CN114917213B

CN114917213B - Mental disorder therapeutic agent comprising amitriptyline and method for treating mental disorder

Info

Publication number: CN114917213B
Application number: CN202210783755.8A
Authority: CN
Inventors: 白钟; 张玉霞; 朱姣; 刘轶; 贺云彪
Original assignee: Hunan Dongting Pharmaceutical Co Ltd
Current assignee: Hunan Dongting Pharmaceutical Co Ltd
Priority date: 2022-07-05
Filing date: 2022-07-05
Publication date: 2023-11-21
Anticipated expiration: 2042-07-05
Also published as: CN114917213A

Abstract

The present invention relates to a psychotic disorder therapeutic agent comprising amitriptyline and a method of treating a psychotic disorder. In one aspect, the invention relates to a pharmaceutical composition comprising: 25 parts of amitriptyline hydrochloride and 0-200 parts of solid pharmaceutical excipients, wherein the pharmaceutical composition is a solid preparation, especially a tablet preparation. The solid pharmaceutical excipients comprise one or more selected from the following: diluents, disintegrants, binders, glidants, lubricants. Also relates to the use of the pharmaceutical composition for the treatment of psychotic disorders. The composition of the present invention exhibits excellent effects as described in the present invention, and particularly, exhibits excellent biological effects for the treatment of mental diseases such as the treatment of various kinds of depression, particularly anxiety or agitation depression.

Description

Mental disorder therapeutic agent comprising amitriptyline and method for treating mental disorder

Technical Field

The invention belongs to the technical field of medicines, relates to a method for treating mental diseases, and also relates to a composition for treating the mental diseases. In particular, the mental diseases are various depression. In particular, the active drug used in the method of treating mental disorders of the present invention is amitriptyline or a pharmaceutically acceptable salt thereof. Because of its potent sedative effect, amitriptyline, an active drug, may be particularly useful in the treatment of anxiety or agitation depression. The composition according to the present invention exhibits excellent effects as described in the present invention, and thus is believed to exert excellent biological effects when used for the treatment of mental diseases such as the treatment of various kinds of depression, particularly anxiety or agitation depression.

Background

Currently, depression (depression) is one of the most common psychological disorders, with continuous and long-term mood depression as the major clinical feature, the most important type of modern physiological disorder, and 3.22 million people worldwide are believed to have varying degrees of depression.

The etiology of depression is not clear to date, but it is believed that many factors in biological, psychological and social environments are involved in the pathogenesis of depression. Biological factors mainly relate to genetic, neurobiochemical, neuroendocrine, neuroregeneration and other aspects; the psychological predisposition closely related to depression is a pre-illness trait such as depressed qi. The adult stage encounters stressful life events, an important trigger condition that leads to the occurrence of clinically significant depressive episodes. However, these factors do not work alone, emphasizing the interaction between genetic and environmental or stress factors, and the point at which such interactions occur, has a significant impact in the occurrence of depression.

Depression may be manifested as a single or repeated episodes of depression, the clinical manifestations of depression being mainly: mood depression is mainly manifested by marked and durable affective depression and pessimistic depression; slow thinking, slow thinking association speed of patients, slow response and blocked thinking; the patient's mental activities are obviously and permanently inhibited; cognitive impairment is mainly manifested by reduced near-memory, impaired attention, prolonged response time, increased alertness, poor abstract thinking ability, difficulty in learning, poor language fluency, spatial perception, coordination of eyes and hands, and reduced thinking flexibility. Cognitive impairment leads to patient social dysfunction and affects the patient's long-term prognosis; somatic symptoms, mainly include sleep disorder, debilitation, anorexia, weight loss, constipation, and pain in any part of the body.

Diagnosis of depression should be based mainly on medical history, clinical symptoms, course of disease, physical examination and laboratory examination, and diagnosis of typical cases is generally not difficult. The internationally common diagnostic criteria are typically ICD-10 and DSM-IV. ICD-10 is mainly adopted in China, and refers to first-onset depression and recurrent depression, and bipolar depression is not included. Patients often have typical symptoms such as low mood, loss of interest and pleasure, poor vigor or tiredness.

Treatment of depressive episodes achieves three goals: (1) the clinical cure rate is improved, the disability rate is reduced to the maximum extent, and the key point is that clinical symptoms are thoroughly eliminated; (2) the life quality is improved; (3) preventing recurrence. The treatment principle of depression mainly comprises: (1) individuation treatment; (2) the dosage is gradually increased, the minimum effective dose is adopted as far as possible, adverse reactions are minimized, and the medication compliance is improved; (3) sufficient pedicure treatment; (4) as single drug administration as possible, such as poor therapeutic effect, conversion therapy, synergistic therapy or combination therapy can be considered, but attention is paid to drug interactions; (5) pre-treatment informed notification; (6) closely observing the change of illness state and adverse reaction during treatment and timely treating; (7) can be combined with psychological treatment to increase curative effect; (8) actively treat other somatic diseases, substance dependence, anxiety disorder and the like which are co-morbid with depression.

Drug therapy is the primary treatment for depressive episodes above moderate. The current first-line antidepressants in clinic mainly comprise selective 5-hydroxytryptamine reuptake inhibitors, 5-hydroxytryptamine and norepinephrine reuptake inhibitors, norepinephrine and specific 5-hydroxytryptamine antidepressants and the like.

