The influence of edema on the bisoprolol blood concentration after bisoprolol dermal patch application: A case-control study.

BACKGROUND: Beta-blocking is important for critically ill patients. Although some patients are required to continue taking beta-blockers after they no longer need critical care, some of these patients have impaired swallowing abilities. Bisoprolol dermal patches have recently been introduced and appear to be a good alternative to oral bisoprolol tablets. However, it is still unclear whether the pharmacodynamics of such patches are affected by edema in patients who have experienced critical care. This study aimed to clarify the effects of systemic edema on beta-blocker absorption from dermal patches in critically ill patients. METHOD: Patients who exhibited tachycardia and impaired swallowing function after critical care were included in this study. They were assigned to either the edema group (n = 6) or no edema group (n = 6) depending on the presence/absence of edema in the lower extremities. A bisoprolol dermal patch was pasted onto each subject, and the blood bisoprolol concentration was checked at 8 timepoints over the next 24 hours. The area under the serum concentration time curve, maximum concentration observed (Cmax), and time of maximum concentration observed were also examined. RESULT: The mean blood bisoprolol concentrations of the 2 groups were not significantly different at 2, 4, 6, 8, 10, 12, 16, or 24 hours after the patch application. The area under the serum concentration time curve and maximum concentration observed were not different between the groups. The mean heart rates of the 2 groups were not significantly different at 6, 12, or 24 hours after the patch application (Student t test, P = .0588, P = .1080, and P = .2322, respectively). CONCLUSION: In this study, the blood concentration of bisoprolol and its heart rate-reducing effects after bisoprolol dermal patch application might not be affected by systemic edema in the lower extremities.

Application of physiologically based biopharmaceutics modeling to understand the impact of dissolution differences on in vivo performance of immediate release products: The case of bisoprolol.

Merck KGaA observed slight differences in the dissolution of Concor® (bisoprolol) batches over the years. The purpose of this work was to assess the impact of in vitro dissolution on the simulated pharmacokinetics of bisoprolol using in vitro-in vivo relationship established with available in vitro dissolution and corresponding plasma concentrations-time data for several bisoprolol batches. A mechanistic absorption model/physiologically based pharmacokinetics model linked with a biopharmaceutics tool such as dissolution testing, namely, physiologically based biopharmaceutics modeling (PBBM), can be valuable in determining a dissolution "safe space." A PBBM for bisoprolol was built using in vitro, in silico, and clinical data. We evaluated potential influences of variability in dissolution of bisoprolol batches on its clinical performance through PBBM and virtual bioequivalence (BE) trials. We demonstrated that in vitro dissolution was not critical for the clinical performance of bisoprolol over a wide range of tested values. Based on virtual BE trials, safe space expansion was explored using hypothetical dissolution data. A formulation with in vitro dissolution reaching 70% dissolved in 15 min and 79.5% in 30 min was shown to be BE to classical fast dissolution of bisoprolol (>85% within 15 min), as point estimates and 90% confidence intervals of the maximum plasma concentration and area under the concentration-time curve were within the BE limits (0.8-1.25).

Comprehensive Exploration of Medications That Affect the Bleeding Risk of Oral Anticoagulant Users.

Oral anticoagulants (OACs) pose a major bleeding risk, which may be increased or decreased by concomitant medications. To explore medications that affect the bleeding risk of OACs, we conducted a nested case-control study including 554 bleeding cases (warfarin, n = 327; direct OACs [DOACs], n = 227) and 1337 non-bleeding controls (warfarin, n = 814; DOACs, n = 523), using a Japanese health insurance database from January 2005 to June 2017. Major bleeding risk associated with exposure to concomitant medications within 30 d of the event/index date was evaluated, and adjusted odds ratios (aORs) were calculated using logistic regression analysis. Several antihypertensive drugs, such as amlodipine and bisoprolol, were associated with a decreased risk of bleeding (warfarin + amlodipine [aOR, 0.64; 95% confidence interval (CI): 0.41-0.98], DOACs + bisoprolol [aOR, 0.51; 95% CI, 0.33-0.80]). As hypertension is considered a significant risk factor for intracranial bleeding in antithrombotic therapy, antihypertensive drugs may suppress intracranial bleeding. In contrast, telmisartan, a widely used antihypertensive drug, was associated with an increased risk of bleeding [DOACs + telmisartan (aOR, 4.87; 95% CI, 1.84-12.91)]. Since telmisartan is an inhibitor of P-glycoprotein (P-gp), the elimination of rivaroxaban and apixaban, which are substrates of P-gp, is hindered, resulting in increased blood levels of both drugs, thereby increasing the risk of hemorrhage. In conclusion, antihypertensive drugs may improve the safety of OACs, and the pharmacokinetic-based drug interactions of DOACs must be considered.

