Pharmaceutical composition for treating post-stroke depression through intestinal route and application thereof

Abstract

The invention discloses a pharmaceutical composition for treating post-stroke depression in an intestinal way and application of the pharmaceutical composition, and belongs to the field of biological medicine. The pharmaceutical composition comprises the following raw material components in parts by weight: 40-50 parts of nutmeg, 15-25 parts of fructus choerospondiatis, 30-40 parts of radix aucklandiae, 30-40 parts of elecampane and 3-5 parts of piper longum. According to three theories of Mongolian medicine and viscera theories, myristica fragrans, fructus choerospondiatis, radix aucklandiae, elecampane and piper longum are subjected to scientific compatibility, and the enema with a remarkable treatment effect on post-stroke depression is developed through intestinal administration. The pharmaceutical composition realizes multi-target collaborative treatment, and has the effects of relieving Zhenyi, strengthening the heart, promoting qi-blood circulation and the like. Clinical test data show that after enema treatment of the pharmaceutical composition, the depressive symptom of a patient is obviously improved, and the daily living ability of the patient is improved. The invention provides a new treatment strategy for clinical treatment of post-stroke depression.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biological medicine, in particular to a drug composition for treating post-stroke depression by intestinal route and application thereof. BACKGROUND

[0002] Stroke is a common disease that harms human health, which is divided into two categories of ischemic and hemorrhagic, and the ischemic stroke accounts for 75% to 85% of the total number of stroke patients. Post-stroke depression (PSD), also known as post-stroke depression, is a common complication after stroke, and the total incidence of PSD is in the range of 25% to 79%. The clinical manifestations mainly include low mood, loss of interest, sleep disorders and other mental symptoms and somatic symptoms. PSD affects the recovery and quality of life of stroke patients.

[0003] The PSD is mainly treated by traditional tricyclic antidepressants and monoamine oxidase inhibitors in western medicine. However, the adverse reaction rate is high. The selective serotonin reuptake inhibitor (SSRI) such as fluoxetine, paroxetine and sertraline is commonly used in clinic. However, the treatment time is 6 to 8 months or more. There are also reports on selective serotonin and norepinephrine reuptake inhibitors (SNRI) and noradrenergic and specific serotoninergic antidepressants (NaSSA), and the efficacy is similar to that of fluoxetine. Therefore, the western medicine treatment of the disease has the disadvantages of high toxic and side effects and long treatment cycle, and it has practical significance to apply safe and effective natural medicine to treat post-stroke depression. SUMMARY

[0004] The present application aims to provide a drug composition for treating post-stroke depression by intestinal route and application thereof, so as to solve the problems existing in the prior art. The drug composition provided by the present application realizes multi-target point synergistic treatment, and has the effects of relieving depression, strengthening heart and promoting blood circulation. The clinical test data shows that the depressive symptoms of patients are significantly improved after the drug composition is enema treated, and the activities of daily living of patients are improved, which provides a new treatment strategy for the clinical treatment of post-stroke depression.

[0005] To achieve the above-mentioned purpose, the present application provides the following solutions:

[0006] The application provides a medicine composition for treating post-stroke depression through an intestinal route, and ingredients of the medicine composition include the following components in parts by weight: 40-50 parts of Myristicae Semen, 15-25 parts of Fructus Choerospondi, 30-40 parts of Radix Aucklandiae, 30-40 parts of Radix Inulae and 3-5 parts of Herba Scutellariae.

[0007] Optionally, ingredients of the medicine composition include the following components in parts by weight: 50 parts of Myristicae Semen, 25 parts of Fructus Choerospondi, 40 parts of Radix Aucklandiae, 40 parts of Radix Inulae and 5 parts of Herba Scutellariae.

[0008] Optionally, the preparation method of the medicine composition includes the following steps: weighing each ingredient and then crushing.

[0009] The application further provides application of the medicine composition in preparation of a medicine for treating post-stroke depression.

[0010] Optionally, the dosage form of the medicine includes oral dosage and enema.

[0011] Optionally, the dosage form of the medicine is enema.

