Development of simultaneous determination of dopamine 2, histamine 1, and muscarinic acetylcholine receptor occupancies by antipsychotics using liquid chromatography with tandem mass spectrometry.

Receptor occupancy is an indicator of antipsychotic efficacy and safety. It is desirable to simultaneously determine the occupancy of multiple brain receptors as an indicator of the efficacy and central side effects of antipsychotics because many of these drugs have binding affinities for various receptors, such as dopamine 2 (D2), histamine 1 (H1), and muscarinic acetylcholine (mACh) receptors. The purpose of this study was to develop a method for the simultaneous measurement of multiple receptor occupancies in the brain by the simultaneous quantification of unlabeled tracer levels using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Rats were pre-administered with a vehicle, displacer, or olanzapine, and mixed solutions of raclopride, doxepin, and 3-quinuclidinyl benzilate (3-QNB) were administered (3, 10, and 30 µg/kg). The brain tissue and plasma tracer concentrations were quantified 45 min later using LC-MS/MS, and the binding potential was calculated. The highest binding potential was observed at 3 µg/kg raclopride, 10 µg/kg doxepin, and 30 µg/kg 3-QNB. Tracer-specific binding at these optimal tracer doses in the cerebral cortex was markedly reduced by pre-administration of displacers. D2, H1, and mACh receptor occupancy by olanzapine increased in a dose-dependent manner, reaching 70-95%, 19-43%, and 12-45%, respectively, at an olanzapine dose range of 3-10 mg/kg. These results suggest that simultaneous determination of in vivo D2, H1, and mACh receptor occupancy is possible using LC-MS/MS.

Investigating the Transepithelial Transport and Enzymatic Stability of Lactononadecapeptide (NIPPLTQTPVVVPPFLQPE), a 19-Amino Acid Casein-Derived Peptide in Caco-2 Cells.

Lactononadecapeptide (LNDP; NIPPLTQTPVVVPPFLQPE), a casein-derived peptide comprising 19 residues, is known for its capacity to enhance cognitive function. This study aimed to explore the transepithelial transport and stability of LNDP. Results showed that LNDP retained over 90% stability after 2 h of treatment with gastrointestinal enzymes. The stability of LNDP on Caco-2 cell monolayers ranged from 93.4% ± 0.9% to 101.1% ± 1.2% over a period of 15-60 min, with no significant differences at each time point. The permeability of LNDP across an artificial lipid membrane was very low with the effective permeability of 3.6 × 10-11 cm/s. The Caco-2 assay demonstrated that LNDP could traverse the intestinal epithelium, with an apparent permeability of 1.22 × 10-6 cm/s. Its transport was significantly inhibited to 67.9% ± 5.0% of the control by Gly-Pro, a competitor of peptide transporter 1 (PEPT1). Furthermore, PEPT1 knockdown using siRNA significantly inhibited LNDP transport by 77.6% ± 1.9% in Caco-2 cell monolayers. The LNDP uptake in PEPT1-expressing HEK293 cells was significantly higher (54.5% ± 14.6%) than that in mock cells. These findings suggest that PEPT1 plays a crucial role in LNDP transport, and LNDP exhibits good resistance to gastrointestinal enzymes.

Palatability evaluation of orally disintegrating tablets using a visual analog scale in clinical trials.

OBJECTIVE: Visual analog scale (VAS) can be used to evaluate multiple parameters. There have been no reports on the verification of order effects or reproducibility of the VAS method for overall palatability of oral dosage forms. The purpose of this study was to assess the validity of a method for evaluating the palatability of orally disintegrating tablets (ODTs) using a 100-mm VAS. MATERIALS AND METHODS: We conducted clinical trials to evaluate the overall palatability, taste, and scent of 3 ODTs (F1, F2, F3) that contained famotidine (20, 10, and 5 mg, respectively). The study protocol was approved by the Research Ethics Committee of the University of Shizuoka, Japan (No. 21 - 36). To investigate the intergroup reproducibility of the VAS evaluation, 40 participants were divided into three groups, and each group underwent human gustatory sensation test of F1, F2, and F3, performed using a crossover design with 6 different tasting sequences. To evaluate intragroup reproducibility of the VAS evaluation, the participants assessed the same ODTs twice. RESULTS: The VAS scores for overall palatability followed the same order (F3>F2>F1) in all groups. The VAS scores for the overall palatability of F1, F2, and F3 did not significantly differ between the first and second evaluations. The Kruskal-Wallis test indicated a minimal impact of the assessment order on ODT evaluations. We confirm the reliability and reproducibility of the VAS method for evaluating ODT palatability. CONCLUSION: The VAS method for assessing ODT palatability provides accurate information and can contribute to the design and manufacture of patient-friendly pharmaceutical products.

