Efonidipine Exerts Cerebroprotective Effect by Down-regulation of TGF-ß/SMAD-2-Dependent Signaling Pathway in Diabetic Rats.

Calcium overload and hyperglycemia are risks of stroke onset in diabetics. Our study was designed to elucidate the beneficial role of calcium channel blockers by targeting voltage-gated calcium channels in diabetes-associated cerebrovascular complications. Diabetes was induced using the neonatal streptozotocin rat model. After confirmation of diabetes, middle cerebral artery occlusion (MCAO) was carried out. The pre-treatment with 1 mg/kg/day efonidipine was administered for the period of 4 weeks. After 24 h of ischemic induction surgery, the neurological score was determined, and blood was collected for determination of biochemical parameters. Treatment with efonidipine showed a significant reduction in post-ischemic brain infract volume, brain hemisphere weight difference, neurological score, Na+-K+ ATPase activity, serum CK-MB, and LDH levels in normoglycemic and hyperglycemic MCAO-induced animals. While no significant changes in glucose and lipid levels were observed by treatment, efonidipine significantly decreased the levels of malondialdehyde, acetylcholine esterase, and nitrite levels and increased the levels of antioxidant markers in both normoglycemic and hyperglycemic MCAO animals. TGF-ß and VEGF were found to be down-regulated after treatment with efonidipine in gene expression study. In conclusion, the study data supports the cerebroprotective role of efonidipine in diabetic animals possibly through TGF-ß/SMAD-2 signaling pathway.

Gellan gum based gastroretentive tablets for bioavailability enhancement of cilnidipine in human volunteers.

Cilnidipine, a fourth-generation both L-and N-type calcium channel blocker (CCB) is safe and effective in lowering blood-pressure without reflex tachycardia compared to other dihydropyridine CCBs. However, its low solubility coupled with extensive first-pass metabolism results in very low oral bioavailability. Thus the study aimed to improve oral bioavailability of Cilnidipine by increasing its gastrointestinal transit-time and mucoadhesion. Gastroretentive tablets were prepared by direct-compression technique using gellan gum as hydrogel forming polymer and sodium bicarbonate as gas-generating agent. Statistical optimization was carried out by design approach which showed that gellan gum has significant impact on floating lag time, mucoadhesive strength, % drug release at 1 h and time to release 90% of drug. Drug release study revealed that optimized tablets prolonged drug release for 12 h and followed anomalous-diffusion indicating drug release is by coupling of both diffusion and erosion mechanism. Intragastric behaviour of formulation in human volunteers revealed that radio-opaque tablets remain buoyant in stomach for more than 6 h with sufficient mucoadhesion. Comparative pharmacokinetic profiling in human subjects revealed that relative bioavailability of Cilnidipine GR tablets was enhanced compared to reference tablets. Thus concluded that gastroretentive tablets to be promising strategy for improved oral bioavailability of Cilnidipine for effective treatment of hypertension.

Treatment effect of lacidipine and amlodipine on clinic and ambulatory blood pressure and arteria stiffness in a randomised double-blind trial.