Amitriptyline hydrochloride, amitriptyline Hydrochloride, molecular formula c20h23n·hcl, molecular weight 313.87, chemical name: n, N-dimethyl-3- [10, 11-dihydro-5H-dibenzo (a, d) cycloheptatrien-5-ylidene ] -1-propanamine hydrochloride salt having the chemical structural formula:

amitriptyline hydrochloride is one of the antidepressants for primary insomnia at present, belongs to tricyclic antidepressants, mainly acts by blocking the reabsorption of norepinephrine and 5-hydroxytryptamine, and can also block neurotransmitters such as acetylcholine, histamine and the like. Amitriptyline hydrochloride is used for treating various depression, has strong sedative effect, and is mainly used for treating anxiety or agitation depression in clinical indications. In addition, amitriptyline hydrochloride is also useful in pediatric therapy for the treatment of childhood hyperactivity. The clinical application method is that the normal dosage of the medicine for adults is 25mg once, 2 to 3 times a day, then the medicine gradually increases to 150 to 250mg a day according to the illness state and tolerance condition, 3 times a day, the high dosage is not more than 300mg a day, and the maintenance dosage is 50 to 150mg a day.

Currently, amitriptyline hydrochloride is mainly prepared from tablets, and CN109157525A (Chinese patent application No. 201811245265.2, dongting) discloses an amitriptyline hydrochloride tablet, which comprises the following components in percentage by weight: 35-40% of amitriptyline hydrochloride, 25-30% of corn starch, 5-8% of dextrin, 5-8% of pregelatinized starch, 8-10% of calcium hydrophosphate, 6-8% of sucrose, 0.5-1% of hydroxypropyl methyl cellulose, 1-3% of low-substituted hydroxypropyl cellulose, 1-3% of silicon dioxide, 0.5-2% of fructus amomi powder, 0.5-1% of carboxymethyl starch sodium, 0.5-1% of magnesium stearate and 1-2% of coating premix.

The typical preparation method of the tablet comprises the following steps: 1) Weighing raw materials according to a proportion, uniformly mixing amitriptyline hydrochloride, corn starch, dextrin, pregelatinized starch, calcium hydrophosphate, sucrose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose, crushing, and sieving with a 100-mesh sieve to obtain a mixture; 2) Adding silicon dioxide and fructus Amomi powder into the mixture, mixing uniformly, putting into a granulator, boiling and mixing for 5 minutes, then spraying absolute ethyl alcohol accounting for 20% of the total mass of the mixture, opening steam for drying after spraying, controlling the air inlet temperature to 100 ℃, controlling the air outlet temperature to 40 ℃, and drying for 10 minutes, wherein the moisture content of the obtained granules is 1-2%; 3) Sequentially adding magnesium stearate and carboxymethyl starch sodium into the dried granules, finishing the granules by a granule finishing machine with a 10-mesh sieve, putting the granules into a lifting hopper mixer, mixing at a rotating speed of 10 revolutions per minute for 15 minutes, and tabletting by a tablet press after uniformly mixing to obtain amitriptyline hydrochloride tablets; dissolving the opadry gastric soluble coating powder and the flavoring agent in water to obtain a coating solution with the mass concentration of 5-10%, and coating the amitriptyline hydrochloride tablets in a high-efficiency coating machine to obtain the amitriptyline hydrochloride tablets.

However, those skilled in the art still expect new methods for treating mental disorders, or for achieving such treatment methods, new beneficial medicaments, e.g., pharmaceutical compositions.

Disclosure of Invention

The present invention aims to provide a novel method for treating mental diseases, or to expect a novel and useful drug such as a pharmaceutical composition for realizing the treatment method, or to provide a novel pharmaceutical composition containing amitriptyline hydrochloride as an active ingredient. It has been unexpectedly found that a pharmaceutical composition comprising amitriptyline hydrochloride prepared by the process of the present invention exhibits one or more advantageous effects, and the present invention has been completed based on such findings.

To this end, the present invention provides in a first aspect a pharmaceutical composition comprising:

25 parts of amitriptyline hydrochloride,

8 to 12 parts by weight of glyceryl behenate,

4 to 6 parts by weight of arginine,

the solid pharmaceutical excipients are 0 to 200 parts by weight, for example 0 to 150 parts by weight, for example 0 to 100 parts by weight.

The pharmaceutical composition according to the first aspect of the invention, which is a solid form of the formulation.

The pharmaceutical composition according to the first aspect of the invention is a formulation in the form of a tablet.

The pharmaceutical composition according to the first aspect of the present invention, wherein the solid pharmaceutical excipients comprise one or more types selected from the group consisting of: diluents, disintegrants, binders, glidants, lubricants. The solid pharmaceutical excipients are the usual excipients for solid preparations, and the selection, the addition amount and the addition mode of the solid pharmaceutical excipients are well known to the person skilled in the preparation field. For example, diluents such as, but not limited to, cornstarch, dextrin, pregelatinized starch, dibasic calcium phosphate, sucrose are typically used to formulate solid formulations, particularly tablets, of suitable size or volume for oral administration. For example, when making tablets, it is beneficial to add an appropriate amount of disintegrant, typically 1 to 10%, such as 2 to 8%, typical disintegrants such as, but not limited to, low substituted hydroxypropyl cellulose, sodium carboxymethyl starch, etc. For example, when the composition is granulated or even further granulated into tablets, it may be advantageous to add an amount of binder of from 0 to 10%, for example from 0 to 8%, typical binders such as but not limited to hydroxypropyl methylcellulose, or may instead moisten the material itself without binder with a wetting agent such as water, ethanol or an ethanol solution to produce tackiness to granulate the material, which wetting agent is removed in the final pharmaceutical composition of the invention (residual traces or pharmaceutically acceptable amounts of wetting agent are unavoidable), which in particular may render the auxiliary materials in the material highly adhesive but not formulated as a binder solution such as the hydroxypropyl methylcellulose promote overall material tackiness enhancement. For example, to facilitate processing of solid formulations in the particulate state, it may be beneficial to increase the flowability of the particles by adding a glidant, typically in an amount of 0 to 5%, such as 0.5 to 4%, of the particulate material, typical glidants such as, but not limited to, silica. For tablets, it is beneficial to avoid sticking of the material, and to add a lubricant, typically 0-5%, such as 0.5-3%, of the final blend material, typical lubricants such as, but not limited to, magnesium stearate.

