Formulation Development and Human In Vitro‐In Vivo Correlation for a Novel,Monolithic Controlled‐Release Matrix System of High Load and Highly Water‐Soluble Drug Niacin

Novel, controlled‐release formulations for high drug load, highly water soluble compound niacin based on polyethylene oxide (PEO) and hydroxypropylmethyl cellulose (HPMC) matrices were developed and investigated. The effect of sodium bicarbonate as a modulator of swelling, erosion, and drug release and its impact on changes in the kinetics of axial swelling and gel strength were evaluated by textural analysis during dissolution study. The drug release rate from PEO‐based matrices was faster and correlated with lower gel strength, greater water uptake, and greater matrix erosion. Slower release rate and greater release duration correlated significantly with greater matrix swelling with negligible matrix erosion for the HPMC‐based matrix system. Inclusion of sodium bicarbonate in the polymeric matrix salted out the macromolecules and increased gel strength and gel viscosity, especially in the vicinity of the swelling fronts. An in vivo study in human subjects after administration of the formulations and a commercial product exhibited similar plasma concentrations. For the formulation of interest, the mean drug fraction absorbed by the body was calculated by the Wagner‐Nelson technique, and a level A “in vitro‐in vivo correlation” was observed between the percent released in vitro and percent absorbed in vivo. The developed formulations appear to be robust and easy to manufacture with maximum flexibility with respect to drug dose, polymeric carriers, duration, and kinetics of drug release.     

Mechanistic study on hydration and drug release behavior of sodium alginate compacts

The influence of sodium alginate viscosity on the dynamics of matrix hydration, solvent front movement, swelling, erosion, and drug release from alginate matrix tablets were examined. The solvent front showed preferential penetration from the radial direction even though matrix swelling showed axial predominance. This study proposed alternative views for the anisotropic behavior of hydrating alginate compacts, namely, formation of gel barrier with different permeability characteristics, tension at the gel-core interface and preferential radial erosion, in addition to an in-depth examination on the contribution of stress relaxation of hydrated polymer as well as core expansion. Alginate matrices demonstrated pH-dependent hydration, swelling and erosion behavior, resulting in pH-dependent drug release mechanisms. Dissolution profiles for alginate matrices of different viscosities were similar in acid but differed upon increase of pH. This was due to the influence of alginate viscosity grade on liquid uptake, erosion and pronounced swelling at near neutral pH.     

Mechanistic Study on Hydration and Drug Release Behavior of Sodium Alginate Compacts

ABSTRACT

The influence of sodium alginate viscosity on the dynamics of matrix hydration, solvent front movement, swelling, erosion, and drug release from alginate matrix tablets were examined. The solvent front showed preferential penetration from the radial direction even though matrix swelling showed axial predominance. This study proposed alternative views for the anisotropic behavior of hydrating alginate compacts, namely, formation of gel barrier with different permeability characteristics, tension at the gel-core interface and preferential radial erosion, in addition to an in-depth examination on the contribution of stress relaxation of hydrated polymer as well as core expansion. Alginate matrices demonstrated pH-dependent hydration, swelling and erosion behavior, resulting in pH-dependent drug release mechanisms. Dissolution profiles for alginate matrices of different viscosities were similar in acid but differed upon increase of pH. This was due to the influence of alginate viscosity grade on liquid uptake, erosion and pronounced swelling at near neutral pH.     

Release of diltiazem hydrochloride from hydrophilic matrices of polyethylene oxide and carbopol

The mucoadhesion, swelling, and drug release behavior of polyethylene oxide (PEO) and carbopol (CP) matrices were studied using a water soluble model drug diltiazem hydrochloride. The mucoadhesive strength of the matrices increased with increase in polymer content. The results showed that PEO was more mucoadhesive than CP. Mucoadhesion of the tablets was dependent upon the swelling. Swelling was ascertained by measuring the axial and radial expansion of matrix tablets following exposure to media of physiological ionic strength. There was a marked increase in the swelling index of matrices containing high polymer content of PEO as compared to CP. Drug release kinetics were found to be closely related to dissolution and swelling properties of the matrices. The release was found to be non-fickian with n (release exponent) values ranging from 0.45-0.58. At a constant polymer content (15.84% w/w), the main contributing factor for the mucoadhesion, swelling, and release was the amount of PEO.     

