Oral delivery strategies for the controlled release of cimetidine

It is advantageous to develop controlled release dosage forms utilising site-specific delivery or gastric retention for those drugs with frequent or high dosing regimes. Cimetidine is a potent and selective H2 -reception antagonist used in the treatment of various gastrointestinal disorders and localisation in the upper gastrointestinal tract could significantly improve the drug absorption. Three strategies were undertaken to prepare controlled release systems for the delivery of cimetidine to the GI tract. Firstly, increasing the contact time of the dosage form with the mucus layer which coats the gastrointestinal tract, may lead to increased gastric residence times. Mucoadhesive microspheres, by forming a gel-like structure in contact with the mucus, should prolong the contact between the delivery system and the mucus layer, and should have the potential for releasing the drug in sustained and controlled manner. Gelatin microspheres were prepared, optimised and characterised for their physicochemical properties. Crosslinking concentration, particle size and cimetidine loading influenced drug release profiles. Particle size was influenced by surfactant concentration and stirring speed. Mucoadheisve polymers such as alginates, chitosans, carbopols and polycarbophil were incorporated into the microspheres using different strategies. The mucoadhesion of the microspheres was determined using in vitro surface adsorption and ex vivo rat intestine models. The surface-modification strategy resulted in highest levels of microsphere adhesion, with chitosan, carbopols and polycarbophil as the most successful candidates for improvement of adhesion, with over 70% of the microspheres retained ex vivo. Specific targeting agent UEA I lectin was conjugated to the surface of gelatin microspheres, which enhanced the adhesion of the microspheres. Alginate raft systems containing antacids have been used extensively in the treatment of gastro-oesophageal disease and protection of the oesophageal mucosa from acid reflux by forming a viscous raft layer on the surface of the stomach content, and could be an effective delivery system for controlled release of cimetidine.

The controlled release of macromolecules from macroporous hydrophyllic polymer matrices

This work has used novel polymer design and fabrication technology to generate bead form polymer based systems, with variable, yet controlled release properties, specifically for the delivery of macromolecules, essentially peptides of therapeutic interest. The work involved investigation of the potential interaction between matrix ultrastructural morphology, in vitro release kinetics, bioactivity and immunoreactivity of selected macromolecules with limited hydrolytic stability, delivered from controlled release vehicles. The underlying principle involved photo-polymerisation of the monomer, hydroxyethyl methacrylate, around frozen ice crystals, leading to the production of a macroporous hydrophilic matrix. Bead form matrices were fabricated in controllable size ranges in the region of 100µm - 3mm in diameter. The initial stages of the project involved the study of how variables, delivery speed of the monomer and stirring speed of the non solvent, affectedthe formation of macroporous bead form matrices. From this an optimal bench system for bead production was developed. Careful selection of monomer, solvents, crosslinking agent and polymerisation conditions led to a variable but controllable distribution of pore sizes (0.5 - 4µm). Release of surrogate macromolecules, bovine serum albumin and FITC-linked dextrans, enabled factors relating to the size and solubility of the macromolecule on the rate of release to be studied. Incorporation of bioactive macromolecules allowed retained bioactivity to be determined (glucose oxidase and interleukin-2), whilst the release of insulin enabled determination of both bioactivity (using rat epididymal fat pad) and immunoreactivity (RIA). The work carried out has led to the generation of macroporous bead form matrices, fabricated from a tissue biocompatible hydrogel, capable of the sustained, controlled release of biologically active peptides, with potential use in the pharmaceutical and agrochemical industries.

