الفهرس 
Abstract
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Abstract
Domperidone is a dopamine (D) antagonist with particular affinity for the D2 subtype receptors in the brain and the peripheral nervous system including the gastrointestinal (GI) tract. Its most notable effect in the GI tract is antagonism of apomorphine- and dopamine-induced changes in GI function, as stimulation of dopaminergic receptors inhibits gastric motility, resulting in a variety of GI symptoms including postprandial bloating and pain, premature satiety, nausea and vomiting, Dopamine antagonists, such as domperidone, have the potential to negate this dopaminergic effect and thereby prevent subsequent GI symptoms.
Domperidone does not cause significant central nervous system side effects as it minimally crosses the blood-brain barrier, the efficacy of domperidone as antiemetic reflects its activity at the chemoreceptor trigger zone (CTZ), which is located in the fourth ventricle of the brain but outside the blood-brain barrier. So there is worldwide experience in utilizing this agent, both as a treatment of gastroparesis as well as a general antiemetic.
Domperidone is available in the local market for oral and rectal administration as tablets, capsules, suspension, syrup, sachets, and suppositories. Domperidone is rapidly and almost completely (93%) absorbed after oral administration. However, the bioavailability of the drug is only about 15% due to extensive first-pass liver and intestinal metabolism.
Hence the poor water solubility of the drug may affect its bioavailability, solid dispersion, melt granulation, and liquisolid compacts techniques with certain water soluble carriers were utilized to improve the solubility and dissolution of domperidone. To overcome deficiencies associated with the oral mode of dosing, an attention has been focused on the possibility of development of rectal dosage forms as an attempt to avoid the first pass metabolism. Furthermore, the evaluation of the plasma concentration of domperidone from healthy rabbits after rectal administration of the prepared suppository formulae, compared to the rectal marketed suppositories Motinorm® (10mg), and marketed oral suspension, Motinorm® (5mg/5ml) were also investigated.
Thus, the thesis has been classified into two parts:
Part- I: Improvement of solubility and dissolution of domperidone via solid dispersion, melt granulation and liquisolid compact techniques.
Part- II:
Chapter 1: Formulation and evaluation of domperidone rectal suppositories.
Chapter 2: Comparative bioavailability studies of domperidone suppositories in rabbits.
PART - I: Improvement of Solubility and Dissolution of Domperidone via Solid Dispersion, Melt Granulation and Liquisolid Compact Techniques
The work in this chapter was an attempt to improve the solubility and dissolution of domperidone adopting three different techniques viz., solid dispersion, melt granulation, and liquisolid compacts techniques. Solid dispersion at (1:1, 1:2, 1:3, 1:5, and 1:7) and melt granulation systems at 1:1, 1:2 and 1:3 drug to polymer ratios were prepared. Several liquisolid formulations containing various ratios of drug: liquid vehicle (ranging from 5 % to 50 % w/w) were formulated. HyDROPhilic carriers viz; PEG 6000, PEG 4000, Pluronic F-127, Pluronic F-68, Myrj 52, Brij 35, mannitol, urea, PVP, Polysorbates, PEG 400, PEG 200, and PG were used. Domperidone solid dispersions were prepared by solvent evaporation method, and melt granulates were prepared by the hot-melt method.
The prepared systems were evaluated for:
a) Solubility and Dissolution Studies:
Solubility results revealed a pronounced enhancement of domperidone solubility in distilled water with the prepared systems compared to the pure drug. The in-vitro dissolution study showed that there is a highly significant difference in % of domperidone dissolved from solid dispersion, melt granulation, and liquisolid compacts systems compared to drug alone (P<0.001), also the differences between amounts of drug dissolved from solid dispersion system compared to the other systems were highly significant (P<0.001). It can be concluded that domperidone aqueous solubility and dissolution were markedly improved via solid dispersion technique with PF-127 at drug: polymer ratio of 1:3, prepared by solvent evaporation method compared to other methods used. The same dispersion system exhibited higher dissolution rate compared to its corresponding physical mixture (at the same ratio). Accordingly, domperidone/ PF-127 solid dispersion 1:3 drug: polymer ratio and the corresponding physical mixture were selected for further investigations.
