Personalised 3D-Printed Mucoadhesive Gastroretentive Hydrophilic Matrices for Managing Overactive Bladder (OAB).

Overactive bladder (OAB) is a symptomatic complex condition characterised by frequent urinary urgency, nocturia, and urinary incontinence with or without urgency. Gabapentin is an effective treatment for OAB, but its narrow absorption window is a concern, as it is preferentially absorbed from the upper small intestine, resulting in poor bioavailability. We aimed to develop an extended release, intragastric floating system to overcome this drawback. For this purpose, plasticiser-free filaments of PEO (polyethylene oxide) and the drug (gabapentin) were developed using hot melt extrusion. The filaments were extruded successfully with 98% drug loading, possessed good mechanical properties, and successfully produced printed tablets using fused deposition modelling (FDM). Tablets were printed with varying shell numbers and infill density to investigate their floating capacity. Among the seven matrix tablet formulations, F2 (2 shells, 0% infill) showed the highest floating time, i.e., more than 10 h. The drug release rates fell as the infill density and shell number increased. However, F2 was the best performing formulation in terms of floating and release and was chosen for in vivo (pharmacokinetic) studies. The pharmacokinetic findings exhibit improved gabapentin absorption compared to the control (oral solution). Overall, it can be concluded that 3D printing technology is an easy-to-use approach which demonstrated its benefits in developing medicines based on a mucoadhesive gastroretentive strategy, improving the absorption of gabapentin with potential for the improved management of OAB.

Cellulase as an "active" excipient in prolonged-release HPMC matrices: A novel strategy towards zero-order release kinetics.

Hydrophilic matrices are of utmost interest for oral prolonged release of drugs. However, they show decreasing release rate over time, mainly due to lengthening of the diffusional pathway across the gel formed upon glass-rubber transition of the polymer. Therefore, achievement of zero-order release kinetics, which could reflect in constant drug plasma levels, is still an open issue. With the aim of improving the release performance of hydroxypropyl methylcellulose (HPMC) systems, the use of cellulolytic enzymes was proposed to aid erosion of the swollen matrix, thereby counteracting the release rate decrease particularly toward the end of the process. The effectiveness of this strategy was evaluated by studying the mass loss and drug tracer release from tableted matrices consisting of high-viscosity HPMC (Methocel® K4M), Acetaminophen and increasing amounts (0.5-10% on HPMC) of a cellulolytic product (Sternzym® C13030). A faster erosion and progressive shift to linearity of the overall release profiles were observed as a function of the enzyme concentration. Release was markedly linear from matrices containing 5 and 10% Sternzym® C13030. In partially coated matrices with these cellulase concentrations, such results were in agreement with data of erosion and swelling front movement, which exhibited early and long-lasting synchronization.

Drug release from magnesium aluminium silicate-polyethylene oxide (PEO) nanocomposite matrices: An investigation using the USP III apparatus.

This work investigated the use of the USP III apparatus in discriminating simulated fed and fasted conditions as well as ionic strength on veegum-polyethylene (PEO) (called clay-PEO matrices hereafter) matrices. The successful formulations were characterised using differential scanning calorimetry (DSC) and evaluated for their physical properties. Isothermal calorimetry (ITC) was used to evaluate the thermodynamics of the complexation processes. The effect of agitation sequences on the matrices as evaluated from the USP III suggested an increase in polymer content to significantly decrease the burst release experienced using diltiazem hydrochloride (DILT) as a model cationic drug. The manufacturing methods showed superior performance in relation to a decrease in burst release over the physical manufactured counterparts. The clay-PEO matrices also showed robustness (no matrix failure) in up to 0.2 M ionic strength solutions mimicking the upper limit experienced in the GI tract. ITC results revealed that the binding between DILT and PEO was enthalpy and entropy-driven. Furthermore, the binding between veegum and DILT in the presence of PEO was shown to be enthalpy-driven and entropically unfavourable, which was also the case for the binding between veegum and PEO thus giving insights to how the matrices were performing on a molecular level.

Non-uniform drug distribution matrix system (NUDDMat) for zero-order release of drugs with different solubility.

