Pharmaceutical composition and its application

Abstract

The pharmaceutical composition of the present invention comprises benfotiamine or its pharmaceutically acceptable salt; and donepezil or its pharmaceutically acceptable salt.Experimental results show that when benfotiamine and donepezil hydrochloride are administered together, they can achieve a more excellent synergistic effect, and can relatively effectively improve the spatial learning and memory ability of AD mice, and this effect is significantly better than that when benfotiamine or donepezil hydrochloride is administered alone, which indicates that the pharmaceutical composition of the present invention has a more excellent pharmaceutical activity in treating Alzheimer's disease.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to a pharmaceutical composition comprising benfotiamine or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof, and the use of the pharmaceutical composition in the manufacture of a medicament for the prevention or treatment of Alzheimer's disease.

Background Art

[0002] Alzheimer's disease (AD, commonly known as senile dementia) is a progressive neurodegenerative disease accompanied by cognitive and behavioral disorders as the main clinical symptoms, and is also the most common type of senile dementia that appears mainly as cognitive impairment and a rapid decline in memory function. According to the World Alzheimer Report 2015, the number of AD patients in the world will increase to 130 million by 2050.

[0003] Donepezil (molecular formula: C 24 H 29 NO3, donepezil hydrochloride is the general form used as a pharmaceutical) is a major drug for treating AD clinically. By inhibiting cholinesterase and increasing acetylcholine levels, it can slow down the progression of AD in the middle and early stages and improve the clinical symptoms of early AD.

[0004] Benfotiamine (molecular formula: C 19 H 23N4O6PS; Chemical Name: S-2-[[(2-Methyl-4-amino-5-pyrimidinyl)methyl]formylamino]-5-phosphonooxy-2,3-pentenyl-3-mercaptobenzoate, benzoylthiamine monophosphate; Abbreviation: BTMP) can improve the low bioavailability of water-soluble vitamin B1, increase the concentration of vitamin B1 in the blood and tissues, and thereby improve the therapeutic effect. Recent studies have shown that benfotiamine can be used for the prevention and treatment of Alzheimer's disease. For example, Patent CN200710041571.X discloses a pharmaceutical composition for the treatment of Alzheimer's disease containing benfotiamine.

[0005] In the prior art, although the above drugs for treating Alzheimer's disease have been disclosed, drugs for effectively reversing or preventing the progression of the disease are not available to date. Therefore, there is a shortage of drugs that are more effective and can improve patient compliance.

Summary of the Invention

[0006] The technical problem to be solved by the present invention is the problem that the pharmacodynamic activity is low and the administration is inconvenient when benfotiamine or donepezil is administered alone.

[0007] To solve the above technical problem, the present invention provides: Benfotiamine or a pharmaceutically acceptable salt thereof; and Donepezil or a pharmaceutically acceptable salt thereof A pharmaceutical composition containing the same is provided.

[0008] Optionally, the weight ratio of benfotiamine or a pharmaceutically acceptable salt thereof to donepezil or a pharmaceutically acceptable salt thereof is (180-400):(3-6), or (180-400):3, or (200-400):3, or 180:3, or 200:3, or 400:3.

[0009] Optionally, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier or excipient.

[0010] Optionally, the pharmaceutically acceptable salt is hydrochloride, hydrobromide, sulfate, acetate, maleate, or tartrate.

[0011] Optionally, the pharmaceutical composition is an oral preparation, and the oral preparation is any one of tablets, capsules, granules, powders, and pills.

[0012] Optionally, the pharmaceutical composition contains benfotiamine and donepezil hydrochloride.

[0013] Optionally, the weight ratio of benfotiamine to donepezil hydrochloride is (180 - 400):(3 - 6).

[0014] Optionally, the weight ratio of benfotiamine to donepezil hydrochloride is 180:6, or 240:6, or 360:6, or 240:3, or 360:3.

[0015] Optionally, the weight ratio of benfotiamine to donepezil hydrochloride is (180 - 360):(3 - 6).

[0016] Optionally, the weight ratio of benfotiamine to donepezil hydrochloride is (200 - 400):(3 - 6).

[0017] Optionally, the weight ratio of benfotiamine to donepezil hydrochloride is (200 - 400):3.

[0018] Optionally, the weight ratio of benfotiamine to donepezil hydrochloride is 200:3, or 400:3.

[0019] Optionally, the pharmaceutical composition contains 3 mg - 10 mg of donepezil hydrochloride.

[0020] Optionally, the pharmaceutical composition contains 150 mg - 600 mg of benfotiamine.

