Methodological Studies of the Determination of Lacidipine in Human Plasma by HPLC-MS/MS / 中国药师

Objective: To develop a method for the determination of lacidipine (LAC) in human plasma.Methods: After liquid-liquid extraction with tert-butyl methyl ether, the plasma samples were analyzed by LC-MS/MS.Using lacidipine-13C8 as the internal standard, a Agilent ZORBAX Eclipse XDB C18 column (150 mm×2.1 mm, 5 μm) was used with the mobile phase consisting of water(containing 5 mmol·L-1 ammonium formate)-acetonitrile(15∶85,v/v)at a flow rate of 0.3 ml·min-1 and with the column temperature at 40 ℃.The ion transitions were performed in a positive electrospray ionization multiple reaction-monitoring mode regarding + as the molecular ion peak of lacidipine and monitoring with m/z 473.5→m/z 410.3, m/z 473.5→m/z 400.1 and m/z 473.5→m/z 354.3.The internal standard was monitored with m/z 481.4→m/z 362.3.Results: The linear range of lacidipine was 0.1-10 ng·ml-1 (r＞0.99) and the lower quantification limit was 0.1 ng·ml-1.The intra-and inter-day RSDs were 3.15%-7.04% and the relative error was from-8.58% to 12.71%.The mean relative recovery of lacidipine was from 107% to 118% (RSD＜15%).The plasma samples were stable at-20℃ for 40 d and kept stable after three repeated freeze-thaw cycles.The prepared samples were stable at room temperature for 24 h and in the automatic sample injector (4℃) for 24 h(RSD＜15%).Conclusion: The developed assay method can be applied in the bioequivalence evaluation and pharmacokinetic studies of lacidipine in human.

Simultaneous Determination of 4 Residual Organic Solvents in Lacidipine Raw Material by GC / 中国药房

OBJECTIVE:To establish a method for simultaneous determination of 4 residual organic solvents such as ethanol,dichloromethane,isopropanol and ethyl acetate in lacidipine raw material.METHODS:GC method was adopted.The determination was performed on DB-624 capillary column at the rate of 2.0 mL/min using nitrogen gas as carrier and FID as the detector by temperature programming.The temperature of detector was set at 250 ℃.Carries gas was nitrogen.The split ratio was 10 ∶ 1.The sample size was 10 μL.RESULTS:The linear ranges of ethanol,dichloromethane,isopropanol and ethyl acetate were 0.259 5-2.076 mg/mL (r=0.999 6),0.055 3-0.316 mg/mL (r=0.999 2),0.342 3-1.956 mg/mL (r=0.999 5),0.370 6-2.118 mg/mL(r=0.999 4),respectively.The limits of quantification were 2.96,2.24,4.4,4.44 μg/mL,and the detection limits were 0.887,0.672,1.3,1.32 μg/ mL,respectively.RSDs of precision,stability and reproducibility tests were all lower than 4.0％.The recoveries were 95.00％-101.17％ (RSD=2.19％,n=9),96.22％-104.53％ (RSD=3.27％,n=9),96.20％-104.90％ (RSD=2.41％,n=9),95.60 ％-104.48 ％ (RSD=2.85 ％,n=9).CONCLUSIONS:The method is simple,sensitive and reliable,and is suitable for simultaneous determination of 4 residual organic solvents in lacidipine raw material.

Functionality advancement of poorly soluble biovariable anti hypertensive Drug by sophisticated SD-FBP technology as per enhanced QbD.

Lacidipine (LCDP) is a dihydropyridine derivative categorized as an Anti-hypertensive Ca+2 channel blocker belonging to BCS class IV drug with low solubility and low permeability which presents a challenge to the formulation scientists. The development of a solid dispersion by solvent evaporation is a practically viable method to enhance dissolution of LCDP from oral dosage form. Solvent evaporation by Fluidized Bed Process (FBP) was the method of choice for SD as it improves wettability with simultaneous increase in porosity of granules resulting enhanced surface area producing higher dissolution rate and bioavailability of poorly water-soluble drug. Thus, the main object of the present invention is to provide stable pharmaceutical dosage form of LCDP with desired dissolution rate i.e. at least 80% drug release within 45 minutes, without use of disintegrant(s) and/or surfactant(s) or without micronization of the active ingredient per se. One more object of this invention is to provide a sophisticated robust process for the preparation of said pharmaceutical dosage form by Quality by Design (QbD) concept focusing on thorough understanding of the product and process by which it is developed and manufactured along with a knowledge of the risks involved in manufacturing by IRMA & FMEA study of the product with process and how best to mitigate those risks by developing design space with DoE & MVDA with outlined control strategy.

Antibacterial & antitoxic effects of the cardiovascular drug lacidipine in an animal model.

Background & objectives: Vibrio cholerae produces acute infection by liberating potent enterotoxin, called cholera toxin in human intestine. Cardiovascular drug lacidipine possessing powerful in vitro action against V. cholerae was tested to determine its possible activity against a toxigenic V. cholerae strain in an established animal model. Methods: In the rabbit intestine four loops were constructed, 3 of which were injected with over night grown V. cholerae 569B culture. Of these, two loops were simultaneously given graded doses (100, 200 μg) of lacidipine, one was left as such for a positive control. The first loop received sterile medium (negative control). After 18 h, contents of all the loops were examined for accumulation of fluid and number of viable cells. Results: Lacidipine when administrated with live V. cholerae 569B, caused a reduction in the number of viable bacteria along with amount of fluid in the loops. The amount of fluid and number of viable cells were much reduced in the loop that had 200 μg of lacidipine than the loop that received 100 μg of the drug. Interpretation & conclusions: Lacidipine has distinct inhibitory action against V. cholerae 569B with respect to both viability and production of cholera toxin in the rabbit ileum. Structural modifications of this compound may possibly lead to procurement of new potent antimicrobial drugs.

