Development of Bitter-Taste Masked Instant Jelly Formulations of Diphenhydramine Hydrochloride with Easy-to-Consume Granules.

This study developed easy-to-consume bitter taste-masking granules for the preparation of instant jelly formulations. Composite granules containing diphenhydramine hydrochloride (DPH) and polymers were prepared via spray drying. The taste-masking effect on DPH was evaluated with acceptable linearity between DPH concentration and intensity of bitterness using an electronic tongue sensor. The results indicated that ι-carrageenan could provide the greatest suppression effect on the DPH bitterness among the polymers selected for preparing spray-dried particles (SDPs). The thixotropic index (TI) of ι-carrageenan was higher than that of the other polymers. In addition, two sulfate groups per two galactose molecules in one unit of ι-carrageenan improved interaction with DPH. Compared to κ-carrageenan, the electrostatic interaction with DPH may be stronger. Easy-to-consume SDPs with ι-carrageenan were used to prepare instant jelly formulations. The instant jelly formulation containing DPH with ι-carrageenan (3.0%) met the criteria for texture properties (hardness, adhesiveness, and cohesiveness) for patients with difficulty swallowing, as specified by the Consumer Affairs Agency. Furthermore, instant jelly enhanced the bitter taste suppression of DPH. Overall, using spray-dried granules with ι-carrageenan, this technique for preparing instant jelly formulations is simple and inhibits the bitter taste of drugs, contributing to the development of oral dosage forms suitable for patients of all ages.

Application of structural and functional pharmacokinetic analogs for physiologically based pharmacokinetic model development and evaluation.

This work provides case studies for the pharmacokinetic (PK) analog approach, where a physiologically based pharmacokinetic (PBPK) model for a target chemical (has no PK data) is evaluated using PK data from a source chemical (has existing PK data). A bottom up PBPK modeling approach (using in vitro and in silico inputs) is used to develop human oral PBPK models for caffeine and diphenhydramine. Models are evaluated using in vivo data from structural and functional PK analogs. At the end of the case studies, in vivo PK data for caffeine and diphenhydramine is introduced and both models were able to simulate plasma concentrations which agreed with the in vivo PK data. To further demonstrate that structural analogs can serve as PK analogs, in vitro metabolism and plasma protein binding was compared for a subset of structurally similar ToxCast chemicals and shown to be similar. Next steps for the PK analog approach should focus on evaluating this concept for a broader set of compounds. Using PK analogs for evaluating and establishing confidence in a PBPK model will ensure that PBPK modeling remains a viable option in animal alternative safety assessments.

Future Oncotargets: Targeting Overexpressed Conserved Protein Targets in Androgen Independent Prostate Cancer Cell Lines.

BACKGROUND: Targeting evolutionarily conserved proteins in malignant cells and the adapter proteins involved in signalling that generates from such proteins may play a cardinal role in the selection of anti-cancer drugs. Drugs targeting these proteins could be of importance in developing anti-cancer drugs. OBJECTIVES: We inferred that drugs like loperamide and promethazine that act as antagonists of proteins conserved in cancer cells like voltage-gated Calcium channels (Cav), Calmodulin (CaM) and drug efflux (ABCB1) pump may have the potential to be re-purposed as an anti-cancer agent in Prostate Cancer (PCa). METHODS: Growth and cytotoxic assays were performed by selecting loperamide and promethazine to target Cav, CaM and drug efflux (ABCB1) pumps to elucidate their effects on androgen-independent PC3 and DU145 PCa cell lines. RESULT: We show that loperamide and promethazine in doses of 80-100µg/ml exert oncocidal effects when tested in DU145 and PC3 cell lines. Diphenhydramine, which shares its targets with promethazine, except the CaM, failed to exhibit oncocidal effects. CONCLUSION: Anti-cancer effects can be of significance if structural analogues of loperamide and promethazine that specifically target Cav, CaM and ABCB1 drug efflux pumps can be synthesized, or these two drugs could be re-purposed after human trials in PCa.

Percutaneous Absorption of Lorazepam, Diphenhydramine Hydrochloride, and Haloperidol from ABH Gel.

