阅读说明：本技术 肝素、或其衍生物、或其可药用盐的新用途 (New use of heparin, or derivative or pharmaceutically acceptable salt thereof ) 是由 张贵民 徐燕 彭涛 于 2020-08-28 设计创作，主要内容包括：本发明属于医药领域,具体涉及肝素、或其衍生物、或其可药用盐在制备预防或治疗精神疾病药物中的用途,所述精神疾病优选为抑郁症、躁狂症、学习记忆能力障碍、失眠症中的一种或两种以上组合的疾病,进一步优选为双相情感障碍。本发明肝素、或其衍生物、或其可药用盐通过常规制备方法制备成组合物,和/或加入情绪稳定剂制备成药物组合物,制备得到的产品解决了双相情感障碍病情复杂、治疗困难及易反复发作的技术难题。肝素不仅对双相情感障碍的抑郁发作和躁狂发作具有显著的双向调节的作用,而且具有毒副作用小、防止反复发作的优点,具有很好的开发为双相情感障碍防治药物的前景。(The invention belongs to the field of medicines, and particularly relates to application of heparin or derivatives thereof or pharmaceutically acceptable salts thereof in preparing a medicine for preventing or treating mental diseases, wherein the mental diseases are preferably combined diseases of one or more than two of depression, mania, learning and memory disorders and insomnia, and are further preferably bipolar affective disorders. The heparin, the derivative thereof or the medicinal salt thereof is prepared into a composition by a conventional preparation method, and/or is added with an emotion stabilizer to prepare a medicinal composition, and the prepared product solves the technical problems of complex conditions, difficult treatment and easy repeated attack of the bipolar affective disorder. The heparin not only has remarkable two-way regulation effect on depressive episode and manic episode of bipolar affective disorder, but also has the advantages of low toxic and side effects and repeated episode prevention, and has good prospect of being developed into a medicament for preventing and treating bipolar affective disorder.)

1. Use of heparin, or a derivative thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of a psychotic disorder.

2. Use according to claim 1, wherein the psychiatric disorder is an affective disorder, preferably a disorder of one or a combination of two or more of depression, mania, learning and memory disorders, insomnia.

3. Use according to claim 2, wherein the affective disorder is bipolar affective disorder.

4. Use according to any of claims 1 to 3, wherein heparin is administered in a dose of 0.02mg/kg to 200mg/kg, preferably 0.2mg/kg to 20 mg/kg.

5. Use of the heparin or the derivative thereof or the pharmaceutically acceptable salt thereof according to claim 1 and pharmaceutically acceptable auxiliary materials in preparing a medicament for preventing or treating mental diseases.

6. Use according to claim 5, wherein the psychiatric disorder is an affective disorder, preferably a disorder of one or a combination of two or more of depression, mania, learning and memory disorders, insomnia, further preferably bipolar disorder.

7. Use according to claim 5 or 6, wherein the medicament is an oral formulation, preferably a tablet, granule, capsule.

8. A pharmaceutical composition, wherein the medicament comprises any one of heparin, derivatives thereof, or pharmaceutically acceptable salts thereof and a mood stabilizer.

9. The pharmaceutical composition of claim 8, wherein the mood stabilizer is any one or a combination of more than two of lamotrigine, valproate, gabapentin, topiramate, oxcarbazepine, carbamazepine, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone, lithium or osanetant.

10. The pharmaceutical composition according to claim 8 or 9, wherein the pharmaceutical composition is for use in the manufacture of a medicament for the prevention or treatment of a psychiatric disorder, preferably a disorder selected from the group consisting of depression, mania, learning and memory disorders, insomnia, and combinations thereof, and further preferably bipolar disorder.

Technical Field

The invention belongs to the field of medicines, and relates to a new medical application of heparin or derivatives thereof or pharmaceutically acceptable salts thereof, in particular to an application in preparing medicines for preventing or treating mental diseases.

