Amlodipine Formulation Research Articles

Does Price Really Matter for Generic Alternatives? Supervised learning Approaches in Deciding the Right Price for Acceptable Quality Attributes of Amlodipine Besylate among Generic Alternatives.

The price and safety of finished pharmaceutical preparations are two major concerns while prescribing medicine. In this work, machine learning-based classification models were developed with respect to the quality attributes of 258 samples covering 9 marketed amlodipine (AMLO) formulations. The quantitation of AMLO and its three sulfonate ester genotoxic impurities of besylate counter ion was settled using a validated high-performance liquid chromatography-diode-array detection method. The classification of correlation between dependent and independent variables was exercised using linear discriminant analysis models. The linear dispersion of acceptable quality attributes was significantly different for AMLO besylate formulation with unit price per tablet "<1 Rs." Although the correlations between price and quality are well-understood associations group centroid distance for price group "2-3 Rs." and "1-2 Rs." reveal that acceptable quality dispersion was similar for both groups. Nonetheless, a higher price could allow storage of the finished formulation to be kept on the shelf for a longer period.

Scale-Up Strategy in Quality by Design Approach for Pharmaceutical Blending Process with Discrete Element Method Simulation.

An approach combining quality by design (QbD) and the discrete element method (DEM) is proposed to establish an effective scale-up strategy for the blending process of an amlodipine formulation prepared by the direct compression method. Critical process parameters (CPPs) for intermediate critical quality attributes (IQAs) were identified using risk assessment (RA) in the QbD approach. A Box–Behnken design was applied to obtain the operating space for a laboratory-scale. A DEM model was developed by the input parameters for the amlodipine formulation; blending was simulated on a laboratory-scale V-blender (3 L) at optimal settings. The efficacy and reliability of the DEM model was validated through a comparison of simulation and experimental results. Change of operating space was evaluated using the validated DEM model when scaled-up to pilot-scale (10 L). Pilot-scale blending was simulated on a V-blender and double-cone blender at the optimal settings derived from the laboratory-scale operating space. Both pilot-scale simulation results suggest that blending time should be lower than the laboratory-scale optimized blending time to meet target values. These results confirm the change of operating space during the scale-up process. Therefore, this study suggests that a QbD-integrated DEM simulation can be a desirable approach for an effective scale-up strategy.

Synthesis, characterization and development of validated RP-HPLC method for the estimation of process-related impurity diethyl 4-(3-chlorophenyl)-2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate from amlodipine bulk and formulation

The synthesis, characterization and quantitation of process related impurity diethyl 4-(3-chlorophenyl)-2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate from amlodipine bulk and Tablet formulations. The scheme was performed by using Hantzch pyridine synthesis. The impurity was recrystallized and preliminary evaluation was done on lab scale viz. Melting point, TLC and elemental analysis. The melting point of impurity was found to be 158-160 0 C. The TLC of impurity was carried out by using benzene: pyridine: methanol in the ratio of 5:3:2 was selected as mobile phase for quantification of impurity. The Rf value of the impurity was found to be 0.80. The conformation of synthesized Amlodipine impurity was carried out by using sophisticated instrument such as, FT-IR, NMR, GC-MS, and RP-HPLC method was developed to identify and quantify the Amlodipine impurity in bulk and formulation as per ICH Q2B guidelines. The method was found to be linear, precise, accurate, robust and rugged. Finally diethyl 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate impurity synthesized and quantified from amlodipine bulk and Tablet formulations. Quantization of process related impurity of amlodipine in bulk and tablets was carried out. Impurity was found in bulk and in tablet I & II it was found to be 0.215%, 0.276%.and 0.323% respectively. As per the ICH limit the amount of impurity is more than 0.1% indicates that the impurity found in bulk and tablet formulations is potential impurity.

Randomized placebo-controlled clinical trial of a chewable formulation of amlodipine for the treatment of hypertension in client-owned cats.