PURPOSE: In a randomised, double-blind trial, we investigated effects of lacidipine on clinic and ambulatory blood pressure (BP) and arterial stiffness in patients with mild-to-moderate hypertension, as compared with amlodipine. MATERIALS AND METHODS: Previously untreated and treated patients (n = 269, 50-80 years of age) with clinic hypertension (a clinic systolic/diastolic BP 140-180/<110 mmHg and <160/100 mmHg, respectively) were randomly assigned to double-dummy treatment with lacidipine (4-6 mg/day) or amlodipine (5-7.5 mg/day) for 20 weeks. The primary efficacy variable was the change in 24-h ambulatory systolic BP at 20 weeks of treatment. Arterial stiffness was measured as brachial-ankle pulse wave velocity (PWV). RESULTS: After 20 weeks of treatment, 24-h systolic BP decreased from 141.3 ± 14.0 and 138.3 ± 12.8 mmHg at baseline, respectively, in the lacidipine (n = 134) and amlodipine groups (n = 135), by a least square mean (±SE) change of 15.2 ± 1.3 and 15.5 ± 1.3 mmHg, respectively, with a between-group difference (95% confidence interval [CI]) of 0.3 mmHg (-3.4 to 4.1, p = 0.86). Similar results were observed for other ambulatory BP components and clinic BP. Clinic and ambulatory pulse rate did not significantly change in either group (p ≥ 0.21). PWV decreased significantly (p < 0.001) from baseline in both groups, with a non-significant between-group difference of 0.24 m/s (p = 0.45). The incidence rate of adverse events was 30.3% (n = 40) and 27.5% (n = 36) in the lacidipine and amlodipine groups, respectively (p = 0.61). No serious adverse event occurred in the trial. CONCLUSIONS: Lacidipine effectively lowers clinic and ambulatory BP in patients with mild-to-moderate hypertension and significantly improves arterial stiffness, similarly as amlodipine.

Cilnidipine loaded poly (ε-caprolactone) nanoparticles for enhanced oral delivery: optimization using DoE, physical characterization, pharmacokinetic, and pharmacodynamic evaluation.

Cilnidipine (CND), an anti-hypertensive drug, possesses low oral bioavailability due to its poor aqueous solubility, low dissolution rate, and high gut wall metabolism. In the present study, an attempt has been made to prepare CND loaded polycaprolactone based nanoparticles (CND-PCL-NPs) by nanoprecipitation method applying the concepts of Design of Experiments. Critical factors affecting particle size and loading efficiency (LE%) were assessed by a hybrid design approach, comprising of Mini Run Resolution IV design followed by Box-Behnken design. Particle size, PDI, zeta potential and LE% of optimized formulations of CND-PCL-NPs were 220.3 ± 2.6 nm, 0.25 ± 0.1, -19.5 ± 0.9 mV, and 46.4 ± 1.8%, respectively. No significant changes were observed in the physical stability of nanoparticles when stored at 25 °C/60% RH over a period of 3 months. Oral pharmacokinetic studies revealed that Fabs of CND-PCL-NPs (0.55) were significantly higher than the CND suspension (0.26). Pharmacodynamic studies have revealed that the mean percent reduction in systolic blood pressure (% ΔSBP) was significantly higher in the case of CND-PCL-NPs (42%) as compared to CND suspension (24%). Optimized CND-PCL-NPs offer great potential in providing higher and sustained antihypertensive effect compared to conventional formulations of CND.

Pharmacodynamic, pharmacokinetic and physical characterization of cilnidipine loaded solid lipid nanoparticles for oral delivery optimized using the principles of design of experiments.

Cilnidipine (CND), an anti-hypertensive drug, is known to have low oral bioavailability due to its poor aqueous solubility, low dissolution rate and high gut wall metabolism. In the present study, CND loaded compritol based nanoparticles (CND-CMP-NPs) were prepared by emulsification-solvent evaporation method applying the concepts of design of experiments. Critical factors affecting particle size and loading efficiency (LE%) were assessed by hybrid design approach, comprising of Mini Run Resolution IV design followed by Box-Behnken design. Particle size, PDI, zeta potential and LE% of optimized formulations of CND-CMP-NPs were 207.1 ± 2.9 nm, 0.27 ± 0.1, -22.2 ± 1.9 mV and 15.9 ± 1.3% respectively. No significant changes were observed in physical stability of NPs when stored at 25 °C/60% RH over a period of three months. Pharmacokinetic studies revealed that Fabs of CND-CMP-NPs (0.66) was significantly higher than the free CND (0.27). The Cmax and AUC0-∞ of CND-CMP-NPs (572.4 ± 25.3 ng/mL and 5588.6 ± 229.5 ng/mL × h) were significantly higher (Pcal < 0.0001) as compared to free CND (363.6 ± 23.5 ng/mL and 2316.1 ± 163.6 ng/mL × h). MRT of CND-CMP-NPs (9.8 ± 0.9 h) was significantly higher (Pcal < 0.0001) as compared to free CND (5.7 ± 0.5 h). Pharmacodynamic studies showed a maximum of 38% decrease in systolic blood pressure with more than 20% drop in systolic blood pressure sustained for a total duration of 64 h in the case of CND-CMP-NPs as compared to free CND. CND-CMP-NPs not only provide higher and sustained plasma levels of CND but also higher and sustained antihypertensive therapy as compared to free CND.

