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      Immediate release tablet formulation of varenicline salicylate and comparative pharmacokinetic study in human volunteers

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          Abstract

          Purpose

          To develop an immediate release-type tablet containing varenicline salicylate (VRC-S), a smoking cessation agent, formulation and stability studies were performed. The in vitro dissolution and in vivo pharmacokinetic (PK) behavior of the tablets were compared with those of the commercial product (Champix) as a reference.

          Materials and methods

          The characteristics of the powder were investigated by particle morphology, size distribution, solubility, hygroscopicity, differential scanning calorimetry, and powder X-ray diffraction. Based on the drug–excipient compatibility test, different VRC-S tablets were prepared with the selected excipients through direct compression or wet granulation method and subjected to a dissolution test. The stability of the most promising VRC-S tablet (F4) was evaluated under accelerated conditions (40°C and 75% relative humidity). Further, the dissolution and human pharmacokinetic profiles of the F4 tablet and Champix were compared.

          Results

          VRC-S showed a positively skewed unimodal size distribution with a specific surface area of 2.02 m 2/g, single endothermic peak of 225.2°C in differential scanning calorimetry, crystalline internal structure in powder X-ray diffraction, aqueous solubility of 244.7 mg/mL, and hygroscopicity of 0.256 mg/g. The wet granulation method was preferred for tablet preparation and employed the following excipients: microcrystalline cellulose and anhydrous dibasic calcium phosphate as diluents, croscarmellose sodium as a disintegrant, and colloidal silicon dioxide and magnesium stearate as lubricants. The F4 tablet was stable for 6 months under accelerated conditions. The dissolution of VRC was pH independent, revealing f 2 values of 76.49 and 68.38 at pH 1.2 and pH 6.8, respectively. After the oral administration of F4 tablet and Champix to healthy human volunteers, pharmacokinetic parameters, including time to reach the maximum plasma concentration (T max), maximum plasma concentration (C max), and area under the curve from 0 to infinity (AUC inf), were compared. The values of 90% CI were 0.972–1.035 for C max and 0.982–1.075 for AUC inf, which was indicative of the bioequivalence of both products.

          Conclusion

          VRC-S–containing F4 tablet might be a good candidate for smoking cessation treatment.

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          Most cited references 26

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          Sample sizes for clinical trials with normal data.

           S Julious (2004)
          This article gives an overview of sample size calculations for parallel group and cross-over studies with Normal data. Sample size derivation is given for trials where the objective is to demonstrate: superiority, equivalence, non-inferiority, bioequivalence and estimation to a given precision, for different types I and II errors. It is demonstrated how the different trial objectives influence the null and alternative hypotheses of the trials and how these hypotheses influence the calculations. Sample size tables for the different types of trials and worked examples are given. Copyright 2004 John Wiley & Sons, Ltd.
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            Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid.

            The preclinical pharmacology of the alpha4beta2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline, a novel smoking cessation agent is described. Varenicline binds with subnanomolar affinity only to alpha4beta2 nAChRs and in vitro functional patch clamp studies in HEK cells expressing nAChRs show that varenicline is a partial agonist with 45% of nicotine's maximal efficacy at alpha4beta2 nAChRs. In neurochemical models varenicline has significantly lower (40-60%) efficacy than nicotine in stimulating [(3)H]-dopamine release from rat brain slices in vitro and in increasing dopamine release from rat nucleus accumbens in vivo, while it is more potent than nicotine. In addition, when combined with nicotine, varenicline effectively attenuates the nicotine-induced dopamine release to the level of the effect of varenicline alone, consistent with partial agonism. Finally, varenicline reduces nicotine self-administration in rats and supports lower self-administration break points than nicotine. These data suggest that varenicline can reproduce to some extent the subjective effects of smoking by partially activating alpha4beta2 nAChRs, while preventing full activation of these receptors by nicotine. Based on these findings, varenicline was advanced into clinical development and recently shown to be an effective and safe aid for smoking cessation treatment.
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              The accumulated evidence on lung cancer and environmental tobacco smoke.

              To estimate the risk of lung cancer in lifelong non-smokers exposed to environmental tobacco smoke. Analysis of 37 published epidemiological studies of the risk of lung cancer (4626 cases) in non-smokers who did and did not live with a smoker. The risk estimate was compared with that from linear extrapolation of the risk in smokers using seven studies of biochemical markers of tobacco smoke intake. Relative risk of lung cancer in lifelong non-smokers according to whether the spouse currently smoked or had never smoked. The excess risk of lung cancer was 24% (95% confidence interval 13% to 36%) in non-smokers who lived with a smoker (P < 0.001). Adjustment for the effects of bias (positive and negative) and dietary confounding had little overall effect; the adjusted excess risk was 26% (7% to 47%). The dose-response relation of the risk of lung cancer with both the number of cigarettes smoked by the spouse and the duration of exposure was significant. The excess risk derived by linear extrapolation from that in smokers was 19%, similar to the direct estimate of 26%. The epidemiological and biochemical evidence on exposure to environmental tobacco smoke, with the supporting evidence of tobacco specific carcinogens in the blood and urine of non-smokers exposed to environmental tobacco smoke, provides compelling confirmation that breathing other people's tobacco smoke is a cause of lung cancer.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                09 October 2018
                : 12
                : 3377-3392
                Affiliations
                [1 ]College of Pharmacy, Chung-Ang University, Heuksuk-ro, Dongjak-gu, Seoul 06974, Republic of Korea, ywchoi@ 123456cau.ac.kr
                [2 ]College of Pharmacy, Dankook University, Dandae-ro, Dongnam-gu, CheonanChungnam 31116, Republic of Korea
                [3 ]College of Pharmacy, Keimyung University, Dalgubeol-daero, Daegu 42601, Republic of Korea
                [4 ]CTCBIO INC., Hyundaikia-ro, Paltan, Hwaseong, Gyeonggi 18576, Republic of Korea
                [5 ]Center for Biomaterials, Korea Institute of Science & Technology (KIST), Hwarang-ro, Seongbuk-gu, Seoul 02792, Republic of Korea
                Author notes
                Correspondence: Young Wook Choi, College of Pharmacy, Chung-Ang University, 84 Heuksuk-ro, Dongjak-gu, Seoul 06974, Republic of Korea, Tel +82 2 820 5609, Fax +82 2 826 3781, Email ywchoi@ 123456cau.ac.kr
                [*]

                These authors contributed equally to this work

                Article
                dddt-12-3377
                10.2147/DDDT.S178456
                6186768
                © 2018 Kwak et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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