Gastrointestinal disturbances, such as nausea and vomiting,
are considered amongst the main adverse effects associated with
oral anticancer drugs due to their fast release in the gastrointestinal tract (GIT).
Sustained release formulations with proper release profiles can overcome some side
effects of conventional formulations. The current study was designed to prepare
sustained release tablets of Capecitabine, which is approved by the Food and Drug
Administration (FDA) for the treatment of advanced breast cancer, using hydroxypropyl
methylcellulose (HPMC), carbomer934P, sodium alginate, and sodium bicarbonate.
Tablets were prepared using the wet granulation method and characterized such that
floating lag time, total floating time, hardness, friability, drug content, weight uniformity,
and
After cardiovascular disease, cancer is the second reason for death. Prostate, lung, colon, and breast cancers are the most common forms of cancer. The present treatments for cancer include surgery, chemotherapy, hormone therapy, gene therapy, and radiation therapy. Currently, chemotherapeutic drugs are the most common type of cancer treatment. However, the administration of high doses of these drugs leads to some adverse toxic effects. As some reports indicated, many side effects, such as systemic side effects, diarrhea, and gastrointestinal problems will appear in anticancer therapy [
Many drugs, such as Anthracyclines, Taxanes (Docetaxel, Paclitaxel), Gemcitabine, Vinorelbine, Carboplatin, Trastuzumab, Lapatinib, Cyclophosphamide, Methotrexate, Adriamycin, Epirubicin, Mitoxantrone, Bevacizumab, and Capecitabine, are used in breast cancer. The use of these drugs is strongly recommended to make sure that the side effects and high dosage of these drugs are balanced [
Capecitabine, 5′-deoxy-5-fluoro-N-((pentyloxy) carbonyl)-cytidine, is a fluoropyrimidine carbamate which has an antineoplastic activity. This chemical is a prodrug of 5′-deoxy-5-fluorouridine (5′-DFUR), which is enzymatically converted
Important problems of Capecitabine as to the current clinical treatment are a short half-life and its rapid metabolism in the liver. Therefore, the administration of high doses of Capecitabine leads to some undesirable side effects [
Sustained release (SR) tablets of anticancer drugs could not only provide an optimum plasma concentration with less frequent administration but also help decrease the side effects of conventional dosage forms, such as GIT problems [
There are several advantages to making sustained release antineoplastic drugs like Capecitabine. These drugs show fewer side effects, have longer half-lives, require less frequent dosages, and improve efficacy. Thus, there would be better patient compliance and less variation in plasma/blood levels [
Capecitabine was a kind gift from Osvah Pharmaceutical Company (Tehran, Iran). The 5 FU was provided from sigma Aldrich (KL, Malaysia). HPMC K4M was supplied by Sigma Chemicals. Sodium alginate and sodium bicarbonate were purchased from R&M chemicals (KL, Malaysia),carbomer934p was purchased from Noveon, polyethylene glycol 3500 from Merck, magnesium stearate from Mallinckrodt, and lactose from HMbG chemicals (United State of America). All reagents were of analytical or pharmaceutical grade.
Sustained release tablets were formulated with different types and ratios of polymers using the wet granulation method, and then tablets were compressed directly by a single punch machine. Capecitabine was mixed with carbomer934p as a control release agent, with HPMC K4M as a binder, sodium alginate for gel forming, and sodium bicarbonate to extend floating time. All components were mixed for 10 min, and then Isopropyl alcohol was added dropwise to make a good wet mass of granules. After remixing for 5 min, the granules were passed through a 400
Different formulations of tablets with different concentrations (%).
