الفهرس 
GENERAL INTRODUCTION
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Nimesulide is a non-steroidal anti-inflammatory drug (NSAID). It’s a cyclogenase-2 (Cox-2) specific inhibitor. It exhibits analgesic, antipyretic and anti-inflammatory activities.
Nimesulide is used in management of osteoarthritis, pain and dysmenorrheal. It’s also used in management of the signs and symptoms of rheumatoid arthritis in adults.
Nimesulide is practically insoluble in water, which hinders its formulation into aqueous solutions, also, this limits its dissolution prior to its absorption and, hence could limit its bioavailability upon administration.
In the present thesis, various techniques were applied to improve the dissolution rate of nimesulide, viz: loading onto surface of certain adsorbents, and interaction with cyclodextrins in solid state. Furthermore, the physicochemical characteristics of the prepared solid systems were studied by differential scanning calorimetry (DSC), powder x-ray diffraction and infrared spectroscopy (IR). Additionally, nimesulide was formulated into rectal suppositories and its anti-inflammatory and anti-pyretic activities were evaluated.
As an integral part of this thesis, attempts were made to discuss the main mechanism(s) responsible for dissolution rate improvement of the drug.
Accordingly, this thesis comprises the following parts:
Part I: Preformulation Studies of Nimesulide
The work in this part was divided into three chapters
Chapter 1
Preparation and Characterization of Certain Adsorbates
of Nimesulide with Various Adsorbents
In this chapter, solvent deposited systems of nimesulide with certain adsorpates were prepared. The investigated adsorbents were Florite®, Avicel PH101, Veegum and Aerosil 200. Two techniques were used to prepare the adsorbates, solvent deposition method and cogrinding method. Certain drug to carrier ratios were prepared (1:1, 1:3 and 1:5 w/w). Also, simple physical mixtures were prepared in the same ratios.
To fulfill this goal, the work in this chapter includes the following:
1- Preparation of loaded mixtures (adsorbates):
The loaded mixtures of nimesulide with the used adsorbents were prepared by solvent deposition and cogrinding techniques. The loaded mixtures were made in the following drug : carrier weight ratios (1:1, 1:3 and 1:5 w/w).
2- Characterization of the prepared systems:
The physicochemical properties of the nimesulide loaded systems as well as the physical mixtures of the drug with the used adsobents were investigated by DSC, powder x-ray diffractometry and IR spectroscopy. The dissolution rate was measured according to the dispersed particulate method.
The results obtained from this chapter revealed that:
1- DSC, powder X-ray diffractometry and IR spectroscopy data revealed that there is no evidence of a true interaction between nimesulide and different adsorbents.
2- A higher increase in nimesulide dissolution rate could be achieved upon its adsorption on the investigated adsorbents.
3- The enhancement of nimesulide dissolution rate depends on both the nature of the adsorbent and the ratio of the adsorbent to the drug in the prepared mixtures.
4- The ground mixture and solvent deposition systems using Florite® as an adsorbent provided the highest dissolution rate for nimesulide.
5- The dissolution rate of nimesulide from the coground system is higher than that from solvent deposited system.
Chapter 2
Preparation and Characterization of Nimesulide-Cyclodextrin Binary Systems in Solid State
The aim of this chapter was to study the possibilities of complex formation of nimesulide with certain cyclodextrins, namely -CD, -CD, hydroxypropyl--CD (HP--CD) and dimethyl--CD (DM--CD). Furthermore, the dissolution characteristics of the prepared systems of nimesulide with the used CDs were studied.
To fulfill this goal, the work in this chapter includes consists of the following steps:
1- Preparation of solid inclusion complexes:
The solid mixtures of nimesulide with the investigated cyclodextrins were prepared by physical mixing, coevaporation and cogrinding techniques.
2- Characterization of the prepared inclusion complexes:
The physicochemical properties of solid complexes of nimesulide with cyclodextrins were investigated using DSC, powder x-ray diffraction and IR spectroscopy. Also, the dissolution rate of nimesulide from the prepared inclusion complexes was determined according to the dispersed amount method.
The results obtained from this work indicate that:
1- DSC, powder x-ray diffraction and IR studies prove that there is no inclusion complex of nimesulide into -CD or HP--CD cavities.
2- Formation of partial complex of nimesulide with DM--CD in their ground mixture.
3- Cogrinding technique of nimesulide with the investigated CDs give the highest dissolution rate of the drug among the other used systems.
4- The effect of various CDs on dissolution rate of nimesulide can be arranged in the following order: DM--CD > HP--CD > -CD >
-CD.
Chapter 3
Preparation and Characterization of Nimesulide-Cyclodextrin Ternary Systems
The aim of the study in this chapter was to investigate the combined effect of different concentrations of a third polymeric substance like
PEG 4000, PEG 6000, PVP 40000 or PVP 250000 on the CD complexation efficiency. Moreover, the physicochemical properties of the prepared ternary solid systems of nimesulide with -CD and the added polymers were evaluated by DSC and x-ray diffraction studies.
To fulfill this goal, the work in this chapter includes the following:
1- Preparation of solid ternary systems:
The ternary systems of nimesulide / -CD (1:1 molar ratio) in presence of 1%, 3% or 5% w/w of PEG 4000, PEG 6000, PVP 40000 or PVP 250000 were prepared by coevaporation and cogrinding methods.