Investigating the potential of utilizing glycerosomes as a novel vesicular platform for enhancing intranasal delivery of lacidipine.

Lacidipine is a potent dihydropyridine calcium channel blocker used for management of hypertension and atherosclerosis. The drug has low and fluctuating oral bioavailability owing to its extensive hepatic first-pass metabolism and reduced water solubility. Accordingly, this work aimed at overcoming the aforementioned challenges through the formulation of intranasal nano-sized lacidipine glycerosomes. Box-Behnken was successfully employed for the formulation and in vitro optimization of the glycerosomes. Statistical analysis revealed that cholesterol concentration exhibited a significant effect on the vesicle size, while Phospholipon® 90G and glycerol concentrations exhibited significant effects on both entrapment efficiency and deformability index. The optimized formulation showed spherical shape, good deformability, vesicular size of 220.25 nm, entrapment efficiency of 61.97%, and enhanced ex vivo permeation by 3.65 fold compared to lacidipine suspension. Confocal laser scattering microscope revealed higher penetration depth via nasal mucosa for rhodamine labelled glycerosomes (up to 60 µm) in comparison to rhoadamine dye solution (26 µm). In addition, the optimized lacidipine glycerosomes caused significant reduction in methylprednisolone acetate-induced hypertension in rats for up to 24 h in comparison to oral drug suspension. Histopathological assessment showed intact nasal mucosal epithelial lining with no signs of inflammation or necrosis confirming the safety and tolerability of the proposed glycerosomes. The declared results highlights the potential of utilizing the proposed glycerosomes as safe and effective platform for intranasal delivery of lacidipine.

A post-marketing survey evaluating the safety and efficacy of a fixed-dose single-pill combination of cilnidipine and valsartan in patients with hypertension: Real-world JSH 2014 and 2019 implementations.

METHODS: : The home blood pressure control by a single-pill combination of cilnidipine and valsartan (HOPE-Combi) survey sought to evaluate the safety and efficacy of cilnidipine 10 mg/valsartan 80 mg single-pill combination (SPC of Cil/Val) treatment in patients with hypertension for over 12 months. Of 2622 subjects' data; we analyzed 2572 cases for safety and 2372 cases for efficacy. RESULTS: Adverse drug reaction (ADR) incidence rate was 3.77% (97 of 2572 patients). The frequency of ADRs did not differ between patients aged <75 years and those aged ≥75 years (3.70% vs. 3.93%, respectively); between patients with and without chronic liver disease (CLD; 6.44% vs. 3.54%, respectively); and between patients with and without chronic kidney disease (CKD; 5.26% vs. 3.59%, respectively). Office systolic blood pressure (BP) was reduced from 149.5 ± 19.6 mmHg to 133.5 ± 14.8 mmHg (-15.8 mmHg, P < .01); pulse rate was also reduced 75.5 ± 12.2 bpm to 73.5 ± 11.3 bpm (-1.8 bpm, P < .01) after 12 months. CONCLUSIONS: : The SPC of Cil/Val was safe and effective in treating BP of hypertensive patients in real-world settings.

L-Type Calcium Channel Blocker Enhances Cellular Delivery and Gene Silencing Potency of Cell-Penetrating Asymmetric siRNAs.

