A pharmaceutical composition and its use in the preparation of a medicament for inhibiting ethanol self-administration preference

Abstract

The application discloses a kind of pharmaceutical composition and its purposes in preparation for inhibiting the autonomous intake preference of ethanol. The pharmaceutical composition includes lorcaserin and midazolam. The pharmaceutical composition for inhibiting the autonomous intake preference of ethanol provided by the application can effectively reduce the desire of body to alcohol, is used to treat alcohol dependence, and has significant long-acting characteristics. When the pharmaceutical composition is administered to mice, the absolute amount of active ethanol intake of mice and the relative proportion of ethanol intake compared with the amount of drinking water can be significantly reduced, and the inhibitory effect can last at least 6 days, which is expected to update the treatment plan for alcohol addiction in clinic.

Description

Technical Field

[0001] This invention relates to a pharmaceutical composition and its use in the preparation of a medicament for inhibiting voluntary ethanol intake preference, belonging to the field of pharmaceutical technology. Background Technology

[0002] Alcohol dependence is persistent and prone to relapse, resulting in low treatment and cure rates. Current medications for alcohol addiction often have limitations, such as unsatisfactory efficacy and short duration of action. Therefore, developing alcohol addiction treatment drugs based on novel targets and exploring new alcohol addiction treatment properties of known drugs are of great practical significance. Summary of the Invention

[0003] The main objective of this invention is to provide a pharmaceutical composition and its use in the preparation of a medicament for suppressing voluntary ethanol intake preference, thereby overcoming the shortcomings of the prior art.

[0004] To achieve the aforementioned objectives, the technical solution adopted by this invention includes: This invention provides a pharmaceutical composition for inhibiting voluntary ethanol intake preference, comprising lorcaserin and midazolam.

[0005] The present invention also provides the use of the aforementioned pharmaceutical composition in the preparation of a medicament for inhibiting voluntary ethanol intake preference.

[0006] Compared with the prior art, the beneficial effects of the present invention are as follows: the pharmaceutical composition provided by the present invention for inhibiting the voluntary intake preference of ethanol can effectively reduce the body's craving for alcohol, and can be used to treat alcohol dependence. It also has significant long-term effects. When the pharmaceutical composition is administered to mice, it can significantly reduce the absolute amount of ethanol actively ingested by mice and the relative proportion of ethanol intake compared with drinking water, and the inhibitory effect can last for at least 6 days. Attached Figure Description

[0007] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0008] Figure 1 This is a typical embodiment of the present invention showing that lorcaserin does not affect the relative preference of mice for active uptake of 10% ethanol; Figure 2 This is a graph showing that lorcaserin does not affect the absolute content of mice's active uptake of 10% ethanol in a typical embodiment of the present invention. Figure 3This is a diagram showing that lorcaserin does not affect the total amount of fluid ingested by mice in a typical embodiment of the present invention; Figure 4 This is a graph showing the relative preference of mice for actively consuming 10% ethanol in a short period of time, as described in a typical embodiment of the present invention, using midazolam. Figure 5 This is a graph showing the absolute reduction in the active uptake of 10% ethanol by midazolam in mice during a short period of a typical embodiment of the present invention. Figure 6 This is a diagram showing that midazolam does not affect the total amount of fluid ingested by mice in a typical embodiment of the present invention; Figure 7 This is a typical embodiment of the present invention showing that the lorcaserin / midazolam combination can significantly and persistently inhibit the relative preference of mice for active uptake of 10% ethanol. Figure 8 This is a graph showing that, in a typical embodiment of the present invention, the lorcaserin / midazolam combination significantly and persistently inhibits the absolute amount of active uptake of 10% ethanol in mice. Figure 9 This is a graph showing that, in a typical embodiment of the present invention, the lorcaserin / midazolam combination does not affect the total amount of fluid ingested by mice. Detailed Implementation

[0009] In view of the deficiencies of the prior art, the inventors of this case, through long-term research and extensive practice, have proposed the technical solution of this invention. The technical solution of this invention will be clearly and completely described below. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0010] Specifically, as one aspect of the technical solution of the present invention, a pharmaceutical composition is involved in the use of ethanol self-intake preference, comprising: lorcaserin and midazolam.