The pharmaceutical composition according to the first aspect of the invention is prepared by the following process:

(1) Mixing amitriptyline hydrochloride and arginine, crushing into powder capable of passing through 120 meshes, uniformly mixing the mixed powder with powdery glyceryl behenate (capable of passing through 60 meshes), heating a mixing container to 85 ℃ under a stirring state, preserving heat, stirring for 25-30 min, and cooling at room temperature to obtain a powdery pharmaceutical composition (capable of passing through 80 meshes, for example); and, optionally,

(2) Mixing the powdery pharmaceutical composition obtained in the step (1) with solid pharmaceutical excipients to prepare a solid pharmaceutical preparation.

It has been unexpectedly found that the combination of an active agent with arginine and glyceryl behenate by the process described above exhibits an improved bioavailability effect.

The pharmaceutical composition according to the first aspect of the present invention, wherein the solid pharmaceutical excipients comprise:

a diluent: corn starch, dextrin, pregelatinized starch, calcium hydrogen phosphate, sucrose,

And (2) an adhesive: hydroxypropyl methylcellulose (e.g., 60RT 50),

Disintegrating agent: low substituted hydroxypropyl cellulose, sodium carboxymethyl starch (e.g. fast disintegrating king),

Glidant: silicon dioxide,

And (3) a lubricant: magnesium stearate.

The pharmaceutical composition according to the first aspect of the present invention, wherein the solid pharmaceutical excipients comprise, per 25 parts by weight of amitriptyline hydrochloride:

15 to 25 parts by weight of corn starch, for example 21 parts by weight, 4 to 7 parts by weight of dextrin, for example 5.7 parts by weight, 2 to 5 parts by weight of pregelatinized starch, for example 3.6 parts by weight, 4 to 7 parts by weight of calcium hydrogen phosphate, for example 5.7 parts by weight, 3 to 6 parts by weight of sucrose, for example 4.3 parts by weight,

0.2 to 0.5 part by weight, for example, 0.36 part by weight, of hydroxypropyl methylcellulose (for example, 60RT50 type),

1 to 2 parts by weight of low-substituted hydroxypropyl cellulose, for example 1.4 parts by weight, 0.2 to 0.5 part by weight of carboxymethyl starch sodium (for example fast disintegrating king), for example 0.36 part by weight,

Silica 0.5 to 1 part by weight, for example 0.7 part by weight, magnesium stearate 0.5 to 1 part by weight, for example 0.7 part by weight.

The pharmaceutical composition according to the first aspect of the invention is in the form of a solid pharmaceutical formulation of a tablet.

The pharmaceutical composition according to the first aspect of the present invention, which is in the form of a solid pharmaceutical formulation of a tablet, wherein the step (2) of mixing the powdered pharmaceutical composition obtained in the step (1) with a solid pharmaceutical excipient to prepare a solid pharmaceutical formulation comprises the steps of:

(2a) Pulverizing each solid medicinal adjuvant into powder capable of passing through 100 mesh sieve;

(2b) Uniformly mixing the powdery pharmaceutical composition obtained in the step (1) with a diluent (such as corn starch, dextrin, pregelatinized starch, calcium hydrophosphate and sucrose), a binder (such as hydroxypropyl methylcellulose), a disintegrating agent (such as low-substituted hydroxypropyl cellulose) and a glidant (such as silicon dioxide) to obtain a mixture;

(2c) Mixing the mixture in a boiling granulator for 5 minutes, spraying absolute ethyl alcohol accounting for 15-25% of the total weight of the mixture, for example, 20%, and boiling and drying after spraying until the water content of the particles is 1-2%;

(2d) Adding disintegrating agent (such as carboxymethyl starch sodium) and lubricant (such as magnesium stearate) into the above dry granule, mixing, granulating (such as 10 mesh sieve) to obtain final mixed granule, and tabletting with tablet press to obtain tablet-type pharmaceutical composition.

The pharmaceutical composition according to the first aspect of the present invention, wherein the solid pharmaceutical formulation in the form of a tablet is further coated.

The pharmaceutical composition according to the first aspect of the present invention, wherein the coating is a gastric-soluble coating material. In one embodiment, the coating material weight is 1 to 4%, such as 1 to 3% of the core weight.

The pharmaceutical composition according to the first aspect of the invention is a coated tablet having the following formulation:

25 parts of amitriptyline hydrochloride,

8 to 12 parts by weight of glyceryl behenate,

4-6 parts of arginine;

the following solid pharmaceutical excipients:

15 to 25 parts by weight of corn starch, for example 21 parts by weight,

Dextrin 4-7 parts by weight, for example 5.7 parts by weight,

2 to 5 parts by weight, for example 3.6 parts by weight, of pregelatinized starch,

4 to 7 parts by weight of calcium hydrogen phosphate, for example 5.7 parts by weight,

3 to 6 parts by weight of sucrose, for example 4.3 parts by weight,

1 to 2 parts by weight, for example 1.4 parts by weight, of low-substituted hydroxypropylcellulose,

Sodium carboxymethyl starch (e.g. fast disintegrating king) 0.2-0.5 weight parts, e.g. 0.36 weight parts,

0.5 to 1 part by weight of silica, for example 0.7 part by weight,

0.5 to 1 part by weight of magnesium stearate, for example 0.7 part by weight,

The coating material is 1-4% by weight, e.g. 1-3% by weight, of the tablet core.

