| Abstract: |
Tuberculosis (TB) continues to be one of the deadliest diseases in the world. Our inability to control TB remains our greatest health failure. TB is caused by an acid-fast bacillus, Mycobacterium tuberculosis. TB may infect any part of body, but it is usually confined to the lungs due to the high-oxygen demand of the organism and route of transmission. Rifampicin and isoniazide are still the most important in the treatment of TB. The aim of this work is to formulate rifampicin and isoniazide in different pharmaceutical formulation as suppositories. This thesis is divided into two parts each consists of two chapters.Part I: Formulation and evaluation of rifampicin suppositories.Chapter I:Formulation and in-vitro evaluation of rifampicin in different suppository bases.1- In this chapter suppositories of one gram each containing 100 mg of rifampicin were prepared using different bases, namely Witepsol H15, Witepsol S58, Witepsol E76, PEG (two different formulations) and modified glycerogelatin.2- The suppositories were stored for six months at ambient room temperature, in a refrigerator and in an incubator at 37±1ºC.3- Quality control for both fresh and stored suppositories was investigated. It was found that several signs of aging have occurred during storage conditions. The most stable types were those formulated in fatty bases and stored in refrigerator.4- In-vitro release of rifampicin from fresh suppositories was studied in Sorensen’s phosphate buffer pH 7.4 at 37±0.5 ºC. The release of rifampicin from different suppository bases could be arranged as follows:PEG2> PEG1> MGG> Witepsol S58> Witepsol H15> Witepsol E76. It was obvious that the release rate was most rapid from the water soluble bases due to the hyDROPhobic nature of rifampicin.5- In-vitro release of stored rifampicin suppositories was studied in Sorensen’s phosphate buffer pH 7.4 at 37±0.5 ºC. The release of rifampicin from different suppository bases was affected greatly by the type of the base. It was obvious that Witepsol S58 base stored in refrigerator temperature for six months gave the most proper release.6- Effect of enhancers as SLS, Tween 80, Cetrimide and Brij 92 on release of rifampicin from different suppository bases was studied in Sorensen’s phosphate buffer pH 7.4 at 37±0.5 ºC. The release of rifampicin from different suppository bases was affected greatly by the types and concentrations of enhancer. It was obvious that the highest release of rifampicin was occurred from formulations containing 0.4% SLS in Witepsol S58, 0.8% Tween 80 in Witepsol S58, 1.2% Cetrimide in Witepsol S58 and 0.4% Brij 92 in PEG2.7- Release and permeation of rifampicin from isolated rectum of rabbit as natural membrane was studied.8- Analysis of data by linear regression indicated that, the release of rifampicin from different suppository bases followed mainly diffusion model.Chapter II:In-vivo evaluation of the selected suppository formulations of rifampicin.In this chapter, formulations that showed the highest release and permeation of rifampicin in-vitro were selected for in-vivo study. Those formulations were PEG2 with 0.4 % Brij 92 and Witepsol H15 with 1.2 % Brij 92. The following results were obtained:1- The drug plasma levels after rectal administration were compared to those obtained after oral administration of the same dose. After four hours Cmax of rifampicin was 23.91±2.74 μg/ml for oral suspension compared to 43.03±1.76 μg/ml and 28.90±1.37 μg/ml for PEG2 with 0.4% Brij 92 and Witepsol H15 with 1.2 % Brij 92 suppositories.2- The calculated AUC for oral suspension, PEG2 with 0.4 % Brij 92 and Witepsol H15 with 1.2 % Brij 92 suppositories were found to be 100.37±2.98, 208.19±6.87 and 148.86±7.96 μg.h/ml respectively.3- The comparative bioavailability of rifampicin from PEG2 with 0.4 % Brij 92 and Witepsol H15 with 1.2 % Brij 92 suppositories were 207.42 % and 148.31 % respectively, in relation to that after oral administration.Part II: Formulation and evaluation of isoniazide suppositories.Chapter I:Formulation and