Mustafa Khamis

Targeted prodrugs in oral drug delivery: the modern molecular biopharmaceutical approach

Introduction: The molecular revolution greatly impacted the field of drug design and delivery in general, and the utilization of the prodrug approach in particular. The increasing understanding of membrane transporters has promoted a novel ‘targeted-prodrug approach utilizing carrier-mediated transport to increase intestinal permeability, as well as specific enzymes to promote activation to the parent drug. Areas covered: This article provides the reader with a concise overview of this modern approach to prodrug design. Targeting the oligopeptide transporter PEPT1 for absorption and the serine hydrolase valacyclovirase for activation will be presented as examples for the successful utilization of this approach. Additionally, the use of computational approaches, such as DFT and ab initio molecular orbital methods, in modern prodrugs design will be discussed. Expert opinion: Overall, in the coming years, more and more information will undoubtedly become available regarding intestinal transporters and potential enzymes that may be exploited for the targeted modern prodrug approach. Hence, the concept of prodrug design can no longer be viewed as merely a chemical modification to solve problems associated with parent compounds. Rather, it opens promising opportunities for precise and efficient drug delivery, as well as enhancement of treatment options and therapeutic efficacy.

Computer-assisted design for paracetamol masking bitter taste prodrugs

AbstractIt is believed that the bitter taste of paracetamol, a pain killer drug, is due to its hydroxyl group. Hence, it is expected that blocking the hydroxy group with a suitable linker could inhibit the interaction of paracetamol with its bitter taste receptor/s and hence masking its bitterness. Using DFT theoretical calculations we calculated proton transfers in ten different Kirby’s enzyme models, 1–10. The calculation results revealed that the reaction rate is linearly correlated with the distance between the two reactive centers (rGM) and the angle of the hydrogen bonding (α) formed along the reaction pathway. Based on these results three novel tasteless paracetamol prodrugs were designed and the thermodynamic and kinetic parameters for their proton transfers were calculated. Based on the experimental t1/2 (the time needed for the conversion of 50% of the reactants to products) and EM (effective molarity) values for processes 1–10 we have calculated the t1/2 values for the conversion of the three prodrugs to the parental drug, paracetamol. The calculated t1/2 values for ProD 1–3 were found to be 21.3 hours, 4.7 hours and 8 minutes, respectively. Thus, the rate by which the paracetamol prodrug undergoes cleavage to release paracetamol can be determined according to the nature of the linker of the prodrug (Kirby’s enzyme model 1–10). Further, blocking the phenolic hydroxyl group by a linker moiety is believed to hinder the paracetamol bitterness.n FigureConversion of bitterless paracetamol prodrug to bitter paracetamol via an electron transfer process

Removal of diclofenac potassium from wastewater using clay-micelle complex

The presence of an ionized carboxyl group in the widely used non-steroidal anti-inflammatory (NSAID) drug diclofenac potassium results in a high mobility of diclofenac and in its low sorption under conditions of slow sand filtration or subsoil passage. No diclofenac degradation was detected in pure water or sludge during one month. Tertiary treatments of wastewater indicated that the effective removal of diclofenac was by reverse osmosis, but the removal by activated carbon was less satisfactory. This study presents an efficient method for the removal of diclofenac from water by micelle–clay composites that are positively charged, have a large surface area and include large hydrophobic domains. Adsorption of diclofenac in dispersion by charcoal and a composite micelle (otadecyltrimethylammonium [ODTMA] and clay [montmorillonite]) was investigated. Analysis by the Langmuir isotherm revealed that charcoal had a somewhat larger number of adsorption sites than the composite, but the latter had a significantly larger binding affinity for diclofenac. Filtration experiments on a solution containing 300 ppm diclofenac demonstrated poor removal by activated carbon, in contrast to very efficient removal by micelle–clay filters. In the latter case the weight of removed diclofenac exceeded half that of ODTMA in the filter. Filtration of diclofenac solutions at concentrations of 8 and 80 ppb yielded almost complete removal at flow rates of 30 and 60 mL min−1. One kilogram of ODTMA in the micelle–clay filter has been estimated to remove more than 99% of diclofenac from a solution of 100 ppb during passage of more than 100 m3.