The pharmaceutical composition according to the first aspect of the present invention, which is a coated tablet, is prepared by the steps of:

(1) Mixing amitriptyline hydrochloride and arginine, crushing into powder capable of passing through 120 meshes, uniformly mixing the mixed powder with powdery glyceryl behenate (capable of passing through 60 meshes), heating a mixing container to 85 ℃ under a stirring state, preserving heat, stirring for 25-30 min, and cooling at room temperature to obtain a powdery pharmaceutical composition (capable of passing through 80 meshes, for example);

(3) And (3) coating the tablet obtained in the step (2 d) as a tablet core to obtain a coated tablet.

Further, the second aspect of the present invention provides a method of preparing a pharmaceutical composition comprising:

25 parts of amitriptyline hydrochloride,

8 to 12 parts by weight of glyceryl behenate,

4 to 6 parts by weight of arginine,

0 to 200 parts by weight of solid pharmaceutical auxiliary material, for example 0 to 150 parts by weight, for example 0 to 100 parts by weight; the method comprises the following steps:

The method according to the second aspect of the invention, wherein the pharmaceutical composition is a formulation in solid form.

The method according to the second aspect of the invention, wherein the pharmaceutical composition is a formulation in the form of a tablet.

The method according to the second aspect of the present invention, wherein the solid pharmaceutical excipients comprise one or more types selected from the group consisting of: diluents, disintegrants, binders, glidants, lubricants. The solid pharmaceutical excipients are the usual excipients for solid preparations, and the selection, the addition amount and the addition mode of the solid pharmaceutical excipients are well known to the person skilled in the preparation field. For example, diluents such as, but not limited to, cornstarch, dextrin, pregelatinized starch, dibasic calcium phosphate, sucrose are typically used to formulate solid formulations, particularly tablets, of suitable size or volume for oral administration. For example, when making tablets, it is beneficial to add an appropriate amount of disintegrant, typically 1 to 10%, such as 2 to 8%, typical disintegrants such as, but not limited to, low substituted hydroxypropyl cellulose, sodium carboxymethyl starch, etc. For example, when the composition is granulated or even further granulated into tablets, it may be advantageous to add an amount of binder of from 0 to 10%, for example from 0 to 8%, typical binders such as but not limited to hydroxypropyl methylcellulose, or may instead moisten the material itself without binder with a wetting agent such as water, ethanol or an ethanol solution to produce tackiness to granulate the material, which wetting agent is removed in the final pharmaceutical composition of the invention (residual traces or pharmaceutically acceptable amounts of wetting agent are unavoidable), which in particular may render the auxiliary materials in the material highly adhesive but not formulated as a binder solution such as the hydroxypropyl methylcellulose promote overall material tackiness enhancement. For example, to facilitate processing of solid formulations in the particulate state, it may be beneficial to increase the flowability of the particles by adding a glidant, typically in an amount of 0 to 5%, such as 0.5 to 4%, of the particulate material, typical glidants such as, but not limited to, silica. For tablets, it is beneficial to avoid sticking of the material, and to add a lubricant, typically 0-5%, such as 0.5-3%, of the final blend material, typical lubricants such as, but not limited to, magnesium stearate.

The method according to the second aspect of the present invention, wherein the solid pharmaceutical excipients comprise:

And (2) an adhesive: hydroxypropyl methylcellulose (e.g., 60RT 50),

Glidant: silicon dioxide,

And (3) a lubricant: magnesium stearate.

According to the method of the second aspect of the present invention, the solid pharmaceutical excipients comprise, per 25 parts by weight of amitriptyline hydrochloride:

The method according to the second aspect of the invention, wherein the pharmaceutical composition is in the form of a solid pharmaceutical formulation of a tablet.

The method according to the second aspect of the present invention, wherein the pharmaceutical composition is in the form of a solid pharmaceutical formulation of a tablet, wherein the step (2) of mixing the powdered pharmaceutical composition obtained in step (1) with a solid pharmaceutical excipient to prepare a solid pharmaceutical formulation comprises the steps of:

The method according to the second aspect of the invention, wherein the solid pharmaceutical formulation in the form of a tablet is further coated.

The method according to the second aspect of the invention, wherein the coating is a gastric-soluble coating material. In one embodiment, the coating material weight is 1 to 4%, such as 1 to 3% of the core weight.

The method according to the second aspect of the present invention, wherein the pharmaceutical composition is a coated tablet having the following material formulation:

25 parts of amitriptyline hydrochloride,

8 to 12 parts by weight of glyceryl behenate,

4-6 parts of arginine;

the following solid pharmaceutical excipients:

15 to 25 parts by weight of corn starch, for example 21 parts by weight,

Dextrin 4-7 parts by weight, for example 5.7 parts by weight,

3 to 6 parts by weight of sucrose, for example 4.3 parts by weight,

0.5 to 1 part by weight of silica, for example 0.7 part by weight,

0.5 to 1 part by weight of magnesium stearate, for example 0.7 part by weight,

The method according to the second aspect of the invention comprises the steps of:

Further, the third aspect of the present invention provides the use of a pharmaceutical composition according to any one of the first aspect of the present invention or a pharmaceutical composition prepared by a method according to any one of the embodiments of the second aspect of the present invention in the manufacture of a medicament for the treatment and/or prophylaxis of psychotic disorders.

