Barish, (2016) Study of Anticancer Nanoparticles for Colorectal Cancer. Doctoral thesis, The Tamilnadu Dr. M.G.R. Medical University, Chennai.
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Abstract
In summary, in this study we have developed and optimized nanocarrier system for colorectal delivery using natural and colon specific polymers. The 5Fluorouracil and Irinotecan hydrochloride loaded polymeric nanoparticles were formulated and characterized for its physiochemical parameters. 5 Fluorouracil is potent anticancer drug used in therapy of colorectal cancer which is associated with the several limitations. So there is a need of alternate novel delivery system to enhance the drug availability in colon. To find out the physico chemical interaction between 5 Fluorouracil and Chitosan, FT-IR analysis were carried out and found to be compatible with each other. The crystallinity of the 5 Fluorouracil loaded chitosan nanoparticles was investigated using DSC and it was found that the drug included in the nanoparticles was in amorphous form. In this study several 5 Fluorouracil loaded chitosan nanoparticle formulations were prepared and determined the particle size, zeta potential, morphology, entrapment efficiency, drug loading, nanoparticle yield, in vitro drug release, in vitro cytotoxicity, stability studies of 5 Fluorouracil loaded chitosan nanoparticles, formulation of compression coated khaya gum and guar gum tablets containing the drug 5 Fluorouracil, 5 Fluorouracil unconjugated nanoparticles, 5 Fluorouracil conjugated nanoparticles and their evaluation such as hardness, friability, disintegration, uniformity content, dissolution studies without rat cecal content and Albino with rat cecal content and in vivo pharmacokinetics study using New Zealand male white rabbits , analysed by HPLC. The statistical analysis was done for in vivo pharmacokinetic parameters. This study established that the ionic gelation technique could be utilised to load hydrophilic drugs and fabricate the size range of 200 nm. The concentration of chitosan, tripoly phosphate and sonication time robustly effect the particle size formation of the chitosan nanoparticles. The chitosan nanoparticles consists of 0.6% chitosan and 0.2% tripoly phosphate was chosen as the optimized formulation (F3). The particle size of optimized 5 Fluorouracil loaded chitosan nanoparticles was 232 ± 4 nm with favourable polymer dispersity index of 0.30±0.07.The zeta potential of the resultant formulation was 5 ±1 indicating the good physical stability of formulated nanoparticles. The morphology of the developed 5 Fluorouracil loaded chitosan nanoparticles was analysed in TEM and AFM. TEM studies revealed that the 5 Fluorouracil loaded chitosan nanoparticles was in sub spherical shape with the size range of 200 nm for individual particles. The 3D images of AFM further confirmed the morphology of the nanoparticles which are sub spherical separated from each other without any aggregation. The drug loading of the optimised 5 Fluorouracil loaded chitosan nanoparticles (F3) was 79.2±0.6%. The entrapment efficiency of the optimised 5 Fluorouracil loaded chitosan nanoparticles (F3) was 69.2±0.7% and the nanoparticle yield of the optimised 5 Fluorouracil loaded chitosan nanoparticles (F3) was 83.4± 0.7%. The in vitro drug release of the 5 Fluorouracil loaded chitosan nanoparticles was evaluated for 24 hrs and it was found to be 98.2±1.4 %( F3). It showed a sustained release and the mechanism of the drug release of the 5 Fluorouracil loaded chitosan nanoparticles followed the Fickian diffusion controlled release. In vitro cytotoxicity investigations suggested the efficacy of the prepared 5 Fluorouracil loaded chitosan nanoparticles conjugated with hyaluronic acid and thus it can be prospective carrier to distribute hydrophilic drugs to target cancer in colorectum. The ICH guidelines were followed to determine stability studies for the formulations of 5 Fluorouracil loaded chitosan nanoparticles and the particle size was evaluated periodically for 0-6 months, the initial particle size at day zero was 232 ± 6 and the particle size after 6 months was 247±9. It revealed that the formulation had favourable physical appearance with no drug leakage during the storage. The in vitro dissolution studies with Albino rat cecal content of 5 Fluorouracil compression coated tablets, 5 Fluorouracil unconjugated nanoparticle compression coated tablets, 5 Fluorouracil conjugated nanoparticle compression coated tablets using different ratios (400mg, 450 mg and 500 mg) of colon specific polymer khaya gum, revealed that the percentage drug release of the 5 Fluorouracil compression coated tablets with 400 mg khaya gum was 72.57±0.13%, 5 Fluorouracil unconjugated nanoparticle compression