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Abstract
Rofecoxib is a member of new class of
anti-arthritis and analgesia medication. It is a cylcooxygenase-2 (cox-2) specific inhibitor.
Rofecoxib is used in managements of osteoarthritis, Pain, and dysmenorrheal. It is also used in the symptomatic managements of the signs and symptoms of rheumatoid arthritis in adults.
Rofecoxib 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 solubility and the dissolution rate of the rofecoxib, viz: solid dispersions with certain water soluble carriers, cyclodextrins complexation and loading onto surface of certain adsorbents. Also, our investigations were extended for evaluating the effect of co-grinding technique of rofecoxib with different additives. Furthermore, the physicochemical characteristics of the prepared solid systems were investigated by IR- spectroscopy, DSC and powder X-ray diffraction. The release of rofecoxib from those systems was also investigated.
Additionally, capsules and tablets containing different drug systems were prepared, evaluated according to USP XXV and compared with the commercial product available in the market. Rofecoxib suppositories were also formulated to counteract its extensive first pass effect in the liver. Moreover, the anti-inflammatory activity of rofecoxib from the selected dosage forms was evaluated in rats.
As an, integral part of this work, attempts were made to enhance the solubilization of rofecoxib by using different types of non – ionic surfactants, macromolecules, cyclodextrins derivatives, hydrotropic agents and co-solvents.
Also, the main mechanism (s) responsible for improvement dissolution of the drug and interaction between the drug and macromolecules or cyclodextrins was also investigated in solid state.
Thus, this thesis comprises the following parts:
Part Ι: Preformulation studies on rofecoxib.
The work in this part composed of four chapters.
Chapter 1
Solubilization of rofecoxib using certain non-ionic surfactants, macromolecules, cyclodextrins, hydrotropic agents and co-solvents.
The aim of this chapter was to study the effect of different additives on the aqueous solubility of rofecoxib. So, the work in this chapter includes the following:
A- Solubilization by certain non-ionic surfactants:
The effect of certain non-ionic surfactants namely; Tween 80 and 20, Brij 35 and 58 and Myrj 52, 53 and 59 on the aqueous solubility of rofecoxib at two different temperatures (25, 37ºC) was studied.
B- Solubilization by certain macromolecules:
Solubility of rofecoxib was studied in solutions of polyethylene glycols (PEG 4000 and PEG 6000), polyvinyl pyrrolidone (PVP 40000 and PVP 250000) at different temperatures (25, 37ºC).
C- Solubilization by certain cyclodextrins:
Solubility of rofecoxib in different molar concentrations of β-CD and HP-β-CD at different temperatures (25, 37ºC) was studied.
D- Effect of certain hydrotropic agents on the aqueous solubility of rofecoxib.
D.1. Effect of sugar and sugar alcohol.
D.2. Effect of urea and thiourea.
D.3. Effect of potassium citrate and sodium benzoate on the aqueous solubility of the drug was studied.
E- Solubilization by co-solvents:
The solubility of rofecoxib was investigated by using binary solvent systems. These systems were prepared by mixing on of the following solvents (Dioxan, Glycerol, Acetamide, PEG 400 and PEG 600) with water in different concentrations.
The results of this work as follows:
1- The used non-ionic surfactants have a pronounced enhancing effect on the aqueous solubility of rofecoxib. Tween 80 showed the highest solubilizing capacity for rofecoxib compared to the other investigated non-ionic surfactants.
2- PVP 40000 gave the highest solubility for rofecoxib among the investigated macromolecules PEG 4000, PEG 6000 and PVP 250000.
3- HP-β-CD gave the higher stability constant and solubilization efficincy toward rofecoxib compared to of β-CD. Rofecoxib solubility increased linearly as a function of cyclodextrins concentration and showed the features of AL type phase solubility diagram which indicates the formation of 1:1 drug – CDs complexes in solution.
4- Hydrotropic agents were considered as a powerful tool for increasing the aqueous solubility of rofecoxib especially thiourea and sodium benzoate which led to increase the aqueous solubility of the drug about 167 and 48 fold respectively.
5- Rofecoxib aqueous solubility has been improved using different co-solvents. Dioxan exhibited the highest solubilizing power on rofecoxib than the other investigated co-solvents.
