Release kinetics of highly porous floating tablets containing cilostazol
Graphical abstract
Introduction
The gastroretentive drug delivery system refers to a dosage form that can prolong the gastric emptying time of a drug. One of the most practical and promising mechanisms in achieving gastroretention is flotation. It can prolong gastric retention time by causing the dosage form, which has a lower density than that of gastric fluid, to float. Previously, studies on novel floating dosage forms have shown promising results [1]. However, most of the dosage forms developed were gas-generating systems, which had inherent problems of either long floating lag time or short floating duration [2], [3], [4]. This was caused by the contradictory effects of the gas-generating agent and the swellable polymer on water diffusion into the matrix and on matrix integrity [5].
Some studies were successful in eliminating the floating lag time of their tablets. This was made possible by incorporating low-density excipients such as polypropylene foam powder [6], [7], calcium silicate [8], and lipid materials [9] into the formulations. However, polypropylene foam powder is not yet approved by the FDA, and an excessive amount of calcium silicate or lipid material was required (3–10 times the weight of the drug), limiting the versatile use of these materials. Furthermore, it has been reported that the complexity of floating dosage forms (e.g., gas-generating agents) hinders the straightforward relationship between release kinetics and formulation variables [5].
Recently, a highly porous tablet was prepared by sublimation [10]. This floating tablet was novel in that it had no floating lag time while maintaining a long floating duration time. This was enabled by including volatile materials or sublimating agents such as l-menthol or dl-camphor in the formulations, which generated pores after their sublimation. Consequently, the density of the tablet was sufficiently low to allow immediate buoyancy on dissolution media while maintaining physical integrity by excluding gas-generating agents in the formulation. This type of floating tablet has also eliminated potential health risks as the sublimating agents can be removed from the tablet by sublimation. It was previously reported that the amount of residual sublimating agent was well below the permissible dose set by regulatory agencies [11].
However, volatile materials such as menthol or camphor are not commonly used in conventional sustained-release tablets. Accordingly, it is essential to assess the critical aspects of these excipients for successful scale-up and commercialization. Considering that these volatile materials are eliminated after sublimation, the most important aspect is their flow properties, as poor flow and agglomeration may lead to segregation and poor dose uniformity.
Cilostazol is a quinolinone derivative and inhibits phosphodiesterase type 3 (PDE-3), which is predominantly distributed to and regulates physiological responses in platelets. Clinically, it is well known as an anti-platelet agent that inhibits platelet aggregation. However, cilostazol has adverse effects such as severe headaches, assumed to be caused by high concentrations in the blood [12]. On the other hand, some studies show that the absorption site of cilostazol is limited to the upper part of the small intestine [13], which challenges a successful development of a sustained release dosage form. Therefore, cilostazol was chosen as a model drug for the proposed gastroretentive tablet in this study.
Another distinctive property of cilostazol is its low solubility [14]. However, only a few studies have investigated release kinetics of surfactant-mediated dissolution [15], [16]. Further, previous studies of floating porous matrices have only focused on hydrophilic drugs or solid dispersions of hydrophobic drugs [10], [11]. To our knowledge, this is the first study investigating release kinetics of a very hydrophobic drug from swellable and highly porous matrices, although there have been many studies covering release kinetics of floating tablets.
Recently, percolation theory was applied to pharmaceutical dosage forms, which has generated a considerable research interest [17], [18], [19]. One of the most important parameters in percolation theory is percolation threshold. It is a critical concentration point above which a infinite percolating cluster or a continuous phase may be formed. However, previous studies have only concentrated on identifying the percolation threshold of soluble drugs with different hydrophilicities, and there remains a need for investigating the percolation threshold of water insoluble drugs.
The purposes of this study were to prepare highly porous sustained-release cilostazol gastroretentive tablets by using the sublimation method and to investigate their release kinetics. Therefore, the effects of hydroxypropyl methylcellulose (HPMC) content, porosity, and surfactant concentration in dissolution media on release kinetics were observed. Excipient percolation threshold was also identified by comparing release kinetics and erosion profiles. In addition, suitable volatile material for a sublimating agent was selected by comparing flow properties. Cilostazol was selected as a model drug not only because of its clinical necessity for a sustained release dosage form but also because of its insoluble property to identify the important factors in determining the release profile of a hydrophobic drug.
Section snippets
Materials
Cilostazol (Hangzhou Pharma & Chem Co., Ltd., Hangzhou, China; solubility in water at 37 °C, 4.6 ± 0.3 μg/mL), hydroxypropyl cellulose (HPC) (Klucel® LF, Ashland, Inc., Covington, KY, USA), HPMC (Metolose® 65SH-4000, Shin-Etsu Chemical Co., Ltd., Tokyo, Japan), l-menthol (Sigma-Aldrich, St. Louis, MO, USA), dl-camphor (Junsei chemical Co. Ltd., Tokyo, Japan), microcrystalline cellulose (MCC) (Avicel® PH 102, FMC BioPolymer, Philadelphia, PA, USA), magnesium stearate (Acros Organics, Geel, Belgium),
Particle size analysis of camphor, menthol, and representative formulations
One of the most important factors noted in determining physicochemical properties of highly porous tablets by using the sublimation method was the type of volatile materials due to its uncommon use in oral dosage forms in pharmaceutical industry. Camphor and menthol were candidates for the sublimating agent for the tablets prepared in this study, and they were compared for their flow properties.
As shown in Table 2, the volume weighted mean particle size was larger for menthol than that of
Conclusions
The floating tablets containing cilostazol were prepared using the sublimation technique. The tablets floated with no lag time until the end of the dissolution test. Twisted blade methods could yield qualitative results with higher repeatability than those obtained using conventional methods. Additionally, observing the fluctuation in the torque-distance profile provided a firm evidence for powder agglomeration. As a result, menthol could be selected as a sublimating agent because of its good
Conflicts of interest (COI)
The authors declare no conflict of interest.
Acknowledgments
This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (grant number NRF-2016R1A2B4007101).
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