الفهرس 
genral introduction
methodologyOnly 14 pages are availabe for public view
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Abstract
Summary
Delivery of therapeutic agents through the buccal route provides a number of advantages such as avoidance of gastrointestinal degradation and hepatic first pass metabolism due to direct access of the drug into the systemic circulation. In addition, buccal drug delivery offers a relatively large surface area of absorption, ease of accessibility, simple delivery devices, and feasibility of controlled drug delivery.
Drug absorption through the oral mucosal membranes requires that the drug dissolves sufficiently in a very small volume of saliva, which may represent an obstacle for poorly soluble drugs. In addition, the most important determinant of buccal delivery is the degree of permeability of the mucosa. Therefore, release enhancers and permeation enhancers may be utilized to improve drug release and overcome the permeability barrier. Permeation enhancers act by increasing the retention time of drug around the buccal mucosa, interact with the buccal mucosal protein and intercellular lipid, or enhance the drug partitioning across the buccal mucosa.
Fluvastatin sodium (FVS) is an antilipidemic agent used to reduce plasma cholesterol levels and prevent cardiovascular disease. However, it undergoes extensive hepatic first pass metabolism causing an absolute oral bioavailability of ~29%. With its low oral bioavailability, short half-life of 1-3 hours, and suitable molecular weight of 433.46 g/mol, FVS was considered a good candidate for buccal route administration which has the benefit of escaping first pass effect as the drug passes directly into the bloodstream resulting in a reduction of dose and dose-dependent adverse events.
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This work aimed at formulating bioadhesive buccal discs of FVS to guarantee unidirectional accurate dose delivery in order to improve its bioavailability.
The work in this thesis is divided into two chapters:
Chapter I: Formulation and evaluation of bioadhesive buccal discs of fluvastatin sodium.
Chapter II: In-vivo relative bioavailability of the selected bioadhesive buccal disc formulation.
Chapter I
Formulation and Evaluation of Bioadhesive Buccal Discs of Fluvastatin Sodium
The objective of this chapter was to develop bioadhesive discs for the buccal delivery of fluvastatin sodium. Different formulations were designed using various bioadhesive polymers, release enhancers, and permeation enhancers to control drug release, drug permeation, and bioadhesion properties of the prepared discs.
The bioadhesive discs were prepared by direct compression method using several bioadhesive polymers such as guar gum, sodium alginate, sodium carboxymethyl cellulose, carbopol 934P, and hydroxypropylmethyl cellulose. Ethyl cellulose was applied as a backing layer. Microcrystalline cellulose and polyethylene glycol 6000 (PEG 6000) were used as release enhancers. Different permeation enhancers such as bile salts, surfactants, fatty acids, and solvents were tested to improve the permeability through buccal mucosa.
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The prepared disc formulations were evaluated for the following:
1- In-vitro drug release.
2- Drug permeation across chicken pouch mucosa.
3- Ex-vivo bioadhesion.
a. Bioadhesion force.
b. Bioadhesion time.
4- Evaluation of physicochemical characteristics of the selected formulation (F27).
a. Drug release and kinetic analysis.
b. Drug content uniformity.
c. Disc thickness.
d. Disc hardness.
e. Disc surface pH.
f. Swelling index.
5- Effect of aging.
The results of the chapter revealed the following:
1. Drug release rate was improved by using the release enhancers MCC and PEG 6000 and by forming HPMC polymer blends with GG, SALG, CP, or SCMC.
2. selected formulations which showed ≥ 80% drug release in 3 h with high initial flux without disc fragmentation were: F6 (GG/MCC), F10 (GG/PEG), F21 (SCMC/HPMC/MCC), and F25 (SCMC/HPMC/PEG).
3. Initial permeation results of the aforementioned selected four formulations were in the range of 3.2-6.6% drug permeation in 4 h.
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4. The formulation (F10) containing 70 mg guar gum as the bioadhesive polymer and 30 mg PEG 6000 as the release enhancer showed significantly higher permeation compared to the others (p = 0.0271). It was selected for the permeation study with the incorporation of permeation enhancers.
5. Sodium deoxycholate (4%) was found to be the most effective permeation enhancer with F10 giving an enhancement ratio of 1.741.
6. The formulation (F10) was modified by decreasing the guar gum ratio and increasing the PEG 6000 ratio resulting in improved permeation in the presence of 4% sodium deoxycholate and was given the code (F27).
7. The selected formulation (F27) showed drug release of 95.4% in 80 min, drug permeation through chicken pouch membrane of 75.6% in 4 h with permeation flux (Jss) of 3.84 mg cm-2 h-1, ex-vivo bioadhesion strength of 2.543 g, and bioadhesion time of 4.87 h.
8. Korsmeyer-Peppas release exponent (n) was found to be 0.742, indicating anomalous (non-Fickian) drug release kinetics for F27.
9. The physicochemical characteristics of F27 buccoadhesive discs were within the acceptable range with a drug content of 98.6 ± 1.46 %, thickness of 1.94 ± 0.042 mm, disc hardness of 58.67 ± 5.033 N, surface pH of 6.31 ± 0.017, and disc swelling index of 0.715 ± 0.04 in 2 h.
10. Accelerated stability results of F27 at 40°C/75% RH for 3 months indicated that there was a significant decrease in drug content to 95.3% (p=0.0514). Therefore, as previously reported, it is recommended to include an alkalizing agent such as 5 mg
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aluminum hydroxide to the formulation to minimize FVS hydrolysis upon storage.
11. There were no significant changes in other pharmaceutical parameters such as in-vitro drug release, drug permeation, and bioadhesion strength and time after accelerated stability.
12. The buccoadhesive disc formulation of choice (F27) which contained 21.06 mg fluvastatin sodium equivalent to 20 mg fluvastatin, 40 mg guar gum, 60 mg PEG 6000, and 4.8 mg sodium deoxycholate with 80 mg ethyl cellulose backing layer was the selected formula for the in-vivo relative bioavailability study in chapter II.
Chapter II
In-Vivo Relative Bioavailability of the selected Bioadhesive Buccal Disc Formulation
In this chapter, the performance of the selected bioadhesive discs of fluvastatin sodium (F27) was studied in 6 healthy human volunteers using a commercial peroral product (Lescol®, Novartis) as a reference formulation.
The volunteers applied F27 buccal discs (containing 20 mg fluvastatin) to the buccal region behind the lower lips and were asked to remove the discs after 6 h. After a one-week period, Lescol® (containing 20 mg fluvastatin) was administered perorally with 200 ml water. Blood samples were collected for 8 hours. LC-MS/MS was used to quantify plasma concentrations of fluvastatin using atorvastatin as an internal standard.
The results of this chapter revealed an approximate 1.5-fold increase in bioavailability, due to bypassing the hepatic first pass effect, meanwhile
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avoiding shooting blood levels with Cmax of 30.74 ng/ml and tmax of 2.33 h, which may result in a better efficacy and safety profile. Consequent dose reduction of 32% is, therefore, possible due to the significant increase in bioavailability eventually leading to less dose-related adverse events and less cost.
Controlled release was successfully achieved as indicated by the significantly higher HVD of fluvastatin when given in the buccal formulation F27 (4.45 h) compared to (1.44 h) in the peroral formulation Lescol® (p=0.0012).
There was a positive correlation (r = 0.9617) between fractions permeated ex-vivo using chicken pouch mucosa and fractions absorbed in-vivo.
Therefore, there is a good potential of the prepared buccoadhesive disc formulation F27 for systemic delivery circumventing the hepatic first pass metabolism with added advantages of sustained drug delivery.