BackgroundThere is an unmet clinical need for a cat‐specific formulation of amlodipine to treat hypertensive cats.ObjectivesTo assess the efficacy of chewable amlodipine tablets in reducing systolic blood pressure (SBP) in cats diagnosed with systemic arterial hypertension.AnimalsSeventy‐seven client‐owned cats with systemic hypertension were included (median age 14 years).MethodsThe study was randomized, double‐blinded, and placebo‐controlled. Forty‐two cats received 0.125–0.50 mg/kg amlodipine once daily for 28 days; 35 cats received placebo. After 28 days all cats continued with amlodipine for 2–3 months in an open‐label phase. Blood pressure was measured using high definition oscillometry. A responder was defined as a cat showing a decrease of SBP to <150 mmHg at 28 days or a decrease from baseline ≥15%.ResultsSixty‐one cats completed the study. The responder rate was 63% in amlodipine group and 18% in placebo group. Cats receiving amlodipine were 7.9 (95% CI 2.6–24.1) times more likely to be classified as responders when compared to those receiving placebo (P < .001). From a mean (±SD) baseline value of 181 (±12) mmHg, SBP decreased to 154 (±17) mmHg with amlodipine and to 170 (±21) mmHg with placebo (P < .001). The voluntary acceptance rate of amlodipine formulation was 73%.Conclusions and Clinical ImportanceThe chewable amlodipine tablet effectively reduced SBP compared with placebo in hypertensive cats, and was well‐tolerated. It can be used concomitantly with angiotensin‐converting enzyme inhibitors and in cats with chronic kidney disease.

Comparative Bioavailability of Two Amlodipine Formulations in Healthy Volunteers

The present study was conducted to find out whether the bioavailability of a 10 mg amlodipine (CAS 88150-42-9) tablet (Intervask, "test") was equivalent to that that of a reference formulation ("reference"). The pharmacokinetic parameters assessed in this study were area under the serum concentration-time curve from time zero to 144 h (AUCt), area under the serum concentration-time curve from time zero to infinity (AUCinf), the peak serum concentration of the drug (Cmax), time needed to achieve the peak serum concentration (tmax), and elimination half life (t(1/2)). This was a cross-over, randomized, single-blind study which included 12 healthy male and female volunteers under fasting condition. In each of the two study periods (separated by a washout of 3 weeks) a single dose of test or reference drug was administered. Blood samples were taken up to 144 h post dose, the plasma was separated and the concentrations of amlodipine were determined by a LC/MS method. The mean AUCt, AUCinf, Cmax, and t(1/2) were 353.15 ng x h/mL, 417.86 ng x h/mL, 8.08 ng/mL, and 48.04 h, respectively, for the test drug and 359.99 ng x h x mL(-1), 408.23 ng x h/mL, 8.22 ng/mL, and 43.81 h, respectively, for the reference drug. The median Tmax of the test drug and reference drug were 8.0 h and 8.5 h, respectively. The point estimators of the ratios test/reference drug for AUCt, AUCinf, and Cmax were 96.26%, 99.48%, and 97.03%, respectively. Furthermore, the 90% confidence intervals of the mean ratio of In-transformed were 83.73-110.68% for AUCt, 81.79-120.99% for AUCinf, and 81.94-114.81% for Cmax. It can be concluded that the two amlodipine tablets (test drug and reference drug) are bioequivalent in terms of the rate and extent of absorption.

Efficacy, Safety, and Palatability of RACTAB® Formulation Amlodipine Orally Disintegrating Tablets

Objective: The aim of this study was to confirm the efficacy, safety, and expected palatability of amlodipine orally disintegrating tablets (ODT) [RACTAB® formulation (Towa, Osaka, Japan)]. We report the re-analyzed results of 1687 cases in clinical settings obtained through postmarketing surveillance in Japan. Method: Study subjects were patients receiving treatment for the first time with amlodipine ODT for hypertension under routine care. A multicenter central registration system was used for this prospective survey. The survey was conducted from October 2008 to October 2010. The observational period was 12 weeks, during which time surveys on outpatient blood pressure, adverse events, palatability, etc. were conducted. Results: Blood pressure stabilized following treatment, and both systolic and diastolic blood pressures were favorably controlled. Adverse events observed were not significantly different from those observed during drug use trials of amlodipine formulations reported in 2003. Moreover, palatability of amlodipine ODT showed a 99.6% (227 of 228 cases) favorable patient acceptance, which is consistent with the initial design concept of RACTAB® formulation. Conclusions: The results of this postmarketing surveillance study indicated that the efficacy, safety, and palatability of amlodipine ODT met our expectations (dissolves quickly in the mouth, tastes good, and is not rough on the tongue). Accordingly, amlodipine ODT are believed to be an easy-to-use formulation for prescribing doctors, dispensing pharmacists, and patients receiving treatment.

Efficacy, safety, and palatability of RACTAB(®) formulation amlodipine orally disintegrating tablets.