Development of photosensitive liposomes for the controlled release of drugs

The facility to controlled triggered release from a “cage” system remains a key requirement for novel drug delivery. Earlier studies have shown that Bis-Azo PC based photosensitive liposomes are beneficial for drug delivery. Thus, the aim of this project was to develop photosensitive liposomes that can be used for the controlled release of drugs through UV irradiation, particularly therapeutic agents for the treatment of psoriasis. Bis-Azo PC was successfully synthesized and incorporated into a range of liposomal formulations, and these liposomes were applied for the controlled release of BSA-FITC. Bis-Azo PC sensitized liposomes were prepared via interdigitation fusion method. IFV containing optimum cholesterol amount in terms of protein loading, stability and photo-trigger release of protein was investigated. Further studies investigated the stability and triggered release of the HMT from IFV. Finally, permeation behavior of HMT and HMT-entrapped IFV through rat skin was examined using Franz cell. Results from protein study indicated that the stable entrapment of the model protein was feasible as shown through fluorescence spectroscopy and maximum of 84% protein release from IFV after 12 min of UV irradiation. Moreover, stability studies indicated that IFV were more stable at 4 0C as compared to 25 0C. Hence, DPPC:Chol:Bis-Azo PC (16:2:1) based IFV was chosen for the controlled release of HMT and these studies exhibited that photo-trigger release and stability data of HMT-entrapped IFV are in line with the protein results. Franz cell work inferred that HMT-entrapped IFV attributed to slower skin permeation as compared to HMT. CLSM also demonstrated that HMT can be used as a fluorescent label for the in vitro skin study. Overall, the work highlighted in this thesis has given useful insight into the potentials of Bis-Azo PC based IFV as a promising carrier for the treatment of psoriasis.

Development of nanostructured hydrogel for spatial and temporal controlled release of active compounds

L’utilisation de nanovecteurs pour la livraison contrôlée de principes actifs est un concept commun de nous jours. Les systèmes de livraison actuels présentent encore cependant des limites au niveau du taux de relargage des principes actifs ainsi que de la stabilité des transporteurs. Les systèmes composés à la fois de nanovecteurs (liposomes, microgels et nanogels) et d’hydrogels peuvent cependant permettre de résoudre ces problèmes. Dans cette étude, nous avons développé un système de livraison contrôlé se basant sur l’incorporation d’un nanovecteur dans une matrice hydrogel dans le but de combler les lacunes des systèmes se basant sur un vecteur uniquement. Une telle combinaison pourrait permettre un contrôle accru du relargage par stabilisation réciproque. Plus spécifiquement, nous avons développé un hydrogel structuré intégrant des liposomes, microgels et nanogels séparément chargés en principes actifs modèles potentiellement relargués de manière contrôlé. Ce contrôle a été obtenu par la modification de différents paramètres tels que la température ainsi que la composition et la concentration en nanovecteurs. Nous avons comparé la capacité de chargement et la cinétique de relargage de la sulforhodamine B et de la rhodamine 6G en utilisant des liposomes de DOPC et DPPC à différents ratios, des nanogels de chitosan/acide hyaluronique et des microgels de N-isopropylacrylamide (NIPAM) à différents ratios d’acide méthacrylique, incorporés dans un hydrogel modèle d’acrylamide. Les liposomes présentaient des capacités de chargement modérés avec un relargage prolongé sur plus de dix jours alors que les nanogels présentaient des capacités de chargement plus élevées mais une cinétique de relargage plus rapide avec un épuisement de la cargaison en deux jours. Comparativement, les microgels relarguaient complétement leur contenu en un jour. Malgré une cinétique de relargage plus rapide, les microgels ont démontré la possibilité de contrôler finement le chargement en principe actif. Ce contrôle peut être atteint par la modification des propriétés structurelles ou en changeant le milieu d’incubation, comme l’a montré la corrélation avec les isothermes de Langmuir. Chaque système développé a démontré un potentiel contrôle du taux de relargage, ce qui en fait des candidats pour des investigations futures.

Synchronized and controlled release of metformin hydrochloride/glipizide from elementary osmotic delivery

The combination of metformin hydrochloride (MTF) and glipizide (GLZ) is second-line medication for diabetes mellitus type 2 (DMT2). In the present study, elementary osmotic pump(EOP)tablet is designed to deliver the combination of MTF and GLZ in a sustained and synchronized manner. By analyzing different variables of the formulation, sodium hydrogen carbonate is introduced as pH modifier to improve the release of GLZ, while ethyl cellulose acts as release retardant to reduce the burst release phase of MTF. A two factor, three level face-centered central composite design (FCCD) is applied to investigate the impact of different factors on drug release profile. Compared with conventional tablets, the elementary osmotic pump (EOP) tablet demonstrates a controlled release behavior with relative bioavailability of 99.2% for MTF and 99.3% for GLZ. Data also shows EOP tablet is able to release MTF and GLZ in a synchronized and sustained manner both in vitro and in vivo