The objective of this project was to study the percutaneous absorption of lorazepam, diphenhydramine hydrochloride, and haloperidol from a topical Pluronic lecithin organogel, also known as ABH gel, across the porcine ear skin and verify its suitability for topical application. ABH gel was prepared using lecithin in isopropyl palmitate solution (1:1) as an oil phase and 20% w/v Poloxamer 407 solution as an aqueous phase. The gel was characterized for pH, viscosity, drug content, and thermal behavior. A robust high-performance liquid chromatography method was developed and validated for simultaneous analysis of lorazepam, diphenhydramine hydrochloride, and haloperidol. The percutaneous absorption of lorazepam, diphenhydramine hydrochloride, and haloperidol from ABH gel was carried out using Franz cells across the Strat-M membrane and pig ear skin. The pH of ABH gel was found to be 5.66 ± 0.13. The retention time of diphenhydramine hydrochloride, haloperidol, and lorazepam was found to be 5.2 minutes, 7.8 minutes, and 18.9 minutes, respectively. The ABH gel was found to be stable for up to 30 days. Theoretical steady state plasma concentrations (CSS) of diphenhydramine hydrochloride, haloperidol, and lorazepam calculated from flux values were found to be 1.6 ng/mL, 0.13 ng/mL, and 2.30 ng/mL, respectively. The theoretical CSS of diphenhydramine hydrochloride, haloperidol, and lorazepam were much lower than required therapeutic concentrations for antiemetic activity to relieve chemotherapy-induced nausea and vomiting. From the percutaneous absorption data, it was evident that ABH gel failed to achieve required systemic levels of lorazepam, diphenhydramine hydrochloride, and haloperidol following topical application.

Bitterness-Suppressing Effect of Umami Dipeptides and Their Constituent Amino Acids on Diphenhydramine: Evaluation by Gustatory Sensation and Taste Sensor Testing.

Diphenhydramine, a sedating antihistamine, is an agonist of human bitter taste receptor 14 (hTAS2R14). Diphenhydramine hydrochloride (DPH) was used as a model bitter medicine to evaluate whether the umami dipeptides (Glu-Glu and Asp-Asp) and their constituent amino acids (Glu, Asp) could suppress its bitterness intensity, as measured by human gustatory sensation testing and using the artificial taste sensor. Various concentrated (0.001-5.0 mM) Glu-Glu, Asp-Asp, Glu and Asp significantly suppressed the taste sensor output of 0.5 mM DPH solution in a dose-dependent manner. The effect of umami dipeptides and their constituent amino acids was tending to be ranked as follows, Asp-Asp > Glu-Glu >> Gly-Gly, and Asp > Glu >> Gly (control) respectively. Whereas human bitterness intensity of 0.5 mM DPH solution with various concentrated (0.5, 1.0, 1.5 mM) Glu-Glu, Asp-Asp, Glu and Asp all significantly reduced bitterness intensity of 0.5 mM DPH solution even though no statistical difference was observed among four substances. The taste sensor outputs and the human gustatory sensation test results showed a significant correlation. A surface plasmon resonance study using hTAS2R14 protein and these substances suggested that the affinity of Glu-Glu, Asp-Asp, Glu and Asp for hTAS2R14 protein was greater than that of Gly-Gly or Gly. The results of docking-simulation studies involving DPH, Glu-Glu and Asp-Asp with hTAS2R14, suggested that DPH is able to bind to a space near the binding position of Glu-Glu and Asp-Asp. In conclusion, the umami dipeptides Glu-Glu and Asp-Asp, and their constituent amino acids, can all efficiently suppress the bitterness of DPH.

SR-FTIR spectro-microscopic interaction study of biochemical changes in HeLa cells induced by Levan-C60, Pullulan-C60, and their cholesterol-derivatives.

Objects of the present study are improved fullerene C60 drug carrier properties trough encapsulation by microbial polysaccharides, levan (LEV), pullulan (PUL), and their hydrophobized cholesterol-derivatives (CHL and CHP), that show better interaction with cancer cells. The zeta potential, polydispersity index, and the diameter of particles were determined, and their cytotoxicity against three cancer cell lines were tested. Biochemical changes in HeLa cells are analyzed by synchrotron radiation (SR) FTIR spectro-microscopy combined with the principal component analysis (PCA). The most significant changes occur in HeLa cells treated with LEV-C60 and correspond to the changes in the protein region, i.e. Amide I band, and the changes in the structure of lipid bodies and membrane fluidity are evident. The highest cytotoxicity was also induced by LEV-C60. In HeLa cells, cytotoxicity could not be strictly associated with biochemical changes in lipids, proteins and nucleic acids, but these findings are significant contribution to the study of the mechanism of interaction of C60-based nanoparticles with cellular biomolecules. In conclusion, LEV, PUL, CHL, and CHP enhanced fullerene C60 potential to be used as target drug delivery system with the ability to induce specific intracellular changes in HeLa cancer cells.

