Dokument: Melt Extruded Drug Formulations for Individual Dosing by the Solid Dosage Pen
| Titel: | Melt Extruded Drug Formulations for Individual Dosing by the Solid Dosage Pen | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=33413 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20150413-152232-8 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Laukamp, Eva Julia [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Breitkreutz, Jörg [Betreuer/Doktorvater] Prof. Dr. Kleinebudde, Peter [Gutachter] | |||||||
| Stichwörter: | Melt extrusion, individual dosing, device, paediatrics, geriatrics | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | This work focuses on the development, the manufacturing, and the characterisation of melt-extruded rods for the application by the Solid Dosage Pen (SDP) - a device which permits individual dosing by cutting slices of pre-defined heights from these rods. The field of application of the SDP was broadened to drugs with higher doses, like the chosen model drug carbamazepine (CBZ), by the production of rods with a larger diameter (4 mm) and the new design of the existing prototype of the SDP.
First, small scale production techniques were elaborated to conduct an excipient screening for the formulation development. A high pressure capillary rheometer allowed for the manufacturing of ram extrudates with only 10 g material input. This way, the exploration of mechanical properties, dissolution behaviour, and solid state characteristics was feasible at small scale. Second, and based on the experiences in the small-scale, extrudates containing polyethylene glycols (PEGs) and poloxamers as excipients were produced by twin screw melt extrusion. Furthermore, co-extrusion as a new and more sophisticated technique was successfully applied. By the adjustment of the dissolution behaviour, the mechanical properties, and the process parameters of the extrudates appropriate coat and core formulations were chosen. Third, for the embedding of multiparticulates into a matrix, CBZ micropellets were manufactured and coated with Eudragit® RS/RL, PVAc and PVAc/PVA-PEG. These micropellets, sized 300 to 450 µm, were then successfully incorporated into rods via ram extrusion due to their adequate tensile strength and due to a low solubility of the film coating within the matrix. By the utilisation of different matrices, added excipients, pore-forming agents, drug loadings and applied production techniques tailored dissolution kinetics were achieved with immediate, biphasic, and sustained release characteristics. For hydrophilic matrices like PEGs with different molecular weights, a higher CBZ loading resulted in lower drug dissolution rates. For lipophilic matrices like stearic acid or poly(ε caprolactone) the dissolution rates were low and pore-forming agents only marginally impinged on the CBZ release. Nevertheless, for drugs with a higher solubility, matrix formulations based on lipophilic matrices could be valuable. Extrudates exhibiting sustained release characteristics showed cube root kinetics, whereas wax coated (co )extrudates followed a zero order release mechanism after 3 h. Dissolution profiles with constant CBZ release over time and without a burst effect were made accessible by the micropellet loaded rods (MPLRs) containing Eudragit® RS/RL and PVAc coated CBZ micropellets. The addition of PVA-PEG as a pore-forming agent within the PVAc film increased the drug dissolution rate of the sustained release micropellets but also changed the dissolution mechanism. The different mechanisms of drug liberation depended on the applied coating polymers and were explained amongst others by the investigation of the pellets’ surface morphology and cross-cuts via SEM before and after dissolution. Finally, dose dependent dissolution behaviour of sustained release formulations was minimised by applying a wax-coating via co-extrusion and even completely overcome by the embedding of micropellets into rods. The dissolution profiles of the extrudates and co extrudates as well as the micropellet loaded rods containing PVAc/PVA-PEG coated pellets did not alter after storage at ambient temperature and 45 % RH. As an outlook, the approach of the MPLR opens up new possibilities like enteric coated dosage forms for the SDP. For the first time, the mechanical properties of rods intended for the application by the SDP were systematically investigated by the evaluation of the maximum cutting force, the tensile strength and the E modulus. While cuttability was mainly influenced by the utilised binder, both tensile strength and E modulus were affected by the CBZ loading. Moreover, the mechanical properties were purposefully modulated by suitable excipients and the optical appearance of the sliced doses was improved by PEG 1,500. The formulations in conjunction with the device were shown to be generally suitable for patient centred treatment: The required cutting forces for the drug loaded rods (below 41.9 ± 1.7 N) were in the range of the manual forces of different age groups, resulting in appropriateness even for the elderly and for school children. Due to their adequate mechanical properties and in the case of the co extrudates due to a suitable layer adhesion of core and coat, all drug and micropellet loaded rods were sliceable by the newly designed SDP. As no hard edges or splinters occurred, a safe swallowing can be assumed. The mass uniformity of sliced doses was influenced by the mechanical properties of the rods: Firstly, formulations which exhibited a cut were more suitable for the utilisation of the SDP than those exhibiting a break. Secondly, tensile strength and E modulus were shown to be valuable indicators for the applicability of the SDP. A tensile strength below 9.1 ± 0.3 MPa and an E modulus below 135.9 ± 7.2 MPa were determined as thresholds for future formulation development. Regarding the uniformity of dosage units the pharmacopoeial requirements were met for extrudates containing PEG 1,500 and also for the dual drug release co extrudates. Contrarily, for the wax coated co extrudate differences of the process parameters between the core- and the coat-layer resulted in unsatisfying content uniformities. For MPLRs including particles sized below 350 µm a precise drug delivery of single doses was reached. A thorough understanding of the solid state properties of CBZ within the formulations was built up within this work. Solid state analysis via XRPD, SEM or Raman-spectroscopy, for example, revealed that the utilised manufacturing techniques did not change the modification of the drug and all formulations enclosed the required modification of CBZ III. To conclude, innovative production processes, new analytic methods and novel formulations were established for peroral solid dosage forms for the SDP. The melt-extruded formulations allowed for individual dosing by the SDP and could therefore provide a new platform in personalised medicine as well as in paediatrics and geriatrics. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische Technologie und Biopharmazie | |||||||
| Dokument erstellt am: | 13.04.2015 | |||||||
| Dateien geändert am: | 13.04.2015 | |||||||
| Promotionsantrag am: | 16.12.2014 | |||||||
| Datum der Promotion: | 21.01.2015 |
