the best in-vitro release of the drug, and the data correlated well with the results obtained through the cellulose membrane. These data were treated with various kinetic principles to determine the relevant parameters, such as, the steady state flux, the diffusion coefficient and the permeability coefficient etc. Using these information, the samples were evaluated for delivering drug via diadermatic dosage form.     

In Vitro Release and Diffusion Studies of Promethazine Hydrochloride from Polymeric Dermatological Bases Using Cellulose Membrane and Hairless Mouse Skin

The study was designed to investigate the feasibility of developing a transdermal drug dosage form of promethazine hydrochloride (PMH). The in vitro release and diffusion characteristics of PMH from various dermatological polymeric bases were studied using cellulose membrane and hairless mouse skin as the diffusion barriers. These included polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), cross-linked microcrystalline cellulose, and carboxyl methyl cellulose sodium (Avicel® CL-611), and a modified hydrophilic ointment USP. In addition, the effects of several additive ingredients known to enhance the drug release from topical formulations were evaluated. The general rank order for the drug release from these formulations using cellulose membrane was observed to be PEG > HMPC > Avicel CL-611 > hydrophilic ointment base. The inclusion of the additives had little or no effect on the drug diffusion from these bases, except for the hydrophilic ointment formulation containing 15% ethanol, which provided a significant increase in the drug release. However, when these formulations were studied for drug diffusion through the hairless mouse skin, the Avicel CL-611 base containing 15% ethanol exhibited the optimum drug release. The data also revealed that this formulation gave the highest steady-state flux, diffusion, and permeability coefficient values and correlated well with the amount of drug release.     

Oral-based controlled release formulations using poly(acrylic acid) microgels

Aim: To investigate the release of hydrophobic and hydrophilic substances from tablets containing Pemulen and Carbopol as excipients. Method: The dissolution patterns of a hydrophobic (diazepam) and a hydrophilic active substance (midodrine-HCl) from different tablet formulations containing a nonmodified polyacrylic microgel (Carbopol 981 F) or a hydrophobically modified polyacrylic microgel (Pemulen®) have been studied. Possible differences in dissolution in phosphate buffer (pH 6.8) and in 0.1 M HCl between tablets produced using wet granulation and direct compression were also investigated. Results: Tablets produced by wet granulation had a greater effect on the release of active substance from the tablets. No major differences were observed in the release patterns of the hydrophilic substance midodrine-HCl from wet granulated tablets based on Carbopol and Pemulen. However, the release pattern of the more hydrophobic drug substance, diazepam, differed considerably between the two polymers. Wet granulation gave reproducible release patterns. The release patterns from the polymers differed considerably at pH 6.8 but were similar at low pH. Conclusions: The release of the diazepam from the hydrophobic polymer Pemulen was very slow, and the release was close to zero order.     

In vitro release and diffusion studies of promethazine hydrochloride from polymeric dermatological bases using cellulose membrane and hairless mouse skin

The study was designed to investigate the feasibility of developing a transdermal drug dosage form of promethazine hydrochloride (PMH). The in vitro release and diffusion characteristics of PMH from various dermatological polymeric bases were studied using cellulose membrane and hairless mouse skin as the diffusion barriers. These included polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), cross-linked microcrystalline cellulose, and carboxyl methyl cellulose sodium (Avicel CL-611), and a modified hydrophilic ointment USP. In addition, the effects of several additive ingredients known to enhance the drug release from topical formulations were evaluated. The general rank order for the drug release from these formulations using cellulose membrane was observed to be PEG > HMPC > Avicel CL-611 > hydrophilic ointment base. The inclusion of the additives had little or no effect on the drug diffusion from these bases, except for the hydrophilic ointment formulation containing 15% ethanol, which provided a significant increase in the drug release. However, when these formulations were studied for drug diffusion through the hairless mouse skin, the Avicel CL-611 base containing 15% ethanol exhibited the optimum drug release. The data also revealed that this formulation gave the highest steady-state flux, diffusion, and permeability coefficient values and correlated well with the amount of drug release.     

