The influence of fillers on theophylline release from clay matrices

Abstract: The objectives of this study were to investigate the suitability of magnesium aluminium silicate (MAS) (Veegum®) to control drug release of a model drug, theophylline, from tablet matrices. To this end, the performance of three commonly used fillers namely: lactose, microcrystalline cellulose (Avicel PH102; MCC), and pre-gelatinized starch, Starch 1500 PGS), were evaluated against Veegum®. The physico-mechanical properties of the tablet matrices were studied along with dissolution studies to determine the effect of single or binary mixtures of the excipients on the drug release pattern. A DSC hydration methodology was also employed to characterize the states of water present in the tablet matrices and to determine any impact on drug release. Formulations containing MAS alone produced compacts with the lowest hardness (4.5 kp) whereas formulations containing MCC alone produced the hardest tablets (17.2 kp). Dissolution studies suggested that matrices containing MAS alone released the theophylline quickest as compared to lactose, MCC or PGS. It was difficult to establish a trend of the bound and free water states in the tablet matrices; however the formulation containing only MAS had the highest bound water at 29 %. The results therefore show that theophylline does not interact with MAS. As such the dominant factor in controlling drug release using MAS requires interaction or intercalation with a cationic drug. In the absence of this however, other excipients can play a role in controlling drug release. Keywords: Veegum, clay matrices, DSC hydration, Magnesium aluminium silicate, filler

Evaluation of sesamum gum as an excipient in matrix tablets

In developing countries modern medicines are often beyond the affordability of the majority of the population. This is due to the reliance on expensive imported raw materials despite the abundance of natural resources which could provide an equivalent or even an improved function. The aim of this study was to investigate the potential of sesamum gum (SG) extracted from the leaves of Sesamum radiatum (readily cultivated in sub-Saharan Africa) as a matrix former. Directly compressed matrix tablets were prepared from the extract and compared with similar matrices of HPMC (K4M) using theophylline as a model water soluble drug. The compaction, swelling, erosion and drug release from the matrices were studied in deionized water, 0.1 N HCl (pH 1.2) and phosphate buffer (pH 6.8) using USP apparatus II. The data from the swelling, erosion and drug release studies were also fitted into the respective mathematical models. Results showed that the matrices underwent a combination of swelling and erosion, with the swelling action being controlled by the rate of hydration in the medium. SG also controlled the release of theophylline similar to the HPMC and therefore may have use as an alternative excipient in regions where Sesamum radiatum can be easily cultivated

The use of various organic solvents to tailor the properties of Ibuprofen-glucosamine HCl solid dispersions

A fast release dosage form is desirable to improve the absorption of poorly water soluble drugs. Ibuprofen (IBU) is a BCS class II drug that exhibits poor dissolution rate in the gastrointestinal (GI) tract. The aim of the present study is to use various organic solvents to prepare solid dispersions of IBU in the presence of glucosamine HCl (GL), which acts as a carrier to enhance the dissolution of ibuprofen. Different ratios of ibuprofen and glucosamine were dissolved in various organic solvents to obtain the solid dispersions of ibuprofen-glucosamine mixtures. The physic-chemical/solid state analysis of the samples investigated using SEM, DSC, FT-IR and XRPD, particle size analysis and in vitro dissolution studies showed that the type of solvent has a big influence on the dissolution. Ibuprofen-glucosamine solid dispersions obtained from acetone produced better dissolution compared to that of other organic solvents. The effect of water in binary mixtures of acetone or ethanol was also investigated and the results showed that when the ratio of acetone to water was 75:25, the highest dissolution was obtained. Solid state analysis ruled out any chemical interaction between the dug and carrier even in the presence of various organic solvents which indicates a good stability of the solid dispersions to enhance the dissolution rate of ibuprofen. It was also investigated via XRPD analysis that the ibuprofen retained its crystallinity without any adverse effect on the dissolution rates