On-Demand Manufacturing of Direct Compressible Tablets: Can Formulation Be Simplified?

PURPOSE: Oral direct compressible tablets are the most frequently used drug products. Manufacturing of tablets requires design and development of formulations, which need a number of excipients. The choice of excipients depends on the concentration, manufacturability, stability, and bioavailability of the active pharmaceutical ingredients (APIs). At MIT, we developed a miniature platform for on-demand manufacturing of direct compressible tablets. This study investigated how formulations could be simplified to use a small number of excipients for a number of different API's in which long term stability is not required. METHOD: Direct compressible tablets of five pharmaceutical drugs, Diazepam, Diphenhydramine HCl, Doxycycline Monohydrate, Ibuprofen, and Ciprofloxacin HCl, with different drug loadings, were made using direct compression in an automated small scale system.. The critical quality attributes (CQA) of the tablets were assessed for the quality standards set by the United States Pharmacopeia (USP). RESULTS: This miniature system can manufacture tablets - on-demand from crystalline API using the minimum number of excipients required for drug product performance. All drug tablets met USP quality standards after manufacturing and after 2 weeks of accelerated stability test, except for slightly lower drug release for Ibuprofen. CONCLUSIONS: On-demand tablets manufacturing where there is no need for long term stability using a flexible, miniature, automated (integrated) system will simplify pharmaceutical formulation design compared to traditional formulations. This advancement will offer substantial economic benefits by decreasing product time-to-market and enhancing quality.

Time-temperature superposition principle for the kinetic analysis of destabilization of pharmaceutical emulsions.

The time-temperature superposition principle (TTSP) was applied to the destabilization kinetics of a pharmaceutical emulsion. The final goal of this study is to predict precisely the emulsion stability after long-term storage from the short-period accelerated test using TTSP. As the model emulsion, a cream preparation that is clinically used for the treatment of pruritus associated with chronic kidney disease was tested. After storage at high temperatures ranging from 30 to 45 °C for designated periods, the emulsion state was monitored using magnetic resonance imaging, and then the phase separation behaviors observed were analyzed according to the Arrhenius approach applying TTSP. The Arrhenius plot showed a biphasic change around 35 °C, indicating that the separation behaviors of the sample were substantially changed between the lower (30-35 °C) and higher (35-45 °C) temperature ranges. This study also monitored the coalescence behavior using a backscattered light measurement. The experiment verified that the destabilization was initiated by coalescence of oil droplets and then it eventually led to obvious phase separation via creaming. Furthermore, we note the coalescence kinetics agreed well with the phase separation kinetics. Therefore, in the case of the sample emulsion, the coalescence behavior has a dominant influence on the destabilization process. This study offers a profound insight into the destabilization process of pharmaceutical emulsions and demonstrates the promising applicability of TTSP to pharmaceutical research.

Gold nanoparticles for enhanced ionization and fragmentation of biomolecules using LDI-MS.

New applications for gold nanoparticles (AuNPs) in laser desorption ionization mass spectrometry are presented here. This work expands on previous biomolecule studies and introduces carbohydrates, steroids, bile acids, and other small molecules as a focus. Broad trends in ionization are observed, and specifically of interest are new species that have not previously been reported from AuNPs (e.g., [M + Au]+ ). Interesting fragmentation effects have been observed for diphenhydramine, including similarity to electron impact mass spectra and possible radical driven reactions, providing insight into the mechanism of ionization when using AuNPs.

Preparation, Characterization, and Formulation Development of Drug-Drug Protic Ionic Liquids of Diphenhydramine with Ibuprofen and Naproxen.

