الفهرس 
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Abstract
General Summary
Human mycotic diseases are considered as a life-threatening for patients undergoing cancer chemotherapy or having immunosuppressive diseases such as AIDS. In the recent years, the risk of human mycotic diseases has been extensively increased with progress increase in these types of patients. Although there is many of antifungal agents available, their efficacy may not be completely achieved in the treatment of human mycoses due to their limited water solubility and poor absorption in the gastro-intestinal tract.
Miconazole nitrate (MN) is a broad-spectrum antifungal agent suitable for the treatment of many mycotic infections as alternative drug to amphotericine B. MN is applied topically in the treatment of mycotic infections of the skin, hair and mucous membranes and also, it is given systemically either oral for the treatment of candidiasis or intravenously in the treatment of systemic infections. The drawback in the therapeutic application and efficacy of this drug from its topical or oral dosage forms is its very low water solubility with consequent poor absorption. Thus, the enhancement of aqueous solubility and dissolution properties of MN would be improved bioavailability properties of MN from its different formulations intended for oral use.
The work in this thesis was aimed to several objectives. The mainly objectives are solubilization of MN by using different types of cyclodextrins and water-soluble polymers & preparation and evaluation of effective oral dosage forms of MN.
In order to achieve these objectives, the work in this thesis was divided into 3 parts:-
Part ”1”
Solubilization Of Miconazole nitrate Using
Different Techniques
- This part included two chapters :
Chapter ”Ι”
Solubilization Of Miconazole nitrate Using
Cyclodextrins Complexation
The work in this chapter concerned with the thermodynamics properties of complexation of MN with two cyclodextrins (CDs); β-cyclo-dextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). The effect of CDs concentrations on the aqueous solubility of MN was studied. Co-evaporation, freeze-drying and physical mixing were employed for the preparation of MN inclusion systems with β-CD and HP-β-CD. IR spectroscopy, X-ray diffractometry and differential scanning calorimetry (DSC) were used for the study of interactions between MN and either β-CD or HP-β-CD in solid state. The effect of CDs complexation on the dissolution rate of MN was evaluated in different dissolution media.
** The results obtained showed that : 1- Phase solubility patterns of MN with both investigated CDs, β-CD and
HP-β-CD, showed AL Type diagrams and the aqueous solubility of MN
is increased as a function of CDs concentrations.
2- IR spectroscopy, X-ray diffractometry and DSC studies demonstrated
formation of partial complexes between MN and the investigated CDs.
3- The dissolution rate of MN from the different prepared solid systems
was better than that of MN untreated. Freeze-dried products of MN
with β-CD or HP-β-CD showed higher dissolution rate than that of
co-evaporates.
4- Increasing the wettability effect of dissolution medium leads to a high
increase in the dissolution rate of MN from all the different prepared
solid systems.
Chapter ”П”
Solubilization Of Miconazole nitrate Using
Water Soluble Carriers Dispersion
The work in the following chapter dealled with the interaction of MN with different water-soluble carriers. The phase solubility diagram of MN with the different water-soluble carriers used have been studied. Preparation of solid systems of MN with the water soluble carriers used was done by using different techniques such as physical mixing, co-evaporation, co-grinding and co-fusion. Evaluation of the interactions in the prepared MN-carriers solid systems was carried out by DSC, IR, and X-ray diffractometry methods. Studying of the effects of carriers types, MN-carriers ratios and the method of preparation on the dissolution rate profile of MN from its different prepared solid systems were carried out in different dissolution media
** The results obtained, showed that : - 1- The aqueous solubility of MN was increased as function of water-
soluble polymers concentrations. The solubilizition efficiency of the
water-soluble polymers investigated can be arranged as followed:
PEG 6000 > PEG 4000 > PVP 40000 > PVP 250000.
2- The results of IR spectroscopy, DSC and powder X-ray diffractometry
studies indicated that a sort of interaction found between MN and the
water-soluble polymers used. The extent of interaction is variable and
depends on both the type of water-soluble polymers and the method of
solid dispersion used. 3- The different prepared solid dispersion systems showed improvement
in the dissolution rate of MN. This improvement was increased as
the molecular weight and/or the weight fraction of the water-soluble
polymer increase.
4- MN solid systems prepared by co-fusion with EEG 6000, at drug-
polymer ratio I:2, showed the highest improvement in the dissolution
rate of MN.
