Mini-tablets and mini-matrices as multiple-unit systems intended for modified drug deliveryAleksovski, Aleksandar (Avtor) Dreu, Rok (Mentor) Mini-tablets could be defined as tablets with diameter up to 3mm. They are produced in a robust and stable compression process on standard tablet presses equipped with multi-tip tooling and matrices with multiple die opening. During the compression process strict control over applied pressure, material flow properties and tooling alignment is required in terms of avoiding tooling damage and obtaining suitable product. Mini-tablets represent contemporary platform for development of modified release multiple-unit drug delivery systems (MDDS), providing similar advantages over single unit systems as pellets. Mini-tablets can be further used for combining different release kinetics or different (in)compatible active compounds in one system. These features may improve the therapeutic outcome of the medication, reduce dosing frequency and polypharmacotherapy, which is especially important for geriatric and hospitalized patients. Due to their small size mini-tablets proved to be an easy way of drug administration, due to the facilitated swallowing, when administrated as single unit or as multiple units mixed with soft food. Additionally, by merging two or more mini-tables on demand flexible doses could be obtained regarding patient’s age, weight or condition. Mini-tablets have been successfully employed as MDDS providing different drug release outcomes such as extended release, pulsatile release, targeted release etc. Within the thesis scope a MDDS, based on mini-tablets varying in the matrix and coating composition, was developed with purpose of obtaining specific sigmoidal and zero-order release kinetics of a model drug paliperidone, which was imposed by the marketed product designed as osmotic pump. MDDS was based on combination of one mini-tablet aimed to start drug release in the duodenum and provide slower delivery and three mini-tablets aimed to start delivering paliperidon in the ileo-colonic region, but with faster release rate. This action was achieved through application of a polymeric mixture of polyvinyl acetate and polyvinyl pyrolidone (Kollidon® SR) as matrix former, lactose as soluble diluent and magnesium hydroxide as pH modifier in different amounts, which induced extended drug release with different rates through 24 hours. Additionally, by coating the units with different pH soluble acrylic polymers a desired, delayed drug release with regard to specific GIT pH and transit times was obtained. Combined effect led to obatining in-vitro similar release pattern (sigmoidal) when compared to the reference drug. Obtained mini-tablets fulfilled the pharmacopoeia requirements for the mass and content uniformity, friability and also tended to be robust, when exposed to dissolution testing at variable gastric conditions and were also stable. Computer based program for release profile screening was designed during the studies and was successfully employed in extracting alternative mini-tablet combinations, giving also similar drug delivery outcome as the original drug. Hot-melt extrusion (HME) and prilling are gaining importance in the last period as simple and continuous methods for production of MDDS. In HME powder mixtures are introduced in heated barrel with rotating screw/s where they are mixed, kneaded, (partialy)melted and conveyed to an end plate die which determines the size and shape of the final product. During the process a control over material feed rate, barrel temperature profile, screw speed, residence time of the material and torque is essential. Main advantages of HME are seen in its continuous nature, single-pot characteristics, solvent free processing, minimal requirements for suitable flow properties and compressibility of the materials, ease of production differently shaped products, suitability for PAT implementation etc. Main disadvantage of HME is heat generation, which makes it unsuitable for thermolabile compounds. By careful selection of active compounds and excipients HME has been successfully applied in improving drug solubility, modified release, taste masking etc. Prilling is also continuous and solvent free technology where molten masses are dripped through a nozzle in a cooling tower where previously formed drops are solidified into spherical solid particles with uniform size and shape. Main disadvantages of prilling are limited heat transfer to cooling fluid during solidification and the need of high towers, which enable complete solidification of the droplets. Prilling is relatively unknown technique in the pharmaceutical field and till now it has been employed only in a few studies dealing with the design of immediate and extended release MDDS. Pharmaceutically approved lipids are suitable excipients for processing by HME or prilling due to their low melting temperatures and low viscosities of molten masses. Additionally, they are considered as biocompatible, compatible with many other compounds and cost-effective. Due to the hydrophobicity of some of them, lipids could be used as matrix former in extended release systems. Main drawback of lipids is seen in their possible physical instability during processing and/or storage, which may compromise the final outcome of the product. Within this thesis extended release mini-matrices based on metoprolol tartrate (MPT) as highly soluble model drug and either glyceryl palmitostearate (GPS) or glyceryl behenate (GB) as lipid matrix former were designed and evaluated. Mini-matrices were produced by three different techniques: hot-melt extrusion, prilling and compression (of untreated powders and melt granulated materials) of mini-tablets. Hot-melt extrusion and compression of granules appeared as reproducible and robust methods for producing extended release mini-matrices. Glycerid-MPT powder mixtures tend to have poor flow properties and therefore direct compression of powders was not taken into consideration for further investigations. Prilling showed to be susceptible to melt viscosity and was solely employed for melts containing lowest drug amount. Dissolution results of all fresh products pointed that release rate depends on drug loading and the unit/particle size. GB based matrices were in general more porous and provided faster drug release compared to same type of matrices based on GPS. The production technique also tended to determine the porosity of the units with HME providing most porous structure while tableting and prilling gave denser units. When comparing different units based on the same glyceride, GPS showed diverse drug release patterns when being processed by the three methods, while in case of GB this phenomenon did not appear. In all obtained units drug was homogenously dispersed throughout the matrix and no significant interaction between it and the lipid carrier were noticed, therefore these two factors were eliminated as possible impacts over drug delivery rate and pattern. Thermal and X-ray powder diffraction investigations demonstrated significant alteration in the solid state properties of the used glycerides after stability studies under room conditions (GPS units) and conditions of elevated temperature (GPS and GB units), which were seen as causes inducing changes in the drug delivery rate and pattern after storage. GB matrices were in general unaffected by the composition of the dissolution media while GPS units tended to show faster drug release when medium pH was increased and when tested under biorelevant fed state conditions. Drug release patterns of GB based matrices proved to be unaffected by the production type, dissolution conditions and storage at room temperatures. GB was therefore identified as robust matrix former. [A. Aleksovski]20162023-01-11 12:39:12Doktorsko delo/naloga143762sl