Diphenhydramine (DPH) has been used with ibuprofen (IBU) or naproxen (NAP) in combined therapies to provide better clinical efficacy as an analgesic and sleep aid. We discovered that DPH can form protic ionic liquids (PILs) with IBU and NAP, which opens the opportunity for a new delivery mode of these combination drugs. [DPH][IBU] and [DPH][NAP] PILs exhibit low ionicity, as confirmed by Fourier transform infrared and 1H NMR spectroscopy, and accompanied by low diffusivity, high viscosity, and poor ionic conductivity. Evaluation of pharmaceutical properties of the two PILs showed that these PILs, despite high solubility and good wettability, exhibited low dissolution rates, owing to the poor dispersion of the PIL drops and the resultant small surface area during dissolution. However, when loaded into a mesoporous carrier, the PIL-carrier composites exhibited improved dissolution rates along with excellent flow properties and easy handling. Oral capsules of both PILs were developed using such composites. Such capsule products exhibited acceptable drug release and bioavailability as demonstrated by a predictive artificial stomach-duodenum dissolution test.

Fundamental study of the ultrasonic induced degradation of the popular antihistamine, diphenhydramine (DPH).

Diphenhydramine (DPH) the active ingredient in Benadryl, has been detected in streams, rivers and other surface water sources. As a bioactive compound, DPH impacts human health even at low concentrations. Ultrasonic irradiation at 640 kHz leads to the rapid degradation of DPH in aqueous solution. Radical scavenging experiments and detailed product studies indicate the DPH degradation involves direct pyrolysis and degradation reactions mediated by the hydroxyl radicals produced during cavitation. The degradation can be modeled by pseudo-first order kinetics yielding rate constants k of 0.210, 0.130, 0.082, 0.050, 0.035, 0.023 min-1 at the initial concentrations of 2.8, 5.2, 13.9, 27.0, 61.0, 160.0 µmol L-1, respectively. The degradation process follows the Langmuir-Hinshelwood (heterogeneous) model with a partition coefficient, KL-H = 0.06 µmol·L-1and reactivity constant kr = 1.96 µmol min-1·L-1. A competition kinetic study conducted employing the hydroxyl radical trap, coumarin, illustrates that DPH was degraded primarily by hydroxyl radical mediated processes. Computational studies employing Gaussian 09 basis set provide fundamental insight into the partitioning of the reaction pathways and the degradation mechanisms. The study demonstrates the ultrasonic degradation of DPH is rapid, follows simple kinetic expressions and is accurately modeled using computational methods.

Elucidation of the orientation of selected drugs with 2-hydroxylpropyl-ß-cyclodextrin using 2D-NMR spectroscopy and molecular modeling.

This project aims to study the nature of interaction and orientation of selected drugs such as dexamethorphan HBr (DXM), diphenhydramine HCl (DPH), and lidocaine HCl (LDC) inclusion complexes with hydroxyl-propyl ß-cyclodextrin (HP-ß-CD) using 1HNMR spectroscopy, 2D-NMR ROESY and molecular-modeling techniques. Freeze-drying technique was used to formulate the inclusion complexes between DXM, DPH and LDC with HP-ß-CD (1:1 M ratio) in solid state. Inclusion complex formation was initially characterized by Fourier transform-infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and scanning electron microscopy (SEM) techniques. Further characterization of inclusion complexes to determine the interaction of DXM, DPH and LDC with HP-ß-CD was performed using the 1HNMR spectroscopy, 2D-NMR ROESY and molecular modeling techniques. Inclusion complexes of DXM, DPH and LDC with HP-ß-CD were successfully prepared using the freeze-drying technique. Preliminary studies with FT-IR, DSC, XRD and SEM indicated the formation of inclusion complexes of DXM, DPH and LDC with HP-ß-CD at 1:1 M ratio. 1HNMR study showed a change in proton chemical shift upon complexation. 2D-NMR ROESY (two-dimensional) spectroscopy gave an insight into the spatial arrangement between the host and guest atoms. 2D-ROESY experiments further predicted the direction of orientation of guest molecules, indicating the probability that amino moieties of DXM, DPH and LDC are inside the hydrophobic HP-ß-CD cavity. Cross-peaks of inclusion complexes demonstrated intermolecular nuclear Overhauser effects (NOE) between the amino protons in DXM, DPH and LDC and H-atoms of HP-ß-CD. Molecular modeling studies further confirmed the NMR data, providing a structural basis of the individual complex formations. Microsecond time-level molecular dynamics and metadynamics simulations indicate much stronger binding of DXM to HP-ß-CD and more dynamic behavior for DPH and LDC. In particular, LDC can exhibit multiple binding modes, and even spent some time (∼1-2%) out of the carrier, proving the dynamic nature of the complex. To conclude, 2D-NMR and molecular dynamic simulations elucidate the formation of inclusion complexes and intermolecular interactions of DXM, DPH and LDC with HP-ß-CD.