The use according to the third aspect of the invention, wherein the psychotic disorder is depression.

The use according to the third aspect of the invention wherein the psychotic disorder is anxiety or agitation depression.

Further, a fourth aspect of the present invention provides a method of treating and/or preventing a psychotic disorder, comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a pharmaceutical composition according to any of the first aspect of the present invention or a pharmaceutical composition prepared according to any of the embodiments of the second aspect of the present invention.

The method according to the fourth aspect of the invention, wherein the psychotic disorder is depression.

The method according to the fourth aspect of the invention, wherein the psychotic disorder is anxiety or agitation depression.

Among the steps of the above-described preparation method of the present invention, although the specific steps described therein are distinguished in some details or language description from the steps described in the preparation examples of the following detailed description, the above-described method steps can be fully summarized by one skilled in the art based on the detailed disclosure of the present invention as a whole.

Any of the embodiments of any of the aspects of the invention may be combined with other embodiments, provided that they do not contradict. Furthermore, in any of the embodiments of any of the aspects of the present invention, any technical feature may be applied to the technical feature in other embodiments as long as they do not contradict. The present invention is further described below.

All documents cited herein are incorporated by reference in their entirety and are incorporated by reference herein to the extent they are not inconsistent with this invention. Furthermore, various terms and phrases used herein have a common meaning known to those skilled in the art, and even though they are still intended to be described and explained in greater detail herein, the terms and phrases used herein should not be construed to be inconsistent with the ordinary meaning in the sense of the present invention.

Amitriptyline hydrochloride is an antidepressant with sedative effect. The mechanism of action in humans is not yet clear. It is not a monoamine oxidase inhibitor and does not act primarily by stimulating the central nervous system. Amitriptyline inhibits the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonin neurons. Pharmacologically, this effect may enhance or prolong neuronal activity, as reuptake of these biogenic amines is of physiological importance in terminating the delivery event. Some believe that this interference with reuptake of norepinephrine and/or serotonin is the basis for the antidepressant activity of amitriptyline.

Amitriptyline hydrochloride has the strongest sedative effect in tricyclic antidepressants, can obviously improve emotion of a depressed patient, and is suitable for treating anxiety or agitation depression. The antidepressant effect of amitriptyline hydrochloride can improve the emotion of various depressive patients, and improve the symptoms such as slow thinking, slow behavior, inappetence and the like. The general administration for 7-10 days can produce obvious curative effect. Amitriptyline hydrochloride has strong sedative and hypnotic effects. Amitriptyline hydrochloride is suitable for various types of depression, such as endogenous depression, climacteric depression, reactive depression and the like. The curative effect is better than that of imipramine for patients with anxiety and depression symptoms. In addition, amitriptyline hydrochloride has a certain curative effect on functional enuresis.

In addition, amitriptyline, which is widely used as an antidepressant and analgesic, has been found to directly stimulate the growth of brain nerve cells, thereby promoting brain development. Experiments show that amitriptyline can directly promote the development of nerve growth factors in the brain, maintain the oxygen content and the glucose content in nerve cells, and excite the nerve cells to extend neurites outwards so as to connect other nerve cells. In addition, amitriptyline can inhibit the production of the neurotoxin rhodopsin. This shows a mechanism of pharmacodynamics that is different from that of many antidepressants. Amitriptyline is a tricyclic antidepressant and is currently widely used to treat migraine and neuropathic conditions caused by diabetes.

The present inventors have found that the pharmaceutical composition prepared by using the method of the present invention exhibits excellent effects.

Drawings

Fig. 1: chromatograms of two controls, amitriptyline and internal standard, were added to the blank plasma (t= 7.907min for amitriptyline peak, t= 10.034min for clomipramine peak).

Detailed Description

The following examples of the invention are provided for illustrative purposes only and are not intended to be construed as limiting the invention in any way. Those skilled in the art will recognize that conventional variations and modifications may be made to the following embodiments without departing from the spirit or scope of the invention.

The present invention generally and/or specifically describes the materials used in the test as well as the test methods. Although many materials and methods of operation are known in the art for accomplishing the objectives of the present invention, the present invention will be described in as much detail herein. It will be clear to those skilled in the art that hereinafter, unless otherwise indicated, the materials and methods of operation used in the present invention are well known in the art.

In the preparation of the composition below, when the proportion of the ingredients is expressed in terms of parts by weight, each batch is not less than 250 g in terms of the active ingredient. In various examples of the present invention for preparing tablets, the tablets are compressed at the time of compression to a specification containing 25mg amitriptyline hydrochloride per tablet, unless otherwise specified.

Example 1: preparation of pharmaceutical compositions

Prescription:

25 parts by weight of amitriptyline hydrochloride,

10 parts by weight of glyceryl behenate,

5 parts by weight of arginine,

solid pharmaceutical excipients:

21 parts by weight of corn starch,

5.7 parts by weight of dextrin,

3.6 parts by weight of pregelatinized starch,

5.7 parts by weight of calcium hydrophosphate,

4.3 parts by weight of sucrose,

0.36 part by weight of hydroxypropyl methylcellulose (60 RT50 type),

1.4 parts by weight of low-substituted hydroxypropyl cellulose,

Sodium carboxymethyl starch (fast disintegrating king) 0.36 weight portions,

0.7 part by weight of silicon dioxide,

0.7 part by weight of magnesium stearate,

coating material:

the eudragit gastric soluble coating premix is 2% of the tablet core weight.

