Pharmacokinetics of a novel liquid controlled release codeine formulation

Codeine is an important opioid anti-tussive agent whose short half-life (2.9?±?0.7?h) requires that it be administered at 4-h intervals when formulated as a simple aqueous solution. Liquid controlled release codeine formulations such as an older Codipertussin^® formulation, which contained codeine bound to an ion exchange resin and coated with a retardant polymer, achieved an equivalent bioavailability when administered every 12?h. An accompanying paper described the development and in vitro characterization of a novel Codipertussin^® formulation containing a non-coated codeine:ion exchange resin (Amberlite IR 69 F) complex. In this study, the bioavailability of codeine from this new liquid controlled release formulation was investigated in an open label, single center, randomized, steady-state, cross-over study in healthy male volunteers. Participants received either 69.7?mg codeine as the controlled release liquid form every 12?h or 23.2?mg codeine in solution every 4?h. Controlled release from the suspension of beads protracted the apparent mean half life of codeine from 3.2?h to 8.2?h, while the mean AUC_{0–12 h} was unchanged. In vivo codeine release profiles were further derived by the numerical deconvolution method, using the data from the drug solution as weighting function for the body system. Comparison of the data obtained with the in vitro release data presented in our earlier work showed an acceptable in vitro–in vivo correlation, which was described as in vitro–in vivo relationship, indicating the power of the in vitro method to predict in vivo pharmacokinetic behavior.     

In vitro-in vivo correlation and comparative bioavailablity of vincamine in prolonged-release preparations

Developing an in vitro dissolution test that gives good correlation with in vivo data for a particular drug product is an important objective. Available dissolution data of vincamine prolonged-release preparations show different in vitro release behavior at different pH using the conventional dissolution techniques. This does not allow development of an in vitro-in vivo correlation (IVIVC). In the present work, the flow-through cell (FTC) dissolution system (USP apparatus 4) was utilized to compare the release rate of three marketed prolonged-release oral formulations of vincamine; namely, a brand innovator formulation used as the reference and two formulations from different manufacturers as test products. Both the open and closed systems of FTC were used at variable pH. A comparative bioavailability study was then conducted in 16 healthy volunteers for a test versus the reference product by administering a single dose of 60 mg in a crossover design. Vincamine plasma concentrations were analyzed by a sensitive high-performance liquid chromatography (HPLC) method. This was followed by assessment of IVIVC according to level A as specified by USP 23; the absorbed fraction of vincamine was determined using the Wagner-Nelson method. The results indicated that the pH of the medium affects the release rate pronouncedly. The relative bioavailability based on C_max and AUC_0-12 were found to be 83.15% and 84.15%, respectively. Good correlation was obtained between fraction absorbed in vivo and fraction dissolved in vitro by applying the open system of the FTC. This technique gave the most favorable results with regard to the percentage vincamine released and the IVIVC     

Moment Analysis for the Evaluation of In Vitro Drug Release and In Vivo Bioavailability of Theophylline Microcapsules

Abstract

Statistical moment analysis has been used to establish an in vitro-in vivo correlation for five types of theophylline ethylcellulose microcapsules prepared by using various concentrations of ethylene-vinyl acetate (EVA) copolymer as a coacervation-inducing agent. The concentration of EVA copolymer was found to be played an important function in the controlled release of theophylline microcapsules. Correlations were found between the in vitro dissolution behavior, e.g., MDT _0→7, in vitro' and the rate of bioavailability, e.g., Cmax, Tmax, MDT _{in vivo} or MRT_0→2, although there was no valid correlation with the extent of bioavailability, e.g., AUC_0→27. Thus, moment analysis by studying the quantitative in vitro-in vivo correlations relating to drug release was validated.     

Reformulation of a codeine phosphate liquid controlled-release product

Background: Ion-exchange resins have been successfully used to create drug formulations providing controlled drug release that are easy to swallow, are sufficiently stable, and have good taste-masking characteristics. The objective of the present study was to replace the ion-exchange resin in a proven delayed release codeine preparation with a new resin able to provide the beneficial properties of the original formulations without the need for Eudragit coating to comply with modern manufacturing regulations. Methods: Nine cationic exchangers with different particle meshes, form, and pore structures were optimally loaded with codeine and their respective in vitro codeine release profiles were compared using the USP XXIII paddle method. Results: The most favorable release profiles were obtained with Amberlite IR 69 F and with Dowex 50 × 8?100. The former was used to prepare the formulated drug–resin complexes as it was available in a pharmaceutically pure form. Both, the cough syrup and concentrate formulations exhibited drug release profiles equivalent to the nonformulated drug–resin complex. These profiles as well as initial free codeine levels, the purity, and the identity were moreover maintained for a storage period of at least 6 months. Conclusion: The in vitro dissolution profiles demonstrated that the use of ion exchanger is most suitable for the development of sustained release codeine formulations.     

