CN110368375B - Sustained release compositions for depression and related disorders and methods of preparation thereof - Google Patents

Sustained release compositions for depression and related disorders and methods of preparation thereof Download PDF

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CN110368375B
CN110368375B CN201910588200.6A CN201910588200A CN110368375B CN 110368375 B CN110368375 B CN 110368375B CN 201910588200 A CN201910588200 A CN 201910588200A CN 110368375 B CN110368375 B CN 110368375B
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解晶
齐兴四
毛涛
陈鹏伟
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Affiliated Hospital of University of Qingdao
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Abstract

The invention relates to a slow-release composition and a preparation method thereof, in particular to a slow-release composition for depression and related diseases and a preparation method thereof, wherein the composition comprises the following components in parts by weight: an active core layer including curcumin analogs, active probiotics, indole diketone derivatives and adhesive; a skeleton middle layer including skeleton material and plasticizer; a sustained release outer layer comprising a sustained release material and an anti-tack agent, wherein the indole dione derivative is 1,5, 6-tris (4-methoxyphenyl) indole dione. The sustained-release composition can slowly release the effective components of the active core layer in the gastrointestinal tract of mammals, has unexpected prevention and/or treatment effects on a plurality of symptoms caused by depression and related diseases, can be used for preparing pharmaceutical preparations for preventing and/or treating the diseases, composite sustained-release composition preparations and the like, and effectively enhances the physiological utilization rate.

Description

Sustained release compositions for depression and related disorders and methods of preparation thereof
Technical Field
The invention relates to a sustained-release composition and a preparation method thereof, in particular to a sustained-release composition for depression and related diseases and a preparation method thereof.
Background
With the development of society and economy, the rhythm is accelerated, the competition is fierce, and the incidence of various psychosomatic diseases in people of different ages is continuously increased under the influence of psychological factors, social factors, bad behaviors of human beings and life styles. A survey promulgated by the world health organization indicates that depression due to emotional stress is in the region of 2 to 4 million people worldwide each year, with 65% of U.S. professionals being mindful of negative emotions. Depression is a manifestation of negative emotional enhancement, with patients feeling depressed mood, heartthrobbing throughout the day, underestimation of self-intelligence ability, and overestimation of peripheral difficulty. The patients feel depressed mood, worry about palpitation throughout the day, the self intelligence ability is estimated too low, and the peripheral difficulty is estimated too high. The light patients are funny, have no choice but lack mental and physical strength and are unwilling to move, and are worried about full face, eyes are lacrimated, and the consciousness is life-like and bad, and are indeed inferior. Serious patients have a worry outbreak. That is, the patient cannot find a way out of the worries that are unbearable. Beginning to roll over uneasily, people will feel all desperate and will suddenly have suicidal ideation and behavior. Patients with this disease are often accompanied by slow thought, decreased speech and movement, and hypovolemia.
The data published by the World Health Organization (WHO) show that the incidence of depression is on an increasing trend year by year, and the number of depression patients is more than 3 hundred million worldwide, wherein 8900 million people exist in major depression patients. About 80 million suicide causes of depression worldwide each year, and suicide has become the second cause of death for people in the age group of 15-29 years. The health report of WHO in 2001 indicates that the proportion of depression in the global disease burden is the largest (11.9%), which is far more than that of chronic diseases such as diabetes and hypertension. It is expected that by 2020, the functional disability due to major depression will rise to position 2 of the general disease class, second only to ischemic heart disease. Taking the medicine is the main means for treating depression. The antidepressant drugs mainly comprise monoamine oxidase inhibitors (MAOI), Tricyclic (TCAs) antidepressant drugs and selective 5-hydroxytryptamine (5-HT) recovery inhibitors. With the development of the pharmaceutical industry, new drugs such as venlafaxine, nefazodone and the like come out endlessly, but at present, Tricyclic (TCAs) antidepressant drugs and selective 5-hydroxytryptamine (5-HT) recovery inhibitors are the most widely used in clinic. Although the current medicine is the most effective method for treating depressive disorder, the problems of low effective rate of the medicine, serious adverse reaction and the like still exist.
The above background disclosure is only for the purpose of assisting understanding of the inventive concept and technical solutions of the present invention, and does not necessarily belong to the prior art of the present patent application, and should not be used for evaluating the novelty and inventive step of the present application in the case that there is no clear evidence that the above content is disclosed at the filing date of the present patent application.
Disclosure of Invention
The invention aims to provide a sustained-release composition for depression and related diseases, which can slowly release active core layer effective components in gastrointestinal tracts of mammals, has unexpected prevention and/or treatment effects on a plurality of symptoms caused by depression and related diseases, can be used for preparing pharmaceutical preparations, composite sustained-release composition preparations and the like for preventing and/or treating the diseases, and effectively enhances the physiological utilization rate.
The invention also aims to provide a method for preparing the sustained-release composition for depression and related diseases, wherein microbial polysaccharides are selected as a framework material, and the retention time of the sustained-release composition in the gastrointestinal tract of a body is prolonged by utilizing the adhesion of a gel network, so that the active ingredients of an active core layer can be slowly released, and the prepared pellet is round, smooth, not easy to break, high in yield, and has more regular roundness and bulk density.
To achieve the above object, the present invention includes the following items [1] to [3 ].
[1] A sustained release composition for the prevention and/or treatment of depression and related disorders in a mammal, said composition comprising the following three-layer structure:
-an active core layer comprising curcumin analogues, active probiotic bacteria, indole dione derivatives and a binder;
-a skeleton middle layer comprising a skeleton material and a plasticizer;
-a slow release outer layer comprising a slow release material and an anti-adhesive agent.
In the summary and the preferred embodiment of the invention, the weight ratio of the curcumin analogue to the indole dione derivative is 0.1-10: 0.1-10; preferably, the weight ratio is 1 to 10:1, and more preferably 4 to 5: 1.
In the summary and preferred embodiment of the present invention, the active core layer of the present invention comprises at least one curcumin analogue selected from the following formulas (1) to (5) for preventing and/or treating depression and related disorders in mammals: 3,5- (E) -bis (3-hydroxy-4-methoxybenzylidene) piperidin-4-one hydrochloride (1); 3,5- (E) -bis (2, 5-dimethoxybenzylidene) piperidin-4-one hydrochloride (2); 3,5- (E) -bis (3, 4-bis-methoxybenzylidene) piperidin-4-one hydrochloride (3); 3,5- (E) -bis (2,4, 5-trimethoxybenzylidene) piperidin-4-one hydrochloride (4); 3,5- (E) -bis (3,4, 5-trimethoxybenzylidene) piperidin-4-one hydrochloride (5) of the formulae (1) to (5) below:
Figure BDA0002115205090000021
Figure BDA0002115205090000031
in summary and preferred embodiments of the present invention, the reactive core layer according to the present invention comprises a reactive probiotic selected from the group consisting of lactobacillus reuteri and bifidobacterium longum in combination for the prevention and/or treatment of depression and related disorders in mammals.
