Development of a New Bioequivalent Omeprazole Product.

Background and Objectives: The enteric form of omeprazole is one of the most commonly prescribed medications. Similarly to Europe, Kazakhstan relies on the localization of pharmaceutical drug production as one of its primary strategies to ensure that its population has access to affordable and good-quality medicines. This study comprehensively describes the technologically available development of bioequivalent delayed-release omeprazole. Materials and Methods: Various regimes and technological parameters were tested on laboratory- and production-scale equipment to establish a technical process where a functional and gastro-protective layer is essential. According to the ICH guidance on stability testing and Kazakhstan local rules, stability studies were conducted under conditions appropriate for climate zone II. The comparison of the rate and extent of absorption with subsequent assessment of the bioequivalence of the generic and reference drugs after a single dose of each drug at a dose of 40 mg was performed. Results: The quantitative and qualitative composition and technology of producing a new generic enteric form of omeprazole in capsules were developed and implemented at the manufacturing site of solid forms. Dissolution profiles in media with pH 1.2 and 6.8 were proven. During the accelerated six-month and long-term twelve-month studies, the developed formulation in both packaging materials at each control point passed the average weight and mass uniformity test, dissolution test, acid-resistance stage test, buffer stage test, impurity assay, and microbiological purity test and met all the specification criteria. A bioequivalence study in 24 healthy volunteers compared against the innovative drug showed the bioequivalency of the new generic system. The obtained values from the test and reference products were 1321 ± 249.0 ng/mL and 1274 ± 233 ng/mL for Cmax, 4521 ± 841 ng·h /mL and 4371 ± 695 ng·h /mL for AUC0-t, and 4636 ± 814 ng·h /mL and 4502 ± 640 ng·h /mL for AUC0-∞. Conclusions: Using affordable technologies, a bioequivalent generic delayed-release formulation of 20 and 40 mg omeprazole has been developed.

Stability of Omeprazole Extemporaneous Oral Solution in Chopin Base.

Omeprazole is the progenitor of proton pump inhibitors. It is used for the treatment of ulcer and gastroesophageal reflux in dosages ranging from 10 mg/day to 40 mg/day, calibrated according to the patient's age and body weight. In this study, the authors provide a report on the preparation of an extemporaneous liquid formulation of omeprazole using fast oral solution Chopin a hydroxypropyl-?-cyclodextrin liquid base (pH 8 to 9) that is able to solubilize the drug. A solubility study of the drug in the liquid vehicle and a physical-chemical stability study of the 1-mg/mL formulation at 4°C and 25°C were performed. Analyses were carried out by using a high-pressure liquid chromatographic analytical method. Results showed that the intrinsic solubility of the drug in Chopin base was 5.33 mg/mL ± 0.23 mg/mL at 25°C and that omeprazole was chemically stable when the formulation was stored at 4°C over a period of 3 months, while its shelf life at 25°C was only 9 days. This study has demonstrated that the resulting liquid formulation is suitable for all patients, in particular children or adults who are unable to take other pharmaceutical dosage forms, which overcomes the limitations of the medicines currently available on the market.

Effect of Elevated pH on the Commercial Enteric-Coated Omeprazole Pellets Resistance: Patent Review and Multisource Generics Comparison.

Omeprazole is a widely used over-the-counter (20 mg) proton pump inhibitor, usually supplied as oral enteric-coated pellets intended to release at pH 5.5 and higher; however, it is sensitive to acidic pH. The likelihood of elevated gastric pH in practice is very high for patients; thus, the aim of this study was to investigate the effect of elevated pH on the performance of commercial omeprazole pellets. Commercial enteric-coated delayed-release pellets were tested with water uptake-weight loss (WU-WL) test at pH range between 1.2 and 4.5 in addition to "gastric" (pH 1.2 or 4.5) and "intestinal" (pH 7.4) phase dissolution tests. The range of physical characteristics of pellets was determined with a single pellet size and sedimentation time measurement, followed by the application of modified Stokes' Law equation. The coefficient of variation of pellet size and density, and volume-density determination coefficient (R2) as descriptors of coating thickness and microstructure variability, degree of ionisation of enteric polymers, aqueous solubility and molecular weight of plasticisers have been found useful to explain commercial delayed-release pellets behaviour during WU-WL and dissolution test. Investigated commercial delayed-release pellets demonstrated pH-dependent WU-WL results. "Gastric phase" dissolution testing of pellets at pH 4.5 showed the highest omeprazole degradation (48.1%) for Nosch Labs, intermediate values of dose loss (23.4% and 17.1%) for Teva and UQUIFA delayed-release pellets, respectively. Lab Liconsa pellets have been found as the least susceptible (3.2% of dose loss). Additionally, "gastric phase" dissolution test at pH 4.5 significantly influenced omeprazole release during the "intestinal phase". The risk of inadequate therapy associated with intake of investigated enteric-coated delayed-release pellets at elevated gastric pH has been found as minimal for Lab Liconsa and has increased from UQUIFA and Teva to Nosh Labs pellets.