Improved Extraction Repeatability and Spectral Reproducibility for Liquid Extraction Surface Analysis-Mass Spectrometry Using Superhydrophobic-Superhydrophilic Patterning.

A major problem limiting reproducible use of liquid extraction surface analysis (LESA) array sampling of dried surface-deposited liquid samples is the unwanted spread of extraction solvent beyond the dried sample limits, resulting in unreliable data. Here, we explore the use of the Droplet Microarray (DMA), which consists of an array of superhydrophilic spots bordered by a superhydrophobic material giving the potential to confine both the sample spot and the LESA extraction solvent in a defined area. We investigated the DMA method in comparison with a standard glass substrate using LESA analysis of a mixture of biologically relevant compounds with a wide mass range and different physicochemical properties. The optimized DMA method was subsequently applied to urine samples from a human intervention study. Relative standard deviations for the signal intensities were all reduced at least 3-fold when performing LESA-MS on the DMA surface compared with a standard glass surface. Principal component analysis revealed more tight clusters indicating improved spectral reproducibility for a human urine sample extracted from the DMA compared to glass. Lastly, in urine samples from an intervention study, more significant ions (145) were identified when using LESA-MS spectra of control and test urine extracted from the DMA. We demonstrate that DMA provides a surface-assisted LESA-MS method delivering significant improvement of the surface extraction repeatability leading to the acquisition of more robust and higher quality data. The DMA shows potential to be used for LESA-MS for controlled and reproducible surface extraction and for acquisition of high quality, qualitative data in a high-throughput manner.

Formulation Development and Evaluation of Diphenhydramine Nasal Nano-Emulgel.

The aim of present study is to formulate diphenhydramine nasal nano-emulgels, having lipophilic nano-sized interior droplets, with better penetration for targeted controlled delivery to mucous membrane. Different diphenhydramine (DPH) nasal nano-emulgels were developed having propylene glycol and olive oil (as permeation enhancers) by using RSM for optimization and then evaluated for physico-chemical characteristics and thermal stability. In-vitro drug release through cellophane membrane was conducted and results were analyzed statistically. Further, gelation, mucoadhesive stress, and ex-vivo and histopathological studies were performed on optimized formulation by using goat nasal membrane. Among all formulations, E2 showed maximum DPH release at higher concentration olive oil (4%) and lower concentration propylene glycol (PG) (25%) within 4 h. All formulations have followed first-order kinetics and drug release mechanism was Fickian diffusion. Analysis of variance (ANOVA) and multiple linear regression analysis (MLRA) were used to compare results among formulations and 3D surface plots were constructed also. Optimized formulation showed immediate prolong gelation in artificial nasal mucosa and excellent mucoadhesive property (72.5 ± 1.5 dynes/cm2). Approximately 97.1% optimized formulation was permeated through membrane within 4 h, having a high flux rate (33.19 ± 0.897 µg/cm2/min) with diffusion coefficient (0.000786 ± 4.56 × 10-5 cm2/min) while drug contents remained on mucosal membrane for 24 h. Histopathologically, change on intra-mucosal surface of excised membrane was observed due to passage of drug through it. In summary, combination of PG and olive oil in nasal DPH nano-emulgel can be utilized successfully for targeted controlled delivery. The optimized formulation has excellent permeability and prolonged residence time on mucosal surface, which prove its good anti-histaminic activity in case of allergic rhinitis.

Diphenhydramine inhibits voltage-gated proton channels (Hv1) and induces acidification in leukemic Jurkat T cells- New insights into the pro-apoptotic effects of antihistaminic drugs.