In summary and preferred embodiments of the present invention, the active probiotics include: lactobacillus reuteri CCFM8631 and Bifidobacterium longum CGMCC 16126. Of course, as the skilled person knows, the probiotic may be provided in pure form, or may be incorporated in a matrix which may advantageously protect the active probiotic during passage through the gastrointestinal tract (including the acidic conditions of the stomach) and enable the live probiotic to reach the intestine, the protective matrix may comprise a sugar (such as maltodextrin), a protein or a fatty component.
In the summary and preferred embodiment of the present invention, at least a part of the active probiotic bacteria of lactobacillus reuteri CCFM8631 is alive, and the active core layer may comprise 105～1011cfu Lactobacillus reuteri CCFM8631/g active core dry weight.
In the summary and preferred embodiment of the present invention, in the live probiotic bacteria, at least a part of the bifidobacterium longum CGMCC16126 is live, the live core layer may comprise 105～1011cfu Bifidobacterium longum CGMCC16126/g dry weight of active core layer.
In the summary and preferred embodiment of the present invention, the indole dione derivative of the present invention is 1,5, 6-tris (4-methoxyphenyl) indole dione. The applicant finds that the tri-substituted indole diketone has the biological activity which is not obviously improved compared with the parent nucleus indole diketone, but the 1,5 and 6 positions of the tri-substituted indole diketone have better prevention and/or treatment effects on depression, anxiety, sleep disorder, particularly depression, anxiety disorder and memory disorder related to depression after being substituted by 4-methoxyphenyl, so that a pharmaceutical preparation, a composite sustained-release composition preparation and the like for preventing and/or treating the disorders can be prepared according to the starting point, the physiological availability of the pharmaceutical preparation, the composite sustained-release composition preparation and the like are increased, and the drug effect is prolonged.
In the summary and preferred embodiment of the present invention, the binder in the active core layer is at least one selected from pregelatinized starch, pharmaceutical grade hypromellose, polyvinylpyrrolidone and hypromellose.
In the summary and preferred embodiment of the present invention, the amount of the binder added in the present invention is 1.0 to 8.0 wt% of the active core layer.
In the summary and the preferred embodiment of the present invention, the weight of the middle layer of the framework is increased by 5 to 10 wt%.
In the summary and preferred embodiment of the present invention, the framework material of the middle layer of the framework is at least one selected from monascus polysaccharide, pectin, flavobacterium gum, pullulan gum, alpha-glucan and cyclodextrin; preferably at least one of pectin and pullulan. The invention selects the microbial polysaccharides obtained by microbial fermentation as the framework material of the middle layer of the framework, not only has wide material sources and low price, but also has stable and edible property and no harm to organisms, and in addition, the invention can also form a hydrophilic gel framework for the framework of the active core layer, and utilizes the adhesiveness of a gel network to increase the residence time of the sustained-release composition in the gastrointestinal tract of the organisms, thereby slowly releasing the active ingredients of the active core layer, improving the bioavailability and prolonging the time limit for the efficacy exertion.
In the invention content and the preferred embodiment, the plasticizer of the middle layer of the framework is at least one selected from sodium benzoate, sodium salicylate, sodium citrate, sodium p-aminobenzoate, meglumine and glucose.
According to the invention and the preferable embodiment, the weight of the slow-release outer layer is increased by 5-30 wt%.
In the summary and preferred embodiment of the present invention, the sustained-release material in the sustained-release outer layer of the present invention is at least one selected from the group consisting of polylactic acid, polycarbonate, polyamide, polyurethane, polyimide, polyglycolic acid, and polylactic acid-polyglycolic acid copolymer; preferably at least one of polylactic acid, polycarbonate, polyglycolic acid and polylactic acid-polyglycolic acid copolymer.
In the summary and preferred embodiment of the present invention, the anti-sticking agent in the sustained-release outer layer is selected from at least one of magnesium stearate, aerosil, hydrogenated vegetable oil, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 4000 and polyethylene glycol 5000; preferably at least one of magnesium stearate, hydrogenated vegetable oil, polyethylene glycol 400 and polyethylene glycol 600.
In the sustained-release composition for preventing and/or treating mammalian depression and related diseases, the substituted 4-methoxyphenyl at the 1,5 and 6 positions of the indole dione derivative in the active core layer can show better preventing and/or treating effects on depression, anxiety, sleep disorder, particularly depression, anxiety disorder and memory disorder related to depression, particularly, the curcumin analogue helps to enhance the limiting effect of the indole dione derivative on the depression and related diseases, and the active core layer active composition which is combined with active probiotics selected from the combination of lactobacillus reuteri and bifidobacterium longum has unexpected preventing and/or treating effects on the following symptoms caused by the depression and related diseases: depression, anxiety, sleep disorders, sleep disturbances and broader but less noticeable persistent physiological symptoms such as mood depression, pessimism, joylessness, decreased interest, reaction retardation, memory impairment, cognitive dysfunction, spatial perception impairment, stiff wood, thought occlusion, disinterest, negative boredom, lack of strength, loss of appetite, weight loss, palpitation, chest distress, body irregularity, anger, enemy, anergy, vigilance, high vigilance, excessive anxiety, fatigue, decreased libido, impotence, premature ejaculation, amenorrhea and treatment unresponsive, and combinations thereof; in addition, the sustained-release composition for preventing and/or treating depression and related diseases of mammals can obtain good drug release behavior, more regular roundness, bulk density and yield, can effectively increase the physiological utilization degree and prolong the drug effect, and has the advantages of simple preparation method, lower cost and good application prospect.
[2] The process for preparing the sustained-release composition for preventing and/or treating depression and related disorders in mammals of item [1], comprising the steps of:
-forming the active core components into wet granules;
-subjecting the wet granulate to an extrusion spheronization treatment and drying to obtain an active core pellet, being an active core layer;
-preparing an auxiliary material comprising a framework material and a plasticizer into a hydrogel coating agent, putting the active core layer pill into a fluidized bed, spraying the hydrogel coating agent and drying to prepare a framework pill which is an active core layer and a framework middle layer;
-preparing an auxiliary material comprising a sustained-release material and an anti-sticking agent into a sustained-release coating solution, putting the matrix pellet into a fluidized bed, spraying the sustained-release coating solution and drying to prepare the sustained-release composition; optionally, the method further comprises the step of sieving the sustained-release composition, preferably sieving the sustained-release composition by a sieve of 15-30 meshes.