Crosslinking of gelatin-based drug carriers by genipin induces changes in drug kinetic profiles in vitro

Hydrogels are extensively studied as carrier matrices for the controlled release of bioactive molecules. The aim of this study was to design gelatin-based hydrogels crosslinked with genipin and study the impact of crosslinking temperature (5, 15 or 25°C) on gel strength, microstructure, cytocompatibility, swelling and drug release. Gels crosslinked at 25°C exhibited the highest Flory–Rehner crosslink density, lowest swelling ratio and the slowest release of indomethacin (Idn, model anti-inflammatory drug). Diffusional exponents (n) indicated non-Fickian swelling kinetics while drug transport was anomalous. Hydrogel biocompatibility, in vitro cell viability, cell cycle experiments with AH-927 and HaCaT cell lines indicated normal cell proliferation without any effect on cell cycle. Overall, these results substantiated the use of genipin-crosslinked hydrogels as a viable carrier matrix for drug release applications.     

Incorporation of calcium salts into xanthan gum matrices: hydration,erosion and drug release characteristics

Xanthan gum (XG), a hydrophilic biopolymer with modified release properties, was used to produce directly compressed matrix tablets containing a model drug, sodium p-aminosalicylate. Three formulations were prepared, each containing a different calcium dihydrate salt: calcium chloride, calcium sulfate or dibasic calcium phosphate. The aim of the investigation was to relate the calcium ion content and solubility of the calcium salt to the in vitro drug release profile of the xanthan matrices. Tablet hydration, erosion and drug release were determined in distilled water using the British Pharmacopoeia (BP) paddle method. The data showed that the overall drug release was the greatest with addition of calcium sulfate, followed by calcium chloride and dibasic calcium phosphate. The chloride salt formulation displayed the greatest percentage erosion due to rapid mass loss during the initial phase, followed by those with sulfate or phosphate salts. As xanthan gel viscosity increased and drug release was also found to be lower, it can be concluded that drug release is influenced by the solubility of the salt present in the formulation, since these parameters determine the viscosity and structure of the gel layer.     

The Influence of Hydro-Alcoholic Media on Hypromellose Matrix Systems

Hydrophilic matrices are widely used for extended release drug delivery, with hypromellose (HPMC) being a popular rate-controlling carrier. The FDA has recently issued an alert regarding the potential negative influence of alcohol on extended release dosage forms.

The aim of this study was to investigate the hydroalcoholic solution effect on hydration, gel formation and drug release from HPMC matrices. None of the investigated matrix formulations (felodipine, gliclazide, and metformin hydrochloride) resulted in dose-dumping when exposed to ethanol solutions.

HPMC compacts made of three different viscosity grades of Methocel showed consistent swelling and gel formation when exposed to hydroalcoholic media.     

The influence of hydro-alcoholic media on hypromellose matrix systems

Hydrophilic matrices are widely used for extended release drug delivery, with hypromellose (HPMC) being a popular rate-controlling carrier. The FDA has recently issued an alert regarding the potential negative influence of alcohol on extended release dosage forms.

The aim of this study was to investigate the hydroalcoholic solution effect on hydration, gel formation and drug release from HPMC matrices. None of the investigated matrix formulations (felodipine, gliclazide, and metformin hydrochloride) resulted in dose-dumping when exposed to ethanol solutions.

HPMC compacts made of three different viscosity grades of Methocel showed consistent swelling and gel formation when exposed to hydroalcoholic media.     