The preparation method comprises the following steps:

(1) Mixing amitriptyline hydrochloride and arginine, crushing into powder which can pass through 120 meshes, uniformly mixing the mixed powder with powdery glyceryl behenate (passing through 60 meshes), heating a mixing container to 85 ℃ under a stirring state, preserving heat, stirring for 25-30 min, and cooling at room temperature to obtain a powdery pharmaceutical composition (passing through 80 meshes);

(2b) Uniformly mixing the powdery pharmaceutical composition obtained in the step (1) with diluents (corn starch, dextrin, pregelatinized starch, calcium hydrophosphate and sucrose), binders (hydroxypropyl methylcellulose), disintegrants (low-substituted hydroxypropyl cellulose) and glidants (silicon dioxide) to obtain a mixture;

(2c) Mixing the mixture in a boiling granulator for 5 minutes, spraying absolute ethyl alcohol accounting for 20 percent of the total weight of the mixture, and boiling and drying after spraying until the moisture content of the particles is 1-2 percent;

(2d) Adding disintegrating agent (carboxymethyl starch sodium) and lubricant (magnesium stearate) into the above dry granule, mixing, granulating (10 mesh sieve) to obtain final mixed granule, and tabletting with tablet press to obtain tablet-type pharmaceutical composition.

For parameters of the steps, refer to example 1 of CN109157525a (chinese patent application No. 201811245265.2, forum), for example: the boiling granulator is produced by Changzhou Lima drying engineering Co., ltd, the lubricant is sprayed and then dried by steam, the air inlet temperature is controlled to be 100 ℃, the air outlet temperature is controlled to be 40 ℃, and the moisture content of the obtained particles is removed to 1-2% after drying for 10 minutes; the used granulator is a YK-160 granulator of a Chengzhi pharmaceutical machinery factory in Hunan; the tablet press is ZP-5B/9B/7B tablet press of Guangzhou morning carving mechanical equipment Co., ltd, and the hardness of the tablet is kept within the range of 5-6 kg; the opadry gastric soluble coating powder is suspended in water to a coating solution with the concentration of 5-10%, amitriptyline hydrochloride tablets are coated in a high-efficiency coating machine, the rotating speed of a pot is 5 rpm when the coating solution is sprayed, the air inlet temperature is 80 ℃, and the air outlet temperature is 55 ℃. Although processes for preparing tablets are well known in the art, the process parameters are the same as those described above, unless otherwise specified, in other embodiments of the present invention for preparing the compositions.

Example 2: preparation of pharmaceutical compositions

Prescription:

25 parts by weight of amitriptyline hydrochloride,

12 parts by weight of glyceryl behenate,

4 parts by weight of arginine,

solid pharmaceutical excipients:

15 parts by weight of corn starch,

7 parts by weight of dextrin,

2 parts by weight of pregelatinized starch,

7 parts by weight of calcium hydrophosphate,

3 parts by weight of sucrose,

0.5 part by weight of hydroxypropyl methylcellulose (60 RT50 type),

1 part by weight of low-substituted hydroxypropyl cellulose,

Sodium carboxymethyl starch (fast disintegrating king) 0.5 weight portion,

0.5 part by weight of silicon dioxide,

1 part by weight of magnesium stearate,

coating material:

the eudragit gastric-soluble coating premix is 1% of the tablet core weight.

The preparation method comprises the following steps:

(2c) Mixing the mixture in a boiling granulator for 5 minutes, spraying absolute ethyl alcohol accounting for 15 percent of the total weight of the mixture, and boiling and drying after spraying until the moisture content of the particles is 1-2 percent;

Example 3: preparation of pharmaceutical compositions

Prescription:

25 parts by weight of amitriptyline hydrochloride,

8 parts by weight of glyceryl behenate,

6 parts by weight of arginine,

solid pharmaceutical excipients:

25 parts by weight of corn starch,

Dextrin 4 weight portions,

5 parts by weight of pregelatinized starch,

4 parts by weight of calcium hydrophosphate,

6 parts by weight of sucrose,

0.2 part by weight of hydroxypropyl methylcellulose (60 RT50 type),

2 parts by weight of low-substituted hydroxypropyl cellulose,

Sodium carboxymethyl starch (fast disintegrating king) 0.2 weight portion,

1 part by weight of silicon dioxide,

0.5 part by weight of magnesium stearate,

coating material:

the eudragit gastric soluble coating premix is 3% of the tablet core weight.

The preparation method comprises the following steps:

(2c) Mixing the mixture in a boiling granulator for 5 minutes, spraying absolute ethyl alcohol accounting for 25 percent of the total weight of the mixture, and boiling and drying after spraying until the moisture content of the particles is 1-2 percent;

Example 11: preparation of pharmaceutical compositions

With reference to the formulation and preparation of example 1, only arginine was not added.

Example 12: preparation of pharmaceutical compositions

Referring to the formulation and the process of example 1, the only differences are that no glyceryl behenate was added and step (1) was changed to: amitriptyline hydrochloride and arginine are mixed and then crushed into powder which can pass through 120 meshes, thus obtaining the powdery pharmaceutical composition.

Example 13: preparation of pharmaceutical compositions

Referring to the formulation and the preparation of example 1, the only differences are that no arginine was added and no glyceryl behenate was added and step (1) was changed to: amitriptyline hydrochloride is crushed into powder which can pass through 120 meshes, and the amitriptyline hydrochloride is obtained (the amitriptyline hydrochloride is a bulk drug and is used for mixing with a diluent and the like in the step (2 b)). This example 13 was essentially the same as example 1 of CN109157525a (chinese patent application No. 201811245265.2, forcible) except that no fructus Amomi powder was added, and the preparation process was not substantially different.

