Amorphous solid dispersion of nisoldipine by solvent evaporation technique: preparation, characterization, in vitro, in vivo evaluation, and scale up feasibility study.

The present study was designed to determine the applicability of a newly derived dimensionless number precipitation parameter, "supersaturation holding capacity (SHC)" in development of amorphous solid dispersion (ASD) of a rapidly crystallizing drug, nisoldipine. Also, ASD preparation from lab scale formulation technique to scalable spray drying technique followed by oral bioavailability study was demonstrated. Solution state screening of polymers was performed by determining nucleation induction time (tin) and SHC. With screened polymers, lab scale ASDs of nisoldipine were prepared using rotary evaporation (solvent evaporation) method, and the optimized stable ASDs were scaled up by spray drying. The ASDs were characterized by DSC, PXRD, and FTIR for amorphous nature and evaluated for apparent solubility, dissolution, and solid-state stability improvement. The spray dried ASDs were additionally evaluated for micrometric properties and oral bioavailability study.PVP grades demonstrated superior crystal growth inhibition properties (with 2-4-fold enhancements in SHC). ASDs prepared by both lab scale and scale-up technique using PVP stabilized the amorphous nisoldipine via antiplasticization effect that maintained the stability under accelerated stability conditions (40 °C/75% RH) for 6 months. Additionally, FTIR study confirmed the role of intermolecular interactions in amorphous state stabilization of PVP-based solid dispersions. PVP-based spray dried ASDs improved the apparent solubility 4-fold for PVP K17 and more than 3-fold for remaining spray dried ASDs. The enhanced solubility was translated to improved dissolution of the drug when compared with crystalline and amorphous form complementing the outcome of the solution state study. The spray dried ASD showed 2.3 and > 3-fold the improvement in Cmax and AUC (0-24 h) respectively when compared with crystalline nisoldipine during oral bioavailability study which highlights the significance of SHC parameter of polymers. The spray dried ASD has shown improved micromeritics properties then crystalline nisoldipine in terms of flow behavior.This unique study provides a rational strategy for selection of appropriate polymer in development of ASDs that can tackle both precipitation during dissolution and amorphous state stabilization in solid state and also considers the SHC in scale-up study. Graphical abstract.

Enhanced bioavailability and antihypertensive activity of nisoldipine loaded nanoemulsion: optimization, cytotoxicity and uptake across Caco-2 cell line, pharmacokinetic and pharmacodynamic studies.

Objective: The present study explored the antihypertensive activity of nisoldipine in oil in water nanoemulsion to improve its oral bioavailability via intestinal lymphatic uptake.Methods: Nanoemulsion was prepared by ultrasonication technique using Peceol, Cremophor EL and Transcutol HP as oil, surfactant and cosurfactant respectively. Optimization was done employing 32 full factorial design. The developed formulation was assessed for in vitro,cell line, ex vivo and in vivo studies.Results: The experimental results indicated homogeneity of the nanoemulsion with globule size of 62.35 ± 2.55 nm and PDI value of 0.108 ± 0.01 with negative zeta potential (-26.2 ± 3.6 mV). Transmission electron microscopy showed spherical oil globules morphology. The in vitro diffusion study showed significant increase in drug release from NE formulations (98.51 ± 2.64%) as compared to plain drug dispersion (29.73 ± 2.15%) in 0.1 N HCl + 0.5% SLS medium. Moreover, higher quantitative and qualitative uptake of nanoemulsion via Caco-2 cells showed superior intestinal absorption and improved therapeutic activity of nisoldipine when compared to drug dispersion. Pharmacokinetic and pharmacodynamic study confirmed significantly (p ˂ 0.05) greater bioavailability and antihypertensive activity of nisoldipine nanoemulsion when compared to its dispersion. These results are visualized in abstract figure.Conclusion: Thus, prepared nanoemulsion showed potential as oral delivery system for nisoldipine with superior oral bioavailability and therapeutic efficacy over drug dispersion.

Comparative study of nisoldipine-loaded nanostructured lipid carriers and solid lipid nanoparticles for oral delivery: preparation, characterization, permeation and pharmacokinetic evaluation.