Matrix and reservoir-type multipurpose vaginal rings for controlled release of dapivirine and levonorgestrel

A matrix-type silicone elastomer vaginal ring providing 28-day continuous release of dapivirine (DPV) - a lead candidate human immunodeficiency virus type 1 (HIV-1) microbicide compound - has recently demonstrated moderate levels of protection in two Phase III clinical studies. Here, next-generation matrix and reservoir-type silicone elastomer vaginal rings are reported for the first time offering simultaneous and continuous in vitro release of DPV and the contraceptive progestin levonorgestrel (LNG) over a period of between 60 and 180days. For matrix-type vaginal rings comprising initial drug loadings of 100, 150 or 200mg DPV and 0, 16 or 32mg LNG, Day 1 daily DPV release values were between 4132 and 6113μg while Day 60 values ranged from 284 to 454μg. Daily LNG release ranged from 129 to 684μg on Day 1 and 2-91μg on Day 60. Core-type rings comprising one or two drug-loaded cores provided extended duration of in vitro release out to 180days, and maintained daily drug release rates within much narrower windows (either 75-131μg/day or 37-66μg/day for DPV, and either 96-150μg/day or 37-57μg/day for LNG, depending on core ring configuration and ignoring initial lag release effect for LNG) compared with matrix-type rings. The data support the continued development of these devices as multi-purpose prevention technologies (MPTs) for HIV prevention and long-acting contraception.

Investigation of properties affecting controlled release of macromolecules from PLGA microspheres

Poly(lactide-co-glycolide), or PLGA, microspheres offer a widely-studied biodegradable option for controlled release of therapeutics. An array of fabrication methodologies have been developed to produce these microspheres with the capacity to encapsulate therapeutics of various types; and produce microspheres of a wide range of sizes for different methods of delivery. The encapsulation, stability, and release profiles of therapeutic release based on physical and thermodynamic properties has also been studied and modeled to an extent. Much research has been devoted to tailoring formulations for improved therapeutic encapsulation and stability as well as selective release profiles. Despite the breadth of available research on PLGA microspheres, further analysis of fundamental principles regarding the microsphere degradation, formation, and therapeutic encapsulation is necessary. This work aims to examine additional fundamental principles related to PLGA microsphere formation and degradation from solvent-evaporation of preformed polymer. In particular, mapping the development of the acidic microenvironment inside the microsphere during degradation and erosion is discussed. Also, the effect of macromolecule size and conformation is examined with respect to microsphere diameter and PLGA molecular weight. Lastly, the effects of mechanical shearing and protein exposure to aqueous media during microsphere formation are examined. In an effort to better understand the acidic microenvironment development across the microsphere diameter, pH sensitive dye conjugated to protein that undergoes conformational change at different acidic pH values was encapsulated in PLGA microspheres of diameters ranging from 40 µm to 80 µm, and used in conjunction with fluorescence resonance energy transfer to measure the radial pH change in the microspheres. Qualitative analysis of confocal micrographs was used to correlate fluorescence intensity with pH value, and obtain the radial pH across the center of the microsphere. Therapeutic encapsulation and release from polymeric microspheres is governed by an interconnected variety of factors, including the therapeutic itself. The globular protein bovine serum albumin, and the elongated and significantly smaller enzyme, lysozyme, were encapsulated in PLGA microspheres ranging from 40 µm to 80 µm in diameter. The initial surface morphology upon microsphere formation, release profiles, and microsphere erosion characteristics were explored in an effort to better understand the effect of protein size, conformation, and known PLGA interaction on the formation and degradation of PLGA microspheres and macromolecule release, with respect to PLGA molecular weight and microsphere diameter. In addition to PLGA behavior and macromolecule behavior, the effect of mechanical stresses during fabrication was examined. Two similar solvent extraction techniques were compared for the fabrication of albumin loaded microspheres. In particular, the homogeneity of the microspheres as well as capacity to retain encapsulated albumin were compared. This preliminary study paves the way for a more rigorous treatment of the effect of mechanical forces present in popular microsphere fabrication. Several factors affecting protein release from PLGA microspheres are examined herein. The technique explored for spatial resolution of the pH inside the microsphere proved mildly effective in producing a reliable method of mapping microsphere pH changes. However, notable trends with respect to microsphere size, PLGA molecular weight, and microsphere porosity were observed. Proposed methods of improving spatial resolution of the acidic microenvironment are also provided. With respect to microsphere formation, studies showed that albumin and lysozyme had little effect on the internal homogeneity of the microsphere. Rather, ionic interactions with PLGA played a more significant role in the encapsulation and release of each macromolecule. Studies also showed that higher instances of mechanical stress led to less homogeneous microspheres with lower protein encapsulation. This suggests that perhaps instead of or in addition to modifying the microsphere formation formulation, the fabrication technique itself should be more closely considered in achieving homogeneous microspheres with desired loading.

