| 1. |
- Abrahmsén-Alami, Susanna, et al.
(author)
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New release cell for NMR microimaging of tablets Swelling and erosion of poly(ethylene oxide)
- 2007
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In: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 342:1-2, s. 105-114
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Journal article (peer-reviewed)abstract
- A small release cell, in the form of a rotating disc, has been constructed to fit into the MRI equipment. The present work show that both qualitative and quantitative information of the swelling and erosion behavior of hydrophilic extended release (ER) matrix tablets may be obtained using this release cell and non-invasive magnetic resonance imaging (MRI) studies at different time-points during matrix dissolution. The tablet size, core size and the gel layer thickness of ER matrix formulations based on poly(ethylene oxide) have been determined. The dimensional changes as a function of time were found to correspond well to observations made with texture analysis (TA) methodology. Most importantly, the results of the present study show that both the erosion (displacement of the gel-dissolution media interface) and the swelling (decrease of dry tablet core size) proceed with a faster rate in radial than in axial direction using the rotating disk set-up. This behavior was attributed to the higher shear forces experienced in the radial direction. The results also indicate that front synchronization (constant gel layer thickness) is associated with the formation of an almost constant polymer concentration profile through the gel layer at different time-points.
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| 2. |
- Bernin, Diana, 1979, et al.
(author)
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Real time MRI to elucidate the functionality of coating films intended for modified release
- 2019
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In: Journal of Controlled Release. - : Elsevier BV. - 0168-3659 .- 1873-4995. ; 311-312, s. 117-124
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Journal article (peer-reviewed)abstract
- Polymer films based on mixtures of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC) have been widely used to coat pellets and tablets to modify the release profile of drugs. For three different EC/HPC films we used 1H and 19F MRI in combination with a designed release cell to monitor the drug, polymer and water in 5 dimensional (5D) datasets; three spatial, one diffusion or relaxation and a temporal dimension, in real time. We observed that the water inflow through the films correlated with the initiation of the dissolution of the drug in the tablet beneath the film. Leaching of the pore forming HPC further accelerated water penetration and resulted in a drug release onset after a hydrostatic pressure was generated below the film indicated by positional changes of the film. For the more permeable film, both water ingress and drug egress showed a large variability of release over the film surface indicating the heterogeneity of the system. Furthermore, the 1H diffusion dataset revealed the formation of a gel layer of HPC at the film surface. We conclude that the setup presented provides a significant level of details, which are not achieved with traditional methods.
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| 3. |
- Caccavo, D., et al.
(author)
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Effects of HPMC substituent pattern on water up-take, polymer and drug release: An experimental and modelling study
- 2017
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In: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 528:1-2, s. 705-713
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Journal article (peer-reviewed)abstract
- The purpose of this study was to investigate the hydration behavior of two matrix formulations containing the cellulose derivative hydroxypropyl methylcellulose (HPMC). The two HPMC batches investigated had different substitution pattern along the backbone; the first one is referred to as heterogeneous and the second as homogenous. The release of both the drug molecule theophylline and the polymer was determined. Additionally, the water concentrations at different positions in the swollen gel layers were determined by Magnetic Resonance Imaging. The experimental data was compared to predicted values obtained by the extension of a mechanistic Fickian based model. The hydration of tablets containing the more homogenous HPMC batch showed a gradual water concentration gradient in the gel layer and could be well predicted. The hydration process for the more heterogeneous batch showed a very abrupt step change in the water concentration in the gel layer and could not be well predicted. Based on the comparison between the experimental and predicted data this study suggests, for the first time, that formulations with HPMC of different heterogeneities form gels in different ways. The homogeneous HPMC batch exhibits a water sorption behavior ascribable to a Fick's law for the diffusion process whereas the more heterogeneous HPMC batches does not. This conclusion is important in the future development of simulation models and in the understanding of drug release mechanism from hydrophilic matrices.
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| 4. |
- Deshmukh, Shivprasad, et al.
(author)
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Injection moulded controlled release amorphous solid dispersions: Synchronized drug and polymer release for robust performance
- 2020
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In: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 575
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Journal article (peer-reviewed)abstract
- A study has been carried out to investigate controlled release performance of caplet shaped injection moulded (IM) amorphous solid dispersion (ASD) tablets based on the model drug AZD0837 and polyethylene oxide (PEO). The physical/chemical storage stability and release robustness of the IM tablets were characterized and compared to that of conventional extended release (ER) hydrophilic matrix tablets of the same raw materials and compositions manufactured via direct compression (DC). To gain an improved understanding of the release mechanisms, the dissolution of both the polymer and the drug were studied. Under conditions where the amount of dissolution media was limited, the controlled release ASD IM tablets demonstrated complete and synchronized release of both PEO and AZD0837 whereas the release of AZD0837 was found to be slower and incomplete from conventional direct compressed ER hydrophilic matrix tablets. The results clearly indicated that AZD0837 remained amorphous throughout the dissolution process and was maintained in a supersaturated state and hence kept stable with the aid of the polymeric carrier when released in a synchronized manner. In addition, it was found that the IM tablets were robust to variation in hydrodynamics of the dissolution environment and PEO molecular weight.