Physicochemical properties and mechanisms of drug release from melt-extruded granules consisting of chlorpheniramine maleate and Eudragit FS

Abstract

The objective of this research project was to characterize the drug release profiles, physicochemical properties and drug–polymer interaction of melt-extruded granules consisting of chlorpheniramine maleate (CPM) and Eudragit® FS. Melt extrusion was performed using a single screw extruder at a processing temperature of 65–75?°C. The melt extrudate was milled, blended with lactose monohydrate and then filled into hard gelatin capsules. Each capsule contained 300?mg CPM granules. The release of CPM was determined with the United States Pharmacopeia dissolution apparatus II using a three-stage dissolution medium testing in order to simulate the pH conditions of the gastrointestinal tract. Pore structure, thermal properties and surface morphologies of CPM granules were studied using mercury and helium pycnometer, differential scanning calorimeter and scanning electron microscope. Sustained release of CPM over 10?h was achieved. The release of CPM was a function of drug loading and the size of the milled granules. The complexation between CPM and Eudragit® FS as the result of counterion condensation was observed, and the interaction was characterized using membrane dialysis and H¹ NMR techniques. In both 0.1?N HCl and phosphate buffer pH 6.8, CPM was released via a diffusion mechanism and the release rate was controlled by the pore structure of the melt-extruded granules. In phosphate buffer pH 7.4, CPM release was controlled by the low pH micro-environment created by CPM, the pore structure of the granules and the in situ complexation between CPM and Eudragit® FS.     

Release and permeation studies of propranolol hydrochloride from hydrophilic polymeric matrices

Abstract

In-vitro release of propranolol hydrochloride, from various hydrophilic polymeric bases was studied. These included: methocel®, avicel® CL-611/ methylcellulose, polyvinyl alcohol/gelatin based systems. Several additives, such as, ethyl alcohol, dimethylsulfoxide (DMSO) and polyethylene glycol-400 were included in the formulations for possible enhancement of the drug release. The release studies were carried out using the cellulose membrane and the hairless mouse skin as the diffusion barriers. The general rank order for the drug release through these membranes was observed to be: the methocel® matrix > the avicel® CL-611 matrix > the polyvinyl alcohol/gelatin matrix > and the emulsion base. The additives in the formulations had little or no effect in enhancing the drug release. However, when the hairless mouse skin was soaked in (DMSO) for one hour prior to its use in the diffusion studies, the drug release was found to increase by 40% from the methocel® matrix formulation.

The drug release data were treated with various kinetic principles to assess the relevant parameters, such as the diffusion, partition and permeability coefficients. Using these information, the formulations were screened for their suitability to deliver propranolol hydrochloride via the diadermatic dosage form.     

Enhanced topical delivery of tacrolimus by a carbomer hydrogel formulation with transcutol P

Tacrolimus (TAC), a non-steroidal anti-inflammatory and immunosuppressive agent, is used for the treatment of atopic dermatitis (AD) and skin immune diseases. TAC-loaded topical hydrogel formulations composed of carbomer, carnosine, transcutol P (diethylene glycol monoethyl ether) and humectant were prepared. For comparison, TAC-loaded topical cream-type formulations were also prepared and commercially available TAC ointment was used as a reference. A drug release study in vitro revealed that the total amount of TAC released from hydrogels over 24?h was approximately 30 times greater than that for the reference formulation. Compared to the reference ointment and creams, carbomer gel formulations showed higher skin permeation and retention of TAC (significantly different at p?相似文献   

Investigation of the effect of various shellac coating compositions containing different water-soluble polymers on in vitro drug release

In this study drug pellets were coated with aqueous shellac coating formulations containing different amounts of polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), and carbomer 940. The coating level needed for enteric coating was determined. The influence of different amounts of PVA, HPMC, and carbomer on drug release and mechanism; the porosity, and the stability of shellac coatings was investigated. The results show that the incorporation of different concentrations of HPMC into shellac coatings, due to the increasing of pores, could considerably increase the drug release from the pellets in purified water. Moreover, the swelling effect of carbomer 940 leads to much more diffusivity through shellac coatings in water. In addition, PVA results in small cracking in the films and much more diffusion of drug in water. Furthermore, all coating systems containing different hydrophilic polymers that were used in the present work could prevent the dissolution of drug in simulated gastric juice for 2 hours. On the other hand, a rapid and complete release of drug within 45 minutes was observed in simulated intestinal fluid. Drug release from shellac coated pellets and ones containing different amounts of carbomer was affected between 3-6 months, whereas shellac coatings containing different amounts of PVA or HPMC show the same dissolution profiles with small deviation after 12 months.     