2- Characterization of the prepared ternary systems:
DSC and powder x-ray diffractometry were employed for characterization of the prepared ternary systems. The dissolution rate was measured according to the dispersed amount method.
The results obtained show that:
1- DSC and x-ray diffraction studies indicate the absence of any interaction between nimesulide and any component of the prepared ternary system in the solid state.
2- A marked increase in the dissolution rate of nimesulide is obtained in case of coground mixture and coevaporate of ternary systems than that of the corresponding physical mixtures and the plain drug.
3- The increase of nimesulide dissolution rate is higher from the ternary system than from the respective binary ones.
4- The highest drug dissolution rate is obtained from nimesulide / -CD / PEG 6000 ternary system prepared by cogrinding method.
5- The addition of small amounts of a third polymeric substance to nimesulide / -CD system is a useful strategy for improving the solubilizing and complexing ability of -CD toward the drug. Thus, allowing less amount of -CD to be used offering an evident economic advantage as well.
Part II: Formulation and Evaluation of Nimesulide Rectal Suppositories
The work in this part comprises two chapters
Chapter 1
Formulation and In-Vitro Evaluation of Nimesulide
Rectal Suppositories
The aim of the work in this chapter was to formulate nimesulide rectal suppositories using both water soluble and fatty suppository bases.
The fatty bases used were cocoa butter, witepsol H15, witepsol E75, suppocire AM and suppocire CM. The water soluble bases used were a blend of polyethylene glycols with different molecular weight and weight ratios. Nimesulide suppositories containing coground mixtures of the drug with either Florite® in a ratio of 1:3 w/w or HP--CD in 1:1 molar ratio were prepared. Also nimesulide suppositories containing coground mixture of the ternary solid system; nimesulide / -CD / PEG 6000 were prepared. The effect of addition of different concentrations of non-ionic surfactants namely; Tween 80, Myrj 49 and Brij 58 were studied. All the prepared nimesulide suppositories were produced by the fusion method.
The prepared nimesulide suppositories were evaluated with regard to the drug content, uniformity of weight, disintegration time, melting range and hardness.
Release studies of nimesulide from the prepared suppositories were carried out by using USPXXV dissolution apparatus II (paddle type) in phosphate buffer of pH 7.4 at 37°C.
The obtained results revealed that:
1- The nature of the suppository bases and its chemical structure affect the release rate of nimesulide from the prepared suppositories.
2- The tested suppository bases can be arranged according to the release rate of nimesulide as follows: PEGs > suppocire AM > witepsol E75 > coca butter > witepsol H15 > suppocire CM.
3- Suppository base composed of PEG 1500 : PEG 6000 (75:25 weight ratio) provide the highest drug release.
4- Incorporation of certain types of surfactant into fatty based suppositories improve the rate of drug release considerably as follows: Brij 58 > Myrij 49 > tween 80.
5- The incorporation of Brij 58 (7.5% weight ratio) into suppocire AM suppository bases containing coground mixtures of nimesulide / Florite® or nimesulide / -CD / PEG 6000 give the highest drug release.
Chapter 2
Evaluation of the Anti-Inflammatory and Antipyretic Activities of Nimesulide Rectal Suppositories on Rats
The aim of the work in this chapter is to evaluate the anti-inflammatory and anti-pyretic activities of nimesulide in the prepared suppository formulae which show the highest drug release and comparing it with the commercial nimesulide® suppositories using hind paw edema method and yeast induced pyrexia in rats method, respectively.
Statistical treatment of the obtained results of the anti-inflammatory and antipyretic activities were also done.
The obtained results revealed that:
1- All the tested formulae and the commercial sulide® suppositories show statistically significant increase in the anti-inflammatory activity by time.
2- Formula no. 38 which contains coground mixture of nimesulide /
-CD / PEG 6000 using suppocire AM as a suppository base, in presence of 7.5% w/w Brij 58 show the highest anti-inflammatory activity.
3- All the tested formulae show statistical significant increase in the antipyretic activity by time.
4- Formulae no. 38 show the highest antipyretic activity.
Part III: Stability Studies of Nimesulide in Selected Prepared Rectal Suppositories
In this part, the effect of aging on the selected formulae of the prepared nimesulide rectal suppositories was studied. The selected formulae were stored for six months at room temperature (25°C) and in the refrigerator (4°C) and were evaluated for their physical characteristics, dissolution behaviour and drug content.
Also, stability studies on the selected formulae of suppositories were done and the degradation of nimesulide in the prepared suppositories was monitored by using high performance liquid chromatography (HPLC) and thin layer chromatography (TLC). The degradation reactions of nimesulide at room temperature (25°C) and in the refrigerator (4°C) were determined according to zero-order and first-order reaction kinetics. The order of the reaction and the decomposition rate constant were determined according to the most fit correlation coefficient.
The obtained results indicate that:
1- The aged formulae of nimesulide suppositories stored at room temperature or in the refrigerator for six months show good physical stability, dissolution characteristics and chemical stability.
2- HPLC study indicates the absence of any degradation products in the selected formulae of the prepared suppositories stored for six months.
3- TLC study indicates also the absence of any decomposition products of nimesulide in the selected formulae of the prepared suppositories stored for six months.
4- The stability of nimesulide in the selected formulae of the suppositories follow first-order reaction kinetics.