Nisoldipine (ND) has low oral bioavailability (5%) due to first-pass metabolism. Previously, solid lipid nanoparticles (SLNs) of ND were reported. In this study, nanostructured lipid carriers (NLCs) of ND are developed to enhance the oral bioavailability. ND-NLCs were prepared using hot homogenization-ultrasonication method, using oleic acid and trimyristate as liquid lipid and solid lipid, respectively. Prepared NLCs are evaluated for an optimal system using measuring size, zeta potential, entrapment efficiency, in-vitro release and in-situ absorption studies. Further, in vivo pharmacokinetic (PK) studies of NLC were conducted in rats comparison with SLN and suspension as controls. Size, ZP and EE of optimized NLCs were found to be 110.4 ± 2.95 nm, -29.4 ± 2.05 mV and 97.07 ± 2.27%, respectively. Drug loaded into NLCs was converted to amorphous form revealed by differential scanning calorimeter (DSC) and X-ray diffractometry (XRD) technique and nearly spherical in shape by scanning electron microscopy (SEM) studies. Drug release and absorption of ND were prolonged from ND-NLCs and ND-SLNs. From the PK results, NLCs showed 2.46 and 1.09-folds improvement in oral bioavailability of ND compared with suspension and SLNs formulations, respectively. Taken together, the NLCs and SLNs are used as carriers for the enhancement of oral bioavailability of the ND.

Comparative evaluation of proliposomes and self micro-emulsifying drug delivery system for improved oral bioavailability of nisoldipine.

The objective of this study was to develop proliposomal formulation and self micro-emulsifying drug delivery system (SMEDDS) for a poorly bioavailable drug, nisoldipine and to compare their in vivo pharmacokinetics. Proliposomes were prepared by thin film hydration method using different lipids such as Soy phosphatidylcholine (SPC), Hydrogenated Soy phosphatidylcholine (HSPC), Dimyristoylphosphatidylcholine (DMPC) and Dimyristoyl phosphatidylglycerol sodium (DMPG), Distearyl phosphatidylcholine (DSPC), and Cholesterol in various ratios. SMEDDS formulations were prepared using varying concentrations of Capmul MCM, Labrasol, Cremophor EL and Tween 80. Both proliposomes and SMEDDS were evaluated for particle size, zeta potential, in vitro drug release, in vitro permeability and in vivo pharmacokinetics. In vitro drug release was carried out in purified water using USP type II dissolution apparatus. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA) and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague-Dawley rats. Among the different formulations, proliposomes with drug:DMPC:cholesterol in the ratio of 1:2:0.5 and SMEDDS with Capmul MCM (13.04% w/w), Labrasol (36.96% w/w), Cremophor EL (34.78% w/w) and Tween 80 (15.22% w/w) demonstrated the desired particle size and zeta potential. Enhanced drug release was observed with proliposomes and SMEDDS compared to pure nisoldipine in purified water after 1h. Nisoldipine permeability across PAMPA and everted rat intestinal perfusion models was significantly higher with proliposomes and SMEDDS. Following single oral administration of proliposomes and SMEDDS, a relative bioavailability of 301.11% and 239.87% respectively, was achieved compared to pure nisoldipine suspension.

Pharmacokinetic and pharmacodynamic studies of nisoldipine-loaded solid lipid nanoparticles developed by central composite design.