[0011] The structural formula of lorcaserin in this invention is shown below: .

[0012] The structural formula of midazolam in this invention is shown below: .

[0013] In this invention, ethanol autonomous intake preference refers to the relative percentage and absolute amount of alcohol that mice autonomously ingest when faced with both water and 10% ethanol in a free-moving state. Animal experiments showed that intravenous injection of lorcaserin or midazolam alone into the tail vein of mice failed to downregulate the mice's autonomous ethanol intake preference, or only slightly and briefly. However, combined injection of the two drugs significantly and persistently inhibited the mice's autonomous drinking preference. Specifically, administration of the aforementioned combination significantly reduced the absolute amount of ethanol actively ingested and the relative proportion of ethanol intake to water consumption in mice, and this inhibitory effect lasted for at least 6 days.

[0014] In this invention, lorcaserin does not affect the relative preference of mice for active intake of 10% ethanol; lorcaserin does not affect the absolute amount of active intake of 10% ethanol in mice; and lorcaserin does not affect the total amount of fluid ingested by mice spontaneously.

[0015] In this invention, clomidazolam reduces the relative preference of mice for voluntary intake of 10% ethanol in the short term; midazolam reduces the absolute amount of voluntary intake of 10% ethanol in mice in the short term; midazolam does not affect the total amount of fluid ingested by mice spontaneously.

[0016] In this invention, the lorcaserin / midazolam combination significantly and persistently inhibits the relative preference of mice for active uptake of 10% ethanol; the lorcaserin / midazolam combination significantly and persistently inhibits the absolute amount of active uptake of 10% ethanol in mice; and the lorcaserin / midazolam combination does not affect the total amount of fluid ingested spontaneously by mice.

[0017] In some preferred embodiments, the mass ratio of lorcaserin to midazolam is 1:3 to 1:10.

[0018] Furthermore, the mass ratio of lorcaserin to midazolam is 1:6.

[0019] In some preferred embodiments, when the pharmaceutical composition is applied to a mouse model, it can at least reduce the absolute amount of ethanol actively ingested by the mice.

[0020] In some preferred embodiments, when the pharmaceutical composition is applied to a mouse model, it can inhibit the active ingestion of ethanol in mice for more than 6 days.

[0021] Furthermore, the ethanol used is an ethanol solution with a volume fraction of 5-20%.

[0022] In some preferred embodiments, the pharmaceutical composition further includes a pharmaceutically acceptable carrier and / or excipient; wherein the pharmaceutically acceptable derivative is selected from at least one of pharmaceutically acceptable salts, polymorphs, cocrystals, radiolabeled forms, and combinations thereof.

[0023] Furthermore, the carrier and / or excipient can be any known pharmaceutically acceptable carrier and excipient suitable for such use. The term "pharmaceutical carrier" as used herein has the meaning well known to those skilled in the art, and can include any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delay agents, salts, preservatives, pharmaceuticals, pharmaceutical stabilizers, gels, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, similar substances, and combinations thereof.

[0024] In some preferred embodiments, the dosage form of the pharmaceutical composition includes any one of injection, oral liquid, capsule, tablet, and granule.

[0025] The novel drug combination of this invention effectively reduces the body's craving for alcohol, treating alcohol dependence, and exhibits significant long-lasting effects, meaning a single dose lasts for at least six days. This drug composition holds promise for updating clinical treatment regimens for alcohol addiction.

[0026] Another aspect of the present invention provides the use of the aforementioned pharmaceutical composition for inhibiting voluntary ethanol intake preference in the preparation of a medicament for inhibiting voluntary ethanol intake preference.

