Combined application of nicotine and theobromine in relieving bipolar affective disorder as well as product and preparation method of nicotine and theobromine

Abstract

The invention belongs to the technical field of medicines, and particularly relates to combined application of nicotine and theobromine in relieving bipolar affective disorder as well as a product and a preparation method of the product. The problems that traditional western medicines are large in curative effect fluctuation, have addiction risks, are obvious in side effects and the like are solved, the anti-anxiety characteristic of nicotine and the analgesic and sedative effects of theobromine are used for synergistically exerting a multi-dimensional intervention effect, and curative effect superposition is achieved. The invention also determines the ratio of nicotine to theobromine (the mass ratio of nicotine to theobromine is 1: 100-1000), provides a reliable basis for clinical application, and is beneficial to improving the treatment effect. According to the scheme, the technical blank that natural components are combined to be used for treating bipolar affective disorder is filled, a brand new path is provided for intervention of the disease, and important theoretical exploration value and practical application significance are achieved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the combined application of nicotine and theobromine in alleviating bipolar disorder, as well as its products and preparation methods. Background Technology

[0002] Bipolar disorder, a complex and prevalent mental health condition, is characterized by intense and recurring mood swings, which manifest in two extreme states: one is deep depression, or major depressive episodes, in which patients may experience persistent sadness, loss of interest, self-denial, and even suicidal thoughts; the other is abnormally elevated mood, including manic episodes or hypomanic episodes, in which patients are often unusually energetic, have jumping thoughts, talk more, and may even exhibit impulsive behavior or detached thoughts.

[0003] Currently, the primary approach to treating bipolar disorder in clinical practice is Western medicine, with commonly used medications including tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and amino acid-based drugs. While these medications can alleviate depressive symptoms to some extent and help stabilize mood in some patients, they also present several significant challenges. First, the effectiveness is uncertain; different patients respond differently to the same medication, with some experiencing significant improvement initially while others see little benefit. Second, long-term use of these medications can lead to a range of side effects, such as digestive problems like dry mouth and constipation, sleep disturbances like insomnia and drowsiness, and metabolic issues like abnormal weight gain. These side effects not only cause discomfort but may also reduce patient compliance. Furthermore, a considerable number of patients do not respond well to these traditional medications, leading to prolonged treatment periods, increased treatment difficulty, and potentially further deterioration of the condition, placing a heavy emotional and financial burden on patients and their families.

[0004] Therefore, developing a new, safer, and more effective treatment plan has become a crucial issue that urgently needs to be addressed in the field of psychiatry. An ideal treatment plan should effectively alleviate all symptoms of bipolar disorder (including depressive and manic episodes) while minimizing the risk of side effects, improving patient adherence, and enabling them to cooperate more actively and persistently with treatment, thereby achieving long-term stability of the condition and improving quality of life.

[0005] Against this backdrop, natural plant ingredients have gradually become a research hotspot due to their generally good tolerability and low side effects. However, currently, there are no reports of using nicotine and theobromine in combination to treat bipolar disorder. Nicotine, an alkaloid found in tobacco, plays a role in regulating the central nervous system, but it is highly toxic; an oral dose of 40 mg can be fatal to adults, requiring low-dose use, and it is highly addictive. Therefore, its safe and addictive doses must be considered, and its use should be studied using low-dose nicotine. Theobromine, on the other hand, is a methylxanthine compound found in cocoa beans, which has effects such as stimulating the central nervous system and relaxing smooth muscles. Theobromine has a relatively high safe dose; the maximum daily dose for adults should not exceed 1.2g, and the adult LD50 is 1.0g / kg.

[0006] How to scientifically utilize these natural plant components, and develop targeted and effective treatment plans for bipolar disorder through reasonable formulation and combined use, thereby filling the gaps in existing treatment methods and solving the current clinical treatment problems, is undoubtedly a direction with important research value and application prospects, and is also a focus of attention for many researchers and clinicians. Summary of the Invention

[0007] To address the aforementioned shortcomings, this invention provides a scheme for the combined use of low-dose nicotine and theobromine, aiming to effectively alleviate bipolar disorder-like symptoms in animals while reducing the risk of side effects from high-dose use of a single component.