Study of dissolution behavior of matrices tablets based on alginate-gelatin mixtures as prolonged diltiazem hydrochloride release systems

The aim of this work was to develop prolonged diltiazem hydrochloride release matrices based on alginate-gelatin mixtures and establish the drug release mechanism. The erosion, swelling, and dissolution behavior of the tablets in different medium were evaluated. The different polyelectrolyte behavior and gel strength between type A Gelatin and type B Gelatin would explain the different swelling, erosion and dissolution behavior in the media with sudden pH change. The similar dissolution behavior in the pH, which simulates the physiological pH through the gastrointestinal tract, should be explained because the same main species for gelatin A and Gelatin B would be present in this media.     

Study of Dissolution Behavior of Matrices Tablets Based on Alginate—Gelatin Mixtures as Prolonged Diltiazem Hydrochloride Release Systems

ABSTRACT

The aim of this work was to develop prolonged diltiazem hydrochloride release matrices based on alginate-gelatin mixtures and establish the drug release mechanism. The erosion, swelling, and dissolution behavior of the tablets in different medium were evaluated. The different polyelectrolyte behavior and gel strength between type A Gelatin and type B Gelatin would explain the different swelling, erosion and dissolution behavior in the media with sudden pH change. The similar dissolution behavior in the pH, which simulates the physiological pH through the gastrointestinal tract, should be explained because the same main species for gelatin A and Gelatin B would be present in this media.     

Evaluation of the controlled release ability from the poly(2-hydroxyethyl methacrylate-co-3,9-divinyl-2,4,8,10-tetraoxaspiro[5.5]-undecane) polymer network synthesized in the presence of β-cyclodextrin

The study presents the possibility to use the 2-hydroxyethyl methacrylate--HEMA copolymer with a comonomer with spiroacetal moiety, 3,9-divinyl-2,4,8,10-tetraoxaspiro[5.5]-undecane)-U, as polymer network for loading the indomethacin--INN as drug model, and also, the controlled release evaluation of the prepared bioactive system. The macromolecular compounds were prepared by radical dispersion polymerization in the presence of a pair of surfactants. The use of cyclodextrin as surfactant allowed the building of the host-guest complexes by inclusion of hydrophobic molecules. Also, the cyclodextrin supplemented the hydrogen bonds and the hydrophobic interactions responsible for the stability of the achieved complexes. The copolymers composition and the INN inclusion onto the polymeric matrix were confirmed by FTIR analysis. The porous structure of the lyophilized P(HEMA-U) samples was illustrated by SEM images. The swelling studies evidenced the interdependence between P(HEMA-U) network properties and the spiroacetal moiety amount. Thus, the copolymers presented the increase of the equilibrium swelling degree with pH and temperature. Also, the polymeric matrices manifested dual sensitivity with pH and temperature. The in vitro release of the INN drug from the polymeric network as well as the in vivo experimental studies evidenced the benefit consequence of the spiroacetal compound presence. The clinical observation of the experimental groups does not show any behavioral modifications to suggest a possible toxic effect of these polymeric formulations with and without INN.     

Some formulation factors influencing the rate of drug release from bioadhesiw matrices

The development of monolithic matrices with controlled release and mucosa-adhesive properties was investigated. After an initial screening procedure for formulations that showed stability and minimal swelling, the rate of release of a model water soluble drug from various polyacrylic acid containing matrices was evaluated. All the formulations gave a prolonged drug release relative to a lactose containing control formulation. A formulation containing Carbopol 934P and CaCl₂, was found to give the slowest rate of drug release (t_50% of 7.77h), with release kinetics nearest to the ideal zero order. When tested in a modified tensiometer it was found that the inclusion of a relatively high loading of a model drug did not adversely affect the adhesive properties of these formulations.     