In the summary and preferred embodiments of the present invention, the method for preparing the sustained-release composition for preventing and/or treating depression and related disorders in mammals according to item [1] comprises at least one of the following items (1) to (9):
(1) the curcumin analogue is selected from at least one of 3,5- (E) -bis (3-hydroxy-4-methoxybenzylidene) piperidin-4-one hydrochloride, 3,5- (E) -bis (2, 5-dimethoxybenzylidene) piperidin-4-one hydrochloride, 3,5- (E) -bis (3, 4-di-methoxybenzylidene) piperidin-4-one hydrochloride, 3,5- (E) -bis (2,4, 5-trimethoxybenzylidene) piperidin-4-one hydrochloride, 3,5- (E) -bis (3,4, 5-trimethoxybenzylidene) piperidin-4-one hydrochloride;
(2) the active probiotic bacteria are at least partially live and are present in an amount of 105～1011Bifidobacterium longum CGMCC16126 and 10 in cfu/g dry weight of active core layer5～1011Bifidobacterium longum CGMCC16126 of cfu/g of dry weight of the active core layer;
(3) the indole dione derivative is 1,5, 6-tri (4-methoxyphenyl) indole dione;
(4) the weight ratio of the curcumin analogue to the indole dione derivative is 0.1-10: 0.1-10;
(5) the adhesive is selected from at least one of pregelatinized starch, medicinal grade hypromellose, polyvinylpyrrolidone and hypromellose;
(6) the framework material is selected from at least one of monascus polysaccharide, pectin, flavobacterium gum, pullulan gum, alpha-glucan and cyclodextrin;
(7) the plasticizer is selected from at least one of sodium benzoate, sodium salicylate, sodium citrate, sodium p-aminobenzoate, meglumine and glucose;
(8) the slow release material is selected from at least one of polylactic acid, polycarbonate, polyamide, polyurethane, polyimide, polyglycolic acid and polylactic acid-polyglycolic acid copolymer;
(9) the antisticking agent is selected from at least one of magnesium stearate, superfine silica gel powder, hydrogenated vegetable oil, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 4000 and polyethylene glycol 5000.
In the summary and the preferred embodiment of the invention, the extrusion and spheronization treatment conditions are that the extrusion rotating speed is 20-150 r/min and the spheronization rotating speed is 200-500 r/min.
In the invention content and the preferred embodiment of the invention, the active core layer pill can pass through a sieve with 30-50 meshes.
In the summary and the preferred embodiment of the invention, the weight ratio of the curcumin analogue to the indole dione derivative is 0.1-10: 0.1-10.
In the summary and preferred embodiment of the present invention, the weight increase of the middle layer of the framework is 5 to 10 wt%.
According to the invention and the preferred embodiment, the weight of the slow-release outer layer is increased by 5-30 wt%.
In the summary and preferred embodiment of the present invention, the fluidized bed fluidized coating conditions comprise at least one of the following items (1) to (4):
(1) controlling the temperature of the system to be 25-35 ℃;
(2) controlling the frequency of the fan to be 20-40 Hz;
(3) controlling the atomization pressure of the hydrogel coating agent and the slow-release coating liquid to be 0.3-0.5 MPa;
(4) the spraying speed is controlled to be 10-40 r/min.
The curcumin analogue in the sustained-release composition for preventing and/or treating depression and related diseases of mammals helps to enhance the limiting effect of the indole dione derivative on the depression and related diseases, and an active core layer active composition which is combined with active probiotics selected from the combination of lactobacillus reuteri and bifidobacterium longum has unexpected prevention and/or treatment effects on the following symptoms caused by the depression and related diseases: depression, anxiety, sleep disorders, sleep disturbances and broader but less noticeable persistent physiological symptoms such as mood depression, pessimism, joylessness, decreased interest, reaction retardation, memory impairment, cognitive dysfunction, spatial perception impairment, stiff wood, thought occlusion, disinterest, negative boredom, lack of strength, loss of appetite, weight loss, palpitation, chest distress, body irregularity, anger, enemy, anergy, vigilance, high vigilance, excessive anxiety, fatigue, decreased libido, impotence, premature ejaculation, amenorrhea and treatment unresponsive, and combinations thereof; the prepared pellet is round, smooth, not easy to break, high in yield, and has regular roundness and bulk density, and the composition has good drug release behavior, can effectively increase the physiological utilization rate of the sustained-release composition and prolong the drug effect, and has the advantages of simple preparation method, low cost and good application prospect.
[3] Use of the sustained-release composition according to item [1] and/or item [2] for the preparation of a pharmaceutical preparation for the prevention and/or treatment of depression and/or related disorders.
The invention has the beneficial effects that:
1) the 1,5, 6-tri (4-methoxyphenyl) indole diketone has better prevention and/or treatment effects on depression, anxiety, sleep disorder and sleep disorder, particularly on depression, anxiety disorder and memory disorder related to depression, and can be used for preparing pharmaceutical preparations, composite sustained-release composition preparations and the like for preventing and/or treating the symptoms, thereby increasing the physiological utilization rate and prolonging the drug effect;
2) microbial polysaccharides obtained by microbial fermentation are selected as framework materials of the middle layer of the framework, so that the materials are widely available, the price is low, the properties are stable and edible, and the framework is harmless to organisms, in addition, the framework of the active core layer can also form a hydrophilic gel framework, and the residence time of the sustained-release composition in the gastrointestinal tract of the organisms is prolonged by utilizing the adhesion of a gel network, so that the active ingredients of the active core layer can be slowly released, the bioavailability of the sustained-release composition is improved, and the drug effect exertion time limit of the sustained-release composition is prolonged;
3) the curcumin analogue in the invention is helpful for enhancing the limiting effect of the 1,5, 6-tri (4-methoxyphenyl) indole diketone on the depression and related symptoms, and the active core layer active composition which is combined with the active probiotics selected from the combination of lactobacillus reuteri and bifidobacterium longum has unexpected prevention and/or treatment effect on a plurality of symptoms caused by the depression and the related symptoms;
4) the prepared pellet is round, smooth, not easy to break, high in yield, and has regular roundness and bulk density, and the composition has good drug release behavior, can effectively increase the physiological utilization rate of the sustained-release composition and prolong the drug effect, and has the advantages of simple preparation method, low cost and good application prospect.