Thermal,mechanical and drug release characteristics of an acrylic film using active pharmaceutical ingredient as non-traditional plasticizer

Abstract

The objective of this study was to investigate thermal and mechanical properties as well as in vitro drug release of Eudragit® RL (ERL) film using chlorpheniramine maleate (CPM) as either active pharmaceutical ingredient or non-traditional plasticizer. Differential scanning calorimeter was used to measure the glass transition temperature (T_g) of 0–100% w/w CPM in ERL physical mixture. Instron testing machine was used to investigate Young’s modulus, tensile stress and tensile strain (%) of ERL film containing 20–60% w/w CPM. Finally, a Franz diffusion cell was used to study drug release from ERL films obtained from four formulations, i.e. CRHP0/0, CRHP0/5, CRHP2/0 and CRHP2/5. The T_g of ERL was decreased when the weight percentage of CPM increased. The reduction of the T_g could be described by Kwei equation, indicating the interaction between CPM and ERL. Modulus and tensile stress decreased whereas tensile strain (%) increased when weight percentage of CPM increased. The change of mechanical properties was associated with the reduction of the T_g when weight percentage of CPM increased. ERL films obtained from four formulations could release the drug in no less than 10?h. Cumulative amount of drug release per unit area of ERL film containing only CPM (CRHP0/0) was lower than those obtained from the formulations containing traditional plasticizer (CRHP0/5), surfactant (CRHP2/0) or both of them (CRHP2/5). The increase of drug release was a result of the increase of drug permeability through ERL film and drug solubility based on traditional plasticizer and surfactant, respectively.     

The influence of polymeric subcoats and pellet formulation on the release of chlorpheniramine maleate from enteric coated pellets

The influences of aqueous polymeric subcoats and pellet composition on the release properties of a highly water-soluble drug, chlorpheniramine maleate (CPM), from enteric coated pellets were investigated. Three different aqueous polymeric subcoats, Eudragit® RD 100, Eudragit® RS 30D, and Opadry® AMB, were applied to 10% w/w CPM-loaded pellets that were then enteric coated with Eudragit® L 30D-55. Observed drug release from the coated pellets in acidic media correlated with water vapor transmission rates derived for the subcoat films. The influence of pellet composition on retarding the release of CPM from enteric coated pellets in 0.1 N HCl was investigated. The rate of drug release was greatest for pellets prepared with lactose, microcrystalline cellulose, or dibasic calcium phosphate compared with pellets formulated with citric acid and microcrystalline cellulose. Citric acid reduced the pellet micro-environmental pH, decreasing the amount of drug leakage in 0.1 N HCL during the first 2 hr of dissolution. Polymer flocculation was observed when CPM was added to the Eudragit L 30D-55 dispersion. An adsorption isotherm was generated for mixtures of CPM and the polymer and the data were found to fit the Freundlich model for adsorption. Adsorption of CPM to the polymer decreased with the addition of citric acid to the drug-polymer mixtures.     

Design and evaluation in vitro of controlled release mucoadhesive tablets containing chlorhexidine

This investigation deals with the development of buccal tablets containing chlorhexidine (CHX), a bis-bis-guanide with antimicrobial and antiseptic effects in the oral cavity, and able to adhere to the buccal mucosa to give local controlled release of drug. A mucoadhesive formulation was designed to swell and form a gel adhering to the mucosa and controlling the drug release into the oral cavity.

Some batches of tablets were developed by direct compression, containing different amounts of hydroxypropylmethylcellulose (HPMC) and carbomer; changing the amount ratio of these excipients in formulations, it is possible easily modulate the mucoadhesive effect and release of drug. The in vitro tests were performed using the USP 26/NF paddle apparatus, a specifically developed apparatus, and a modified Franz diffusion cells apparatus. This last method allows a simultaneous study of drug release rate from the tablets and drug permeation through the buccal mucosa.

Similar tests have also been carried out on a commercial product, Corsodyl gel^®, in order to compare the drug release control of gel with respect to that of the mucoadhesive tablet, as a formulation for buccal delivery of CHX. While the commercial formulation does not appear to control the release, the formulation containing 15% w/w methocel behaves the best, ensuring the most rapid and complete release of the drug, together with a negligible absorption of the active agent as required for a local antiseptic action in the oral cavity.     