Background

Bipolar disorder is one of the common clinical mental disorders, has the characteristics of complex disease condition, long course of disease, difficult treatment, easy repeated attack and high disability rate, and is usually accompanied by symptoms of depression attack and manic attack which are alternately appeared. Especially, the normal life of the patient is seriously influenced by the learning and memory disorder, insomnia and other symptoms, and further, the physical and mental health of the patient is greatly influenced. With the increasing pressure on people's life and work in recent years, the rate of bipolar affective disorder depressive episodes presents a trend of increasing year by year. In order to improve the depression symptoms of patients in time and stabilize the emotional and psychological states of the patients, the patients need to be provided with drug therapy with less adverse reactions, high safety and good curative effect, so that the physical and psychological states of the patients are effectively improved, and the survival and life quality of the patients are improved.

In the medical field, psychological care intervention is often employed in conjunction with drug care to help patients reduce or even eliminate their symptoms of both mania and depression. From the pharmacological point of view, patients who are in need of mental disorders have great dialectics in terms of medication. For manic patients, usually tranquilizers and for depressed patients, antidepressants are used for treatment, and the mutual resistance of the two medicines is not negligible. In addition, there is a misdiagnosis phenomenon in which bipolar affective disorder is diagnosed as unipolar depression when the condition is diagnosed. Therefore, it is not easy to treat bipolar disorder patients from the diagnosis of the disease. Therefore, the search for an effective drug which has significant efficacy on bipolar disorder and can reduce the recurrence rate thereof becomes the first task of pharmaceutical workers.

Heparin is a class of glycosaminoglycans consisting of a mixture of polysaccharide chains of repeating disaccharide units linked by 1 → 4 bonds, uronic acid and glucosamine. Contains 10-30 disaccharide units, has a molecular weight of 4000-20000 and an average molecular weight of 12000. 2-O-sulfuric acid-alpha-L iduronic acid and 6-O-sulfuric acid-N-sulfuric acid-alpha-D glucosamine are the main monosaccharides thereof, and the repeating units of trisulfuric acid disaccharide composed of them constitute the so-called "regular region" of heparin, which is the main part of the heparin structure, and other monosaccharide residues such as alpha-L-iduronic acid, 6-O-sulfuric acid-N-acetyl-alpha-D glucosamine, beta-D glucuronic acid and 3-6-bis-O-sulfuric acid-N-sulfuric acid-alpha-D glucosamine appear at a very low frequency in the "non-regular region". The presence of a certain number of 6-position unsulfurized glycosamines and 2-O-sulfuric acid- α -D glucuronic acid makes 10 different monosaccharides (4 uronic acids and 6 glycosamines) present in heparin, thus making the entire structure of heparin exceptionally complex, and the precise structure of heparin has not been known so far. Corresponding to the complex structure is its complex biological function, since heparin was clinically used as an anticoagulant in 1937, heparin has been a major anticoagulant drug, and besides anticoagulant activity and its associated antithrombotic activity, heparin has recently been found to have biological functions of inhibiting smooth muscle cell proliferation, anti-inflammation, anti-tumor, and anti-virus. However, no application of heparin in bipolar affective disorder has been found so far.

Disclosure of Invention

One of the main objects of the present invention is to provide a new use of heparin, or a derivative thereof, or a pharmaceutically acceptable salt thereof, particularly a use in the preparation of a medicament for preventing or treating a psychiatric disease.

The derivatives of heparin comprise sulfation products and desulfation products of the derivatives in different degrees, and the pharmaceutically acceptable salts of the heparin comprise calcium salts, sodium salts, potassium salts, magnesium salts, iron salts and the like, preferably calcium salts and sodium salts.

Preferably, the psychiatric disorder is an affective disorder psychiatric disorder. More preferably one or a combination of two or more of depression, mania, learning and memory disorders, and insomnia, and still more preferably bipolar disorder. .

The invention provides the dosage of heparin, which is specifically 0.02mg/kg-200mg/kg, preferably 0.2mg/kg-20 mg/kg.

The above object of the present invention is achieved by the following technical solutions:

specific example 1 research results on the improvement effect of heparin on the depressive behavior of rats in depression models show that heparin can significantly improve the depressive state of patients with bipolar disorder and can significantly improve the learning and memory abilities of patients with bipolar disorder.