The efficient delivery of small interfering RNAs (siRNAs) to the target cells is critical for the pharmaceutical success of RNA interference (RNAi) drugs. One of the possible strategies to improve siRNA delivery is to identify auxiliary molecules that augment their cellular uptake. Herein, we performed a chemical library screening in an effort to discover small molecules that enhance the potency of cholesterol-conjugated, cell-penetrating asymmetric siRNAs (cp-asiRNAs). Interestingly, three compounds identified from the screen share a common dihydropyridine (DHP) core and function as L-type calcium channel blockers (CCBs). Using confocal microscopy and quantitative analysis of small RNAs, we demonstrated that the L-type CCBs increased the endocytic cellular uptake of cp-asiRNAs. Furthermore, these small molecules substantially improved the potency of cp-asiRNAs, not only in vitro but also in vivo on rat skin. Collectively, our study provides an alternative pharmacological approach for the identification of small molecules that potentiate the effects of therapeutic siRNAs.

Effect of Lercanidipine on the Pharmacokinetics-Pharmacodynamics of Carvedilol Enantiomers in Patients With Chronic Kidney Disease.

This study evaluates the carvedilol-lercanidipine drug interaction, and the influence of chronic kidney disease (CKD) on both drugs. Patients with high blood pressure (8 with normal renal function [control] and 8 with CKD with estimated glomerular filtration rate categories of G3b to G5 [12-38 mL/min/1.73 m2 ]) were included and prescribed 3 different treatment regimens, a single oral dose of racemic carvedilol 25 mg (CAR), a single oral dose of racemic lercanidipine 20 mg (LER), and single oral doses of CAR plus LER. Blood samples were collected and variations in heart rate were assessed (using isometric exercise with handgrip) for up to 32 hours. Lercanidipine pharmacokinetics were not enantioselective, and were not affected by carvedilol and CKD. Carvedilol pharmacokinetics (data presented as median) were enantioselective with higher plasma exposure of (R)-(+)-carvedilol in both control (103.5 vs 46.0 ng ∙ h/mL) and CKD (190.6 vs 98.9 ng ∙ h/mL) groups. Lercanidipine increased the area under the plasma concentration-time curve of only (R)-(+)-carvedilol in the CKD group (190.6 vs 242.2 ng ∙ h/mL) but not in the control group (103.5 vs 98.7 ng ∙ h/mL). CKD increased plasma exposure (46.0 vs 98.9 ng ∙ h/mL) and effect-compartment exposure (5.5 vs 20.9 ng ∙ h/mL) to (S)-(-)-carvedilol, resulting in higher ß-adrenergic inhibition (10.0 vs 6.1 bpm). Therefore, carvedilol dose titration in CKD patients with estimated glomerular filtration rate categories of G3b to G5 should be initiated, with no more than half the dose used for patients with normal renal function.

A novel transdermal nanoethosomal gel of lercanidipine HCl for treatment of hypertension: optimization using Box-Benkhen design, in vitro and in vivo characterization.

Poor bioavailability of drugs via oral route is the greatest challenge facing drug formulation. To overcome this obstacle, transdermal route was commonly used as an alternative route to improve bioavailability. Lercanidipine HCl (LER) is a vasoselective calcium-channel blocker that has a poor oral bioavailability of 10% due to its hepatic metabolism and low solubility. The main objective of this study was to develop nanoethosomal LER gel for transdermal delivery to increase its skin permeation and promote bioavailability. Nanoethosomes were prepared and optimized using a Box-Behnken design employing ethanol injection method. The design studied the influence of Phospholipon 90G (PL90G), LER, and ethanol concentrations on entrapment efficiency (EE%); vesicle size; % cumulative LER release (CLERR); and cumulative LER permeated per unit area at 24 h Q24 (µg/cm2). The pharmacokinetic parameters of the optimized formulation were determined in rats. Nanoethosomes showed a mean vesicle size between 210.87 and 400.57 nm and EE% ranging from 49.26 to 97.22%. The developed nanoethosomes enhanced % CLERR and Q24 values compared to drug suspension. The experimental parameters of optimized formulation were very close to those calculated by software. The pharmacokinetics study showed three times statistically significant (p < 0.05) enhancement in LER bioavailability following nanoethosomal LER gel transdermal application compared to that of oral LER suspension. Nanoethosomes can be considered as a promising carrier for LER transdermal delivery, thus will be fruitful therapy in hypertension management. Graphical abstract.