Spectrophotometric determination of lacidipine in bulk and tablet dosage form.

New, simple, accurate, sensitive, economical, and reproducible UV-spectrophotometric method was developed and validated for the estimation of Lacidipine in bulk and tablet dosage form. Lacidipine shows maximum absorbance at 615.7 nm and linearity (Beer’s Lamberts law) was found to be in the range of 10-70 μg/ml. The apparent molar absorptivity and Sandell’s sensitivity coefficient were found to be 2.84 x 103 L mol-1 cm-1 and 0.16043 indicating the high sensitivity of the proposed methods. The slope, intercept and correlation coefficient were also calculated. Interference of common excipients with the proposed method was also studied and found there was no interference of common excipients with the proposed method. The method was validated by determining its sensitivity, accuracy and precision which proves the suitability of the developed method for the routine estimation of Lacidipine in pharmaceutical formulations.

Effect of Lacidipine on Blood Pressure and Endothelial Function in Mild-to-Moderate Essential Hypertension Patients With Diabetes in Korea

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the efficacy of lacidipine in reducing blood pressure (BP) and to determine its effect on endothelial function in mild-to-moderate hypertensive patients with type 2 diabetes mellitus (DM). SUBJECTS AND METHODS: This was a prospective, multicenter, open-label, single-arm study, enrolling 290 patients with mild-to-moderate hypertension and type 2 DM. Patients were initially treated with 2 mg lacidipine orally once daily for 4 weeks, which was then increased as necessary every 4 weeks to a maximal dose of 6 mg daily. The primary endpoint was the mean change in systolic blood pressure (SBP) from baseline after 12 weeks of treatment. Secondary endpoints included mean changes in diastolic blood pressure (DBP), flow-mediated vasodilatation (FMD), and serum concentrations of biochemical markers such as high-sensitivity C-reactive protein (hs-CRP), monocyte chemo-attractant protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9), and plasminogen activator inhibitor-1 (PAI-1). RESULTS: Lacidipine treatment significantly reduced SBP by -13.4+/-13.0 mmHg (p<0.001) and DBP by -6.2+/-9.3 mmHg (p<0.001). Lacidipine treatment did not improve endothelial-dependent vasodilatation, despite significantly improved nitroglycerin-induced, endothelial-independent vasodilatation. MCP-1 levels significantly decreased from 283.66+/-110.08 pg/mL to 257.83+/-100.23 pg/mL (p<0.001); whereas there were no significant changes in the levels of hs-CRP, MMP-9, or PAI-1. CONCLUSION: Twelve weeks of treatment with lacidipine was effective and well tolerated in mild-to-moderate hypertensive patients with type 2 DM. In spite of inducing a significant reduction in MCP-1 levels, lacidipine did not improve endothelial function.

Acceptability and tolerability of lacidipine in hypertensive patients.

A multicenter study on the efficacy and tolerability of lacidipine in ambulatory Thai hypertensive patients was carried out in the Out-patient Department at Siriraj Hospital, Ramathibodi Hospital and Rajvidhi Hospital from October 1996 to July 1997. There were 46 patients who had mild to moderate hypertension (DBP>95 mmHg and <115mmHg). The enrolled-patients consisted of male : female = 20 : 26, age ranged between 23-69 years (51.98+9.49 years). The study showed that lacidipine 2-6 mg given once daily was able to normalize sitting BP (DBP < 90 mmHg) in 32 cases (69.4%). Among them, normalization of BP could be achieved by lacidipine 2 mg/d in 24 cases (52.2%), 4 mg/d in 4 cases and 6 mg/d in 2 cases. This study revealed that lacidipine in the therapeutic dose of 2-6 mg/d did not induce reflex tachycardia, metabolic derangement and importantly, did not produce any serious side effects.

EFFECT OF Mn9202 ON 5-HT, TH AND 5-HT RECEPTOR OF CULTURED RAT STOMACH FUNDUS SMOOTH MUSCLE CELLS / 解剖学报

Objective To study the effects of DHPs calcium antagonist Mn9202 and lacidipine on 5-HT、TH and 5-HTR of rat stomach fundus smooth muscle cells. Methods It's effects was investigated by using immunocytochemistry and image analysis of stom- ach fundus smooth muscle cells in culture and compared with cyprohetadine(antagonist of 5-HT). Results 5-HT、TH and 5-HTR im- munoreactive substances were existed in SFSMC. The results of image analysis indicated that the content of 5-HT. TH and 5-HTR were significantly lower when using Mn9202.lacidipine and cyprohetadine. Conclusion The results suggest that the rat stomach fundus smooth muscle cells possess 5-HT autocrine function, and DHPs calcium antagonist reduce the number of 5-HT receptor in the rat stomach fundus smooth muscle cells though the reduction of 5-HT sythesis, this results conform with cyprohetadine (antagonist of 5 - HT).