A decrease in the drug release rate over time typically affects the performance of hydrophilic matrices for oral prolonged release. To address such an issue, a Non-Uniform Drug Distribution Matrix (NUDDMat) based on hypromellose was proposed and demonstrated to yield zero-order release. The system consisted of 5 overlaid layers, applied by powder layering, having drug concentration decreasing from the inside towards the outside of the matrix according to a descending staircase function. In the present study, manufacturing and performance of the described delivery platform were evaluated using drug tracers having different water solubility. Lansoprazole, acetaminophen and losartan potassium were selected as slightly (SST), moderately (MST) and highly (HST) soluble tracers. By halving the thickness of the external layer, which contained no drug, linear release of HST and MST was obtained. The release behavior of the NUDDMat system loaded with a drug having pH-independent solubility was shown to be consistent in pH 1.2, 4.5 and 6.8 media. Based on these results, feasibility of the NUDDMat platform by powder layering was demonstrated using drugs having different physico-technological characteristics. Moreover, its ability to generate zero-order release was proved in the case of drugs with water solubility in a relatively wide range.

Novel hydrophilic matrix system with non-uniform drug distribution for zero-order release kinetics.

A decrease in the release rate over time is typically encountered when dealing with hydrophilic matrix systems for oral prolonged release due to progressive increase of the distance the drug molecules have to cover to diffuse outwards and reduction of the area of the glassy matrix at the swelling front. In order to solve this issue, a novel formulation approach based on non-uniform distribution of the active ingredient throughout the swellable polymer matrix was proposed and evaluated. Various physical mixtures of polymer (high-viscosity hypromellose) and drug tracer (acetaminophen), having decreasing concentrations of the latter, were applied by powder-layering onto inert core seeds. The resulting gradient matrices showed to possess satisfactory physico-technological characteristics, with spherical shape and consistent thickness of the layers sequentially applied. The non-uniform matrix composition pursued was confirmed by Raman mapping analysis. As compared with a system having uniform distribution of the drug tracer, the multi-layer formulations were proved to enhance linearity of release. The simple design concept, advantageous technique, which involves no solvents nor high-impact drying operations, and the polymeric material of established use make the delivery platform hereby proposed a valuable strategy to improve the performance of hydrophilic matrix systems.

Evaluating the swelling, erosion, and compaction properties of cellulose ethers.

Swelling, erosion, deformation, and consolidation properties can affect the performance of cellulose ethers, the most commonly used matrix former in hydrophilic sustained tablet formulations. The present study was designed to comparatively evaluate the swelling, erosion, compression, compaction, and relaxation properties of the cellulose ethers in a comprehensive study using standardised conditions. The interrelationship between various compressional models and the inherent deformation and consolidation properties of the polymers on the derived swelling and erosion parameters are consolidated. The impact of swelling (Kw) on erosion rates (KE) and the inter-relationship between Heckel and Kawakita plasticity constants was also investigated. It is evident from the findings that the increases in both substitution and polymer chain length led to higher Kw, but a lower KE; this was also true for all particle size fractions regardless of polymer grade. Smaller particle size and high substitution levels tend to increase the relative density of the matrix but reduce porosity, yield pressure (Py), Kawakita plasticity parameter (b-1) and elastic relaxation. Both KW versus KE (R2 = 0.949-0.980) and Py versus. b-1 correlations (R2 = 0.820-0.934) were reasonably linear with regards to increasing hydroxypropyl substitution and molecular size. Hence, it can be concluded that the combined knowledge of swelling and erosion kinetics in tandem with the in- and out-of-die compression findings can be used to select a specific polymer grade and further to develop and optimize formulations for oral controlled drug delivery applications.

Spray-dried high-amylose sodium carboxymethyl starch: impact of α-amylase on drug-release profile.

Spray-dried high-amylose sodium carboxymethyl starch (SD HASCA) is a promising pharmaceutical excipient for sustained-release (SR) matrix tablets produced by direct compression. The presence of α-amylase in the gastrointestinal tract and the variations of the gastric residence time of non-disintegrating dosage forms may affect the presystemic metabolism of this excipient and, consequently, the drug-release profile from formulations produced with SD HASCA. In this study, the influence of α-amylase and the residence time in acidic conditions on the drug-release profile was evaluated for a once-daily acetaminophen formulation (Acetaminophen SR) and a once-daily tramadol hydrochloride formulation (Tramadol SR). Both formulations were based on SD HASCA. α-Amylase concentrations ranging from 0 IU/L to 20000 IU/L did not significantly affect the drug-release profiles of acetaminophen and tramadol hydrochloride from SD HASCA tablets (f2 > 50) for all but only one of the studied conditions (f2 = 47). Moreover, the drug-release properties from both SD HASCA formulations were not significantly different when the residence time in acidic medium was 1 h or 3 h. An increase in α-amylase concentration led to an increase in the importance of polymer erosion as the main mechanism of drug-release instead of drug diffusion, for both formulations and both residence times, even if release profiles remained comparable. As such, it is expected that α-amylase concentration and residence time in the stomach will not clinically affect the performance of both SD HASCA SR formulations, even if the mechanism of release itself may be affected.