Chapter 2
Physicochemical characterization of rofecoxib with certain hyDROPhilic polymers
The aim of this chapter was to study the interaction of rofecoxib with some hyDROPhilic carriers in solid state. Two types of hyDROPhilic carriers were used throughout this work, namely: PEGs and PVP. The influence of weight ratios of the drug to the carrier as well as the molecular weight of the PEGs on the drug dissolution were investigated. PEG 4000 and PEG 6000 as well as PVP 40000 were used in weight ratio of 1:1, 1:3 and 1:5 w/w (drug: carrier).
This study includes the following steps:
1- Preparation of solid dispersions:
In this work, solid dispersions of rofecoxib with PEGs 4000 and PEG 6000 as well as PVP 40000 were prepared by coevapoartion and co-grinding techniques. Solid dispersions were prepared in 1:1, 1:3 and 1:5 w/w (drug: carrier).
2- Characterization of the prepared solid dispersions:
IR- spectroscopy, powder X-ray diffraction and DSC were employed for characterization of the prepared systems and elucidating some of their physicochemical properties and the nature of the interaction between the drug and the carriers in solid state. Also, dissolution was determined according to the dispersion amount method under sink conditions.
from the results of this work, it could be concluded that:
1- The co-grinding or coevaporate technique with PEG or PVP provide a promising way to increase the dissolution rate of the poorly water soluble drug rofecoxib.
2- Increasing the concentration of the polymer (PEG or PVP) led to higher release rate of the drug from the used different systems. It can be concluded that PVP 40000 was identified as optimum carrier to enhance the in-vitro dissolution rate of rofecoxib.
3- The maximum dissolution rate, which was obtained about 9- folds higher than drug alone was obtained with the co-ground mixtures at ratio of (1:5 w/w drug: PVP 40000).
4- The co-ground, coevaporates and physical mixtures with different carriers showed faster dissolution rate of the drug in the following order: PVP 40000 > PEG 6000 > PEG 4000. The observation of co-grinding systems by powder X-ray diffraction and differential scanning calorimetry indicated that rofecoxib exists as less crystalline form within the investigated carriers.
Chapter 3
Physicochemical characterization of rofecoxib with certain adsorbents
In this chapter, solvent deposited systems of rofecoxib with certain adsorbents were prepared. The investigated adsorbents were veegum, Florite ® and Avicel pH 101. Two techniques were used to prepare the adsorbates, solvent deposited method co-grinding method. Different drug to carrier ratios were prepared, (viz. 1:1, 1:3 and 1:5). Also, simple physical mixtures were prepared in the same ratios.
To fulfill this goal, the work in this chapter consisted of:
1- Preparation of loaded mixtures (adsorbates):
The loaded mixtures of rofecoxib with the used adsorbents were prepared by solvent deposition and co-grinding techniques. The loaded mixtures were made in the following drug: carrier weight ratios (1:1, 1:3 and 1:5).
2- Characterization of the prepared systems:
The physicochemical properties of the rofecoxib loaded systems as well as the physical mixtures of the drug with the used adsorbents were investigated by IR spectroscopy and DSC. Powder X-ray of some of the prepared systems was also done. The dissolution rate was measured according to the dispersed amount method under sink conditions.
The results obtained from this chapter indicated that:
1- DSC and X-ray diffraction studies indicate that crystalline rofecoxib was converted into amorphous state in the presence of Avicel pH 101 at ratio of (1:5 w/w drug: carrier) using co-grinding technique.
2 -A higher increase in rofecoxib dissolution rate could be achieved upon its adsorption on the used adsorbents.
3 -The enhancement in rofecoxib 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 Avicel as excipient has the highest dissolution rate for rofecoxib.
5- The dissolution of rofecoxib from the co-ground system was higher than solvent deposited system.
Chapter 4
Interaction of rofecoxib with β-CD and HP-β-cyclodextrin in the solid state
The aim of this chapter was to study the inclusion complex formation of rofecoxib with certain cyclodextrins, namely: β-cyclodextrin and HP-β-cyclodextrin. The interaction of rofecoxib with the used cyclodextrins was also investigated. Furthermore, the dissolution characteristics of the prepared inclusion complexes were studied.