OBJECTIVE: Nisoldipine (ND) is a potential antihypertensive drug with low oral bioavailability. The aim was to develop an optimal formulation of ND-loaded solid lipid nanoparticles (ND-SLNs) for improved oral bioavailability and pharmacodynamic effect by using a two-factor, three-level central composite design. Glyceryl trimyristate (Dynasan 114) and egg lecithin were selected as independent variables. Particle size (Y1), PDI (Y2) and entrapment efficiency (EE) (Y3) of SLNs were selected as dependent response variables. METHODS: The ND-SLNs were prepared by hot homogenization followed by ultrasonication. The size, PDI, zeta potential, EE, assay, in vitro release and morphology of ND-SLNs were characterized. Further, the pharmacokinetic (PK) and pharmacodynamic behavior of ND-SLNs was evaluated in male Wistar rats. RESULTS: The optimal ND-SLN formulation had particle size of 104.4 ± 2.13 nm, PDI of 0.241 ± 0.02 and EE of 89.84 ± 0.52%. The differential scanning calorimetry and X-ray diffraction analyses indicated that the drug incorporated into ND-SLNs was in amorphous form. The morphology of ND-SLNs was found to be nearly spherical by scanning electron microscopy. The optimized formulation was stable at refrigerated and room temperature for 3 months. PK studies showed that 2.17-fold increase in oral bioavailability when compared with a drug suspension. In pharmacodynamic studies, a significant reduction in the systolic blood pressure was observed, which sustained for a period of 36 h when compared with a controlled suspension. CONCLUSION: Taken together, the results conclusively demonstrated that the developed optimal ND-SLNs caused significant enhancement in oral bioavailability along with pharmacodynamic effect.

Studies on separation and pharmacokinetics of m-nisoldipine enantiomers in beagle dog plasma by LC/MS/MS.

A rapid, sensitive and selective liquid chromatography-tandem mass spectrometric (LC/MS/MS) method was developed and validated for the separation and determination of m-nisoldipine enantiomers in beagle dog plasma. Samples were pretreated by a single-step protein precipitation with acetonitrile. After m-nisoldipine racemic administration to beagle dogs, samples of m-nisoldipine enantiomers in beagle dog plasma were separated and determined on a ULTRON ES-OVM column (150 × 4.6 mm, 5 µm) at 20°C with a mobile phase consisted of methanol-acetonitrile-ammonium acetate (pH 7.0; 2mM) (15:15:70, v/v/v) at a flow rate of 0.8 mL/min. Chromatograms were monitored at 237 nm, and the API 4000 triple quadrupole mass spectrometer was operated in multiple reaction monitoring (MRM) scan mode using ElectroSpray ionization (ESI) source. The good linearity (rs=0.9958 and rr=0.9983) were found in the range 0.25-20 ng/mL. The lower limit of quantification (LLOQ) obtained was 0.25 ng/mL (n=6). All the validation data, such as accuracy, precision, intra-day and inter-day repeatability, were within the required limits. The method was successfully applied to separation and pharmacokinetics of m-nisoldipine enantiomers in beagle dog plasma. The result of statistics analysis shows that there are no significant differences between R-(-)-m-nisoldipine and S-(+)-m-nisoldipine (p>0.05). The study provides necessary evidences for the research and new drug development of m-nisoldipine enantiomers.

Preparation of a novel glycidyl methacrylate-based monolith and its application for the determination of m-nisoldipine in human plasma.

A new method has been developed for preparing monolithic materials by polymerisation of the oil-in-water (O/W) emulsions with nonion-surfactant (Pluronic F68). Morphology of monolithic materials is studied by scanning electron microscopy. The properties of the column are investigated, and the column exhibits the ability of low backpressure and fast analysis. Using this monolithic column, on-line sample clean-up and screening of m-nisoldipine in human plasma samples have been investigated. Chromatography is performed by reversed-phase high-performance liquid chromatography (RP-HPLC) on a C(18) column with UV detection at 237 nm. The linear range of m-nisoldipine in human plasma is 2-200 ng/mL (r = 0.9992, n = 7). And the limit of detection is 1.5 ng/mL. The 12-h pharmacokinetic profile of m-nisoldipine in mice after oral administration has been investigated. The results indicate that the method could be used for monitoring of m-nisoldipine and enabled simple and rapid assay of the drugs in human plasma.

Tissues distribution of R-(-)- and S-(+)-m-nisoldipine after single enantiomer administration in rats.