Relationships between surface free energy, surface texture parameters and controlled drug release in hydrophilic matrices.

The study of controlled release and drug release devices has been dominated by considerations of the bulk or average properties of material or devices. Yet the outermost surface atoms play a central role in their performance. The objective of this article has been to characterize the surface of hydrophilic matrix tablets using the contact angle (CA) method to ascertain the surface free energy, and atomic force microscopy (AFM) and confocal microscopy (CM) for the physical characterization of the surface of the hydrophilic matrix. The surface free energy results obtained show that hydroxypropylmethylcellulose K15M hinders the spreading of water on the surface of the tablet, such that the concentration of HPMC K15M increases the reaction rate of the hydrophobic interactions between the chains of HPMC K15M which increases with respect to the rate of penetration of water into the tablet. In this study, we developed a new method to characterize the swelling of the tablets and established a relationship between the new method based on microswelling and the swelling ratio parameter. The surface texture parameters have been determined and the morphology of the tablets of the different formulations and the evolution of the surface morphology after interacting with the water, swelling and forming a gel layer were characterized. This work represents significant progress in the characterization of matrix tablets.

Insights into the mechanisms of chitosan-anionic polymers-based matrix tablets for extended drug release.

The aim of this study was to investigate drug release mechanisms from physical mixtures of chitosan-anionic polymers-based matrix tablets and to obtain a comprehensive understanding about release characteristics. Six types of anionic polymers (i.e., Eudragit(®) L100, sodium alginate, carrageenan, carboxymethylcellulose sodium, carbomer and xanthan gum) and two model drugs (i.e., theophylline and metoprolol succinate) with varied solubility were chosen. Texture analyzer, differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) were applied to better understand drug release mechanisms. In vitro release experiments were conducted in a pH-changing medium to simulate the physiological condition of the gastrointestinal tract. Interestingly, a common phenomenon was observed in all the CS-anionic polymers-based matrix tablets investigated here, that is, the inner layer of the swollen tablets was coated by CS-anionic polymer polyelectrolyte complexes (PEC)-based film formed by self-assembly. Formation of the in situ self-assembled film was further confirmed by texture analysis, DSC, and FTIR. It was further identified that properties of the film were influenced by the characteristics of anionic polymers and the physiological conditions of the gastrointestinal tract. Moreover, this novel structure could alter swelling and erosion-based release mechanisms of the tablets. In addition, drug release characteristics from CS-anionic polymer systems depended on the properties of anionic polymers and the drug solubility. In conclusion, our studies may broaden current views on cationic polymer-anionic polymer-based oral matrix tablets for extended release.

Drug release from matrix tablets: physiological parameters and the effect of food.

INTRODUCTION: As dissolution plays an important and vital role in the drug-delivery process of oral solid dosage forms, it is, therefore, essential to critically evaluate the parameters that can affect this process. AREAS COVERED: The consumption of food as well as the physiological environment and properties of the gastrointestinal tract, such as its volume and composition of fluid, the fluid hydrodynamics, properties of the intestinal membrane, drug dose and solubility, pKa, diffusion coefficient, permeability and particle size, all affect drug dissolution and absorption rate. There are several dissolution approaches that have been developed to address the conditions as experienced in the in vivo environment, as the traditional dissolution being a quality control method is not biorelevant and as such do not always produce meaningful data. This review also describes the development of a systematic way that differentiates between robust and non-robust formulations by varying the effects of agitation and ionic strength through the use of the automated United States Pharmacopeia type III Bio-Dis apparatus. EXPERT OPINION: With the improved understanding of the physiological parameters that can affect the oral bioperformance of dosage forms, strides have, therefore, been made in making dissolution testing methods more biologically based with the view of obtaining more in vitro-in vivo correlations.

The design of controlled-release formulations resistant to alcohol-induced dose dumping--a review.

The concomitant intake of alcoholic beverages together with oral controlled-release opioid formulations poses a serious safety concern since alcohol has the potential to alter the release rate controlling mechanism of the dosage form which may result in an uncontrolled and immediate drug release. This effect, known as alcohol-induced dose dumping, has drawn attention of the regulatory authorities. Thus, the Food and Drug Administration (FDA) recommends that in vitro drug release studies of controlled-release dosage forms containing drugs with narrow therapeutic range should be conducted in ethanolic media up to 40%. So far, only a limited number of robust dosage forms that withstand the impact of alcohol are available and the development of such dosage forms is still a challenge. This review deals with the physico-chemical key factors which have to be considered for the preparation of alcohol-resistant controlling dosage forms. Furthermore, appropriate matrix systems and promising technological strategies, which are suitable to prevent alcohol-induced dose dumping, are discussed.