The invention adopts the technical scheme to provide the model essay, makes up the defects of the prior art, and has reasonable design and convenient operation.
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In order to make the aforementioned and other objects, features, and advantages of the invention, as well as others which will become apparent, reference is made to the following description taken in conjunction with the accompanying drawings in which:
FIG. 1 is a schematic diagram of the dissolution rate of the sustained release composition for preventing and/or treating depression and related disorders in a mammal in artificial gastric juice;
FIG. 2 is a schematic diagram of the dissolution rate of the sustained release composition for preventing and/or treating depression and related disorders in an artificial intestinal fluid;
FIG. 3 is a schematic illustration of the antidepressant effect of the sustained release composition for preventing and/or treating depression and related disorders in mammals on a rat model.
Detailed Description
Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The present invention uses the methods and materials described herein; other suitable methods and materials known in the art may be used. The materials, methods, and examples described herein are illustrative only and are not intended to be limiting. All publications, patent applications, patents, provisional applications, database entries, and other references mentioned herein, and the like, are incorporated by reference herein in their entirety. In case of conflict, the present specification, including definitions, will control.
Other features and advantages of the invention will be apparent from the following detailed description, the accompanying drawings, and the claims.
For the words "for example" and "such as" and grammatical equivalents thereof, the phrase "without limitation" should be understood to follow general usage unless explicitly stated otherwise. As used herein, the word "about" refers to variations due to experimental error. Unless expressly stated otherwise, all measurements described herein, whether or not explicitly used, are to be understood as being modified by the word "about". As used herein, the singular forms "a," "an," and "the" ("a," "an," and "the") include plural referents unless the context clearly dictates otherwise.
In one embodiment of the present invention, a method for preparing 1,5, 6-tris (4-methoxyphenyl) indole dione is provided, which comprises the following steps:
1) dissolving 1.0g of 6-bromoindole dione and 1g of N-bromosuccinimide in 3ml DMF, reacting at room temperature for 24h, pouring the mixture into ice water after TLC detection reaction is completed to generate a red solid, filtering, collecting precipitate, and recrystallizing the precipitate with methanol to obtain 5, 6-dibromoindole dione;
2)0.5g5, 6-dibromoindole-dione, 0.3g 4-methoxyphenylboronic acid, 0.06g PdCl2、0.3gCH3Dissolving COOK in 5mL of 1, 4-dioxane, reacting at 135 deg.C under the protection of argon gas with microwave for 30min, detecting by TLC, and reactingPouring the mixture into 50mL of water, extracting the reaction solution for 3 times by using dichloromethane, combining organic phases, washing the organic phases by using saturated NaCl, drying the organic phases by using anhydrous sodium sulfate, and performing rotary evaporation to obtain a solid product, namely 5, 6-bis (4-methoxyphenyl) indole dione;
3)0.1g of 5, 6-bis (4-methoxyphenyl) indole dione, 0.15g of anhydrous potassium carbonate and 0.05g of 4-methoxybenzyl chloride are dissolved in 2mLDMF at room temperature, the reaction is carried out for 12h, after the TLC detection reaction is completed, the mixture is poured into ice water, the reaction liquid is extracted for 3 times by dichloromethane, organic phases are combined, the organic phases are dried by anhydrous sodium sulfate, rotary evaporation is carried out, a crude product is eluted by an eluent which is a mixture of petroleum ether and ethyl acetate with the ratio of V10: 1-1: 1, and the mixture is purified by silica gel column chromatography with 200-300 meshes to obtain the solid compound 1,5, 6-tris (4-methoxyphenyl) indole dione.
Example 1: the prescription of the sustained-release composition comprises 1:
the present embodiments provide a sustained release composition for preventing and/or treating depression and related disorders in a mammal, the composition comprising the following three-layer structure:
-an active core layer comprising curcumin analogues, active probiotic bacteria, indole dione derivatives and a binder;
-a skeleton middle layer comprising a skeleton material and a plasticizer;
-a slow release outer layer comprising a slow release material and an anti-adhesive agent.
In the preferred embodiment, the weight ratio of the curcumin analogue to the indole dione derivative is 5: 1.
In the preferred embodiment, the curcumin analogue of the active core layer is 3,5- (E) -bis (3-hydroxy-4-methoxybenzylidene) piperidin-4-one hydrochloride.
In a preferred embodiment, the reactive core layer according to the present invention comprises reactive probiotics selected from the group consisting of lactobacillus reuteri and bifidobacterium longum in combination for the prevention and/or treatment of depression and related disorders in mammals.
In a preferred embodiment of the present invention, the active probiotics comprise: lactobacillus reuteri CCFM8631 and Bifidobacterium longum CGMCC 16126.
In the preferred embodimentIn the active probiotic bacteria, at least a part of Lactobacillus reuteri CCFM8631 is alive, and the content of Lactobacillus reuteri CCFM8631 is 1010cfu/g active core dry weight.
In the preferred embodiment, the active probiotic bacteria comprise Bifidobacterium longum CGMCC16126, wherein at least a part of the Bifidobacterium longum CGMCC16126 is alive, and the content of the Bifidobacterium longum CGMCC16126 is 1010cfu/g active core dry weight.
In the preferred embodiment, the indole dione derivative is 1,5, 6-tris (4-methoxyphenyl) indole dione. The applicant finds that the tri-substituted indole diketone has the biological activity which is not obviously improved compared with the parent nucleus indole diketone, but the 1,5 and 6 positions of the tri-substituted indole diketone have better prevention and/or treatment effects on depression, anxiety, sleep disorder, particularly depression, anxiety disorder and memory disorder related to depression after being substituted by 4-methoxyphenyl, so that a pharmaceutical preparation, a composite sustained-release composition preparation and the like for preventing and/or treating the disorders can be prepared according to the starting point, the physiological availability of the pharmaceutical preparation, the composite sustained-release composition preparation and the like are increased, and the drug effect is prolonged.
In the preferred embodiment, the binder in the active core layer of the present invention is hypromellose, and the addition amount of the binder in the active core layer is 5 wt%.
In the preferred embodiment, the weight increase of the middle layer of the skeleton is 10 wt%.
In the preferred embodiment, the skeleton material of the middle layer of the skeleton is pullulan glue. The invention selects the microbial polysaccharides obtained by microbial fermentation as the framework material of the middle layer of the framework, not only has wide material sources and low price, but also has stable and edible property and no harm to organisms, and in addition, the invention can also form a hydrophilic gel framework for the framework of the active core layer, and utilizes the adhesiveness of a gel network to increase the residence time of the sustained-release composition in the gastrointestinal tract of the organisms, thereby slowly releasing the active ingredients of the active core layer, improving the bioavailability and prolonging the time limit for the efficacy exertion.