Efficacy and safety of a combination antihypertensive drug (olmesartan plus azelnidipine): "Issues with hypertension studies in real-world practice".

Background: This study investigated whether a combination drug containing an angiotensin II receptor blocker (ARB) and a calcium channel blocker (CCB) could provide effective antihypertensive therapy.Methods: A multicenter, prospective, open-label study was conducted at the clinics of Clinical Research Network. The subjects had uncontrolled blood pressure (BP) despite ARB or CCB monotherapy. The effect on both office and home BP was examined after patients switched to a combination drug (REZ: containing 20 mg of olmesartan [OL] and 16 mg of azelnidipine [AZ]).Results: A total of 78 patients were enrolled. After switching to REZ, a significant and sustained reduction of office BP was observed. The proportion of patients who achieved the target for both office and home BP was an increase from 0% to 55%. Switching from amlodipine to REZ resulted in a significant and sustained decrease of office and home BP. There was also a significant decrease of home pulse rate (PR), but office PR was unchanged. To determine the accuracy of the BP and PR values reported by patients, the frequency of each number as the first digit was determined. The frequency of "0" was extremely high for both office and home BP values, and the same was noted for home PR values.Conclusion: The results of this study suggested that switching from a single drug to combination therapy with REZ could achieve a stronger antihypertensive effect. However, concern was raised regarding the methods of BP and PR measurement and recording in this clinical trial involving general practitioners.

[Nephroprotective effect of calcium channel blocker lercanidipine in treatment of patients with urolithiasis and urinary tract obstruction and monitoring of the serum cytokine profile].

OBJECTIVE: to evaluate the nephroprotective effect of lercanidipine, its effect on the dynamics of creatinine clearance and blood cytokine levels in patients with nephrolithiasis with obstructive uropathy during renal drainage. MATERIAL AND METHODS: 66 patients were included in the study with concretions of the pelvic segment and the presence of obstruction according to instrumental methods of examination. In order to prevent the occurrence of infectious complications before lithotripsy patients the first stage was performed installation of nephrostomic drainage, followed by antibacterial, anti-inflammatory therapy. Patients were divided into 2 groups: the first (33 patients) received standard therapy, the second (33 people) additionally received lercanidipine at a dose of 10 mg per day for 1 month. Determined the concentration of IL-8, VEGF, MCP-1, G-CSF and GM-CSF in the blood serum by the method of solid-phase ELISA. The glomerular filtration rate was calculated using the CKD-EPI formula. All studies were performed at the preoperative stage, on 7, 14, 21 and 28 days after renal drainage. RESULTS: In the appointment of lercanidipine, there was a more rapid decrease in levels of IL-8, VEGF, MS-1, GM-CSF in serum (21 days), and an improvement in renal function, compared with the group that did not receive nephroprotective therapy. CONCLUSION: The administration of lercanidipine may contribute to a more rapid recovery of renal function and normalization of blood cytokine levels. This drug can be used in the complex treatment of patients with nephrolithiasis with obstructive uropathy.

Chronological Delivery of Antihypertensive Drugs in Bilayered Core-in-Cup Buccoadhesive Tablets: In Vitro and In Vivo Evaluation.

