Soft tabletting of MCC 102 and UICEL-A/102 pellets into multiple unit pellet systems

Balzano, Vincenzo. Soft tabletting of MCC 102 and UICEL-A/102 pellets into multiple unit pellet systems. 2009, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_8669

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Multiple Unit Pellet Systems, widely known as MUPS, are tablets consisting of spherical, granular subunits (pellets). Thanks to their prompt disintegration into the single subunits immediately after administration, they transit shortly in stomach and promptly disperse across the huge surface area of the small intestine stabilizing the overall bioavailability and reducing the risk of dose dumping and local irritations. If until two decades ago pellets were exclusively filled into hard gelatine capsules, they represent nowadays the ideal subunits for multiparticulate tablets. In fact, MUPS present all the advantages of the production of tablets compared to capsules: lower production costs, higher production rates, reduced risk of tampering, lower tendency of adhering to oesophagus during swallowing and better patient compliance. Despite this, the compaction of pellets into tablets is a complex technology: MUPS must be robust enough but still disintegrate into their subunits within short time, and, not less importantly, they should retain the dissolution profile of the original subunits. At this scope, the pellets should undergo a soft compaction, without breakage of the pellet coating layer nor formation of matrix tablets. Such ideal MUPS may be strived optimizing the proportions between three crucial factors: the pellet cores, the coating materials and the embedding excipients. Not many studies have focused so far on the simultaneous optimization of these three variables. Cellulose, and in particular microcrystalline cellulose, is one of the major excipients in solid dosage formulations. It presents four polymorphic forms, out of which the form I and II have pharmaceutical relevance. The form I, which behaves plastically when compressed, is extremely widespread as a filler-binder for MUPS. Unfortunately, it does not possess prevalent disintegration properties, so that a disintegrant must be added if prompt disintegration is strived. Kumar et al. developed a new Cellulose II pharmaceutical aid named UICEL-A/102 through alkali treatment of Avicel PH 102 and successive hydrolysis with ethanol and oven dry. So far, UICEL-A/102 has been extensively studied as potential multifunctional excipients (filler and disintegrant) in tablet formulations, whereas its employing as a multifunctional excipient in MUPS has been not yet investigated. The aim of this study was on the one hand the multifactorial investigation of crucial parameters involved in the compaction of pellets into MUPS, on the other hand the evaluation of the suitability of UICEL-A/102 as filler in two different kind of pellets formulations for MUPS (homogeeous pellets from direct pelletization, inhomogeneous pellets from dry powder layering). In the end, a robust technology for UICEL-A/102 MUPS production was suggested and discussed. To this scope, MCC 102 (Cellulose I) and UICEL-A/102 (Cellulose II) were compared as pellet filler and embedding excipients in MUPS for controlled release. In the first part of the study, MCC 102 and UICEL-A/102 were separately mixed with Sodium Diclofenac, directly pelletized, coated with Kollicoat® SR 30 D to 20% w/w weigth gain and compacted into MUPS. In the second part of the study, a binary mixture of MCC 102 or UICEL-A/102 and Sodium Diclofenac was layered on neutral cores (Suglets® or Cellets®), in order to produce inhomogeneous pellets by means of dry powder layering technology. These pellets were then coated and compacted into MUPS according to the same procedure employed for the previous pellet batches. In the case of homogeneous pellets of either MCC 102 or UICEL-A/102, the MUPS formulations overcame compaction deformed rather than ruptured, as proved by comparison between the dissolution profiles and the SEM and CLSM images before and after compaction. Both MCC 102 and UICEL-A/102 MUPS resulted to be mechanically robust (crushing strength of 70-100 N), fast disintegrating in water (≤ 3 min) and maintained the same release profile and almost the same superficial and inner morphology of their uncompressed subunits. Compared with MCC pellets, UICEL-A/102 pellets proved to be generally less spherical and more porous. Nonetheless, they could be homogenously coated and also retained their dissolution profile after compaction into MUPS. The fact that UICEL-A/102 pellets and MUPS presented shorter dissolution times than their MCC counterparts is to ascribe to the prevalent swelling properties of UICEL-A/102. In fact, UICEL-A/102 contained in pellets sped up their dissolution independently of the amount and homogeneity of their coating layer. The multifactorial evaluation of selected parameters (drug loading amount in pellets, type and quantity of filler in pellets, type of disintegrant in MUPS) on response variables (disintegration and dissolution time) brought to an interesting conclusion: UICEL-A/102 was on the one hand favourable filler and disintegrant for immediate disintegration, on the other hand it proved to be unsuited as filler in pellets for extended release. MCC 102 MUPS, conversely, were appropriately delayed formulations, mainly due to retention of their subunits characteristics. In the case of inhomogeneous pellets, only UICEL-A/102 pellets proved to be favourable subunits; in fact, MUPS made of UICEL-A/102 pellet featured pretty good robustness (crushing strength of 90-120 N) and rapid disintegration (disintegration time ≤ 12 min), whereas MUPS made of MCC 102 were too compact (200-300 N) and did not disintegrate before 50 min. This dichotomy was put in relation with the fact that UICEL-A/102 coated and uncoated pellets were less compact and more porous than their MCC 102 counterparts. In addition, the choice of Cellets® rather than Suglets® as basic neutral cores in dry powder layering had a significant impact on the characteristics of UICEL-A/102 MUPS. In fact, UICEL-A/102 MUPS whose subunits had Cellets® cores retained the release profile of their uncompressed subunits more then their counterparts having Suglets® as subunit cores. This suggests that subunits with a MCC core contributed significantly to the softness of the compaction, this difference being associable with a plastic behaviour of Cellets® in contrast with the rather elastic behaviour of Suglets® during compaction. On the one hand, it can be claimed that dry powder layering produced UICEL-A/102 pellets with less prevalent disintegration properties, which were therefore more suitable for controlled release MUPS. On the other hand, the presence of a hard core in those pellets favored the partial rupture of their coating layer during compaction, resulting in a faster drug release after compaction, especially in the case of Suglets® as non pareils. Actually, the pellets produced via dry powder layering contained proportionally less UICELA/102 than their homologous prepared via direct pelletization (20% vs. 60% w/w). This means that the use of UICEL-A/102 as unique multifunctional excipients is rather suggested in pellets and MUPS for immediate release, while its employing as layering excipients on neutral core is very promising in the development of MUPS for extended release.
Advisors:Leuenberger, Hans
Committee Members:Betz, Gabriele and Hoogevest, Peter van
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie
UniBasel Contributors:Betz, Gabriele
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:8669
Thesis status:Complete
Number of Pages:156
Identification Number:
edoc DOI:
Last Modified:22 Jan 2018 15:50
Deposited On:26 Jun 2009 08:25

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