Permeation of Naproxen from Saturated Solutions and Commercial Formulations Through Synthetic Membranes

Abstract

The release of naproxen through synthetic membranes, mounted in modified Franz-type diffusion cells, was evaluated, either from saturated solutions or from commercially available topical formulations containing 10% naproxen. The results obtained showed that the porous type synthetic membranes chosen (cellulose acetate and polyethersulphone) can be used for assessing product performance in quality control procedures. The formulations interacted with the solid membranes (silicone and EVA) to change their diffusional characteristics. However, transfer in the membrane, and not the formulation was rate controlling. These membranes could not therefore be used in assessing product release performance for quality control.     

Release of Urea from Semisolid Formulations Using a Multilayer Membrane System

A method for the determination of in vitro release of urea from semisolid formulations using a multilayer membrane system (MMS) has been developed. The artificial model membranes consisted of collodion as the matrix and glycerol as the hydrophilic acceptor phase. The method can be employed as a tool for comparison of in vitro release profile of semisolid formulations and, thus, can be used as a quality control procedure for assuring lot-to-lot uniformity.     

Comparison of in Vitro Release Rates of Nitroglycerin by Diffusion Through a Teflon Membrane to the USP Method

The in vitro release profile of nitroglycerin (GTN) from different transdermal patches through synthetic membranes has been determined and compared to the USP adapted release rate method. Five different nitroglycerin transdermal test formulations were compared to commercially available Nitro-Dur®. All formulations display similar release rate profiles when tested by the USP adapted release rate method. In contrast, significant differences among the tested formulations were observed by using a synthetic Teflon membrane. In these studied an attempt was made to develop a simple, reliable, and reproducible method for testing the release of GTN from different transdermal patches in vitro.     

Comparison of in Vitro Release Rates of Nitroglycerin by Diffusion Through a Teflon Membrane to the USP Method

Abstract

The in vitro release profile of nitroglycerin (GTN) from different transdermal patches through synthetic membranes has been determined and compared to the USP adapted release rate method. Five different nitroglycerin transdermal test formulations were compared to commercially available Nitro-Dur®. All formulations display similar release rate profiles when tested by the USP adapted release rate method. In contrast, significant differences among the tested formulations were observed by using a synthetic Teflon membrane. In these studied an attempt was made to develop a simple, reliable, and reproducible method for testing the release of GTN from different transdermal patches in vitro.     

Controlled-release naproxen using micronized ethyl cellulose by wet-granulation and solid-dispersion method

This study has been undertaken to develop a controlled-release tablet dosage form of naproxen using ethocel (ethyl cellulose) as the rate-controlling polymer. The formulations were made by employing the conventional wet-granulation method and the solid-dispersion method. Tablets made by both methods were compared for their controlled-release dissolution profiles. Both methods were useful in developing the controlled-release formulations of naproxen with desirable properties. However, the amount of polymer required to make a formulation with the desired release profile was 33% less via solid dispersion than via wet granulation. A cumulative 88% of naproxen was released from the solid-dispersion formulation, compared with 84% from the wet-granulation formulation.     

Preparation and irradiation of Pluronic F127-based thermoreversible and mucoadhesive hydrogel for local delivery of naproxen

To improve physical properties and modulate the mucoadhesive hydrogel formulation via cross-linking by radiation, hydrogels were prepared using thermoreversible polymer Pluronic F127 (PF127) and mucoadhesive polymer carbopol 934P (C934P). As a model drug, naproxen was loaded in the hydrogel formulation. Sol-gel transition temperatures of hydrogels were measured by the tube-inversion method. The mucoadhesive potential of each formulation was determined by measuring the force required to detach the formulation from oral mucosal tissue. To strengthen the mechanical properties, the formulations were irradiated using an electronic beam. Drug release from the hydrogels and the cytotoxicity of each formulation were investigated. Sol-gel transition temperatures of the formulations were decreased by the addition of carbopol and were close to body temperature. The mucoadhesive force of the PF127 formulation was increased by addition of carbopol. In vitro release was sustained and the release rate was reduced by the addition of carbopol. After irradiation, the mucoadhesive force was increased about five-fold especially in the case of PF127 23% (9.7 kPa) and in vitro release was not sustained further. In conclusion, the use of a PF127 formulation incorporating a mucoadhesive polymer could effectively and safely improve oral residence time and absorption of naproxen. Irradiated formulations showed permanent cross-linking and improved properties.     

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.     

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.     

