A composition containing an extract of the dried root of Indigofera hancockii

Abstract

A composition containing an extract of the dried root of Polygala tenuifolia and a method for treating major depressive disorder are provided. [Solution] The present invention relates to a method for treating major depressive disorder by orally administering a composition containing Polygala tenuifolia (dried root) extract (PDC-1421) to a subject. A solid dosage form of PDC-1421 can be prepared in a gelatin capsule. Oral administration of PDC-1421 in healthy volunteers was safe and well tolerated at daily doses of 380 mg to 3800 mg. The composition can be administered chronically for at least 25 days. Daily doses are administered once daily, twice daily, or three times daily, with each dose being 380 to 760 mg of plant extract.

Description

Technical Field

[0001] The present invention relates to In a method for treating major depressive disorder, orally administered to a subject, a composition containing an extract of Radix Polygalae, that is, the dried root of Polygala tenuifolia Willd the substance .

Background Art

[0002] In 2015, approximately 216 million people (3% of the world's population) suffered from major depressive disorder (GBD 2015 Disease and Injury Incidence and Prevalence Collaborators (October 2016). "Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990 - 2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1545 - 602.; classified according to the DSM - IV - TR (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, American Psychiatric Association, Washington DC, 2000)).

Summary of the Invention

Problems to be Solved by the Invention

[0003] Patients with depression are treated with first-line antidepressants such as selective serotonin reuptake inhibitors (SSRI), but 40% to 50% of patients do not respond to the administered antidepressants. Furthermore, the recurrence of depressive episodes increases the mortality rate and the attempted suicide rate to 21% (Sartorius N, Angstt J. Suicide in population subgroups. Int Clin Psychopharmacol. 2001; 16 Suppl 2: 2p preceding S1.). Therefore, new types of antidepressants with higher efficacy and safety are needed for the treatment of depression.

Means for Solving the Problem

[0004] The present invention is a composition for oral administration to a subject in need in a method for treating major depressive disorder (MDD). The composition contains a plant extract in an amount of 2280 to 3800 mg per day dose. The plant extract is obtained by the following i) to iii). i) An aqueous extract from the dried whole roots of Astragalus membranaceus var. mongholicus is evaporated in vacuo to concentrate to 400 kg and filtered through a centrifugal filter. ii) The concentrate obtained in i) is filtered through a chromatographic resin column filtered and the over-eluate is collected. iii) The filtered eluate is evaporated and concentrated in vacuo and dried by a spray dryer. The plant extract is composed of escroester (34%), saponin (18%) and xanthone (17%).

[0005] In some embodiments, the composition is administered in an oral dosage form.

[0006] In some embodiments, the composition further contains silicon dioxide and magnesium stearate and is in the form of capsules.

[0007] In some embodiments, the composition is administered at the onset of symptoms of depressive disorder.

[0008] In some embodiments, the composition is administered chronically.

[0009] In some embodiments, the composition is administered according to a schedule throughout the day.

[0010] In some embodiments, the daily dose is administered once, twice, or three times a day.

[0011] In some embodiments, each dose is 380 - 760 mg of the plant extract.

[0012] In some embodiments, it is administered daily for at least 25 days. to be 。

[0013] In some embodiments, the subject is evaluated at the end of the administration and at least one month later.

[0014] The evaluation includes administering and evaluating the results of the Montgomery - Asberg Depression Rating Scale (MADRS) and / or the Hamilton Depression Rating Scale (HAM - D - 17) and / or the Hamilton Anxiety Rating Scale (HAM - A) and / or the Clinical Global Impression Scale (CGI) and / or the Columbia - Suicide Severity Rating Scale (C - SSRS).

Brief Description of the Drawings

[0015]

Figure 1

Modes for Carrying Out the Invention

[0016] All of the features disclosed in this specification can be combined in any combination. Alternative features that serve the same, equivalent, or similar purposes can replace each feature disclosed in this specification. Therefore, unless explicitly stated otherwise, each feature disclosed is merely an example of a general series of equivalent or similar features.