Association Between Dose and Plasma Concentration of Bisoprolol in Patients with Heart Failure (CVI ARO 6).

Although bisoprolol is used widely to treat patients with heart failure (HF), little information is available regarding the association between the dose of bisoprolol administered and the bisoprolol plasma concentration (Bis-PC) in real-world clinical practice.This was a single-center, observational study in 114 patients with HF receiving once-daily bisoprolol. After determination of trough Bis-PC, the relationship between the dose of bisoprolol and Bis-PC was analyzed. In a multiple linear regression model, the dose of bisoprolol and estimated creatinine clearance (reciprocal number) were identified as independent predictors. HF severity and hepatic function were not associated with Bis-PC.Bis-PC was increased by renal dysfunction, which explained most of the discrepancy between the dose of bisoprolol administered and Bis-PC.

Population pharmacokinetic analysis of bisoprolol in type 2 diabetic patients with hypertension.

PURPOSE: Given that it has been reported that type 2 diabetes mellitus may affect the pharmacokinetics of a large number of drugs and that there are still no published population pharmacokinetic (PopPK) analyses in routinely treated patients with hypertension and type 2 diabetes mellitus as comorbid condition, the aim of this study was to determine PK variability of bisoprolol in 70 Serbian patients using the PopPK approach. METHODS: PopPK analysis was conducted using a nonlinear mixed effects model (NONMEM), version 7.3.0 (Icon Development Solutions). In our patients, a total daily dose of bisoprolol ranged from 1.25 to 10 mg. The drug was administrated orally as a single daily dose or in two divided doses per day. RESULTS: A wide range of the drug concentrations were noted (1-103 ng/mL) in the population consisted of the adult patients with type 2 diabetes mellitus. From a total of 21 separately assessed covariates, our results indicated that only creatinine clearance could have a potential impact on the variability of the clearance of bisoprolol. CONCLUSION: Routine assessment of renal function should be carried out before the initiation of treatment with bisoprolol in order to individualize the dose and to prevent possible accumulation and adverse drug reactions.

The influence of viscosity-enhancing agents on oral absorption of drugs.

The objective of this study was to evaluate the influence of viscosity-enhancing agents on oral absorption of metoprolol (MPL) and bisoprolol (BPL). Although the viscosity values were similar for MPL and BPL in hydroxypropyl methylcellulose (HPMC, 1.2 % (w/w)) and polyvinyl alcohol (PVA, 8.8 % (w/w)) solutions, the order of diffusion rate constants of the drugs in media were phosphate buffer solution (reference) > HPMC solution > PVA solution. In in vivo rat intestinal absorption experiments showed that the Cmax and AUC values of the drugs were lowest when they were administered into the rat jejunum in a PVA solution. In vitro binding studies showed that this may have been due to adsorption of the drugs to PVA molecules, resulting in decreased free fractions of the drugs. Our results indicated that intestinal absorption of the drugs in PVA solution was influenced both by decreased diffusion of the drugs and by interaction with PVA. Since various viscosity-enhancing agents are widely used as pharmaceutical and food additives, these findings may be of significance for understanding therapeutic efficacy and safety of oral drug products.

S-amlodipine-bisoprolol combination therapy caused elevated transaminases and triglyceride levels in healthy Chinese subjects: a randomized controlled, open-label, multiple-dose pharmacokinetic interaction study.

Introduction: S-amlodipine is main anti-hypertensive active enantiomer of amlodipine. Bisoprolol is a ß-blocker particularly suitable for hypertensive patients with sinus tachycardia. We evaluated the pharmacokinetic interaction between S-amlodipine and bisoprolol in healthy Chinese subjects. Areas covered: Thirty-two subjects were randomly divided into two equal groups. Subjects in group A were administered S-amlodipine 5 mg for 10 days followed by S-amlodipine 5 mg plus bisoprolol 5 mg for 7 days. Subjects in group B were administered bisoprolol 5 mg for 7 days, followed by S-amlodipine 5 mg plus bisoprolol 5 mg for 10 days. Blood samples were collected for evaluation of pharmacokinetic interaction. Tolerability was evaluated by interview, vital signs, 12-lead ECGs, physical examination, and clinical laboratory tests. Expert opinion: The geometric mean ratio (90% CI) for amlodipine AUCτ,ss and Css-max during the monotherapy and combination therapy periods were 1.0389 (0.9879, 1.0926) and 1.0213 (0.9556, 1.0915). For bisoprolol, it was 1.0193 (0.9834, 1.0566) and 0.9989 (0.9133, 1.0925). Most adverse events were mild-moderate. There was high incidence of elevated alanine aminotransferase, aspartate aminotransferase, and triglyceride.This study found no pharmacokinetic interaction between S-amlodipine and bisoprolol. Alanine aminotransferase, aspartate aminotransferase, and triglycerides should be closely monitored.