Drug Release Test to Assess Quality of Topical Formulations in Japanese Market

Abstract

Three release test methods—watch glass method, rotating dialyses cell method, and disk assembly method (DA)—were assessed for use in a quality control procedure for four different semisolid topical formulations containing indomethacin (IDM). Although minor modification in the methods to optimize the release rate was necessary for each formulation, DA proved superior to the other two Methods and thus was used to assess the quality of topical formulations on the Japanese market. First, DA was used for a storage test of hydrophilic ointments and cataplasms; difference in the release profiles of IDM from these formulations showed changes with time, which suggests the usefulness of DA for checking lot-to-lot uniformity. Second, dermal patch and tape as transdermal delivery systems containing nitro-glycerin or isosorbide dinitrate were investigated. Since different sizes and shapes of these products are available, various assemblies of DA were required to Pt individual products. Different release patterns were obtained among the products for both drugs. These results suggest that DA is a simple, reproducible, and more useful quantitative release test for quality control of topical formulations.     

Drug Release Test to Assess Quality of Topical Formulations in Japanese Market

Three release test methods—watch glass method, rotating dialyses cell method, and disk assembly method (DA)—were assessed for use in a quality control procedure for four different semisolid topical formulations containing indomethacin (IDM). Although minor modification in the methods to optimize the release rate was necessary for each formulation, DA proved superior to the other two Methods and thus was used to assess the quality of topical formulations on the Japanese market. First, DA was used for a storage test of hydrophilic ointments and cataplasms; difference in the release profiles of IDM from these formulations showed changes with time, which suggests the usefulness of DA for checking lot-to-lot uniformity. Second, dermal patch and tape as transdermal delivery systems containing nitro-glycerin or isosorbide dinitrate were investigated. Since different sizes and shapes of these products are available, various assemblies of DA were required to Pt individual products. Different release patterns were obtained among the products for both drugs. These results suggest that DA is a simple, reproducible, and more useful quantitative release test for quality control of topical formulations.     

In vitro dissolution of two oral controlled release preparations of diclofenac sodium.

The development of controlled release formulations has brought about the need for appropriate quality control methods such as in vitro dissolution testing. Such tests are principally designed to obtain correlation with the in vivo performance of the formulation (1,2,3). If an in vitro test can be defined offering a good correlation the test may serve for routine quality control or may be useful in screening new drug formulations.     

Discriminatory dissolution method for quality control measurements of carbamazepine immediate release tablets based on in vitro--in vivo investigations

The purpose of this study was to identify a discriminatory dissolution method able to predict the in vivo performance of tablet formulations designed for carbamazepine (CBZ). After evaluation of dissolution medium and rotation speed using a 2? central composite design and investigation of the in vivo release behaviors in beagle dogs, the dissolution method of CBZ 100?mg tablets was validated using a USP apparatus II, at a rotation speed of 75?rpm, and 900?ml deaerated water with 0.5% sodium lauryl sulfate (w/v) as the dissolution medium. Dissolution profiles were evaluated by the Weibull parameters and the modified fit factor, ?^(1,area). The in vitro-in vivo relationship of CBZ tablets was examined. Compared with the results from the USP and Chinese Pharmacopoeia monograph, the proposed system provides a superior discriminatory method. Since the dissolution method in pharmacopoeia for CBZ tablets is unable to distinguish between a good and a bad product, the method presented here can be used for the quality control testing of CBZ tablets.     

Process capability: a criterion for optimizing multiple response product and process design

In this research, we consider the maximization of process capability as the criterion in product/process design that is used for selecting preferred design factor levels and propose several approaches for single and multiple response performance measure designs. All of these approaches assume that the relationship between a process performance measure and a set of design factors is represented via an estimate of a response surface function. In particular, we develop; (i) criteria for selecting an optimal design, which we call MCpk and MCpm; (h) mathematical programming formulations for maximizing MCpk and MCpm, including formulations for maximizing the desirability index (Harrington, 1965) and for maximizing the standardized performance criteria (Barton and Tsui, 1991) as special cases of the formulation for maximizing MCpk, (iii) formulations for considering cost when maximizing MCpk and MCpm, (iv) a means for assessing propagation of error; (v) a robust design method for assessing design factor effects on residual variance; (vi) a means for assessing the optimality of a proposed solution: and (vii) an original application in the screening of printed circuit board panels.     