[0021] The present invention further provides the use of the above pharmaceutical composition in the manufacture of a medicament for the prevention or treatment of Alzheimer's disease.

[0022] Compared with the prior art, the present invention has the following advantages: The pharmaceutical composition provided by the present invention contains benfotiamine or a pharmaceutically acceptable salt thereof; and donepezil or a pharmaceutically acceptable salt thereof. From the results of the water maze test, after the combined administration of benfotiamine and donepezil hydrochloride, a good synergistic effect is obtained, the spatial learning and memory ability of AD mice is improved, and the effect is significantly better than that when benfotiamine or donepezil hydrochloride is administered alone. The results of this indicate that the pharmaceutical composition of the present invention has good pharmaceutical activity in the treatment of Alzheimer's disease.

[0023] Furthermore, according to the present invention, by preparing a combined preparation of benfotiamine and donepezil hydrochloride, the administration can be facilitated and the patient's medication compliance can be improved.

Brief Description of the Drawings

[0024]

Figure 1

Figure 2

Figure 3

[0025] Although it has been disclosed in the prior art that donepezil or benfotiamine can be used alone for the treatment of Alzheimer's disease, it has not been clarified or recognized that the combination of these two drugs may be more beneficial in the manufacture of a medicament for the prevention or treatment of Alzheimer's disease. The inventors of the present invention have found that donepezil and benfotiamine can achieve a synergistic effect that is significantly superior to the effect of the active ingredient when used alone.

[0026] The present invention provides a pharmaceutical composition comprising benfotiamine or a pharmaceutically acceptable salt thereof; and donepezil or a pharmaceutically acceptable salt thereof. From the results of the water maze test, after co-administering benfotiamine and donepezil hydrochloride, a good synergistic effect was obtained, and the spatial learning and memory abilities of AD mice were improved, and the effect was significantly superior to that when benfotiamine or donepezil hydrochloride was administered alone. This result indicates that the pharmaceutical composition of the present invention has good pharmaceutical activity in the treatment of Alzheimer's disease. Furthermore, according to the present invention, by preparing a combined preparation of benfotiamine and donepezil hydrochloride, administration can be facilitated and patient compliance can be improved.

[0027] In order to more easily understand the above-mentioned objects, features and advantages of the present invention, a detailed description of specific embodiments of the present invention is provided below.

[0028] Unless otherwise specified, in the present invention, generally, the sources of materials or reagents used are not particularly limited, and for example, they can be commercially available.

[0029] Example 1 The active ingredients contained in the composition are: 150 mg of benfotiamine; and 5 mg of donepezil hydrochloride.

[0030] Preparation method: Weigh benfotiamine and donepezil hydrochloride APIs in a predetermined amount, and add at least one pharmaceutically acceptable carrier or excipient to prepare an oral formulation. The oral formulation may be any of tablets, capsules, granules, powders and pills.

[0031] Example 2 The active ingredients contained in the composition are: 200 mg of benfotiamine; and 5 mg of donepezil hydrochloride.

[0032] Preparation method: Weigh benfotiamine and donepezil hydrochloride APIs in a predetermined amount, and add at least one pharmaceutically acceptable carrier or excipient to prepare an oral formulation. The oral formulation may be any of tablets, capsules, granules, powders and pills.

[0033] Example 3 The active ingredients contained in the composition are: 300 mg of benfotiamine; and 5 mg of donepezil hydrochloride.

[0034] Preparation method: Weigh benfotiamine and donepezil hydrochloride APIs in a predetermined amount, and add at least one pharmaceutically acceptable carrier or excipient to prepare an oral formulation. The oral formulation may be any of tablets, capsules, granules, powders and pills.

[0035] Example 4 The active ingredients contained in the composition are: 400 mg of benfotiamine; and 5 mg of donepezil hydrochloride.

[0036] Preparation method: Weigh benfotiamine and donepezil hydrochloride APIs in a predetermined amount, and add at least one pharmaceutically acceptable carrier or excipient to prepare an oral formulation. The oral formulation may be any of tablets, capsules, granules, powders and pills.

[0037] Example 5 The active ingredients contained in the composition are: 600 mg of benfotiamine; and 5 mg of donepezil hydrochloride.

[0038] Preparation method: Weigh the benfotiamine and donepezil hydrochloride APIs in predetermined amounts, and add at least one pharmaceutically acceptable carrier or excipient to prepare an oral formulation. The oral formulation may be any of tablets, capsules, granules, powders and pills.

[0039] Example 6 The active ingredients contained in the composition are: 400 mg of benfotiamine; and 3 mg of donepezil hydrochloride.