Population Pharmacokinetic Analysis of Bisoprolol in Patients With Acute Coronary Syndrome.

To date, many questions about the extent and cause of pharmacokinetic (PK) variability of even the most widely studied and prescribed ß1-adrenergic receptor blockers, such as metoprolol and bisoprolol, remain unanswered. Given that there are still no published population pharmacokinetic (PopPK) analyses of bisoprolol in routinely treated patients with acute coronary syndrome (ACS), the aim of this study was to determine its PK variability in 71 Serbian patients with ACS. PopPK analysis was conducted using a nonlinear mixed-effects model (NONMEM), version 7.3.0 (Icon Development Solutions). In each patient, the same formulation of bisoprolol was administered once or twice daily at a total daily dose of 0.625-7.5 mg. We separately assessed the effects of 31 covariates on the PKs of bisoprolol, and our results indicated that only 2 covariates could have possible influence on the variability of the clearance of bisoprolol: the mean daily dose of the drug and smoking habits of patients. These findings suggest that possible autoinduction of drug metabolism by higher total daily doses and induction of cytochrome P450 isoform 3A4 (CYP3A4) by cigarette smoke in liver could be the potential causes of increased total clearance of bisoprolol in patients with ACS.

Bioequivalence and Pharmacokinetics of Bisoprolol-Amlodipine 5 mg/5 mg Combination Tablet versus Bisoprolol 5 mg Tablet and Amlodipine 5 mg Tablet: An Open-Label, Randomized, Two-Sequence Crossover Study in Healthy Chinese Subjects.

BACKGROUND: The pharmacokinetics of bisoprolol and amlodipine administered as a fixed-dose combination (FDC) tablet have not been sufficiently studied in healthy Chinese subjects to support a medical need for using the FDC in hypertension. OBJECTIVE: This study was conducted to compare the pharmacokinetic profiles of the bisoprolol-amlodipine FDC tablet with the bisoprolol tablet and amlodipine tablet administered concomitantly under both fasting and fed conditions. METHODS: An open-label, randomized, two-period, two-sequence crossover study was designed under both fasting and fed conditions. The plasma concentrations of bisoprolol and amlodipine were analyzed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay, and the pharmacokinetic parameters of maximum concentration (Cmax) and area under the concentration-time curve (AUC) were used to evaluate bioequivalence. RESULTS: The point estimate of geometric mean ratios of Cmax and AUC from the time of dosing to the last measurable concentration (AUCt) for bisoprolol were 97.85% and 99.46% in the fasting state, and 93.87% and 98.95% in the fed state, respectively. For amlodipine, the geometric mean ratios of Cmax and AUCt were 100.03% and 96.76% in the fasting state, and 106.56% and 103.07% in the fed state. No cases of treatment-emergent adverse events were reported during the entire study period. CONCLUSIONS: Bioequivalence was achieved for bisoprolol and amlodipine FDC under both fasting and fed conditions, and all treatments were safe and well tolerated by all study subjects. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03226275.

ß-Blocker Dialyzability in Maintenance Hemodialysis Patients: A Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: There is a paucity of data available to describe drug dialyzability. Of the available information, most was obtained before implementation of modern hemodialysis membranes. Our study characterized dialyzability of the most commonly prescribed ß-blockers in patients undergoing high-flux hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients on hemodialysis (n=8) were recruited to an open label, pharmacokinetic, four-way crossover trial. Single doses of atenolol, metoprolol, bisoprolol, and carvedilol were administered on separate days in random order to each patient. Plasma and dialysate drug concentrations were measured, and dialyzability was determined by the recovery clearance and arterial venous difference methods. RESULTS: Using the recovery clearance method, the dialytic clearance values for atenolol, metoprolol, bisoprolol, and carvedilol were 72, 87, 44, and 0.2 ml/min, respectively (P<0.001). Applying the arterial venous difference method, the dialytic clearance values of atenolol, metoprolol, bisoprolol, and carvedilol were 167, 114, 96, and 24 ml/min, respectively (P<0.001). CONCLUSIONS: Atenolol and metoprolol are extensively cleared by hemodialysis compared with the negligible dialytic clearance of carvedilol. Contrary to estimates of dialyzability on the basis of previous literature, our data indicate that bisoprolol is also dialyzable. This finding highlights the importance of conducting dialyzability studies to definitively characterize drug dialytic clearance.

