Compositions and their use in the preparation of medicaments for the treatment and / or prevention of depression

Abstract

This invention relates to the pharmaceutical field, and more particularly to compositions and their use in the preparation of remedies for treating and / or preventing depression. The invention provides compositions comprising: scopolamine hydrobromide and idebenone. This invention utilizes the differentiated pathways of action of these two existing marketed drugs to construct a complementary therapeutic system that rapidly relieves depression and provides long-term repair of brain metabolism and neurological function. This achieves synergistic effects, reduces toxicity, and improves the effectiveness of combined treatment for depression, filling a technological and patent gap in the treatment of depressive disorders and facilitating standardized clinical research and industrialization.

Description

Technical Field

[0001] This invention relates to the field of pharmaceuticals, and more particularly to compositions thereof and their use in the preparation of medicaments for the treatment and / or prevention of depression. Background Technology

[0002] Depression is a common chronic and disabling mental illness in clinical practice. Its pathogenesis involves multiple pathological mechanisms, including central neurotransmitter disorders, brain energy metabolism disorders, neuroinflammatory damage, downregulation of neurotrophic factors, and abnormal central microcirculation. Currently, first-line treatments mainly consist of SSRIs and SNRIs, which generally have drawbacks such as delayed onset of action (2-4 weeks), a high proportion of treatment-resistant cases, poor efficacy in improving co-occurring cognitive decline, mental fatigue, and brain metabolic damage, and significant side effects with long-term use. These limitations fail to meet the clinical needs for rapid symptom control, long-term restorative effects, and improvement of cognitive comorbidities.

[0003] Scopolamine hydrobromide tablets are a classic drug already marketed in China. Current product information only indicates its use for smooth muscle spasm, microcirculatory disturbances, vertigo, and organophosphate poisoning; it does not indicate its use for treating depression. Recent studies have confirmed that scopolamine hydrobromide can cross the blood-brain barrier and exert its potential by antagonizing central cholinergic receptors, activating the prefrontal glutamate signaling pathway, upregulating BDNF neurotrophic factor in the brain, improving central microcirculation, and inhibiting neuroinflammation. It possesses the potential to rapidly relieve depression, acute anxiety, and somatization symptoms, although its specific clinical efficacy remains unclear.

[0004] Idebenone tablets are a clinically mature, marketed drug for improving brain metabolism. The product information indicates its use in treating brain function impairment caused by chronic cerebrovascular disease and traumatic brain injury, improving memory loss and subjective neurological symptoms. It is not approved for use in treating depression. Multiple studies have confirmed that idebenone, as a mitochondrial coenzyme Q10 analog, can activate brain mitochondrial respiratory function, improve brain energy metabolism, scavenge central oxidative free radicals, and reduce neurooxidative stress damage. It can effectively improve core symptoms in depressed patients such as cognitive decline, mental fatigue, lack of motivation, and persistent low mood. It also has a beneficial effect on chronic depression mediated by abnormal brain metabolism and vascular-related depression; however, its efficacy as a monotherapy is still unclear.

[0005] A search revealed no existing patents or published literature that disclose a combination of scopolamine hydrobromide and idebenone for the treatment of depression, nor any clinical application of these two drugs. The mechanisms of action of these two drugs against depression are complementary, and there is no technological inspiration required. Therefore, there is room for innovation in developing synergistic antidepressant drug compositions. Summary of the Invention

[0006] In view of this, the present invention provides a composition and its use in the preparation of a medicament for the treatment and / or prevention of depression. The present invention utilizes the differentiated pathways of two existing marketed drugs to construct a complementary therapeutic system that rapidly relieves depression and provides long-term repair of brain metabolism and neural function, achieving the technical effects of synergistic efficacy and reduced toxicity, and improving the effectiveness of treatment for depression. This fills the technical and patent gap in the combined treatment of depressive disorders and is suitable for standardized clinical research and industrialization.

[0007] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0008] The present invention provides a composition comprising: scopolamine hydrobromide and idebenone.

[0009] In some embodiments of the present invention, the mass ratio of scopolamine hydrobromide to idebenone in the above composition is (1~6):(5~10).

[0010] In some embodiments of the present invention, the mass ratio of scopolamine hydrobromide to idebenone in the above composition is 1:6.

[0011] The present invention also provides the use of the above composition in the preparation of medicaments for treating and / or preventing depression.

[0012] In some embodiments of the present invention, the above-described applications include: mild to moderate depression and / or severe depression.

[0013] In some embodiments of the present invention, the above-described applications include: treatment-resistant depression and / or recurrent depression.

[0014] In some embodiments of the present invention, in the above applications, the depression includes one or more of the following: depression combined with anxiety disorder, chronic depressive disorder with cognitive decline / abnormal brain metabolism, and post-stroke depression.