Interface-Mediated Mechanism of Action-The Root of the Cytoprotective Effect of Immediate-Release Omeprazole.

Omeprazole is usually administered under an enteric coating. However, there is a Food and Drug Administration-approved strategy that enables its release in the stomach. When locally absorbed, omeprazole shows a higher efficacy and a cytoprotective effect, whose mechanism was still unknown. Therefore, we aimed to assess the effect of the absorption route on the gastric mucosa. 2D and 3D models of dipalmitoylphosphatidylcholine (DPPC) at different pH values (5.0 and 7.4) were used to mimic different absorption conditions. Several experimental techniques, namely, fluorescence studies, X-ray scattering methodologies, and Langmuir monolayers coupled with microscopy, X-ray diffraction, and infrared spectroscopy techniques, were combined with molecular dynamics simulations. The results showed that electrostatic and hydrophobic interactions between omeprazole and DPPC rearranged the conformational state of DPPC. Omeprazole intercalates among DPPC molecules, promoting domain formation with untilted phospholipids. Hence, the local release of omeprazole enables its action as a phospholipid-like drug, which can reinforce and protect the gastric mucosa.

Esomeprazole inhibits the lysosomal cysteine protease legumain to prevent cancer metastasis.

Legumain is a newly discovered lysosomal cysteine protease that can cleave asparagine bonds and plays crucial roles in regulating immunity and cancer metastasis. Legumain has been shown to be highly expressed in various solid tumors, within the tumor microenvironment and its levels are directly related to tumor metastasis and poor prognosis. Therefore, legumain presents as a potential cancer therapeutic drug target. In this study, we have identified esomeprazole and omeprazole as novel legumain small molecule inhibitors by screening an FDA approved-drug library. These compounds inhibited enzyme activity of both recombinant and endogenous legumain proteins with esomeprazole displaying the highest inhibitory effect. Further molecular docking analysis also indicated that esomeprazole, the S- form of omeprazole had the most stable binding to legumain protein compared to R-omeprazole. Transwell assay data showed that esomeprazole and omeprazole reduced MDA-MB-231 breast cancer cell invasion without effecting cell viability. Moreover, an in vivo orthotopic transplantation nude mouse model study showed that esomeprazole reduced lung metastasis of MDA-MB-231 breast cancer cells. These results indicated that esomeprazole has the exciting potential to be used in anti-cancer therapy by preventing cancer metastasis via the inhibition of legumain enzyme activity. Graphical abstract.

Spectroscopic study of in situ-formed metallocomplexes of proton pump inhibitors in water.

Proton pump inhibitors, such as omeprazole, pantoprazole and lansoprazole, are an important group of clinically used drugs. Generally, they are considered safe without direct toxicity. Nevertheless, their long-term use can be associated with a higher risk of some serious pathological states (e.g. amnesia and oncological and neurodegenerative states). It is well known that dysregulation of the metabolism of transition metals (especially iron ions) plays a significant role in these pathological states and that the above drugs can form complexes with metal ions. However, to the best of our knowledge, this phenomenon has not yet been described in water systems. Therefore, we studied the interaction between these drugs and transition metal ions in the surrounding water environment (water/DMSO, 99:1, v/v) by absorption spectroscopy. In the presence of Fe(III), a strong redshift was observed, and more importantly, the affinities of the drugs (represented as binding constants) were strong enough, especially in the case of omeprazole, so that the formation of a metallocomplex cannot be excluded during the explanation of their side effects.