[0017] (List of Abbreviations and Definitions) AE Adverse Event CGI Clinical Global Impression Scale C-SSRS Columbia Suicide Severity Rating Scale DSSS Depression and Somatic Symptoms Scale HAM-D-17 Hamilton Depression Rating Scale HAM-A Hamilton Anxiety Rating Scale MADRS Montgomery-Asberg Depression Rating Scale NRI Norepinephrine Reuptake Inhibitor

[0018] <Example 1: Preparation of Onji (Astragalus membranaceus var. mongholicus) Extract PDC-1421>

[0019] The dried whole roots of Astragalus membranaceus var. mongholicus are treated twice in water, that is, for 1 hour at a ratio of 100 kg to 800 kg under reflux and for another 1 hour at a ratio of 100 kg to 700 kg under reflux. After mixing the two treated mixtures, an aqueous extract is obtained. The aqueous extract is concentrated to 400 kg by evaporation in vacuo and filtered through a centrifugal filter. Then, the obtained concentrate is filtered through a chromatographic resin column. A specific filtration eluent is recovered. The eluent is concentrated by evaporation in vacuo and dried by a spray dryer to obtain a powder product PDC-1421.

[0020] <Example 2: In Vivo Tetrabenazine-Induced Hypothermia Assay>

[0021] Approximately 70% of PDC-1421 in Example 1 is composed of escin (34%), saponin (18%) and xanthone (17%). Some active compounds of the powder product in Example 1, polygalatenoside A / B / C (Fraction 2-1), polygalaxanthone III, sibiricoside A5, and 7-O-methylmangiferin are also discovered by an in vivo tetrabenazine-induced hypothermia test (one of the rodent models for evaluating antidepressant-like activity in mice). Imipramine (positive control), PDC-1421, Fraction 1-10 to 19, Fraction 1-33, Fraction 2-1 (main component is polygalatenoside A / B / C), Fraction 2-3, TMCA, polygalaxanthone III, onjisaponin B, sibiricoside A5, 7-O-methylmangiferin and sibirikaxanthone B were dissolved in water for injection (WFI) and administered by forced oral administration. The dose was 10 mL / kg. The test substances and vehicle (WFI) were administered by forced oral administration to a group of 8 male ICR mice weighing 23 ± 3 g 60 minutes before an intraperitoneal injection of tetrabenazine (TBZ, 85 mg / kg). Body temperature was recorded before the TBZ challenge (0 minute) and at 60, 90 and 120 minutes later. The temperature recovery rate (%) of the test substances is shown in Figure 1.

[0022] <Example 3: Preclinical Trials of Recommended Dosage and Administration Route>

[0023] The determination of the initial dose is important when a new drug is administered to humans for the first time. Based on the FDA guidance document, the starting dose of this trial was estimated using the NOAEL of the toxicity test. Table 2 summarizes the MRSD of 60 kg humans / day calculated from the NOAEL of a 28-day repeated-dose test using a 75-fold safety margin with rats and dogs.

Table 1

[0024] Based on these calculations, the inventors proposed a starting dose of 380 mg / day for PDC-1421. In this Phase I trial, healthy subjects personAdminister PDC-1421 once (orally) and examine its safety. The starting dose and dosing regimen are 380 mg of PDC-1421 (one capsule of PDC-1421 capsules) once a day after meals.

[0025] <Example 4: Preparation of PDC-1421 Capsules>

[0026] The solid dosage form of the extract of Onjii (Itoshimehagi) (PDC-1421) can be prepared into gelatin capsules by conventional techniques known to those skilled in the art. In a preferred embodiment of the present invention, the matrix contains two excipients. Among them, the first excipient can constitute about 2-10%, more preferably 5%, of the filler with silicon dioxide acting as a flow promoter. Magnesium stearate, the second excipient serving as a lubricant, can constitute about 2-10%, more preferably 5%, of the filler.

Table 2

[0027] <Example 5: Phase I in Healthy Subjects> person In

[0028] In the Phase I trial, a total of 85 subjects person were screened at the test facility, and 30 subjects person were enrolled. These are 9 subjects person in Cohort A who received PDC-1421 (380 mg) person and 2 who received placebo person . Among the 7 subjects person who received PDC-1421 person , 1 person did not have clinical test data at baseline. 8 subjects person in Cohort B who received PDC-1421 (1140 mg) person and 2 who received placebo person . 4 subjects person in Cohort C who received PDC-1421 (2280 mg) person . 3 subjects person who received PDC-1421 and 1 who received placeboperson in cohort C of 4 person subjects person administered PDC-1421 (3800 mg) of 7 person and 2 administered placebo person in cohort D of 9 person subjects person and of 7 person subjects of PDC-1421 person of which 1 person had abnormal test values in the screening test.