Objective: The aim of this study was to confirm the efficacy, safety, and expected palatability of amlodipine orally disintegrating tablets (ODT) [RACTAB® formulation (Towa, Osaka, Japan)]. We report the re-analyzed results of 1687 cases in clinical settings obtained through postmarketing surveillance in Japan.Method: Study subjects were patients receiving treatment for the first time with amlodipine ODT for hypertension under routine care. A multicenter central registration system was used for this prospective survey. The survey was conducted from October 2008 to October 2010. The observational period was 12 weeks, during which time surveys on outpatient blood pressure, adverse events, palatability, etc. were conducted.Results: Blood pressure stabilized following treatment, and both systolic and diastolic blood pressures were favorably controlled. Adverse events observed were not significantly different from those observed during drug use trials of amlodipine formulations reported in 2003. Moreover, palatability of amlodipine ODT showed a 99.6% (227 of 228 cases) favorable patient acceptance, which is consistent with the initial design concept of RACTAB® formulation.Conclusions: The results of this postmarketing surveillance study indicated that the efficacy, safety, and palatability of amlodipine ODT met our expectations (dissolves quickly in the mouth, tastes good, and is not rough on the tongue). Accordingly, amlodipine ODT are believed to be an easy-to-use formulation for prescribing doctors, dispensing pharmacists, and patients receiving treatment.

Comparative pharmacokinetic and pharmacodynamic characteristics of amlodipine besylate and amlodipine nicotinate in healthy subjects

Amlodipine, a dihydropyridine calcium antagonist, is prescribed for the management of angina and hypertension, and is sold as amlodipine besylate. However, a new salt formulation, amlodipine nicotinate, has recently been developed. Here, we evaluated the comparative pharmacokinetic and pharmacodynamic characteristics of the nicotinate and besylate forms of amlodipine. A randomized, 2-way crossover study was conducted in 18 healthy male volunteers to compare the pharmacokinetics and pharmacodynamics of these two forms, i.e. amlodipine nicotinate (test) and amlodipine besylate (reference), after administration of a single dose of 5 mg of each drug and a washout period between doses of 4 weeks. Blood samples for the pharmacokinetic analysis of amlodipine were obtained over the 144-hour period after administration. Systolic and diastolic blood pressures and pulse rates were recorded immediately prior to each blood sampling. All participants completed both treatment periods, and no serious adverse events occurred during the study period. After administering a single dose of each formulation, mean AUC0-infinity and Cmax values were 190.91+/-60.49 ng x h/ml and 3.87+/-1.04 ng/ml for the test formulation and 203.15+/-52.05 ng x h/ml and 4.01+/-0.60 ng/ml for the reference formulation, respectively. The 90% confidence intervals of test/reference mean ratios for AUC0- infinity and Cmax fell within the predetermined equivalence range of 80 - 125%. Pharmacodynamic profiles including systolic and diastolic blood pressures and pulse rates exhibited no significant differences between the two formulations. The two amlodipine formulations showed similar pharmacokinetic and pharmacodynamic characteristics and the new amlodipine formulation, amlodipine nicotinate, was found to be equivalent for pharmacokinetics to the currently available amlodipine besylate with respect to the rate and extent of amlodipine absorption.

Pharmacokinetic and pharmacodynamic characteristics of a new S-amlodipine formulation in healthy Korean male subjects: A randomized, open-label, two-period, comparative, crossover study