in-vitro evaluation of isoniazide in different suppository Bases.1- In this chapter suppositories of one gram each containing 50 mg of isoniazide were prepared using different bases, namely Witepsol H15, Witepsol W45, Witepsol E76, PEG (two different formulations) and modified glycerogelatin.2- The suppositories were stored for six months at ambient room temperature, in a refrigerator and in an incubator at 37±1ºC.3- Quality control for both fresh and stored suppositories was investigated. It was found that several signs of aging have occurred during storage conditions. The most stable types were those formulated with fatty bases, PEG1 and PEG2 and stored in refrigerator.4- In-vitro release of isoniazide from fresh suppositories was studied in Sorensen’s phosphate buffer pH 7.4 at 37±0.5 ºC. The release of rifampicin from different suppository bases could be arranged as follows:Witepsol H15> Witepsol W45> MGG> PEG1> PEG2> Witepsol E76. It was obvious that the release rate was most rapid from the Witepsol H15 due to the hyDROPhilic nature of isoniazide.5- In-vitro release of stored isoniazide suppositories was studied in Sorensen’s phosphate buffer pH 7.4 at 37±0.5 ºC. The release of isoniazide from different suppository bases was affected greatly by the type of the base. It was obvious that Witepsol W45 base stored in refrigerator temperature for six months gave the most proper release.6- Effect of enhancers SLS, Tween 80, Cetrimide and Brij 92 on release of isoniazide from different suppository bases was studied in Sorensen’s phosphate buffer pH 7.4 at 37±0.5 ºC. The release of isoniazide from different suppository bases was affected greatly by the type and concentrations of enhancer. It was obvious that the highest release of isoniazide was occurred with 0.8 % SLS in Witepsol H15, 1.2 % Tween 80 in Witepsol H15, 0.4 % Cetrimide in Witepsol H15 and 1.2% Brij 92 in Witepsol H15.7- Release and permeation of isoniazide through isolated rectum of rabbit as a model of natural membrane, was studied.8- Analysis of data by linear regression indicated that, the release of isoniazide from different suppository bases followed mainly diffusion model except in case of Witepsol E76, the release of isoniazide followed zero order kinetics.Chapter II:In-vivo evaluation of the selected suppository formulations of isoniazide.In this chapter, formulations that showed a highest release and permeation of isoniazide in-vitro were selected for in-vivo study. Those formulations were 0.8 % SLS in Witepsol H15 and 1.2 % Tween 80 in Witepsol H15 suppositories. The following results were obtained:1- The drug plasma levels after rectal administration were compared to those obtained after oral administration of the same dose. The Cmax of isoniazide was 21.93±1.77 μg/ml, 14.42±0.34 μg/ml and 6.44±0.15 μg/ml two hour after the administration for an oral solution, Witepsol H15 with 0.8% SLS and Witepsol H15 with 1.2% Tween 80 suppositories respectively.2- The calculated AUC for oral solution, Witepsol H15 with 0.8 % SLS and Witepsol H15 with 1.2 % Tween 80 suppositories were found to be 23.71±1.27, 17.52±0.28 and 12.28±1.21 μg.h/ml respectively.3- The comparative bioavailability of isoniazide from Witepsol H15 with 0.8 % SLS and Witepsol H15 with 1.2 % Tween 80 suppositories were 73.89 % and 51.79 % respectively, in relation to that after oral administration. Although the bioavailability of isoniazide is lower than that after oral administration yet its concentration in the blood exceeds the minimum effective concentration in case of both rectal formulations.Tuberculosis (TB) continues to be one of the deadliest diseases in the world. Our inability to control TB remains our greatest health failure. TB is caused by an acid-fast bacillus, Mycobacterium tuberculosis. TB may infect any part of body, but it is usually confined to the lungs due to the high-oxygen demand of the organism and route of transmission. Rifampicin and isoniazide are still the most important in the treatment of TB.
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