Predicting muscarinic receptor occupancy in human bladder mucosa from urinary concentrations of antimuscarinic agents for overactive bladder.

To assess the pharmacologically relevant and selective muscarinic receptor occupancy in the bladder mucosa, we considered not only plasma drug concentrations but also urinary drug concentrations. The purpose of this study was to predict muscarinic receptor occupancy in the human bladder mucosa based on urinary concentrations in response to clinical dosages of antimuscarinic agents used to treat overactive bladder. The calculated mean plasma or serum unbound steady state concentrations were 0.06-11 nM in clinical dosages of five antimuscarinic agents. Urinary concentrations calculated from the mean plasma or serum and renal clearance ranged between 19 nM and 2 µM, which were >10-fold higher than the Ki values for bladder muscarinic receptors excluding propiverine. Bladder mucosal muscarinic receptor occupancy estimated from the urinary concentrations and the Ki values was >90 % at a steady state in clinical dosages of five antimuscarinic agents. The bladder muscarinic receptor occupancy was higher than that in the parotid gland calculated based on the mean plasma or serum unbound concentrations and Ki values for muscarinic receptors in the parotid gland. These results suggest that sufficient and selective muscarinic receptor occupancy by antimuscarinic agents, to exert pharmacological effects, in the bladder mucosa can be predicted using urinary concentrations.

Development of an on-site therapeutic drug monitoring method using a portable spectrometer.

We report on the development of an on-site therapeutic drug monitoring (TDM) method for vancomycin (VCM) utilizing a portable spectrometer and commercially available immunoturbidimetric assay reagents designed for automated clinical chemistry analyzers. The method enables the quantification of VCM in plasma samples within 10 min, with a good correlation between the measured values and the theoretical values (r2 = 0.995). The intra and inter-day precisions were found to be below 12.5% and 17.7%, respectively. Moreover, we established a correlation between the quantitative values using this method and those measured through HPLC-UV and automated clinical chemistry analyzers, showing good reliability (R2 = 0.970 and 0.951, respectively). This method allows anyone to rapidly perform TDM at the bedside and is expected to be used to evaluate appropriate drug therapy.

Palatability of Aripiprazole Gummies Prepared from Commercially Available Products: Pharmaceutical Formulation for Improving Patient Adherence.

Good adherence to medication is critical for successfully treating psychiatric disorders. Tailor-made pharmaceutical formulations can provide a suitable dosage form to meet the specific needs of individual patients who exhibit poor adherence to industrially manufactured products. Herein, we prepared aripiprazole (ARP) gummies (ARP-Gs) using a commercially available ARP formulation. We aimed to clarify the palatability of ARP-Gs by performing a gustatory sensation test in healthy volunteers. We performed two types of organoleptic masking of ARP-Gs, cocoa- and fruit-flavoured gummies (6.0 mg of ARP/3.5 g of gummy), and conducted two different gustatory sensation tests for each ARP-G. Ten young, healthy volunteers (mean ± standard deviation, 23.7 ± 1.2 years) were enrolled in each trial. The overall palatability of ARP-Gs was evaluated using the 100-mm visual analogue scale (VAS). Receiver operating characteristic (ROC) curve analysis was performed between VAS scores of total ARP-G palatability and acceptability assessed using a 5-point rating scale. Among cocoa-flavoured ARP-Gs, those combining aspartame, cocoa powder, and banana flavour (ABC-ARP-G) exhibited the highest VAS scores for total palatability. Similarly, the VAS scores of grapefruit-flavoured ARP-Gs (GF-ARP-G) showed the highest values considering all fruit-flavoured ARP-Gs. The VAS scores for ABC-ARP-G and GF-ARP-G greatly exceeded the cut-off values of acceptability calculated using the ROC curve. We developed two types of ARP-Gs with organoleptic masking as tailor-made pharmaceutical formulations. ABC-ARP-Gs and GF-ARP-Gs could be acceptable in patients. ARP-Gs could be an alternative to currently available pharmaceutical formulations to enhance their adherence and meet the specific needs of individual patients.