In Vitro-In Vivo Correlation and Comparative Bioavailablity of Vincamine in Prolonged-Release Preparations

Developing an in vitro dissolution test that gives good correlation with in vivo data for a particular drug product is an important objective. Available dissolution data of vincamine prolonged-release preparations show different in vitro release behavior at different pH using the conventional dissolution techniques. This does not allow development of an in vitro-in vivo correlation (IVIVC). In the present work, the flow-through cell (FTC) dissolution system (USP apparatus 4) was utilized to compare the release rate of three marketed prolonged-release oral formulations of vincamine; namely, a brand innovator formulation used as the reference and two formulations from different manufacturers as test products. Both the open and closed systems of FTC were used at variable pH. A comparative bioavailability study was then conducted in 16 healthy volunteers for a test versus the reference product by administering a single dose of 60 mg in a crossover design. Vincamine plasma concentrations were analyzed by a sensitive high-performance liquid chromatography (HPLC) method. This was followed by assessment of IVIVC according to level A as specified by USP 23; the absorbed fraction of vincamine was determined using the Wagner-Nelson method. The results indicated that the pH of the medium affects the release rate pronouncedly. The relative bioavailability based on C_max and AUC_0–12 were found to be 83.15% and 84.15%, respectively. Good correlation was obtained between fraction absorbed in vivo and fraction dissolved in vitro by applying the open system of the FTC. This technique gave the most favorable results with regard to the percentage vincamine released and the IVIVC     

Development of monolithic osmotic pump tablet system for isosorbide-5-mononitrate delivery and evaluation of it in vitro and in vivo

The objective of this study is to develop the monolithic osmotic pump tablet system (MOTS) containing isosorbide-5-mononitrate (5-ISMN), and to evaluate its in vitro and in vivo properties. The influences of tablet formulation variables, size and location of the delivery orifice, membrane variables, and pH value of the dissolution medium on 5-ISMN release from MOTS have been investigated. These results demonstrated that the tablet core played an important role in MOTS, and membrane variables could affect the 5-ISMN release rate. The optimal formulation of 5-ISMN MOTS was determined by uniform design. Furthermore, the dog pharmacokinetics and relative bioavailability of the test formulation (5-ISMN MOTS) have been compared with the reference formulation (Imdur: 60 mg/tablet, a sustained release, SR, tablet system) following an oral single dose of 60 mg given to each of six Beagle dogs. The mean drug fraction absorbed by the dog was calculated by the Wagner-Nelson technique. The results showed that drug concentration in plasma could be maintained more stable and longer after the administration of 5-ISMN MOTS compared with the matrix tablets of Imdur, and a level A "in vitro-in vivo correlation" was observed between the percentage released in vitro and percentage absorbed in vivo. It is concluded that 5-ISMN MOTS is more feasible for a long-acting preparation than 5-ISMN SR tablet system as once-a-day treatment, and it is very simple in preparation, and can release 5-ISMN at the rate of approximately zero order for the combination of hydroxypropylmethyl cellulose as retarder and NaCl as osmogent.     

Porous carrier based floating granular delivery system of repaglinide

A floating granular delivery system consisting of calcium silicate (CS) as porous carrier; repaglinide (Rg), an oral hypoglycemic agent; and hydroxypropyl methylcellulose K4M (HPMC K4M), ethyl cellulose (EC) and carbopol 940 (CP940) as matrix forming polymers was prepared and evaluated for its gastro-retentive and controlled release properties. The effect of various formulation and process variables on the particle morphology, micromeritic properties, in vitro floating behavior, drug content (%) and in vitro drug release was studied. The transit of floating granules of optimized formulation in the gastrointestinal (GI) tract was monitored by gamma scintigraphy in albino rabbits. The optimized formulation was compared in vivo with lactose granules (RgSCLG) prepared from identical polymers with their optimized composition ratio. Repaglinide-loaded optimized formulation was orally administered to albino rabbits and blood samples collected were used to determine pharmacokinetic parameters of Rg from floating granular formulation. Results were compared with pharmacokinetic parameters of marketed tablet formulation of Rg. The optimized formulation (RgSCG4) demonstrated favorable in vitro floating and release characteristics. Prolonged gastric residence time (GRT) of over 6 hr was achieved in all subjects for calcium silicate based floating granules of Rg. The relative bioavailability of Rg-loaded floating granules increased 3.8-fold in comparison to that of its marketed capsule. The designed system, combining excellent buoyant ability and suitable drug release pattern, offered clear advantages in terms of increased bioavailability of repaglinide.     

