الفهرس 
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Abstract
Sulpiride (Sul) is a substituted benzamide antipsychotic that is reported to be a selective antagonist of central dopamine (D2, D3, and D4) receptors. It is also claimed to have mood elevating properties. Sulpiride (Sul) is mainly used in the treatment of psychoses such as schizophrenia. Sulpiride has a poor solubility in water and so a low oral bioavailability.
The objective of this study is to enhance the solubility of sulpiride by solid dispersion technique, then to formulate and evaluate several pharmaceutical dosage forms containing sulpiride (Sul) or its solid dispersion such as suppositories, topical formulations and microspheres.
The present study was divided into five parts as following:
Part (I)
Formulation and Evaluation of Sulpiride Solid Dispersions
The purpose of this part was to improve the dissolution rate of sulpiride since it is poorly water soluble.
• Physical mixtures (PMs) and solid dispersions (SDs) of sulpiride with each of B-cyclodextrin, Lactose anhydrous, Glucose anhydrous and Eudragit E100 in ratios of 1:0.5, 1:1 and 1:2 (drug to carrier W/W), with Polyethylene glycol (PEG) 4000 in ratios of 1:1, 1:3 and 1:5, with Polyethylene glycol (PEG) 6000 in ratios of 1:1, 1:3, 1:5, 1:7 and 1:9, with tartaric acid in ratios of 1:0.125, 1:0.1875 and 1:0.25, with Urea, Poloxamer 188 and Maltose monohydrate in ratios of 1:1, 1:2 and 1:3 and with polyvinyl pyrrolidone (PVP) K30 in ratios of 1:0.5, 1:1, 1:2 and 1:3 were prepared. SDs of sulpiride with urea in ratio of 1:2 containing , Brij 35 (1%), Brij 52 (1%), Brij 92 (1%), Mrij59 (1%) , Tween 80 (0.5-1-2-5%), Transcutol (1%), Cetrimide (1%) and Sodium lauryl sulphate (SLS) (1%) were also prepared.
• All previously mentioned SDs were prepared by solvent evaporation method.
• The equilibrium solubility of sulpiride in presence of different concentrations of the above mentioned carriers was determined at 25°C and the influence of different pH on the solubility of sulpiride was also examined.
• The dissolution of all prepared samples (PMs and SDs) was carried out in distilled water.
• Some SDs and PMs as well as individual components were subjected to inspection by FTIR spectroscopy, DSC and X-ray powder diffraction.
Results revealed that:
• The used carriers can be ranked according to their effect on increasing the aqueous solubility of sulpiride as following: tartaric acid > PVP > PEG 4000 > urea > glucose > lactose > maltose > PEG 6000 > poloxamer 188 > β-cyclodextrin.
• The solubility decreased with increasing pH (higher in acidic rather than in alkaline one).
• The type of carrier and drug to carrier ratio had great influence on the rate and extent of dissolution of sulpiride from its PMs and SDs. Tartaric acid had the most influential effect on the rate and the extent of dissolution of sulpiride, followed by PEG 4000, PVP, glucose, PEG 6000, maltose, lactose, eudragit E100, poloxamer 188, urea and finally β-cyclodextrin at ratios of (1:0.25) , (1:5), (1:1) , (1:1) , (1:5) , (1:2) , (1:1) , (1:1) , (1:2) , (1:2) and (1:1) respectively.
• The incorporation of different surfactants in sulpiride – urea solid dispersion (1:2) did not produce a significant effect or produced a decrease in the release of sulpiride from these systems.
• Physical characterization of all systems prepared revealed structural changes in the prepared SDs from that of the plain drug, which may account for increased dissolution rates.
It was concluded that SDs showed increased dissolution rate as compared to the pure drug.
Part (II)
Formulation and Evaluation of Suppository Bases Containing Sulpiride or its Solid Dispersion
The aim of this part was to formulate and determine the release of sulpiride or its solid dispersion with tartaric acid in ratio 1:0.25 w/w drug to carrier from different suppository bases.