Binding of omeprazole to protein targets identified by monoclonal antibodies.

Omeprazole is the most commonly used proton pump inhibitor (PPI), a class of medications whose therapeutic mechanism of action involves formation of a disulfide linkage to cysteine residues in the H+/K+ ATPase pump on gastric secretory cells. Covalent linkage between the sole sulfur group of omeprazole and selected cysteine residues of the pump protein results in inhibition of acid secretion in the stomach, an effect that ameliorates gastroesophageal reflux and peptic ulcer disease. PPIs, though useful for specific conditions when used transiently, are associated with diverse untoward effects when used long term. The mechanisms underlying these potential off-target effects remain unclear. PPIs may, in fact, interact with non-canonical target proteins (non-pump molecules) resulting in unexpected pathophysiological effects, but few studies describe off-target PPI binding. Here, we describe successful cloning of monoclonal antibodies against protein-bound omeprazole. We developed and used monoclonal antibodies to characterize the protein target range of omeprazole, stability of omeprazole-bound proteins, and the involvement of cysteines in binding of omeprazole to targets. We demonstrate that a wide range of diverse proteins are targeted by omeprazole. Protein complexes, detected by Western blotting, are resistant to heat, detergents, and reducing agents. Reaction of omeprazole occurs with cysteine-free proteins, is not fully inhibited by cysteine alkylation, occurs at neutral pH, and induces protein multimerization. At least two other clinically used PPIs, rabeprazole and tenatoprazole, are capable of binding to proteins in a similar fashion. We conclude that omeprazole binds to multiple proteins and is capable of forming highly stable complexes that are not dependent on disulfide linkages between the drug and protein targets. Further studies made possible by these antibodies may shed light on whether PPI-protein complexes underlie off-target untoward effects of chronic PPI use.

Enhanced Antigiardial Effect of Omeprazole Analog Benzimidazole Compounds.

Giardiasis is a diarrheal disease that is highly prevalent in developing countries. Several drugs are available for the treatment of this parasitosis; however, failures in drug therapy are common, and have adverse effects and increased resistance of the parasite to the drug, generating the need to find new alternative treatments. In this study, we synthesized a series of 2-mercaptobenzimidazoles that are derivatives of omeprazole, and the chemical structures were confirmed through mass, 1H NMR, and 13C NMR techniques. The in vitro efficacy compounds against Giardia, as well as its effect on the inhibition of triosephosphate isomerase (TPI) recombinant, were investigated, the inactivation assays were performed with 0.2 mg/mL of the enzyme incubating for 2 h at 37 °C in TE buffer, pH 7.4 with increasing concentrations of the compounds. Among the target compounds, H-BZM2, O2N-BZM7, and O2N-BZM9 had greater antigiardial activity (IC50: 36, 14, and 17 µM on trophozoites), and inhibited the TPI enzyme (K2: 2.3, 3.2, and 2.8 M-1 s-1) respectively, loading alterations on the secondary structure, global stability, and tertiary structure of the TPI protein. Finally, we demonstrated that it had low toxicity on Caco-2 and HT29 cells. This finding makes it an attractive potential starting point for new antigiardial drugs.

A Drug Content, Stability Analysis, and Qualitative Assessment of Pharmacists' Opinions of Two Exemplar Extemporaneous Formulations.

Despite a decline in the number of active pharmaceutical ingredients prepared extemporaneously using proprietary products, there remains a need for such products in the community (for example, liquid medicines for paediatrics which may be otherwise commercially unavailable). A lack of experience and quality assurance systems may have diminished pharmacist's confidence in the extemporaneous preparation process; therefore, pharmacists were asked to prepare two proprietary products, omeprazole and amlodipine. The resulting products were characterised in terms of variability in drug quantity, stability, particle size and antimicrobial properties. Furthermore, a self-administered questionnaire was used to assess 10 pharmacists' opinions on the perceived complexity of the extemporaneous compounding process and their overall confidence in the final extemporaneously compounded products. Drug content studies revealed that 88.5% and 98.0% of the desired drug content was obtained for omeprazole and amlodipine, respectively. Antimicrobial properties were maintained for both drugs, however variability in particle size, particularly for amlodipine, was evident between formulations. While pharmacists who partook in the study had some or high confidence in the final products, they reported difficulty formulating the suspensions. Findings from this study provide insight into pharmacists' views on two extemporaneously prepared products and highlight the variability obtained in preparations prepared by different pharmacists.