[Pharmacokinetic risk factors of beta-blockers overdose in the elderly: Case report and pharmacology approach]. / Facteurs de risque pharmacocinétiques de surdosage en bêta-bloquants chez les patients âgés : cas clinique et rationnel pharmacologique.

Beta-blockers are widely prescribed in elderly patients and may induce severe adverse drug reactions. We report a case of bisoprolol-induced bradycardia in an elderly patient with impaired renal function and use of cytochrome P450 inhibitors. A literature review has been performed in order to analyze pharmacokinetic risk factors of beta-blockers overdosing in geriatrics. Various mechanisms can result in decreased elimination of beta-blockers. These mechanisms vary according to the beta-blocker agent and may be combined in some individuals, especially elderly patients. This can lead to unexpected overexposure. Knowledge about drug interactions and pharmacokinetic elimination pathways is important for preventing overexposure and adverse drug reactions when using beta-blockers.

Quantification of Bisoprolol and Metoprolol in Simultaneous Human Serum and Cerebrospinal Fluid Samples.

BACKGROUND: Bisoprolol and metoprolol are moderately lipophilic, beta(1)-selective betablockers reported to cause adverse effects in the central nervous system (CNS), such as sleep disturbance, suggesting that both drugs may reach relevant concentrations in the brain. CNS beta(2)-receptor blockade has been suspected to be related to such effects. The higher molecular size of bisoprolol (325 Dalton) and the higher beta(1)-selectivity compared to metoprolol (267 Dalton) would suggest a lower rate of CNS effects. METHODS: To address the pharmacokinetic background of this assumption, we quantified to which extent these beta(1)-blockers are able to enter the cerebrospinal fluid (CSF) in 9 (bisoprolol group) and 10 (metoprolol group) neurological patients who had received one of the drugs orally for therapeutic purposes prior to lumbar puncture. We quantified their total concentrations by liquid chromatography/tandem mass spectrometry in paired serum and CSF samples. RESULTS: Median (interquartile range) in CSF reached 55% (47-64%) of total serum concentrations for bisoprolol and 43% (27-81%) for metoprolol, corresponding to 78% (67-92%) and 48% (30-91%) of respective unbound serum concentrations. CONCLUSION: The extent of penetration of bisoprolol and metoprolol into the CSF is similar and compatible with the assumption that both drugs may exert direct effects in the CNS.

Population Pharmacokinetic Analysis of Bisoprolol in Patients with Stable Coronary Artery Disease.

BACKGROUND AND OBJECTIVES: Bisoprolol is a selective beta adrenergic antagonist commonly used in treatment of coronary artery disease (CAD). The aim of our analysis was to estimate and identify different factors that could affect bisoprolol clearance (CL) and develop a population pharmacokinetic model in patients with stable coronary artery disease (CAD). METHODS: Population pharmacokinetic analysis was performed by using sixty-six plasma concentrations from the same number of patients (mean age 60.26 ± 9.68 years; mean total body weight 80.37 ± 12.93 kg) with CAD. We examined the effects of various clinical and demographic parameters using nonlinear mixed-effect modeling (NONMEM) with ADVAN1 with TRANS2 subroutine. The pharmacokinetics of bisoprolol in patients with CAD were suitably defined by an oral one-compartment model. RESULTS: The typical mean value for bisoprolol CL, estimated by the base model, in the target population was 6.76 l/h. The only demographic covariate which affected bisoprolol pharmacokinetic variability was creatinine clearance (CLcr). The final model of bisoprolol clearance was described by following equation: CL (l/h) = 2.83 + 0.0385 × CLcr (ml/min). Validation of the final model was performed in a group of 17 patients using the validation set and bootstrapping analysis. CONCLUSIONS: These findings suggest that one of the causes of clearance of bisoprolol variability in patients with CAD is the difference in renal function.

Mechanism study on ion-pair complexes controlling skin permeability: Effect of ion-pair dissociation in the viable epidermis on transdermal permeation of bisoprolol.