Hypertension shows circadian blood pressure rhythms (day-night pattern) that urge the delivery of antihypertensive drugs at the right time in the desired levels. Thus, a bilayered core-in-cup buccoadhesive tablet was formulated that immediately releases olmesartan, to give a burst effect, and controls azelnidipine release, to prolong its therapeutic effect. The main challenge was the poor bioavailability of azelnidipine due to its poor aqueous solubility and first-pass effect. Hence, liquisolid compact buccoadhesive tablets were prepared to enhance solubility, dissolution profiles, and bypass the oral route. Two factorial designs were conducted to study the type and concentration effect of the mucoadhesive polymers on the dissolution and mucoadhesion of olmesartan and azelnidipine. Characterization studies were conducted regarding drug content, surface pH, water uptake, mucoadhesive strength, in vitro release, and ex vivo permeability. The core-in-cup olmesartan/azelnidipine buccoadhesive tablet showed similar release profile to the statistically optimized formulae of each drug. In vitro dissolution study showed enhanced release of azelnidipine than the directly compressed tablets, to comply with the regulatory standards of controlled release systems. In vivo pharmacokinetic study of olmesartan and azelnidipine conducted on human volunteers against Rezaltas® 10/8 mg tablet showed percentage relative bioavailability of 106.12 and 470.82%, respectively. Graphical Abstract.

Exploration of supersaturable lacidipine ternary amorphous solid dispersion for enhanced dissolution and in vivo absorption.

Amorphous solid dispersion stands out among different formulation strategies for the improvement of dissolution rate and bioavailability via generating supersaturated drug solution, which provides a higher solubility than the crystalline counterpart, leading to a promoted intestinal absorption. Soluplus (SOL), termed as the fourth generation of solid dispersion carrier, presented a preferable effect on supersaturation maintaining and bioavailability enhancement for poorly water soluble drugs. However, some binary drug/SOL systems still suffer from insufficient dissolution and unsatisfied in vivo absorption. Thus, taking Lacidipine (LCDP) as a model drug, the aim of this study was to explore a ternary amorphous solid dispersion consisted of SOL and a surfactant to further increasing the dissolution rate and in vivo absorption. First of all, various surfactants were screened via equilibrium solubility enhancement and sodium dodecyl sulfate (SDS) was selected as the most effective candidate. Thereafter, the influence of SOL/SDS and drug/carrier weight ratio on the supersaturation maintaining was investigated. The supersaturated drug solutions were spray dried and the in vitro release, pharmacokinetic behavior as well as physical stability were investigated. It was found that although combination use of SOL and SDS did not present remarkable advantage in supersaturation maintenance in liquid state, 6-7 times higher dissolution rate under non-sink condition was noticed at SOL/SDS ratio 3:1 after spray drying, for LCDP/SOL/SDS based formulation compared to that of the binary LCDP/SOL system, which was maintained even after 92.5% humidity and 60 °C accelerated stability test. Moreover, compared to the LCDP/SOL formulation, approximately 3.3 and 3.7-fold increase in C max and AUC0-∞ was achieved with LCDP/SOL/SDS based formulation. In conclusion, the presented SDS could not only be regarded as solubility enhancer but also dissolution or bioavailability promoter, highlighting its potential application in ternary supersaturable amorphous solid dispersion for further increasing the dissolution and in vivo absorption of poorly water soluble drugs.

Lacidipine attenuates reserpine-induced depression-like behavior and oxido-nitrosative stress in mice.

Depression is a serious medical illness displaying high lifetime prevalence, early-age onset that adversely affects socio-economic status. The bidirectional association between oxidative stress and calcium-signaling adversely affects the monoaminergic neuron functions that instigate the pathogenesis of depression. The present study investigates the effect of lacidipine (LCD), L-type Ca2+-channel blocker, on reserpine-induced depression in mice. Separate groups of mice (Swiss albino, 18-25 g) were administered lacidipine (0.3, 1 and 3 mg/kg, i.p.) daily for 14 days and reserpine (5 mg/kg, i.p.) was injected on day 14. Rectal temperature, catalepsy, and tail-suspension test (TST) were performed 18 h and ptosis scores at 60, 120, 240, 360 min post-reserpine treatment. Whole-brain TBARS, GSH, nitrite, and superoxide dismutase (SOD) and catalase activities were estimated. Reserpine elevated the catalepsy, ptosis, hypothermia, and immobility period in TST owing to the marked increase in oxidative-nitrosative stress in the brain of mice. LCD attenuated the reserpine triggered the rise in catalepsy, ptosis scores, hypothermia, and immobility period in mice. LCD pretreatment attenuated the increase in TBARS and nitrite levels, and the decline of GSH, SOD, and catalase activities in the brain of reserpine injected mice. Bay-K8644 (0.5 mg/kg, i.p.), Ca2+-channel agonist, attenuated these effects of LCD (3 mg/kg) in reserpine-treated mice. It can be inferred that lacidipine (Ca2+ channel antagonist) attenuates depression-like symptoms in reserpine-treated mice. Furthermore, the abrogation of antidepressant-like effects of LCD by Bay-K8644 revealed that modulation of Ca2+-channels might present a potential strategy in the management of depression.