[0012] Optionally, the powder of the medicine composition is soaked in distilled water, filtered, and then the supernatant is used to prepare a medicinal liquid, and the medicinal liquid is used to prepare the enema.

[0013] Optionally, the use method of the medicine includes the step of dripping the medicine into the intestinal tract in the form of enema.

[0014] Optionally, the administration amount of the medicine is 150-300 mL / time / d.

[0015] Optionally, the administration speed of the medicine is 10-15 min / time.

[0016] The application discloses the following technical effects:

[0017] The application combines Myristicae Semen, Fructus Choerospondi, Radix Aucklandiae, Radix Inulae and Herba Scutellariae according to the three roots theory and the viscera theory of Mongolian medicine, and develops an enema with remarkable therapeutic effect on post-stroke depression by administering the enema through an intestinal route. The medicine composition realizes multi-target point synergistic treatment, has the effects of relieving depression, strengthening heart and promoting blood circulation, etc. Clinical test data show that after the enema treatment, the depression symptoms of patients are significantly improved, and the daily life ability of patients is improved. Although a small number of patients feel tired and drowsy during the treatment, the symptoms are mild.

[0018] The enema administration is used innovatively, so that the medicine directly acts on intestinal mucosa, the liver first pass effect is avoided, and the medicine utilization rate is improved; the optimized administration scheme (150-300 mL / time, 10-15 min instillation) is simple and safe in operation.

[0019] The application provides a new treatment strategy for clinical treatment of post-stroke depression. BRIEF DESCRIPTION OF DRAWINGS

[0020] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiments. Obviously, the drawings in the following description only constitute some embodiments of the present application, and for those skilled in the art, other drawings can also be obtained from these drawings without creative labor.

[0021] Fig. 1 ADL score column chart of three groups of PSD patients before and after treatment;

[0022] Fig. 2 HAMD score column chart of three groups of PSD patients before and after treatment;

[0023] Fig. 3 SDS score column chart of three groups of PSD patients before and after treatment;

[0024] In Figs. 1-3 In the table, * represents P<0.05, and ** represents P<0.01. DETAILED DESCRIPTION

[0025] Now, various exemplary embodiments of the present application will be described in detail, which should not be considered as limiting the present application, and should be understood as a more detailed description of some aspects, characteristics and embodiments of the present application.

[0026] It should be understood that the terms described in the present application are only for describing the specific embodiments, and are not used to limit the present application. In addition, for the numerical range in the present application, it should be understood that each intermediate value between the upper limit and the lower limit of the range is also specifically disclosed. Each smaller range between any stated value or intermediate value in the range, and any other stated value or intermediate value in the range is also included in the present application. The upper limit and the lower limit of these smaller ranges can be independently included or excluded from the range.

[0027] All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains, unless indicated otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, the preferred methods and materials are described. All publications mentioned in this specification are herein incorporated by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any reference is not an admission that it is prior art with respect to the present application.

[0028] Many modifications and variations of this application of the application can be made without departing from its spirit or scope, which will be apparent to those skilled in the art. Other embodiments of the application will be apparent to those skilled in the art from consideration of the specification and practice of the application disclosed herein. The specification and examples given are exemplary only.

[0029] As used herein, the terms "comprise", "comprising", "include", "including", "have" and "having" and the like are open-ended and do not exclude additional, unrecited elements or method steps.

[0030] Depression belongs to the category of "mind disease" in Mongolian medicine. Mongolian medicine believes that stroke is caused by the blockage of blood vessels due to the excessive production of Baidagan mucus, leading to the difficulty of blood circulation. The main pathogenic factor of depression is the disorder of Heiyi. The excessive Heiyi interferes with the coordination of Coordi and Baidagan, leading to the imbalance of the three roots, functional disorder, hindering the transmission of white veins, and causing depression. The treatment principle of Mongolian medicine for depression is to regulate Heiyi, balance the three roots, and promote the transmission of white veins. Modern research shows that all oral drugs can be administered through the intestine. There are many traditional administration methods of Mongolian medicine, and the history of intestinal administration is long. This administration method is a characteristic administration method of injecting medicinal liquid with specific effects into the human body through the rectum to induce the disease to the outside. Therefore, the application of natural Mongolian medicine with relatively small toxic and side effects to treat post-stroke depression has unique characteristics and definite curative effect, and has the value of research and development and popularization and use.