In the preferred embodiment, the plasticizer of the middle layer of the framework of the present invention is sodium benzoate.
In the preferred embodiment, the weight gain of the sustained-release outer layer is 5 wt%.
In the preferred embodiment, the sustained-release material in the sustained-release outer layer is polylactic acid.
In the preferred embodiment, the anti-adherent in the outer sustained release layer of the present invention is magnesium stearate.
In the sustained-release composition for preventing and/or treating mammalian depression and related diseases, the substituted 4-methoxyphenyl at the 1,5 and 6 positions of the indole dione derivative in the active core layer can show better preventing and/or treating effects on depression, anxiety, sleep disorder, particularly depression, anxiety disorder and memory disorder related to depression, particularly, the curcumin analogue helps to enhance the limiting effect of the indole dione derivative on the depression and related diseases, and the active core layer active composition which is combined with active probiotics selected from the combination of lactobacillus reuteri and bifidobacterium longum has unexpected preventing and/or treating effects on the following symptoms caused by the depression and related diseases: depression, anxiety, sleep disorders, sleep disturbances and broader but less noticeable persistent physiological symptoms such as mood depression, pessimism, joylessness, decreased interest, reaction retardation, memory impairment, cognitive dysfunction, spatial perception impairment, stiff wood, thought occlusion, disinterest, negative boredom, lack of strength, loss of appetite, weight loss, palpitation, chest distress, body irregularity, anger, enemy, anergy, vigilance, high vigilance, excessive anxiety, fatigue, decreased libido, impotence, premature ejaculation, amenorrhea and treatment unresponsive, and combinations thereof; in addition, the sustained-release composition for preventing and/or treating depression and related diseases of mammals can obtain good drug release behavior, more regular roundness, bulk density and yield, can effectively increase the physiological utilization degree and prolong the drug effect, and has the advantages of simple preparation method, lower cost and good application prospect.
The present invention also provides a method for preparing the sustained release composition for preventing and/or treating depression and related disorders in mammals, comprising the following steps:
-forming the active core components into wet granules;
-subjecting the wet granulate to an extrusion spheronization treatment and drying to obtain an active core pellet, being an active core layer;
-preparing an auxiliary material comprising a framework material and a plasticizer into a hydrogel coating agent, putting the active core layer pill into a fluidized bed, spraying the hydrogel coating agent and drying to prepare a framework pill which is an active core layer and a framework middle layer;
-preparing an auxiliary material comprising a sustained-release material and an anti-sticking agent into a sustained-release coating solution, putting the matrix pellet into a fluidized bed, spraying the sustained-release coating solution and drying to prepare the sustained-release composition.
In the preferred embodiment, the extrusion spheronization treatment conditions are that the extrusion rotation speed is 100r/min and the spheronization rotation speed is 300 r/min.
In the preferred embodiment, the active core pellets can be screened through a 50 mesh screen.
In the preferred embodiment, the weight ratio of the curcumin analogue to the indole dione derivative is 5: 1.
In the preferred embodiment, the weight increase of the middle layer of the skeleton is 10 wt%.
In the preferred embodiment, the weight gain of the slow release outer layer is 5 wt%.
In the preferred embodiment, the conditions for fluidized coating in the fluidized bed include the following items (1) to (4):
(1) controlling the temperature of the system to be 30 ℃;
(2) controlling the frequency of the fan to be 30 Hz;
(3) controlling the atomization pressure of the hydrogel coating agent and the slow-release coating liquid to be 0.3 MPa;
(4) the spraying speed is controlled to be 20 r/min.
The curcumin analogue in the sustained-release composition for preventing and/or treating depression and related diseases of mammals helps to enhance the limiting effect of the indole dione derivative on the depression and related diseases, and an active core layer active composition which is combined with active probiotics selected from the combination of lactobacillus reuteri and bifidobacterium longum has unexpected prevention and/or treatment effects on the following symptoms caused by the depression and related diseases: depression, anxiety, sleep disorders, sleep disturbances and broader but less noticeable persistent physiological symptoms such as mood depression, pessimism, joylessness, decreased interest, reaction retardation, memory impairment, cognitive dysfunction, spatial perception impairment, stiff wood, thought occlusion, disinterest, negative boredom, lack of strength, loss of appetite, weight loss, palpitation, chest distress, body irregularity, anger, enemy, anergy, vigilance, high vigilance, excessive anxiety, fatigue, decreased libido, impotence, premature ejaculation, amenorrhea and treatment unresponsive, and combinations thereof; the prepared pellet is round, smooth, not easy to break, high in yield, and has regular roundness and bulk density, and the composition has good drug release behavior, can effectively increase the physiological utilization rate of the sustained-release composition and prolong the drug effect, and has the advantages of simple preparation method, low cost and good application prospect.
The embodiment also provides the application of the sustained-release composition in preparing a pharmaceutical preparation for preventing and/or treating depression and/or related diseases.
Example 2: the sustained-release composition formula consists of 2:
(1) an active core layer:
Figure BDA0002115205090000121
(2) framework middle layer:
Figure BDA0002115205090000122
(3) a slow release outer layer:
Figure BDA0002115205090000123
the preparation process comprises the following steps:
1) preparing the components of the active core layer into wet granules;
2) the wet granules are treated by sending out and rolling and dried to prepare active core layer pills which are active core layers;
3) preparing auxiliary materials comprising a framework material and a plasticizer into a hydrogel coating agent, putting the active core layer pill into a fluidized bed, spraying the hydrogel coating agent and drying to prepare a framework pill which is an active core layer and a framework middle layer;
4) preparing an auxiliary material containing a slow-release material and an anti-sticking agent into a slow-release coating solution, putting the skeleton pill into a fluidized bed, spraying the slow-release coating solution and drying to prepare the slow-release composition; also comprises sieving the sustained-release composition with a 30-mesh sieve.
The fluidized bed fluidized coating conditions include the following items (1) to (4):
(1) controlling the temperature of the system to be 25 ℃;
(2) controlling the frequency of the fan to be 40 Hz;
(3) controlling the atomization pressure of the hydrogel coating agent and the slow-release coating liquid to be 0.5 MPa;
(4) the spraying speed is controlled to be 40 r/min.
