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      Formulation and bioequivalence studies of choline alfoscerate tablet comparing with soft gelatin capsule in healthy male volunteers

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          The aim of this study was to develop a tablet formulation of choline alfoscerate and to assess its bioequivalence by comparing its pharmacokinetic parameters with those of a commercially available soft gelatin capsule (Gliatilin ®) in healthy Korean male volunteers.

          Materials and methods

          Film-coated tablet formulation was optimized to control the hygroscopicity of choline alfoscerate. Bioequivalence study was performed under fasted condition with a randomized, single-dose, two-period crossover design. Subjects were orally treated with 1,200 mg of test or reference choline alfoscerate (400 mg × three doses) formulation. Blood samples were collected up to 12 hours the day before dosing to correct the baseline level of choline and 12 hours after dosing to obtain drug absorption profile. Pharmacokinetic parameters were determined after analyzing plasma concentration of choline by using LC–MS/MS.


          Hygroscopicity of choline alfoscerate was successfully controlled by adding suitable amount of Neusilin ® (magnesium aluminometasilicate) in the film-coated tablet. Stability of the tablet formulation was also confirmed under the accelerated condition for 3 months. Bioequivalence study showed that the mean area under the plasma concentration–time curve from time 0 to infinity of test tablet and reference soft capsule was 3.428±2.170 and 3.305±1.803 µg⋅h/mL, respectively; the mean C max was 0.365±0.158 and 0.380±0.108 µg/mL, respectively; and the mean T max was 3.51±2.57 and 3.85±3.19 hours, respectively. The 90% CIs for geometric mean ratios of test to reference formulation for AUC 0–t and C max were 84.51%–111.98% and 83.31%–104.10%, respectively, and satisfied the EMA regulatory criteria for bioequivalence.


          Pharmacokinetic parameters including the C max and AUC 0–t determined after oral administration of the two formulations in healthy Korean male volunteers showed that the differences between the formulations (tablet vs soft capsule) were not significant for bioequivalence. Both formulations were well tolerated, with no serious adverse events reported.

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          Most cited references 14

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          Determination of choline, betaine, and dimethylglycine in plasma by a high-throughput method based on normal-phase chromatography-tandem mass spectrometry.

          The quaternary ammonium compounds, choline and betaine, and dimethylglycine (DMG) reside along a metabolic pathway linked to the synthesis of neurotransmitters and membrane phospholipids and to homocysteine remethylation and, therefore, folate status. Lack of a convenient, high-throughput method for the determination of these compounds has prevented population-based studies of their possible associations with lifestyle, nutrition, and chronic diseases. Serum or plasma samples were deproteinized by mixing with three volumes of acetonitrile that contained d(9)-choline and d(9)-betaine as internal standards. We used a normal-phase silica column for the separation of choline (retention time, 2.8 min), betaine (1.3 min), DMG (1.15 min), and internal standards, which were detected as positive ions by tandem mass spectroscopy in the multiple-reaction monitoring mode, using the molecular transitions m/z 104-->60 (choline), m/z 113-->69 (d(9)-choline), m/z 118-->59 (betaine), m/z 127-->68 (d(9)-betaine), and m/z 104-->58 (DMG). For all three metabolites, the assay was linear in the range 0.4-400 micromol/L, and the lower limit of the detection (signal-to-noise ratio = 5) was < or =0.3 micromol/L. The within- and between-day imprecision (CVs) was 2.1-7.2% and 3.5-8.8%, respectively. The analytical recovery was 87-105%. The fasting plasma concentrations (median, 25th-75th percentiles) were 8.0 (7.0-9.3) micromol/L for choline, 31.7 (27.0-41.1) micromol/L for betaine, and 1.66 (1.30-2.02) micromol/L for DMG in 60 healthy blood donors. In individuals who had eaten a light breakfast, plasma concentrations of all three metabolites were significantly (25-30%) higher than in fasting individuals. This is the first method for the combined measurement of choline, betaine, and DMG in human plasma or serum. The assay is characterized by simple sample preparation, no derivatization, high throughput, imprecision (CV) <10%, detection limits below the values seen in volunteers, and the high specificity provided by tandem mass spectroscopy.
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            Cholinergic precursors in the treatment of cognitive impairment of vascular origin: ineffective approaches or need for re-evaluation?