Relationship Between Swelling and Drug Release in a Hydrophilic Matrix

Hydroxypropylmethylcellulose (HPMC) is widely used for controlled-release preparations. The process of drug release is controlled by matrix swelling and polymer dissolution. This study examines the mechanism of behaviour of HPMC in a polymer-drug directly-compressed matrix. The results obtained show that the swelling of HPMC which can be described by first-order kinetics is affected by concentration and viscosity grade of the polymer. This swelling action of HPMC in turn is controlled by the rate of water uptake into the matrices. An inverse relationship exists between the drug release rate and matrix swelling rate. This implies that HPMC swelling is one of the factors affecting drug release. The swelling behaviour of HPMC is therefore useful in predicting drug release.     

A chitosan lactate/poloxamer 407-based matrix containing Eudragit RS microparticles for vaginal delivery of econazole: design and in vitro evaluation

A matrix based on chitosan lactate and poloxamer 407 was evaluated as a delivery system for the vaginal administration of the antifungal drug econazole. The matrix was investigated both containing the pure drug and after introducing microparticles of Eudragit RS 100 containing econazole. Eudragit RS 100 microparticles were prepared using an emulsion-extraction method and dispersed in a solution containing chitosan lactate (2% w/w) and poloxamer 407 (1.7% w/w). The microparticles, obtained with a yield of 64% w/w and an encapsulation efficiency of 42% w/w, had a diameter of less than 2 μm and a drug loading of 13% w/w. The compressed matrices, characterized by DSC, swelling, erosion, release and mucoadhesion studies, had behaviours dependent on the relative amounts of the contained microparticles. The matrix without microparticles (MECN) showed zero-order release kinetics, with a maximum drug-release of 60% w/w, while those containing 50 or 75% w/w microparticles showed a diffusion controlled release up to 8 and 16 h, respectively, and a linear trend after those time intervals, caused by the erosion process, which allowed reaching a drug-release of approximately 100% w/w at 22 h. In in vitro experiments, the matrices were mucoadhesive and active in inhibiting the growth of Candida albicans 796.     

Enhanced Release of Drugs from Silicone Elastomers (II): Induction of Swelling and Changes in Microstructure

Incorporation of glycerol into silicone elastomers was found to enhance the release of hydrophilic drugs as well as to cause the polymeric device to swell as a result of water uptake. There are similarities between the kinetics of drug release from the matrix of silicone elastomers and the kinetics of swelling, water uptake, and leaching of tritiated glycerol, in that they all follow a matrix diffusion-controlled mechanism. The results of absorption, desorption, and resorption kinetic studies suggest that the two processes of swelling and water uptake are reversible. The amount of glycerol which leached out from devices containing up to 20% glycerol was only 4 → 10^-4 to 6 → 10^-4% of the amount of glycerol that had been originally incorporated into the device. A scanning electron microscopic examination of a silicone device containing glycerol revealed a microstructure in which glycerol vesicles are dispersed. In contrast to this, the matrix of a silicone device containing no glycerol was shown to be a continuous network. The microstructure of a glycerol-containing silicone device became more “spongy” after leaching than it was before leaching.     

Oral Sustained Delivery of Atenolol from Floating Matrix Tablets—Formulation and In Vitro Evaluation

Floating matrix tablets of atenolol were developed to prolong gastric residence time and increase drug bioavailability. Atenolol was chosen as a model drug because it is poorly absorbed from the lower gastrointestinal tract. The tablets were prepared by direct compression technique, using polymers such as hydroxypropyl methylcellulose (HPMC K15M, K4M), guargum (GG), and sodium carboxymethylcellulose (SCMC), alone or in combination, and other standard excipients. Tablets were evaluated for physical characteristics viz. hardness, swelling index, floating capacity, thickness, and weight variation. Further, tablets were evaluated for in vitro release characteristics for 8 hr. The effect of effervescent on buoyancy and drug release pattern was also studied. In vitro release mechanism was evaluated by linear regression analysis. GG- and SCMC-based matrix tablets showed significantly greater swelling indices compared with other batches. The tablets exhibited controlled and prolonged drug release profiles while floating over the dissolution medium.     