An established characteristic of neoplastic cells is their metabolic reprogramming, known as the Warburg effect, with greater reliance on energetically less efficient pathways (such as glycolysis and pentose phosphate shunt) compared with oxidative phosphorylation. This results in an overproduction of acidic species that must be extruded to maintain intracellular homeostasis. We recently described that blocking the proton currents in leukemic cells mediated by Hv1 ion channels triggers a marked intracellular acidification and apoptosis induction. Moreover, histamine H1-receptor antagonists were found to induce apoptosis in tumoral cells but the mechanism is still unclear. By using Jurkat T cells, we now show how diphenhydramine inhibits Hv1 mediated currents, inducing a drop in intracellular pH and cellular viability. This provides evidence of a new target structure responsible of the known pro-apoptotic action of antihistaminic drugs.

[Rotational Isomers of Diphenhydramine].

　Diphenhydramine (DP), an antihistaminic agent, may become colored and daker or more fluorescent during storage. Herein, we spectroscopically examined the causes of this phenomenon under various DP storage conditions and durations. The infrared vibration-rotation spectrum shows multiple Gauche (G)-type conformers with different intramolecular n→π* interaction strengths. The splitting pattern of the dimethylamino group protons in the 1H-NMR spectrum indicates that DP is mainly in the G-type with a small portion in the Trans (T)-type. The correlation between the red-shifted peak intensity in the UV•VIS absorbance spectrum and the coloring progression indicates a decreased intramolecular n→π* interaction of the G-type under elevated temperature during storage. Enhanced fluorescence detected in the Excitation•Fluorescence spectrum demonstrates G-type (quenching) to T-type (fluorescent) conformation conversion, which is due to activated internal rotation of the dimethylamino group under elevated storage temperature and electronic excitation in the phenyl groups under light irradiation during storage. A signal detected in the ESR spectrum corresponds to the G-type charge transfer (CT) structure wherein part of the nonbonding electron pair on the N atom is intramolecularly redistributed to the phenyl groups. The CT structure presents the G-type quenching characteristics, whereas weak CT bonding corresponds to coloring. The results indicate that the quenching G-type is converted to T-type by heat or light to become color faded and bright with enhanced fluorescence and that T-type is reverted to G-type after storage under cool and dark conditions or by vacuum distillation to lose fluorescence.

Double-Track Electrochemical Green Approach for Simultaneous Dissolution Profiling of Naproxen Sodium and Diphenhydramine Hydrochloride.

Acquisition of the dissolution profiles of more than single active ingredient in a multi-analyte pharmaceutical formulation is a mandatory manufacturing practice that is dominated by utilization of the off-line separation-based chromatographic methods. This contribution adopts a new "Double-Track" approach with the ultimate goal of advancing the in-line potentiometric sensors to their most effective applicability for simultaneous acquisition of the dissolution profiles of two active ingredients in a binary pharmaceutical formulation. The unique abilities of these sensors for real-time measurements is the key driver for adoption of "green analytical chemistry" (GAC) principles aiming to expand the application of eco-friendly analytical methods With the aim of performing a side-by-side comparison, this work investigates the degree of adherence of ISEs to the 12 principles of GAC in multicomponent dissolution profiling with respect to the HPLC. For the proof of concept, a binary mixture of naproxen sodium (NAPR) and diphenhydramine hydrochloride (DIPH) marketed as Aleve pm® tablets was selected as a model for which dissolution profiles were attained by two techniques. The first "Double-Track" in-line strategy depends on dipping two highly integrated membrane sensors for continuous monitoring of the dissolution of each active pharmaceutical ingredient (API) by tracing the e.m.f change over the time scale. For the determination of NAPR, sensor I was developed using tridodecyl methyl ammonium chloride as an anion exchanger, while sensor II was developed for the determination of DIPH using potassium tetrakis (4-chlorophenyl) borate as a cation exchanger. The second off-line strategy utilizes a separation-based HPLC method via off-line tracking the increase of peak area by UV detection at 220nm over time using a mobile phase of acetonitrile: water (90:10) pH 3. The advantages of the newly introduced "Double-Track" approach regarding GAC principles are highlighted, and the merits of these benign real-time analyzers (ISEs) that can deliver equivalent analytical results as HPLC while significantly reducing solvent consumption/waste generation are described.

Beyond-use dating of lidocaine alone and in two "magic mouthwash" preparations.