Application of a Mixed Optimization Strategy in the Design of a Pharmaceutical Solid Formulation at Laboratory Scale

The objective of this work was to develop an optimization strategy for the design of pharmaceutical formulations. The mixed strategy was used to optimize a dry powder blend containing 500 mg of alpha methyl dopa to be filled into hard gelatin capsules. The experimental plan consisted of assessing blend flow and dissolution rate using formulations manufactured at small laboratory scale, selecting the optimum formulation, and confirming the data. Two optimization techniques were used in the solid pharmaceutical product design: a genetic algorithm (GA) and a downhill simplex technique. The genetic algorithm used in this work was implemented in an interactive form. Data for each generation of formulations were introduced to the computer with the corresponding values of a fitness function, which was determined in experimental form for each individual formulation. The fitness function used to evaluate product performance (capsule) was defined in terms of the dissolution rate multiplied by a weight function that penalizes those formulations with flow index outside a predefined range. The formulation design contained variable concentrations and types of lubricants/glidants. There were 64 combinations of seven agents with discrete ranges of concentrations codified into a 16-bit chromosome. Crossing and mutation operations were implemented with relatively high probabilities, for generations with a relatively small number of individuals, due to the restrictions imposed by the experimental cost. The mixed formulation strategy based on genetic algorithms and downhill simplex was used to obtain sequentially improved formulations based on two desired targets: in vitro dissolution rate and flow properties. The basic downhill simplex method was used to obtain an optimal formulation on the regression response surface obtained from the genetic algorithm data. The results obtained in this work clearly illustrate the potential of the proposed mixed optimization strategy to obtain optimal formulations.     

Application of a Mixed Optimization Strategy in the Design of a Pharmaceutical Solid Formulation at Laboratory Scale

The objective of this work was to develop an optimization strategy for the design of pharmaceutical formulations. The mixed strategy was used to optimize a dry powder blend containing 500 mg of alpha methyl dopa to be filled into hard gelatin capsules. The experimental plan consisted of assessing blend flow and dissolution rate using formulations manufactured at small laboratory scale, selecting the optimum formulation, and confirming the data. Two optimization techniques were used in the solid pharmaceutical product design: a genetic algorithm (GA) and a downhill simplex technique. The genetic algorithm used in this work was implemented in an interactive form. Data for each generation of formulations were introduced to the computer with the corresponding values of a fitness function, which was determined in experimental form for each individual formulation. The fitness function used to evaluate product performance (capsule) was defined in terms of the dissolution rate multiplied by a weight function that penalizes those formulations with flow index outside a predefined range. The formulation design contained variable concentrations and types of lubricants/glidants. There were 64 combinations of seven agents with discrete ranges of concentrations codified into a 16-bit chromosome. Crossing and mutation operations were implemented with relatively high probabilities, for generations with a relatively small number of individuals, due to the restrictions imposed by the experimental cost. The mixed formulation strategy based on genetic algorithms and downhill simplex was used to obtain sequentially improved formulations based on two desired targets: in vitro dissolution rate and flow properties. The basic downhill simplex method was used to obtain an optimal formulation on the regression response surface obtained from the genetic algorithm data. The results obtained in this work clearly illustrate the potential of the proposed mixed optimization strategy to obtain optimal formulations.     

Development and experimental validation of an overlay mortar with biocide activity

Biodeterioration of concrete by microorganism colonisation may be a problem in several structures, especially in irrigation and hydroelectric canals. The main problem in such structures is the proliferation of algae and cyanobacteria that affect the performance of the structure, increase the maintenance costs and affects its durability. A research was conducted to develop a novel cement-based material with biocide activity that can be used as an overlay mortar in existing structures, such as canals and pipes. With this aim, ten commercial biocides were evaluated in a laboratory campaign to assess the effectiveness of the compounds against the microbial colonisation of concrete. Both mono- and multicomponent formulations were designed from the commercial products, to increase their antimicrobial effect obtaining a set of biocide formulations. The formulations were submitted to a flowchart process to determine their influence on the physical properties of the concrete, evaluate the release of the actives, and their antimicrobial efficiency both before and after accelerated aging processes. During the campaign, some formulations were observed to diminish the strength of the concrete. Such behaviour was normally due to the interaction of the active with the cement hydration process. Other formulations showed a high release of active from the concrete in water, compromising the durability of the treatment. In general, monocomponent formulations did not succeed to fulfill all the requirements, thus multicomponent formulations were analysed. One studied multicomponent formulation presented particularly good results in all properties analysed. This product did not significantly change the properties of concrete and the release of active in water from the concrete was low, while the antimicrobial effects were long lasting.     