Tablet characteristics and pharmacokinetics of orally disintegrating tablets containing coenzyme Q10 granules prepared by different methods.

This study aimed to elucidate the characteristics and pharmacokinetics of orally disintegrating tablets (ODTs) containing coenzyme Q10 (CoQ10) granules prepared by spray drying, hot-melting, and wet granulation. The hardness and disintegration times of CoQ10-ODTs containing 5 % crospovidone were 61.6-81.8 N and < 30 s, respectively; these values indicate that the as-prepared ODTs were adequate for clinical use. The hardness and disintegration times of all ODTs did not change significantly after a 28-day storage period at 30 °C/10 % relative humidity (RH), but storage under high temperature and humidity affected their characteristics. The dissolution and pharmacokinetics of CoQ10-ODTs showed that ODTs prepared using the spray-drying method had the highest dissolution and absorbability among the CoQ10-ODTs tested. These results provide useful information for the preparation of ODTs using CoQ10.

Efficacy and safety of propranolol cream in infantile hemangioma: A prospective pilot study.

Infantile hemangioma (IH) is a common tumor in infants that gradually resolves and is often untreated. However, for cosmetic reasons, parents often opt for treatment. Oral propranolol, the first-line therapy for IH, is sometimes associated with several side effects, including hypotension, bradycardia, and hypoglycemia. No clinical studies on topical propranolol have been conducted using standardized procedures. We evaluated the efficacy and safety of topical propranolol in patients with IH. This multicenter, prospective pilot study was conducted from June 2019 to October 2020 and involved eight Japanese infants aged 35-150 days with proliferating IH. Patients were treated with 5% propranolol cream twice daily. We examined the efficacy rate based on central evaluation (complete or near-complete healing of the target hemangioma) at weeks 24 and 12, respectively, compared to baseline values. The efficacy rate at week 24 was 68.8% (95% confidence interval: 44.1-85.9%). The surface area, maximum diameter, and color intensity of the target IH decreased over time. Adverse event and drug-related adverse event rates were 87.5% and 0%, respectively. Propranolol cream may be effective and safe in Japanese patients with IH and may be considered a first-choice treatment for small and superficial IHs in cosmetically problematic areas.

Topical Formulations of Propranolol for Infantile Hemangiomas: Characteristics of Formulations and Three Cases of Infants Administered Topical Propranolol Cream.

Propranolol is used as the first-line treatment for infantile hemangiomas (IHs). As oral formulations can cause systemic adverse drug reactions (ADRs), we prepared topical propranolol formulations and evaluated their pharmaceutical profiles. We also present three cases of pediatric patients with IHs who were treated with the propranolol formulations. Propranolol cream (hydrophilic cream, 1, 3, and 5%) and gels (carboxyvinyl polymer, hydroxypropyl methylcellulose, gellan gum, 1%) were prepared. The in vitro skin permeability of these formulations was assessed using Franz-type diffusion cells. The pharmaceutical profiles, including propranolol content, pH, and ductility, of the propranolol creams were evaluated. For the stability test, similar pharmaceutical evaluations were performed after the creams were stored at 25 °C and 56% relative humidity for 3 months. We examined three patients treated with propranolol cream to investigate the clinical course of IH and adverse events after the propranolol cream was applied for 5-12 months. In the in vitro skin permeability assay, topical propranolol formulations made of hydrophilic cream and gellan gum permeated the most. The amount of propranolol that permeated increased with propranolol concentration. After storage for 3 months, no substantial changes were observed in any pharmaceutical profile. The IHs were discolored in all patients. Tumor size also decreased in some patients. Furthermore, no adverse events caused by propranolol cream were observed during application. In conclusion, propranolol cream can be prepared as a hospital formulation with adequate quality. Topical propranolol therapy is effective in reducing the incidence of systemic ADRs.