b) Infrared Spectrophotometry (IR):
The IR spectra of physical mixtures and the prepared systems, is a superimposition of drug and polymer spectra. These results reveal the absence of well defined interaction between domperidone and the carriers used.
c) Differential Scanning Calorimetry (DSC):
The melting endotherm of domperidone was observed in solid dispersions, melt granulates, and their corresponding physical mixtures as a broad endotherm at a temperature range lower than the melting point of the drug. Also the characteristic features of domperidone peak were appreciably lost. These results may be attributed to the reduction in crystallinity of domperidone in these systems. In the liquisolid compact system, the DSC data displayed complete disappearance of the characteristic peak of domperidone; a fact that agrees with the formation of drug solution in the liquisolid powdered system.
d) Powder- X-Ray Diffraction (P-XRD):
X-ray diffractograms showed that, the physical mixture of drug / PF-127 at (1:3) drug to polymer ratio still showing the characteristic drug peaks, while solid dispersion with the same ratio showed complete absence of the drug characteristic peaks. This supports the transformation of the drug from crystalline to amorphous state.
e) Scanning Electron Microscopy (SEM):
The Photomicrographs of domperidone, PF-127 and domperidone / PF-127 solid dispersion (1:3) as well as physical mixture revealed the absence of crystalline structure of the drug from the solid dispersion system, which confirm the transformation of drug from the crystalline to the amorphous state.
from collected data, it can be concluded that the hyDROPhilic carrier PF-127 at (1:3) drug to polymer ratio exhibited the most remarkable enhancing effect on solubility and dissolution of domperidone.
PART - II
Chapter 1: Formulation and Evaluation of Domperidone Rectal Suppositories
The aim of work in this chapter was to formulate domperidone rectal suppositories using fatty, and water soluble bases. The fatty bases used were cocoa butter, suppocire AM, and witepsol H15 while, gelatin and polyethylene glycols (PEGs) were used as the water soluble type. Suppositories containing co-evaporates with Pluronic F-127 at (1:3) drug to carrier ratio were prepared in poly ethylene glycol base that showed the highest release using different additives namely; Polysorbate 80, 60, 40, 20, Sodium lauryl sulphate, Cetrimide, PVP, Hydroxy propyl methyl cellulose (HPMC) , Lactose, Urea, β- cyclodextrin, Myrj 58 and Brij 35.
The prepared suppositories were subjected to the following investigations:
I- Evaluation of the Physical Characteristics of the Prepared Plain and Medicated Suppositories:
The physical properties of the prepared suppositories viz; weight variation, hardness, disintegration time, melting range and content uniformity were studied. The results revealed that, the prepared suppositories were found to comply with the B.P. requirements with regard to content uniformity, melting range and weight variation. In addition, most of the suppository formulations exhibited suitable hardness and disintegration time.
II- In-vitro Drug Release in Phosphate Buffer pH 7.4:
The in-vitro release of domperidone (10 mg) from the prepared suppositories was carried out using the glass beaker method in phosphate buffer pH 7.4. The obtained results revealed that, the drug release from the water soluble bases was higher than that from the fatty bases.
The release of domperidone from lipophilic fatty suppository bases was dependent on the melting behaviour and chemical composition of the used base, while the release from the water soluble bases was dependent on the dissolution behavior.
Domperidone solid dispersion with Pluronic F-127 formulated in to suppository, showed enhanced release compared to drug alone. Addition of 4% w/w cetrimide as a release enhancer resulted in a highly significant increase in the release. The obtained data proved the superiority of the PEG formulations containing solid dispersion of the drug to Pluronic F-127, ratio 1:3.
III- Kinetic Analysis of Release Data:
The release data was analyzed according to zero, first, second order kinetics also Higuchi diffusion model, Hixon, Baker, and Korsemayer Peppas models. The drug release was found to follow Korsemayer Peppas mechanism from most of the prepared bases.
Chapter 2: Comparative Bioavailability Studi