Starch-free grewia gum matrices: Compaction, swelling, erosion and drug release behaviour

Polysaccharides are suitable for application as hydrophilic matrices because of their ability to hydrate and swell upon contact with fluids, forming a gel layer which controls drug release. When extracted from plants, polysaccharides often contain significant quantities of starch that impacts upon their functional properties. This study aimed to evaluate differences in swelling, erosion and drug release from matrix tablets prepared from grewia gum (GG) and starch-free grewia gum (GDS) extracted from the stems of Grewia mollis. HPMC was used as a control polymer with theophylline as a model drug. Swelling, erosion, and in-vitro release were performed in deionized water, pH1.2 and pH6.8 media. The Vergnaud and Krosmeyer-Peppas model were used for swelling and drug release kinetics, respectively. However, linear regression technique was used to determine the erosion rate. GDS compacts were significantly harder than the native GG and HPMC compacts. GDS matrices exhibited the fastest erosion and drug release in deionised water and phosphate buffer compared with the GG and HPMC. At pH1.2, GDS exhibited greater swelling than erosion, and drug release was similar to GG and HPMC. This highlights the potential of GDS as a matrix for controlled release similar to HPMC and GG at pH1.2 but with a more rapid release at pH6.8. GDS may have wider application in reinforcing compacts with relatively low mechanical strengt

The influence of hydroalcoholic media on the performance of Grewia polysaccharide in sustained release tablets

Co-administration of drugs with alcohol can affect the plasma concentration of drugs in patients. It is also known that the excipients used in the formulation of drugs may not always be resistant to alcohol. This study evaluates effect of varying alcohol concentrations on theophylline release from two grades of Grewia mollis polysaccharides. X-ray microtomography showed that native polysaccharide formulation compacts were not homogenous after the mixing process resulting in its failure in swelling studies. Removal of starch from the native polysaccharide resulted in homogenous formulation compacts resistant to damage in high alcoholic media in pH 6.8 (40%v/v absolute ethanol). Destarched polymer compacts had a significantly higher hardness (375 N) than that of the native polysaccharide (82 N) and HPMC K4 M (146 N). Dissolution studies showed similarity at all levels of alcohol tested (f2 = 57-91) in simulated gastric media (pH 1.2). The dissolution profiles in the simulated intestinal fluids were also similar (f2 = 60-94), with the exception of the native polysaccharide in pH 6.8 (40%v/v absolute ethanol) (f2 = 43). This work highlights the properties of Grewia polysaccharide as a matrix former that can resist high alcoholic effects therefore; it may be suitable as an alternative to some of the commercially available matrix formers with wider applications for drug delivery as a cheaper alternative in the developing world

EFFECT OF BIODEGRADABLE CO-POLYMERS AND DIVALENT CATIONS ON THE SUSTAINED RELEASE ABILITY OF PROPRANOLOL HYDROCHLORIDE LOADED BIOMATERIAL MICROSPHERES

Objective: Propranolol Hydrochloride (PHCL) is used for the treatment of hypertension and angina pectoris; however it has two major problems; short biological halfâ€life and low bioavailability, so the aim of the present work was to develop PHCL mucoadhesive microsphere to prolong the residence time at the absorption site, therefore, increase the bioavailability.Methods: PHCL microspheres were prepared by ionotropic gelation method using nature polymers. Factorial design (33) was used to develop PHCL mucoadhesive microspheres, the independent factors used were polymer type (Sodium carboxymethyl cellulose (Na CMC), and Hydroxyl propyl methyl cellulose (HPMC), Carpobol 940), cross-linking type (calcium chloride, zinc chloride and barium chloride) and the concentration of Chitosan (0.5, 1, 1.5 %w/v). The developed microspheres were physicochemical characterized. The selected formula was selected for mucoadhesive test and in vivo study on human volunteers.Results: The results revealed that the PHCL mucoadhesive microspheres have good flowability, the mean particle sizes ranged from 541 to 815 µm and the entrapment efficiency ranged from 35.6% to 69.53%. The selected PHCL microspheres showed spherical particles with a rough surface and exhibited a slow release over 8h. The pharmacokinetic data of selected PHCL microspheres showed prolonged Tmax, decreased Cmax and AUC0–∞ value of 926.21±40.74ng. h/ml indicating improved relative bioavailability by144.93% compared with marketed tablets.Conclusion: PHCL microspheres were successfully prepared by ionic gelatin method that retards the release and enhances the oral bioavailability.Keywords: Propranolol HCL, Microspheres, Ionic gelation method, Chitosan, Relative bioavailabilit