[0027] In some preferred embodiments, when the drug for inhibiting voluntary ethanol intake preference is applied to a mouse model, it can at least reduce the absolute amount of ethanol actively ingested by the mice.

[0028] In some preferred embodiments, when the drug for inhibiting voluntary ethanol intake preference is applied to a mouse model, it can inhibit the mice's voluntary ethanol intake for more than 6 days.

[0029] Furthermore, the ethanol used is an ethanol solution with a volume fraction of 5-20%.

[0030] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be further described in detail below with reference to the accompanying drawings and several preferred embodiments. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0031] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0032] Unless otherwise specified, the materials and reagents used in the following examples are commercially available, for example: I. Experimental Procedure 1. Laboratory animals: C57BL / 6J mice were purchased from Changzhou Cavens Laboratory Animal Co., Ltd., and bred at Xuzhou Medical University. The mice were housed in a standard animal room with a temperature of 23 ± 2℃ and humidity of 40 ± 10%, following a 12h / 12h (7:00 lighting) diurnal rhythm, and were allowed free access to food. This experiment was approved by the Animal Ethics Committee of Xuzhou Medical University and was strictly conducted in accordance with the Laboratory Animal Care and Usage Guidelines of the National Institutes of Health.

[0033] 2. Reagents: Physiological saline was purchased from Shandong Kelun Pharmaceutical Co., Ltd.; lorcaserin was purchased from Shanghai Hongye Biotechnology Co., Ltd.; and midazolam was purchased from Jiangsu Enhua Pharmaceutical Co., Ltd.

[0034] 3. Experimental Design: Lorcaserin was administered systemically via tail vein injection at a dose of 10 mg / kg. Midazolam was administered systemically via tail vein injection at a dose of 60 mg / kg. A combination of lorcaserin and midazolam was administered systemically via tail vein injection at doses of 10 mg / kg and 60 mg / kg, respectively. Mice were released back into their cages after injection, and subsequent measurements were taken. The main measurement indicators in this experiment were collected under the classic "two-bottle self-indulgent drinking model," specifically: mice were allowed free movement in their cages, and two bottles of liquid were provided simultaneously during the experiment: one bottle of ordinary drinking water and the other of a 10% ethanol solution. Mice chose to drink the water or the ethanol solution according to their individual preference. The experimenter weighed the consumption of both bottles every 24 hours and swapped their positions to avoid any potential positional bias. Statistical analysis was performed on data every 48 hours, where: autonomous ethanol intake preference = weight of ethanol solution ingested / (weight of ethanol solution ingested + weight of water ingested) x 100%; the absolute amount of autonomous ethanol intake was described as the absolute content of ethanol ingested per kilogram of body weight of mice in 24 hours; the total amount of autonomous fluid intake was described as the total mass of all fluids ingested per kilogram of mouse in 24 hours.

[0035] 4. Data Analysis: All values ​​are expressed as mean ± standard error (SEM). For normally distributed data, two-sided independent samples are used for comparisons between two groups. t For comparisons among multiple groups, a two-way ANOVA was used for testing. P A value <0.05 is considered statistically significant.

[0036] II. Experimental Results 1. Lorcaserin does not affect the relative preference of mice for active uptake of 10% ethanol. The free choice of mice when faced with both water and ethanol solutions can fully reflect their willingness to consume alcohol, with the most crucial indicator being the percentage of each liquid consumed. In this study, the inventors continuously observed the mice's preference for ethanol solutions after intravenous injection of saline or lorcaserin. The results are as follows: Figure 1 As shown, compared with the mice injected with saline, the mice injected with lorcaserin showed a slight decreasing trend in their preference for voluntary ethanol intake, but this was not statistically significant, indicating that lorcaserin had a limited effect on the relative preference for voluntary ethanol intake in mice.

