Kavitha, K (2009) Targeted Drug Delivery of Anti Cancer Drug by Applying Gastro Retentive Systems and Its Pharmacological Evaluation. Doctoral thesis, The Tamil Nadu Dr. M.G.R. Medical University, Chennai.
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Abstract
Targeted drug delivery systems are designed to release the medicament continuously in a predetermined pattern for a fixed period of time either systemically or to a specified organ to ensure safety and to improve its efficacy as well as patient compliance. Drug released from these drug delivery systems should be at a desired, predictable and reproducible rate. Gastroretentive system (GRS) is a topic of current interest in the design of controlled release drug delivery systems to target the drug to the site of absorption. It prolongs the residence time of the dosage form at the site of application or absorption and facilitates an intimate contact of the dosage form with the underlying absorption surface and thus contributes to improved and/or better therapeutic performance of the drugs. In the present investigation design of floating tablets (GRS) of fluorouracil for oral controlled release is aimed. Fluorouracil is used in the treatment of cancer. It is sparingly soluble in water and its absorption is dissolution rate limited. Fluorouracil has a short biological half life and erratic absorption. To avoid the dose related toxicity and to prolong its duration of action controlled release products are necessary. The first chapter deals with introduction about the clear advantage of controlled release dosage forms and the advantages derived with gastro retentive system. In this chapter absorption window, modulation of GI transit time, basic gastrointestinal tract physiology, factors affecting gastric retention, classification of floating drug delivery system, evaluation methods are discussed. Gastric cancer, its causes and the treatment were also discussed. Chapter II contains literature review on the gastroretentive systems, fluorouracil and β cyclodextrin. Drug profile, polymer profile and excipient profile are given in chapter III. Preformulation studies of the drug were documented in chapter IV. The characterization of the drug material, 5 fluoro uracil that included physicochemical properties such as melting point, loss on drying, bulk and tapped density were done. A compatibility study for polymer and drug was carried out to assess any interaction, by IR spectroscopy. The spectra showed no interaction had occurred with the excipients. As fluorouracil is sparingly soluble in water, it was complexed with β cyclodextrin to enhance the solubility of the drug. The aqueous solubility and dissolution rate of 5-fluorouracil can be increased by inclusion complexation with β-cyclodextrin. Molecular-modeling studies support the formation of stable molecular inclusion complexation of 5-fluorouracil with β-cyclodextrin monomer (1:1). Complexes were prepared by physical mixture, kneading, co evaporation and freeze drying methods. Two ratios 1:1 and 1:2 were formulated. These eight complexes were subjected to Phasesolubility study, molecular modeling to confirm the ratio and dissolution study. The complexes formed were confirmed by DSC studies. Phase solubility profile indicated that the solubility of 5-fluorouracil increased in the presence of β-cyclodextrin monomer. Results obtained by different characterization techniques clearly indicate that the freezedrying method leads to formation of solid state complexes between 5-fluorouracil and β-cyclodextrin. The complexation of 5-fluorouracil with β-cyclodextrin lends an ample credence for better therapeutic efficacy. Complexation and the enhancement of solubility are discussed in chapter V. In the present work, a floating gastro retentive drug delivery system was developed and fabricated containing the drug 5 fluoro uracil. The aim of the work was to get a modified release pharmaceutical dosage form that could be used in the treatment of cancer. Floating drug delivery system are well proved and documented to be therapeutically superior to conventional dosage system in number of studies. In chapter VI the optimization of the tablet process parameters was performed to find out the optimum operational conditions and to optimize the formula. The tablets were obtained by wet granulation method for all the formulations F- I to F- XII and evaluated for the buoyancy lag time and floating time, hardness, weight variation and drug content. Based on the performance with respect to buoyancy lag time, floating time and the release characteristics, the formulation (F- IX) was selected as the best formula as it showed a buoyancy time of 24 seconds and a floatation time of 24 hours. This formulation (F- 9) showed a sustained release rate throughout its release period. Two batches F- IXA and F- IXB of the prototype formulations F- IX were prepared and studied for the reproducibility. It was found that the physiochemical properties remained intact and the release characteristic was more or less the same pointing to good reproducibility. Chapter VII describes about the floating 5 fluorouracil microspheres which are multi-particulate matrix type system containing uniformly dispersed or dissolved drug. Floating Microspheres were prepared by emulsion solvent evaporation process by using four different polymethacrylates having different permeability characteristics. The main objective of the preparation was to select the formulation which would provide optimum release till 12 hours and improve the gastric residence of the drug by staying in the stomach for long time. The drug entrapment efficiency of the formulations (M1 to M16) was affected only by drug polymer ratio. This drug polymer ratio also influenced the particle size of the microspheres. This was due to the