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| 5. |
- Govender, Rydvikha, 1989, et al.
(author)
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Enabling modular dosage form concepts for individualized multidrug therapy: Expanding the design window for poorly water-soluble drugs
- 2021
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In: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 602
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Journal article (peer-reviewed)abstract
- Multidrug dosage forms (aka combination dosage forms, polypills, etc.) create value for patients through reduced pill burdens and simplified administration to improve adherence to therapy. Enhanced flexibility of multidrug dosage forms would provide further opportunities to better match emerging needs for individualized therapy. Through modular dosage form concepts, one approach to satisfy these needs is to adapt multidrug dosage forms to a wider variety of drugs, each with a variety of doses and release profiles. This study investigates and technically explores design requirements for extending the capability of modular multidrug dosage form concepts towards individualization. This builds on our recent demonstration of independent tailoring of dose and drug release, which is here extended towards poorly water-soluble drugs. The challenging design requirement of carrying higher drug loads in smaller volumes to accommodate multiple drugs at their clinical dose is here met regarding dose and release performance. With a modular concept, we demonstrate high precision (<5% RSD) in dose and release performance of individual modules containing felodipine or naproxen in Kollidon VA64 at both a wide drug loading range (5% w/w and 50% w/w drug) and a small module size (3.6 mg). In a forward-looking design-based discussion, further requirements are addressed, emphasizing that reproducible individual module performance is predictive of dosage form performance, provided the modules are designed to act independently. Therefore, efforts to incorporate progressively higher drug loads within progressively smaller module volumes will be crucial to extend the design window further towards full flexibility of future dosage forms for individualized multidrug therapy.
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| 6. |
- Govender, Rydvikha, 1989, et al.
(author)
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High Content Solid Dispersions for Dose Window Extension: A Basis for Design Flexibility in Fused Deposition Modelling
- 2020
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In: Pharmaceutical Research. - : Springer Science and Business Media LLC. - 1573-904X .- 0724-8741. ; 37:1
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Journal article (peer-reviewed)abstract
- Purpose: This study uses high drug content solid dispersions for dose window extension beyond current demonstrations using fused deposition modelling (FDM) to; i) accommodate pharmaceutically relevant doses of drugs of varying potencies at acceptable dosage form sizes and ii) enable enhanced dose flexibility via modular dosage form design concepts. Methods: FDM was used to generate ~0.5 mm thick discs of varying diameter (2–10 mm) from melt-extruded feedstocks based on 10% to 50% w/w felodipine in ethyl cellulose. Drug content was determined by UV spectroscopy and dispensing precision from printed disc mass. Results: Mean felodipine content was within ±5% of target values for all print volumes and compositions including contents as high as ~50% w/w. However, poor dispensing precision was evident at all print volumes. Conclusions: In pursuit of dose flexibility, this successful demonstration of dose window extension using high content solid dispersions preserves FDM design flexibility by maintaining applicability to drugs of varying potencies. The achieved uniformity of content supports the application of varying content solid dispersions to modular dosage form concepts to enhance dose flexibility. However, poor dispensing precision impedes its utilisation until appropriate compatibility between FDM hardware and materials at varying drug contents can be attained.
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| 7. |
- Govender, Rydvikha, 1989, et al.
(author)
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Independent tailoring of dose and drug release via a modularized product design concept for mass customization
- 2020
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In: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 12:8, s. 1-24
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Journal article (peer-reviewed)abstract
- Independent individualization of multiple product attributes, such as dose and drug release, is a crucial overarching requirement of pharmaceutical products for individualized therapy as is the unified integration of individualized product design with the processes and production that drive patient access to such therapy. Individualization intrinsically demands a marked increase in the number of product variants to suit smaller, more stratified patient populations. One established design strategy to provide enhanced product variety is product modularization. Despite existing customized and/or modular product design concepts, multifunctional individualization in an integrated manner is still strikingly absent in pharma. Consequently, this study aims to demonstrate multifunctional individualization through a modular product design capable of providing an increased variety of release profiles independent of dose and dosage form size. To further exhibit that increased product variety is attainable even with a low degree of product modularity, the modular design was based upon a fixed target dosage form size of approximately 200 mm3 comprising two modules, approximately 100 mm3 each. Each module contained a melt-extruded and molded formulation of 40% w/w metoprolol succinate in a PEG1500 and Kollidon® VA64 erodible hydrophilic matrix surrounded by polylactic acid and/or polyvinyl acetate as additional release rate-controlling polymers. Drug release testing confirmed the generation of predictable, combined drug release kinetics for dosage forms, independent of dose, based on a product’s constituent modules and enhanced product variety through a minimum of six dosage form release profiles from only three module variants. Based on these initial results, the potential of the reconfigurable modular product design concept is discussed for unified integration into a pharmaceutical mass customization/mass personalization context.