Gummi Formulations Comprising Amenamevir Solid Dispersions with Polyvinyl Alcohol.

The aim of the present study was to determine whether solid dispersions (SDs) are applicable to gummi formulations. Amenamevir was selected as a model of a poorly water-soluble drug, and polyvinyl alcohols (PVAs) with various degrees of hydrolysis (PVA 66, PVA 80, PVA 88, and PVA 66/88) were used as SD carriers. Design of experiments (DOE) was used to develop a gummi formulation that was suitable for an amenamevir SD using SD with PVA 66. Dissolution studies and clinical sensory tests on 11 formulations calculated by DOE revealed that a gummi formulation comprising 10.5% gelatin and 22.8% water was suitable for SD of the drug. Gummi formulations comprising amenamevir SDs with various PVAs were prepared using the determined gummi formulation, and their ability to dissolve amenamevir, their stability, and their oral absorption in dogs were evaluated. The results suggested that PVA 66, PVA 66/88, and PVA 80 were appropriate in terms of dissolution, stability, and in vivo absorption, respectively. Considering these results comprehensively, it was concluded that PVA 80, which enabled the highest degree of absorption, was the most suitable SD carrier for gummi formulations. Thus, it was possible to apply a PVA SD of amenamevir to gummi formulations.

Prediction of the Area under the Curve Using Limited-Point Blood Sampling in a Cocktail Study to Assess Multiple CYP Activities.

A cocktail study is an in vivo evaluation method to assess multiple CYP activities via a single trial and single administration of a cocktail drug that is a combination of multiple CYP substrates. However, multiple blood samples are required to evaluate the pharmacokinetics of a CYP probe drug. A limited-point sampling method is generally beneficial in clinical studies because of the simplified protocol and reduced participant burden. The aim of this study was to evaluate whether a limited-point plasma concentration analysis of CYP substrates in a cocktail drug could predict their area under the curve (AUC). We created prediction models of five CYP substrates (caffeine, losartan, omeprazole, dextromethorphan, and midazolam) using multiple linear regressions from the data of two cocktail studies, and then performed predictability analysis of these models using data derived from data in the co-administration with inducer (rifampicin) and inhibitors (fluvoxamine and cimetidine). For the administration of inhibitors, the AUC prediction accuracy (mean absolute error (MAE)) were <39.5% in Model 1 and <26.2% in Model 2 which were created using 1- and 4-point sampling data. MAE shows larger values in the administration of inducer in compared with the administration of inhibitors. The accuracy of the prediction in Model 2 could be acceptable for screening of inhibitions. MAE for caffeine, dextromethorphan, and midazolam were acceptable in the model that used 4 sampling points from all data. The use of this method could reduce the burden on the subject and make it possible to evaluate each AUC in a minimally invasive manner.

Evaluation of Disappearance Time and Palatability of Foams in the Oral Cavities of Healthy Volunteers, and Preparation of Drug-Containing Foam Formulations for Use in the Treatment of Oral Mucositis.

Oral mucositis is one of the most common adverse effects of radiation and chemotherapy in treatments of cancers. Some clinical guidelines have focused on the prevention and treatment of oral mucositis, and thus, a mouthwash containing drugs is often recommended. In this study, we aimed to evaluate the disappearance time and palatability in the oral cavities of healthy volunteers in foams prepared from different concentrations of the three viscosity grades of methylcellulose (SM-4, -100, -400). In addition, we prepared foam formulations of drugs (benzydamine, dexamethasone, allopurinol and rebamipide) for use as a prevention and treatment of oral mucositis. There was a significant relationship between the foam drainage ratios at 5-15 min and the disappearance time in the oral cavities. The significant relationship of foam densities to the foam disappearance time and overall palatability in a clinical study were observed. Thus, the foam density is considered an important parameter and reflects these clinically important properties. The foam from SM-4 has the longest disappearance time and the best palatability followed by foams from the 4 and 1% SM-4. Drug contents in drug-containing foam formulations which were prepared with 1-4% SM-4 represented 101-112% of the loaded drug contents, and the relative standard deviations of drug contents were <2.2%, which suggests that these formulations had pharmaceutically acceptable properties. This is the first report in regard to foam formulations containing drugs for the prevention and treatment of oral mucositis, and these formulations could be potentially useful for the prevention and treatment of oral mucositis.