increase or decrease in the viscosity of dispersed phase in different ratio of drug and polymer. The percentage floating of the microspheres were above 70% which was found to be satisfactory. The dissolution profiles of various microspheres containing different ratio of drug and polymer indicated that the release of 5 fluorouracil was more and faster from Eudragit RL100 polymer than Eudragit RS100. The combination of two different types of polymers having different permeabilities (RL and RS-type) in the same drug: polymer ratio would have almost same release rate. Burst effect was more in the microspheres containing drug: polymer ratio of 1:1 than 1:2 ratio. The different release profiles for microspheres were fitted into the different models, zero order, first order, Higuchi model and Peppas model. It was revealed that most of the formulations followed Higuchi and Peppas model with P < 0.001.From the results the formulation M 8 was found to have desired properties with maximum release. Hence to check the reproducibility two batches M17 and M18 were prepared with the same formulation as that of M8 and HPMC. HPMC is a hydrophilic polymer. It was expected to have more controlled release of the drug. The formulation M17 and M18 were evaluated for floating behaviour, drug content and dissolution study. It was revealed that floating microspheres containing 5 fluorouracil with desired micromeritic properties and varied matrix permeability can be prepared from polymethacrylates with different permeability characteristics. The improvement or retardation of drug release rate, demonstrated the feasibility of this formulation strategy for controlled delivery of 5 fluorouracil. Indirectly, the inclusion of slightly water soluble drug, 5 fluorouracil into the polymethacrylates increases its solubility. The selected best formulations F IXB and M18 were subjected to invivo studies, in chapter VIII, like determination of invivo floating behavior and invivo anti tumor activity. The formulations were given to the rabbits by intubation method and the invivo floating behavior was studied by roentographic study. It was found to be floating inside the rabbit stomach as can be seen from the X Ray. The invivo antitumour activity was performed in albino mice to show that the formulations were better than the plain dug 5 fluorouracil. The parameters studied were effect of formulations on EAC tumor model and effect of formulations on solid tumor model. The gain in the body weight analysis, % inhibition of life span and mean survival time were calculated and analyzed statistically. Cytological studies showed that the formulation M18 and F IXB showed sustained and better antitumor activity when compared to plain drug. In chapter IX Stability studies were performed for the selected formulations at 40°C and 75 % RH for three months according to ICH guidelines. The drug release characteristics of the formulations were evaluated before and after storage and compared. The formulations were found to be stable during the storage period. CONCLUSION: The following are the conclusions drawn from the results of the investigation. The aqueous solubility and dissolution rate of fluorouracil were markedly enhanced by complexation with β cyclodextrin. • The phase solubility diagram of FU-βCD was of B Type and the increase in solubility was due to the formation of 1:1 M complex. The complexes formed are adequately stable confirmed by DSC studies and Molecular modeling studies. • Solid inclusion complexes of FU-βCD exhibited higher rates of dissolution than the plain FU. • A 2.5 fold increase in the dissolution rate of FU was observed with FU-βCD (1:1) inclusion complexes prepared by freeze drying technique. The floating effervescent tablets were formulated by employing cyclodextrin complexes, HPMC K 100 as Polymer and sodium bicarbonate as gas generating agent. • Release of fluorouracil from these tablets depended on their composition of drug polymer ratio and the viscosity of the polymer. • Drug release from these tablets was diffusion controlled (Higuchi) with fickian pattern and followed zero order kinetics. The SEM photomicrographs confirmed the diffusion pattern with erosion. The floating microspheres were formulated with different types of polymethacrylates. • Release of drug from the microspheres depended on the permeability of the different polymethacrylates. • Drug release from the floating microspheres with better release (M18) showed a higuchi diffusion pattern and followed zero order kinetics. The anti cancer efficiency of 5-FU loaded gastroretentive formulations are comparatively higher than the pure drug. This may help to reduce the total dose required for cancer therapy and ultimately, may in turn reduce the dose related systemic side effects which is the major goal and scope of this work. It may be concluded that the formulation of floating effervescent tablets and floating microspheres of 5 fluoro uracil is feasible and may be manufactured with reproducible characteristics even from batch to batch. Therefore, a stomach – specific Gastro retentive tablet and microsphere of 5 fluorouracil were formulated and characterized. It was found to reduce the unwanted dose dependent side effects, at other sites, by targeted drug delivery to gastric tumors. This may serve as an alternative to painful intravenous therapy.
| Item Type: | Thesis (Doctoral) |
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| Uncontrolled Keywords: | Anti Cancer Drug, Gastro Retentive Systems, Pharmacological Evaluation, Targeted Drug Delivery. |
| Subjects: | PHARMACY > Pharmacy Practice |
| Depositing User: | Devi S |
| Date Deposited: | 27 Jun 2017 07:53 |
| Last Modified: | 15 Sep 2022 11:37 |
| URI: | http://repository-tnmgrmu.ac.in/id/eprint/429 |
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