[0008] The technical solution of this invention is as follows: On the one hand, this invention provides the application of nicotine combined with theobromine in the preparation of drugs to alleviate bipolar disorder.

[0009] Specifically, the mass ratio of nicotine to theobromine is 1:100-1000, specifically, the mass ratio is 1:100, 1:101, 1:102, 1:103, 1:104, 1:105, 1:106, 1:107, 1:108, 1:109, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, 1:190, 1:200, 1:300, 1:400, 1:500, 1:600, 1:700, 1:800, 1:900, 1:1000, and any value within the range.

[0010] Preferably, in some embodiments, the mass ratio of nicotine to theobromine may be 1:100.

[0011] Preferably, in other embodiments, the mass ratio of nicotine to theobromine may be 1:500.

[0012] Preferably, in other embodiments, the mass ratio of nicotine to theobromine may be 1:1000.

[0013] Specifically, the dosage of nicotine in the drug is 0.01 mg / kg; the dosage of theobromine is 1-10 mg / kg.

[0014] Preferably, in some embodiments, the amount of nicotine in the drug is 0.01 mg / kg; and the amount of theobromine is 1 mg / kg.

[0015] Preferably, in some other embodiments, the amount of nicotine in the drug is 0.01 mg / kg; and the amount of theobromine is 5 mg / kg.

[0016] Preferably, in some other embodiments, the amount of nicotine in the drug is 0.01 mg / kg; and the amount of theobromine is 10 mg / kg.

[0017] Specifically, the drug also includes pharmaceutically acceptable excipients.

[0018] Preferably, the pharmaceutically acceptable excipient is selected from at least one of diluents, lubricants, binders, disintegrants, and preservatives.

[0019] Preferably, the diluent is selected from at least one of starch, lactose, microcrystalline cellulose, or mannitol; The lubricant is selected from at least one of magnesium stearate, talc, polyethylene glycol, or sodium dodecyl sulfate. The adhesive is selected from at least one of starch paste, hydroxypropyl methylcellulose, povidone, or gelatin; The disintegrant is selected from at least one of dry starch, sodium carboxymethyl starch, sodium croscarmellose, or croscarmellose. The preservative is selected from at least one of sodium benzoate, potassium sorbate, methylparaben, ethylparaben, or benzalkonium bromide.

[0020] Specifically, the drug is present in the form of an oral preparation; the oral preparation form is a tablet, capsule, oral liquid preparation, granule, chewable tablet, lozenge, sublingual tablet, sustained-release tablet, controlled-release tablet, enteric-coated tablet, or orally disintegrating tablet.

[0021] Specifically, the drug is in the form of an injection; the injection form may be an intravenous injection, intramuscular injection, subcutaneous injection, sustained-release injection, powder injection, lyophilized injection, or intraperitoneal injection.

[0022] Specifically, the nicotine and theobromine are derived from natural plant extracts or chemically synthesized.

[0023] In another aspect, the present invention provides a pharmaceutical composition in which the active ingredients include nicotine and theobromine.

[0024] Specifically, the mass ratio of nicotine to theobromine is 1:100-1000, specifically, the mass ratio is 1:100, 1:101, 1:102, 1:103, 1:104, 1:105, 1:106, 1:107, 1:108, 1:109, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, 1:190, 1:200, 1:300, 1:400, 1:500, 1:600, 1:700, 1:800, 1:900, 1:1000, and any value within the range.

[0025] Preferably, in some embodiments, the mass ratio of nicotine to theobromine may be 1:100.

[0026] Preferably, in other embodiments, the mass ratio of nicotine to theobromine may be 1:500.

[0027] Preferably, in other embodiments, the mass ratio of nicotine to theobromine may be 1:1000.

[0028] Specifically, the pharmaceutical composition further includes pharmaceutically acceptable excipients.

[0029] Preferably, the pharmaceutically acceptable excipient is selected from at least one of diluents, lubricants, binders, disintegrants, and preservatives.