Test example 1: amitriptyline pharmacokinetic study

In this test example, reference is made to Shen Yuan (Shen Yuan, et al, reversed-phase high performance liquid chromatography for measuring amitriptyline concentration in rat plasma, nanno pharmaceutical, 2009,7 (2): 88) and the like, and pharmacokinetic studies were conducted on the compositions prepared by the present invention.

1. Material

High performance liquid chromatograph system: agilent1260 unit pump (C02-0312), waters e2695 quaternary pump (C02-0319), agilent1260-2489UV/Vis detector, agilent OpenLab Empower workstation; the remaining instruments were all commercially available conventional instruments.

Amitriptyline hydrochloride reference substance (provided by the inventor inspection department, batch number 200603, content > 98%), internal standard clomipramine hydrochloride (provided by the inventor inspection department, batch number 200816, content > 98%), reagent such as acetonitrile and the like are chromatographic purity, reagent such as triethylamine and the like are analytical purity; the experimental water is double distilled water.

Male SD rats weighing 180-200 g, supplied by Hunan university of traditional Chinese medicine, SYXK 2019-0009.

2. Chromatographic conditions

C18 chromatographic column (Inspire, 4.6X250 mm,5 μm), C18 guard column (phenome x),

mobile phase: acetonitrile-0.03 mol/mL ammonium acetate buffer (acetic acid and/or triethylamine to ph=5.0) (40:60),

flow rate: 1.0mL/min of the total weight of the mixture,

detection wavelength: the wavelength of the light is 240nm,

column temperature: 40 ℃.

Sample injection amount: 20 μl.

3. Methodology investigation

3.1. Preparation of reference substance solution

Precisely weighing amitriptyline hydrochloride reference substance 20.0mg, preparing reference substance stock solution with concentration of 200 mug/mL by acetonitrile, diluting by mobile phase, preparing reference substance series working solutions with concentrations of 0.5, 1.0, 2.5, 5.0, 10.0, 25.0 and 50.0 mug/mL respectively, and preserving at 4 ℃.

3.2. Internal standard solution

The clomipramine hydrochloride reference substance 15mg was precisely weighed. An internal standard stock solution with a concentration of 150. Mu.g/mL was prepared with methanol, and the stock solution was diluted with water to an internal standard solution with a concentration of 15. Mu.g/mL and stored at 4 ℃.

3.3. Plasma sample processing

200 mu L of rat blank plasma or drug-containing plasma is placed in a 10mL centrifuge tube, 50 mu L of internal standard clomipramine hydrochloride solution is precisely added, vortex is carried out for 30s, 0.5mol/L sodium hydroxide is added for 50 mu L, vortex is carried out for 30s, 2mL of tert-butyl methyl ether is added, vortex is carried out for 1min,3000r/min is carried out for 5min, the upper organic phase is taken, nitrogen in water bath at 40 ℃ is used for drying, the residue is dissolved by 100 mu L of mobile phase, and sample injection detection is carried out.

3.4. Standard curve preparation

180 mu L of rat blank plasma is taken, 20 mu L of amitriptyline hydrochloride control series working solution is precisely added, and the plasma drug concentration is respectively 0.05, 0.10, 0.25, 0.50, 1.0, 2.5 and 5.0 mu g/mL. Then, 50 mu L of internal standard clomipramine hydrochloride solution is precisely added into each tube, the plasma sample is treated according to the plasma sample treatment method, and sample injection detection is carried out. Linear regression is performed by taking the peak area ratio A of amitriptyline hydrochloride and an internal standard substance as an ordinate and the concentration C (mug/mL) of an object to be detected as an abscissa, wherein a regression equation is as follows: a=1427.28c+11.36, r=0.9998, and the linear range is 0.05 to 5.0 μg/mL.

3.5. Specificity of the method

And (3) respectively adding the reference substance into the blank plasma and the blank plasma, treating the blank plasma and the plasma sample according to the above method, and injecting the treated blank plasma and the treated plasma sample into a liquid chromatograph. The retention time of amitriptyline was about 8min and the retention time of the internal standard was about 10min. Endogenous impurities do not interfere with the separation assay of the analyte. Typical chromatograms of the blank plasma plus amitriptyline and the internal standard are shown in figure 1.

3.6. Recovery and precision test

Preparing high, medium and low concentration quality control samples according to the method of '3.4 standard curve preparation', preparing reference substance plasma with the concentration of an object to be detected of 0.05, 0.5 and 5.0 mug/mL, extracting, detecting the peak area of the reference substance by sample injection after the extraction treatment by the method, and calculating the extraction recovery rate by the ratio of the peak area detected by directly sample injection without extraction of the reference substance solution with the corresponding concentration. The recovery rate and the daytime precision of the method are also examined (see Table 1).

Table 1: HPLC method for determining recovery and precision of amitriptyline in plasma (n=6)

As can be seen from the results of the above table, the present invention determines amitriptyline in plasma

4. Administration of drugs

Reagent: the four coated tablets prepared in step (3) of the four examples of example 1, example 11, example 12 and example 13 were ground into fine powder and then the amount of the active ingredient was converted into a drug solution, and the drug solution was formulated into a concentration of about 1ml of the drug solution per animal by oral administration using a 1% sodium carboxymethyl cellulose suspension.