Development and Stability Study of an Omeprazole Suppository for Infants.

BACKGROUND AND OBJECTIVE: Omeprazole is a proton pump inhibitor (PPI) that is used in acid suppression therapy in infants. In this study we aimed to develop a pediatric omeprazole suppository, with good physical and chemical stability, suitable for pharmaceutical batch production. METHODS: The composition of the suppository consisted of omeprazole, witepsol H15 and arginine (L) base. To achieve evenly distributed omeprazole suspension suppositories, the temperature, stirring rate, and arginine (L) base amount were varied. A previously validated quantitative high-performance liquid chromatography-ultraviolet method was modified and a long-term stability study was performed for one year. RESULTS: Evenly distributed omeprazole suspension suppositories were obtained by adding 100 mg arginine (L) base and pouring at a temperature of 34.7 °C and a stirring speed of 200 rpm. The long-term stability study showed no signs of discoloration and a stable omeprazole content between 90 and 110% over 1 year if stored in the dark at room temperature. CONCLUSION: We developed a pediatric omeprazole suppository. This formulation may provide a good alternative to manipulated commercial or extemporaneously compounded omeprazole oral formulations for infants. Clinical studies are needed to establish efficacy and safety in this young population.

The Effect of Manufacturer on the Compounding of Omeprazole Suspensions and Their Stability Assessment.

In New Zealand, there are no liquid formulations of omeprazole commercially available, therefore suspensions must be extemporaneously compounded from solid dosage forms for patients with swallowing difficulties. The funding for solid dosage forms of omeprazole changes frequently, often every one to two years, without consideration of the impact this may have when extemporaneously compounded liquid dosage forms are required. This study examined suspensions compounded from various solid dosage forms of omeprazole with the purpose of identifying suitable quality formulations and evaluating their chemical and physical stability. Six different solid dosage forms of omeprazole that are available in New Zealand, including capsules, tablets, and powder, were used to prepare 2-mg/mL suspensions in 8.4% w/v sodium bicarbonate solution. The suspensions were then assessed visually for quality and by quantifying sedimentation rate over 120 minutes. Two products, stored in amber bottles at either 4°C or 25°C, demonstrated acceptable quality over a 30-day period whilst monitoring physical and chemical stability on day 0, 7, 14, 20, and 30. Four of the formulated suspensions were deemed to be of poor quality due to either a lack of uniformity or rapid sedimentation, attributes that could lead to inaccurate dosing. Acceptable quality suspensions were prepared from Losec and Dr. Reddy's brands of omeprazole 20-mg capsules. For both brands, a change in color was observed after 20 days and 7 days when stored at 4°C and 25°C, respectively. Chemical stability was determined using a stability-indicating high-performance liquid chromatographic method, with >90% of the active remaining for 30 days when kept at 4°C, and 20 days when stored at 25°C. Not all brands are suitable for extemporaneously compounding omeprazole suspensions. Losec and Dr. Reddy's brands of capsules were suitable to prepare quality omeprazole suspensions. Omeprazole suspensions compounded from these products are stable for 20 days if stored at 4°C and protected from light.

Calycosin Influences the Metabolism of Five Probe Drugs in Rats.

BACKGROUND: Calycosin (CAL), a type of O-methylated isoflavone extracted from the herb Astralagusmembranaceus (AM), is a bioactive chemical with antioxidative, antiphlogistic and antineoplastic activities commonly used in traditional alternative Chinese medicine. AM has been shown to confer health benefits as an adjuvant in the treatment of a variety of diseases. AIM: The main objective of this study was to determine whether CAL influences the cytochrome P450 (CYP450) system involved in drug metabolism. METHODS: Midazolam, tolbutamide, omeprazole, metoprolol and phenacetin were selected as probe drugs. Rats were randomly divided into three groups, specifically, 5% Carboxymethyl cellulose (CMC) for 8 days (Control), 5% CMC for 7 days + CAL for 1 day (single CAL) and CAL for 8 days (conc CAL), and metabolism of the five probe drugs evaluated using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: No significant differences were observed for omeprazole and midazolam, compared to the control group. T max and t1/2 values of only one probe drug, phenacetin, in the conc CAL group were significantly different from those of the control group (T max h: 0.50±0.00 vs 0.23±0.15; control vs conc CAL). C max of tolbutamide was decreased about two-fold in the conc CAL treatment group (conc vs control: 219.48 vs 429.56, P<0.001). CONCLUSION: Calycosin inhibits the catalytic activities of CYP1A2, CYP2D6 and CYP2C9. Accordingly, we recommend caution, particularly when combining CAL as a modality therapy with drugs metabolized by CYP1A2, CYP2D6 and CYP2C9, to reduce the potential risks of drug accumulation or ineffective treatment.