[0037] 2. Lorcaserin does not affect the absolute amount of 10% ethanol actively ingested by mice. The absolute amount of ethanol actively ingested is another key indicator for evaluating whether propofol affects the ethanol response in mice. The actual absolute amount of ethanol ingested by mice was continuously observed after intravenous injection of saline or lorcaserin. The results are as follows: Figure 2 As shown, compared with the mice injected with saline, the absolute amount of ethanol spontaneously ingested by mice injected with a single dose of propofol showed a slight decreasing trend, but this was not statistically significant, indicating that the effect of a single systemic administration of lorcaserin on the absolute amount of ethanol spontaneously ingested by mice was limited.

[0038] 3. Lorcaserin does not affect the total amount of fluid ingested spontaneously by mice. Both water and liquid alcohol are liquid substances. To investigate whether lorcaserin has a general effect on the intake of liquid substances in mice in this case, the total amount of all liquids ingested by mice (including water and 10% alcohol) was continuously observed after intravenous injection of saline or lorcaserin. The results are as follows: Figure 3 As shown, compared with the mice injected with saline, the total amount of fluid ingested by the mice injected with lorcaserin once was roughly the same, which was not statistically significant, indicating that systemic administration of lorcaserin did not affect the mice's general preference for liquid substances.

[0039] 4. Midazolam reduced the relative preference for active uptake of 10% ethanol in mice in the short term. The free choice of mice when faced with both water and ethanol solutions can fully reflect their willingness to consume alcohol, with the most crucial indicator being the percentage of each liquid consumed. In this case, the inventors continuously observed the mice's preference for ethanol solutions after intravenous injection of saline or midazolam via the tail vein. The results are as follows... Figure 4 As shown, compared with the mice injected with saline, the preference for voluntary ethanol intake in mice injected with midazolam after a single injection was significantly reduced, and gradually recovered after two days. This indicates that midazolam can inhibit the relative preference for voluntary intake of 10% ethanol in mice in a short period of time (about 2 days).

[0040] 5. Midazolam reduces the absolute amount of 10% ethanol actively ingested in mice in the short term. The absolute amount of ethanol actively ingested is another key indicator for evaluating whether propofol affects the ethanol responsiveness of mice. The actual absolute amount of ethanol ingested by mice was continuously observed after intravenous injection of saline or midazolam. The results are as follows: Figure 5 As shown: Compared with the mice injected with saline, the absolute amount of ethanol spontaneously ingested by mice in the single injection of midazolam was significantly reduced, and gradually recovered after two days. This indicates that a single systemic administration of midazolam can inhibit the absolute amount of ethanol spontaneously ingested by mice in a relatively short period of time (about 2 days).

[0041] 6. Midazolam does not affect the total amount of fluid ingested spontaneously by mice. Both water and liquid alcohol are liquid substances. To investigate whether midazolam would have a general effect on the intake of liquid substances in mice, the total amount of all liquids ingested by mice (including water and 10% alcohol) was continuously observed after intravenous injection of saline or midazolam. The results are as follows: Figure 6 As shown, compared with the mice injected with saline, the total amount of fluid ingested by the mice injected with a single dose of midazolam was roughly the same, which was not statistically significant, indicating that systemic administration of midazolam did not affect the mice's general preference for liquid substances.

[0042] 7. The combination of lorcaserin and midazolam significantly and persistently inhibited the relative preference for active uptake of 10% ethanol in mice. Given that both lorcaserin and midazolam may potentially inhibit spontaneous alcohol uptake in mice, but with limited effects, the inventors explored whether combining the two drugs could produce better results. Mice were administered a single intravenous injection of either saline or a lorcaserin / midazolam mixture via tail vein, and their preference for the ethanol solution was subsequently observed. The results are as follows: Figure 7 As shown, compared with mice injected with saline, a single injection of lorcaserin / midazolam mixture significantly inhibited the mice's preference for spontaneous ethanol intake, and this effect lasted for at least 6 days. This indicates that the lorcaserin / midazolam combination can play a synergistic role, amplifying the inhibitory effect of each on spontaneous alcohol consumption and significantly and persistently downregulating the body's preference for spontaneous alcohol intake.

