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24 HealtH & nutrition Figure 4 The layers of the MDD system Source: Glatt GmbH Binder droplets Powder Starting germ Figure 5 Device for measuring the trans epithelial electrical resistance 333 Solubility improvement through melt extrusion is not only at tractive for the development of new pharmaceuticals but can also benefit those that are already on the market. For example, they offer new prospects for life cycle management through new, optimized medical applications and the new patent protection made possible by it. A new patent can be acquired when, for example, the solubility improvement achieves bioequivalence—the same bioavailability with far less of the active ingredient. This is good for patients, and keeps down costs in the health system. Biopharmaceuticals: the modular drug-delivery system Biopharmaceuticals (also called biologicals) are used in the treatment of inflammatory diseases such as rheumatism and Crohn’s disease, as well as cancer, kidney diseases and metabolic disorders. Their importance is growing steadily. Administered in simple tablet form, they would frequently degrade in the gastrointestinal tract and be poorly reabsorbed. So most of the time, they have to be injected—a form of therapy that not only costs more than tablet intake but tends to be unpopular with patients. The digestive system is designed to break down the biomolecules from food into their component parts, and then transport them over the cell barriers into the bloodstream. Unprotected biologicals suffer the same fate—they are digested and thereby rendered ineffective. Here, Evonik scientists have set to work and developed innovative formulation concepts that can now allow a change to peroral administration for small to mediumsized biologicals. With elements34 Issue 1|2011 Cell monolayer Spraying Rolling Drying/solidifying Layer formation Pellet Apical compartment Basolateral compartment Liquid bridge Solid bridge First layer “Onion” structure Filter 312 Resistance indicator various exipients, they have created a modular drug delivery system (MDD) that they can use to quickly develop individual formulations and improve the peroral bioavailability of biologicals. Biologicals belong to differing substance classes, which is why the initial challenge was to find a formulation that could be applied to as many different classes of active ingredients as possible. By combining different modules, different active ingredients can be addressed. Evonik thus offers its customers the opportunity to bring a variety of different medicines to the market with one technology platform. Small and mediumsized biologicals can be formulated as microparticles or minipellets, in which each particle preserves the module of the MDD system required for the active ingredient—each individual particle, therefore, is a completely formulated system. The dosing unit of the active ingredient is spread over a large number of particles, that are assembled to a capsule or tablet. This multiunit dosage form has considerable pharmacological advantages over a monolithic system, including faster stomach passage, better distribution on the surface of the intestine, increased safety in use, and prevention of overdose due to a damaged dosage form. The multiparticle dosage forms of Evonik‘s Pharma Polymers Business Line are manufactured in conventional production processes, and can also be used in GMPcompliant production processes—a requirement for use in the pharmaceutical industry. Embedded in a 500 µm microparticle of the modular MDD system, biologicals actually survive passage through the stomach
additional polymer platForm Evonik acquires Resomer® activities from Boehringer Ingelheim Evonik and Boehringer Ingelheim Pharma GmbH & Co. KG have signed a contract for the sale of Resomer® activities to Evonik. According to the agreement, Evonik will acquire the entire product range of standard and customer-specific polymers for the production of medical applications and pharmaceutical formulations. Resomer® monomers are based on lactic and glycolic acids, and are obtained from renewable raw materials through fermentation. The polymers are completely biodegradable in the body. Thus, the oral EUDRAGIT® polymer platform of Evonik’s Pharma Polymers Business Line will be expanded by an additional parenteral polymer platform, and the Pharma market segment of the entire company strategically strengthened. The copolymers of the lactic and glycolic acids of the Resomer® brand are used in such applications as peptidebased extended-release medications for treating cancer, because an outer enteric polymer coating protects them from being attacked by the stomach acid. The particles continue to migrate undamaged to the intestine, where the outer layer selectively dissolves in the upper or lower intestinal segment, as a reaction to the pH level and composition. Released at the desired location, and now free from their exterior coating, the particles are protected by yet another component that prevents enzymatic digestion. Another module imparts mucosal compatibility to allow them to overcome the layer of mucous that covers the epithelial cells of the intestinal wall like a barrier. Finally, the active ingredient is released into the bloodstream, alone and unharmed, through the intestinal wall. The ability of the formulation to facilitate the transport of the active ingredient across the cell barrier is called a penetration enhancing effect. This effect is supported by an additional module that has a temporarily positive influence on the transport of the active ingredient. The pellet structure: modules in layers The pellets consist of various layers that are produced in two steps (Fig. 4). First, the core containing the active ingredient is formed, for example, by extrusion. This core is then wrapped in a coating made of several layers that contain a variety of components. Spray coating is a standard process used to build the EUDRAGIT® layers. To produce the particles, the components are applied layer by layer in one process step. For customers a particular advantage is not having to acquire special equipment for the process. They can also work with HealtH & nutrition 25 which ensure a therapeutic effect for up to six months. The lactic acid polymers are also used in medical technology. The advantage here is that these biodegradable polymers dissolve quickly and gently in the body following their utilization phase, and therefore preclude the need for additional surgeries for removal purposes. The polymers also allow the embedding of pharmaceutical agents, such as growth factors or antiobiotics, that have a positive effect on the healing process. Biodegradable polymers are preferred in the pharmaceutical industry for formulating innovative biotechnological active ingredients. While growth is stagnant all across the pharmaceutical market, it is significantly higher in the market for biotechnological active ingredients. With the new Resomer® polymer platform, Evonik’s Pharma Polymers Business Line has entered the dynamic growth market of biotechnological active ingredients. extruders and fluid bed plants—two standard processes in the pharmaceutical industry. The practical test: in-vivo studies The MDD system successfully completed two invivo studies conducted in collaboration with pharmaceutical companies. One peptidebased and one nonpeptidebased active ingredient were tested. The first study used a peptidebased active ingredient that is already on the market, and is administered both nasally and perorally. With peroral administration, the active ingredient shows an absolute bioavailability of below 0.1 percent (compared to par enteral dosage). It was formulated with three of the four Evonik modules: a gastrointestinal targeting component, an enzyme inhibiting component, and a penetrationimprovement component. The transport of various pellet formulations was determined in the cell culture on a layer of standardized intestinal cells (CaCo 2 cells) (Fig. 5). This single layer represents a barrier for the active ingredient, and is marked by high trans epithelial electrical resistance (TEER). As soon as the electrical resistance in this model drops, it is likely that a penetration enhancing effect is present (Fig. 6, p. 26). This effect is often correlated with the intestinal barrier’s physiological resistance to the diffusion of the active ingredient. Only in this condition can a sufficient quantity of the active ingredient pass through the cell layer. The measure ments showed that the active ingredient can diffuse through the layer only if the pellet formulation contains a 333 elements34 Issue 1|2011
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