Suppositories of one gram each containing 50 mg of sulpiride or its equivalent of solid dispersion were prepared using different bases, namely witepsol W25, witepsol H15, witepsol E75, suppocire NA, suppocire A, glycerogelatin and polyethylene glycol (three different formulae FA, FB, FC).
• The suppositories (containing SD) were stored for six months at ambient room temperature, in a refrigerator at 4ºC and in an incubator at 37±1ºC.
• Quality control for suppositories was investigated.
• In-vitro release of sulpiride from both fresh and stored suppositories was studied in Sorensen’s phosphate buffer pH 7.4 at 37±0.5 ºC.
Results revealed that:
• The release of sulpiride from different suppository bases was arranged in the following descending order : Glycerogelatin > Witepsol H15 >PEG F(A) > PEG F(B) > PEG F(C) > Witepsol W25 > Suppocire NA > Suppocire A > Witepsol E75.
• Incorporation of sulpiride - tartaric acid solid dispersion into different suppository bases increased the release of Sulpiride from all bases compared to the control.
• The release from different suppository bases (containing SD) was significantly affected during the storage (at ambient room temperature and in the refrigerator for six months) except Glycerogelatin, Suppocire NA and Suppocire A.
• Storage of different suppository bases (containing SD) in the incubator caused melting of the fatty bases and glycerolgelatin base just after two days. On the other hand, the release from PEG suppository bases (containing SD) was significantly affected during the storage in the incubator for six months.
• Glycerogelatin suppositories showed the best results of the drug release and stability on storage eiher in the refrigerator or at ambient room temperature).
• The data of release from suppositories containing SD followed Higuchi diffusion model, while the data of release from suppositories containing sulpiride followed zero order.
Part (III)
Formulation and Evalution of Topical Formulations Containing Sulpiride and its Solid Dispersion
The aim of this part was to formulate and determine the release of sulpiride or its solid dispersion with tartaric acid in ratio 1:0.25 w/w drug to carrier from different topical formulations.
Topical formulae containing 50 mg of sulpiride or its equivalent of solid dispersion in each one gram of the topical formulae were prepared.
• Topical bases comprises ointment bases , gel base and emulgel base. The ointment bases were water soluble, absorption, oleaginous and emulsion bases (o/w and w/o cream bases). The gel base was hydroxypropyl methylcellulose (HPMC) gel. The emulgel base was hydroxypropyl methylcellulose (HPMC) emulgel.
• Topical formulations were stored for six months at ambient room temperature and in an incubator at 37±1ºC.
• In-vitro release of sulpiride from fresh topical formulations was studied in Sorensen’s phosphate buffer pH 7.4 and pH 5.5 at 37±0.5 ºC.
• In-vitro release of sulpiride from stored topical formulations was studied in Sorensen’s phosphate buffer pH 5.5 at 37±0.5 ºC.
Results revealed that:
• The amount of sulpiride released from water soluble, gel and emulgel bases was greater than that released from other bases.
• The amount of sulpiride released from O/W emulsion base was greater than that released from W/O emulsion base.
• No drug is released from the absorption, oleaginous and W/O emulsion bases.
• Incorporation of sulpiride - tartaric acid solid dispersion in different topical bases showed an increase in the release of the drug.
• The release from different formulations was not significantly affected during the storage at ambient room temperature for six months except water soluble and emulgel bases containing solid dispersion.
• The release from different formulations was significantly affected during the storage in the incubator 37±1ºC except O/W cream containing sulpiride.
• The data of the release from formulations containing SD followed Higuchi diffusion model either in pH 5.5 or pH 7.4, while the data of the release from formulations containing sulpiride followed Zero order kinetics in pH 7.4 and Higuchi diffusion model in pH 5.5.