Understanding and managing the impact of HPMC variability on drug release from controlled release formulations.

The purpose of this study is to identify critical physicochemical properties of hydroxypxropyl methylcellulose (HPMC) that impact the dissolution of a controlled release tablet and develop a strategy to mitigate the HPMC lot-to-lot and vendor-to-vendor variability. A screening experiment was performed to evaluate the impacts of methoxy/hydroxypropyl substitutions, and viscosity on drug release. The chemical diversity of HPMC was explored by nuclear magnetic resonance (NMR), and the erosion rate of HPMC was investigated using various dissolution apparatuses. Statistical evaluation suggested that the hydroxypropyl content was the primary factor impacting the drug release. However, the statistical model prediction was not robust. NMR experiments suggested the existence of structural diversity of HPMC between lots and more significantly between vendors. Review of drug release from hydrophilic matrices indicated that erosion is a key aspect for both poorly soluble and soluble drugs. An erosion rate method was then developed, which enabled the establishment of a robust model and a meaningful HPMC specification. The study revealed that the overall substitution level is not the unique parameter that dictates its release-controlling properties. Fundamental principles of polymer chemistry and dissolution mechanisms are important in the development and manufacturing of hydrophilic matrices with consistent dissolution performance.

Desarrollo de nuevos sistemas de liberación modificada y administración oral para el tratamiento de la tuberculosis / Development of new oral drug delivery systems for tuberculosis treatment

INTRODUCCION: El tratamiento de la tuberculosis requiere de la administración conjunta de rifampicina (RIF) e isoniacida (ISO). RIF se descompone en medio ácido al producto 3-FRSV, que en presencia de ISO forma IH. La liberación secuencial de RIF en estómago e ISO en intestino podría llevar a un incremento en la estabilidad de RIF. En una etapa previa RIF e ISO se asociaron a los polielectrolitos carboximetilcelulosa (CMC) y ácido algínico (AA), respectivamente, para obtener los materiales portadores CMC-RIF y AA-ISO que permiten la liberación inmediata de RIF y sostenida ISO. Los mismos pueden ser comprimidos para formar matrices hidrofílicas polielectrolico-fármaco (MHPF).OBJETIVO: Evaluar el impacto de la liberación secuencial de RIF e ISO en la estabilidad de RIF en condiciones simulando el contenido gástrico.METODOS: Los estudios de liberación desde las MHPF MCM-RIF + AA-ISO se realizaron en fluido gástrico simulado, utilizando referencia soluciones de RIF o RIF + ISO y la matric CMC-RIF en las mismas condiciones. La evaluación se realizó durante 2 hs, a 37ºC utilizando el aparato 2. La cuantificación se realizó mediante un método de HPLC indicativo de estabilidad, que permitió identificar ambos fármacos y sus productos de degradación.RESULTADOS: La MHPF CMC-RIF presenta muy rápida velocidad de disolución. La combinación de las MHPF CMC-RIF y AA-ISO permite la liberación selectiva e inmediata de RIF en medio ácido, con mínimos niveles concominantes de ISO, permitiendo una reducción en la formación de IH. Este producto de descomposición ha sido asociado con incremento en los eventos hepatotóxicos asociados a la combinación de RIF e ISO. Sin embargo, CMC acelera la degradación de RIF a 3-FRSV.CONCLUSIONES: La liberación secuencial de RIF e ISO permite reducir la formación de IH y es una estrategia adecuada para el desarrollo de comprimidos bi-capa. La optimización de la estabilidad requiere la adecuación de la capa de liberación inmediata de RIF.

INTRODUCTION: Tuberculosis treatment requires the administration of a combination of rifampicin (RIF) and isoniazid (ISO). In acidic media RIF decomposes to 3-FRSV, which in the presence of ISO forms IH. The sequential release of RIF in the stomach and ISO in the intestine could lead to an increase in RIF stability. In a previous work RIF and ISO were associated to the polyelectrolytes carboxymethylcellulose (CMC) and alginic acid (AA) to obtain carrier material CMC-RIF and AA-ISO that allow immediate release of RIF sustained of ISO. These materials can be compressed to form swellable drug polyelectrolyte matrices (SDPM).OBJECTIVE: To evaluate the impact of the sequential release of RIF and ISO in the stability of RIF in conditions simulating gastric contents.METHODS: Release studies were carried out from SDPM CMC-RIF + AA-ISO in simulated gastric fluid using as references RIF or RIF + ISO solutions under the same conditions. Samples were taken for 2 hs at 37ºC, using apparatus 2. The presence of both drugs and degradation products was analyzed by a stability indicating HPLC techinique.RESULTS: The SDPM CMC-RIF presented very fast release rate. The combination of SDPM CMC-RIF and AA-ISO permits selective and immediate release of RIF in acidic media, with minumum levels of ISO, with noticeable reduction of IH formation. This product has been associated with an increased frequency in hepatotoxic events associated with RIF and ISO combination. However, CMC accelerated degradation of RIF to 3-FRSV.CONCLUSIONS: Sequential release of RIF and ISO allowed a reduction in the formation of IH and seemed to be a suitable strategy for the development of bilayer tablets. Stability optimization should include adapting the immediate release layer of RIF.