Background: Amlodipine, a dihydropyridine calcium channel antagonist, is prescribed for the management of angina and hypertension. It is used therapeutically as a racemic mixture, composed of S- and R-enantiomers, but its calcium channel-blocking effect is confined to S-amlodipine; R-amlodipine has 1000-fold less activity than its S-enantiomer. Objective: The objective of this study was to compare the pharmacokinetic and pharmacodynamic properties and safety profiles of a newly developed amlodipine formulation, composed wholly of S-amlodipine, with those of the conventionally prescribed racemic formulation. Methods: This randomized, open-label, 2-period, comparative, crossover study was conducted with healthy volunteers at the Gil Medical Center and Gachon Medical School, Incheon, Korea. Male subjects, aged 20 to 50 years, were eligible to participate if their weight was within 20% of ideal body weight and if they were judged by physicians to be healthy. All subjects were randomly assigned in a 1:1 ratio to 1 of 2 treatment sequences: (1) a single dose of the test amlodipine formulation ( S-enantiomer amlodipine 5 mg PO) (Lodien™ [Hanlim Pharmaceutical Co., Seoul, Korea]) in the first study period, followed by a single dose of the reference amlodipine formulation (racemate 10 mg PO) (Norvasc® [Pfizer Pharmaceuticals Korea Ltd., Seoul, Korea]) in the second study period, or (2) a single dose of the reference formulation in the first study period, followed by a single dose of the test formulation in the second period. A 3-week washout occurred between study periods. Blood samples for pharmacokinetic analysis of S-amlodipine were collected at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 48, 72, 96, 120, 144, and 168 hours after drug administration. Pharmacodynamic variables (ie, systolic and diastolic blood pressure and heart rate) were measured at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 48, and 72 hours after administration. Safety profiles were also assessed. Hematology, biochemistry, electrocardiography, and urinalysis were performed at baseline and end of study. Adverse events were monitored throughout the study period. Pharmacokinetic characteristics were compared using noncompartmental analysis. Pharmacokinetic equivalence was concluded if the geometric mean ratios of the plasma C max and AUC were within the predetermined range of 80% to 125%. Results: Twenty-six healthy Korean male volunteers were screened and 18 subjects (mean [SD] age, 23.4 [1.5] years [range, 21–26 years]; mean [SD] weight, 69.3 [6.8] kg [range, 60-88 kg]) were enrolled and completed the study. The plasma concentration-time profiles of S-amlodipine were comparable after administration of both formulations. The mean (SD) values for C max AUC from time 0 to the last available measurement (AUC last), and AUC from 0 to infinity (AUC 0−∞) for the reference formulation (3.0 [0.6] ng/mL, 151.4 [35.7] ng - h/mL, and 175.3 [45.1] ng - h/mL, respectively) did not differ significantly from those for the test formulation (3.1 [0.6] ng/mL, 139.7 [40.3] ng - h/mL, and 161.7 [43.8] ng - h/mL, respectively). The calculated 90% Cls for the corresponding ratios of log*transformed C max, AUCO 0−∞, and AUC last were 97.56% to 112.51%, 86.31% to 98.74%, and 83.46% to 100.04%, respectively, which met the predetermined criteria for pharmacokinetic equivalence. Despite the single administration, significant changes in maximal blood pressure and heart rate were observed after drug administration for both formulations, compared with baseline values (all, P < 0.001). However, no significant differences were observed between the 2 formulations in terms of pharmacodynamic profiles, and no clinically relevant changes were observed for either formulation with respect to physical examination, hematology, biochemistry, electrocardiography, or urinalysis. Neither formulation caused any serious adverse events. Conclusions: Two amlodipine formulations were found to be equivalent in terms of the pharmacokinetics of S-amlodipine. The newly developed formulation, comprised of only S-amlodipine, had pharmacodynamic profiles comparable to those of the conventional racemic amlodipine formulation in these healthy Korean male subjects. Both formulations were well tolerated.

Pharmacokinetics of a new amlodipine formulation: Bioequivalent and not affected by CYP3A5 genotype

Background/Aims Amlodipine is among the most widely used antihypertensive drugs. This study aimed to compare pharmacokinetic properties of test formulation (T), amlodipine orotate, with those of reference one (R), amlodipine besylate, and to evaluate the impact of CYP3A5 genotype on the pharmacokinetics. Methods A randomized, single-blind, crossover study with a 2-week washout period was performed at the Clinical Trial Center, Seoul National University Hospital (Korea). A single 10 mg dose was administered orally to 24 healthy male volunteers with CYP3A5*1/*3 (n= 9), *3/*3 (n= 15) genotypes. After dosing, serial blood samples were collected for a period of 144h. Plasma concentrations were determined by LC/MS/MS and the pharmacokinetic parameters were analyzed by non-compartmental analysis. Results Pharmacokinetic comparison did not show differences between the formulations: area under the curve (AUCinf) 336 versus 329 ng*h/mL, maximum plasma concentration (Cmax) 6.89 versus 6.46 ng/mL, elimination half-life 44.0 versus 42.6h for T and R formulations, respectively. The geometric mean ratios (90% CI) of the AUCinf and Cmax were 1.06 (0.95–1.19) and 1.10 (0.99–1.24), respectively. These values were within the equivalence range of 0.80–1.25. Apparent clearances (CL/F) according to CYP3A5 genotype were not significantly different in both T (P=.18) and R (P=.79). Conclusions Two formulations of amlodipine are bioequivalent and their pharmacokinetics may not be affected by CYP3A5 genotype. Clinical Pharmacology & Therapeutics (2005) 77, P78–P78; doi: 10.1016/j.clpt.2004.12.189

Efficacy and Safety of Amlodipine Camsylate(Amodipin(TM)) for Treatment of Essential Hypertension