Solid self-nanoemulsifying drug delivery system filled in enteric coated hard gelatin capsules for enhancing solubility and stability of omeprazole hydrochloride.

Omeprazole has poor water solubility, low stability in acidic solutions, and is subject to first pass metabolism resulting in low bioavailability. The objective was to enhance the dissolution and stability by preparing a solid-self nanoemulsifying drug delivery system (SNEDDS) and filling it in enteric coated HGCs. Drug solubility in many oils, surfactants, and cosurfactants was studied. Different SNEDDS were prepared and ternary phase diagrams were constructed. The optimum SNEDDS was evaluated. It was converted into solid by adsorption onto Neusilin® US2, and evaluated. Emulsions formed using Capryol 90, Cremophor RH 40, and ethanol formed spontaneously and were clear. Droplet size was 19.11 ± 3.11 nm, PDI was 0.18 ± 0.05, and zeta potential was -3.9 ± 1.56 mV. Non-medicated SNEDDS was thermodynamically stable. Cloud point was 88 ± 2 °C. Encapsulation efficiency and drug loading of solid-SNEDDS were 98.56 ± 0.44 and 1.29 ± 0.01%, respectively. Flow properties were much enhanced. Crystalline drug was adsorbed/precipitated onto Neusilin® US2 in amorphous form. Dissolution rate was enhanced as compared to commercial products and unprocessed drug. The drug was unstable at the accelerated stability conditions. Accordingly, the traditional stability study at 25 °C should be conducted. In conclusion, the solid-SNEDDS filled in enteric coated HGCs enhanced the dissolution rate and stability in acidic pH.

Omeprazole as a potent activator of human cytosolic aldehyde dehydrogenase ALDH1A1.

BACKGROUND: Accumulation of lipid aldehydes plays a key role in the etiology of human diseases where high levels of oxidative stress are generated. In this regard, activation of aldehyde dehydrogenases (ALDHs) prevents oxidative tissue damage during ischemia-reperfusion processes. Although omeprazole is used to reduce stomach gastric acid production, in the present work this drug is described as the most potent activator of human ALDH1A1 reported yet. METHODS: Docking analysis was performed to predict the interactions of omeprazole with the enzyme. Recombinant human ALDH1A1 was used to assess the effect of omeprazole on the kinetic properties. Temperature treatment and mass spectrometry were conducted to address the nature of binding of the activator to the enzyme. Finally, the effect of omeprazole was evaluated in an in vivo model of oxidative stress, using E. coli cells expressing the human ALDH1A1. RESULTS: Omeprazole interacted with the aldehyde binding site, increasing 4-6 fold the activity of human ALDH1A1, modified the kinetic properties, altering the order of binding of substrates and release of products, and protected the enzyme from inactivation by lipid aldehydes. Furthermore, omeprazole protected E. coli cells over-expressing ALDH1A1 from the effects of oxidative stress generated by H2O2 exposure, reducing the levels of lipid aldehydes and preserving ALDH activity. CONCLUSION: Omeprazole can be repositioned as a potent activator of human ALDH1A1 and may be proposed for its use in therapeutic strategies, to attenuate the damage generated during oxidative stress events occurring in different human pathologies.

Compatibility of Flavoring Agents in Compounding Extemporaneous Omeprazole Oral Liquid.

