Study of the Structural Chemistry of the Inclusion Complexation of 4-Phenylbutyrate and Related Compounds with Cyclodextrins in Solution: Differences in Inclusion Mode with Cavity Size Dependency.

4-phenylbutyrate (PB) and structurally related compounds hold promise for treating many diseases, including cancers. However, pharmaceutical limitations, such as an unpleasant taste or poor aqueous solubility, impede their evaluation and clinical use. This study explores cyclodextrin (CD) complexation as a strategy to address these limitations. The structural chemistry of the CD complexes of these compounds was analyzed using phase solubility, nuclear magnetic resonance (NMR) spectroscopic techniques, and molecular modeling to inform the choice of CD for such application. The study revealed that PB and its shorter-chain derivative form 1:1 αCD complexes, while the longer-chain derivatives form 1:2 (guest:host) complexes. αCD includes the alkyl chain of the shorter-chain compounds, depositing the phenyl ring around its secondary rim, whereas two αCD molecules sandwich the phenyl ring in a secondary-to-secondary rim orientation for the longer-chain derivatives. ßCD includes each compound to form 1:1 complexes, with their alkyl chains bent to varying degrees within the CD cavity. γCD includes two molecules of each compound to form 2:1 complexes, with both parallel and antiparallel orientations plausible. The study found that αCD is more suitable for overcoming the pharmaceutical drawbacks of PB and its shorter-chain derivative, while ßCD is better for the longer-chain derivatives.

Study of the inclusion complexes formed between 4-phenylbutyrate and α-, ß- and γ-cyclodextrin in solution and evaluation on their taste-masking properties.

OBJECTIVES: 4-Phenylbutyrate (PB), which is used in the management of urea cycle disorders, has an unpleasant taste leading to poor patient compliance. Existing PB formulations though helpful, have some limitations in their use. This study reports on attempts to mask this unpleasant taste by complexing PB with cyclodextrins (CDs) to improve patient compliance. METHODS: α, ß and γCD were used as CDs. Phase solubility studies, circular dichroism, 1H-NMR spectroscopy, including ROESY, and molecular modelling were used to investigate and characterize the PB-CD interactions in solution. The taste-masking effect of the CDs was evaluated using in vitro taste sensor measurements. KEY FINDINGS: PB interacts with α, ß and γCD in solution to form 1:1, 1:1 and 1:2 CD: PB inclusion complexes, respectively, with stability constants in the order αCD > ßCD > γCD. Taste evaluation revealed that the CDs significantly mask the taste of PB through the formation of the inclusion complexes. Notably, αCD masked the bitter taste of PB to 30% of the initial taste at a 1:1 molar ratio. CONCLUSION: αCD significantly masks the unpleasant taste of PB in solution and can be used to formulate PB to address the limitations of existing formulations and improve patient compliance and quality of life.

Syringe-dispensed omega-3 lipid injectable emulsions should be stored under airtight refrigeration: A proposal for the efficient supply of unapproved precious lipid resources.

BACKGROUND: Both fish-oil lipid injectable emulsion (FO-ILE) and mixed-oil lipid injectable emulsion (MO-ILE) are key components of parenteral nutrition and require importation into Japan, and they are easily oxidized after opening. Given the small daily volumes of these lipids dispensed in infants and children with intestinal failure (IF), the purpose of the study was to identify the optimal storage method. METHODS: Lipids were prepared in polypropylene syringes in the following manner: air-sealing and photoprotection, air-sealing only, photoprotection only, and uncovered. Samples were stored for 14 days at 4°C or 26°C. The degree of oxidative degradation was evaluated by measuring malondialdehyde (MDA) concentration and pH and comparing them to the values measured immediately after opening. RESULTS: For FO-ILE, the increase in MDA concentration for 14 days was insignificant in air-sealed samples, regardless of photoprotection (+0.45 µM, P = 1.0) or no photoprotection (+0.52 µM, P = 1.0). This trend was more pronounced at 4°C than at 26°C (P < 0.01). The maximum pH decrease was 0.08 at 4°C. MO-ILE exhibited an insignificant increase in MDA concentration for 14 days with air-sealed samples, regardless of photoprotection (+0.36 µM, P = 0.11) or no photoprotection (+0.33 µM, P = 0.76). This trend was more pronounced at 4°C than at 26°C (P < 0.01). The maximum pH decrease was 0.12 at 4°C. For soybean-oil lipid injectable emulsion, the trend was similar with no considerable deterioration. CONCLUSION: Syringe-dispensed FO-ILE and MO-ILE stored under airtight refrigeration remained undeteriorated for 14 days. Our results are considered clinically valuable when supplying these expensive resources for infants with IF.