Verification of a cocktail approach for quantitative drug-drug interaction assessment: a comparative analysis between the results of a single drug and a cocktail drug.

A cocktail approach is a method to comprehensively evaluate the activity of cytochrome P450 enzymes (CYPs) by co-administering multiple CYP substrates. This is the first report that compares the results from a cocktail study to a single substrate separate administration study (single study) with concomitant administration of CYP inducers/inhibitors. The validity of a cocktail study for use as a quantitative drug-drug interactions (DDIs) assessment was evaluated.We administered a cocktail drug (caffeine, losartan, omeprazole, dextromethorphan, midazolam) with rifampicin, cimetidine or fluvoxamine. A comparative analysis was performed between the results of a cocktail study and single studies. The results of single studies were obtained from a literature review and the trials of single substrate separate administration.A strong positive correlation of the AUC ratio of all drugs between single studies and the cocktail study was obtained. The ratio of AUC change of 12 combinations converged to 0.82-1.09, and 2 combinations ranged between 0.74-1.32.The differences in the degree of interaction between the single studies and cocktail study are acceptable to evaluate DDIs for almost all combinations. Our results indicate that a cocktail study is an adequate and quantitative evaluation method for DDIs.

Impact of community pharmacist-led intensive education on the control of serum phosphate levels in haemodialysis patients.

Background Administration of phosphate binders can decrease serum phosphate levels and improve the prognosis of patients on dialysis. However, patients are often non-adherent to phosphate binder medication. Although community pharmacist-led education could be effective in the maintenance of adherence to phosphate binder medication, its impact has not been evaluated. Objective We aimed to evaluate the impact of community pharmacist-led intensive education focusing on phosphate binders for patients receiving haemodialysis. Setting The study comprising three phases (baseline phase, intervention phase, and follow-up phase) was conducted at the Yamauchi Pharmacy, Japan. Method Six pharmacists provided intensive education focusing on phosphate binders to patients receiving haemodialysis. As intensive education, a sheet containing checks for the remaining phosphate binders and information advising the patients on the use of the drugs was issued. Using the check sheet filled in by the patient, the pharmacists repeatedly provided education appropriate to the individual patient's medication status and level of understanding to encourage the correct use of phosphate binders for 8 weeks (intervention phase). We investigated their serum phosphate levels from their medical records from 2 months before the start of intensive education (baseline phase) to 8 months after the end of the education (follow-up phase). Main outcome measure Serum phosphate levels in patients receiving haemodialysis after intensive education by community pharmacists. Results Fifty patients were enrolled in this study. During the intervention phase, serum phosphate levels in the patients with high and the highest serum phosphate level (6-7 mg/dL and ≥ 7 mg/dL, respectively) significantly decreased by 6.9% (P = 0.007) and 10.9% (P = 0.034), respectively. The levels remained below the baseline value throughout the follow-up phase in patients with the highest serum phosphate level. Conclusion Community pharmacist-led education focusing on phosphate binders affects short- and long-term management of serum phosphate levels in patients receiving haemodialysis, especially the patients whose levels were initially high.

Clinical evaluation of drug-drug interactions between the cytochrome P450 substrates selexipag and clopidogrel in Japanese volunteers.