coated tablets with 400 mg khaya gum was 80.57±0.05% and of 5 Fluorouracil conjugated nanoparticle compression coated tablets with 400 mg khaya gum was 92.57±0.09% , which were more than the percentage drug release compared to other ratios of khaya gum and it was found that the % drug release with Albino rat cecal content was higher from all formulations when compared to in vitro drug release studies without rat cecal content. The in vitro dissolution studies with Albino rat cecal content of 5 Fluorouracil compression coated tablets, 5 Fluorouracil unconjugated nanoparticle compression coated tablets, 5 Fluorouracil conjugated nanoparticle compression coated tablets using different ratios (400mg, 450 mg and 500 mg) of colon specific polymer guar gum, revealed that the percentage drug release of the 5 Fluorouracil compression coated tablets with 400 mg guar gum was 74.27± 0.08%, 5 Fluorouracil unconjugated nanoparticle compression coated tablets with 400 mg guar gum was 82.27±0.05% and of 5 Fluorouracil conjugated nanoparticle compression coated tablets with 400 mg guar gum was 94.27±0.12% which were more than the percentage drug release compared to other ratios of guar gum and it was found that the % drug release with Albino rat cecal content was higher from all formulations when compared to in vitro drug release studies without rat cecal content. In vivo pharmacokinetic studies conducted in New Zealand male white rabbits exhibited the Cmax of 5 Fluorouracil conjugated nanoparticles compression coated tablets using khaya gum was 4300 ± 2.5 ng/ml and the AUC of 5 Fluorouracil conjugated nanoparticles compression coated tablets using khaya gum was 4900 ± 6.6 ng/hr/ml which were higher when compared with Cmax of 4100 ± 3.4 ng/ml of 5 Fluorouracil unconjugated nanoparticles compression coated tablets using Khaya gum and with the AUC 4700 ±6.4 ng/hr/ml of 5 Fluorouracil unconjugated nanoparticles compression coated tablets using Khaya gum. The Cmax and AUC of 5 Fluorouracil unconjugated nanoparticles compression coated tablets using Khaya gum were higher when compared with Cmax (1015±5.8 ng/ml) and the AUC (2965±3.6ng/hr/ml) of 5 Fluorouracil nanoparticles compression coated tablets using Khaya gum. A significant report was also found with other pharmacokinetic parameters also such as time of peak concentration, half life, elimination half life and Volume of distribution. In vivo pharmacokinetic studies conducted in New Zealand male white rabbits exhibited the Cmax of 5 Fluorouracil conjugated nanoparticles compression coated tablets using guar gum was 4700 ± 2.5 ng/ml and the AUC of 5 Fluorouracil conjugated nanoparticles compression coated tablets using guar gum was 6400 ± 2.4 ng/hr/ml which were higher when compared with Cmax (4400 ±1.4 ng/ml) of 5 Fluorouracil unconjugated nanoparticles compression coated tablets using guar gum and with the AUC (5400 ±2.9 ng/hr/ml) of 5 Fluorouracil unconjugated nanoparticles compression coated tablets using guar gum. The Cmax and AUC of 5 Fluorouracil unconjugated nanoparticles compression coated tablets using guar gum were higher when compared with Cmax (1195±5.8 ng/ml) and the AUC (4800±3.6) of 5 Fluorouracil nanoparticles compression coated tablets using guar gum. A significant report was also found with other pharmacokinetic parameters also such as time of peak concentration, half life, elimination half life and Volume of distribution. Irinotecan Hydrochloride is potent anticancer drug used in therapy of colorectal cancer which is associated with the several limitations. So there is a need of alternate novel delivery system to enhance the drug availability in colon. To find out the physico chemical interaction between the drug and polymer, FT-IR was carried out and was found to be compatible with each other. The crystallinity of the Irinotecan Hydrochloride loaded chitosan nanoparticles were investigated using DSC and it was found that the drug included in the nanoparticles was in amorphous. In this study several Irinotecan Hydrochloride loaded chitosan nanoparticle formulations were prepared and determined the particle size, zeta potential, morphology, entrapment efficiency, drug loading, nanoparticle yield, in vitro drug release, in vitro cytotoxicity and stability studies of Irinotecan Hydrochloride loaded chitosan nanoparticles, formulation of compression coated khaya gum and guar gum tablets containing the drug Irinotecan Hydrochloride, Irinotecan Hydrochloride nanoparticles, conjugated Irinotecan Hydrochloride nanoparticles and their evaluation such as hardness, friability, disintegration, uniformity content, dissolution studies without rat cecal content and with rat cecal content and in vivo pharmacokinetics study using New Zealand male white rabbits, analysed by