[0030] Preferably, the diluent is selected from at least one of starch, lactose, microcrystalline cellulose, or mannitol; The lubricant is selected from at least one of magnesium stearate, talc, polyethylene glycol, or sodium dodecyl sulfate. The adhesive is selected from at least one of starch paste, hydroxypropyl methylcellulose, povidone, or gelatin; The disintegrant is selected from at least one of dry starch, sodium carboxymethyl starch, sodium croscarmellose, or croscarmellose. The preservative is selected from at least one of sodium benzoate, potassium sorbate, methylparaben, ethylparaben, or benzalkonium bromide.

[0031] Specifically, the drug is present in the form of an oral preparation; the oral preparation form is a tablet, capsule, oral liquid preparation, granule, chewable tablet, lozenge, sublingual tablet, sustained-release tablet, controlled-release tablet, enteric-coated tablet, or orally disintegrating tablet.

[0032] Specifically, the drug is in the form of an injection; the injection form may be an intravenous injection, intramuscular injection, subcutaneous injection, sustained-release injection, powder injection, lyophilized injection, or intraperitoneal injection.

[0033] Specifically, the nicotine and theobromine are derived from natural plant extracts or chemically synthesized.

[0034] In another aspect, the present invention provides a method for preparing the aforementioned pharmaceutical composition, the method comprising mixing nicotine and theobromine with pharmaceutically acceptable excipients, the mixing method including physical mixing, solvent dissolution, emulsification or lyophilization.

[0035] Specifically, the physical mixing includes direct uniform mixing (applicable to solid dosage forms, such as tablets and powders).

[0036] Specifically, the solvent dissolution includes dissolving the drug in solvents such as water and ethanol (e.g., oral liquids, injections).

[0037] Specifically, the emulsification includes aqueous formulations (such as creams, emulsion injections) for lipid-soluble drugs.

[0038] Specifically, the lyophilization (freeze-drying) includes the preparation of heat-labile drugs into lyophilized powders (such as lyophilized powder for injection).

[0039] The beneficial effects of the present invention are: (1) This invention combines nicotine and theobromine to form a systematic natural ingredient treatment plan, which overcomes the problems of insufficient efficacy, drug addiction and other side effects in the existing Western medicine treatment of bipolar disorder; (2) This invention makes full use of the potential mechanisms of action of nicotine and theobromine to achieve synergistic therapeutic effects. It not only exerts the anti-anxiety effect of nicotine, but also utilizes the analgesic and sedative effect of theobromine, thereby working together to act on multiple pathological aspects of bipolar disorder. (3) The pharmaceutical composition provided by the present invention is a natural plant ingredient with good tolerability and safety. It can effectively relieve or treat bipolar disorder in animals without obvious adverse reactions, thus solving the problem of large drug side effects in existing treatment plans. (4) By optimizing the ratio of nicotine and theobromine and the administration regimen, this invention has established an effective dosage range, providing a scientific basis for clinical application and helping to improve the therapeutic effect; (5) This invention provides a novel treatment plan for bipolar disorder, filling the gap in the use of natural ingredients in combination in the existing technology, and has important theoretical and practical significance. Detailed Implementation

[0040] The present invention will be further clearly and completely illustrated below through embodiments. These embodiments are only some examples of the present invention and are not intended to limit the present invention, but are only for illustrating the present invention. Unless otherwise specified, the experimental methods used in the following embodiments are all conventional experiments, and the materials and reagents used in the following embodiments are commercially available unless otherwise specified.

[0041] Main experimental reagents and instruments of this invention 1. Reagents and consumables: Nicotine (99.9% purity, Toronto Research Chemicals, Canada), theobromine (99.9% purity, Toronto Research Chemicals, Canada), varanoslin (98%, dihydrochloride form, Sigma-Aldrich, USA), disposable syringes, sodium pentobarbital (>99.0%, Beijing Jiehui Biotechnology Co., Ltd.).