Scaffolds for controlled release of cartilage growth factors

International audience

Development of nanostructured hydrogel for spatial and temporal controlled release of active compounds

L’utilisation de nanovecteurs pour la livraison contrôlée de principes actifs est un concept commun de nous jours. Les systèmes de livraison actuels présentent encore cependant des limites au niveau du taux de relargage des principes actifs ainsi que de la stabilité des transporteurs. Les systèmes composés à la fois de nanovecteurs (liposomes, microgels et nanogels) et d’hydrogels peuvent cependant permettre de résoudre ces problèmes. Dans cette étude, nous avons développé un système de livraison contrôlé se basant sur l’incorporation d’un nanovecteur dans une matrice hydrogel dans le but de combler les lacunes des systèmes se basant sur un vecteur uniquement. Une telle combinaison pourrait permettre un contrôle accru du relargage par stabilisation réciproque. Plus spécifiquement, nous avons développé un hydrogel structuré intégrant des liposomes, microgels et nanogels séparément chargés en principes actifs modèles potentiellement relargués de manière contrôlé. Ce contrôle a été obtenu par la modification de différents paramètres tels que la température ainsi que la composition et la concentration en nanovecteurs. Nous avons comparé la capacité de chargement et la cinétique de relargage de la sulforhodamine B et de la rhodamine 6G en utilisant des liposomes de DOPC et DPPC à différents ratios, des nanogels de chitosan/acide hyaluronique et des microgels de N-isopropylacrylamide (NIPAM) à différents ratios d’acide méthacrylique, incorporés dans un hydrogel modèle d’acrylamide. Les liposomes présentaient des capacités de chargement modérés avec un relargage prolongé sur plus de dix jours alors que les nanogels présentaient des capacités de chargement plus élevées mais une cinétique de relargage plus rapide avec un épuisement de la cargaison en deux jours. Comparativement, les microgels relarguaient complétement leur contenu en un jour. Malgré une cinétique de relargage plus rapide, les microgels ont démontré la possibilité de contrôler finement le chargement en principe actif. Ce contrôle peut être atteint par la modification des propriétés structurelles ou en changeant le milieu d’incubation, comme l’a montré la corrélation avec les isothermes de Langmuir. Chaque système développé a démontré un potentiel contrôle du taux de relargage, ce qui en fait des candidats pour des investigations futures.

Development and In Vitro Evaluation of Propranolol Hydrochloride Controlled Release Tablets Using HPMC as Matrix Former