Prodrugs of Acyclovir – A Computational Approach

Density functional theory calculation results demonstrated that the efficiency of the acid‐catalyzed hydrolysis of Kirby’s acid amides 1–15 is strongly dependent on the substitution on the C–C double bond and the nature of the amide N‐alkyl group. Further, the results established that while in the gas phase the hydrolysis rate‐limiting step is the tetrahedral intermediate formation in polar solvents such as water, the rate‐limiting step could be either the formation or the collapse of the tetrahedral intermediate depending on the substitution on the C–C double bond and on the amide nitrogen substituent. Based on a linear correlation between the calculated and experimental effective molarities, the study on the systems reported herein could provide a good basis for designing prodrug systems that are less hydrophilic than their parental drugs and can be used, in different dosage forms, to release the parent drug in a controlled manner. For example, based on the calculated log effective molarities values, the predicted t1/2 (a time needed for 50% of the reactant to be hydrolyzed to products) for acyclovir prodrugs, ProD 1–4, was 29.2u2003h, 6097u2003days, 4.6u2003min, and 8.34u2003h, respectively. Hence, the rate by which acyclovir prodrug releases acyclovir can be determined according to the structural features of the linker (Kirby’s acid amide moiety).

Simultaneous HPLC analysis of pseudophedrine hydrochloride, codeine phosphate, and triprolidine hydrochloride in liquid dosage forms

An HPLC method using UV detection is proposed for the simultaneous determination of pseudophedrine hydrochloride, codeine phosphate, and triprolidine hydrochloride in liquid formulation. C18 column (250mmx4.0mm) is used as the stationary phase with a mixture of methanol:acetate buffer:acetonitrile (85:5:10, v/v) as the mobile phase. The factors affecting column separation of the analytes were studied. The calibration graphs exhibited a linear concentration range of 0.06-1.0mg/ml for pseudophedrine hydrochloride, 0.02-1.0mg/ml for codeine phosphate, and 0.0025-1.0mg/ml for triprolidine hydrochloride for a sample size of 5microl with correlation coefficients of better than 0.999 for all active ingredients studied. The results demonstrate that this method is reliable, reproducible and suitable for routine use with analysis time of less than 4min.

Prodrugs of fumarate esters for the treatment of psoriasis and multiple sclerosis—a computational approach

AbstractDensity functional theory (DFT) calculations at B3LYP/6-31xa0G (d,p) and B3LYP/6-311u2009+u2009G(d,p) levels for the substituted pyridine-catalyzed isomerization of monomethyl maleate revealed that isomerization proceeds via four steps, with the rate-limiting step being proton transfer from the substituted pyridinium ion to the C=C double bond in INT1. In addition, it was found that the isomerization rate (maleate to fumarate) is solvent dependent. Polar solvents, such as water, tend to accelerate the isomerization rate, whereas apolar solvents, such as chloroform, act to slow down the reaction. A linear correlation was obtained between the isomerization activation energy and the dielectric constant of the solvent. Furthermore, linearity was achieved when the activation energy was plotted against the pKa value of the catalyst. Substituted-pyridine derivatives with high pKa values were able to catalyze isomerization more efficiently than those with low pKa values. The calculated relative rates for prodrugs 1–6 were: 1 (406.7), 2 (7.6u2009×u2009106), 3 (1.0), 4 (20.7), 5 (13.5) and 6 (2.2u2009×u2009103). This result indicates that isomerizations of prodrugs 1 and 3–5 are expected to be slow and that of prodrugs 2 and 6 are expected to be relatively fast. Hence, prodrugs 2 and 3–5 have the potential to be utilized as prodrugs for the slow release of monomethylfumarate in the treatment of psoriasis and multiple sclerosis.n FigureSubstituted pyridine-catalyzed isomerization of monomethylmaleate (prodrug, cis-isomer) to monomethylfumerate (parental drug, trans-isomer)