Drug-Tea Polyphenol Interaction (III) Incompatibility between Aripiprazole Oral Solution and Green Tea.

The details of incompatibility between aripiprazole (ARIP) oral solution and green tea were examined. When the ARIP oral solution was mixed with a commercial PET bottled green tea beverage, the residual rate of ARIP in the mixed solution decreased to 15.7-17.6%. Mixing with ARIP reduced the content of gallate-type green tea polyphenols (GTPs) in the mixed solution but not the content of non-gallate-type GTPs. Furthermore, using pH 3.0 lactic acid buffer, 2.23 mM ARIP solution and 2.23 mM GTP solution were prepared, and the same volumes of ARIP solution and GTP solution were mixed. When the gallate-type GTP solution was mixed, the residual rate of ARIP in the mixed solution decreased. On the other hand, when the non-gallate-type GTP solution was mixed, the residual rate of ARIP in the mixed solution did not decrease. From the above results, it was found that the main reason for the incompatibility between ARIP oral solution and green tea was the formation of an insoluble substance composed of ARIP and gallate-type GTPs in green tea. Furthermore, experimental results using the continuous variation method revealed that ARIP and (-)-epigallocatechin gallate, which is the most representative gallate-type GTP, interact at a molar ratio of 3 : 2.

Incompatibility between propericiazine oral solution and tea-based drink.

Here, we studied the incompatibility between an oral solution of propericiazine (PCZ), an antipsychotic drug, and various commercially available bottled tea-based drinks. When 0.5 mL of the PCZ oral solution (10 mg/mL) was mixed with 16.5 mL of a tea-based drink (such as green tea, oolong tea, and black tea), the residual PCZ content declined to approximately 50% in some mixed solutions. After mixing with other tea-based drinks, the residual PCZ content declined to approximately 30%, while in others, it changed very little. The residual PCZ content declined immediately after mixing with tea-based drinks, but the rate remained almost unchanged for the next 24 h. Furthermore, the pH of the mixture increased to 4.5-5.1 after the oral solution of PCZ (original pH 3.8) was diluted with various tea-based drinks. Afterwards, the pH did not change for 24 h. The mixture became cloudy immediately after diluting PCZ oral solution with tea-based drinks, and the insoluble substance gradually precipitated. In order to elucidate factors responsible for the decline in the content of PCZ, a (-)-epigallocatechin gallate solution, which is a main ingredient of green tea polyphenol, was mixed with the PCZ oral solution. After mixing, the residual PCZ content declined to approximately 60-75%. On the other hand, the content of PCZ did not decline when a (-)-epigallocatechin solution was mixed with the PCZ oral solution. The results from this study demonstrated that PCZ content was reduced after dilution in tea-based drinks because of the interaction between PCZ and polyphenol with a galloyl group in tea-based drinks.

[Mechanism of interaction between risperidone and tea catechin (2) influence of presence of galloyl group in catechin on insoluble complex formation with risperidone].

The influence of the presence of a galloyl group in catechin on complexation with risperidone (RISP) was examined using (--)-epigallocatechin gallate (EGCg) and (--)-epigallocatechin (EGC), which are present in green tea as tea catechins. By quantitative analysis using HPLC, it was found that EGCg formed an insoluble complex with RISP for concentration dependence, whereas EGC did not. The large contribution of the galloyl group of catechin to form an insoluble complex with RISP was recognized in this study. In a molecular modeling study, it was found that the EGCg-R complex (EGCg with RISP) formed three hydrogen bonds between the hydroxyl groups of EGCg and the two N atoms and an O atom of RISP. The hydrogen bond between the hydroxyl group of the galloyl ring in EGCg and the N atom of the piperidine ring in RISP stabilized EGCg-R more energetically. The EGC-R complex (EGC with RISP) also formed three hydrogen bonds, but the N atom of the piperidine ring in RISP did not participate in hydrogen bond formation. According to the calculation using the COSMO-RS method, the water solubility of the EGCg-R complex was 1/26 that of the EGC-R complex. Therefore, the EGCg-R complex was difficult to dissolve in water. In the (1)H-NMR spectra of RISP in DMSO-d(6), although chemical shifts of protons near the N atom on the piperidine ring moved downfield on the addition of EGCg, no change in chemical shifts of these protons was observed on the addition of EGC. Therefore, based on these results, the galloyl group of EGCg contributes to the formation of an insoluble complex between tea catechin and RISP, and this insoluble complex is stabilized by the hydrogen bond between the hydroxyl group of the galloyl ring in EGCg and the N atom of the piperidine ring in RISP.