The purpose of this paper was to produce controlled-release matrices with 120 mg of propranolol hydrochloride (PHCl) employing hydroxypropyl methylcellulose (HPMC, Methocel (R) K100) as the gel forming barrier. Although this class of polymers has been commonly used for direct compression, with the intent of use reduced polymer concentrations to achieve controlled drug release, in this study tablets were produced by the wet granulation process. HPMC percentages ranged from 15-34 % and both soluble and non soluble diluents were tested in the 10 proposed tablet compositions. Dissolution testing of matrices was performed over a 12 h period in 1.2 pH medium (the first 2 h) and in pH 6.8 (10 h). Dissolution kinetic analysis was performed by applying Zero-order, First-order and Higuchi models with the aim of elucidating the drug release mechanism. All physical-chemical characteristics such as average weight, friability, hardness, diameter, height, and drug content were in accordance to the pharmacopeial specifications. Taking into account that PHCl is a very soluble drug, low concentrations (15 %) of HPMC were sufficient to reduce the drug release and to promote controlled release of PHCl, presenting good dissolution efficiencies, between 50 % and 63 %. The Higuchi model has presented the best fit to the 15 % HPMC formulations, indicating that the main release mechanism was diffusion. It could be concluded that the application of the wet granulation method reduced matrices erosion and promoted controlled release of the drug at low HPMC percentages.

Release of vancomycin and teicoplanin from a plasticized and resorbable gelatin sponge: in vitro investigation of a new antibiotic delivery system with glycopeptides.

BACKGROUND: The aim of this study was to evaluate the efficacy of sustained release of vancomycin and teicoplanin from a resorbable gelatin glycerol sponge, in order to establish a new delivery system for local anti-infective therapy. MATERIALS AND METHODS: 60 plasticized glycerol gelatin sponges containing either 10 or 20% gelatin (w/v) were incubated in vancomycin or teicoplanin solution at 20 degrees C for either 1 or 24 h. In vitro release properties of the sponges were investigated over a period of 1 week by determining the levels of vancomycin and teicoplanin eluted in plasma using fluorescent polarization immunoassay. The rate constant and the half-life for the antibiotic release of each group were calculated by linear regression assuming first order kinetics. RESULTS: Presoaking for 24 h was associated with a significant increase in the total antibiotic release in all groups opposed to 1 h of incubation, except for the 10% sponges presoaked in teicoplanin. Doubling the gelatin content of the sponges from 10 to 20% significantly increased the total release of antibiotic load only in teicoplanin-containing sponges after 24 h incubation. In all corresponding groups investigated, release of vancomycin was more prolonged compared to teicoplanin, which allowed a gradual release beyond 5 days. The half-life (h +/- SEM) of both types of vancomycin-containing sponges was significantly prolonged by 24 h incubation in comparison to 1 h incubation (29.1 +/- 5.9 vs 5.9 +/- 1.0; p < 0.001, 30.0 +/- 2.1 vs 11.1 +/- 1.9; p < 0.001). However, neither doubling the gelatin content of the sponges nor a prolonged incubation was associated with a significantly prolonged delivery of teicoplanin. CONCLUSION: This study demonstrated a better diffusion-controlled release of vancomycin-impregnated glycerol gelatin sponges compared to those pretreated with teicoplanin. The plasticized glycerol gelatin sponge may be a promising carrier for the application of vancomycin to infected wounds for local anti-infective therapy.

On the release of metronidazole from natural rubber latex membranes

The controlled release of drugs can be efficient if a suitable encapsulation procedure is developed, which requires biocompatible materials to hold and release the drug. In this study, a natural rubber latex (NRL) membrane is used to deliver metronidazole (MET), a powerful antiprotozoal agent. MET was found to be adsorbed on the NRL membrane, with little or no incorporation into the membrane bulk, according to energy dispersive X-ray spectroscopy. X-ray diffraction and FTIR spectroscopy data indicated that MET retained its structural and spectroscopic properties upon encapsulation in the NRL membrane, with no molecular-level interaction that could alter the antibacterial activity of MET. More importantly, the release time of MET in a NRL membrane in vitro was increased from the typical 6-8 h for oral tablets or injections to ca. 100 h. The kinetics of the drug release could be fitted with a double exponential function, with two characteristic times of 3.6 and 29.9 h. This is a demonstration that the induced angiogenesis known to be provided by NRL membranes can be combined with a controlled release of drugs, whose kinetics can be tailored by modifying experimental conditions of membrane fabrication for specific applications. (C) 2010 Elsevier B.V. All rights reserved.

On the release of metronidazole from natural rubber latex membranes

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Multifunction hexagonal liquid-crystal containing modified surface TiO2 nanoparticles and terpinen-4-ol for controlled release

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)