[0031] The application develops a drug composition for treating post-stroke depression through the intestinal tract based on the principle of treating "mind disease" in Mongolian medicine. The raw materials of the drug composition include the following components in parts by weight: nutmeg 40-50 parts, broad hovenia 15-25 parts, saussurea 30-40 parts, inula 30-40 parts, and bittersweet 3-5 parts.

[0032] In the specific embodiments of the present application, the raw material of the pharmaceutical composition comprises the following components by weight: 50 parts of Myristicae Fructus, 25 parts of Choerospondiatis Fructus, 40 parts of Aucklandiae Radix, 40 parts of Inulae Radix and 5 parts of Zosterae Herba. Among them, Myristicae Fructus is warm in nature and has the effects of calming the heart, promoting blood circulation and benefiting the heart; Choerospondiatis Fructus is also warm in nature and has the effects of calming the heart and promoting blood circulation; Aucklandiae Radix has the effect of regulating the heart and blood; Inulae Radix is neutral in nature and has the effects of regulating the heart and blood and relieving pain; Zosterae Herba has the effects of expelling the phlegm, regulating the body fluid, and relieving pain.

[0033] The preparation method of the medicine is as follows: the medicine is weighed, crushed, sieved through a 100-250 mesh screen, soaked in distilled water, filtered, and the supernatant is taken and dropped through the anus.

[0034] The Mongolian medicine classic "Ganlu Sibu" contains various different administration routes, such as oral administration, buccal administration, sticking, dripping, smearing, external application, blowing medicine, immersion, enema, fumigation, wrapping and compression, and carrying. The Mongolian medicine takes the overall view as the main guiding ideology and believes that the life phenomenon of the human body is a comprehensive and complex activity process. The life activities among the three roots and seven elements, the five zang organs and six fu organs, the internal organs and organs, and the local and whole body are coordinated and influenced with each other, maintaining the dynamic balance of the internal environment of the human body. Based on this, the present application starts from the physiological and pathological characteristics of the large intestine, is guided by the theory of zang-fu organs and holism, and treats the "heart" disease through the intestinal administration, which is scientific, effective and unique.

[0035] In some specific embodiments of the present application, the mass-volume ratio of the medicine mixture and the warm water for soaking is 8g:200mL; optionally, the warm water is 38-40℃ warm water.

[0036] Optionally, the specific administration mode of the intestinal administration is as follows: the supernatant of the medicine composition is filled into an intestinal flushing bag, the patient's hips are raised by 10cm, the anus is fully exposed, the intestinal flushing bag catheter is gently inserted into the anus by 10-15cm, the medicine liquid is slowly dropped, the administration amount is 150-300mL / time / d, and the administration speed is 10-15min / time.

[0037] Preparation of the medicine composition of Example 1

[0038] The raw material of the medicine composition comprises the following components by weight: 50 parts of Myristicae Fructus, 25 parts of Choerospondiatis Fructus, 40 parts of Aucklandiae Radix, 40 parts of Inulae Radix and 5 parts of Zosterae Herba.

[0039] Myristicae Fructus 50g, Choerospondiatis Fructus 25g, Aucklandiae Radix 40g, Inulae Radix 40g and Zosterae Herba 5g are weighed according to the above weight parts.

[0040] The weighed raw materials are crushed and sieved through a gradient (100-250 mesh) to obtain the powder of the medicine composition.

[0041] Specific application of the pharmaceutical composition of Example 2 in the treatment of post-ischemic stroke depression

[0042] 1. General information of clinical patients

[0043] From October 2023 to December 2024, 84 patients who met the study criteria were collected in the Department of Encephalopathy of the International Mongolian Medicine Hospital of Inner Mongolia Autonomous Region. All patients were fully informed of the intestinal therapy order and treatment plan before the test, and the therapeutic effect and time arrangement of intestinal therapy were explained in detail, and the informed consent of the patients was obtained.