[0040] Preparation method: Weigh the benfotiamine and donepezil hydrochloride APIs in predetermined amounts, and add at least one pharmaceutically acceptable carrier or excipient to prepare an oral formulation. The oral formulation may be any of tablets, capsules, granules, powders and pills.

[0041] Example 7 The active ingredients contained in the composition are: 400 mg of benfotiamine; and 6 mg of donepezil hydrochloride.

[0042] Preparation method: Weigh the benfotiamine and donepezil hydrochloride APIs in predetermined amounts, and add at least one pharmaceutically acceptable carrier or excipient to prepare an oral formulation. The oral formulation may be any of tablets, capsules, granules, powders and pills.

[0043] Example 8 The active ingredients contained in the composition are: 200 mg of benfotiamine; and 6 mg of donepezil hydrochloride.

[0044] Preparation method: Weigh benfotiamine and donepezil hydrochloride APIs in a predetermined amount, add at least one pharmaceutically acceptable carrier or excipient, and prepare an oral formulation. The oral formulation may be any of tablets, capsules, granules, powders, and pills.

[0045] Hereinafter, the effects of the pharmaceutical compositions provided herein are compared with the effects of using benfotiamine, donepezil hydrochloride, and vitamin B1 alone in the Morris water maze test.

[0046] Experimental Example 1: Morris water maze test 1. Experimental principle In water, rodents have a strong motivation to escape from the water environment and can escape from the water environment most quickly and directly. The process of learning to escape from the water environment reflects the learning ability of animals. Intentional swimming according to the surrounding environment and to a safe place (such as a platform) in the water can reflect the spatial learning and memory ability of animals.

[0047] 2. Test protocol 2.1. Materials (1) Test animals The test animals were male APP / PS1 / Tau mice and C57BL / 6 wild-type mice. The mice were 8 months old, weighed 250 - 300 g, and were purchased from the Jackson Laboratory.

[0048] App / PS1 / Tau mice are APP / PS1 / tau triple transgenic Alzheimer's disease (3×Tg-AD) model mice. In these model mice, Aβ deposition occurs several months earlier than the pathological changes of tau protein, and a more realistic clinical process of Alzheimer's disease pathology can be simulated.

[0049] (2) Main formulations CMC-Na (Sodium Carboxymethyl Cellulose), Shanghai Sinopharm Chemical Reagent Co., Ltd., Batch Number: 20181203; BTMP (Benfotiamine), Shanghai Raising Biotechnology Co., Ltd., Batch Number: 1908002; Donepezil Hydrochloride, Eisai (China) Co., Ltd., Batch Number: 1704019.

[0050] 2.2. Information on the Preparation and Administration of Drugs (1) Preparation of Drugs Preparation of 0.7% m / v CMC Na (Sodium Carboxymethyl Cellulose): Weigh 0.7 g of sodium carboxymethyl cellulose and dissolve it in 100 ml of purified water to obtain 0.7% m / v CMC-Na.

[0051] Preparation of 10 mg / ml Vitamin B1 Solution (Dosage: 200 mg / kg): Weigh 500 mg of vitamin B, add 0.7% m / v CMC-Na to make 50 ml, and obtain a 10 mg / ml solution.

[0052] Preparation of 10 mg / ml BTMP Suspension (Dosage: 200 mg / kg): Weigh 500 mg of BTMP, add 0.7% m / v CMC-Na to make 50 ml, and obtain a 10 mg / ml BTMP suspension.

[0053] Preparation of 20 mg / ml BTMP Suspension (Dosage: 400 mg / kg): Weigh 500 mg of BTMP, add 0.7% m / v CMC-Na to make 25 ml, and obtain a 20 mg / ml BTMP suspension.

[0054] Preparation of 0.075 mg / ml Donepezil Hydrochloride Suspension (Dosage: 1.5 mg / kg): Grind 1 tablet of donepezil hydrochloride tablet (containing 5 mg of donepezil hydrochloride), add 0.7% m / v CMC-Na to make 66.67 ml, and obtain a 0.075 mg / ml donepezil hydrochloride suspension.

[0055] Preparation of 0.15 mg / ml donepezil hydrochloride suspension (dose: 3.0 mg / kg): One tablet of donepezil hydrochloride (containing 5 mg of donepezil hydrochloride) was ground, 0.7% m / v of CMC-Na was added to make 33.33 ml, and 0.15 mg / ml of donepezil hydrochloride suspension was obtained.