Synergetic effect of nucleation and crystal growth inhibitor on in vitro-in vivo performance of supersaturable lacidipine solid dispersion.

Limited supersaturation maintaining duration is the main challenge for amorphous solid dispersion design. Nucleation or crystal growth inhibitors may function in different ways but the combination use of nucleation and crystal growth inhibitors in supersaturated system is rarely explored. Thus, using Lacidipine (LCDP) as a Biopharmaceutical Classification System (BCS) II model drug, the aim of this study was to explore whether the combination use of nucleation and crystal growth inhibitors could provide a synergistic effect on the in vitro-in vivo performance of poorly water-soluble drugs. First of all, based on compatibility screening using solubility parameter (Δδ) and crystallization inhibition efficiency as criteria, soluplus (SOL) and gum arabic (GA) were selected as the most effective nucleation and crystal growth inhibitor respectively. Thereafter, the supersaturated drug solutions were spray dried and characterized. The in vitro release, physical stability as well as pharmacokinetic behavior were investigated. It was found that the combination use of SOL and GA did not present remarkable advantage in prolonging the supersaturation time in solution state. However, their synergistic effect in equilibrium solubility and dissolution enhancement was noticed at SOL/GA ratio 3:1, with 5-7 times higher dissolution rate observed for LCDP/SOL/GA based formulation compared with that of LCDP/SOL, which was maintained even after three months accelerated stability test under non-sink condition. Moreover, compared to the LCDP/SOL formulation, approximately 2.8 and 2.5-fold increase in the maximum plasma concentration (Cmax) and the area under the plasma-time curve (AUC0-∞) was achieved with LCDP/SOL/GA based formulation. Possible mechanism of the synergistic effect was elucidated, indicating GA may penetrate into SOL particles providing both electrostatic and steric stabilization. In conclusion, the combination use of screened nucleation and crystal growth inhibitors might be an efficient approach to design supersaturated drug delivery system.

[Infrequent systemic drug interaction: repeated syncope caused by combined treatment with timolol-containing eye drops and lercanidipine tablet]. / Ritka szisztémás gyógyszer-interakció: timololtartalmú szemcsepp és lerkanidipintabletta együttes alkalmazása során ismétlodoen jelentkezo syncope.

The control and planning of the treatment of hypertensive patients need specific attention. As regards concomitant diseases and treatments, glaucoma and the use of eye drops should be taken into consideration. The ingredients of the administered eye drops get through the nasolacrimal canal and can be absorbed by the nasal mucosa. Because of the lack of enterohepatic 'first pass' effect, they can act systemically - like after intravenous administration. This way they can cause systemic side effects. The authors present a case of a patient, too, who was examined and medically checked regularly for years with negative results because of repeated syncope. It became clear only at the Hypertension Centre that the timolol-containing combined eye drops caused the symptoms. The authors draw attention to the fact that in the case of systemic side effects which can be connected to beta-blocking agents (blood pressure fall, bradycardia, breathing disturbance, depression), the role of the eye drops should be taken into consideration. At the same time, the possibility of the systemic drug interactions should not be forgotten either. The interaction with dihydropyridine-type calcium-channel blockers can be of great importance. In these cases, after consultation with an ophthalmologist, the glaucoma treatment with eye drops containing beta-blockers should be modified. Orv Hetil. 2019; 160(8): 309-313.

Congruent release of drug and polymer: A "sweet spot" in the dissolution of amorphous solid dispersions.