Rapid, sensitive, and selective high-performance liquid chromatography methods were developed and validated for determination of m-nisoldipine enantiomers in rat tissues. All of the samples were prepared based on a simple and efficient liquid-liquid extraction method. After validating that no racemation occurred by ULTRON ES-OVM (Japan), m-nisoldipine enantiomers were determined, respectively, on a reverse-phase C(18) column (5 microm, 250 x 4.6 mm). This method was applied to study tissue distribution of m-nisoldipine enantiomers in rats after a single administration of m-nisoldipine enantiomers. By the two-sample t test, there were basically no significant differences between the two enantiomers in each tissue ( p > .05), which indicates that they may have the same potency in rats. In small intestine, lung, liver, and spleen, the concentrations of R-(-)- and S-(+)-m-nisoldipine were high at 30 and 150 min than that at 90 min, which showed that m-nisoldipine enantiomers may have the phenomenon of hepatoenteral circulation. A small quantity of the prototype of R-(-)- and S-(+)-m-nisoldipine in brain showed that they can cross the blood-brain barrier to arrive at the brain tissue. The high quantity of distribution in lung and brain implied that the lipophilicity of the drug was powerful.

Pharmacokinetics of oral doses of telmisartan and nisoldipine, given alone and in combination, in patients with essential hypertension.

This randomized, single-blind, parallel-group study was performed to assess pharmacokinetic interactions potentially occurring during concomitant use of telmisartan and nisoldipine. Patients with essential hypertension (n = 37) were treated with once-daily doses of telmisartan, nisoldipine, or their combination for 6 weeks. The regimen was started at low dose with an increase of dosage after 3 weeks of treatment. AUC(ss) (132%; P < .01) of telmisartan applied in doses of 80 mg was significantly higher after concomitant application with nisoldipine (10 mg), whereas CL/f(ss) (-54%; P < .05) and Vz/f(ss) (-72%; P < .05) were significantly lower. Regarding pharmacokinetic parameters of nisoldipine, significant differences between treatment groups were not detected. In conclusion, the results of this study strongly suggest that concomitant treatment with nisoldipine enhances telmisartan bioavailability in hypertensive individuals. Larger crossover trials will have to establish these observations and investigate whether interaction of both drugs affects telmisartan efficacy and tolerability in clinical use.

Validated LC-MS-MS method for determination of m-nisoldipine polymorphs in rat plasma and its application to pharmacokinetic studies.

A sensitive and specific liquid chromatography-tandem mass spectrometric (LC-MS-MS) method has been developed to determine m-nisoldipine in rat plasma. Sample was pretreated by a single-step protein precipitation with acetonitrile, in contrast to the liquid-liquid procedure frequently used for the extraction of 1,4-dihydropyridines from biologic samples. Separation of analyte and internal standard (I.S.) was performed on a Symmetry RP-C(18) analytic column (50 mm x 4.6 mm, 3.5 microm) with a mobile phase consisting of acetonitrile-water (80:20, v/v) at a flow rate of 0.5 ml/min. The API 4000 triple quadrupole mass spectrometer was operated in multiple reaction monitoring (MRM) scan mode using TurboIonSpray ionization (ESI) source. The method was sensitive with a lower limit of quantification (LLOQ) of 0.2 ng/mL, with good linearity (r>or=0.9982) over the linear range of 0.2-20 ng/mL. All the validation data, such as accuracy, precision, and inter-day repeatability, were within the required limits. The method was successfully applied to pharmacokinetic and relative bioavailability studies of m-nisoldipine polymorphs in rats.

Dynamic and kinetic disposition of nisoldipine enantiomers in hypertensive patients presenting with type-2 diabetes mellitus.