[0056] Preparation of 10 mg / ml BTMP suspension + 0.075 mg / ml donepezil hydrochloride suspension (dose: 200 mg / kg of BTMP suspension + 1.5 mg / kg of donepezil hydrochloride suspension): 20 mg / ml of BTMP suspension and 0.15 mg / ml of donepezil hydrochloride suspension were prepared respectively, and equal amounts were uniformly mixed before administration to obtain 10 mg / ml of BTMP suspension + 0.075 mg / ml of donepezil hydrochloride suspension.

[0057] Preparation of 5 mg / ml BTMP suspension + 0.075 mg / ml donepezil hydrochloride suspension (dose: 100 mg / kg of BTMP suspension + 1.5 mg / kg of donepezil hydrochloride suspension): 10 mg / ml of BTMP suspension and 0.15 mg / ml of donepezil hydrochloride suspension were prepared respectively, and equal amounts were uniformly mixed before administration to obtain 5 mg / ml of BTMP suspension + 0.075 mg / ml of donepezil hydrochloride suspension.

[0058] (2) Information on administration

Table 1

[0059] 2.3. Test method Mice in the blank control group, model group and test group were administered intragastrically for 8 weeks according to the dosage / specification in 2.2, and the training and test of the water maze were started in the last week of administration. The training and test of the water maze were carried out for 6 days with 5 days of training and 1 day of test. Also, during the period of training and test of the water maze (6 days in total), the conditions such as indoor lighting were kept constant, the room was kept quiet, and environmental and human interferences were excluded.

[0060] (1) Preparation before the test: An appropriate amount of water with a water temperature maintained at 22 ± 3°C was put into the water maze pool, and a platform was installed at a fixed position 1 cm below the water surface (target section). Titanium dioxide was added until the water color became white and the platform was no longer clearly visible.

[0061] (2) Training period (days 1 - 5): Each mouse was placed on the platform for 15 seconds before the first section training each day (to increase the mouse's sense of security towards the platform), and then the mouse was placed in the section where the platform was installed in the pool (with the head facing the wall), and the swimming time was set to 60 seconds. If the platform was discovered within 60 seconds and the mouse stayed on it for 5 seconds, it was considered a successful discovery of the platform. If the platform could not be discovered, the time was recorded as 60 seconds, the mouse was guided to the platform and kept there for 20 seconds, and then the mouse was taken out, and the training of this mouse in this section was completed.

[0062] After the first section training, the training of the remaining three sections was carried out in order. In these trainings, it was not necessary to place the mouse on the platform and hold it for 15 seconds before training. The interval between the two - section trainings of each mouse was set to 10 - 15 minutes. In this way, continuous training was carried out for 5 days.

[0063] (3) Test period (day 6): The platform was removed 24 hours after the completion of the last training, and the mouse was placed on the side opposite to the first platform section (i.e., the position farthest from the platform). The time the mouse stayed in the target section (the section where the platform was initially placed), the number of times it passed the first platform position (the number of times it passed the platform), and the time it first passed the first platform position (latency) were recorded and used as indicators to evaluate the mouse's spatial learning and memory ability.

[0064] 3. Test results Compared with the blank control group, the latency of the mice in the model group increased significantly, the number of times passing through the platform decreased, the time staying in the target compartment decreased significantly, and there were significant differences. These results indicate that transgenic mice are different from normal mice in spatial learning and memory ability and are suitable for spatial learning and memory training. Compared with the model group, the positive control group and the test group showed significant improvements in latency, the number of times passing through the platform, and the time staying in the target compartment, and all had significant differences. The results are shown in Table 1.

[0065]

Table 2

[0066] When the indicators for evaluating the effectiveness of the compound are latency, the number of times passing through the platform, and the time staying in the target compartment, the ranking is blank control group, BTMP + donepezil hydrochloride, 1 / 2BTMP + donepezil hydrochloride, BTMP, donepezil hydrochloride, VB1, and model group (ranked in order of excellent performance). The results are shown in Figures 1 - 3. These results indicate that VB1 did not significantly improve the learning and memory of AD mice, while BTMP, donepezil hydrochloride, BTMP + donepezil hydrochloride, and 1 / 2BTMP + donepezil hydrochloride significantly improved the spatial memory and learning ability of AD mice. The combined administration of BTMP and donepezil hydrochloride had the highest improvement effect, and the improvement effect was significantly higher than that when BTMP and donepezil hydrochloride were administered alone.