[0015] In some embodiments of the present invention, in the above applications, the dosage of scopolamine hydrobromide in the composition is 0.25~0.5 mg / kg; the dosage of idebenone is 1~1.5 mg / kg.

[0016] In some embodiments of the present invention, in the above applications, the dosage of scopolamine hydrobromide in the composition is 0.25 mg / kg; the dosage of idebenone is 1.5 mg / kg.

[0017] The present invention also provides a medicament comprising: the above-described composition and pharmaceutically acceptable excipients.

[0018] In some embodiments of the present invention, the dosage form of the above-mentioned drug includes: oral dosage form or non-oral administration formulation.

[0019] In some embodiments of the present invention, the oral dosage form of the above-mentioned drug includes one or more of oral tablets, capsules, and sustained-release formulations.

[0020] In some embodiments of the present invention, the non-oral administration formulation of the above-described medicament includes: an injection and / or a transdermal patch.

[0021] The composition of this invention is a non-obvious multi-target synergistic system. The mechanisms of action of the two drugs do not overlap, do not antagonize, and are highly complementary, producing an unexpected therapeutic effect of 1+1>2.

[0022] 1. Scopolamine hydrobromide (rapid-acting module): Through central muscarinic receptor antagonism, it rapidly activates the prefrontal glutamate neural pathway, upregulates BDNF expression in the brain, quickly inhibits central nervous system inflammation, and improves cerebral microcirculation. It can relieve depression, tension, anxiety, somatic discomfort, and acute mood disorders in a short time, solving the core pain point of slow onset of traditional antidepressants and is responsible for rapid symptom control in the acute phase of clinical practice.

[0023] 2. Idebenone (long-acting repair module): Targets the brain mitochondrial energy metabolism pathway, repairs damaged brain nerve cells, clears central oxidative stress damage, continuously improves brain blood and oxygen supply and nerve metabolism function, and provides long-term relief for core symptoms of depression such as anhedonia, mental fatigue, memory loss, and poor concentration. It also improves chronic depression mediated by abnormal brain metabolism and is responsible for long-term stabilization and reducing relapse rate during the clinical recovery period.

[0024] 3. Overall synergistic advantages: The combined use of the two drugs simultaneously covers the six core pathological mechanisms of depression, namely "neurotransmitter disorder, microcirculatory disturbance, neuroinflammation, oxidative stress, brain metabolic damage, and insufficient neurotrophic factors." It can not only quickly control depressive episodes but also provide long-term repair of nerve and brain function damage, taking into account both symptom relief and etiological intervention, thus providing a new treatment option for depression. Detailed Implementation

[0025] This invention discloses compositions and their use in the preparation of medicaments for treating and / or preventing depression.

[0026] It should be understood that the expression “one or more of…” individually includes each of the objects described after the expression, as well as various different combinations of two or more of the described objects, unless otherwise understood from the context and usage. The expression “and / or” combined with three or more described objects should be understood to have the same meaning, unless otherwise understood from the context.

[0027] The terms “including,” “having,” or “containing,” including the use of their grammatical synonyms, should generally be understood as open-ended and non-restrictive, for example, not excluding other unstated elements or steps, unless otherwise specifically stated or understood from the context.

[0028] It should be understood that the order of the steps or the order in which certain actions are performed is not important as long as the invention remains operational. Furthermore, two or more steps or actions can be performed simultaneously.

[0029] The use of any and all instances or exemplary language such as “e.g.” or “including” in this document is merely intended to better illustrate the invention and is not intended to limit the scope of the invention unless the claims are made. No language in this specification should be construed as indicating that any unclaimed element is essential to the practice of the invention.

[0030] Furthermore, the numerical ranges and parameters used to define the present invention are approximate values, and the relevant values ​​in the specific embodiments have been presented as precisely as possible. However, any value inevitably contains standard deviations due to individual test methods. Therefore, unless explicitly stated otherwise, it should be understood that all ranges, quantities, values, and percentages used in this disclosure are modified with the word "approximately". Here, "approximately" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a specific value or range.

[0031] This invention provides a synergistic pharmaceutical composition for the treatment of depression, comprising scopolamine hydrobromide and idebenone as active ingredients, combined with pharmaceutically acceptable excipients or carriers. Both scopolamine hydrobromide and idebenone are already available as marketed oral active pharmaceutical ingredients and oral formulations.

[0032] The compositions of the present invention can be prepared as oral tablets, capsules, sustained-release formulations, injections or transdermal patches, preferably as ordinary oral tablets / capsules, and are adapted to routine clinical administration methods.

[0033] The pharmaceutical compositions of the present invention are used to prepare remedies for the treatment or adjunctive treatment of the following conditions: mild to moderate depression, severe depression, treatment-resistant depression, recurrent depression, depression combined with anxiety disorder, chronic depressive disorder with cognitive decline / abnormal brain metabolism, and post-stroke depression.