OBJECTIVE: Nisoldipine (N) is a dihydropyridine calcium antagonist marketed as a racemic mixture and used for the treatment of hypertension. In the present study, we investigated the influence of type-2 diabetes mellitus (DM) on the enantioselective pharmacokinetic and dynamic parameters of N. METHODS: Seventeen hypertensive patients, nine of them with DM, were investigated in a cross-over study with administration of rac-N as coat-core tablets (20 mg day(-1)) or placebo for 15 days each. Serial blood samples (0-24 h) were collected on the 15th day, and 24-h ambulatory blood pressure (BP) monitoring was simultaneously evaluated. N enantiomers in plasma samples were analysed using chiral high-performance liquid chromatography combined with gas chromatography/mass spectrometry. The enantiomeric ratios differing from one were evaluated using the Wilcoxon test, and the results are reported as means with the 95% confidence intervals. A lidocaine (L) test was carried out as an in vivo marker of CYP3A4 (and CYP1A2) activities. RESULTS: The following differences were observed between the (+)-N and (-)-N enantiomers, respectively, in the patients presenting with DM (means and ranges): C(max) 3.9 (1.7-6.1) ng ml(-1) versus 0.7 (0.4-1.0) ng ml(-1), AUC(0-24) 51.5 (29.0-74.0) ng ml(-1) h versus 9.4 (5.9-12.8) ng ml(-1) h, and Cl/f 3.6 (1.9-5.4) l h(-1) kg(-1) versus 18.7 (11.7-25.7) l h(-1) kg(-1). The Cl/f value of (+)-N was lower (Mann-Whitney test) in patients with DM: 6.0 (4.3-7.5) l h(-1) kg(-1) versus 3.6 (1.9-5.4) l h(-1) kg(-1). The same observation was made for the (-)-N, with Cl/f reaching 38.8 (26.8-51.0) l h(-1) kg(-1) and 18.7 (11.7-25.7) l h(-1) kg(-1) for the non-diabetic and DM groups, respectively. The L test resulted in higher ratios (P < 0.05) of plasma L/MEGX concentrations (30 min after i.v. L) for DM (11.1 vs 18.6). N significantly reduced systolic and diastolic BP (P < 0.05, Wilcoxon test) in all patients investigated relative to placebo. No differences in BP reduction were observed between diabetic and non-diabetic patients. N significantly increased noradrenaline concentrations in plasma of both patient groups. The data also demonstrated that the plasma concentrations of noradrenaline 30 min after N administration were lower (P < 0.05) in diabetic (mean 2.86 pmol ml(-1)) than in non-diabetic patients (4.80 pmol ml(-1)). CONCLUSIONS: The present data permit us to infer that type-2 diabetes mellitus alters the kinetic disposition of the (+)-N eutomer and (-)-N distomer, presumably due to a lower activity of CYP3A4, although it does not modify the clinical effect brought about by the reduction in BP.

[Effect of grapefruit pulp on the pharmacokinetics of the dihydropyridine calcium antagonists nifedipine and nisoldipine].

The effect of the intake of 200 g of grapefruit pulp (corresponding to one grapefruit) on the pharmacokinetics of the calcium antagonists nifedipine (NF) and nisoldipine (NS) were investigated in 8 healthy Japanese male volunteers. A crossover design was used for the study: group I did not ingest any grapefruit (control group); group II ingested grapefruit 1 h after drug administration; and group III ingested grapefruit 1 h before drug administration. The intake of grapefruit pulp increased the plasma concentrations of both NF and NS, an effect that has previously been reported with grapefruit juice. The increase was most marked when grapefruit was eaten before drug administration. For both NF and NS, subjects who ingested grapefruit 1 h before drug administration exhibited a greater Cmax and AUC0-24 than did subjects in the control group. For NF, the Cmax was 1.4 times higher and the AUC0-24 1.3 times larger in group III than in group I. For NS, the Cmax was 1.5 times higher and the AUC0-24 1.3 times larger in group III than in group I. The increase in the AUC0-24 was significant for both drugs (p < 0.05). The finding that the ratios of Cmax and AUC0-24 for unchanged drug and metabolites did not vary greatly among the three groups for either drug suggests that the increase in serum concentration produced by grapefruit intake may be due to other factors than an inhibitory effect on drug metabolism. Also, the increases in Cmax and AUC0-24 of NS produced by grapefruit intake were smaller than those produced by grapefruit juice intake, indicating that grapefruit pulp and juice have different effects on the pharmacokinetics.

Enantioselective assay of nisoldipine in human plasma by chiral high-performance liquid chromatography combined with gas chromatographic-mass spectrometry: applications to pharmacokinetics.