AIMS: The strong cytochrome P450 (CYP) 2C8 inhibitor gemfibrozil has been demonstrated to increase the area under the plasma concentration-time curve from 0 to infinity (AUC0-∞ ) of ACT-333679, an active metabolite of selexipag, by 11-fold. Similarly to gemfibrozil, the CYP2C8 inhibitor clopidogrel increased ACT-333679 concentration by 1.9-fold after a single loading dose (300 mg once daily) and 2.7-fold after repeated treatment with the maintenance dose (75 mg once daily) in Europeans. However, the effects of clopidogrel on the pharmacokinetics of selexipag and ACT-333679 have not been fully elucidated in the Japanese population. METHODS: We investigated the effect of clopidogrel on the pharmacokinetics of selexipag and ACT-333679 in 14 healthy Japanese volunteers. RESULTS: The concomitant administration of clopidogrel with selexipag did not influence the maximum concentration and AUC0-∞ of selexipag, whereas it significantly increased AUC0-∞ of ACT-333679 by approximately 1.90-fold (90% confidence interval 1.69-2.14) without changing the maximum concentration. When selexipag was administered 1 day after clopidogrel was discontinued, the increase in AUC0-∞ of ACT-333679 was 1.37-fold (90% confidence interval 0.93-2.02), suggesting that, although the inhibitory effect of clopidogrel on CYP2C8 was reduced, it persisted for at least 1 day after withdrawal. CONCLUSION: Our results demonstrated the impact of clopidogrel on the pharmacokinetics of selexipag and its active metabolite and suggested that selexipag should be carefully prescribed with clopidogrel with dose adjustment or reducing the dosing frequency in Japanese clinical settings.

Combining Powder Formulations of Drugs with Food and Beverages to Improve Palatability.

The taste of medicines can significantly affect patient adherence. Pediatric patients often cannot take powder medicines because of their unpleasant taste. Therefore, patients' parents and health care professionals, including pharmacists, often combine medicines with food or beverages to make them easier for pediatric patients to consume because this can reduce their unpleasant taste. The purpose of this study was to evaluate the palatability of powder formulations of azithromycin and carbocysteine and explore their combination with food or beverages to improve palatability for pediatric patients. We quantitatively evaluated the palatability of powder formulations by performing the gustatory sensation test using the visual analog scale score. The gustatory sensation tests were performed on 16 healthy adult volunteers (age 23.0 ± 2.6 years) and indicated that some food and beverages improved the palatability of the powder formulations of azithromycin and carbocysteine. The results of this study indicate that ice cream improves the palatability of azithromycin, while yogurt improves the palatability of carbocysteine. Moreover, the subjects recommended these same combinations for pediatric patients. This study suggests that some foods and beverages improve the palatability of powder formulations, thereby decreasing the possibility that pediatric patients will refuse medications because of their unpleasant taste.

Morphological evaluation of low-dose midazolam granules by laser Raman microscopy.

Raman analysis has higher sensitivity for the detection of active pharmaceutical ingredients (APIs) than additives; thus, it is expected to be used for the evaluation of low-content preparations. The purpose of this study was to clarify the usefulness of granule morphology assessment using Raman analysis in the development of low-content formulations. In this study, midazolam was used as a model drug to prepare granules as a low-content formulation. Raman images were used to visualize the distribution of ingredients on the surface of the granules, determine the particle size of midazolam bound to the granules, and investigate the types of excipient components to which midazolam is bound. It was suggested that midazolam particles of a certain size were difficult to bind to excipients and had particularly low adhesion to mannitol. It was revealed that this phenomenon caused the segregation of the content of midazolam particles in the granules. Therefore, to obtain granules with good content uniformity, it was considered necessary to control the particle size of the API and select an additive that does not differ in adhesiveness to the main drug. Additionally, the findings obtained by morphological observation could be clarified by the quantitative evaluation of additives using Raman.

Evaluation of Weight Variation in Mini-Tablets Manufactured by a Multiple-Tip Tool.