To fulfill this goal, the work in this chapter consists of the following steps:
1-Preparation of solid inclusion complexes:
The solid complexes of rofecoxib with the investigated cyclodextrins were prepared by coevaporation and co-grinding techniques.
2- Characterization of the prepared inclusion complexes:
The physicochemical properties of rofecoxib solid inclusion complexes with cyclodextrins were investigated by IR spectroscopy, DSC and powder X-ray diffraction. Also, the dissolution rate of rofecoxib from the prepared inclusion complexes was determined according to the dispersed amount method under sink conditions.
The results obtained from this work showed that:
1- Rofecoxib can form inclusion complex with HP-β-cyclodextrin.
2- β-CD and HP-β-CD are useful in enhancing the dissolution rate of water insoluble drugs such as rofecoxib.
3- The dissolution characteristics of rofecoxib-HP-β-cyclodextrin systems were better than those of rofecoxib-β-cyclodextrin systems.
4- Co-grinding method is so far the best method for complexation, particularly if rofecoxib combined with HP-β-CD.
Part ΙΙ: Formulation and Evaluation of Rofecoxib in Different Dosage Forms
The work in this part was divided into three chapters:-
Chapter 1
Investigation of interaction between rofecoxib and certain capsule and tablet excipients
In this chapter, differential scanning calorimetry (DSC) and infrared spectroscopy (IR) were used to investigate the compatibility of rofecoxib with certain excipients namely; anhydrous lactose, Sta-rx starch 1500, cellactose, tabletose, magnesium stearate and stearic acid. This was achieved by comparing the DSC and IR curves of rofecoxib and each of the investigated excipients alone with curves of physical mixture (1:1 w/w) of rofecoxib and excipients. The results indicate that there is no evidence for interaction between rofecoxib and any of these excipients.
Chapter 2
Formulation and evaluation of rofecoxib capsules
The aim of this work was to prepare rofecoxib capsules containing different additives and excipients. The prepared rofecoxib capsules are evaluated and subjected to anti-inflammatory activity study using ANOVA test.
The work in this chapter includes the following:
1- Preparation of rofecoxib capsules containing rofecoxib alone or rofecoxib with directly compressible vehicles as diluents.
2- Preparation of rofecoxib capsules containing co-ground mixtures of rofecoxib with either PVP 40000 or Avicel pH 101 in 1:5 (w/w ratio).
3- Characterization of the prepared capsules by weight variation and drug content.
4- Dissolution studies for the prepared capsules. The method described in the USP XXV was used to study the dissolution characteristics of the prepared capsules.
5- The anti-inflammatory activity of rofecoxib in the selected formulae of the prepared capsules (formulae No. 6, 10), showing the highest in-vitro release rate was determined using paw edema method in rats.
The obtained results indicated that:
1- The prepared capsules comply with the USP XXV pharmacopoeial requirements.
2- Formulae No. 6, No. 10 contain co-ground mixture of rofecoxib with PVP 40000 or Avicel pH 101 and Sta-Rx starch as filler show higher release of the drug than the other prepared capsules.
3- There is a significant difference in the anti-inflammatory effect between the prepared rofecoxib capsules and the standard reference indomethacin.
Chapter 3
Formulation and evaluation of rofecoxib tablets
The aim of this work was to prepare rofecoxib tablets containing different additives and excipients. The prepared rofecoxib tablets are evaluated and compared with the commercial rofecoxib product.
The work in this chapter includes the following:
1- Preparation of rofecoxib tablets with different directly compressed vehicles by direct compression and wet granulation techniques.
2- Preparation of rofecoxib tablets containing co-ground mixtures of the drug with either PVP 40000 or Avicel pH 101 in a ratio of 1:5 (w/w) by direct compression techniques.
3- Characterization of the prepared tablets by weight variation, drug content, tablet diameter, thickness, disintegration time, friability and hardness.
4- Dissolution studies for the prepared tablets. The method described in the USP XXV was used to study the dissolution characteristics of the prepared tablets.
5- The anti-inflammatory activity of the prepared rofecoxib tablets (formula No. 3), showing the highest in-vitro release rate was determined using paw edema method in rats.