Nisoldipine, a second-generation dihydropyridine calcium antagonist, is a racemate compound used in the treatment of hypertension and coronary heart disease. This study presents an enantioselective HPLC-GC-MS method for the analysis of nisoldipine in human plasma and establishes confidence limits for its application to pharmacokinetic studies. Plasma samples were basified and extracted with toluene. The enantiomers were resolved on a Chiralcel OD-H column using hexane-ethanol (97.5:2.5, v/v) and the (+)- and (-)-fractions were collected separately with the diode array detector switched off. For the quantification of the nisoldipine enantiomers a GC-MS with an Ultra 1 Hewlett-Packard column was used with the detector operated in the single-ion monitoring mode with electron-impact ionization (m/z 371.35 and 270.20 for nisoldipine and m/z 360.00 for the internal standard, nitrendipine). The method proved to be suitable for pharmacokinetic studies based on the low quantification limit (0.05 ng/ml for each enantiomer) and the broad linear range (0.05-50.0 ng/ml for each enantiomer). Low coefficients of variation (<15%) were demonstrated for both within-day and between-day assays. No interference from drugs associated with nisoldipine treatment was observed. The enantioselective pilot study on the kinetic disposition of nisoldipine administered in the racemic form to a hypertensive patient using a multiple dose regimen revealed the accumulation of the (+)-enantiomer with an AUC(0-24) (+)/(-) ratio of approximately 8. Both enantiomers were quantified in plasma at a time interval of 24 h. This HPLC-GC-MS method is reliable, selective and sensitive enough to be used in clinical pharmacokinetic studies on the enantioselective disposition of nisoldipine in humans.

Relationship between time after intake of grapefruit juice and the effect on pharmacokinetics and pharmacodynamics of nisoldipine in healthy subjects.

A clinical study was performed in eight healthy volunteers to investigate the effect of various timing of grapefruit juice intake on nisoldipine pharmacokinetics and pharmacodynamics, and to validate our pharmacokinetic model. The subjects were given 10 mg oral nisoldipine with water (control), or 5 mg oral nisoldipine with 200 mL grapefruit juice (G0) or with water at 14 (G14), 38 (G38), 72 (G72) or 96 hours (G96) after a 7-day period of thrice-daily intake of grapefruit juice. Grapefruit juice ingestion did not affect heart rate or the effect area during the first 8 hours of heart rate after nisoldipine administration, although significant decreases of systolic and diastolic blood pressure were caused in G0 by coadministration of grapefruit juice with nisoldipine. Headaches were reported by 3, 2, and 1 persons in G0, G14, and G38, respectively, but no subjects in G72 and G96 reported headaches. Compared with the control group, the maximum plasma concentration of nisoldipine was significantly increased after grapefruit juice intake in G0 and G14, and the plasma concentration was significantly increased at each time in G0 to G72. Therefore the effect of grapefruit juice decreased time dependently and lasted for at least 3 days after intake. Furthermore, our model gave predicted values in good agreement with the observed values. It is therefore necessary to withhold grapefruit juice for at least 3 days before administration of the drug to prevent grapefruit juice-nisoldipine interaction.

Nisoldipine coat-core and heart rate response during treatment of hypertension.

Nisoldipine coat-core (nisoldipine CC), an extended-release once-daily formulation, is an effective treatment for mild-to-moderate hypertension, providing sustained blood pressure control over the 24-hour dosing interval. Nisoldipine CC is highly vascular selective. It causes neither reflex tachycardia nor symptomatic bradycardia; it lacks significant negative inotropy at therapeutic doses; and it does not affect circadian variation in blood pressure or heart rate. Data suggest that the lack of reflex sympathetic activation in response to the blood pressure-lowering effect of nisoldipine CC is due to the smooth onset of action of nisoldipine CC, causing resetting of the baroflex. The neutral heart rate profile of nisoldipine CC confers potential therapeutic advantages over several other calcium channel blockers, in particular, the short-acting agents, in the treatment of hypertension.

The effect of ketoconazole on the pharmacokinetics, pharmacodynamics and safety of nisoldipine.

