Metronidazole (MTZ), a drug used for the treatment of protozoal infections caused by protozoa and anaerobic microorganisms, was conjugated to linear or branched poly(ethylene glycol) of 5,000, 10,000 and 20,000 Da. An ester linkage between polymer and drug was used in the coupling to yield a polymeric prodrug. The modification allowed overcoming the known MTZ solubility problem leading us to obtain a bioconjugate more suitable for parental administration. The conjugates of various molecular weight polymers have been tested in vitro toward chemical degradation and digestive enzymes. It was found that molecular weight and shape of PEG is critical for the prodrugs stability. Good resistance in the stomach acidic media was found and a slow release of the drug in the large intestinal fluid may take place. In vivo studies carried out following i.v. or s.c. administration to mice revealed improved pharmacokinetics properties upon conjugation.
A series of new 1-[3-(4-arylpiperazinyl-1-yl)-2-(N-alkylcarbamoyloxy)propyl]-pyrrolidin-2-one derivatives (4a-12a) were synthesised and tested for their electrocardiographic, antiarrhythmic and antihypertensive activity, as well as for the alpha1- and alpha2-adrenoceptor binding affinities. Of the newly synthesised derivatives, 1-{2-(N-2-methylethylcarbamoiloxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl)]propyl}pyrrolidin-2-one dihydrochloride (10a) was the most active in prophylactic antiarrhythmic tests, its ED50 value equalling 2.7 mg kg(-1), and the therapeutic index being 75.2; moreover, compound 10a was also found to possess hypotensive activity. A preliminary molecular modelling study suggested that the selected alpha1-AR antagonist distances and angles between pharmacophoric features, estimated for the tested compounds, were in good agreement with the parameters evaluated for ligands.
In this research, the effect of mucoadhesive polymers such as hydroxyl propyl methyl cellulose (HPMC) with viscosity grade 60 and 500 mPas, sodium carboxy methyl cellulose (NaCMC) and carbopol 934 (Cp 934) alone or in combination with each other on the release profile of prednisolone was studied and mucoadhesion strength of these buccoadhesive formulations was evaluated. The results showed that the release of prednisolone from HPMC with viscosity grade 60 mPas and Cp 934 alone was fast and their mucoadhesion strengths was low. On the other hand, the release rates of prednisolone from the HPMC viscosity grade 500 mPas and NaCMC and mucoadhesion strengths were moderate and suitable. The results showed that with different blends of HPMC viscosity grade 500 mPas or NaCMC and Cp 934 with increasing in HPMC or NaCMC/Cp 934 ratio a remarkable decrease in the rate of drug release and an appreciable increase in the mucoadhesion strength was observed. Except from the formulations prepared with HPMC viscosity grade 60 and 500 mPas, other formulation had more fluctuations in release profiles and their kinetics of release were not fitted to zero order model.
Two sensitive spectrophotometric and atomic absorption spectrometric procedures have been developed for determination of cinchocaine hydrochloride (Cin.Cl) in pure form and in pharmaceutical formulation. The spectrophotometric method was based on formation of an insoluble colored ion-associate between the cited drug and tetrathiocyanatocobaltate (CoTC) or hexathiocyanatochromate (CrTC) which dissolved and extracted in an organic solvent. The optimal experimental conditions for quantitative extraction such as pH, concentration of the reagents and solvent were studied. Toluene and iso-butyl alcohol proved to be the most suitable solvents for quantitative extraction of Cin-CoTC and Cin-CrTC ion-associates with maximum absorbance at 620 and 555 nm, respectively. The optimum concentration ranges, molar absorptivities, Ringbom ranges and Sandell sensitivities were also evaluated. The atomic absorption spectrometric method is based on measuring of the excess cobalt or chromium in the aqueous solution, after precipitation of the drug, at 240.7 and 357.9 nm, respectively. Linear application ranges, characteristic masses and detection limits were 57.99-361.9, 50.40 and 4.22 microg ml(-1) of Cin.Cl, in case of CoTC, while 37.99-379.9, 18.94 and 0.81 microg ml(-1) in case of CrTC.
The determination of furosemide and spironolactone in a capsule formulation has been investigated using techniques such as Vierordt's method and derivative spectroscopy dA/dλ and d2A/dλ2 applying the zero-crossing technique following reported methods. In our hands, using standard mixtures, these methods gave unreliable results. We have therefore investigated the use of ratio spectra derivative spectrophotometry for this determination. The technique of ratio spectra derivative spectrophotometry was developed in 1990, and has recently been used for a number of analyses of co-formulated products. The method was applied to the analysis of standard mixtures of the two drugs and the combined contents of 20 capsules resulting in values (mean ± standard deviation) of 102.1 ± 1.9% and 101.4 ± 4.0% of the stated content for furosemide and spironolactone, respectively. Similarly, the analysis of individual capsules resulted in values of 101.5 ± 1.6% and 102.2 ± 1.4% of the stated content for furosemide and spironolactone, respectively.