Desarrollo de nuevos sistemas de liberación modificada y administración oral para el tratamiento de la tuberculosis / Development of new oral drug delivery systems for tuberculosis treatment

INTRODUCCION: El tratamiento de la tuberculosis requiere de la administración conjunta de rifampicina (RIF) e isoniacida (ISO). RIF se descompone en medio ácido al producto 3-FRSV, que en presencia de ISO forma IH. La liberación secuencial de RIF en estómago e ISO en intestino podría llevar a un incremento en la estabilidad de RIF. En una etapa previa RIF e ISO se asociaron a los polielectrolitos carboximetilcelulosa (CMC) y ácido algínico (AA), respectivamente, para obtener los materiales portadores CMC-RIF y AA-ISO que permiten la liberación inmediata de RIF y sostenida ISO. Los mismos pueden ser comprimidos para formar matrices hidrofílicas polielectrolico-fármaco (MHPF).OBJETIVO: Evaluar el impacto de la liberación secuencial de RIF e ISO en la estabilidad de RIF en condiciones simulando el contenido gástrico.METODOS: Los estudios de liberación desde las MHPF MCM-RIF + AA-ISO se realizaron en fluido gástrico simulado, utilizando referencia soluciones de RIF o RIF + ISO y la matric CMC-RIF en las mismas condiciones. La evaluación se realizó durante 2 hs, a 37ºC utilizando el aparato 2. La cuantificación se realizó mediante un método de HPLC indicativo de estabilidad, que permitió identificar ambos fármacos y sus productos de degradación.RESULTADOS: La MHPF CMC-RIF presenta muy rápida velocidad de disolución. La combinación de las MHPF CMC-RIF y AA-ISO permite la liberación selectiva e inmediata de RIF en medio ácido, con mínimos niveles concominantes de ISO, permitiendo una reducción en la formación de IH. Este producto de descomposición ha sido asociado con incremento en los eventos hepatotóxicos asociados a la combinación de RIF e ISO. Sin embargo, CMC acelera la degradación de RIF a 3-FRSV.CONCLUSIONES: La liberación secuencial de RIF e ISO permite reducir la formación de IH y es una estrategia adecuada para el desarrollo de comprimidos bi-capa. La optimización de la estabilidad requiere la adecuación de la capa de liberación inmediata de RIF.

INTRODUCTION: Tuberculosis treatment requires the administration of a combination of rifampicin (RIF) and isoniazid (ISO). In acidic media RIF decomposes to 3-FRSV, which in the presence of ISO forms IH. The sequential release of RIF in the stomach and ISO in the intestine could lead to an increase in RIF stability. In a previous work RIF and ISO were associated to the polyelectrolytes carboxymethylcellulose (CMC) and alginic acid (AA) to obtain carrier material CMC-RIF and AA-ISO that allow immediate release of RIF sustained of ISO. These materials can be compressed to form swellable drug polyelectrolyte matrices (SDPM).OBJECTIVE: To evaluate the impact of the sequential release of RIF and ISO in the stability of RIF in conditions simulating gastric contents.METHODS: Release studies were carried out from SDPM CMC-RIF + AA-ISO in simulated gastric fluid using as references RIF or RIF + ISO solutions under the same conditions. Samples were taken for 2 hs at 37ºC, using apparatus 2. The presence of both drugs and degradation products was analyzed by a stability indicating HPLC techinique.RESULTS: The SDPM CMC-RIF presented very fast release rate. The combination of SDPM CMC-RIF and AA-ISO permits selective and immediate release of RIF in acidic media, with minumum levels of ISO, with noticeable reduction of IH formation. This product has been associated with an increased frequency in hepatotoxic events associated with RIF and ISO combination. However, CMC accelerated degradation of RIF to 3-FRSV.CONCLUSIONS: Sequential release of RIF and ISO allowed a reduction in the formation of IH and seemed to be a suitable strategy for the development of bilayer tablets. Stability optimization should include adapting the immediate release layer of RIF.