Abstract
Objective: To develop two different oral formulations such as 5-fluorouracil (5-FU) tablets and oxaliplatin (OX) microspheres which were further filled into capsules and coated with pH-sensitive polymer (eudragit S-100) for the chronotherapeutic treatment of colon cancer (Fluorouracil: Oxaliplatin regimen) to perform as a substitute for intravenous (IV) route based chronomodulated chemotherapy.
 Methods: The 5-FU tablet formulation was prepared with alginate and guar gum polymers in varied concentrations using wet granulation technique in two varieties such as granules coated and tablet coated formulations using eudragit RSPO as coating material to achieve controlled drug release. Alongside OX microspheres were formulated using the ionotropic gelation methodology in combination with alginate and chitosan polymers in varying concentrations to accomplish a time-controlled drug release. Prepared formulations were evaluated for pre-compression and post-compression parameters, percentage yield, percentage drug entrapment, Fourier transformed infrared spectroscopy (FT-IR), Differential scanning calorimetry (DSC), Scanning electron microscopy (SEM), In vitro and Ex vivo dissolution studies.
 Results: Pre-compression and post-compression parameters for 5-FU tablets were satisfied with Indian pharmacopeia specifications. The entrapment efficiency of OX microspheres were increased due to the elevated concentration of polymers up to a certain level as seen in A7M, further greater the concentration of polymer resulted in a decline of entrapment efficiency as seen in A4M and A8M. The optimized formulations A14T and A14M were shown in vitro drug release of 90.36 % by 24 h and 79.63 % by 9 h respectively.
 Conclusion: The two different oral formulations of 5-FU (Tablets) and OX (Microspheres) were found to be successful in controlled drug release. Therefore they can be efficiently used to control the rate of drug release to the colon in synchronization with the circadian timing system in the belief of improved therapeutic efficacy, tolerability and overall survival rate of cancer patients. Hence it is promised to be a better alternative for intravenous route based chronomodulated chemotherapy.
Highlights
Colon cancer is one of the three most widespread categories of cancers, that accounts for more than 1.5 million cases, along with 8,62,000 deaths in the year 2018 [1, 2]
It has been demonstrated that leucovorin (LV), 5-fluorouracil (5-FU) and oxaliplatin (OX) regimen offers better therapeutic efficacy, tolerability and insignificant adverse effects than 5-FU alone or other regimens to treat progressive colorectal cancer [5]
Int J App Pharm, Vol 12, Issue 5, 2020, 118-130 the present study aims to formulate pH-dependent, controlled release mini-tablets of 5-FU and OX microspheres which are further filled in capsules and thereafter coated with pH-sensitive polymer for delivering a drug into colon region at a specified concentration to treat colon cancer by adopting chronomodulated schedules to obtain patient compliance along with increased tolerability and to overcome unnecessary toxicity associated with the 5-FU and OX
Summary
Colon cancer is one of the three most widespread categories of cancers, that accounts for more than 1.5 million cases, along with 8,62,000 deaths in the year 2018 [1, 2]. It has been demonstrated that leucovorin (LV), 5-fluorouracil (5-FU) and oxaliplatin (OX) regimen offers better therapeutic efficacy, tolerability and insignificant adverse effects than 5-FU alone or other regimens to treat progressive colorectal cancer [5] Most often these chemotherapeutic drugs are administered via the intravenous route, which in turn accumulates on healthy cells/tissues owing to non-specific dispersal of chemotherapeutic drugs [6, 7]. The oral route of delivering drugs is extensively adopted and the most readily accepted route of administration, with the dominance of being patient compliance, convenience, and invulnerability [8] It regards as a secure and more logical administration route for the treatment of colorectal conditions such as colon cancer. The formulation has to be made in such a way that it releases drugs in colonic pH [10,11,12]
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