Specific example 2 results of a study on the improvement effect of heparin on the depressive behavior of a manic model rat show that heparin can significantly improve the manic state of a patient with bipolar disorder and can significantly improve the insomnia state of a patient with bipolar disorder.

The results of clinical trials show that: when used for treating patients with bipolar disorder, heparin not only has remarkable curative effect and small toxic and side effect, but also has the advantage of preventing relapse compared with other treatment medicaments.

The invention also aims to provide the application of the composition prepared from heparin or derivatives thereof or pharmaceutically acceptable salts thereof and pharmaceutically acceptable auxiliary materials in preparing the medicines for preventing or treating mental diseases. The mental disease is an affective disorder mental disease, preferably one or more combined diseases of depression, mania, learning and memory ability disorder and insomnia, and more preferably bipolar affective disorder.

Furthermore, the composition can be prepared into oral preparations, preferably, the pharmaceutical dosage forms are tablets, granules and capsules.

The above tablets, granules and capsules are prepared by conventional preparation processes.

The invention also aims to provide a pharmaceutical composition, wherein the pharmaceutical composition comprises any one of heparin, derivatives thereof or pharmaceutically acceptable salts thereof and a mood stabilizer.

Preferably, the mood stabilizer can be any one or a combination of more than two of lamotrigine, valproate, gabapentin, topiramate, oxcarbazepine, carbamazepine, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone, lithium or osanetant.

The application of the pharmaceutical composition in preparing the medicament for preventing or treating the mental diseases is preferably one or more combined diseases of depression, mania, learning and memory disorders and insomnia, and is further preferably bipolar disorder.

Compared with the prior art, the advantages of the heparin in the prevention and treatment of the bipolar affective disorder are as follows:

(1) the curative effect is remarkable, and the toxic and side effects are small;

(2) heparin has the advantage of effectively preventing the recurrence of bipolar disorder compared to other therapeutic drugs.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The present invention is further illustrated below by specific examples in order to provide those skilled in the art with a full understanding of the present invention, but it should be understood by those skilled in the art that the examples of the present invention are not to be construed as limiting the present invention in any way.

During the study we found: heparin derivatives and pharmaceutically acceptable salts of heparin can achieve technical effects similar to those of heparin, but the examples are not limited to the heparin derivatives and the pharmaceutically acceptable salts of heparin.

EXAMPLE 1 preparation of heparin tablets

Mixing heparin, microcrystalline cellulose and sodium carboxymethyl starch uniformly, adding appropriate amount of starch slurry to make soft mass, granulating, drying, grading, adding magnesium stearate, mixing, and tabletting.

Example 2 preparation of heparin granules

And (3) adding microcrystalline cellulose and sucrose into heparin, uniformly mixing, granulating, drying, grading and subpackaging to obtain the heparin.

EXAMPLE 3 preparation of heparin capsules

Mixing heparin and croscarmellose sodium, granulating, drying to obtain granule, grading, adding magnesium stearate, mixing, making into capsule, and packaging.

EXAMPLE 4 preparation of heparin pellets

Adding appropriate amount of starch into heparin, and making into pill.

Example 5 preparation of heparin syrups

Heating heparin, sucrose and water to boil, dissolving, filtering, concentrating to obtain syrup, boiling, and cooling to obtain syrup.

Example 1 improvement of Depression behavior of rat model for Depression by heparin

1. Test method

The method comprises the step of randomly dividing 30 healthy male SD rats with SPF (specific pathogen free) class weight of 200-220 g into a normal control group, a model group and an experimental group, wherein each group comprises 10 rats. The model group and the experimental group of rats establish a depression rat model by combining isolated culture with chronic mild unpredictable stimulation according to a reference method, and the control group is normally raised. During the modeling period, the experimental group was gavaged with 125mg/kg of heparin, which was the heparin tablet prepared in example 1, and the control group and the model group were gavaged with 0.9% NaCl equivalent for 4 weeks. The model group rats were associated with typical water intake, decreased exploratory behavior, weight loss, decreased interest, dull hair color and other depressive symptoms.