In a previous study, the results of which were provided in an article published in the International Journal of Pharmaceutical Compounding, it was determined that FLAVORx's Grape flavor in extemporaneously compounded omeprazole oral liquid was found suitable. A follow-up study was conducted in which the authors explored four additional flavors (Professional Compounding Centers of America's Cherry Concentrate and their Orange Concentrate, and FLAVORx's Bubble Gum flavor and their Watermelon flavor) to allow pharmacists and patients greater flexibility and options to flavor omeprazole oral liquid. Oral liquids were compounded using 20-mg omeprazole delayed-release capsules, 8.4% sodium bicarbonate, and each of four flavors to reach drug concentration at 2 mg/mL and flavor at 1.2% v/v (n=3). After the delayed-release pellets were disintegrated, the prescription bottles were stored in cold temperature overnight. For flavor alone in 8.4% sodium bicarbonate solution, samples were prepared the same as above except no omeprazole delayed-release capsules were added. High-performance liquid chromatographic assay was adopted from the United States Pharmacopeia's Omeprazole Monograph, but it is for the unflavored oral liquid. In order to ensure assay robustness, stability indication tests, 0.1 N HCl (acid), 0.1 N NaOH (base), 50°C (heat), and 3% hydrogen peroxide were also performed to the flavored omeprazole oral liquids, as well as to the individual flavor alone in sodium bicarbonate solution without omeprazole. Professional Compounding Centers of America's Cherry Concentrate, Orange Concentrate, and FLAVORx's Watermelon flavor showed no interference with the drug, and the assays were robust. However, FLAVORx's Bubble Gum flavor displayed five mini peaks at 280 nm with one embedded in omeprazole peak. The resolution of a Bubble Gum peak immediately next to an omeprazole peak computed by column kinetics was 0.91, while the separation factor was 1.15. A good separation is generally >1.5. This study examined only the Cherry Concentrate, Orange Concentrate, Bubble Gum flavor, and Watermelon flavor from the specified manufacturers. An insignificant interference was shown between FLAVORx's Bubble Gum flavor with omeprazole. The results are not intended to infer that all brands of the same flavor names would react the same way. Omeprazole and all four studied flavors should be protected from oxidation insult.

Development and evaluation of an omeprazole-based delayed-release liquid oral dosage form.

Modified-release oral dosage forms are commonly used in pharmaceutics to delay or sustain the release of drugs. Nowadays, they are only marketed as solid dosage forms such as capsules or tablets. Therefore, the development of a liquid oral dosage form with modified-release properties has been keenly awaited to increase the compliance of patients with a swallowing impairment, such as paediatric, older or critically ill patients. In this study, a new technology has been developed that consists of multi-layered particles suspended extemporaneously in a syrup, using omeprazole as a model drug. The coating procedure was optimized to obtain a yield of minimum 90% w/w and a mean diameter below 500 µm. Eudragit® E100 and Eudragit® L100-55 were used to prevent the early release of omeprazole in the syrup and in the acidic environment of the stomach, respectively. These polymers allowed the stability of the coated particles to be ensured when dispersed in a liquid and the enteric release of the drug to be targeted. It was demonstrated that our new system presented similar release performances to existing marketed enteric dosage forms. It is able to protect omeprazole for 2 h in acidic medium at pH 1.2, while omeprazole was entirely released at pH 6.8 within 45 min. Once the final suspension is prepared extemporaneously, it presents sufficient stability to guarantee the administration of multiple doses filled into a syrup bottle and kept for a limited storage time at room temperature (e.g. up to 10 doses to be administered within 10 days).

Facile radiolabeling optimization process via design of experiments and an intelligent optimization algorithm: Application for omeprazole radioiodination.

The major uses of radiopharmaceuticals (RP) in clinical areas are diagnosis and/or therapy. The present study aimed to utilize the application of fractional factorial design analysis (FFDA) coupled with particle swarm optimization algorithm (PSO) to assess the optimization of RP production process. In this regard, omeprazole (OMP), which is gastric parietal cell proton pump inhibitor (PPI), was radiolabeled with iodine-125 (125 I) isotope in order to be used as a radiotracer for stomach imaging. Different factors that affect radiolabeling process were studied. According to the proposed design, just 16 experimental runs of radiolabeling process were performed using the extremes of each factor. In addition, one run was executed at the mean point of each factor. Undesirable maximum radiolabeling yield (RY) of radioiodinated omeprazole (125 I-OMP) was deduced from application of FFDA (88.4%). Furthermore, after applying PSO with changing limits of one factor, the maximum RY of 125 I-OMP was found to be 93.78%. Moreover, the practically verification from optimum conditions, which obtained from PSO, was found to give an RY of 93.99%. Overall, the findings of this study confirmed the potential use of that hybrid design for optimization of radiolabeling processes.