HPLC. The statistical analysis was done for in vivo pharmacokinetic parameters This study established that the ionic gelation technique can be used to load hydrophilic drugs and fabricate the size range of 200 nm. The concentration of chitosan, tripoly phosphate and sonication time robustly effect the particle size formation of the chitosan nanoparticles. The chitosan nanoparticles composed of 0.6% chitosan and 0.2% tripoly phosphate was chosen as the optimized formulation (F3). The particle size of optimized Irinotecan Hydrochloride loaded chitosan nanoparticles was 172± 4 nm with favourable polymer dispersity index of 0.30 ± 0.07 and the zeta potential was found to be 4 ±1 indicating the good physical stability of formulated nanoparticles. The morphology of the Irinotecan Hydrochloride loaded chitosan nanoparticles was analysed in TEM and AFM.TEM studies revealed that the Irinotecan Hydrochloride loaded chitosan nanoparticles was in sub spherical shape with the size range of 200 nm for individual particles. The 2D images of AFM further confirmed the morphology of the Irinotecan Hydrochloride loaded chitosan nanoparticles which are sub spherical separated from each other without any aggregation. The drug loading of the optimised Irinotecan Hydrochloride loaded chitosan nanoparticles (F3) was 89.7± 0.7%. The entrapment efficiency of the optimised Irinotecan Hydrochloride loaded chitosan nanoparticles was ranged 85.8±0.5% and the nanoparticle yield of the optimised Irinotecan hydrochloride loaded chitosan nanoparticles (F3) was 93.7±0.9 %. The in vitro drug release of the Irinotecan hydrochloride loaded CS-NP was evaluated for 24 hrs and it was found to be 99.4±1.0% (F3).It showed a sustained release and the drug release from the nanoparticles adopted the Fickian diffusion controlled release. In vitro cytotoxicity investigations suggested the efficacy of the prepared Irinotecan hydrochloride loaded chitosan nanoparticles conjugated with hyaluronic acid and which can be prospective carrier to distribute hydrophilic drugs to target cancer in colorectum. The ICH guidelines were followed to determine stability studies for Irinotecan Hydrochloride loaded chitosan nanoparticles and the particle size was evaluated periodically for 0-6 months, the initial particle size at day zero was 172 ± 8 and the particle size after 6 months was 185±4. It revealed that the formulation had favourable physical appearance with no drug leakage during the storage. The in vitro dissolution studies with Albino rat cecal content of Irinotecan Hydrochloride compression coated tablets, Irinotecan Hydrochloride unconjugated nanoparticle compression coated tablets, Irinotecan Hydrochloride conjugated nanoparticle compression coated tablets using different ratios (400mg, 450 mg and 500 mg) of colon specific polymer khaya gum, revealed that the percentage drug release of the Irinotecan Hydrochloride compression coated tablets with 400 mg khaya gum was 74.15±0.04%, Irinotecan Hydrochloride unconjugated nanoparticle compression coated tablets with 400 mg khaya gum was 83.15±0.03% and of Irinotecan Hydrochloride conjugated nanoparticle compression coated tablets with 400 mg khaya gum was 94.15±0.04% , which were more than the percentage drug release compared to other ratios of khaya gum and it was found that the % drug release with Albino rat cecal content was higher from all formulations when compared to in vitro drug release studies without rat cecal content. The in vitro dissolution studies with Albino rat cecal content of Irinotecan Hydrochloride compression coated tablets, Irinotecan Hydrochloride unconjugated nanoparticle compression coated tablets, Irinotecan Hydrochloride conjugated nanoparticle compression coated tablets using different ratios (400mg, 450 mg and 500 mg) of colon specific polymer guar gum, revealed that the percentage drug release of the Irinotecan Hydrochloride compression coated tablets with 400 mg guar gum was 76.21±0.04%, Irinotecan Hydrochloride unconjugated nanoparticle compression coated tablets with 400 mg guar gum was 85.21±0.05% and of Irinotecan Hydrochloride conjugated nanoparticle compression coated tablets with 400 mg guar gum was 96.21±0.09 % which were more than the percentage drug release compared to other ratios of guar gum and it was found that the % drug release with Albino rat cecal content was higher from all formulations when compared to in vitro drug release studies without rat cecal content. In vivo pharmacokinetic studies conducted in New Zealand white rabbits exhibited the Cmax of Irinotecan Hydrochloride conjugated nanoparticles compression coated tablets using khaya gum was 5100 ± 4.5 ng/ml and the AUC of Irinotecan Hydrochloride conjugated nanoparticles compression coated tablets using Khaya gum was 