[0042] 2. Experimental Apparatus: Open Field Behavior System (Shanghai Xinruan Information Technology Co., Ltd.), Transparent Acrylic Glass Cylinder (Shanghai Xinruan Information Technology Co., Ltd.), Behavioral Video Recording and Analysis System (Shanghai Xinruan Information Technology Co., Ltd.) Example 1 1.1 Experimental Methods 1.1.1 Feeding and grouping of laboratory mice C57BL / 6J mice (Beijing Vital River Laboratory Animal Company), male, 2 months old, 20-25 g, with normal physiological rhythms, were housed in an environment (indoor relative humidity 50-60%, ambient temperature 22±2 ℃) with free access to water and food. The stocking density was 6 mice / cage. The experimenter manipulated each mouse for 3 consecutive days to familiarize them with the handling and other experimental procedures, reducing stress.

[0043] Mice were randomly divided into groups of 12 mice each using a random number table. The grouping scheme is shown in Table 1. Table 1

[0044] 1.1.2 Modeling and Treatment of Bipolar Disorder in Mice (1) Modeling of bipolar disorder in mice: Varnosorline (0.5 mg / kg) was injected intraperitoneally once a day at a fixed time for 3-9 consecutive days. The modeling effect of different modeling days was compared by behavioral indicators of open field test and forced swimming test. As shown in Table 2, it was found that the modeling was successful on the 5th day and the bipolar disorder behavior was relatively stable.

[0045] Table 2 Comparison of behavioral indicators at different modeling times

[0046] (2) Nicotine treatment: Vanastrin (0.5 mg / kg) was injected intraperitoneally once a day at a fixed time for 5 consecutive days. On the 5th day of modeling, nicotine (0.01 mg / kg) was injected intraperitoneally 10 minutes later, and behavioral tests were performed, including the open field test and the forced swimming test, to observe the effect of alleviating bipolar disorder.

[0047] (3) Theobromine treatment: Vanastrin (0.5 mg / kg) was injected intraperitoneally once a day at a fixed time for 5 consecutive days. On the 5th day of modeling, theobromine (1 mg / kg) was injected intraperitoneally 10 minutes later, and behavioral tests were performed, including the open field test and the forced swimming test, to observe the effect of alleviating bipolar disorder.

[0048] (4) Nicotine + theobromine combined treatment: Vanaslin (0.5 mg / kg) was injected intraperitoneally once a day at a fixed time for 5 consecutive days. On the 5th day of modeling, the three groups of animals were injected intraperitoneally with nicotine (0.01 mg / kg) + theobromine (1 mg / kg), nicotine (0.01 mg / kg) + theobromine (5 mg / kg), and nicotine (0.01 mg / kg) + theobromine (10 mg / kg) respectively. After 10 minutes, behavioral tests were carried out, including the open field test and the forced swimming test, to observe the effect of alleviating bipolar disorder.

[0049] (5) Positive drug treatment: Vanastolin (0.5 mg / kg) is injected intraperitoneally once a day at a fixed time for 5 consecutive days. On the 5th day of modeling, lithium chloride (10 mg / kg) is administered intraperitoneally for 10 minutes. Behavioral tests are then performed, including the open field test and the forced swimming test, to observe the effect of lithium chloride in relieving bipolar disorder and to compare it with the effects of other treatments in this patent.

[0050] (6) Control group: The same volume of 0.9% saline was injected into the peritoneum at a fixed time every day for 5 consecutive days. On the 5th day of modeling, behavioral tests were conducted, including the open field test and the forced swimming test.

[0051] 1.1.3 Behavioral Testing After modeling and drug administration, open field test and forced swimming test were used to evaluate behavioral indicators of bipolar disorder in mice.

[0052] To avoid interference between behavioral tests, both the model group and the nicotine treatment group were further divided into two subgroups (n=6 per group): one subgroup underwent only the open field test, and the other subgroup underwent only the forced swimming test. The saline control group and the positive drug control group also underwent the corresponding tests as needed.

[0053] The study verified the alleviating effect of nicotine on bipolar disorder-like behaviors by comparing behavioral indicators (such as time spent in the open field and time spent immobile during swimming).

[0054] (1) Open field experiment a. Before the experiment, the animals should be allowed to acclimatize to the testing environment for 30-60 minutes; b. Once the animal is placed in the testing chamber, the testing begins. The testing time should be 5-10 minutes, and the entire process should be recorded on video. c. During each experiment, the animal should be placed in the center of the test box from the same location and direction, and the behavioral video recording system should record the time the animal spends in the center of the open field.