Example 3: the prescription of the sustained-release composition comprises 3:
(1) an active core layer:
Figure BDA0002115205090000131
(2) framework middle layer:
Figure BDA0002115205090000132
(3) a slow release outer layer:
Figure BDA0002115205090000133
the preparation process comprises the following steps:
1) preparing the components of the active core layer into wet granules;
2) the wet granules are treated by sending out and rolling and dried to prepare active core layer pills which are active core layers;
3) preparing auxiliary materials comprising a framework material and a plasticizer into a hydrogel coating agent, putting the active core layer pill into a fluidized bed, spraying the hydrogel coating agent and drying to prepare a framework pill which is an active core layer and a framework middle layer;
4) preparing sustained-release coating liquid from auxiliary materials containing sustained-release materials and an anti-sticking agent, putting the skeleton pill into a fluidized bed, spraying the sustained-release coating liquid, and drying to obtain the sustained-release composition.
The fluidized bed fluidized coating conditions include the following items (1) to (4):
(1) controlling the temperature of the system to be 35 ℃;
(2) controlling the frequency of the fan to be 40 Hz;
(3) controlling the atomization pressure of the hydrogel coating agent and the slow-release coating liquid to be 0.3 MPa;
(4) the spraying speed is controlled to be 20 r/min.
Example 4: the slow release composition formula consists of 4:
(1) an active core layer:
Figure BDA0002115205090000141
(2) framework middle layer:
Figure BDA0002115205090000142
(3) a slow release outer layer:
Figure BDA0002115205090000143
Figure BDA0002115205090000151
the preparation process comprises the following steps:
1) preparing the components of the active core layer into wet granules;
2) the wet granules are treated by sending out and rolling and dried to prepare active core layer pills which are active core layers;
3) preparing auxiliary materials comprising a framework material and a plasticizer into a hydrogel coating agent, putting the active core layer pill into a fluidized bed, spraying the hydrogel coating agent and drying to prepare a framework pill which is an active core layer and a framework middle layer;
4) preparing an auxiliary material containing a slow-release material and an anti-sticking agent into a slow-release coating solution, putting the skeleton pill into a fluidized bed, spraying the slow-release coating solution and drying to prepare the slow-release composition; also comprises a step of sieving the sustained-release composition, wherein the sieve mesh number is 20 meshes.
The fluidized bed fluidized coating conditions include the following items (1) to (4):
(1) controlling the temperature of the system to be 32 ℃;
(2) controlling the frequency of the fan to be 35 Hz;
(3) controlling the atomization pressure of the hydrogel coating agent and the slow-release coating liquid to be 0.4 MPa;
(4) the spraying speed is controlled to be 30 r/min.
Example 5: the slow release composition formula comprises 5:
(1) an active core layer:
Figure BDA0002115205090000152
(2) framework middle layer:
Figure BDA0002115205090000153
Figure BDA0002115205090000161
(3) a slow release outer layer:
Figure BDA0002115205090000162
the preparation process comprises the following steps:
1) preparing the components of the active core layer into wet granules;
2) the wet granules are treated by sending out and rolling and dried to prepare active core layer pills which are active core layers;
3) preparing auxiliary materials comprising a framework material and a plasticizer into a hydrogel coating agent, putting the active core layer pill into a fluidized bed, spraying the hydrogel coating agent and drying to prepare a framework pill which is an active core layer and a framework middle layer;
4) preparing an auxiliary material containing a slow-release material and an anti-sticking agent into a slow-release coating solution, putting the skeleton pill into a fluidized bed, spraying the slow-release coating solution and drying to prepare the slow-release composition; also comprises the step of sieving the sustained-release composition by a 30-mesh sieve.
The fluidized bed fluidized coating conditions include the following items (1) to (4):
(1) controlling the temperature of the system to be 30 ℃;
(2) controlling the frequency of the fan to be 30 Hz;
(3) controlling the atomization pressure of the hydrogel coating agent and the slow-release coating liquid to be 0.45 MPa;
(4) the spraying speed is controlled to be 40 r/min.
Example 6:
example 6 is essentially the same as example 1 except that the weight ratio of curcumin analog to the indole dione derivative in example 6 is 500: 1.
Example 7:
example 7 is essentially the same as example 1 except that the weight ratio of curcumin analog to the indole dione derivative in example 7 is 100: 1.
Example 8:
example 8 is essentially the same as example 1 except that the weight ratio of curcumin analog to the indole dione derivative in example 8 is 1: 1.
Example 9:
example 9 is essentially the same as example 1 except that the weight ratio of curcumin analog to the indole dione derivative in example 9 is 1: 100.
Example 10:
example 10 is essentially the same as example 1 except that the weight ratio of curcumin analog to the indole dione derivative in example 10 is 1: 500.
Comparative example 11:
comparative example 11 is essentially the same as example 6 except that the weight ratio of curcumin analog to the indole dione derivative in comparative example 11 is 500:0, i.e., no indole dione derivative is added to the active core layer of comparative example 11.
Comparative example 12:
comparative example 12 is substantially the same as example 10 except that the weight ratio of curcumin analog to the indole dione derivative in comparative example 12 is 0:500, i.e., no curcumin analog is added to the active core layer of comparative example 12.
Comparative example 13:
comparative example 13 is essentially the same as example 1, except that the active probiotic of comparative example 13 is 1010cfu/g active core dry weight of Lactobacillus reuteri CCFM 8631.
Comparative example 14:
comparative example 14 is essentially the same as example 1, except that the active probiotic of comparative example 14 is 1010cfu/g active core layer dry weight of Bifidobacterium longum CGMCC 16126.
Comparative example 15:
comparative example 15 is essentially the same as example 1 except that no binder is added to the active core layer of comparative example 15, i.e., the weight ratio of 3,5- (E) -bis (3-hydroxy-4-methoxybenzylidene) piperidin-4-one hydrochloride to 1,5, 6-tris (4-methoxyphenyl) indole dione added is 5:1, accounting for 100 wt% of the active core layer weight.
Comparative example 16:
comparative example 16 is substantially the same as example 1 except that no backbone material is added to the middle layer of the backbone of comparative example 16, i.e., the middle layer of the backbone, which has been increased by 10 wt%, is entirely sodium benzoate.
Comparative example 17:
comparative example 17 is substantially the same as example 1 except that no plasticizer is added to the middle layer of the skeleton of comparative example 17, i.e., the skeleton middle layer, which has been increased by 10 wt%, is entirely pullulan.
Comparative example 18:
comparative example 18 is substantially the same as example 1 except that the sustained-release outer layer of comparative example 18 is not added with the sustained-release material, i.e., the sustained-release outer layer whose weight is 5 wt% is entirely magnesium stearate.
