الفهرس 
General IntroductionOnly 14 pages are availabe for public view
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Abstract
Statins play a critical part in avoiding heart diseases caused by high blood cholesterol levels and atherosclerotic clumps, which lower cholesterol levels by limiting the enzyme HMG-CoA reductase. Several members of the statin group have low solubility and bioavailability. Simvastatin (SVA) is one of the most regularly prescribed statins. The gastrointestinal bioavailability of SVA in humans is less than 5% owing to its slower dissolution rate in the gastrointestinal tract and major first-pass effect. The restricted bioavailability and poor water solubility of SVA have recently been tackled by a number of ways. These ways includes nanoparticles, micronization, solid dispersion, cyclodextrin complexation, microemulsion, liposomes, phospholipid complexes, self-micro emulsifying drug delivery systems (SMEDDS) as well as other methods or techniques. The most advantageous property of SLN is that it more appealing stability pattern than other nanoparticulate formulations and enhanced bioavailability.
Aims and objectives: This thesis studied the design and evaluation of solid lipid nanoparticles for simvastatin drug, in an attempt to enhance the bioavailability of simvastatin (SVA) drug following oral administration.
Methods: Preformulation characterization is a critical step in determining the physicochemical features of a drug for an intended route of administration. Generally preformulation studies include solubility, pH measurement and drug partitioning. Preformulation studies can help in selecting a desirable, stable, and cost-efficient formulation. The goal of this chapter is to calibrate the SVA drug and perform solubility tests on various media to determine the best media for improving SVA solubility. SVA was found to be a poorly water soluble drug with an aqueous solubility of 0.03 mg/mL it found also that it not affected by pH changes. SVA was measured effectively using UV-VIS Spectrophotometry at 238 nm with methanol as the solvent at different pH levels and different media. Different pH and different media could be as followed: methanol, methanol: distilled water, methanol: hydrochloric acid buffer (HCL pH 1.2), methanol: phosphate buffer (PBS at pH 6.8), methanol: distilled water containing (0.1 % w/v) sodium lauryl sulfate (SLS), methanol: HCL at PH 1.2 solution containing (0.1 % w/v) SLS, methanol: PBS at pH 6.8 solution containing (0.1 % w/v) SLS, and methanol: PBS 6.8 solution containing (0.1 % w/v) SLS. Calibration tests have proceeded to determine the best figure with an ideal correlation coefficient (R2) of nearly 0.995. This coefficient is required to detect the concentration of an unknown sample. And also to determine the degree of recognition and the degree of quantitation. The solubility test was then performed at different pH levels in the following media: deionized water, 0.1 N HCL solution pH 1.2, phosphate buffer pH 6.8 solution, sodium lauryl sulfate (SLS) with phosphate buffer solution (PBS), and buffer solutions including SLS/HCL (0.1 %) at 37°c (similar to the body temperature). This test is required to determine the optimal pH that increases SVA drug solubility.
Key research findings: The results showed that SVA is more soluble in PBS-SLS at pH 6.8 than in DW-SLS at pH 4.0, with solubility’s of 391.276 µg/ml, 330.95 µg/ml, and 0.145 µg/ml, respectively.
How to prepare SVA-loaded polymeric solid lipid nanoparticles? Generally, there are several ways to extract SLNs such as high-pressure homogenization (hot or cold), melt dispersion technique, phase inversion temperature method (PIT), and solvent injection method. All techniques required SLNs, which are primarily consisting of solid lipids and surfactants, with organic salts functioning as emulsifiers. Knowing that, the physicochemical properties of the SLNs affect their behavior in both vitro and vivo experimental. The hot homogenization technique has used in this thesis. The advantages of this technique are that high temperatures reduce the viscosity of the inner phase. That fact resulted in a reduction in the particle size of SLN. Unlike other techniques, this one also has very high long-term stability. SLN was prepared by using specific lipids, which are (Precirol ATO5, Geleol mono- and diglycerides, Gelucire 43/01 pellets, and Compritol 888 ATO) and two stabilizers (poloxamer 407 and tween 80) to generate SLN. The characteristics needed to evaluate SLNs include particle size, zeta potential, drug release, entrapment efficiency (% EE) and surface morphology.
The results show that all studied batches were observed in nanoscale range and its particle size were observed within 332-1000 nm with good stability behavior confirmed by higher zeta-potential values of -21.86 mV. The prepared SLN has the highest entrapment efficiency reached to 98% with good drug controlling and lower initial rapid release behavior. Studied SLN has also been visualized using electron microscopy and it showed spherical shape with smooth and uniform particle distribution.
The SVA-loaded polymer of SLN is coated with hydrophilic polymers, for example, chitosan and alginate. When a medication or any active ingredients are carefully mixed with a polymer (whether natural or synthetic), the active agent is released from the material in a controlled drug delivery way. Simvastatin (a medication with mild acidity) will be combined with the hydrophilic polymer of preference (alginate or chitosan). Simvastatin’s undesirable physicochemical characteristics such as its low water solubility, strong protein binding and increased first pass metabolism, decrease the drug absorption which lead to the reduction of the SVA drug bioavailability. So on polymers should be capable of preserving their structural integrity from harsh condition of the GI tract while dissolving or releasing the medicine. The coating of the SVA drug enhanced its bioavailability by achieving sustained release conditions, enhancing absorption, reducing side effects, and creating a new commercial market opportunity to recover the failure of drugs to be delivered through conventional methods. The characteristics needed to evaluate coated-SLNs with different concentrations of chitosan and alginate include particle size, zeta potential, drug release, entrapment efficiency (% EE), and viscosity.
According to the findings, coated F 6 and F 11 outputs were in the nanoscale range. AL-coated SLN has a negative zeta potential, meanwhile chitosan-coated SLN has a positive zeta potential. The entrapment efficiency of the prepared formulation ranged from 97–100%. F 6 (CS 1%) obeys shear thinning, having the highest viscosity. In-vitro drug analysis for the optimized formula (F 6 CS 1%) revealed good drug control with a lower release of approximately 3.03% in lower pH values after 2 hr and 15.67% in high pH values after 24 hr.
An animal study for the Evaluation of the optimized SLN and coated-SLN formulations was performed. This study includes investigation of the plasma concentration of SVA drug by administering the two best formulations orally to albino rabbits. Calibration for SVA in plasma using HPLC has been separately achieved. A comparison of the enhanced SVA bioavailability and confirmation of the results obtained from the previous in vitro characterization were chosen in addition to the in vivo study to determine the two formulas. The determination of plasma concentration and pharmacokinetics in the rabbit model were used to assess oral bioavailability in vivo. Furthermore, the determined plasma concentration of SVA loaded SLN and coated-SLN formulations showed enhanced oral bioavailability compared with the control.
Conclusion: SVA loaded SLN and SVA-coated SLN formulations demonstrated acceptable physical stability, enhanced bioavailability, and sustained release for more than 10 h, unlike SVA suspension.