2. Detecting the index

(1) Open field test

After the administration, the open field test is carried out according to the method of reference literature, the number of the horizontal movement lattices and the vertical erection times of the rat within 4min are observed and recorded, the sum of the horizontal and vertical scores is calculated to be the number of the autonomous activities, and the immobility time is recorded.

(2) Method for testing and detecting learning and memory functions of rat by Morris water maze

After intervention, each group of rats was subjected to localized voyage experiments and space exploration experiments using Morris water maze test system according to the reference methods (ApoE4 age-dependent increase in susceptibility to stress-induced depressive-like behavior and decline in learning and memory).

3. Test results

(1) Effect of heparin on Depression rat behavior

The number of the autonomous activities of the rats in the model group is reduced compared with that of the rats in the normal control group (P is less than 0.01), while the number of the autonomous activities of the rats in the experimental group is increased compared with that of the rats in the model group (P is less than 0.01); compared with the control group, the model group has longer standing time (P is less than 0.01), and the experimental group has shorter standing time (P is less than 0.05), which shows that the heparin can obviously improve the depression state of the depression model rats. Specific results are shown in table 1.

TABLE 1 Effect of heparin on Depression behavior in Depression rats

Group of	Number of autonomous actions (n)	Dead time(s)
			Normal control group	48.08±12.34	19.49±8.76
Model set	19.64±3.89##	38.73±7.46##
			Experimental group	39.99±9.57&&	29.77±6.23&

Compared with the normal control group, the composition has the advantages that,^##P<0.01; in comparison to the set of models,^&P<0.05，^&&P<0.01。

(2) influence of heparin on learning and memory ability of depression rats

Model group rat Morris water maze positioning navigation experiment 1, 2, 3, 4d latency period is prolonged compared with normal control group (P < 0.05); the experimental group is shortened (P is less than 0.05) compared with the model group; compared with a control group, the number of times of crossing the Morris water maze space exploration experiment in the model group is reduced (P is less than 0.01), and compared with the model group, the number of times of crossing the experiment in the experiment group is increased (P is less than 0.05), which shows that the heparin can remarkably improve the learning and memory ability of the rat in the depression model. The specific results are shown in Table 2.

TABLE 2 Effect of heparin on learning and memory ability of depressed rats

Compared with the normal control group, the composition has the advantages that,^#P<0.05，^##P<0.01; in comparison to the set of models,^&P<0.05。

EXAMPLE 2 improvement of depressive behavior of rat model of mania by heparin

1. Molding method

The method comprises the following steps of dividing 60 healthy male SD rats with SPF (specific pathogen free) class weight of 200-220 g into a normal control group, a model group and an experimental group according to a random digital table method, wherein each group comprises 20 rats. The model group and the experimental group adopt a modified multi-platform sleep deprivation method (MMPM) method to establish a mania model (refer to a method for changing the expression of neuronal nitric oxide synthase after sleep deprivation and influencing the influence of refreshment). Rats can eat and drink water on the platform by themselves, and the water in the rat box is changed every day. Rats were acclimated on the platform for 1h each day, i.e. week I before the experiment. After the experiment started, rats were all on the platform except the water tank for water change, for a total of 7 days. The normal control group adopts a mouse box with the same size as the model group, but a platform is not placed at the bottom of the mouse box, a fine wire mesh is placed on the bottom of the mouse box, the rat is placed on the mesh, water is placed under the mesh until the distance from the mesh is 1cm, so that the rat can obtain normal sleep, and other conditions are the same.

2. Intervention method

The blank control group and the model group are not subjected to intervention treatment, and heparin is administered to the treatment group according to the amount of 125mg/kg for intervention treatment. The heparin used was the heparin tablet prepared in example 1.

3. Detecting the index

(1) Rat autonomic behavior determination

Using the Open-Field method (OIT), 1 rat was placed in an Open box grid each time, 3min each time. The horizontal score is the number of squares crossed horizontally by the rat, 3 or 4 claws of the rat are specified to enter the same grid and is marked as 1 score; the vertical score was measured by supporting the body with 2 hind paws, leaving the floor with 2 forepaws, 1 score for each 1-off, and 1 time before the start of the experiment and 1 time after the end of the experiment.