[0055] (2) Forced swimming experiment a. Maintain quiet during the experiment, with no significant changes in light, and keep the room temperature between 20-25℃; b. The experiment was conducted in a transparent plexiglass cylinder (30 cm high × 18 cm diameter) filled with water at a depth of 10 cm and a temperature of (23±2)℃; c. At the start of the experiment, the mice were placed in water for 6 minutes, and the entire process was recorded on video. At the end of the test, the animals were removed from the water and returned to their cages, and the behavioral video recording system recorded the cumulative immobility time of each mouse for the last 4 minutes.

[0056] 1.1.4 Results The behavioral test results of mice in different groups are shown in Table 3. Among them, the center dwell time in the open field test represents the manic state in bipolar disorder-like behavior, and the longer the center dwell time, the more obvious the manic state. The immobility time in the forced swimming behavior represents the depressive state in bipolar disorder-like behavior, and the longer the time, the more obvious the depressive state.

[0057] For single treatment groups, the central dwell time in the nicotine treatment group and theobromine treatment group was significantly shorter than that in the model group, indicating that nicotine has a certain alleviating effect on manic-like behavior in bipolar disorder.

[0058] In the combination therapy group, low-dose nicotine combined with different doses of theobromine significantly reduced central dwell time in open field behavior and immobility time in forced swimming behavior, indicating that combination therapy was superior to single therapy. Furthermore, the behavioral results became more pronounced with increasing theobromine dosage, further demonstrating that the use of low-dose nicotine and different doses of theobromine in combination therapy has a significant advantage over single-compound treatment.

[0059] Compared with the known positive control drug lithium chloride, the combination of the two substances was more effective in alleviating bipolar disorder-like behavior than lithium chloride, further indicating that the combination of the two substances has certain therapeutic value in improving the behavior of animals with bipolar disorder.

[0060] Table 3. Results of behavioral tests on mice under different treatments (mean ± standard deviation, n=6)

[0061] Note: * indicates a significant difference between the groups compared with the bipolar disorder model group (P<0.05), ** indicates a highly significant difference between the groups compared with the bipolar disorder model group (P<0.01), and *** indicates a highly significant difference between the groups compared with the bipolar disorder model group (P<0.001).

[0062] Comparative Example 1 The "Nicotinic Acid + Theobromine Treatment Group-4" was established: On the 5th day of modeling, nicotine (0.02 mg / kg) and theobromine (1 mg / kg) were administered intraperitoneally. Behavioral tests, including the open field test and the forced swimming test, were then conducted to observe the effect on alleviating bipolar disorder. Other procedures were the same as in the previous example.

[0063] The results are shown in Table 4. For the combined treatment group, after treating mice with a nicotine to theobromine ratio (1:50) outside the dose protection range, it was found that the central dwell time in open field behavior did not change significantly compared with the single treatment group, and the immobility time in forced swimming behavior did not change significantly compared with the single treatment group. This indicates that the combined treatment effect of this dose ratio does not have a significant advantage over single treatment.

[0064] The effect of nicotine and theobromine in a ratio of 1:50 outside the dose protection range on alleviating bipolar disorder-like behavior in mice was significantly weaker than that of lithium chloride, a known positive control drug, further demonstrating the therapeutic value of the two substances in a combined ratio in the range of 1:100-1:1000.

[0065] Table 4. Results of behavioral tests on mice under different treatments (mean ± standard deviation, n=6)

[0066] Note: * indicates a significant difference between the groups compared with the bipolar disorder model group (P<0.05), and *** indicates an extremely significant difference between the groups compared with the bipolar disorder model group (P<0.001).

[0067] Comparative Example 2 Aripiprazole is known to have a clear therapeutic effect on bipolar disorder in animals and humans. Theobromine in Example 1 was replaced with aripiprazole, and everything else was the same as in the example. The effect of using the two in combination was observed.