Comparative example 19:
comparative example 19 is substantially the same as example 1 except that the sustained-release outer layer of comparative example 19 is not added with an anti-sticking agent, i.e., the sustained-release outer layer whose weight is 5 wt% is entirely polylactic acid.
Experimental example 1: determination of physical Properties of sustained Release compositions:
the physical properties of the sustained-release compositions of examples 1 to 10 and comparative examples 11 to 19 of the present invention were examined by measuring the physical properties of the three aspects of roundness, bulk density and yield. The three physical parameters mentioned above were tested by the following methods (which indicate normal practice if specific conditions are not indicated):
roundness: placing 1g of the pellets on a flat plate, lifting one side of the flat plate, and measuring an angle (phi) between an inclined plane and the horizontal plane before the pellets start to roll;
bulk density: taking a proper amount of pellets, slowly passing through a glass funnel, pouring into a measuring cylinder, measuring the volume of the pellets, and calculating the bulk density of the pellets;
yield: collecting the 15-30 mesh pellets, weighing, dividing by the theoretical pellet amount, and calculating the yield.
The statistical results are shown in table 1. As can be seen from Table 1, the pellets in the preferred embodiment of the present invention have high roundness, bulk density and yield, and good physical regularity, which is beneficial to increase of physiological utilization.
TABLE 1 pellet roundness, bulk Density and yield
Figure BDA0002115205090000181
Figure BDA0002115205090000191
Experimental example 2: determination of the influence of the binder and its concentration on roundness, bulk density and yield:
according to the formula 2 of the sustained-release composition, the influence of the type and concentration of the adhesive on the physical parameters of the pellet is examined by using pure water and 0.01 wt%, 0.1 wt%, 1.0 wt% and 10 wt% of pregelatinized starch as the adhesive respectively. The results show that the moldability is poor by using water as a binder, and the material viscosity is poor, so that more fine powder is generated; when the content of the adhesive is 1.0-8.0 wt%, the obtained pellets have high regularity, smoothness, difficult breakage and high yield; higher binder content resulted in material agglomeration and poor classification. Therefore, the content of the binder is selected to be 1.0-8.0 wt%.
Experimental example 3: determination of the influence of the weight gain of the middle layer of the framework on the roundness, the bulk density and the yield:
according to the formula 2 of the slow release composition, the influence of different weight gains of the middle layer of the skeleton on the physical parameters of the pellet is respectively examined by the proportion of 0.05 wt% of monascus polysaccharide, 0.05 wt% of sodium benzoate, 0.5 wt% of monascus polysaccharide, 0.5 wt% of sodium benzoate, 1.5 wt% of monascus polysaccharide, 1.5 wt% of sodium benzoate, 6.0 wt% of monascus polysaccharide, 6.0 wt% of sodium benzoate, 7.5 wt% of monascus polysaccharide and 7.5 wt% of sodium benzoate. The result shows that the weight gain is less than 5 wt%, the weight gain is easy to be broken, the fine powder is more, and the yield is low; while a weight gain of more than 10 wt% wastes material and coating time. Therefore, the weight increase of the middle layer of the framework is selected to be 5.0-10.0 wt%.
Experimental example 4: dissolution rate determination of the sustained-release composition in artificial gastric juice and artificial intestinal juice:
preparing artificial gastric juice: taking 16.4mL of dilute hydrochloric acid, adding about 800mL of water and 10g of pepsin, stirring uniformly, adding water and fixing the volume to 1000 mL.
Preparing artificial intestinal juice: potassium dihydrogen phosphate (6.8 g) was taken and 500mL of water was added. Adjusting the pH to 6.8 with 0.4% sodium hydroxide solution; dissolving pancreatin 10g in water, mixing the two solutions, and adding water to 1000 mL.
Setting the rotation speed of a stirring paddle of a dissolution instrument to be 100r/min, setting the water bath temperature to be 37 +/-1.0 ℃, selecting an artificial gastric juice or an artificial intestinal juice as a dissolution medium, sampling 5mL of a sustained-release composition sample after the sustained-release composition sample is put in 1, 2, 3 and 4 hours respectively, filtering with a 0.3-micrometer microfiltration membrane, simultaneously supplementing the dissolution medium with the same temperature, measuring 1,5, 6-tri (4-methoxyphenyl) indole dione by HPLC (high performance liquid chromatography), calculating the dissolution rate of 1, 2, 3 and 4 hours, and respectively setting the statistical results as shown in figure 1 (artificial gastric juice) and figure 2 (artificial intestinal juice).
As can be seen from the graphs in fig. 1 and 2, the sustained-release composition provided by the present application is slowly and incompletely dissolved in the artificial gastric juice, but can be slowly released in the artificial intestinal juice and the dissolution degree thereof is relatively complete, and particularly, the sustained-release composition in preferred example 1 of the present application has a relatively excellent dissolution profile in the artificial intestinal juice, so that the active ingredient in the active core layer is slowly released, the bioavailability thereof is improved, and the time period for the efficacy thereof to be exerted is prolonged.
Experimental example 5: animal model experiment of sustained release composition antidepression:
the animal model of "new environment feeding inhibition" is widely used in antidepressant research, so the experimental study of the sustained-release composition antidepressant is carried out by using the animal model in the experimental example, which is specifically as follows.
Selecting 180-200 g female rats for experimental study, firstly injecting chloral hydrate into 400mg/kg physiological saline in an intraperitoneal mode for general anesthesia, and cutting ovaries to eliminate the periodic influence of the variation of the estrogen level on the animal behaviors; after two weeks of recovery, animals were divided into 1 control group (group C) and 19 treatment groups (P1-P10 for examples 1-10, respectively, and P11-P19 for comparative examples 11-19), and 5 animals in each group were repeated and fasted for 24 hours.
Preparing a mixed solution containing 1% ethanol, 1% DMSO, 15% Solutol and 83% normal saline, and directly gavaging a 1.0mL/Kg rat by a control group with the mixed solution; the sustained-release compositions in examples 1-10 and comparative examples 11-19 were diluted 100 times with the above mixed solution, and the rats of 1.0mL/Kg were gavaged with the sustained-release composition diluent according to the treatment groups. The "new environment feeding inhibition" animal model was tested 2h after administration.
The "fresh environment feeding inhibition" experiment was started by placing the experimental animals in the corners of a dark cage of 75cm x 50cm at 09: 00-16: 00 in a semi-dark room. Three standard rat bars were placed in the well illuminated center of the cage, except that there were no objects or markers in the cage. Rats were allowed to scout the cages for at most 6min and started eating food placed in the center of the cage, and the time from the start of the experiment to the start of eating was measured and recorded. After each experiment, the bottom and four walls of the cage were thoroughly washed with 70% ethanol and the food was replaced with fresh food.