The obtained results indicated that:
1- The physicochemical properties of the prepared tablet comply with the USP XXV pharmacopoeial requirements.
2- Direct compression technique can be used successfully for the preparation of rofecoxib tablets, and has better dissolution characteristics for the drug over the tablets prepared by wet granulation technique.
3- Tablets containing co-ground mixture of rofecoxib with PVP 40000 or Avicel pH 101 and Sta-Rx starch as filler (formula 2, 3) gave the fastest dissolution rate among the other prepared tablets.
4- There is a significant difference in the anti-inflammatory effect between the prepared rofecoxib tablets and the commercially marketed rofecoxib tablets.
Chapter 4
Formulation and evaluation of rofecoxib suppositories
The aim of this work in this chapter was to formulate rofecoxib suppositories dosage forms. Suppositories were produced using both fatty, amphiphilic and water soluble suppository bases.
The work in this chapter includes the following:
1- Preparation of rofecoxib suppositories in fatty bases namely; cocoa butter and witepsol E75.
2- Preparation of rofecoxib suppositories in amphiphilic bases namely; suppocire AM and suppocire CM.
3- Preparation of rofecoxib suppositories in water soluble bases; mixtures of PEGs with different molecular weight and weight ratios.
4- Preparation of rofecoxib suppositories containing co-ground mixtures of the drug with either PVP 40000 or Avicel pH 101 in a ratio 1:5 w/w, using cocoa butter and witepsol E75 as suppository bases.
5- Preparation of rofecoxib suppositories containing non-ionic surfactants namely; Tween 80, Brij 58 or Myrj 52 in different concentrations, using cocoa butter and witepsol E75 as suppository bases.
6- The prepared suppositories were produced by fusion method, and evaluated with regard to drug content, uniformity of weight, disintegration time as well as the other physical parameters such as appearance, melting range and breaking test.
7-Dissolution studies of rofecoxib from the prepared suppositories were carried out using XXV dissolution procedures in phosphate buffer of pH 7.4.
8- The anti-inflammatory activity of rofecoxib in the prepared rofecoxib suppositories, according to maximum release rate of the drug, formula No. 2. (PEG 6000: PEG1000; 75:25%w/w), and formula No.29. (Cocoa butter containing 10% Tween 80 % w/w), was carried out on the caragenin induced paw edema in rats.
The obtained results revealed that;
1- The nature of the suppository bases and its nature affect rofecoxib release.
2- The tested suppository bases can be arranged according to their rofecoxib release as follows: PEGs > cocoa butter > witepsol E75 > suppocire AM > suppocire CM.
3- Suppository base composed of PEG1000: PEG6000 (25: 75 %w/w) provided the highest drug release (92%).
4- Incorporation of rofecoxib in the form of co-ground mixture improves the drug release from fatty suppository bases. The highest drug release was obtained from cocoa butter suppository base containing co-ground with PVP 40000.
5- The used non-ionic surfactants can be arranged according to the percentage of rofecoxib released as follows: Tween 80 > Brij 58 > Myrj 52.
6- The incorporation of 10%w/w tween 80 in witepsol E 75 and cocoa butter suppository bases led to increase the percentage of rofecoxib released (92.6 and 89.01% respectively), while (12.7 and 14.5% of the drug respectively, was released from the same suppository bases without Tween 80.
Part ΙΙΙ
Stability studies of rofecoxib in certain prepared pharmaceutical dosage forms
In this part, the following stability studies were carried out;
1- Effect of aging (shelf-storage):
The selected formulae of the prepared rofecoxib capsules and tablets were stored at room temperature. The selected formulae of the prepared rofecoxib suppositories were stored at room temperature and in a refrigerator. The drug content was determined after storage for 15, 30, 60, 90, 120, 150 and 180 days.
2- Accelerated stability testing:
The selected formulae of the prepared capsules and tablets were stored at 3 temperatures 30, 37 and 45ºC for six months and 75% relative humidity. The drug content was determined at the beginning of the test and after storage for 15, 30, 60, 90, 120, 150 and 180 days using HPLC and TLC techniques.
The results indicated that the selected formulae of the prepared rofecoxib dosage forms were stable under the previous conditions after six months.