Porous Carrier Based Floating Granular Delivery System of Repaglinide

ABSTRACT

A floating granular delivery system consisting of calcium silicate (CS) as porous carrier; repaglinide (Rg), an oral hypoglycemic agent; and hydroxypropyl methylcellulose K4M (HPMC K4M), ethyl cellulose (EC) and carbopol 940 (CP940) as matrix forming polymers was prepared and evaluated for its gastro-retentive and controlled release properties. The effect of various formulation and process variables on the particle morphology, micromeritic properties, in vitro floating behavior, drug content (%) and in vitro drug release was studied. The transit of floating granules of optimized formulation in the gastrointestinal (GI) tract was monitored by gamma scintigraphy in albino rabbits. The optimized formulation was compared in vivo with lactose granules (RgSCLG) prepared from identical polymers with their optimized composition ratio. Repaglinide-loaded optimized formulation was orally administered to albino rabbits and blood samples collected were used to determine pharmacokinetic parameters of Rg from floating granular formulation. Results were compared with pharmacokinetic parameters of marketed tablet formulation of Rg. The optimized formulation (RgSCG₄) demonstrated favorable in vitro floating and release characteristics. Prolonged gastric residence time (GRT) of over 6 hr was achieved in all subjects for calcium silicate based floating granules of Rg. The relative bioavailability of Rg-loaded floating granules increased 3.8-fold in comparison to that of its marketed capsule. The designed system, combining excellent buoyant ability and suitable drug release pattern, offered clear advantages in terms of increased bioavailability of repaglinide.     

Preparation and in vivo evaluation of spray dried matrix type controlled-release microparticles of tamsulosin hydrochloride for orally disintegrating tablet

The objective of this study was to achieve an optimal formulation of spray dried matrix type controlled-release (MTCR) microparticles containing tamsulosin hydrochloride for orally disintegrating tablet. To control the release rate of tamsulosin hydrochloride, Acrylate-methacrylate copolymer (Eudragit(?) L-100 or Eudragit(?) S-100) and ethylcellulose were employed on the composition of MTCR microparticles. Physicochemical properties of MTCR microparticles such as particle size and SEM were characterized. Pharmacokinetic parameters of tamsulosin hydrochloride were evaluated in the rats after oral administration. MTCR microparticles were spherical microparticles of around 10 μm diameter with a corrugated surface. ODTs containing MTCR microparticles were disintegrated within 30 s and MTCR microparticles were able to control the release rate of tamsulosin hydrochloride following Fickian diffusion mechanism. The in vitro release rates of tamsulosin hydrochloride from MTCR microparticles were proportional to the ratio of Acrylate-methacrylate copolymer to ethylcellulose. Moreover, MTCR microparticles retarded the in vivo release rate of tamsulosin hydrochloride without reducing the bioavailability. Our results suggest that MTCR microparticles may be potential oral dosage forms to control the release and to improve the bioavailability of tamsulosin hydrochloride.     

Oral sustained delivery of theophylline and cimetidine from in situ gelling pectin formulations in rabbits

The aim of this study was to evaluate the potential of an in situ gelling pectin formulation as a vehicle for the oral sustained delivery of theophylline and cimetidine. In vitro studies demonstrated diffusion-controlled release of theophylline from 1, 1.5, and 2% w/v pectin gels. Release of this drug from 1.5% w/v pectin gels formed in situ in rabbit stomach was sustained over a period of 12 hours giving a theophylline bioavailability some seven fold higher than when administered from a commercial syrup. In contrast, interactions between cimetidine and pectin led to weak gelation of the pectin sols that prevented any meaningful determination of in vitro release characteristics. Similarly, in vivo release profiles from pectin formulations containing cimetidine were similar to that from a solution of this drug in buffer, indicative of weak gelation. Examination of the content of the rabbit stomach 5 hours after administration of 1.5% w/v pectin sols containing drug confirmed gel formation, but gels containing cimetidine were noticeably softer than those containing theophylline.     