HPMC | S.A | Car | S.B | Lac | PEG | Mg.St | Cap | Total | |
---|---|---|---|---|---|---|---|---|---|
F1 | 20 | 20 | 1.6 | 13.3 | 35 | 6.6 | 3.3 | 150 | 300 |
F2 | 20 | 20 | 3.3 | 13.3 | 33.3 | 6.6 | 3.3 | 150 | 300 |
F3 | 20 | 20 | 4.6 | 13.3 | 32 | 6.6 | 3.3 | 150 | 300 |
F4 | 16.6 | 16.6 | 3.3 | 13.3 | 40 | 6.6 | 3.3 | 150 | 300 |
F5 | 16.6 | 20 | 3.3 | 13.3 | 36.6 | 6.6 | 3.3 | 150 | 300 |
F6 | 16.6 | 23.3 | 3.3 | 13.3 | 33.3 | 6.6 | 3.3 | 150 | 300 |
F7 | 20 | 16.6 | 3.3 | 13.3 | 36.6 | 6.6 | 3.3 | 150 | 300 |
F8 | 20 | 20 | 3.3 | 13.3 | 33.3 | 6.6 | 3.3 | 150 | 300 |
F9 | 20 | 23.3 | 3.3 | 13.3 | 30 | 6.6 | 3.3 | 150 | 300 |
F10 | 23.3 | 16.6 | 3.3 | 13.3 | 33.3 | 6.6 | 3.3 | 150 | 300 |
F11 | 23.3 | 20 | 3.3 | 13.3 | 30 | 6.6 | 3.3 | 150 | 300 |
F12 | 23.3 | 23.3 | 3.3 | 13.3 | 26.6 | 6.6 | 3.3 | 150 | 300 |
The dissolution results of all formulations in 0.1 N HCl were specified to Higuchi, Korsmeyer-Peppas, Hixson-Crowell, Weibull, and first order and zero order kinetic models. The model with the maximum correlation coefficient was considered to be the best model [
The floating lag time (FLT) is the time taken for a tablet to rise on medium surface, and total floating time (TFT) is the floating duration that a tablet remained on surface. To determine the floating lag time, tablets (
To evaluate tablet hardness, 10 tablets of each formulation were tested for diametrical crushing strength using a hardness tester (Dr. schleuniger, 6D-Tablet Tester).
The friability of the SR tablets (
Hardness and friability values were determined and reported as mean ± SD.
To evaluate the drug content through a uniformity test, 10 tablets of each formulation were crushed and suspended in 0.1 N HCL to remove the Capecitabine from the tablets. After 24 hours, media were filtrated and measured by a UV spectrophotometer (Shimadzu 1601) at 214 nm [
An electronic balance (Mettler Toledo, 3-MS-S/MS-L, Switzerland) was used to accurately weigh ten tablets which were randomly selected. The results are expressed as mean values ± SD [
A dissolution test was performed for 24 hours using the ERWEKA DT70 dissolution machine according to American pharmacopeia [
Two formulations (commercial (Xeloda) and prepared tablet) were compared in terms of drug release.
At the end, all results were analyzed using Microsoft Excel. The dissolution test was repeated 4 times for each formulation.
The standard curve was constructed using six different concentrations of Capecitabine, ranging from 100 to 12.5 mg. To make a standard curve, 5 mg of Capecitabine was dissolved in 50 mL of 0.1 N HCL. Then, 3 mL of each dilution was measured by UV spectrophotometer (Shimadzu 1601).
To study the quality of the finished product under a variety of conditions (time, humidity, and temperature) and to evaluate the formulation, stability studies were prepared for 6 and 12 months according to the ICH (International Conference on Harmonization) procedures. After storage, all samples were analyzed for their physical characterizations.
Tablets (
Storage conditions for tablet stability test.
Type of study | Condition | Time |
---|---|---|
Accelerated | 40°C |
6 months |
Long term | 25°C |
12 months |
All the tablets were packed in polyethylene bags. The bags were clamped using clamping tape and double-packed by putting in cardboard with a plywood lid and the lid was sealed [
The results were evaluated by one-way analysis of variance (ANOVA) using Duncan’s multiple comparison test. Differences were considered significant at
The sustained release Capecitabine floating tablets were developed using release-retarding gel-forming polymers HPMC K4M, Na alginate, and carbomer934P, accompanied by sodium bicarbonate as a gas-forming agent and lactose as filler.
Table
Drug release and floating profiles of twelve formulations.