PURPOSE: Beyond-use dating (BUD) of lidocaine alone and in two "magic mouthwash" preparations stored in amber oral syringes at room temperature was determined. METHODS: Two formulations of mouthwash containing oral topical lidocaine 2% (viscous), diphenhydramine 2.5 mg/mL, and aluminum hydroxide-magnesium hydroxide-simethicone were prepared in 1:1:1 and 1:2.5:2.5 ratios, divided into 3-mL samples, and stored in unit-dose oral amber syringes. Unit-dose single-product lidocaine samples were also prepared to serve as controls and stored in oral amber syringes. The lidocaine concentrations in these samples were measured periodically for 90 days. A stability-indicating high-performance liquid chromatographic method was developed and validated for system suitability, accuracy, repeatability, intermediate precision, specificity, linearity, and robustness. RESULTS: Based on the calculated percentages versus the initial concentration and the results from an analysis of variance comparing the two formulations, a BUD of 21 days is deemed appropriate for both magic mouthwash formulations. Based on the stability data, published safety concerns, and lack of efficacy in combination, packaging and dispensing lidocaine separately from other ingredients are recommended when administering magic mouthwash mixtures. Utilizing a 90-day BUD, lidocaine can be packaged separately from other magic mouthwash ingredients in individual dosage units and applied to the oral cavity using the swish-and-spit method. The delivery of the diphenhydramine and aluminum hydroxide-magnesium hydroxide-simethicone could be separated, allowing for a swish-and-swallow method of administration. CONCLUSION: A BUD of 21 days is recommended for lidocaine prepared with diphenhydramine and aluminum hydroxide-magnesium hydroxide-simethicone in ratios of 1:1:1 and 1:2.5:2.5 and stored at room temperature in amber oral plastic syringes.

Involvement of Proton-Coupled Organic Cation Antiporter in Varenicline Transport at Blood-Brain Barrier of Rats and in Human Brain Capillary Endothelial Cells.

Varenicline is a selective partial α4ß2 nicotinic acetylcholine receptor agonist, which is used to help achieve smoking cessation. Here, we investigated varenicline transport at the blood-brain barrier by means of in vivo microdialysis, in situ brain perfusion, and brain efflux index measurements in rats, and in vitro uptake studies in human brain capillary endothelial cells. Microdialysis demonstrated that varenicline is actively transported from blood to brain in rats. Blood-to-brain uptake transport of varenicline, as measured by the in situ brain perfusion technique, was strongly inhibited by diphenhydramine, a potent inhibitor of proton-coupled organic cation (H+/OC) antiporter. However, brain efflux index study showed that brain-to-blood efflux transport of varenicline was not inhibited by diphenhydramine. In human brain capillary endothelial cells, varenicline was taken up time- and concentration-dependently. The uptake was dependent on an oppositely directed proton gradient, but was independent of extracellular sodium and membrane potential. The uptake was inhibited by a metabolic inhibitor, and by substrates of H+/OC antiporter, but not by substrates or inhibitors of OCTs, OCTNs, PMAT, and MATE1, which are known organic cation transporters. The present results suggest that the H+/OC antiporter contributes predominantly to varenicline uptake at the blood-brain barrier.

Suppression in Bitterness Intensity of Bitter Basic Drug by Chlorogenic Acid.

The purpose of the study was to evaluate suppression of the bitterness intensity of bitter basic drugs by chlorogenic acid (CGA) using the artificial taste sensor and human gustatory sensation testing and to investigate the mechanism underlying bitterness suppression using 1H-NMR. Diphenhydramine hydrocholoride (DPH) was the bitter basic drug used in the study. Quinic acid (QNA) and caffeic acid (CFA) together form CGA. Although all three acids suppressed the bitterness intensity of DPH in a dose-dependent manner as determined by the taste sensor and in gustatory sensation tests, CFA was less effective than either CGA or QNA. Data from 1H-NMR spectroscopic analysis of mixtures of the three acids with DPH suggest that the carboxyl group, which is present in both QNA and CGA but not CFA, interact with the amine group of DPH. This study showed that the bitterness intensity of DPH was suppressed by QNA and CGA through a direct electrostatic interaction with DPH as confirmed in 1H-NMR spectroscopic analysis. CGA and QNA may therefore be useful bitterness-masking agents for the basic drug DPH.