Determination of digoxin clearance in Japanese elderly patients for optimization of drug therapy: a population pharmacokinetics analysis using nonlinear mixed-effects modelling.

BACKGROUND: Optimal use of digoxin in the elderly population requires information about the drug's pharmacokinetics and the influence of various factors on the drug's disposition. However, because of sampling restrictions, it is often difficult to perform traditional pharmacokinetic studies in elderly patients. OBJECTIVE: This study was conducted to determine the apparent total clearance of digoxin from serum after oral administration (CL/F) and to establish the role of patient characteristics in estimating doses of digoxin for elderly patients (age ≥65 years), using routine therapeutic drug monitoring data. METHODS: Analyses of the pharmacokinetics of digoxin were conducted using the nonlinear mixed-effects modelling (NONMEM®) software, a computer program designed to analyse pharmacokinetics in study populations by allowing pooling of data. Steady-state data (140 observations) obtained by routine therapeutic drug monitoring following repeated oral administration of digoxin in 94 hospitalized elderly patients (age ≥65 years) were analysed to establish the role of patient characteristics in estimating doses of digoxin for elderly patients. RESULTS: Estimates generated by NONMEM® indicated that digoxin CL/F was influenced by the demographic variables of total bodyweight (TBW), serum creatinine (SCr), age (AGE), presence of congestive heart failure (CHF), concomitant administration of the calcium channel antagonists (calcium channel blockers [CCBs]: verapamil, diltiazem or nifedipine), sex (SEX) and elderly clearance factor (trough serum concentration of digoxin; [C(trough)] θ). The full version of the final NONMEM® model was where CCB is 1 for concomitant administration of a CCB and is 0 otherwise; CHF is 1 for patients with CHF and is 0 otherwise; SEX is 0 for male and is 1 for female; and the elderly clearance factor C(trough)-0.180 is 1 for digoxin C(trough) <1.7 ng/mL. CONCLUSIONS: We developed a new model for elderly patient dosing of digoxin with good predictive performance. Clinical application of the findings of the present study to patient care may permit selection of an appropriate initial digoxin maintenance dose, thus enabling the clinician to achieve a desired therapeutic effect. However, the digoxin dosage regimen should be based on an appraisal of the individual patient's clinical need for the drug.

Population pharmacokinetic investigation of digoxin in Japanese infants and young children.

To establish the role of patient characteristics in estimating doses of digoxin for infants and young children using routine therapeutic drug monitoring data, the steady-state blood-level data (n = 245) after repetitive oral administration in 117 hospitalized infants and young children were analyzed using nonlinear mixed effects modeling (NONMEM), a computer program designed for analyzing drug pharmacokinetics in study populations through pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished using a 1-compartment pharmacokinetic model. Estimates generated by NONMEM indicated that the clearance of digoxin (CL/F; L/h) was influenced by the following demographic variables: total body weight (TBW), presence of congestive heart failure (CHF), and infant-young children clearance factor (trough serum concentration of digoxin; Conc). These influences could be modeled by the equation CL/F (L/h) = 0.302 · TBW (kg)¹·¹7 · 0.905(CHF) · Conc (trough serum digoxin concentration >1.7 ng/mL)⁻°·54°; F = 0.754, where CHF is 1 for presence of congestive heart failure, 0 otherwise; F is bioavailability, 1 for elixirs, 0.754 for powders; and Conc⁻°·54° is 1 for digoxin concentration <1.7 ng/mL. Clinical application of the model to patient care may permit selection of an appropriate initial maintenance dose, thus enabling the clinician to achieve the desired therapeutic effect. However, the digoxin dosage regimen for the individual patient should be based on a careful appraisal of his or her clinical need for the drug.

[Mechanism of interaction between risperidone and tea catechin(1)complex formation of risperidone with epigallocatechin gallate].

The mechanism of complexation between risperidone (RISP) and (-)-epigallocatechin gallate (EGCg) was clarified by ¹H-NMR and molecular modeling studies. RISP and EGCg formed an insoluble complex with a 1 : 1 stoichiometry in aqueous solution. In the ¹H-NMR spectra of RISP in DMSO-d6, the chemical shifts of protons neighboring the N atom on the piperizine ring clearly moved downfield upon formation of the complex. In the molecular modeling study, the ¹H-chemical shifts for nine optimized structures of the complex were calculated to compare them with those of the experimental results. Only one conformer with the second minimum energy for the complex supported the downfield shifts of RISP protons. It was found from the structure of the complex that the two hydrogen bonds between hydroxyl groups of the galloyl ring in EGCg and N atoms in RISP, one of which was on the piperizine ring, were formed to stabilize the complex.