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| 8. |
- Govender, Rydvikha, 1989, et al.
(author)
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Therapy for the individual: Towards patient integration into the manufacturing and provision of pharmaceuticals
- 2020
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In: European Journal of Pharmaceutics and Biopharmaceutics. - : Elsevier BV. - 1873-3441 .- 0939-6411. ; 149, s. 58-76
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Research review (peer-reviewed)abstract
- Individualized therapy with pharmaceutical products aims to elicit predictable and optimized treatment responses from specific patients. Doing so requires production platforms and technology capable of tailoring products to individual patient needs. However, despite recent manufacturing innovations and key technologies on the rise, e.g. continuous manufacturing and additive manufacturing (3D printing), the prevailing production paradigm employed in the pharmaceutical industry is mass production. Although mass production is efficient and cost-effective, it is typically based on a ‘one-size-fits-all’ product concept and lacks the flexibility and agility required to fully meet the needs of the individual patient. Indeed, we present data that confirm a suspected major imbalance between the recent medical evolution underpinning personalized/precision medicine and the recent advances in the associated manufacturing technologies. In this context we target the needs of the individual as a main driver for pharmaceutical products which support individualized therapy. We particularly address that a wider integration of critical patient dimensions into the manufacture and provision of pharmaceutical products is pivotal for enabling a patient-centric and efficient mass customization-based production paradigm. Here, we present a critical review of the area and its inherent challenges which aims to clarify key design requirements for establishing mass customization opportunities. Through primary sources of scientific information for individualized therapies, patient needs are captured, analysed, and conceptualized. This summarized set of key drivers provides the basis for a proposed patient-centric framework of requirements for use in design of product and production platforms for mass customization. The extent to which emerging pharmaceutical manufacturing technologies satisfy key individual patient needs is explored through a high-level assessment against the proposed patient-centric framework, with special attention paid to oral dosage forms. Altogether this holistic review and position paper, with its constituent steps, reveals major gaps in the evolution of Product-Process-Production approaches and solutions required for producing affordable individualized/personalized pharmaceuticals that respond to the needs and demands of the individual patient. Lastly, in a brief commentary and outlook, we suggest key research directions for closing gaps and addressing manufacturing technology challenges. We also articulate the importance of tackling them in a holistic, integrated way, together with challenges in product individualization and personalization.
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| 9. |
- Kaunisto, Erik, et al.
(author)
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A mechanistic modelling approach to polymer dissolution using magnetic resonance microimaging
- 2010
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In: Journal of Controlled Release. - : Elsevier BV. - 0168-3659 .- 1873-4995. ; 147:2, s. 232-241
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Journal article (peer-reviewed)abstract
- In this paper a computationally efficient mathematical model describing the swelling and dissolution of a polyethylene oxide tablet is presented. The model was calibrated against polymer release, front position and water concentration profile data inside the gel layer, using two different diffusion models. The water concentration profiles were obtained from magnetic resonance microimaging data which, in addition to the previously used texture analysis method, can help to validate and discriminate between the mechanisms of swelling, diffusion and erosion in relation to the dissolution process. Critical parameters were identified through a comprehensive sensitivity analysis, and the effect of hydrodynamic shearing was investigated by using two different stirring rates. Good agreement was obtained between the experimental results and the model. (C) 2010 Elsevier B.V. All rights reserved.
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| 10. |
- Kaunisto, Erik, et al.
(author)
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Mechanistic modelling of drug release from a polymer matrix using magnetic resonance microimaging.
- 2013
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In: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 1879-0720 .- 0928-0987. ; 48:4-5, s. 698-708
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Journal article (peer-reviewed)abstract
- In this paper a new model describing drug release from a polymer matrix tablet is presented. The utilization of the model is described as a two step process where, initially, polymer parameters are obtained from a previously published pure polymer dissolution model. The results are then combined with drug parameters obtained from literature data in the new model to predict solvent and drug concentration profiles and polymer and drug release profiles. The modelling approach was applied to the case of a HPMC matrix highly loaded with mannitol (model drug). The results showed that the drug release rate can be successfully predicted, using the suggested modelling approach. However, the model was not able to accurately predict the polymer release profile, possibly due to the sparse amount of usable pure polymer dissolution data. In addition to the case study, a sensitivity analysis of model parameters relevant to drug release was performed. The analysis revealed important information that can be useful in the drug formulation process.
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