Though ion-pair strategy has been widely used in transdermal drug delivery system, knowledge about the molecular mechanisms involved in the skin permeation processes of ion-pair complexes is still limited. In the present study, a homologous series of fatty acids were chosen to form model ion-pair complexes with bisoprolol (BSP) to rule out the influence of functional groups on polar surface area, stability and other physicochemical properties of ion-pair complexes. The ion-pair complexes were characterized by FTIR, thermal analysis, and 1H NMR. The skin permeability of BSP as well as its ion-pair complexes was investigated by in vitro skin permeation experiments then visualized by CLSM. The skin permeability coefficient (kp) of BSP ion-pair complex was negatively related to its n-octanol/water apparent partition coefficient (P'o/w) in the hydrophobic vehicle caprylic/capric triglyceride, (log kp=-1.657-1.229 log P'o/w), suggesting that the instability of ion-pair complexes due to their dissociation in the viable epidermis (VED) played an important role in controlling the skin permeability of BSP, which was further proved by 1H NMR and molecular docking. These findings broadened our understanding about the molecular mechanisms involved in the skin permeation processes of ion-pair complexes.

Analysis of Clinical Efficacy and Adverse Effects of ß-Blocking Agents Used Clinically for Chronic Heart Failure.

Clinical efficacy and adverse effects of the ß-blocking agents, carvedilol, bisoprolol, and metoprolol were analyzed theoretically, and then compared quantitatively, for the purpose of determining their proper use for chronic heart failure. Initially, we evaluated occupancy binding to the ß1 and ß2 receptors (Фssß1 and Фssß2) by these drugs. Thereafter, we examined the relationship between Фssß1 values and left ventricular ejection fraction (LVEF) increase rate to determine efficacy. The result showed that the efficacy with carvedilol could be attained with a lower Фssß1 value than the others. Therefore, we constructed a model under the assumption that ß-blocking agents exert both indirect action of LVEF increase through the ß1 receptor and direct action on ryanodine receptor 2. Using the model, it was suggested that these drugs have no differences in regard to the efficacy, while it was clarified theoretically that only carvedilol produces an effect that directly involves ryanodine receptor 2 at clinical doses. We also investigated decreases in heart rate and forced expiratory volume in 1 s as adverse effects of ß-blocking agents using a ternary complex model. It was indicated that carvedilol is less likely to induce a heart rate decrease. Meanwhile, it was also suggested that the risk of an asthmatic attack was higher for carvedilol at clinical doses. Our results are considered useful for selection of a proper ß-blocking agent and its administration at a reasonable dose for successful heart failure therapy.

Bioequivalence study of 2.5 mg film-coated bisoprolol tablets in healthy volunteers.

BACKGROUND: Bisoprolol is one of the most widely used beta-blockers characterised by cardioselectivity, and it has no intrinsic sympathomimetic activity. It is commonly used in the treatment of coronary heart disease and heart failure. AIM: The aim of study was to assess the bioequivalence of the film-coated tablets containing 2.5 mg of bisoprolol (Bisocard® - the medicinal product) to the original medicinal product (Concor Cor 2.5® - the reference). METHODS: A randomised, open-label, two-period, crossover, single-dose, relative bioavailability study was conducted in fasted healthy Caucasian volunteers. A single 10-mg oral dose (four tablets of 2.5 mg) of the test or reference product was followed by a 14-day wash-out period, after which the subjects received the alternative product. Blood was sampled within a period of 60 h post administration in pre-specified time points. Bisoprolol concentrations were determined by a validated LC-MS/MS method. The products were considered bioequivalent if the 90% confidence interval (CI) of the log-transformed geometric mean ratios (test vs. reference) for AUC(0-t), AUC(0-∞), and Cmax were within 80-125% limits. Adverse events were monitored during the study based on the subject claims and clinical parameters. RESULTS: Twenty-six healthy male and female volunteers (mean age ca. 29 years; body mass index 22.7 kg/m²) were in-cluded in the study, and 24 completed the clinical part. The geometric mean ratios (test/reference) for the log-transformed AUC(0-t), AUC(0-∞), and Cmax were 95.16% (90% CI 92.52-97.87%), 95.08% (90% CI 92.40-97.83%), and 100.00% (90% CI 94.83-105.45%), respectively. There were no significant differences in the pharmacokinetic parameters between the test and reference formulations. No serious adverse events were reported. CONCLUSIONS: The results of this single-dose study in healthy Caucasian volunteers indicate that Bisocard®; 2.5 mg film-coated tablets are bioequivalent to the reference product - Concor Cor 2.5®; 2.5 mg film-coated tablets. Both products had similar safety profile and have been well tolerated.