Background and Objectives:Amlodipine camsylate (Amodipin), a newly developed amlodipine formulation, has similar physical properties and pharmacokinetic equivalency to that of the conventional formulation (amlodipine besylate, Norvasc®). Subjects and Methods:This prospective, randomized, double-blind, parallel designed, multicenter study was conducted at a total of 7 sites. 95 patients with mild to moderate essential hypertension were enrolled. Following the 2 week administration of a placebo, the patients received 5 mg of amlodipine once a day for a total of 8 weeks. If either the blood pressure was ≥140/90 mmHg or the sitting diastolic blood pressure had not decreased by ≥10 mmHg from those at the baseline after 4 weeks of treatment, the dose of amlodipine was increased to 10 mg. The blood pressure was measured twice every 4 weeks and mean value recorded. Results:The diastolic and systolic blood pressures were significantly decreased with both amlodipine camsylate (baseline DBP: 97.4±5.8 mmHg, 8 th week DBP: 84.1±8.8 mmHg, mean differences: -13.3±7.4) and amlodipine besylate (baseline DBP: 95.9±5.9 mmHg, 8 th week DBP: 83.2±9.2 mmHg, mean differences: -12.4±8.3). The incidence of drug related adverse events was similar in both groups. Conclusion: This study suggests that once-a-day monotherapy of amlodipine camsylate is effective for the control of blood pressure in patients with essential hypertension, without significant adverse events. (Korean Circulation J 2005;35:247-252)

Randomized, open-label, two-period crossover comparison of the pharmacokinetic and pharmacodynamic properties of two amlodipine formulations in healthy adult male Korean subjects

Background: Amlodipine, a third-generation dihydropyridine calcium antagonist, is prescribed in the management of angina and hypertension. A newly developed amlodipine formulation (amlodipine camsylate) is associated with similar physical properties, melting point, and solubility—and improved stability against long-term stability test and accelerated temperature test—compared with the conventional formulation (amlodipine besylate). Objective: This study was performed to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties and safety profiles of a newly developed amlodipine formulation with a conventional formulation in healthy male subjects. Methods: This randomized, open-label, 2-period crossover comparative study was conducted at the Clinical Trial Center, Gil Medical Center, Gachon Medical School (Incheon, Korea). Eighteen healthy male Korean subjects aged 20 to 40 years were enrolled. All subjects received a single oral dose (5-mg tablet) of a conventional (reference) or newly developed (test) amlodipine formulation. Blood samples for PK analysis of amlodipine were obtained during the 144-hour period after dosing. Systolic and diastolic blood pressure (BP) (SBP and DBP, respectively) and pulse rate (PR) were measured just before each blood sampling. Assessment of safety profiles, including hematology and biochemistry, electrocardiography, urinalysis, and monitoring of adverse events (AEs), was performed. Results: All participants completed both treatment periods. Their mean (SD) age was 22.3 (1.5) years (range, 20–25 years) and their mean (SD) body weight was 67.9 (5.6) kg (range, 57–77 kg). The plasma concentration-time profiles of amlodipine were similar after administration of the 2 formulations. The reference and test formulations were pharmacokinetically equivalent. The 90% CIs for the mean treatment ratios of the log-transformed peak plasma concentration and the area under the plasma concentration-time curve were within the predetermined equivalence range of 80% to 125%. Despite administration of a single dose, significant maximal changes in SBP, DBP, and PR were achieved after drug administration for both formulations compared with baseline values (all, P < 0.001). No significant differences in PD profiles were found between the 2 formulations. No clinically relevant changes were observed in physical, biochemical, hematologic, electrocardiographic, or urinalysis findings during the study. Neither formulation caused any AEs during the study. Conclusions: The 2 amlodipine formulations were pharmacokinetically equivalent and showed similar PD characteristics in these healthy male subjects.

Amlodipine Besylate–Excipients Interaction in Solid Dosage Form

This article studies the compatibility of amlodipine besylate in its solid formulations with various drug excipients. The various factors affecting amlodipine besylate stability were studied using high‐performance liquid chromatography (HPLC). It has been found that binary 1:1 mixtures of amlodipine besylate and an excipient are stable at 65°C and 40°C/75% RH. Further investigations were conducted to study the stability of amlodipine besylate in multicomponent mixtures, including mixtures with actual formulations. The study reveals that mixtures of lactose, magnesium stearate, and water induce some instability on amlodipine besylate. The major degradation product confirmed by HPLC‐mass spectrometry is amlodipine besylate glycosyl. This is in conformity with the well‐known Maillard reaction between primary amines and lactose. Thus, lactose‐free amlodipine formulations are recommended from the safety, quality, efficacy, and process cost points of view.