Physiochemical and drug release properties of liquisolid formulations in comparison to their physical mixture counterparts

A thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosophy (PhD).Various techniques have been used for modifying the release properties of drugs over the past years. Techniques such as liquisolid technology have raised a lot of interest in many researchers which can be employed to enhance or sustain dissolution. Various liquisolid (LS) tablets of diltiazem containing Polysorbate 80 as a non-volatile solvent for sustained release were prepared. PolyoxTM is an attractive pharmaceutical polymer used in controlled release dosage forms mainly because of its insensitivity to the pH of the biological medium and ease of production. The aim of this study was to investigate the influence of several formulation factors i.e., the PolyoxTM grade at different molecular weight (MW), PolyoxTM particle size and ratio, the AEROSIL® grade, the use of diluent, polymer type and the drug type as well as their interactions on drug release from LS formulation in comparison to their physical mixture (PM). The result showed that PolyoxTM MW was a key determining step in achieving sustained release, with the higher MW of PolyoxTM resulting in a more delayed release profile. The delayed DTZ release could be related to the rate and extend of hydrogel formation on the tablet surface. The P–CMRs and net–CMRs of both LS and PM formulation powders also showed increasing trends with increasing the MW of PolyoxTM. The release of DTZ from both LS and conventional tablets showed mostly decreasing trends with increasing PolyoxTM concentration and decreasing PolyoxTM particle size distribution. This could be attributed to the formation of stronger and thicker gel layers on the tablet surfaces in the case of higher concentrations of PolyoxTM. The results also showed LS tablets to produce slower release of drug than their PM counterparts, regardless of PolyoxTM particle size. The release profile of the DTZ from both LS tablets and their counterpart PM tablets showed decreasing trends with increasing the surface area of hydrophilic AEROSIL® (from 65 m2/g to 225 m2/g). This could be due to the higher tensile strength (TS) of the tablets containing AEROSIL® particles with higher surface area compared to those prepared using AEROSIL® particles having lower surface areas. Also, the result showed that comparing the different diluents showed that hydrogenated vegetable oil (HVO) provided the slowest release pattern of DTZ across diluents used in both the LS compacts and PM tablets. This could be attributed to hydrophobicity imparted by HVO to matrix system when in contact with aqueous medium it takes a longer time to penetrate into the tablet. Drug release from LS tablets was affected by the polymer type. The release was in the order: Eudragit® RL < Eudragit® RS < Hypromellose < PolyoxTM < Psyllium. Hydrophilic Psyllium provided a slowest DTZ release across the different polymers used in the preparation of both the LS and PM compacts. The incorporation of Psyllium into PolyoxTM further elicited a decrease in drug release rate from individual polymer matrices. This was ascribed to the reduced entrance of aqueous media into the matrix due to the presence of the stronger viscose gel within the two hydrophilic matrices compared to individual Psyllium and PolyoxTM. The ratio between PolyoxTM and Psyllium has critically influenced diltiazem release profile. The results showed that matrices containing (Psyllium:PolyoxTM) at 1:1 ratio can slow down the drug release more than the matrices compacts containing 1:3 and 3:1 (Psyllium:PolyoxTM) ratio. The results also suggest that the ii combination of PolyoxTM and Psyllium at 1:1 ratio showed robust dissolution against pH and rotational speed and therefore indicates an appropriate sustained-release profile. The dissolution rate of PolyoxTM:Psyllium from different pure drugs showed a decreasing trend with an increase in their solubility. The solid state analysis studied in this work confirms the presence of a fraction of the drug mass in a solubilised state within polysorbate 80 in LS powders. Regardless of all variables used in this study, LS formulations showed slower drug release than their PM counterparts. In conclusion, the mechanical properties of LS formulation are poor in comparison to their counterpart PM. Therefore, further work is required to improve the hardness of LS tablet comprehensively.Tertiary Education Trust Fund (TETFUND