OBJECTIVE: The primary aim of the present study was to investigate the effect of ketoconazole on the pharmacokinetics of nisoldipine. METHODS: A single dose of nisoldipine 5 mg immediate-release tablet was administered either alone or in combination with ketoconazole 200 mg (4 days pretreatment and concomitant administration) in a randomized crossover trial in seven healthy male Caucasian volunteers. Plasma concentration-versus-time profiles of nisoldipine and its metabolite M9 were determined. RESULTS: Pre-treatment with and concomitant administration of ketoconazole resulted in a 24-fold and 11-fold, increase in mean AUC and Cmax of nisoldipine, respectively, compared with treatment with nisoldipine 5 mg alone. The ketoconazole-induced increase in plasma concentration of the metabolite M9 was of similar magnitude. CONCLUSION: The interaction is attributed to inhibition of cytochrome 3A4-mediated first-pass metabolism. Ketoconazole and other antifungal drugs of the substituted imidazole type as well as other potent inhibitors of cytochrome 3A4 should not be used concomitantly with nisoldipine.

Rapid-release and coat-core formulations of nisoldipine in treatment of hypertension, angina, and heart failure.

Nisoldipine, a dihydropyridine calcium antagonist, has greater vascular selectivity than other calcium channel antagonists and does not depress the intact myocardium in vivo. It should be taken on an empty stomach. Both rapid-release and coat-core formulations are available for clinical use, but only the coat-core formulation extends antihypertensive, antiischemic, and antianginal effects throughout the dosing interval when given once daily. The coat-core formulation in daily doses of 10 to 40 mg does not cause the proischemic effects reported with the rapid-release formulation. When given as monotherapy, the coat-core formulation is highly effective in lowering blood pressure to a similar extent as other long-acting calcium channel blockers, diuretics, beta-blockers, or angiotensin-converting enzyme (ACE) inhibitors. The antihypertensive effects are potentiated when the coat-core formulation of nisoldipine is given in combination with lisinopril. In patients with stable angina pectoris nisoldipine coat-core increases exercise duration, reduces anginal frequency and myocardial ischemia, and is effective as monotherapy or in combination with a beta-blockers. In monotherapy the drug is as effective as other long-acting calcium channel blockers or a beta-blocker. The effects of nisoldipine coat-core in patients with heart failure are unclear at present.

Clinical pharmacokinetics of nisoldipine coat-core.

Nisoldipine, a calcium antagonist of the dihydropyridine type, is the active ingredient of the controlled release nisoldipine coat-core (CC) formulation. In humans, the absorption from nisoldipine CC occurs across the entire gastrointestinal tract with an increase in bioavailability in the colon because of the lower concentrations of metabolising enzymes in the distal gut wall. Although nisoldipine is almost completely absorbed, its absolute bioavailability from the CC tablet is only 5.5%, as a result of significant first-pass metabolism in the gut and liver. Nisoldipine is a high-clearance drug with substantial interindividual and relatively lower intraindividual variability in pharmacokinetics, dependent on liver blood flow. Nisoldipine is highly (> 99%) protein bound. Its elimination is almost exclusively via the metabolic route and renal excretion of metabolites dominates over excretion in the faeces. Although nisoldipine is administered as a racemic mixture, its plasma concentrations are almost entirely caused by the eutomer as a result of highly stereoselective intrinsic clearance. Nisoldipine CC demonstrates linear pharmacokinetics in the therapeutic dose range and its steady-state pharmacokinetics are predictable from single dose data. Steady-state is reached with the second dose when the drug is given once daily and the peak-trough fluctuations in plasma concentration is minimal. Plasma-concentrations of nisoldipine increase with age. Careful dose titration according to individual clinical response is recommended in the elderly. Nisoldipine CC should not be used in patients with liver cirrhosis, though dosage adjustments in patients with renal impairment are not necessary. Inter-ethnic differences in its pharmacokinetics are not evident. Owing to inhibition of metabolising enzymes, a small dosage adjustment decrement for nisoldipine CC may be required when it is given in combination with cimetidine. Concomitant ingestion of nisoldipine with grapefruit juice should be avoided. Inducers of cytochrome P450 (CYP) 3A4, e.g. rifampicin (rifampin) and phenytoin should not be combined with nisoldipine CC, as they may reduce its bioavailability and result in a loss of efficacy. The concomitant use of other drugs which may produce marked induction or inhibition of CYP3A4 is contraindicated. Concomitant intake of the CC tablet with high fat, high calorie foods resulted in an increase in the maximum plasma concentrations of nisoldipine. The 'food-effect' can be avoided by administration of the CC tablet up to 30 minutes before the intake of food [corrected]. Plasma concentrations of nisoldipine are related to its antihypertensive effect via a maximum effect model. Nisoldipine CC once daily produce reductions in blood pressure which are maintained over 24 hours in the absence of relevant effects on heart rate.