Formulation | Release % | Floating lag time (s) | Total floating time (h) |
---|---|---|---|
F1 | 100 | 30 | 20 |
F2 | 83.665 | 70 | 24 |
F3 | 76.3 | 81 | 24 |
F4 | 100 | 35 | 20 |
F5 | 90.305 | 45 | 24 |
F6 | 84.711 | 60 | 24 |
F7 | 98.286 | 60 | 24 |
F8 | 83.665 | 70 | 24 |
F9 | 78.82 | 85 | 24 |
F10 | 86.666 | 60 | 24 |
F11 | 80.54 | 80 | 24 |
F12 | 75.226 | 200 | 0.5 |
s: second; hr: hour.
The investigated gastric floating systems employed sodium bicarbonate (NaHCO3) as a gas-forming agent, which is trapped in a hydrogel matrix (HPMC K4M and Na alginate). The
The floating lag time for most formulations was below 90 seconds, regardless of the content of polymers used (Table
As the amount of carbomer934P increased, TFT decreased—this could be due to the high affinity of carbomer towards water, which promotes water penetration into polymeric matrices, leading to increased density. As the amount of HPMC K4M increased, the total floating time increased—this is because of the increased gel strength of the matrices, which prevents the escape of involved CO2 from the matrices, leading to decreased density. As the amount of SA increased, TFT decreased—this is because of the poor gelling strength of SA compared to HPMC K4M that was previously reported [
Depending on the type and concentration of polymers, variable drug release profiles were successfully tailored.
The dissolution profile of the best formulation (formulation F7) according to standard curve and R2 (Figure
Calibration curve of Capecitabine in HCL 0.1 N.
The influence of carbomer934P, HPMC K4M, and Na alginate on the release of capecitabine from the floating tablets in 0.1 N HCl (pH 1.2) at
The influence of carbomer934P on the release of Capecitabine from the SR tablets in 0.1 N HCl (pH 1.2) at
The influence of HPMC K4M in F4, F7, and F10 on the release of Capecitabine from the SR tablets in 0.1 N HCl (pH 1.2) at
The influence of Na alginate in F4, F5, and F6 on the release of Capecitabine from the SR tablets in 0.1 N HCl (pH 1.2) at
The influence of Na alginate in F7, F8, and F9 on the release of Capecitabine from the SR tablets in 0.1 N HCl (pH 1.2) at
The results of
As this and previous studies [
An immediate release rate was achieved following the dissolution of a commercial brand of Capecitabine 150 mg tablets in 0.1 N HCl. Indeed, 100% of the drug was released within 40 min (Figure
Release profiles of a commercial brand of Capecitabine and F7 (
To establish the mechanism of drug release, all data from the dissolution studies of floating tablets were obtained and fitted in kinetic models (Table
Mathematical release modeling of sustained release capecitabine floating tablets.
Formulations code | Zero order |
First order |
Higuchi |
Hixson-Crowell |
Korsmeyer-Peppas |
---|---|---|---|---|---|
F1 | 0.964 | 0.818 | 0.983 | 0.908 | 0.482 |
F2 | 0.996 | 0.972 | 0.977 | 0.990 | 0.576 |
F3 | 0.992 | 0.959 | 0.970 | 0.980 | 1.606 |
F4 | 0.871 | 0.974 | 0.962 | 0.940 | 0.413 |
F5 | 0.989 | 0.968 | 0.988 | 0.993 | 0.558 |
F6 | 0.996 | 0.926 | 0.954 | 0.963 | 0.564 |
F7 | 0.989 | 0.851 | 0.988 | 0.960 | 0.596 |
F8 | 0.996 | 0.972 | 0.977 | 0.990 | 0.575 |
F9 | 0.997 | 0.943 | 0.955 | 0.969 | 0.625 |
F10 | 0.993 | 0.936 | 0.980 | 0.973 | 0.590 |
F11 | 0.998 | 0.951 | 0.962 | 0.976 | 0.621 |
F12 | 0.992 | 0.954 | 0.967 | 0.976 | 1.644 |
Acc | 0.922 | 0.857 | 0.986 | 0.955 | 0.464 |
Long | 0.955 | 0.894 | 0.997 | 0.918 | 0.464 |
Previous studies have reported that tablet hardness not only had a slight effect on drug release profiles but was also a determining factor with regards to buoyancy of the tablets. Increasing the hardness would possibly lead to prolongation of the floating lag time by affecting the rate of the tablet penetration by the dissolution medium. Also, the percentage friability for all formulae was less than 1%, indicating good mechanical resistance. The physicochemical properties of the tablets are as summarized in Table
All tablet formulae showed (Table
Comparison of physical properties of all formulations.