Graphene Oxide Tablets for Sample Preparation of Drugs in Biological Fluids: Determination of Omeprazole in Human Saliva for Liquid Chromatography Tandem Mass Spectrometry.

In this study, a novel sort of sample preparation sorbent was developed, by preparing thin layer graphene oxide tablets (GO-Tabs) utilizing a mixture of graphene oxide and polyethylene glycol on a polyethylene substrate. The GO-Tabs were used for extraction and concentration of omeprazole (OME) in human saliva samples. The determination of OME was carried out using liquid chromatography-tandem mass spectrometry (LC⁻MS/MS) under gradient LC conditions and in the positive ion mode (ESI+) with mass transitions of m/z 346.3→198.0 for OME and m/z 369.98→252.0 for the internal standard. Standard calibration for the saliva samples was in the range of 2.0⁻2000 nmol L-1. Limits of detection and quantification were 0.05 and 2.0 nmol L-1, respectively. Method validation showed good method accuracy and precision; the inter-day precision values ranged from 5.7 to 8.3 (%RSD), and the accuracy of determinations varied from -11.8% to 13.3% (% deviation from nominal values). The extraction recovery was 60%, and GO-Tabs could be re-used for more than ten extractions without deterioration in recovery. In this study, the determination of OME in real human saliva samples using GO-Tab extraction was validated.

High-resolution continuum source graphite furnace atomic absorption spectrometry for screening elemental impurities in drugs to adhere to the new international guidelines.

New guidelines for the limits of elemental impurities in drug products were introduced by the International Council for Harmonization in 2014. While the guidelines define a limit for each element, the complete quantification of the 24 elements included is, in fact, unnecessary. An accurate "pass/fail" test to determine whether the threshold was exceeded or not could be valuable in this context. In this study, a screening procedure using the features of high-resolution continuum source graphite furnace atomic absorption spectrometry for the evaluation of 12 elements in three different drugs was developed. The three-dimensional absorbance spectrum including time and wavelength in the vicinity of the main line of the element allows for a pass/fail decision related to the presence or absence of the element in the sample. Additionally, the bi-dimensional absorbance-wavelength spectrum defines the elements captured in the window when additional peaks are seen in the spectrum. The analysis of the selected drugs included sample digestion, the definition of pyrolysis and atomization temperatures, determination of the limit of detection and other validation parameters for each element. The evaluation of the spectra, both three- and bi-dimensional, revealed that only three elements, Cr, Ni, and Cu, were present in the samples in amounts above the LOD and therefore "fail" in the test. Nevertheless, they were quantified, and the analysis revealed that their levels were below the permitted daily exposure, which are at least 6 times higher than the LOD of the selected elements. Operating in a routine mode, the proposed method is a good option for the evaluation of elemental impurities in drug active ingredients or drug final products.

Tetrameric and polymeric silver complexes of the omeprazole scaffold; synthesis, structure, in vitro and in vivo antimicrobial activities and DNA interaction.

Two complexes [AgI(pmtbH)]4 (1) and {[Ag4(pmtbH)4(NO3)4·2X}n (2) (where pmtbH is 2-[(2-pyridinylmethyl)thio]-1H-benzimidazole and X is H2O or MeOH) were synthesised and structurally characterised. Complex 2 showed therapeutic potential against Candida albicans, Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa but complex 1 did not show significant activity in vitro. Further in vivo studies using larvae of the insect Galleria mellonella indicated that complex 2 significantly stimulates the immune system and that pre-treatment with the complex offers appreciable protection against all three bacteria. Real-time flow cytometry data support the observed antimicrobial profile of complex 2 and suggest the antimicrobial response may be linked to a form of bacterial programmed cell death (PCD). Complex 2 was found to interact with DNA in the bacterial and fungal cells but it did not cleave plasmid DNA isolated from the three bacteria.