[0029] Physical examinations were determined to be "normal" in all body systems of each cohort, and there were no subjects with DLT and toxicity grades. person

[0030] All changes in vital signs from baseline in the PDC-1421 and placebo groups were mild and did not exceed the limits of the normal range. Furthermore, all toxicity grades of vital signs were the lowest at grade 1, systolic blood pressure, which increased by >20 mm / Hg from baseline at 4 hours. No medical intervention / treatment was required. There was no correlation between the change from baseline or the change in the toxicity grade of vital signs among the doses of PDC-1421.

[0031] All changes in clinical laboratory data from baseline in the PDC-1421 group were mild and there were no clinically significant deviations from the normal range. Furthermore, the toxicity grades of clinical laboratory data in the PDC-1421 group and the placebo group were the lowest grade 1. No medical intervention / treatment was required. There was no correlation between the change from baseline or the change in the toxicity grade of clinical laboratory tests among the doses of PDC-1421. Only 2 cases of grade 2 toxicity (glucose for 24 hours in cohort A and glucose for 4 hours in cohort B) were observed in the placebo group, and no medical intervention / treatment was required for these cases.

[0032] ECG was determined to be "normal" at each time point and in each cohort. Subjects with DLT and toxicity grades person ​There was none. In each cohort, the C-SSRS was 0 for all suicidal ideation, strength of suicidal ideation, and suicidal behavior.

[0033] No serious adverse events were observed, and no subjects were discontinued due to adverse events person There were none, and no abnormalities were observed in physical examinations, vital signs, electrocardiograms, clinical test values, or the C-SSRS throughout the administration period, and the oral administration of PDC-1421 in healthy subjects was safe, with good tolerance at doses from 380 mg to 3800 mg. During the administration period, 5 person subjects person had 8 mild adverse events shown in Table 3. The severity of all these 5 adverse events was mild and did not require medical treatment. No correlation was observed between the dose of PDC-1421 and placebo in terms of the number, severity, relationship, and outcome of adverse events. Furthermore, in the clinical trial, there were no deviations in electrolyte levels and no significant gastrointestinal discomfort during monitoring. There were two mild adverse events such as a decrease in heart rate and an increase in systolic blood pressure. The decrease in heart rate was associated with the canine telemetry test, but the increase in systolic blood pressure was not. person In summary, no serious adverse events were observed, and no cases were discontinued due to adverse events. No clinically significant findings were observed in physical examinations, vital signs, electrocardiograms, clinical test values, and the C-SSRS throughout the treatment period. The oral administration of PDC-1421 in healthy volunteers was safe and well tolerated for doses of 380 mg to 3800 mg.

[0034] <Example 6: Subjects with major depressive disorder (MDD)

[0035] <in Phase II person in

[0036] This Phase II clinical trial was for the treatment of MDD personThe purpose was to evaluate the safety and efficacy of PDC-1421. This study consisted of two parts. The Part I study was a multi-center, open-label, dose-escalation evaluation using two dose levels (1 or 2 capsules three times a day, 1140 mg or 2280 mg / day) continuously. The Part II study was a multi-center randomized (1:1:1), double-blind, placebo-controlled, parallel-group study with three study groups to compare the efficacy and safety profiles of two dose levels of PDC-1421 capsules (1 or 2 capsules three times a day) versus a control (placebo, three times a day).

[0037] The primary objective was to evaluate the efficacy profile of PDC-1421 capsules in major depressive disorder (MDD) using the Montgomery-Åsberg Depression Rating Scale (MADRS). The secondary objectives were to evaluate the efficacy and safety profiles of PDC-1421 capsules in MDD using other assessment scales.

[0038] In Part I, 12 person subjects person were randomized into cohort 1 (low-dose group, N = 6) and cohort 2 (high-dose group, N = 6). All subjects person completed the study and there were no withdrawals from Part I. In Part II, 60 person subjects person (50 person at a Taiwan facility and 10 person at a US facility) were randomly assigned to three study groups: (1) low-dose group (N = 19), (2) high-dose group (N = 19), and (3) placebo group (N = 20). A total of 48 subjects completed the trial and 12 subjects discontinued the trial (low-dose group: N = 5, high-dose group: N = 2, placebo group: N = 5) (Tables 5 and 6).