Hardness (N) | Friability (%) | Drug content (%) | Weight uniformity (mg) | |
---|---|---|---|---|
F1 | 57 | 0.35 |
|
|
F2 | 76 | 0.26 |
|
|
F3 | 81 | 0.22 |
|
|
F4 | 55 | 0.35 |
|
|
F5 | 62 | 0.29 |
|
|
F6 | 68 | 0.25 |
|
|
F7 | 69 | 0.31 |
|
|
F8 | 76 | 0.26 |
|
|
F9 | 80 | 0.21 |
|
|
F10 | 95 | 0.19 |
|
|
F11 | 104 | 0.11 |
|
|
F12 | 112 | 0.103 |
|
|
Drug release and physical properties of stored tablet.
Formulation | Release % | Floating lag time | Total floating time | Hardness (N) | Friability (%) | Drug content (%) | Weight uniformity (mg) |
---|---|---|---|---|---|---|---|
ACC | 99.216 | 80 s | 20 h | 57 | 0.30 |
|
|
Long | 100 | 65 s | 23 h | 65 | 0.33 |
|
|
Drug uniformity results were found to be good among different formulations, where the percentage of drug content ranged from 98.06% to 99.86%.
The optimum formulation (F7) was packed according the standard procedures, and was analyzed by dissolution and physical characterization procedures after storage (Tables
Comparison of the release profiles of F7 and stored tablets (
The drug release of the stored samples was slightly affected by the different storage conditions, indicating that either heat or humidity affected the permeability of the polymeric matrix.
Accelerated test (which carried out at 40°C and 75% humidity) affected the floating ability of tablets by slight decrease in floating time.
Before and after conducting the stability studies, statistical analyses of the results for storage months were carried out by one-way ANOVA. No significant difference (
F7 stability test after 6 months: there was no significant effect of accelerated term on F7 stability conditions at the
F7 stability test after 12 months: there was no significant effect in release rate and stability of F7 after 12 months at the
F7 stability test in 6 and 12 months: there was no significant effect of 6 months and 12 months on stability condition at the
The purpose of this study was to prepare a sustained release tablet of Capecitabine with a 24-hour gradual release with concurrent floating. In doing so, various polymers, such as HPMC K4M, sodium alginate, and sodium bicarbonate, were tested. Also, characterization tests such as floating lag time, total floating time, release measurements, hardness, friability, content uniformity, and weight uniformity were performed. Comparisons of all release studies showed that the drug release depended on the ratio of two polymers—HPMC K4M, which was used as a binder; and sodium alginate, which created gel-forming capabilities in the tablet.
Microgram
Accelerated time
Active pharmaceutical ingredient
British pharmacopeia
Capecitabine
Carbomer934p
Food and Drug Administration
Hydroxypropyl methylcellulose
Lactose
Long term
Milligram
Magnesium stearate
Minute
Millimeter
Degree Celsius
PolyEthylene glycol
Relative humidity
Sodium alginate
Sodium bicarbonate
United States of pharmacopeia
Ultraviolet.
There is no conflict of interests in this project.
This study was supported by research a Grant from IPPP, Universiti of Malaya, Malaysia (Grant no. PS202/2010B). The authors thank Osvah Pharmaceutical Company, Tehran, Iran, for their gift of Capecitabine and also Mrs. Fatemeh Allah Bedashti for her friendship and assistance.