Recently, owing to their pharmaceutical and clinical utility, mini-tablets have been well studied by researchers. Mini-tablets are usually manufactured by compression molding using a multiple-tip tool in a rotary tableting machine. Owing to their special structure, ensuring uniformity is a very important challenge in the manufacturability of mini-tablets using the multiple-tip tool. In this study, we aimed to evaluate the weight variation in mini-tablets produced by a multiple-tip tool, which is considered to be the root cause affecting the uniformity, and to investigate the physical properties of drug granules and tableting conditions in a rotary tableting machine that could reduce this weight variation. In addition, the relationship between these factors and response was visualized using response surface analysis. It was shown that the weight variation in mini-tablets produced by a multiple-tip tool was reduced when using a forced feeder compared with an open feeder. Furthermore, in the case of an open feeder, the optimal range of the average particle size diameter of drug granules and the rotational speed of the rotating disc in the rotary tableting machine were determined from response surface analysis. It was suggested that it is possible to reduce the weight variation in the mini-tablets by selecting drug granules with an average particle size diameter of 100-150 µm and using tableting conditions with a rotational speed of 40-60 rpm. This study elucidated the factors that affect uniformity and determined their optimal range for the manufacture of mini-tablets.

The µ-opioid receptor gene polymorphism 118A>G weakens the pharmacological action of buprenorphine.

AIMS: Opioids are commonly used analgesics for moderate to severe pain, but levels of drug effect vary among individuals. As for the mechanisms underlying these individual differences, there have been reports suggesting effects of polymorphisms in the gene encoding µ-opioid receptor (OPRM1). However, whether these polymorphisms affect the actions of µ-opioid receptor partial agonists has yet to be determined. This study aimed to assess differences in the pharmacological actions of buprenorphine, a µ-opioid receptor partial agonist, due to a polymorphism (A118G, rs1799971) in the OPRM1 gene in humans. MATERIALS AND METHODS: Ten healthy adult men (5 with OPRM1 c.118AA and 5 with OPRM1 c.118GG) received a single intravenous dose of buprenorphine hydrochloride at 0.001 mg/kg. Blood samples were collected up to 360 minutes after drug administration to assess the pharmacokinetics of buprenorphine. Nociceptive thresholds (temperature), digital symbol substitution test (DSST), and visual analog self-rating scale (VAS) for subjective symptoms were also evaluated over time to assess the pharmacodynamics. RESULTS: Nociceptive thresholds were significantly increased in the AA as compared to the GG group after buprenorphine administration (p = 0.025), while the DSST scores were significantly lower in the AA group (p < 0.001). The VAS scores for drowsiness (p < 0.001), malaise (p < 0.001), nausea (p < 0.001), and euphoria (p = 0.004) were higher in the AA than in the GG group. CONCLUSION: Levels of pharmacological actions of a µ-opioid receptor partial agonist vary in accordance with a polymorphism in the OPRM1 gene (A118G).

Evaluation of in Vitro and in Vivo Transdermal Absorption of Solifenacin Succinate.

Solifenacin (Sol), an antimuscarinic agent has been widely used for the treatment of overactive bladder. Transdermal formulations can be administered without water as well as absorbed slowly into the blood over a long period of time. The aim of this study was to develop cream and tape formulations of Sol, and evaluate the transdermal permeation and absorption of the drug from the two formulations in vitro and in vivo, respectively. In the preparation of cream formulation, Sol succinate was dissolved in purified water, and the mixture was added to the hydrophilic cream. Then, aqueous sodium hydroxide was added to the cream. In the tape formulation, Sol succinate was dissolved in a solvent with propylene glycol, diisopropanolamine, triethyl citrate, and EUDRAGIT E100. The dissolved solvent was poured onto a polyethylene film. Cream (5%) and tape (15%) formulations demonstrated high skin permeability. Addition of an adsorption enhancer (N-methyl-2-pyrrolidone) did not further increase the level of skin permeability. In subsequent in vivo experiments in rats, both the cream and tape formulations led to slow absorption of Sol into plasma, with increased t1/2 compared with oral administration. Plasma Sol concentrations peaked 24 h after transdermal application and the drug was still detectable in plasma 72 h after application. Additionally, the cream (5%) and tape (15%) formulations resulted in a higher area under the plasma concentration vs. time curve from 0 to 72 h (AUC0-72) compared with oral formulation (30 mg/kg). In conclusion, significant in vitro permeability and in vivo absorption of Sol from the transdermal formulations were observed.