[0039] Results of efficacy

[0040] In the ITT population, the net change in MADRS from baseline to week 6 was -9.21, -13.19, and -9.20 in the low-dose group, high-dose group, and placebo group, respectively. In the PP population, the net change in MADRS from baseline to week 6 was -10.40, -13.40, and -8.64 in the three treatment groups, respectively. A greater decrease in the mean score of MADRS was observed in the high-dose group compared with the low-dose group and the placebo group in both the ITT and PP populations, but the group differences did not reach statistical significance.

[0041] The net changes in MADRS, HAM-D-17, HAM-A, DSSS-depression, and CGI-severity in the ITT population, as well as the response rates in MADRS and HAM-D-17 at week 6, are summarized in Table 4 below.

Table 4

[0042] In the ITT population, the net change in HAM-D-17 from baseline to week 6 was -8.8, -11.0, and -8.7 in the low-dose group, high-dose group, and placebo group, respectively. In the PP population, the net change in HAM-D-17 from baseline to week 6 was -10.0, -11.1, and -7.9 in the three treatment groups, respectively. A greater decrease in the mean score of HAM-D-17 was observed in the high-dose group compared with the low-dose group and the placebo group in both the ITT and PP populations, but the group differences did not reach statistical significance (P = 0.406 for ITT, P = 0.392 for PP).

[0043] Significant group differences in the net changes in HAM-D-17 and HAM-A in the second-week ITT population were found among the three groups (P = 0.038 for HAM-D-17 and P = 0.041 for HAM-A). Post hoc comparisons demonstrated significant differences between the high-dose group and the placebo group in HAM-D-17 (-7.90 vs. -4.30, adjusted P = 0.039) and HAM-A (-5.38 vs. -2.90, adjusted P = 0.022), but not between the low-dose group and the placebo group. Subjects who took two PDC-1421 capsules three times a day until the second week person showed greater improvement compared to the placebo group (net change = 3.6 for HAM-D-17 and 2.48 for HAM-A).

[0044] At week 6, for MADRS, no significant between-group differences in response rates were observed in the ITT population (P = 0.230), and almost significant differences were observed in the PP population (P = 0.062). The proportion of "responders" at week 6 was highest in the high-dose group (low-dose group vs. high-dose group vs. placebo group = 32% [n = 6] vs. 52% [n = 11] vs. 35% [n = 7] in the ITT group and 33% [n = 5] vs. 53% [n = 8] vs. 29% [n = 4] in the PP group).

[0045] At week 2, for HAM-D-17, significant group differences were found among the three treatment groups in both the ITT population and the PP population (P = 0.028 and 0.037, respectively). In the ITT and PP populations, the proportion of "responders" was highest in the low-dose group, followed by the high-dose group and the placebo group (low-dose vs. high-dose vs. placebo = 26% vs. 14% vs. 10% in the ITT and 27% vs. 20% vs. 14% in the PP).

[0046] Safety results

[0047] Safety evaluations were based on the ITT population that took at least one dose of IP and had any post-baseline safety data collected.

[0048] Regarding the incidence of TEAE, at least one case of TEAE was observed in a total of 4 cases (33.3%) in each dosing cohort of the Part I trial, and a total of 32 cases (53.3%) in the Part II trial. Among them, 12 cases (63.2%) were in the low-dose group, 11 cases (52.4%) were in the high-dose group, and 9 cases (45.0%) were in the placebo group.

[0049] Regarding more common TEAE, the most frequently reported TEAE in Part I were "infectious and parasitic diseases" (total: n = 2 [16.7%], low dose: n = 1, high dose: n = 1), and "mental disorders" (total: n = 2 [16.7%], low dose: n = 0, high dose: n = 2). In Part II, the most commonly reported TEAE were "gastrointestinal disorders" (total: n = 17 [28.3%], low dose: n = 7, high dose: n = 5, placebo: n = 5), "nervous system disorders" (total: n = 4 [6.7%], low dose: n = 1, high dose: n = 2, placebo: n = 1), and "mental disorders" (total: n = 4 [6.7%], low dose: n = 3, high dose: n = 0, placebo: n = 1). Among the TEAE with an incidence of 5% or more, more subjects in both the low-dose group and the high-dose group (n = 3 in each group) reported person "thirst" than in the placebo group (n = 1).

[0050] Regarding the severity, a total of 6 cases of TEAE were evaluated as mild or moderate in the Part I trial, and a total of 68 cases of TEAE were recorded in the Part II trial (event number: low-dose group vs. high-dose group vs. placebo group = 20 vs. 26 vs. 22), with 53 cases being mild (19 vs. 17 vs. 17), 14 cases being moderate (1 vs. 9 vs. 4), and 1 case being evaluated as severe in the placebo group. No deaths or serious adverse events were observed in this trial.