[0044] 1.1 Diagnostic criteria

[0045] 1.1.1 Diagnostic criteria for stroke

[0046] The diagnosis of stroke refers to the diagnostic criteria in the "Guidelines for the Diagnosis and Treatment of Ischemic Stroke in China (2014)"

[33] . The following characteristics can be diagnosed:

[0047] (1) Acute onset, symptoms often occur suddenly;

[0048] (2) Focal neurological deficits are the main ones, and occasionally there are global deficits;

[0049] (3) Imaging (CT / MRI) confirms the presence of a responsible lesion;

[0050] (4) Exclude intracranial tumors, vascular malformations, and similar conditions.

[0051] 1.1.2 Diagnostic criteria for depression

[0052] The diagnosis of depression refers to the International Classification of Diseases, 10th Edition (ICD-10)

[34] . The diagnostic criteria are as follows:

[0053] (1) Course criteria: lasting > 2 weeks and excluding organic diseases;

[0054] (2) Symptom criteria: typical symptoms (low mood, decreased interest, lack of energy) with at least 3 general symptoms (decreased attention, self-esteem or self-condemnation, suicidal ideation and behavior, insomnia, decreased appetite);

[0055] (3) Severity stratification: mild (typical + > 2 general symptoms), moderate (typical + > 3 general symptoms), severe (all typical symptoms + > 4 general symptoms).

[0056] 1.1.3 Mongolian medicine diagnostic criteria

[0057] The study refers to the "Mongolian medical diagnosis and treatment effect standard"

[35] and "Chinese medical encyclopedia-Mongolian medicine"

[15] diagnosis of Mongolian depression standard: combined with the pulse, tongue and other diagnosis of badagan, heyi caused by depression. With depression, suspicious, hypochondriac, due to stimulation of disease or symptoms, with irritability, loss of interest and appetite, and long-term anxiety, sadness and other emotions.

[0058] 1.2 inclusion criteria

[0059] 1.2.1 inclusion criteria

[0060] (1) age 18-90 years old;

[0061] (2) imaging diagnosis of ischemic stroke (CT / MRI confirmed), NIHSS score 5-15 points (moderate stroke);

[0062] (3) HAMD-17 score 17-24 points (moderate depression);

[0063] (4) post-stroke depression and no history of mental illness;

[0064] (5) agree and sign the informed consent form.

[0065] 1.2.2 exclusion criteria

[0066] (1) patients with transient ischemic attack, cerebral hemorrhage;

[0067] (2) allergic to the drugs in this study;

[0068] (3) stroke caused by craniocerebral trauma, space-occupying lesion, hematopathy and atrial fibrillation;

[0069] (4) unstable vital signs and accompanied by consciousness disorder;

[0070] (5) patients with severe focal neurological deficits who cannot complete the scale assessment;

[0071] (6) use of antidepressants, cognitive function improving drugs or other drugs that may interfere with efficacy evaluation within the past 3 months;

[0072] (7) patients with anorectal or digestive system diseases (such as ulcerative colitis) who cannot tolerate the intestinal therapy of Mongolian medicine.

[0073] 1.3 dropout criteria

[0074] (1) poor compliance, not taking the drug according to the prescribed method and course;

[0075] (2) loss of follow-up, unable to continue participating in the trial;

[0076] (3) Patients who develop serious adverse events during the study that make it inappropriate to continue participation;

[0077] (4) Patients who voluntarily withdraw for their own reasons during the study.

[0078] The 84 patients were randomly divided into three groups by random method, the drug composition prepared in Example 1 for enema treatment group, the drug composition prepared in Example 1 for oral control group 1, and the western medicine flupenthixol melitracen tablet for oral control group 2, each group has 28 cases.

[0079] All patients were fully informed of the enema medical order and treatment plan before the test, the therapeutic effect and time arrangement of enema were explained in detail, and the informed consent of the patients was obtained.