Preparation and in vitro/in vivo evaluation of azilsartan osmotic pump tablets based on the preformulation investigation

The objective of this study was to design and evaluate azilsartan osmotic pump tablets. Preformulation properties of azilsartan were investigated for formulation design. Azilsartan osmotic pump tablets were prepared by incorporation of drug in the core and subsequent coating with cellulose acetate and polyethylene glycol 4000 as semi-permeable membrane, then drilled an orifice at the center of one side. The influence of different cores, compositions of semipermeable membrane and orifice diameter on azilsartan release were evaluated. The formulation of core tablet was optimized by orthogonal design and the release profiles of various formulations were evaluated by similarity factor (f₂). The optimal formulation achieved to deliver azilsartan at an approximate zero-order up to 14?h. The pharmacokinetic study was performed in beagle dogs. The azilsartan osmotic pump tablets exhibited less fluctuation in blood concentration and higher bioavailability compared to immediate-release tablets. Moreover, there was a good correlation between the in vitro dissolution and in vivo absorption of the tablets. In summary, azilsartan osmotic pump tablets presented controlled release in vitro, high bioavailability in vivo and a good in vitro-in vivo correlation.     

Preparation of Codeine-Resinate and Chlorpheniramine-Resinate Sustained-Release Suspension and its Pharmacokinetic Evaluation in Beagle Dogs

ABSTRACT

Using ion exchange resins (IERs) as carriers, a dual-drug sustained release suspension containing codeine, and chlorpheniramine had been prepared to elevate drug safety, effectiveness and conformance. The codeine resinate and chlorpheniramine resinate beads were prepared by a batch process and then impregnated with Polyethylene glycol 4000 (PEG 4000), respectively. The PEG impregnated drug resinate beads were coated with ethylcellulose as the coating polymer and di-n-butyl-phthalate as plasticizer in ethanol and methylene chloride mixture by the Wurster process. The coated PEG impregnated drug resinate beads were dispersed in an aqueous suspending vehicle containing 0.5% w/w xanthan gum and 0.5% w/w of hydroxypropylmethylcellulose of nominal viscosity of 4000 cps, obtaining codeine resinate and chlorpheniramine resinate sustained-release suspension (CCSS).

Codeine phosphate and chlorpheniramine maleate were respectively loaded onto AMBERLITE® IRP 69, and PEG 4000 was used to impregnate drug resinate beads to maintain their geometry. Ethylcellulose with di-n-butyl-phthalate in ethanol and methylene chloride mixture for the coating of drug resinate beads was performed in Glatt fluidized bed coater, where the coating solution flow rate was 8–12 g/min, the inlet air temperature was 50–60°C, the outlet air temperature was 32–38°C, the atomizing air pressure was 2.0 bar and the fluidized air pressure was adjusted as required. Few significant agglomeratation of circulating drug resinate beads was observed during the operation. The film weight gained 20% w/w and 15% w/w were suitable for the PEG impregnated codeine resinate and chlorpheniramine resinate beads, respectively. Residual solvent content increased with coating level, but inprocess drying could reduce residual solvent content.

In the present study, the rates of drug release from both drug resinate beads were measured in 0.05M and 0.5M KCl solutions. The increased ionic strength generally accelerated the release rate of both drugs. But the release of codeine from its resinate beads was much more rapid than chloropheneramine released from its resinate beads in the same ionic strength release medium. The drug release specification of the CCSS, where release mediums were 0.05M KCl solution for codeine and 0.5M KCl solution for chlorpheniramine, was established to be in conformance with in vivo performance.

Relative bioavailability and pharmacokinetics evaluation of the CCSS, using commercial immediate-release tablets as the reference preparation, were performed following a randomized two-way crossover design in beagle dogs. The drug concentrations in plasma were measured by a validated LC-MS/MS method to determine the pharmacokinetic parameters of CCSS. This LC-MS/MS method demonstrated high accuracy and precision for bioanalysis, and was proved quick and reliable for the pharmacokinetic studies. The results showed that the CCSS had the longer value of T_max and the lower value of C_max, which meant an obviously sustained release effect, and its relative bioavailability of codeine and chlorpheniramine were (103.6 ± 14.6)% and (98.1 ± 10.3)%, respectively, compared with the reference preparation. These findings indicated that a novel liquid sustained release suspension made by using IERs as carriers and subsequent fluidized bed coating might provide a constant plasma level of the active pharmaceutical ingredient being highly beneficial for various therapeutic reasons.     

