الفهرس 
General introductionOnly 14 pages are availabe for public view
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Abstract
Etodolac (ETD) is a nonsteroidal anti-inflammatory medication (NSAID), with selectivity for the Cox-2 enzyme. It is anti-inflammatory, analgesic, and antipyretic. Due to its poor solubility, etodolac, like other nonsteroidal anti-inflammatory medications causes stomach irritation and ulcers with long-term use. ETD is classed as a BCS Class II medication, which is poorly water soluble and extremely permeable, according to the Biopharmaceutical Classification System (BCS). As a result, dissolution is the rate-limiting stage in medication absorption. So, solubility enhancement of ETD was performed before development of fast dissolving tablets (FDTs) to achieve the maximum absorption and bioavailability and reducing the side effects. The bitter taste of the drug was another problem which was overcome by employing Aspartame as a sweetener in the formulation of the FDTs.
As a suitable alternative to conventional pills and capsules, FDTs have attracted considerable attention. They are solid dosage forms that dissolve and disintegrate in the oral cavity without the need for water within seconds.
Aims and objectives: The thesis was concerned with the formulation and evaluations of fast dissolving tablets to achieve the maximum absorption and bioavailability.
Methods: Solid dispersion of etodolac was performed using various hydrophilic carriers as sorbitol and cyclodextrins by co-evaporation method using different superdisintegrants including: crospovidone (CP) and croscarmellose sodium (CCS) and camphor as subliming agent for achieving the fast disintegration characteristics. Drug content, in vitro dissolution rate, FT-IR spectroscopy and TGA of the prepared solid dispersions and inclusion complexes were investigated. The best solid dispersion was formulated into the fast dissolving tablets. Etodolac FDTs were developed using Box-Bhenken design. The produced ETD fast-dissolving tablets were evaluated for weight variation, thickness, hardness, and friability, in addition to disintegration time, wetting time, drug content, and in vitro dissolution characteristics. Bioavailability study of ETD was carried out on rabbits in order to investigate the amount and rate at which Etodolac is absorbed from the investigated FDTs.
Results: The formulations demonstrated greater solubility than the corresponding physical mixtures and the pure drug. The order of increasing solubility was as follows: HP-β-CD > α-CD > Sorbitol. IR tests revealed may be interactions between the medicine and the carriers. TGA studies approved the drug’s transformation into an amorphous state, which shows noticeably improved solubility behavior. It was determined that drug release from inclusion complex was raised to 80% compared to pure drug, indicating that it is the optimal formulation for enhancing the solubility of Etodolac.
In chapter 2, after selection of the best formulation depending on profiles of in vitro dissolution of ETD from the prepared systems, Etodolac FDTs were developed by using Box-Bhenken design. Depend on the selection of 3 independent variables, X1, X2, X3 (Croscarmellose Sodium Concentration), (Crospovidone Concentration), and (camphor concentration) respectively, fifteen tablet formulas were produced.
The experimental work in this chapter included the following items:
1. Pre-compression characterization of tablets powders blend including Angle of repose, bulk density, the Carr’s index (percent compressibility), and the Hausner’s factor.
2. Post-compression characterization of prepared ETD fast dissolving tablets includes weight variations, medication content, and disintegration time, wetting time, in vitro release studies, and % friability, and hardness, thickness.
The obtained data demonstrated that:
1- Powder blends of all the prepared tablet formulations were free flowing and showed excellent flowability parameters.
2- All of the manufactured tablets met the pharmacopeial parameters for uniformity of weight, thickness, drug content, wetting time, and in vitro disintegration time, while also exhibiting acceptable values of hardness and friability.
3- The in vitro release of ETD from all of the produced tablets was conducted for 45 minutes in a phosphate buffer with a pH of 6.8. F8 got a maximum release of 94.1% after 10 minutes.
4- Compared to the other formulations, F6 was the best formula based on the medium results for drug content, percentage friability and percent amount released at 10 minutes.
Kinetic Studies of in vitro release of the prepared Etodolac FDTs
The kinetics of in vitro release profiles of ETD from 15 FDT formulations were represented numerically. The release of ETD from FDTs was found to follow the first-order model for all formulations except F8 and F10, which followed the Higuchi diffusion model.
In chapter 3, the prepared ETD FDTs were optimized using surface response methodology adopting correlation between the independent variables: X1 (Croscarmellose sodium), X2 (Crospovidone) and X3 (camphor) and the dependent variables namely, Y1 (disintegration time), Y2 (% friability) and Y3 (Etodolac amount released at 10 minutes)
Using Box-Bhenken and contour plots with either three-dimensional or two-dimensional designs, the link between the dependent and independent variables was explained further.
The results obtained showed:
1- A negative correlation exists between the disintegration times (Y1) and the concentrations of CCS sodium (X1) or camphor (X3).
2- A positive correlation exists between the disintegration times (Y1) and the concentrations of CP (X2).
3- A negative correlation exists between the percentage friability and the concentrations of CP (X2).
4- A positive correlation exists between the percentage friability (Y2) and the concentration of CCS sodium (X1) or camphor (X3).
5- There is a positive correlation between the quantities of ETD produced at 10 minutes (Y3) and the concentrations of CCS sodium (X1) or CP (X2).
6- A negative correlation exists between the amount of ETD produced after 10 minutes (Y3) and the concentration of camphor (X3).
7- The optimized formula of ETD FDT (F6) contained (+1/24 mg) croscarmellose sodium, (0/20 mg) crospovidone and (-1/10 mg) camphor.
In chapter 4, the bioavailability study of ETD was carried out on rabbits in order to investigate the extent and the rate of Etodolac absorption from the investigated FDTs (F6 and F8) as they resulted in the best ETD in vitro release. They were compared to pure drug. The pharmacokinetic parameters: Cmax, Tmax, Kabs, Kel, t90, AUC0-t, AUC0-∞, ClT and Vd were determined.
The obtained results showed that:
1. The absorption of Etodolac from the selected FDTs formulae was faster than that of pure drug.
2. Formulation of Etodolac FDTs was resulted in a significant improvement in Etodolac bioavailability.
Conclusion: This study concluded that the optimized solid dispersion improved dissolution rate of ETD. Moreover, the fast dissolving tablets of ETD containing the optimized solid dispersion showed good physical properties.