[0080] 2. Preparation of drug solution

[0081] The drug composition prepared in Example 1 was mixed with warm water (39℃±1℃) according to the ratio of 8g:200mL and soaked for 10 minutes, the supernatant was taken and filled into a disposable intestinal flushing bag for standby.

[0082] 3. Treatment method and detection

[0083] Under the premise of consistent basic treatment, the treatment group: applied the drug composition prepared in Example 1 for enema treatment. Take the supernatant of the drug composition prepared in Example 1. After the patient empties the large and small intestine, the patient is placed in a lateral position, the buttocks are elevated by 10cm, the disposable enema bag tube is smeared with paraffin oil, slowly inserted into the patient's anus, the depth is about 15-20cm, and the enema is dripped. After the enema is completed, the patient is asked to persist for about 30 minutes, and the patient is encouraged to prolong the drug retention time so as to fully absorb the drug solution. 1 time / day, for 2 weeks of treatment. Control group (1): oral administration of the drug composition powder prepared in Example 1. 3g after breakfast, 1 time / day, for 2 weeks of treatment. Control group (2): western medicine flupenthixol melitracen tablet, 1 tablet / 10mg after breakfast and lunch, patients over 60 years old, 1 tablet / 10mg after breakfast, for 2 weeks of treatment.

[0084] Before and after treatment, the stroke scale (NIHSS), the activities of daily living scale (ADL), the Hamilton depression scale (HAMD-17), the self-rating depression scale (SDS), and the side effect rating scale (SERS) were scored.

[0085] 4. Results

[0086] 4.1 Comparison of activities of daily living (ADL) scores of PSD patients in three groups

[0087] After a course of treatment, the ADL (activities of daily living scale) score results of PSD (post-stroke depression) patients in the three groups before and after treatment are shown in Table 1 and Fig. 1 .

[0088] Table 1 ADL scores of three groups of PSD patients

[0089]

[0090] Note: # represents P<0.01 for intragroup comparison.

[0091] From Fig. 1 and Table 1, the comparison of the ADL scores of the three groups of PSD patients before treatment showed no statistically significant difference (P>0.05). In terms of intragroup comparison: the ADL scores of the three groups of PSD patients after treatment were statistically significantly different from those before treatment (P<0.05). In terms of intergroup comparison: the ADL scores of the drug composition enema treatment group were compared with those of the drug composition oral control group 1 and the western medicine flupenthixol melitracen tablet control group 2 after treatment, and the differences were not statistically significant (P>0.05).

[0092] 4.2 Comparison of Hamilton Depression Scale (HAMD-17) scores of three groups of PSD patients

[0093] After a course of treatment, the HAMD-17 (Hamilton Depression Scale) scores of the three groups of PSD patients before and after treatment are shown in Table 2 and Fig. 2 .

[0094] Table 2 HAMD scores of three groups of PSD patients

[0095]

[0096] Note: # represents P<0.01 for intragroup comparison.

[0097] From Fig. 2 and Table 2, the comparison of the HAMD scores of the three groups of PSD patients before treatment showed no statistically significant difference (P>0.05). In terms of intragroup comparison: the HAMD scores of the three groups of PSD patients before treatment were statistically significantly different from those after treatment (P<0.01). In terms of intergroup comparison: the HAMD scores of the drug composition enema treatment group were compared with those of the drug composition oral control group 1 and the western medicine flupenthixol melitracen tablet control group 2 after treatment, and the differences were not statistically significant (P>0.05).

[0098] 4.3 Comparison of standard scores of Self-Rating Depression Scale (SDS) of three groups of PSD patients

[0099] After a course of treatment, the SDS (Self-Rating Depression Scale) scores of the three groups of PSD patients before and after treatment are shown in Table 3 and Fig. 3 .

[0100] Table 3 SDS scores of three groups of PSD patients

[0101]

[0102] Note: Intragroup comparison #P<0.01, intergroup comparison, treatment group vs. control group 1 *P<0.05.