Part (IV)
Formulation and Evaluation of Sulpiride Loaded Microspheres
The aim of this part was to enhance bioavailability of sulpiride and reduce the frequency of administration.
• Microspheres were prepared by the emulsion non-solvent evaporation technique using Eudragit RS100 and Ethyl cellulose, span 80 , light liquid paraffin and acetone under vigorous agitation.
• The effect of changing the drug: polymer ratio, surfactant concentration, oil viscosity, stirring rate, the internal phase volume and polymer type on the particle size, the entrapment efficiency , the yield and the release of the drug was demonstrated.
• In-vitro release of sulpiride from microspheres was studied in Sorensen’s phosphate buffer pH 7.4 and in pH 1.2 (0.1 N Hcl) at 37±0.5 ºC.
Results revealed that:
• The decrease in the particle size and the entrapment efficiency and the increase in the release rate for Eudragit RS100 and Ethyl cellulose microspheres were achieved by decreasing the drug : polymer ratio, increasing the surfactant concentration, oil viscosity, stirring rate, or internal phase volume (except the entrapment efficiency of Ethyl cellulose microspheres which was decreased by decreasing the internal phase volume).
• The yield of Eudragit RS100 and Ethyl cellulose microspheres was increased by increasing the drug : polymer ratio, surfactant concentration and internal phase volume and by decreasing the oil viscosity and stirring rate (except the yield of Eudragit RS100 microspheres which was unaffected by changing the internal phase volume).
• The release of sulpiride in buffer pH 7.4 from Eudragit RS100 microspheres was higher than that from sulpiride loaded Ethyl cellulose microspheres. On the other hand, the particle size of Eudragit RS100 microspheres was lower than those of Ethyl cellulose microspheres. The entrapment efficiency and yield of microspheres did not depend on the polymer type.
• The data of the release of sulpiride form loaded Eudragit RS100 microspheres in buffer pH 7.4 and from loaded Ethyl cellulose microspheres in pH 1.2 (0.1 N HCl) and buffer pH 7.4 followed Higuchi diffusion model.
• Sulpiride loaded Eudragit RS100 are suitable for administration through rectal route to provide controlled release pattern, while sulpiride loaded Ethyl cellulose microspheres are suitable for administration through rectal and oral route to provide controlled release pattern.
Part (V)
In-vivo Evaluation of Certain Formulations of Sulpiride
The aim of this part was to evaluate the bioavailability of sulpiride from the selected formulations (tartaric acid solid dispersion, ethylcellulose microspheres, witepsol H15 suppositories and o/w creams containing sulpiride and tartaric acid solid dispersion).
The bioavailability of sulpiride from the selected formulations was assessed by measuring the pharmacokinetics parameters (Cmax, Tmax, Kel, t1/2, AUC0-24 and AUC0-∞) using rabbits.
The bioavailability study was done using seven groups to test the selected formulations and sulpiride alone.
Results revealed that:
• Tartaric acid solid dispersion had higher Cmax, and AUC values than the control (sulpiride alone). The solid dispersion produced an increase in the relative bioavailability of the plain sulpiride by 1.8 times.
• Ethylcellulose microspheres had lower Cmax value and higher Tmax and AUC values than sulpiride alone. Ethylcellulose microspheres produced the controlled release effect (indicated by lowering the Cmax value and increasing the Tmax value) with increasing the relative bioavailability of the plain sulpiride by 1.3 times.
• Witepsol H15 suppositories containing solid dispersion had higher Cmax, and AUC values than witepsol H15 suppositories containing sulpiride and so the former formulation had higher bioavailability than the later one. Witepsol H15 suppositories containing solid dispersion produced an increase in the relative bioavailability of the plain sulpiride by 1.2 times.
• O/W cream containing solid dispersion had higher Cmax and AUC values than O/W cream containing sulpiride and so the former formulation had higher bioavailability than the later one. O/W cream containing solid dispersion produced an increase in the relative bioavailability of the plain sulpiride by 2.6 times.