Ab initio molecular orbital study of the reactivity of active alkyl groups. VII. Solvent effects on the formation of enolate isomers from 2-butanone with methoxide anion in methanol.

The mechanism of the deprotonation of 2-butanone (1) with methoxide anion (2) was studied by ab initio molecular orbital (MO) methods. Calculations of the thermodynamic stabilities of each complex and the regioselectivity of the reaction were performed using a static isodensity surface polarized continuum model (IPCM) which takes the solvent effect into consideration. The calculated energies of the complexes lead ultimately to the conclusion that the major deprotonation pathway in protic solvents is dependent upon thermodynamically stable complexes with small activation energies under equilibrium control.

Ab initio molecular orbital study of the reactivity of active alkyl groups. VI. Modified reaction model for the elimination process of nitrosation reaction.

The mechanisms of nitrosation of acetone through sodium enolate [CH3COCH2]- Na+ (1) or naked enolate [CH3COCH2]- (2) with tert-butyl nitrite (CH3)3CONO (3) were studied using ab initio molecular orbital (MO) methods. When the modified complex model was used in the elimination process, our results demonstrated the predominant formation of E-1-hydroxy-imino-2-oxo-propane CH3COCH=NOH (4E), in which a counter-cation of the base catalyst did not participate during the reaction. On the other hand, participation of the counter-cation during the reaction contributed to the formation of the Z-isomer of 4 (4Z).

Differentiation of a pair of diastereomeric tertiarybutoxycarbonylprolylproline ethyl esters by collision-induced dissociation of sodium adduct ions in electrospray ionization mass spectrometry and evidence for chiral recognition by ab initio molecular orbital calculations.

The fragmentation of the sodium adduct ions for tert-butoxycarbonyl-L-prolyl-L-proline ethyl ester (Boc-L-Pro-L-Pro-OEt) was compared with that for Boc-D-Pro-L-Pro-OEt in positive-ion electrospray ionization (ESI) mass spectrometry. In the collision-induced dissociation (CID) mass spectra of the [M + Na](+) ions, the abundance of the [M + Na - C(CH(3))(3) + H](+) ion, which is due to the loss of a tert-butyl group from the [M + Na](+) ion for Boc-D-Pro-L-Pro-OEt, was about eight times higher than that for Boc-L-Pro-L-Pro-OEt. In addition, in the CID spectra of the sodium adduct fragment ion ([M + Na - Boc + H](+)), the abundance of the [M + Na - Boc - prolylresidue + H](+) ion, which is due to the loss of prolyl residue from the [M + Na - Boc + H](+) ion for Boc-L-Pro-L-Pro-OEt, was about five times higher than that for Boc-D-Pro-L-Pro-OEt. These results indicate that Boc-L-Pro-L-Pro-OEt was distinguished from Boc-D-Pro-L-Pro-OEt by the CID mass spectra of the sodium adduct ions in ESI mass spectrometry. The optimized geometries of the [M + Na](+) and the [M + Na - Boc + H](+) ions calculated by ab initio molecular orbital calculations suggest that the chiral recognition of these diastereomers was due to the difference of the orientation of a sodium ion to the oxygen and nitrogen atoms in dipeptide derivatives, and to the difference of the total energies between them.

Ab initio molecular orbital study of the reactivity of active alkyl groups. V. Nitrosation mechanism of acetone with syn-form of methyl nitrite.

The mechanisms of nitrosation of acetone through sodium enolate [CH3CO1CH2]-Na+ (1) or naked enolate [CH3CO1CH2]- (2) with methyl nitrite CH3O3NO2 (3), and the reactivity of the syn-form of 3 (syn-3) during the C-N bond formation process were investigated using ab initio molecular orbital (MO) methods. Our results have demonstrated the predominant formation of E-1-hydroxyimino-2-oxo-propane CH3COCH=NOH (4E) when the complex [CH3CO1CH2NO2(O3CH3)]-Na+ was produced kinetically via a metal-chelated pericyclic transition state (TS(CHELATED)), in which the O3 atom of syn-3 was coordinated to the Na+ atom of 1.

Solvent effect on photoisomerisation of 3-methyl-1-phenylbutane-1,2-dione 2-oxime.

Photoisomerisation of (2E)- and (2Z)-3-methyl-1-phenylbutane-1,2-dione 2-oxime (MPBDO) in several solvents was studied. With increasing dielectric constants of solvents, kinetic constants of forward reactions (E-form-->Z-form) did not change appreciably but those of reverse reactions (Z-form-->E-form) decreased. The positive correlation was found between equilibrium constants of photoisomerisation and dielectric constants of solvents.