Oral sustained delivery of atenolol from floating matrix tablets-formulation and in vitro evaluation

Floating matrix tablets of atenolol were developed to prolong gastric residence time and increase drug bioavailability. Atenolol was chosen as a model drug because it is poorly absorbed from the lower gastrointestinal tract. The tablets were prepared by direct compression technique, using polymers such as hydroxypropyl methylcellulose (HPMC K15M, K4M), guargum (GG), and sodium carboxymethylcellulose (SCMC), alone or in combination, and other standard excipients. Tablets were evaluated for physical characteristics viz. hardness, swelling index, floating capacity, thickness, and weight variation. Further, tablets were evaluated for in vitro release characteristics for 8 hr. The effect of effervescent on buoyancy and drug release pattern was also studied. In vitro release mechanism was evaluated by linear regression analysis. GG- and SCMC-based matrix tablets showed significantly greater swelling indices compared with other batches. The tablets exhibited controlled and prolonged drug release profiles while floating over the dissolution medium.     

Effects of Blending a Nonionic and an Anionic Cellulose Ether Polymer on Drug Release from Hydrophilic Matrix Capsules

Blends of hydroxyethylcellulose (HEC) and sodium carboxymethylcellulose (NaCMC) were used to achieve zero order release of chlorpheniramine maleate (CM) from hydrophilic matrix capsules. Dynamic swelling/erosion and response surface measurements were made to provide an insight into the drug release behavior. The drug to total polymer and the HEC to NaCMC ratio influences the rate of drug release. NaCMC appears to influence water uptake and erosion of the matrix mixture. The factors by which zero-order drug release is achieved may include synchronization of the rates of water uptake and polymer erosion even though a constant diffusional pathlength may not be maintained. The combined mixture factorial design presented in this study allows for the characterization and optimization of the drug release profiles.     

A novel three-layered tablet for extended release with various layer formulations and in vitro release profiles

A novel three-layered tablet consisting of a water-soluble mid-layer and two barrier layers with swellable polymers was investigated to develop a preferable once-a-day formulation containing terazosin HCl as a hydrophilic model drug. When the tablet was exposed to a release medium, the medium quickly permeated to the mid-layer and the two barrier layers swelled surrounding the mid-layer rapidly. It facilitated the tablet to absorb a lot of water compared with monolithic matrix. Moreover, formation of a lot of pores in the tablet during dissolution could be observed, suggesting significant water absorption in the inner matrix and swollen polymers of the tablet. Barrier layers influenced drug release profiles significantly, potentially due to differences in viscosity after swelling that produce different diffusion coefficients and mechanical strength. The drug in the mid-layer showed the sigmoid type of release pattern because a period of time might be needed to release the drug from the mid-layer through the barrier layers, but the drug in barrier layers showed the typical release pattern of monolithic matrix. As the amount of water-soluble excipient in the mid-layer increased, the degree of swelling also increased, suggesting that its amount in the layer may affect the overall swelling properties of the tablet. It was also shown that more hydrophilic mid-layer caused faster erosion rate, which was related to the results of swelling property. The three-layered tablets showed more consistent release kinetics than the matrix tablets. These results can give good information for the development of sustained drug delivery systems, especially once-a-day administration.     

Effects of Blending a Nonionic and an Anionic Cellulose Ether Polymer on Drug Release from Hydrophilic Matrix Capsules

Blends of hydroxyethylcellulose (HEC) and sodium carboxymethylcellulose (NaCMC) were used to achieve zero order release of chlorpheniramine maleate (CM) from hydrophilic matrix capsules. Dynamic swelling/erosion and response surface measurements were made to provide an insight into the drug release behavior. The drug to total polymer and the HEC to NaCMC ratio influences the rate of drug release. NaCMC appears to influence water uptake and erosion of the matrix mixture. The factors by which zero-order drug release is achieved may include synchronization of the rates of water uptake and polymer erosion even though a constant diffusional pathlength may not be maintained. The combined mixture factorial design presented in this study allows for the characterization and optimization of the drug release profiles.