Formulation and rheological evaluation of ethosome-loaded carbopol hydrogel for transdermal application

Objective: To select a suitable ethosome-loaded Carbopol hydrogel formulation, specifically tailored for transdermal application that exhibits (i) plastic flow with yield stress of approximately 50–80?Pa at low polymer concentration, (ii) relatively frequency independent elastic (G′) and viscous (G″) properties and (iii) thermal stability.

Methods: Carbopol (C71, C934, C941, C971 or C974) hydrogels were prepared by dispersing Carbopol in distilled water followed neutralization by sodium hydroxide. The effects of Carbopol grade, Carbopol concentration, ethosome addition and temperature on flow (yield stress and viscosity) and viscoelastic (G′ and G″) properties of Carbopol hydrogel were evaluated. Based on the aforementioned rheological properties evaluated, suitable ethosome-loaded Carbopol hydrogel was selected. In-vitro permeation studies of diclofenac using rat skin were further conducted on ethosome-loaded Carbopol hydrogel along with diclofenac-loaded ethosomal formulation as control.

Results: Based on preliminary screening, C934, C971 and C974 grades were selected and further evaluated for flow and viscoelastic properties. It was observed that ethosome-loaded C974 hydrogel at concentration of 0.50 and 0.75% w/w, respectively, demonstrated acceptable plastic flow with distinct yield stress and a frequency independent G′ and G″. Furthermore, the flow and viscoelastic properties were maintained at the 4, 25 and 32?°C. The results from in vitro skin permeation studies indicate that ethosome-loaded C974 hydrogel at 0.5% w/w polymer concentration exhibited similar skin permeation as that of ethosomal formulation.

Conclusion: The results indicate that suitable rheological properties of C974 could facilitate in achieving desired skin permeation of diclofenac while acting as an efficient carrier system for ethosomal vesicles.     

The Influence of Polymeric Subcoats and Pellet Formulation on the Release of Chlorpheniramine Maleate from Enteric Coated Pellets

Abstract

The influences of aqueous polymeric subcoats and pellet composition on the release properties of a highly water-soluble drug, chlorpheniramine maleate (CPM), from enteric coated pellets were investigated. Three different aqueous polymeric subcoats, Eudragit® RD 100, Eudragit® RS 30D, and Opadry® AMB, were applied to 10% w/w CPM-loaded pellets that were then enteric coated with Eudragit® L 30D-55. Observed drug release from the coated pellets in acidic media correlated with water vapor transmission rates derived for the subcoat films. The influence of pellet composition on retarding the release of CPM from enteric coated pellets in 0.1 N HCl was investigated. The rate of drug release was greatest for pellets prepared with lactose, microcrystalline cellulose, or dibasic calcium phosphate compared with pellets formulated with citric acid and microcrystalline cellulose. Citric acid reduced the pellet micro-environmental pH, decreasing the amount of drug leakage in 0.1 N HCL during the first 2 hr of dissolution. Polymer flocculation was observed when CPM was added to the Eudragit L 30D-55 dispersion. An adsorption isotherm was generated for mixtures of CPM and the polymer and the data were found to fit the Freundlich model for adsorption. Adsorption of CPM to the polymer decreased with the addition of citric acid to the drug-polymer mixtures.     

Cataplasm-based controlled drug delivery: development and optimization of a novel formulation

The objective of the present study was to study the formulation variables involved in the development of a novel plasterlike preparation (cataplasm) and to optimize important formulation variables with an aim to maximize the in vitro release of the drug with minimum lag time. Cataplasm was prepared by dispersing a model drug (ibuprofen), humectant (glycerol), adhesive (Indopol H100®), polymer (Carbopol C934P®) with other formulation ingredients in a beaker with an open-blade impeller. The paste was cast on a nonocclusive backing membrane and dried overnight. The diffusion of the model drug was studied across a cellulosic membrane using Franz's diffusion cells. The amounts of three formulation variables, carbopol (X₁), glycerol (X₂), and indopol (X₃) were studied at three levels, and a face-centered cubic design was used to maximize the flux. An optimization procedure for maximum flux and minimum lag time predicted a flux of 97.22 mcg/cm²/hr at X₁ (2% w/w), X₂ (11.75% w/w), and X₃ (6% w/w). An experimental patch prepared with the above concentrations yielded a flux of 90.7 mcg/cm²/hr.