Maha A. Hassan

Synthesis, chemical and enzymatic hydrolysis, and bioavailability evaluation in rabbits of metronidazole amino acid ester prodrugs with enhanced water solubility

A series of amino acid esters (3a‐e) have been synthesized and evaluated as potential prodrugs of metronidazole with the aim of improving aqueous solubility and therapeutic efficacy. The aqueous solubility and the lipophilicity (expressed as the log P value) of metronidazole and its esters were investigated. In general the prodrugs revealed enhanced water solubility compared with metronidazole. N,N‐diethylglycinate hydrochloride (3a) and 4‐ethylpiperazinoacetate (3e) derivatives displayed higher aqueous solubility, which exceeded that of the parent drug by factors of approximately 140 and 100, respectively. All the esters revealed lower log P values than metronidazole except for the 4‐phenylpiperazinoacetate derivative (3f), which was 6.5‐times more lipophilic than metronidazole. The hydrolysis kinetics of the esters were studied in aqueous phosphate buffer (pH 7.4) and 80% human plasma at 37°C. In all cases the hydrolysis followed pseudo‐first‐order kinetics and resulted in a quantitative reversion to metronidazole as evidenced by HPLC analysis. The prodrugs exhibited adequate chemical stability (half‐life, t12, 4–16 h) in aqueous phosphate solution of pH 7.4. In 80% human plasma they were hydrolysed within a few minutes to metronidazole. The esters 3d (methylpiperazinoacetate derivative) and 3f were exempted since their t12 values were approximately 2.5 and 8.5 h, respectively. A comparative pH‐rate profile study of N,N‐diethylglycinate hydrochloride (3a) and 4‐ethylpiperazinoacetate (3e) derivatives in aqueous buffer solution over the pH range 2.2–10 was investigated. The results indicated that 3a showed marked stability at pH 2–6 followed by accelerated hydrolysis at pH 7.4. The basic ester 3e was found to be less stable at lower pH values but exhibited comparative stability at physiological pH. Moreover, in‐vivo experiments in rabbits revealed a higher metronidazole plasma level with sustained release characteristics within the prodrug‐treated animals (10‐ and 2.5‐fold) as compared with the parent drug‐treated group. In conclusion, the designed amino acid esters 3a and 3c‐e might be considered as good candidates for water‐soluble prodrug forms of metronidazole.

Improvement of availability of allopurinol from pharmaceutical dosage forms I : suppositories

Solid dispersion and crystallization of a very slightly water-soluble drug, allopurinol, were prepared using urea, sodium salicylate and beta-cyclodextrin (beta-CD) as carriers. The spectroscopic infra-red (IR), differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD) data indicate a role of these carriers in decreasing the crystallinity of allopurinol and complexing abilities. Solid dispersion and crystallization of the drug with these carriers were used in suppository formulations to investigate their role in enhancement of drug release through the membrane barrier. The bases used included Suppocire AM and the mixture of polyethylene glycols (PEGs). The release rates of allopurinol from lipophilic and hydrophilic suppository bases were examined and compared with those obtained for their inclusion compounds incorporated in the same bases. The prepared suppositories were evaluated for in-vitro drug release, when fresh and on storage. The release of pure allopurinol from the lipophilic base was remarkably higher than that from the hydrophilic one. The release of allopurinol from lipophilic as well as hydrophilic bases was significantly enhanced by crystallization of the drug from 5% w/v of sodium salicylate. Allopurinol crystallized from sodium salicylate, showed enhanced release reaching about 100% in 1 h from the Suppocire AM base. The obtained data from these experiments proved the superiority of the PEG formulations containing coevaporates of the drug to sodium salicylate, ratio 1:1, or of the drug to beta-CD, ratio 1:2; T(90%),12 and 36 min, respectively. A significant decrease of uric acid excretion in rabbits was observed after rectal administration of suppositories containing allopurinol crystallized from sodium salicylate.

A long acting ophthalmic gel formulations of atenolol.

The main aim of pharmacotherapeutics, is the attainment of an effective drug concentration at the intended site of action for a sufficient period of time to elicit the response. In this study a trial was made to formulate atenolol, which is a beta-adrenergic blocker in a topical ophthalmic gel. Two polymers were used in this study, carboxymethylcellulose and sodium alginate in different concentrations. Atenolol was used in concentrations 0.5, 1, and 1.5% w/v. The in vitro release study was carried out. The results showed that the release rate of atenolol from gel preparations decreased as an inverse function of polymer concentration, while the release rate of the drug increased as the initial concentration increased. The data of drug release from the two polymers in different concentrations was plotted against the square root of time, and the diffusion coefficients (D), were calculated from the slope of the equation. Intra-ocular pressure (IOP) measurements of the rabbits eye treated with 1% w/v atenolol solution, and 1% w/v atenolol in two gel formulations with different concentrations of the polymer were determined. The two gel formulations showed that these polymers extended the duration of pressure reducing effect to 8 hr, when compared with atenolol solution. Area above the curve (AAC), maximum response, maximum time of response (tmax), and the duration of action were calculated. The overall results of this study indicated that the gel formulations of atenolol could be used for the development of a long-acting ophthalmic formulation.