[0034] The scopolamine hydrobromide tablets and idebenone tablets of the present invention are both drugs that are already on the market and sold in hospitals.

[0035] The present invention will be further illustrated below with reference to the embodiments:

[0036] Example 1

[0037] Depressive episodes were diagnosed using the Chinese Classification and Diagnostic Criteria for Mental Disorders. Male and female patients aged 18-80 years with a pre-enrollment HAMD-17 total score between 8 and 24 and a depressive mood score of at least 2 were eligible to participate. Patients with suicidal tendencies (HAMD-17 item 3 (suicide) score ≥3), angle-closure glaucoma, benign prostatic hyperplasia with urinary retention, alcoholism, drug abuse, a history of epilepsy, known allergies to anisodamine hydrobromide and idebenone, pregnancy or lactation, intestinal obstruction, severe cardiovascular, cerebrovascular, renal, or pulmonary diseases, or those currently receiving treatment for depression were excluded.

[0038] The HAMD-17 total score from patient enrollment to day 7, day 14, day 28, and the study endpoint (day 56) was used as the efficacy indicator.

[0039] Patients meeting the inclusion criteria were randomly assigned using a random number table to three groups: a combination therapy group (hyoscine hydrobromide tablets + idebenone tablets) (n=35), a hyoscine hydrobromide tablet group (n=33), an idebenone tablet group (n=34), and a placebo group (n=35). Hyoscine hydrobromide tablets were administered 5 mg (1 tablet) three times daily; idebenone tablets were administered 30 mg (1 tablet) three times daily; and the placebo (a blank preparation without hyoscine hydrobromide and idebenone) was administered three times daily. All treatments were continued for 56 days. All patients were prohibited from using medications with a clear indication for depression or anxiety during the treatment period.

[0040] The research results show that:

[0041] At 1, 2, 4, and 8 weeks after medication, the HAMD scores in the combination therapy group were significantly lower than those in the placebo group, the anisodamine hydrobromide group, and the idebenone group (P < 0.05). At 2 weeks and 8 weeks after medication, the changes in HAMD scores from baseline were also significantly greater in the combination therapy group than in the placebo group, the anisodamine hydrobromide group, and the idebenone group (P < 0.05).

[0042] There were no statistically significant differences in HAMD scores at 1, 2, 4, and 8 weeks after drug administration in the scopolamine hydrobromide group and the idebenone group, as well as the changes in HAMD scores from baseline at 2 weeks and 8 weeks after drug administration compared with the placebo group (P > 0.05).

[0043] The reduction rate of HAMD scores at 1, 2, 4, and 8 weeks after medication was analyzed using the Jin Zhengjun method. The results showed that the q-values ​​at each time point were greater than 1, indicating that the combined use of scopolamine hydrobromide tablets and idebenone tablets showed a synergistic effect at the above observation time points.

[0044] The results of this project indicate that the efficacy of scopolamine hydrobromide tablets and idebenone tablets alone in treating mild to moderate depression is comparable to that of placebo. The combined use of scopolamine hydrobromide tablets and idebenone tablets in treating mild to moderate depression is more effective than placebo, with effects starting within one week.

[0045] Table 1. Analysis of HAMD Score Changes and Measured Values

[0046]

[0047] Table 2 HAMD score reduction rate and combined effect

[0048]

[0049] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A composition, characterized in that, include: Scopolamine hydrobromide and idebenone.

2. The composition according to claim 1, characterized in that, The mass ratio of scopolamine hydrobromide to idebenone is (1~6):(5~10).

3. The composition according to claim 1, characterized in that, The mass ratio of scopolamine hydrobromide to idebenone is 1:

6.

4. Use of the composition according to any one of claims 1 to 3 in the preparation of a medicament for treating and / or preventing depression.

5. The application as described in claim 4, characterized in that, The depression mentioned includes mild to moderate depression and / or severe depression.

6. The application as described in claim 4, characterized in that, The depression mentioned includes: treatment-resistant depression and / or recurrent depression.

7. The application as described in claim 4, characterized in that, The depression includes one or more of the following: depression combined with anxiety disorder, chronic depressive disorder with cognitive decline / abnormal brain metabolism, and post-stroke depression.

8. The application as described in any one of claims 4 to 7, characterized in that, The dosage of scopolamine hydrobromide in the composition is 0.25~0.5 mg / kg; the dosage of idebenone is 1~1.5 mg / kg.

9. A drug, characterized in that, include: The composition as described in any one of claims 1 to 3 and pharmaceutically acceptable excipients.

10. The medicament as claimed in claim 9, characterized in that, The dosage forms of the drug include oral dosage forms or non-oral administration formulations.

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