            Inhibition of endogenous acetylcholine degradation through cholinesterase inhibitors represents a milestone in symptomatic treatment of cognitive symptoms in mild to moderate stages of Alzheimer's disease. Cholinesterase inhibitors are also under investigation for treating cognitive dysfunction of cerebrovascular origin, but to date they do not have specific indication for vascular dementia or vascular cognitive impairment. This paper reviews the main clinical studies assessing the activity of cholinergic precursors in the treatment of adult-onset dementia disorders of vascular origin. The first cholinergic precursor used phosphatidylcholine (lecithin) did not show any clear clinical benefit on symptoms of dementia disorders. The same is not true for other phospholipids involved in choline biosynthetic pathways such as cytidine 5'-diphosphocholine (CDP-choline) and choline alphoscerate for which a modest improvement of cognitive dysfunction in dementia of neurodegenerative and vascular origin is documented. Positive results obtained with selected cholinergic precursors cannot be generalized due to the small numbers of patients studied in appropriate clinical trials. However, they probably would justify reconsideration of the most promising molecules in larger carefully controlled studies.
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              Cognitive improvement in mild to moderate Alzheimer's dementia after treatment with the acetylcholine precursor choline alfoscerate: a multicenter, double-blind, randomized, placebo-controlled trial.

              Parallel with the development of hypotheses regarding cholinergic involvement in geriatric memory dysfunction, the first attempts to treat patients with Alzheimer's disease (AD) involved the cholinergic-precursor loading approach. Despite encouraging early results, well-controlled clinical trials did not confirm a clinical utility of cholinergic precursors such as choline and lecithin (phosphatidylcholine) in AD. This study assessed the efficacy and tolerability of the cholinergic precursor choline alfoscerate (CA) in the treatment of cognitive impairment due to mild to moderate AD. In this multicenter, double-blind, randomized, placebo-controlled trial, patients affected by mild to moderate dementia of the Alzheimer type were treated with CA (400-mg capsules) or placebo capsules, 3 times daily, for 180 days. Efficacy outcome measures that were assessed at the beginning of the investigation and after 90 and 180 days of treatment included scores of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), the Mini-Mental State Examination (MMSE), the Global Deterioration Scale (GDS), the Alzheimer's Disease Assessment Scale-Behavioral Subscale (ADAS-Behav), all items of the Alzheimer's Disease Assessment Scale (ADAS-Total), and the Clinical Global Impression (CGI) scale. The Global Improvement Scale (GIS) score was assessed after 90 and 180 days of treatment. A total of 261 patients (132 in the CA group, 129 in the placebo group) were enrolled in the study. The mean (SD) age in the CA group was 72.2(7.5) years (range, 60-80 years), and in the placebo group it was 71.7 (7.4) years(range, 60-80 years). The CA group comprised 105 women and 27 men; the placebo group, 94 women and 35 men. The mean decrease in ADAS-Cog score in patients treated with CA was 2.42 points after 90 days of treatment and 3.20 points at the end of the study (day 180) (P < 0.001 vs baseline for both), whereas in patients receiving placebo the mean increase in ADAS-Cog score was 0.36 point <1 after 90 days of treatment and 2.90 points after 180 days of treatment(P < 0.001 vs baseline). In the CA group, all other assessed parameters (MMSE,GDS, ADAS-Behav, ADAS-Total, and CGI) consistently improved after 90 and 180 days versus baseline, whereas in the placebo group they remained unchanged or worsened. Statistically significant differences were observed between treatments after 90 and 180 days in ADAS-Cog, MMSE, GDS, ADAS-Total, and CGI scores and after 180 days of treatment in ADAS-Behav and GIS scores. The results of this study suggest the clinical usefulness and tolerability of CA in the treatment of the cognitive symptoms of dementia disorders of the Alzheimer type.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                05 April 2019
                : 13
                : 1049-1058
                [1 ]College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea, ddkim@ 123456snu.ac.kr
                [2 ]Central Research Institute, Whanin Pharmaceutical Company, Suwon 16229, Republic of Korea
                Author notes
                Correspondence: Dae-Duk Kim, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea, Tel +82 2 880 7870, Fax +82 2 873 9177, Email ddkim@ 123456snu.ac.kr
                © 2019 Min 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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