Liquid-liquid phase separation (LLPS) occurs following amorphous solid dispersion (ASD) dissolution when the drug concentration exceeds the "amorphous solubility", and is emerging as an important characteristic of formulations that may enhance the oral bioavailability of poorly soluble drugs. The purpose of this research was to identify criteria that impact the rate and extent of drug release and hence the occurrence or not of LLPS upon ASD dissolution. Specifically, the effect of drug log P, phase behavior of the hydrated but undissolved ASD matrix and the relative dissolution rates of drug and polymer were studied as a function of drug loading, using nilvadipine (Nil) (ClogP = 3.04) and cilnidipine (Cil) (ClogP = 5.54) as model drugs. The model polymer was poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA). Nil-PVPVA and Cil-PVPVA ASDs with different drug loadings were prepared. Surface area normalized dissolution rates of both the drug and the polymer from ASD tablets were studied. At a similar and relatively low drug loading (<20% w/w drug), dissolution of both Nil-PVPVA and Cil-PVPVA ASDs was found to switch from rapid, congruent (i.e., simultaneous) release of drug and polymer to incongruent release with slow release of drug. Only ASDs showing congruent release underwent LLPS, with the formation of amorphous drug-rich aggregates (~300nm). Scanning electron microscopy (SEM) and micro-computed tomography (micro-CT) showed the presence of characteristic "pits" on the surface of partially dissolved, incongruently releasing ASD tablets. These most likely arise due to faster polymer release in comparison to drug, whereby the drug-rich composition around these pits was confirmed by energy-dispersive X-ray (EDX) analysis and the surface drug enrichment on the compacts was confirmed by X-ray photoelectron spectroscopy (XPS). This study demonstrates two important findings, firstly, a link between congruent release of drug and polymer and the occurrence of LLPS and secondly, the switch between congruent and incongruent release of drug and polymer is a result of competitive kinetics between phase separation and the release rate of ASD components with minimal influence from drug hydrophobicity for two structural analogues.

Effect of rifampin on enantioselective disposition and anti-hypertensive effect of benidipine.

AIMS: In vitro study showed that benidipine is exclusively metabolized by cytochrome P450 (CYP) 3A. This study evaluated the effect of rifampin on the enantioselective disposition and anti-hypertensive effect of benidipine. METHODS: Benidipine (8 mg) was administered to healthy subjects with or without repeated rifampin dosing, in a crossover design. Plasma concentrations of (S)-(S)-(+)-α and (R)-(R)-(-)-α isomers of benidipine and blood pressure were measured for up to 24 h after dosing. In addition, CYP3A metabolic capacity was evaluated in each subject using oral clearance of midazolam. RESULTS: The exposure of (S)-(S)-(+)-α-benidipine was greater than that of (R)-(R)-(-)-α-benidipine by approximately three-fold following single dose of benidipine. Repeated doses of rifampin significantly decreased the exposure of both isomers. Geometric mean ratios (GMRs) (95% CI) of Cmax and AUC∞ for (S)-(S)-(+)-α-benidipine were 0.14 (0.10-0.18) and 0.12 (0.08-0.18), respectively. GMRs (95% CI) of Cmax and AUC∞ for (R)-(R)-(-)-α-benidipine were 0.10 (0.06-0.17) and 0.10 (0.06-0.17), respectively. Oral clearances of both isomers were increased equally by approximately 10-fold. There were no significant differences in cardiovascular effect following benidipine administration between control and rifampin treatment. CYP3A activity using midazolam did not appear to correlate with oral clearance of benidipine. CONCLUSIONS: After single administration of racemic benidipine, enantioselective disposition of (S)-(S)-(+)-α- and (R)-(R)-(-)-α-benidipine was observed. Treatments with rifampin significantly decreased the exposure of both isomers but appeared to marginally affect its blood pressure-lowering effect in healthy subjects. Impact of coadministration of rifampin on the treatment effects of benidipine should be assessed in hypertensive patients.