Desarrollo de nuevas formulaciones de liberación controlada bajo un programa de calidad por diseño (QbD)

[ES] La finalidad de este trabajo ha sido desarrollar comprimidos matriciales recubiertos para la liberación en el colon de metronidazol bajo un programa de Calidad por Diseño (QbD). Se planteó elaborar comprimidos de 500 mg de metronidazol mediante un proceso de compresión directa seguido de un proceso de recubrimiento usando hidroxipropilmetilcelulosa (HPMC) y chitosan como polímeros hidrófilos y los derivados del polimetacrilato Eudragit® RL 30D (tiempo-dependiente) y Eudragit® FS 30D (pH-dependiente) como polímeros de recubrimiento. Siguiendo las directrices recogidas en las guías ICH Q8 (R2) e ICH Q9 se ha descrito un Perfil de Calidad del Producto (QTPP) y se ha llevado a cabo un Análisis y Evaluación de Riesgos así como el planteamiento de un Diseño de Experimentos (DoE). Los resultados obtenidos de la evaluación y caracterización de los comprimidos se han analizado mediante un análisis estadístico de regresión ANOVA. Se ha optimizado una red neuronal artificial como alternativa al análisis multivariante que permita predecir la liberación de metronidazol desde los comprimidos elaborados. Se han empleado los datos obtenidos de los perfiles de disolución in vitro para predecir el comportamiento in vivo de los comprimidos mediante la realización de simulaciones biofarmacéuticas empleando un modelo ADAM (Advance Dissolution Absorption Model). El resultado del Análisis y Evaluación de riesgos determinó que los factores con un riesgo alto de producir un impacto negativo sobre el QTPP son el grado de viscosidad de la HPMC, el tiempo de mezclado de la mezcla pre-compresión, la proporción en la formulación de los polímeros hidrófilos, la naturaleza de la cubierta empleada y el % en aumento de peso total tras el recubrimiento. Teniendo en cuenta estos factores se elaboró un DoE factorial fraccionado que recogió estos 5 factores, con dos niveles para cada factor y un punto central. El análisis ANOVA de los resultados obtenidos tras la caracterización concluyó que los factores con un impacto estadísticamente significativo sobre las respuestas de los comprimidos elaborados son el ratio HPMC/chitosan dentro de la formulación, el tiempo de mezcla, la naturaleza del polímero de recubrimiento empleado y el % en aumento de peso total tras el recubrimiento, así como la interacción que se produce entre el ratio HPMC/chitosan con el tiempo de mezclado y la interacción entre el ratio HPMC/chitosan con el grado de viscosidad de la HPMC. Se ha planteado un Espacio de Diseño que recoge el intervalo de valores para cada factor estudiado que asegura todas las características descritas en el QTPP. La red neuronal artificial desarrollada mostró buena correlación entre los resultados observados y predichos, constituyendo una alternativa al análisis estadístico convencional. Los resultados de las simulaciones biofarmacéuticas mostraron que el empleo de cubiertas pH-dependientes impide la absorción de metronidazol en las partes superiores del tracto gastrointestinal, mientras que el empleo de cubiertas tiempo-dependientes permite alcanzar valores de concentración en la luz del colon similares independientemente del resto de factores estudiados