Forecasting oral absorption across biopharmaceutics classification system classes with physiologically based pharmacokinetic models.

OBJECTIVES: The aim of this study was (1) to determine how closely physiologically based pharmacokinetic (PBPK) models can predict oral bioavailability using a priori knowledge of drug-specific properties and (2) to examine the influence of the biopharmaceutics classification system class on the simulation success. METHODS: Simcyp Simulator, GastroPlus™ and GI-Sim were used. Compounds with published Biowaiver monographs (bisoprolol (BCS I), nifedipine (BCS II), cimetidine (BCS III), furosemide (BCS IV)) were selected to ensure availability of accurate and reproducible data for all required parameters. Simulation success was evaluated with the average fold error (AFE) and absolute average fold error (AAFE). Parameter sensitivity analysis (PSA) to selected parameters was performed. KEY FINDINGS: Plasma concentration-time profiles after intravenous administration were forecast within an AAFE < 3. The addition of absorption processes resulted in more variability in the prediction of the plasma profiles, irrespective of biopharmaceutics classification system (BCS) class. The reliability of literature permeability data was identified as a key issue in the accuracy of predicting oral drug absorption. CONCLUSION: For the four drugs studied, it appears that the forecasting accuracy of the PBPK models is related to the BCS class (BCS I > BCS II, BCS III > BCS IV). These results will need to be verified with additional drugs.

Bisoprolol pharmacokinetics and body composition in patients with chronic heart failure: a longitudinal study.

PURPOSE: We investigated bisoprolol pharmacokinetics, including longitudinal changes and importance of patient characteristics in chronic heart failure. METHODS: Forty-six patients with chronic heart failure (57 % male, NYHA class I/II/III = 2/36/8) were followed for an average of 8 ± 2 months. At baseline and follow-up, plasma bisoprolol concentrations were determined and body composition was measured using dual-energy X-ray absorptiometry. A bisoprolol pharmacokinetic model was built with non-linear mixed-effects modeling to analyze the association with various parameters of body composition. RESULTS: Mean bisoprolol clearance (10.2 L/h) was 30 % lower than in healthy individuals and correlated with MDRD4-estimated renal function. The mean volume of distribution (230 L) was similar to healthy population and was associated with total body mass and skeletal muscle index (SMI). During follow-up, we observed minor changes in the absorption rate constant (2.83 vs. 2.27 h(-1), P = 0.030) and volume of distribution (227 vs. 250 L, P = 0.004), which are not clinically relevant. CONCLUSIONS: In patients with chronic heart failure, bisoprolol clearance was associated with estimated renal function; thus, in moderately and severely decreased renal function, patients may need to have their dose adjusted. Patients with low body weight or low SMI have greater fluctuations and higher maximal plasma concentrations of bisoprolol because of the lower volume of distribution. Longitudinal changes of bisoprolol pharmacokinetics were not associated with changes in body composition.

Probing the role of chemical enhancers in facilitating drug release from patches: Mechanistic insights based on FT-IR spectroscopy, molecular modeling and thermal analysis.

In patches, a drug must release from patches prior to its percutaneous absorption. Chemical enhancers have been used for several decades, but their roles in drug release from patches are poorly understood. In this work, the roles of chemical enhancers in bisoprolol tartrate (BSP-T) release from patches were probed in vitro and in vivo. More importantly, an innovative mechanism insight of chemical enhancers in drug release process was provided at molecular level. FT-IR spectroscopy and molecular modeling were employed to investigate the influence of chemical enhancers on drug-adhesive interaction. The results showed chemical enhancers like Span 80, which had a strong ability forming hydrogen bonds, could decrease drug-adhesive interaction leading to the release of drug from adhesive of patches. Thermal analysis was conducted to research the influence of chemical enhancers on the thermodynamic properties of patch system. It showed that chemical enhancers promoted the formation of free volume of adhesive, which facilitated drug release process. By contrast, the influence on the thermodynamic properties of BSP-T was less effective in influencing BSP-T release process. In conclusion, chemical enhancers played an important role in facilitating BSP-T release from the adhesive DURO-TAK® 87-2287 of patches by decreasing drug-adhesive interaction and promoting the formation of free volume of adhesive. This work may be an important step in understanding the important roles of chemical enhancers in drug release process.