[0043] 8. The combination of lorcaserin and midazolam significantly and persistently inhibited the absolute amount of active uptake of 10% ethanol in mice. The absolute amount of ethanol actively ingested is another key indicator for evaluating whether propofol affects the ethanol response in mice. The actual absolute amount of ethanol ingested by mice was continuously observed after intravenous injection of saline or a lorcaserin / midazolam mixture. The results are as follows: Figure 8As shown, compared with the mice injected with saline, the absolute amount of ethanol spontaneously ingested by mice injected with a single dose of lorcaserin / midazolam mixture was significantly reduced, and this inhibitory effect lasted for at least 6 days, indicating that a single systemic administration of lorcaserin / midazolam mixture can significantly and persistently inhibit the absolute amount of ethanol spontaneously ingested by mice.

[0044] 9. The combination of lorcaserin and midazolam does not affect the total amount of fluid ingested spontaneously by mice. To investigate whether the sustained inhibitory effect of the lorcaserin / midazolam mixture on ethanol uptake in this case was indirectly caused by a general inhibition of liquid uptake, the total amount of all fluids (including water and 10% alcohol) ingested by mice was continuously observed after intravenous injection of saline or the lorcaserin / midazolam mixture. The results are as follows: Figure 9 As shown, compared with the mice injected with saline, the total amount of fluid ingested by the mice injected with a single dose of lorcaserin / midazolam mixture was roughly the same, which was not statistically significant. This indicates that systemic administration of lorcaserin / midazolam mixture did not affect the mice's general preference for liquid substances.

[0045] In addition, the inventors of this case also conducted experiments with other raw materials, process operations, and process conditions described in this specification, referring to the aforementioned embodiments, and obtained relatively ideal results in all cases.

[0046] It should be understood that the technical solutions of the present invention are not limited to the specific embodiments described above. Any technical modifications made to the technical solutions of the present invention without departing from the spirit and scope of the claims are within the scope of protection of the present invention.

Claims

1. A pharmaceutical composition for inhibiting voluntary ethanol intake preference, characterized in that, include: Lorcaserin and midazolam.

2. The pharmaceutical composition according to claim 1, characterized in that: The mass ratio of lorcaserin to midazolam is 1:3 to 1:

10.

3. The pharmaceutical composition according to claim 1, characterized in that: When the drug composition is applied to a mouse model, it can at least reduce the absolute amount of ethanol actively ingested by the mice.

4. The pharmaceutical composition according to claim 1, characterized in that: When the drug composition is applied to a mouse model, it can inhibit the active ingestion of ethanol in mice for more than 6 days.

5. The pharmaceutical composition according to claim 3 or 4, characterized in that: The ethanol used is an ethanol solution with a volume fraction of 5-20%.

6. The pharmaceutical composition according to claim 1, characterized in that: The pharmaceutical composition further includes a pharmaceutically acceptable carrier and / or excipient; wherein the pharmaceutically acceptable derivative is selected from at least one of pharmaceutically acceptable salts, polymorphs, cocrystals, radiolabeled forms, and combinations thereof.

7. Use of the pharmaceutical composition of any one of claims 1-6 in the preparation of a medicament for inhibiting voluntary ethanol intake preference.

8. The use according to claim 7, characterized in that: When the drug used to inhibit the voluntary intake preference of ethanol is applied to a mouse model, it can at least reduce the absolute amount of ethanol actively ingested by the mice.

9. The use according to claim 7, characterized in that: When the drug used to inhibit the voluntary ethanol intake preference is applied to a mouse model, it can inhibit the mice's voluntary ethanol intake for more than 6 days.

10. The use according to claim 8 or 9, characterized in that: The ethanol used is an ethanol solution with a volume fraction of 5-20%.

Images