[0068] The results are shown in Table 5. For the nicotine + aripiprazole treatment group, after treating mice with a ratio of nicotine to aripiprazole (1:100-1:1000), it was found that the central dwell time in open field behavior did not change significantly compared with the single treatment group, and the immobility time in forced swimming behavior did not change significantly compared with the single treatment group. This indicates that the combined treatment of replacing theobromine with aripiprazole does not have a significant advantage over the single treatment.

[0069] The effect of nicotine + aripiprazole treatment on alleviating bipolar disorder-like behavior in mice was comparable to that of lithium chloride, a known positive control drug, further demonstrating that the therapeutic value of the combination of nicotine and theobromine in this example is superior to that of nicotine + aripiprazole in Comparative Example 2.

[0070] Table 5. Results of behavioral tests in mice under different treatments (mean ± standard deviation, n=6)

[0071] Note: * indicates a significant difference between the groups compared with the bipolar disorder model group (P<0.05), and ** indicates a highly significant difference between the groups compared with the bipolar disorder model group (P<0.01).

[0072] The above detailed description is a specific illustration of one feasible embodiment of the present invention, and this embodiment is not intended to limit the patent scope of the present invention. It should be noted that all equivalent implementations or modifications made without departing from the present invention should be included within the scope of the technical solution of the present invention. Therefore, the protection scope of the present invention should be determined by the appended claims.

Claims

1. Application of nicotine combined with theobromine in the preparation of drugs to alleviate bipolar disorder.

2. The application according to claim 1, characterized in that, The mass ratio of nicotine to theobromine is 1:100-1000.

3. The application according to claim 1, characterized in that, The mass ratio of nicotine to theobromine is 1:

100.

4. The application according to claim 1, characterized in that, The mass ratio of nicotine to theobromine is 1:

500.

5. The application according to claim 1, characterized in that, The mass ratio of nicotine to theobromine is 1:1000.

6. The application according to any one of claims 1-5, characterized in that, The drug also includes pharmaceutically acceptable excipients.

7. The application according to claim 6, characterized in that, The pharmaceutically acceptable excipient is selected from at least one of diluents, lubricants, binders, disintegrants, or preservatives.

8. The application according to claim 7, characterized in that, The diluent is selected from at least one of starch, lactose, microcrystalline cellulose or mannitol; The lubricant is selected from at least one of magnesium stearate, talc, polyethylene glycol, or sodium dodecyl sulfate. The adhesive is selected from at least one of starch paste, hydroxypropyl methylcellulose, povidone, or gelatin; The disintegrant is selected from at least one of dry starch, sodium carboxymethyl starch, sodium croscarmellose, or croscarmellose. The preservative is selected from at least one of sodium benzoate, potassium sorbate, methylparaben, ethylparaben, or benzalkonium bromide.

9. The application according to claim 1, characterized in that, The drug is present in the form of an oral preparation; the oral preparation form is a tablet, capsule, oral liquid preparation, granule, chewable tablet, lozenge, sublingual tablet, sustained-release tablet, controlled-release tablet, enteric-coated tablet or orally disintegrating tablet.

10. The application according to claim 1, characterized in that, The drug is in the form of an injection; the injection form may be an intravenous injection, intramuscular injection, subcutaneous injection, sustained-release injection, powder injection, lyophilized injection, or intraperitoneal injection.

11. A pharmaceutical composition, characterized in that, The active ingredients of the pharmaceutical composition include nicotine and theobromine.

12. The pharmaceutical composition according to claim 11, characterized in that, The mass ratio of nicotine to theobromine is 1:100-1000.

13. The pharmaceutical composition according to claim 11, characterized in that, The mass ratio of nicotine to theobromine is selected from 1:100, 1:500 or 1:1000.

14. The pharmaceutical composition according to claim 11, characterized in that, The pharmaceutical composition also includes pharmaceutically acceptable excipients.

15. The pharmaceutical composition according to claim 11, characterized in that, The nicotine and theobromine are derived from natural plant extracts or chemical synthesis.

16. A method for preparing the pharmaceutical composition according to any one of claims 11-15, characterized in that, The preparation method includes mixing nicotine and theobromine with pharmaceutically acceptable excipients, wherein the mixing method includes physical mixing, solvent dissolution, emulsification or freeze-drying.

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