(2) Sleep latency determination

The rats are deprived of the sleep for 7d in the quick eye movement, the time from the beginning of the lower platform of the rats to the 1 st sleep of the rats (namely the sleep latency period) after the experiment is finished is recorded, and the mania molding success is realized if the time is more than 30 min. The rat falls asleep is defined behaviorally as the rat closes eyes and remains still in bed for 30s or more.

4. Statistical method

The analysis was performed using SPSS20.0 statistical software. The data are expressed as means ± standard deviation, single-factor analysis of variance (ANOVA) is used for multiple comparisons, and q-test is used for pairwise comparison. P <0.05 is statistically significant for the differences.

5. Results

(1) Comparison of general behavior of rats in each group

Model group: after the sleep is deprived for 2d, the sleep shows excitation, and the sleep plays a messy role in different platforms, is sensitive to external slight acousto-optic stimulation and shows a frightened state to the acousto-optic stimulation; after 3 days of sleep deprivation, the patient is dull, slight twitching of the muscles of the head and the face is accompanied by movement of the beard, the patient squats on a platform, falls into water repeatedly due to the beat of tons, climbs the platform after waking up, activities and food intake are reduced, and after stimulation, the patient has aggressive behaviors such as indiscriminate biting and the like. Sleep deprived 5-7d rats were mentally impatient, had little feeding activity, had generalized hair sticking, were extremely irritable, had increased aggressive biting behavior, and resulted in death of 6 rats during biting.

Blank control group: no manic manifestations of the model group.

Experimental groups: compared with a model group, the manic expression is obviously relieved, no animal is killed due to the bite action, and the result shows that the heparin can obviously improve the irritability and aggressive manic state of a manic rat.

(2) Rat autonomic behavior test results

Compared with the normal control group, the horizontal activity score and the vertical activity score of the rats in the model group are remarkably reduced (P <0.01), and the model building is suggested to cause the reduction of the horizontal activity and the vertical activity of the rats. Compared with the model group, the activity score of the heparin group level is obviously higher than that of the model group (P <0.01), which indicates that the heparin can obviously improve the depression state of the manic rats. The specific results are shown in Table 3.

TABLE 3 Effect of heparin on depressive behaviour in manic rats

Group of	n	Horizontal activity score	Vertical activity score
				Normal control group	20	68.44±13.44	13.84±5.41
Model set	14	30.00±10.56##	6.05±5.37##
				Experimental group	20	55.67±9.56&&	7.34±4.59

Compared with the normal control group, the composition has the advantages that,^##P<0.01; in comparison to the set of models,^&&P<0.01。

(3) comparison of sleep latency after experiment in rats of each group

Compared with a normal control group, the sleep latency of the rats in the model group is remarkably prolonged, the difference has statistical significance (P is less than 0.01), and the model building is prompted to cause the sleep latency of the rats to be prolonged; compared with the model group, the sleep latency of the heparin group is obviously shortened, the difference has statistical significance (P <0.01), and the heparin is suggested to obviously improve the insomnia state of the manic rats. The specific results are shown in Table 4.

TABLE 4 Effect of heparin on sleep latency in manic rats

Group of	n	Sleep latency (min)
			Normal control group	20	12.22±3.78
Model set	16	39.07±10.34##
			Experimental group	20	18.98±8.79&&

Compared with the normal control group, the composition has the advantages that,^##P<0.01; in comparison to the set of models,^&&P<0.01。

clinical examples

1.1 general data

60 cases of bipolar affective disorder manic episode patients who were treated and treated in 2015 for 1-12 months were selected and studied, and divided into two groups on average according to the time of admission, and the two groups were set as a control group and an observation group. The 60 patients who were enrolled met the clinical symptoms and diagnostic criteria for manic episodes of bipolar disorder in CCMD-3, excluding patients with other systemic severe disease, patients in pregnancy or lactation, and patients allergic to therapeutic agents. The general patient data are shown in Table 5.

TABLE 5 general patient data

Grouping	Number of examples	Male sex	Female with a view to preventing the formation of wrinkles	Mean age
					Control group	30	19	11	38.35±9.78
Observation group	30	18	12	36.18±7.77

Note: general data comparison of patients, P > 0.05.