[0103] From Fig. 3 As shown in Table 3, the SDS scores of the three groups of PSD patients before treatment showed no statistically significant difference (P>0.05). Intragroup comparison: the SDS scores of the three groups of PSD patients before and after treatment showed statistically significant difference (P<0.01). Inter-group comparison: the SDS scores of the drug composition enema treatment group and the drug composition oral control group 1 after treatment showed statistically significant difference (P<0.05). The SDS scores of the drug composition enema treatment group and the western medicine flupenthixol melitracen tablet control group 2 after treatment showed no statistically significant difference (P>0.05).

[0104] 4.4 Side reactions of three groups of PSD patients during treatment

[0105] After a course of treatment, the SERS (antidepressant side reaction scale) scores of the three groups of PSD patients before and after treatment are shown in Table 4.

[0106] Table 4 Side reactions of three groups of PSD patients

[0107]

[0108]

[0109] As shown in Table 4, during the drug research period, the side reactions of the three groups of PSD patients were evaluated by SERS scale. The results showed that the patients had side reactions such as physical fatigue, dizziness, dry mouth, and drowsiness, but the symptoms were mild, and there was no case of terminating treatment due to serious side reactions. The specific side reactions are as follows: 2 cases of physical fatigue and 1 case of drowsiness occurred in the drug composition enema treatment group, with a side reaction rate of 10.7%; 2 cases of dry mouth occurred in the drug composition oral control group, with mild symptoms, and the side reaction rate was 7.1%; 1 case of physical fatigue, 3 cases of dizziness, 2 cases of dry mouth, and 1 case of drowsiness occurred in the western medicine flupenthixol melitracen tablet control group, with a side reaction rate of 25%. Statistical analysis showed that the side reaction rates of the three groups of PSD patients showed no statistically significant difference (P>0.05).

[0110] In summary, the application develops a kind of drug composition for treating post-stroke depression based on the principle of treating "mind disease" in Mongolian medicine, which can significantly relieve the depressive symptoms of patients, improve the life ability, and has slight adverse reactions, safe and effective, which can provide a new method for clinical treatment of post-stroke depression.

[0111] The above-described embodiments are only to describe the preferred modes of the present application, and not to limit the scope of the present application, and various modifications and improvements to the technical solutions of the present application made by those skilled in the art without departing from the design spirit of the present application shall fall within the protection scope determined by the claims of the present application.

Claims

1. A pharmaceutical composition for treating post-stroke depression by enteral route, characterized in that, The raw materials of the medicine composition include the following components in parts by weight: Myristica fragrans 40-50 parts, Choerospondias axillaris 15-25 parts, Saussurea lappa 30-40 parts, Inula halleri 30-40 parts and Enhalus acoroides 3-5 parts.

2. The pharmaceutical composition of claim 1, wherein, The raw materials of the medicine composition include the following components in parts by weight: Myristica fragrans 50 parts, Choerospondias axillaris 25 parts, Saussurea lappa 40 parts, Inula halleri 40 parts and Enhalus acoroides 5 parts.

3. The pharmaceutical composition of claim 1, wherein, The preparation method of the medicine composition includes the following steps: weighing each raw material and crushing, and then sieving through a 100-250 mesh screen.

4. Use of the medicine composition of any one of claims 1-3 in the preparation of a medicine for treating post-stroke depression.

5. Use according to claim 4, characterized in that, The dosage form of the medicine includes oral dosage and enema.

6. Use according to claim 5, characterized in that, The dosage form of the medicine is enema.

7. Use according to claim 6, characterized in that, The powder of the medicine composition is soaked in distilled water, filtered, and the supernatant is used to prepare a medicinal liquid, which is used to prepare enema.

8. Use according to claim 6, characterized in that, The use method of the medicine includes the step of dripping the medicine into the intestinal tract in the form of enema.

9. Use according to claim 8, characterized in that, The administration amount of the medicine is 150-300 mL / time / d.

10. Use according to claim 8, characterized in that, The administration speed of the medicine is 10-15 min / time.

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