[0067] The results of the water maze test in the present invention show that after the combined administration of benfotiamine and donepezil hydrochloride, a good synergistic effect is achieved, the spatial learning and memory ability of AD mice is improved, and the effect is significantly better than the improvement effect when benfotiamine or donepezil hydrochloride is administered alone, and even better than the improvement effect by vitamin B1. The pharmaceutical composition of the present invention has good pharmaceutical activity in the treatment of Alzheimer's disease.

[0068] Experimental Example 2: Clinical trial A clinical trial study was conducted for 52 weeks on patients with moderate Alzheimer's disease (MMSE 10 - 19 at screening). The test group division and dosing regimen were as follows:

Table 3

[0069] To evaluate the cognitive function level of the patients, the patients at 12 weeks, 24 weeks, 36 weeks, and 52 weeks after administration were scored on the ADAS - cog scale (including 11 items: word recall, naming, command execution, constructional praxis, ideomotor apraxia, orientation, word recognition, recall of test instructions, spoken language ability, phonemic fluency, and language comprehension ability) in a score range of 0 - 70, where a higher score indicates more severe cognitive impairment. The between - group differences in the change of the patient scores from the baseline are shown in the following table.

[0070]

Table 4

[0071] According to the above - mentioned results, the ADAS - cog scores of the patients in the treatment group were improved better than those in the placebo group. In particular, the patients in the treatment group had an improvement of 2.116 in the ADAS - cog score at 36 weeks, with a statistical difference (p = 0.077), and an improvement of 3.331 in the ADAS - cog score at 52 weeks, with a statistical difference (p = 0.029). These results indicate that the combination therapy of benfotiamine and donepezil hydrochloride can significantly delay the progression of Alzheimer's disease.

[0072] On the other hand, during the administration, no serious drug - related side effects were observed in the patients in the treatment group, suggesting that the combination therapy of benfotiamine and donepezil hydrochloride has a good safety profile and the patients can tolerate this therapy well.

[0073] The above has disclosed the present invention, but the present invention is not limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the present invention which is limited only by the appended claims.

Claims

1. A pharmaceutical composition for the prevention or treatment of Alzheimer's disease, benfotiamine or a pharmaceutically acceptable salt thereof; and donepezil or a pharmaceutically acceptable salt thereof comprising, an oral preparation, and the oral preparation is any one of tablets, capsules, granules, powders and pills, said pharmaceutical composition.

2. The weight ratio of benfotiamine or a pharmaceutically acceptable salt thereof to donepezil or a pharmaceutically acceptable salt thereof is (180 - 400):(3 - 6), or (180 - 400):3, or (200 - 400):3, or 180:3, or 200:3, or 400:3, the pharmaceutical composition according to Claim 1.

3. The pharmaceutical composition according to Claim 1, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier or excipient.

4. The pharmaceutically acceptable salt is hydrochloride, or hydrobromide, or sulfate, or acetate, or maleate, or tartrate, the pharmaceutical composition according to Claim 1.

5. The pharmaceutical composition according to Claim 1, wherein the pharmaceutical composition comprises benfotiamine and donepezil hydrochloride.

6. The weight ratio of benfotiamine to donepezil hydrochloride is (180 - 400):(3 - 6), the pharmaceutical composition according to Claim 5.

7. The weight ratio of benfotiamine to donepezil hydrochloride is 180:6, or 240:6, or 360:6, or 240:3, or 360:3, the pharmaceutical composition according to Claim 6.

8. The weight ratio of benfotiamine to donepezil hydrochloride is (180 - 360):(3 - 6), the pharmaceutical composition according to Claim 6.

9. The pharmaceutical composition according to claim 6, wherein the weight ratio of benfotiamine to donepezil hydrochloride is (200 to 400):(3 to 6).

10. The pharmaceutical composition according to claim 9, wherein the weight ratio of benfotiamine to donepezil hydrochloride is (200 to 400):

3.

11. The pharmaceutical composition according to claim 10, wherein the weight ratio of benfotiamine to donepezil hydrochloride is 200:3 or 400:

3.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the pharmaceutical composition contains 3 mg to 10 mg of donepezil hydrochloride.

13. The pharmaceutical composition according to any one of claims 1 to 11, wherein the pharmaceutical composition contains 150 mg to 600 mg of benfotiamine.

14. Use of a pharmaceutical composition in the manufacture of a medicament for the prevention or treatment of Alzheimer's disease, wherein the pharmaceutical composition comprises benfotiamine or a pharmaceutically acceptable salt thereof; and donepezil or a pharmaceutically acceptable salt thereof; the pharmaceutical composition is an oral preparation, and the oral preparation is any one of tablets, capsules, granules, powders and pills.

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