11970 ± 4.0 ng/hr/ml which were higher when compared with Cmax value 4600 ±2.4 ng/ml of Irinotecan hydrochloride unconjugated nanoparticles compression coated tablets using Khaya gum and with the AUC value 10750 ± 4.6 ng/hr/ml of Irinotecan hydrochloride unconjugated nanoparticles compression coated tablets using Khaya gum. The Cmax and AUC of Irinotecan hydrochloride unconjugated nanoparticles compression coated tablets using Khaya gum were higher when compared with Cmax (1378 ± 4.9ng/ml) and the AUC (8831±5.0 ng/hr/ml) of Irinotecan hydrochloride nanoparticles compression coated tablets using Khaya gum. A significant report was also found with other pharmacokinetic parameters also such as time of peak concentration, half life, elimination half life and Volume of distribution. In vivo pharmacokinetic studies conducted in New Zealand white rabbits exhibited the Cmax of Irinotecan hydrochloride conjugated nanoparticles compression coated tablets using guar gum was 5400 ± 2.9 ng/ml and the AUC of Irinotecan hydrochloride conjugated nanoparticles compression coated tablets using guar gum was 12860 ± 3.0 ng/hr/ml which were higher when compared with Cmax (5100 ±1.7 ng/ml) of Irinotecan hydrochloride unconjugated compression coated nanoparticles tablets using guar gum and with the AUC (11780 ± 4.3 ng/hr/ml) of Irinotecan hydrochloride unconjugated nanoparticles compression coated tablets using guar gum. The Cmax and AUC of Irinotecan hydrochloride unconjugated nanoparticles tablets using guar gum were higher when compared with Cmax 1653 ± 1.7 ng/ml and the AUC 9540 ± 4.0 of Irinotecan hydrochloride nanoparticles tablets using guar gum. A significant report was also found with other pharmacokinetic parameters also such as time of peak concentration, half life, elimination half life and Volume of distribution. CONCLUSION: In conclusion, we developed a nanoparticulate drug delivery system for 5 Fluorouracil and Irinotecan hydrochloride using natural biodegradable polymer such as chitosan by ionic gelation method which is simpler, devoid of organic solvents and high temperature. The targeting efficiency was enhanced by conjugating with hyaluronic acid and the data obtained for their particle size, zeta potential, morphology, entrapment efficiency, drug loading, nanoparticle yield, in vitro drug release, in vitro cytotoxicity and its stability were found to be satisfactory. The preparation of 5 Fluorouracil and Irinotecan hydrochloride core tablets and their evaluation such as hardness, friability, disintegration, and uniformity content are within the I.P limits. The dissolution studies without rat cecal content and with Albino rat cecal content of 5 Fluorouracil and Irinotecan hydrochloride loaded chitosan nanoparticles conjugated with hyaluronic acid compression coated tablets, unconjugated 5 Fluorouracil and Irinotecan hydrochloride chitosan nanoparticle compression coated tablets and 5 Fluorouracil and Irinotecan hydrochloride tablets that were compression coated individually with colon specific polymers khaya gum and guar gum revealed that % drug release with Albino rat cecal content were more than without rat cecal content. Further In vivo pharmacokinetic studies using New Zealand male white rabbits analysed by HPLC confirms the better pharmacokinetic parameters of 5 Fluorouracil and Irinotecan hydrochloride loaded chitosan nanoparticle conjugated with hyaluronic acid that were compression coated individually with colon specific polymers khaya gum and guar gum. In addition the statistical analysis using SPSS 17.v software was done and it proved to be the same. Khaya gum and guar gum has been used as a drug carrier which are proficient of shielding the drug being released in acidic atmosphere existing in the stomach and in the small intestine, they are degraded by the colonic bacterial enzymes and release the drug in colon where there is need of local action and it was concluded that khaya gum and guar gum are suitable for preparation of colonspecific formulations and is particularly important as a carrier for the therapy of colorectal cancer. Hence it may be recommended that the formulation of 5 Fluorouracil and Irinotecan hydrochloride as a nanoparticulate drug delivery system will be a promising drug release system for the therapy of colorectal cancer. The future studies may be carried out on clinical trials for the above formulations.
| Item Type: | Thesis (Doctoral) |
|---|---|
| Uncontrolled Keywords: | Anticancer Nanoparticles, Colorectal Cancer. |
| Subjects: | PHARMACY > Pharmaceutics |
| Depositing User: | Subramani R |
| Date Deposited: | 20 Aug 2017 09:00 |
| Last Modified: | 27 Oct 2022 03:28 |
| URI: | http://repository-tnmgrmu.ac.in/id/eprint/2737 |
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