Pharmacokinetics of the controlled-release nisoldipine coat-core tablet formulation.

UNLABELLED: The pharmacokinetics, safety, and tolerability of the novel once-daily "coat-core" formulation of the calcium antagonist nisoldipine were investigated in 4 randomized nonblind studies A-D in 52 healthy volunteers. Immediate-release or intravenous formulations were administered as reference in 3 studies. The objective of the present studies was to select the optimum controlled-release formulation (A), compare it to the immediate-release tablet at steady-state (B), determine the absolute bioavailability (C), and investigate bioequivalence after a small change in composition (D). Comparative pharmacokinetic properties: Mean residence time and apparent terminal half-life of nisoldipine in the coat-core formulation were significantly increased in comparison to administration via the intravenous route or the oral immediate-release formulation. Concentration profiles could be described with a 3-segment input model. Steady-state conditions were established with the second dose of nisoldipine coat-core and accumulation from first dose to steady-state accounted for 46% as expected due to the contribution of AUC beyond 24 h. At steady-state the coat-core formulation produced a plateau-shaped profile of nisoldipine plasma concentrations throughout the 24 h dosing interval and the peak-trough fluctuation was reduced by approximately 4-fold, compared to the immediate-release tablet in a b.i.d. regimen. While the absolute bioavailability of the drug in the coat-core tablet was 5.5%, its relative bioavailability was greater by 1.5-fold compared to the immediate-release tablet. This can be attributed to release of drug in the colon where the contribution of the gut wall to presystemic metabolism is reduced resulting in an increase in bioavailability as compared to stomach and small intestine. The intersubject variability of nisoldipine coat-core pharmacokinetics was comparable to that of the immediate-release tablet. The within-subject (intraindividual) variability was considerably smaller. Based on its pharmacokinetic profile the side chain-hydroxylated metabolite M 9 is not expected to contribute significantly to the antihypertensive effect of nisoldipine coat-core. In vitro/in vivo correlation: There was a rank order correlation between in vitro release rate of 3 different nisoldipine coat-core formulations and their noncompartmental pharmacokinetic parameters, a decrease in dissolution rate leading to increased bioavailability in vivo. Likewise, the mean dissolution times in vitro and in vivo were correlated in rank order. A linear (level A) correlation could be established within approximately 0-6 hours (in vitro) corresponding to 0-12 hours in vivo. The change in slope of the correlation curve after approximately 12 hours (in vivo) most likely reflects changes in both rate and extent of nisoldipine absorption in different sections of the gastrointestinal tract. SAFETY: In the present studies the drug was safe and well tolerated, adverse events related to peripheral vasodilatation being less frequent with the coat-core tablet compared to intravenous or immediate-release formulations.

What does nisoldipine coat core (CC) add to current therapy that is clinically meaningful?

Nisoldipine coat core (CC) is a long-acting dihydropyridine with good tolerability. Ambulatory blood pressure measurements in a large, South African multicenter trial show that it has an excellent trough:peak ratio, and that it reduces the early morning rise in blood pressure without any tachycardia. Nisoldipine CC is an effective antihypertensive agent in both black and nonblack South African ethnic groups. In another South African study, regression of left ventricular hypertrophy was achieved in black patients with severe diastolic hypertension. Safety issues are discussed against the background of the testing of this drug in postinfarct left ventricular dysfunction.