1.2 methods

Control group: the quetiapine fumarate tablets are taken orally in a combined mode, the first dose is 100 mg/day, the treatment course is gradually increased to 400-600 mg/day, and the maximum dose is not more than 800 mg/day; the first dose of the oral valproic acid sodium tablet is 200-400 mg/day, and the dose is gradually increased to 600-1200 mg/day along with the course of treatment. The treatment course is 8 weeks for two groups of patients.

Observation group: heparin, purchased on the market, was administered once daily at a dose of 2 mg/kg.

1.3 determination of therapeutic efficacy

The mental symptoms of 2 groups of patients are evaluated before and after treatment by using a BRMS scoring scale, and the curative effect is judged to be obvious: the BRMS score is reduced by 75 percent before and after treatment, and clinical symptoms disappear or are obviously improved; the method has the following advantages: the BRMS score is reduced by 50-75 percent before and after treatment, and the clinical symptoms are improved; and (4) invalidation: the BRMS score is reduced by less than 50 percent before and after treatment, and the clinical symptoms are not improved basically. Total efficiency was 1-inefficiency.

1.4 evaluation of toxicity and side effects:

1.4.1 toxicity evaluation

Before taking medicine and after taking medicine for 8 weeks, each physical examination is carried out, and the physical examination items are as follows:

(1) general physical examination items: body temperature, pulse, respiration;

(2) routine examination of blood, urine and stool, and treatment before and after treatment;

(3) liver function AST, ALT; renal function BUN, CR and blood glucose; cardiac function CPK, LDH, EKG; blood coagulation function and platelets.

1.4.2 evaluation of side effects

Adverse reactions (dizziness, somnolence, nausea and vomiting) were counted for two groups of patients.

1.5 relapse Rate statistics after drug withdrawal

1.6 statistical methods

The data were all statistically analyzed by SPSS20.0, and the counting data are expressed in (%) and the difference P <0.05 is statistically significant.

2 results

2.1 patient efficacy and comparison

The results show that the overall effective rate of the patients in the observation group is obviously higher than that of the patients in the control group, the difference between the groups is obvious, and the statistical significance is achieved. The specific results are shown in Table 6.

TABLE 6 patient efficacy and comparison [ n (%) ]

Grouping	Number of examples	Show effect	Is effective	Invalidation	Total effective rate
						Control group	30	12(40.0％)	10(33.3％)	8(26.7％)	14(73.3％)
Observation group	30	17(56.7％)	11(36.7％)	2(6.7％)	18(93.4％)﹩

Note: compared with the control group, the compound of the formula,^﹩P<0.05。

2.2 evaluation of toxic side effects of patients

2.2.1 comparison of toxicity responses in two groups of patients

According to the analysis of the physical examination results, 30 patients in the observation group have no abnormal symptoms, and all indexes are in a normal range; the control group showed various degrees of toxic reactions, the most serious of which was liver function impairment.

2.2.2 comparison of side effects in two groups of patients

The incidence rate of adverse reactions of patients in the control group is 10% (dizziness 1 case, lethargy 1 case, nausea and vomiting 1 case and 3 cases in total), wherein irregular menstruation also appears in 10 female patients in the control group; the patients in the observation group have no adverse reactions such as dizziness, somnolence, nausea and vomiting, and the incidence rate is 0% (comparison among the groups, P is less than 0.05).

The above results fully indicate that: compared with the existing medicine for treating bipolar affective disorder, the heparin has the advantage of small toxic and side effects.

2.3 drug withdrawal relapse Rate comparison

After the 8-week treatment course is finished, the medicine taking state is continuously kept for half a year so as to stabilize the state of the illness. Follow-up visit is carried out after the medicine is stopped for 1 year, 11 people in the control group relapse, and the relapse rate is 50.0 percent; relapse was observed in group 1 with a relapse rate of 3.6%.

The above results show that: when used for treating bipolar affective disorder, the heparin not only has obvious curative effect and small toxic and side effect, but also has the advantage of preventing relapse compared with other treatment medicines.