[0051] Regarding the occurrence of adverse events in the discontinued cases, 2 discontinued cases (low-dose group: n = 1, placebo group: n = 1) were due to depression, and 1 case (low-dose group) was due to anxiety. The causal relationship between these events and the investigational drug was negated by the PI. These adverse events may be related to the disease state but not to the treatment.

[0052] Regarding the clinical test values at each scheduled hospital visit, abnormal values with clinical significance (CS) were rarely observed in either the Part I or Part II trials. The triglyceride had the highest abnormal incidence rate of CS (Part I: high-dose group n = 1, Part II: high-dose group n = 3).

[0053] Regarding vital signs and ECG, there were no subjects evaluated as abnormal with CS in the Part I trial. person In the Part II trial, abnormal SBP and DBP with CS were detected in the high-dose group (SBP at 4 weeks and 6 weeks: n = 1, DBP from baseline to 7 weeks: n = 1). All these abnormal blood pressure events were detected in the same subjects with a history of hypertension. person All other values were evaluated as normal or abnormal with non-clinical significance (NCS) without changing to abnormal with CS for either vital signs or ECG.

[0054] In the physical examination, for all scheduled hospital visits in both the Part I and Part II trials, since the subjects did not change from normal to abnormal (NCS or CS), it was suggested that the physical evaluation did not deteriorate during the treatment period and the follow-up period. person Regarding the evaluation of suicidal thoughts and suicidal behaviors, based on the C-SSRS, the incidence rates of "suicidal thoughts" and "suicidal thoughts or suicidal behaviors" were low, and were similar between the two groups in the Part I trial targeting about 1 - 2 subjects, and no "suicidal behavior" was observed during the administration period. In Part II, no "suicidal behavior" was observed in any of the three groups. These results suggest that the treatment with PDC-1421 did not increase the risk of either suicidal thoughts or suicidal behaviors.

[0055] person

[0056] ​​From the above description, those skilled in the art can easily identify the essential features of the present invention and, without departing from its spirit and scope, make various changes and modifications to the present invention to adapt it to various uses and conditions. Therefore, other embodiments are also within the scope of the claims of this application.

[0057] [Table 5] TIFF0007699396000004.tif246158

[0058] [Continuation of Table 5] TIFF0007699396000005.tif247158

[0059] [Table 6] TIFF0007699396000006.tif245158

[0060] [Continuation of Table 6] TIFF0007699396000007.tif246158

Claims

1. A composition for oral administration to a subject in need thereof in a method for treating major depressive disorder, containing a plant extract in an amount of 2280 - 3800 mg per daily dose, wherein the plant extract is, i) An aqueous extract from the dried whole roots of Astragalus membranaceus var. mongholicus is evaporated in vacuo and concentrated to 400 kg, and filtered through a centrifugal filter, ii) The concentrate obtained in i) is filtered through a chromatography resin column, and the filtered eluate is recovered, iii) Obtained by evaporating and concentrating the filtered eluate in vacuo and drying it with a spray dryer, The plant extract is a composition composed of scleroester (34%), saponin (18%) and xanthone (17%).

2. The composition according to claim 1, which is administered in an oral dosage form.

3. The composition according to claim 1, further containing silicon dioxide and magnesium stearate and being in the form of capsules.

4. The composition according to claim 3, which is administered at the onset of symptoms of depressive disorder.

5. The composition according to claim 3, which is administered chronically.

6. The composition according to claim 5, which is administered according to a schedule throughout the day.

7. The composition according to claim 6, wherein the daily dose is administered once a day, twice a day, or three times a day.

8. The composition according to claim 7, wherein each dose is 380 - 760 mg of the plant extract.

9. The composition according to claim 8, which is administered daily for at least 25 days.

10. The composition according to claim 5, wherein the subject is evaluated at the end of administration and at least one month thereafter.

11. The evaluation includes managing and evaluating the results of the Montgomery - Åsberg Depression Rating Scale (MADRS) and / or the Hamilton Depression Rating Scale (HAM - D - 17) and / or the Hamilton Anxiety Rating Scale (HAM - A) and / or the Clinical Global Impression Scale (CGI) and / or the Columbia - Suicide Severity Rating Scale (C - SSRS). The composition according to claim 10.

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