5- Increasing the wettability effect of dissolution medium leads to a high
increase in the dissolution rate of MN from all the different prepared
solid systems.
Part ” II ”
Formulation And Evaluation of Miconazole
nitrate Oral Dosage Forms - This part included two chapters :
Chapter ”Ι”
Miconazole nitrate-Formulation Excipients
Compatibility Studies
The objective of the work in this chapter is aimed to detect and evaluate any possible incompatibility between MN and some commonly used direct compression excipients, as well as other functional excipients like as binder, disintegrator and lubricant. The investigations included anhydrous lactose, spray dried lactose, Avicel pH 101, STA-RX 1500, sorbitol, mannitol, emcompress, starch, Veegum, PVP 25000, magnesium stearate, and talc which represent different drug excipients categories. Physical mixtures of the drug with each of the different excipients investigated were prepared at a ratio of 1:1 w/w. The prepared samples were subjected to infrared spectroscopy (IR) and differential scanning calorimetery (DSC) studies in order to detect the possibility of any interactions between MN and each of the investigated excipients.
** The analysis of IR and DSC data displayed that: 1- MN is compatible with the investigated excipients namely Avicel
pH 101, STA-Rx 1500, anhydrous lactose, emcompress, PVP 25000,
starch, veegum, magnesium stearate and talc in their 1:1 w/w physical
mixtures.
2- The data gathered from IR spectroscopy and DSC studies revealed that
a sort of interaction found between MN and each of spray dried lactose,
sorbitol and mannitol when physically mixed in a ratio 1:1 w/w.
Chapter ”П”
Preparation And Evaluation of Oral Miconazole nitrate
Tablets And Capsules Dosage Forms
In this chapter, different formulae of MN tablets and capsules intended for oral use were prepared. The excipients used in the different formulations included Avicel pH 101, anhydrous lactose, STA-Rx 1500, emcompress, starch, veegum, PVP k25 and talc. The different tablets formulae prepared by direct compression method were subjected to number of the quality control tests involving uniformity of tablets weight and drug content, diameter and thickness uniformity, disintegration time, hardness and friability percent. On the other hand, the prepared capsules of different formulae were evaluated for their weight and drug content uniformity. The dissolution rate characteristics of MN from the different prepared tablet and capsule formulae were investigated in a dissolution medium of 0.1N Hcl containing 0.02% w/v of tween 80.
** The results obtained showed that:
1- The different prepared tablets formulae comply with the pharmacopoeial
requirements specific to each of the investigated tests. 2- Direct compression method produced tablets having good physical and
mechanical properties.
3- The different prepared capsule formulae are uniform in their weight
and drug contents and in an agreement with the pharmacopoeial limits.
4- The prepared capsules displayed better MN dissolution characteristics
than that of the tablets prepared by direct compression technique.
5- The tablets and capsules Formulae containing STA-Rx 1500 showed
good dissolution characteristics.
Part ”III”
Microbiology Studies On Miconazole nitrate
Oral Dosage Forms
The microbiological studies of the antimycotic activity of MN in its selected systems included the following studies :- 1- Studying the effects of cyclodextrins complexation and water-soluble
carriers dispersion on the antimycotic activity of MN aqueous solutions
used to construct the phase solubility diagrams of selected systems.
The study depended on inhibition zone measurements of MN against
C. albicans using a agar-cup diffusion method. 2- Evaluation of the antimycotic activity of co-melts of MN-PEG 6000,
at a drug : polymer ratio 1:2, used in the preparation of different MN
tablets and capsules. The evaluation study depended on comparison of
the inhibition zone diameter displayed by the minimal inhibitory
concentration (M.I.C.) of an intact MN with that produced by the
co-melt of MN-PEG 6000 systems containing a concentration of
MN equivalent to M.I.C. given by an intact MN.
** The results obtained showed that:
1- Both cyclodextrins complexation and water-soluble carriers dispersion improve the antimycotic activity of MN in their aqueous solutions. Moreover, it was found that as cyclodextrins or water-soluble carriers concentrations increased, inhibition zone measurements increased. 2- The co-melt of MN-PEG 6000 solid systems of a drug : polymer ratio 1:2, showing the highest solubility and dissolution results and containing MN concentration equivalent to M.I.C. of intact MN; have highly superior antimycotic activity than intact MN at the same concentration.