The mean and standard deviation of the mean were calculated for each group from the start of the experiment to the start of feeding and the statistical data are shown in figure 3. As can be seen from the graph of fig. 3, the time for feeding to start in the ovariectomized rats placed in a new environment and ingested with the sustained release composition of the preferred embodiment of the present invention is shorter than that in the control animals treated with only the mixed solution, and in the treated rats, the shorter time means that behavior corresponding to depression (i.e., feeding inhibition) is reduced, so that it can be clearly demonstrated that the sustained release composition of the preferred embodiment of the present invention has an antidepressant effect; in particular, the sustained-release composition incorporating a curcumin analog has a more excellent and significant antidepressant effect corresponding to the case where it contains only an indole dione derivative.
Conventional techniques in the above embodiments are known to those skilled in the art, and therefore, will not be described in detail herein.
The above embodiments are merely illustrative, and not restrictive, and those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, all equivalent technical solutions also belong to the scope of the present invention, and the protection scope of the present invention should be defined by the claims.

Claims (7)

1. A sustained-release composition for preventing and/or treating depression in a mammal, characterized in that said composition comprises the following three-layer structure:
-an active core layer comprising curcumin analogues, active probiotic bacteria, indole dione derivatives and a binder;
-a skeleton middle layer comprising a skeleton material and a plasticizer;
-a slow release outer layer comprising a slow release material and an anti-adhesive agent;
the curcumin analogue is selected from at least one of the following:
3,5- (E) -bis (3-hydroxy-4-methoxybenzylidene) piperidin-4-one hydrochloride;
3,5- (E) -bis (2, 5-dimethoxybenzylidene) piperidin-4-one hydrochloride;
3,5- (E) -bis (3, 4-bis-methoxybenzylidene) piperidin-4-one hydrochloride;
3,5- (E) -bis (2,4, 5-trimethoxybenzylidene) piperidin-4-one hydrochloride;
3,5- (E) -bis (3,4, 5-trimethoxybenzylidene) piperidin-4-one hydrochloride;
the active probiotic bacteria are selected from the group consisting of lactobacillus reuteri and bifidobacterium longum;
the indole dione derivative is 1,5, 6-tri (4-methoxyphenyl) indole dione;
the framework material is selected from at least one of monascus polysaccharide, pectin, flavobacterium gum, pullulan gum, alpha-glucan and cyclodextrin;
the plasticizer is selected from at least one of sodium benzoate, sodium salicylate, sodium citrate, sodium p-aminobenzoate, meglumine and glucose;
the slow release material is selected from at least one of polylactic acid, polycarbonate, polyamide, polyurethane, polyimide, polyglycolic acid and polylactic acid-polyglycolic acid copolymer;
the antisticking agent is selected from at least one of magnesium stearate, superfine silica gel powder, hydrogenated vegetable oil, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 4000 and polyethylene glycol 5000.
2. The composition of claim 1, wherein:
the weight of the middle layer of the framework is increased by 5-10 wt%;
the weight gain of the slow release outer layer is 5-30 wt%.
3. A process for preparing the sustained-release composition for preventing and/or treating depression in a mammal according to claim 1, characterized by comprising the steps of:
-forming the active core components into wet granules;
-subjecting the wet granulate to an extrusion spheronization treatment and drying to obtain an active core pellet, being an active core layer;
-preparing an auxiliary material comprising a framework material and a plasticizer into a hydrogel coating agent, putting the active core layer pill into a fluidized bed, spraying the hydrogel coating agent and drying to prepare a framework pill which is an active core layer and a framework middle layer;
-preparing an auxiliary material comprising a sustained-release material and an anti-sticking agent into a sustained-release coating solution, putting the matrix pellet into a fluidized bed, spraying the sustained-release coating solution and drying to prepare the sustained-release composition.
4. The method of claim 3, wherein: the method also comprises the step of sieving the slow release composition by 15-30 meshes.
5. The method according to claim 3, characterized by comprising at least one of the following (1) to (9):
(1) the curcumin analogue is selected from at least one of 3,5- (E) -bis (3-hydroxy-4-methoxybenzylidene) piperidin-4-one hydrochloride, 3,5- (E) -bis (2, 5-dimethoxybenzylidene) piperidin-4-one hydrochloride, 3,5- (E) -bis (3, 4-di-methoxybenzylidene) piperidin-4-one hydrochloride, 3,5- (E) -bis (2,4, 5-trimethoxybenzylidene) piperidin-4-one hydrochloride, 3,5- (E) -bis (3,4, 5-trimethoxybenzylidene) piperidin-4-one hydrochloride;
(2) the active probiotic bacteria are at least partially live and are present in an amount of 105～1011Bifidobacterium longum CGMCC16126 and 10 in cfu/g dry weight of active core layer5～1011Long double of cfu/g active core dry weightBifidobacterium strain CGMCC 16126;
(3) the indole dione derivative is 1,5, 6-tri (4-methoxyphenyl) indole dione;
(4) the weight ratio of the curcumin analogue to the indole dione derivative is 0.1-10: 0.1-10;
(5) the adhesive is selected from at least one of pregelatinized starch, medicinal grade hypromellose, polyvinylpyrrolidone and hypromellose;
(6) the framework material is selected from at least one of monascus polysaccharide, pectin, flavobacterium gum, pullulan gum, alpha-glucan and cyclodextrin;
(7) the plasticizer is selected from at least one of sodium benzoate, sodium salicylate, sodium citrate, sodium p-aminobenzoate, meglumine and glucose;
(8) the slow release material is selected from at least one of polylactic acid, polycarbonate, polyamide, polyurethane, polyimide, polyglycolic acid and polylactic acid-polyglycolic acid copolymer;
(9) the antisticking agent is selected from at least one of magnesium stearate, superfine silica gel powder, hydrogenated vegetable oil, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 4000 and polyethylene glycol 5000.
6. The method according to any one of claims 3 to 5, wherein: the fluidized bed fluidized coating conditions comprise at least one of the following items (1) to (4):
(1) controlling the temperature of the system to be 25-35 ℃;
(2) controlling the frequency of the fan to be 20-40 Hz;
(3) controlling the atomization pressure of the hydrogel coating agent and the slow-release coating liquid to be 0.3-0.5 MPa;
(4) the spraying speed is controlled to be 10-40 r/min.
7. Use of a sustained release composition according to claim 1 or 2 or obtained by a method according to any one of claims 3 to 6 for the preparation of a pharmaceutical formulation for the prevention and/or treatment of depression.
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