Assessment of drug release from oil depot formulations using an in vitro model -- potential applicability in accelerated release testing

In vitro drug release and transport rates from oil depot formulations under nonsink conditions have been investigated in the rotating dialysis cell model. Eight model drug compounds and eight oil vehicle compositions were used for the releaseexperiments. The experimentally obtained apparent first-order rate constants related to the drug appearance in the acceptor phase after initial instillation of a drug-containing oil solution were found to be in excellent agreement with the rate constants obtained from a theoretically derived expression. It was observed that the drug oil-water distribution coefficient was the key parameter influencing the release characteristics. As compared with ketoprofen, flurbiprofen exhibited a higher affinity for the oil, resulting in a significantly lower and more slowly decreasing drug concentrations in the aqueous donor compartment. Release profiles for prilocaine and the more lipophilic agent bupivacaine after incorporation of both drugs in fractionated coconut oil were characterized by a fast release of prilocaine, whereas bupivacaine was liberated much slower to the acceptor phase. The high oil-buffer interfacial area generated in vitro by rotation of the donor cell tends to overestimate release rates in comparison to those expected in vivo, for example, after intra-articular administration of oil solutions. The present in vitro method may constitute a valuable tool in accelerated in vitro release testing of parenteral oil depot formulations in areas comprising formulation design and product quality control.     

Release Kinetics of Tretinoin from Dermatological Formulations

Tretinoin, or retinoic acid, can be used in the treatment of a variety of skin diseases, depending on its concentration. Formulations containing tretinoin 1 % have been used in the therapy of malignant cutaneous diseases, namely, Kaposi 's syndrome. In lower concentrations, it has been used in antiacne formulations and in the treatment of anti-aging effects on photodamaged skin. The aim of the present study was to determine the variation profile of in vitro release of tretinoin, in order to establish the drug's partition coefficient between its carrier and the stratum corneum. The samples studied were formulations of tretinoin 0, 05% in carbopol 940 (a synthetic polymer), sodium carboxymethylcellulose (a semisynthetic polymer), and carob gum (a natural polymer) gels. The release profiles obtained from these formulations were compared to release profiles of retinoid creams. The formulations studied exhibited both good chemical and physical stabilities when submitted to rheological determinations, pH measurements, and drug dosage, throughout a 6-month period. The obtained results show that identical polymer viscosities result in identical release profiles; however, the release kinetics of tretinoin varies strongly in the way in which the drug is incorporated in the formulation (whether it is a solution or a suspension).     

Prediction of in vivo drug performance using in vitro dissolution coupled with STELLA: a study with selected drug products

Prediction of the in vivo performance of the drug product from the in vitro studies is the major challenging job for the pharmaceutical industries. From the current regulatory perspective, biorelevant dissolution media should now be considered as quality control media in order to avoid the risk associated. Physiological based pharmacokinetic models (PBPK) coupled with biorelevant dissolution medium is widely used in simulation and prediction of the plasma drug concentration and in vivo drug performance. The present investigation deals with the evaluation of biorelevant dissolution media as well as in vivo drug performance by PBPK modelling using STELLA® simulation software. The PBPK model was developed using STELLA® using dissolution kinetics, solubility, standard gastrointestinal parameters and post-absorptive disposition parameters. The drug product selected for the present study includes Linezolid film-coated immediate-release tablets (Zyvox), Tacrolimus prolonged-release capsules (Advagraf), Valganciclovir tablets (Valcyte) and Mesalamine controlled-release capsules (Pentasa) each belonging to different biopharmaceutics classification system (BCS). The simulated plasma drug concentration was analyzed and pharmacokinetic parameters were calculated and compared with the reported values. The result from the present investigation indicates that STELLA® when coupled with biorelevant dissolution media can predict the in vivo performance of the drug product with prediction error less than 20% irrespective of the dosage form (immediate release versus modified release) and BCS Classification. Thus, STELLA® can be used for in vivo drug prediction which will be helpful in generic drug development.     

Transdermal delivery controlled by a chitosan membrane

The release of a drug from a transdermal delivery system with a rate controlling chitosan membrane was analyzed in vitro and in vivo. Lidocaine hydrochloride, a local anesthetic, was used as the model drug. The in vitro permeability of various chitosan membranes for the drug was investigated using a Franz diffusion cell. Drug release was slower through chitosan membranes with a higher degree of deacetylation (% DD) and with a larger thickness. A transdermal chitosan patch was developed using a chitosan membrane for rate control and a chitosan hydrogel as a drug reservoir. The most prolonged release in vitro was obtained with a 95% DD chitosan rate controlling membrane. The transport mechanism was found to be non-Fickian. The functionality of this transdermal patch was studied on the forearm of human volunteers by assessing the anesthetic effect. Patches with 70% and 95% DD membranes delayed the anesthetic effect, increasing the delay with increasing % DD. It was concluded that a combination of chitosan membrane and chitosan hydrogel is a good transparent system for controlled drug delivery and that the release kinetics in vitro at least for lidocaine have a predictive value for its anesthetic effect in vivo. The demonstration of a direct relationship between in vitro drug membrane permeability and its physiological effect might be considered as quite unique.