In Situ Ophthalmic Gel of Ciprofloxacin Hydrochloride for Once a Day Sustained Delivery

This article focuses on preparation and evaluation of a once a day ophthalmic delivery system for ciprofloxacin hydrochloride based on the concept of pH-triggered in situ gelation. The in situ gelling system involves the use of polyacrylic acid (Carbopol® 980NF) as a phase transition polymer, hydroxypropyl methylcellulose (Methocel® K100LV) as a release retardant, and ion exchange resin as a complexing agent. Ciprofloxacin hydrochloride was complexed with ion exchange resin to avoid incompatibility between drug and polyacrylic acid. The developed formulation was stable, and nonirritant to rabbit eyes and in vitro drug release was found to be around 98% over a period of 24 hours.     

In situ ophthalmic gel of ciprofloxacin hydrochloride for once a day sustained delivery

This article focuses on preparation and evaluation of a once a day ophthalmic delivery system for ciprofloxacin hydrochloride based on the concept of pH-triggered in situ gelation. The in situ gelling system involves the use of polyacrylic acid (Carbopol® 980NF) as a phase transition polymer, hydroxypropyl methylcellulose (Methocel® K100LV) as a release retardant, and ion exchange resin as a complexing agent. Ciprofloxacin hydrochloride was complexed with ion exchange resin to avoid incompatibility between drug and polyacrylic acid. The developed formulation was stable, and nonirritant to rabbit eyes and in vitro drug release was found to be around 98% over a period of 24 hours.     

Preparation of codeine-resinate and chlorpheniramine-resinate sustained-release suspension and its pharmacokinetic evaluation in beagle dogs

Using ion exchange resins (IERs) as carriers, a dual-drug sustained release suspension containing codeine, and chlorpheniramine had been prepared to elevate drug safety, effectiveness and conformance. The codeine resinate and chlorpheniramine resinate beads were prepared by a batch process and then impregnated with Polyethylene glycol 4000 (PEG 4000), respectively. The PEG impregnated drug resinate beads were coated with ethylcellulose as the coating polymer and di-n-butyl-phthalate as plasticizer in ethanol and methylene chloride mixture by the Wurster process. The coated PEG impregnated drug resinate beads were dispersed in an aqueous suspending vehicle containing 0.5% w/w xanthan gum and 0.5% w/w of hydroxypropylmethylcellulose of nominal viscosity of 4000 cps, obtaining codeine resinate and chlorpheniramine resinate sustained-release suspension (CCSS).

Codeine phosphate and chlorpheniramine maleate were respectively loaded onto AMBERLITE® IRP 69, and PEG 4000 was used to impregnate drug resinate beads to maintain their geometry. Ethylcellulose with di-n-butyl-phthalate in ethanol and methylene chloride mixture for the coating of drug resinate beads was performed in Glatt fluidized bed coater, where the coating solution flow rate was 8-12 g/min, the inlet air temperature was 50-60°C, the outlet air temperature was 32-38°C, the atomizing air pressure was 2.0 bar and the fluidized air pressure was adjusted as required. Few significant agglomeratation of circulating drug resinate beads was observed during the operation. The film weight gained 20% w/w and 15% w/w were suitable for the PEG impregnated codeine resinate and chlorpheniramine resinate beads, respectively. Residual solvent content increased with coating level, but inprocess drying could reduce residual solvent content.

In the present study, the rates of drug release from both drug resinate beads were measured in 0.05M and 0.5M KCl solutions. The increased ionic strength generally accelerated the release rate of both drugs. But the release of codeine from its resinate beads was much more rapid than chloropheneramine released from its resinate beads in the same ionic strength release medium. The drug release specification of the CCSS, where release mediums were 0.05M KCl solution for codeine and 0.5M KCl solution for chlorpheniramine, was established to be in conformance with in vivo performance.