Design and evaluation of a floating ranitidine tablet as a drug delivery system for oral application

In recent years, scientific and technological advances have been made in the research and development of rate-controlled oral drug delivery systems by overcoming physiological obstacles, such as short gastric residence times (GRT), and unpredictable gastric emptying times. Several approaches are currently utilized in the prolongation of GRT, including floating drug delivery systems (FDDs). A drug delivery system for the water-soluble H 2 -receptor antagonist drug, ranitidine hydrochloride, was developed. The floating and controlled-release properties of tablets containing ranitidine HCl, hydroxypropylmethylcellulose (HPMC), and different additives were examined. The study shows that tablet composition and mechanical strength have the greatest influence on floating properties and drug release. Sodium bicarbonate was used as gas-generating agent which enhances tablet flotation. The time taken for tablets to emerge on the water surface (floating lag time), or buoyant time, and the time during which the tablets constantly float on the water surface (duration of floating) were evaluated in a dissolution vessel. The results indicated that buoyancy is strong enough for whole tablets to travel up to the surface and remain on the surface for as long as 24 h. In vitro dissolution was carried out in simulated gastric fluid (enzyme-free) at 37 ± 0.5°C as per USP 22. Drug release from the tablets was sufficiently sustained (12 h) compared to conventional tablets. Drug release best fit both the Higuchi and Peppas models. Moreover, the effect of tablet hardness and stirring rate on the release kinetics was examined. The floating tablets were compared with conventional tablets in fasted rabbits at 150 mg equivalent dose of ranitidine HCl. The pharmacokinetic parameters, maximum plasma concentration (C max ), the time to reach maximum plasma concentration (T max ), and the area under plasma concentration curve (AUC) for 0-12 h were calculated. The relative bioavailability of the floating tablets in relation to the conventional tablets was also calculated.

Pharmacokinetics and analgesic effect of ketorolac floating delivery system

Abstract Objectives: The efficacy of ketorolac tromethamine (KT) floating alginate beads as a drug delivery system for better control of KT release was investigated. The formulation with the highest drug loading, entrapment efficiency, swelling, buoyancy, and in vitro release would be selected for further in vivo analgesic effect in the mice and pharmacokinetics study in rats compared to the tablet dosage form. Methods: KT floating alginate beads were prepared by extrusion congealing technique. KT in plasma samples was analyzed using a UPLC MS/MS assay. Results: The percentage yield, drug loading and encapsulation efficiency were increased proportionally with the hydroxypropylmethyl cellulose (HPMC) polymer amount in the KT floating beads. A reverse relationship was observed between HPMC amount in the beads and the KT in vitro release rate. F3-floating beads were selected, due to its better in vitro results (continued floating for >8 h) than others. A longer analgesic effect was observed for F3 in fed mice as compared to the tablets. After F3 administration to rats, the Cmax (2.2 ± 0.3 µg/ml) was achieved at ∼2 h and the decline in KT concentration was slower. F3 showed a significant increase in the AUC (1.89 fold) in rats as compared to the tablets. Conclusion: KT was successfully formulated as floating beads with prolonged in vitro release extended to a better in vivo characteristic with higher bioavailability in rats. KT in floating beads shows a superior analgesic effect over tablets, especially in fed mice.

Nanosuspension: An Emerging Trend for Bioavailability Enhancement of Etodolac

Etodolac (ET) (poorly soluble drug) nanosuspensions were prepared by both pH shift method and antisolvent techniques in order to increase its dissolution rate. Various stabilizers were used, namely, Tween 20 and 80, HPMC, PVP K44, PVA, PEG 400, NaCMC, and β-cyclodextrin. The prepared nanosuspensions were characterized by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscope (SEM) and evaluated for their particle size, particle size distribution, and in vitro dissolution rate. In general, it was found that the antisolvent method for the preparation of ET nanosuspensions reduced the drug particle size to a higher extent compared to the pH shift method. The dissolution rate of ET in distilled water was markedly enhanced in the nanosized system, as more than 65% of drug dissolved in 10 min from all the nanosuspension formulations except F5 (stabilized with PVP K44) and F8 (stabilized with Tween 20), as compared to less than 20% of crude drug. Nanoparticles prepared by antisolvent method using Tween 80 as a stabilizer were selected for further in vivo study. The in vivo test demonstrated that nanoparticles of ET were well absorbed with a percentage drug absorption value 2.7 times more than that of micrometric size of crude ET.

Formulation and evaluation of quercetin in certain dermatological preparations

Quercetin is a bioactive flavonoid widely used as a health supplement. Quercetin was formulated in different dermatological preparations as gel, emulgel and microemulsion gel. Different gel bases were used for the preparation of quercetin gel as sodium carboxymethylcellulose (NaCMC), Carbopol 934 and Pluronic F-127. Also different formulae of both emulgel and microemulsion gel were prepared using different gel bases and surfactants. These formulations were evaluated for their drug content, in vitro release of the drug from cellophane membrane and skin permeability through hairless mouse skin. The antibacterial activity against Gram positive and Gram negative organisms was also studied. The results of the drug release indicated that the highest release was obtained from the microemulsion gel followed by gel and emulgel, respectively. The same results were obtained for drug penetration through hairless mouse skin. Analysis of the data according to different kinetic mechanisms revealed that the release pattern of the drug from the tested bases followed zero-order and the Higuchi diffusion model. Results also indicated an excellent activity against all tested organisms and the inhibition zone was dependent on the type of formulation used.