Efficiency of advanced wastewater treatment plant system and laboratory-scale micelle-clay filtration for the removal of ibuprofen residues

The efficiency of Al-Quds Waste Water Treatment Plant (WWTP), which includes sequential elements as activated sludge, ultrafiltration, activated carbon column and reverse osmosis, to remove spiked ibuprofen, a non steroid anti inflammatory drug (NSAID), was investigated. Kinetic studies in pure water and in the activated sludge indicated that the drug was stable during one month of observation. Besides, the overall performance of the integrated plant showed complete removal of ibuprofen from wastewater. Activated carbon column, which was the last element in the sequence before the reverse osmosis system, yielded 95.7% removal of ibuprofen. Batch adsorptions of the drug by using either activated charcoal or composite micelle-clay system were determined at 25°C and well described by Langmuir isotherms. Octadecyltrimethylammonium (ODTMA) bromide and montmorillonite were used to prepare the micelle-clay adsorbent, for which the adsorption kinetics are much faster than activated charcoal. Results suggest that integrating clay-micelle complex filters within the existing WWTP may be promising in improving removal efficiency of the NSAID.

Efficiency of membrane technology, activated charcoal, and a micelle-clay complex for removal of the acidic pharmaceutical mefenamic acid

The efficiency of sequential advanced membrane technology wastewater treatment plant towards removal of a widely used non-steroid anti-inflammatory drug (NSAID) mefenamic acid was investigated. The sequential system included activated sludge, ultrafiltration by hollow fibre membranes with 100 kDa cutoff, and spiral wound membranes with 20 kDa cutoff, activated carbon and a reverse osmosis (RO) unit. The performance of the integrated plant showed complete removal of mefenamic acid from spiked wastewater samples. The activated carbon column was the most effective component in removing mefenamic acid with a removal efficiency of 97.2%. Stability study of mefenamic acid in pure water and Al-Quds activated sludge revealed that the anti-inflammatory drug was resistant to degradation in both environments. Batch adsorption of mefenamic acid by activated charcoal and a composite micelle (otadecyltrimethylammonium (ODTMA)–clay (montmorillonite) was determined at 25.0°C. Langmuir isotherm was found to fit the data with Qmax of 90.9 mg g−1 and 100.0 mg g−1 for activated carbon and micelle-clay complex, respectively. Filtration experiment by micelle-clay columns mixed with sand in the mg L−1 range revealed complete removal of the drug with much larger capacity than activated carbon column. The combined results demonstrated that an integration of a micelle-clay column in the plant system has a good potential to improve the removal efficiency of the plant towards NSAID drugs such as mefenamic acid.

Influence of N form (NO3− vs. NH4+) and salinity on tomato yield and fruit composition

The interaction of nitrogen form (NO3 −, vs. NH4 +) and salt stress on the yield and quality of tomato (Lycopersicum. esculentum L. cv. Daniella) fruit was investigated. Four combinations of NO3 −, and NH4 + (0%, 10%, 20% and 40% NH4 +) at 10 mM total nitrogen and two salt levels (0 and 40 mM of NaCl) were used for continuous fertigation. Fruit quality was evaluated based on °Brix, EC and the content of cations, anions, carboxylic acid and sugars. The nitrogen form did not affect the content of mineral nutrients (except K+), carbohydrates and pigments of the fruits substantially, indicating that its composition is under strict metabolic control. However, exposure to salt led to higher °Brix values, and increased contents of Na+, K+ and malate2− in the fruit, particularly at low NH4 + supply. NO3 − contents of the fruits were low irrespective of the N regime and salinity. In contrast, the Cl− content (molar basis) of fruits increased substantially upon exposure to salt, which reinforces the importance of Cl− as an inorganic osmoticum in tomato fruits.