Relative bioavailability and pharmacokinetics evaluation of the CCSS, using commercial immediate-release tablets as the reference preparation, were performed following a randomized two-way crossover design in beagle dogs. The drug concentrations in plasma were measured by a validated LC-MS/MS method to determine the pharmacokinetic parameters of CCSS. This LC-MS/MS method demonstrated high accuracy and precision for bioanalysis, and was proved quick and reliable for the pharmacokinetic studies. The results showed that the CCSS had the longer value of T_max and the lower value of C_max, which meant an obviously sustained release effect, and its relative bioavailability of codeine and chlorpheniramine were (103.6 ± 14.6)% and (98.1 ± 10.3)%, respectively, compared with the reference preparation. These findings indicated that a novel liquid sustained release suspension made by using IERs as carriers and subsequent fluidized bed coating might provide a constant plasma level of the active pharmaceutical ingredient being highly beneficial for various therapeutic reasons.     

Oral Sustained Delivery of Theophylline and Cimetidine from In Situ Gelling Pectin Formulations in Rabbits

ABSTRACT

The aim of this study was to evaluate the potential of an in situ gelling pectin formulation as a vehicle for the oral sustained delivery of theophylline and cimetidine. In vitro studies demonstrated diffusion-controlled release of theophylline from 1, 1.5, and 2% w/v pectin gels. Release of this drug from 1.5% w/v pectin gels formed in situ in rabbit stomach was sustained over a period of 12 hours giving a theophylline bioavailability some seven fold higher than when administered from a commercial syrup. In contrast, interactions between cimetidine and pectin led to weak gelation of the pectin sols that prevented any meaningful determination of in vitro release characteristics. Similarly, in vivo release profiles from pectin formulations containing cimetidine were similar to that from a solution of this drug in buffer, indicative of weak gelation. Examination of the content of the rabbit stomach 5 hours after administration of 1.5% w/v pectin sols containing drug confirmed gel formation, but gels containing cimetidine were noticeably softer than those containing theophylline.     

Oral controlled drug delivery systems based on microporous polymers

Microporous polypropylene (PP) powder shows excellent properties for tabletting. Oral controlled release delivery systems were made by simply blending with drug and compressing to make both matrix and coated tablets. To prevent wetting problems and food interactions, sodium lauryl sulphate (SLS) was adsorbed prior to tabletting on the surface of the microporous PP. In order to reveal possible dosage form-food interactions a new and simple food interaction model (slight modification of the USP XX paddle method) is proposed to standardize both in vitro and in vivo testing procedures. The PP coated oxprenolol tablets show no food interactions when tested in vitro in the food simulation mixture. The same liquid food was used in the in vivo study. The PP coated oxprenolol tablets were given to six male volunteers with and without the food. The absorption profiles, which were calculated by numerical deconvolution, showed hardly any food interactions in vivo. The absolute bioavailability at 12 hours was 38±19% on an empty stomach and 37±20 for the food experiment. The developed coated tablets are able to control the release of oxprenolol at least 12 hours both with and without concomitant food intake. Their bioavailability is comparable to different OROS formulations of oxprenolol controlled release systems based on microporous PP are not only highly effective ones but also low cost formulation products.     

Oral controlled drug delivery systems based on microporous polymers

Abstract

Microporous polypropylene (PP) powder shows excellent properties for tabletting. Oral controlled release delivery systems were made by simply blending with drug and compressing to make both matrix and coated tablets. To prevent wetting problems and food interactions, sodium lauryl sulphate (SLS) was adsorbed prior to tabletting on the surface of the microporous PP. In order to reveal possible dosage form-food interactions a new and simple food interaction model (slight modification of the USP XX paddle method) is proposed to standardize both in vitro and in vivo testing procedures. The PP coated oxprenolol tablets show no food interactions when tested in vitro in the food simulation mixture. The same liquid food was used in the in vivo study. The PP coated oxprenolol tablets were given to six male volunteers with and without the food. The absorption profiles, which were calculated by numerical deconvolution, showed hardly any food interactions in vivo. The absolute bioavailability at 12 hours was 38±19% on an empty stomach and 37±20 for the food experiment. The developed coated tablets are able to control the release of oxprenolol at least 12 hours both with and without concomitant food intake. Their bioavailability is comparable to different OROS formulations of oxprenolol controlled release systems based on microporous PP are not only highly effective ones but also low cost formulation products.     

In vitro and in vivo performance of a multiparticulate pulsatile drug delivery system

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 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.