The fasted 8 hours SD rats were randomly divided into four groups of 6, each of which was orally administered with amitriptyline hydrochloride at a dose of 60mg/kg animal body weight, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h were collected from the retroorbital venous plexus for 0.5mL, heparin anticoagulated, plasma was collected, and plasma sample treatment was performed as "3.3" for each time point, and the plasma concentration was determined and calculated using HPLC method. Animals were fed freely 2 hours after dosing, and were not water-inhibited during the trial.

Next, pharmacokinetic parameters for each group of animals were calculated using non-compartmental model analysis methods using DAS 2.0 pharmacokinetic process analysis software based on the plasma concentration-time curve. AUC 0-48 h was calculated in trapezoidal form for each time point of blood concentration; AUC0 → infinity is calculated as: auc0→infinity=auc0→48h+c48h/λ, C48h is the blood concentration at the last point, λ is the terminal elimination rate constant; lambda is determined by the slope of the linear portion at the end of the log plasma concentration-time curve, t1/2=0.714/lambda; CL/F is apparent clearance; MRT is the average residence time. The pharmacokinetic parameters between the two groups were t-checked using SPSS22.0 statistical software. See table 2.

Table 2: determination of rat amitriptyline pharmacokinetic parameters (x±s, n=6)

Compared to example 1 group, P <0.05.

From the results of the above table, it can be seen that the group of example 1 is significantly higher than the other groups in the important parameters Cmax, AUC0→48h, AUC0→infinity, which are extremely relevant for bioavailability, indicating significantly higher bioavailability of the composition of example 1.

In a supplementary test, the present inventors also referred to the above "test example 1: amitriptyline pharmacokinetic study "the powder pharmaceutical composition obtained in step (1) of example 1 was tested, and the dose administered was also 60mg/kg animal body weight based on amitriptyline hydrochloride, with the result that (n=6): tmax (min) = 62.25 ±22.36, cmax (μg/L) = 109.27 ±22.83, t1/2 (min) = 278.56 ± 59.51, auc0→48h (μg/l·min) = 18184.53 ± 1895.33, auc0→infinity (μg/l·min) = 23027.41 ± 2938.28, CL/F (L/min·kg) =4.51±1.24, MRT (min) = 249.43 ±26.35. These results show that the powdered pharmaceutical composition obtained in step (1) of example 1 has substantially the same bioavailability as the tablet and that the powdered pharmaceutical composition obtained in step (1) is able to impart a higher bioavailability to the final tablet.

Test example 2: dissolution investigation

Taking a test sample, and measuring according to a dissolution rate and release rate measuring method (the first method of the fourth rule 0931 of the year 2020 edition of Chinese pharmacopoeia); taking 900ml of hydrochloric acid solution (9-1000) as a dissolution medium, rotating at 100 revolutions per minute, performing normal operation, taking 10ml of solution after 45 minutes, and filtering; precisely measuring 5ml of the continuous filtrate, placing in a 10ml measuring flask, diluting to scale with dissolution medium, and shaking; measuring absorbance at 239mn according to absorption coefficient of C20H2dN.H2.1 by ultraviolet-visible spectrophotometry (Chinese pharmacopoeia 2020 edition, four-division rule 0401)The amount of elution of each test piece was calculated at 444.

Under the above conditions, the general drug standards prescribe that 25 mg/tablet of amitriptyline hydrochloride tablet should have a dissolution rate of greater than 75% of the indicated amount.

The dissolution rate of the 6 coated tablets (25 mg/tablet) obtained in examples 1 to 3 and examples 11 to 13 was measured by the above measurement method, and the results were (percentages relative to the labeled amount): 92.1%, 89.8%, 91.6%, 92.8%, 89.2%, 90.3%, the results show that the 6 coated tablets have no obvious difference in measurement results under the conditions of pharmacopoeia dissolution measurement, the difference between the results and the bioavailability results shows that the in vitro dissolution rate and the absorption percentage of the tablets have no direct correlation with respect to the prescription/process differences of the embodiments of the invention.

In addition, the final mixed granules obtained in the step (2 d) of examples 1 to 3 and examples 11 to 13 were filled into gelatin hollow capsules of a suitable size, and each capsule was filled with an amount of granules corresponding to 25mg of amitriptyline hydrochloride, to obtain 6 capsules; the dissolution rate of each capsule was measured according to the above-mentioned dissolution rate measurement method, and the results were all 90 to 93%, for example, the dissolution rate of the capsule of example 1 was 91.3%, which is substantially the same as the result of the tablet.

Test example 3: content determination

The present test example refers to the pharmacopoeia method for determining the content of active ingredient in tablets.

Measuring by high performance liquid chromatography (China pharmacopoeia 2020 edition four general rules 0512); octadecylsilane chemically bonded silica is used as a filler, methanol-water-triethylamine (60:40:0.3) (pH value is regulated to 3.1 by phosphoric acid) is used as a mobile phase, and detection wavelength is 240mn; the number of theoretical plates is not less than 3000 calculated according to amitriptyline peaks; taking 20 pieces of a test sample, precisely weighing, grinding, precisely weighing fine powder which is about 50mg of amitriptyline hydrochloride, placing into a 200ml measuring flask, adding a proper amount of mobile phase, shaking to dissolve and dilute the amitriptyline hydrochloride to a scale, shaking uniformly, filtering, precisely weighing a proper amount of continuous filtrate, and diluting with the mobile phase to prepare a solution containing about 0.02mg of amitriptyline hydrochloride per 1ml as a test sample solution; taking a proper amount of amitriptyline hydrochloride reference substance, adding a mobile phase to dissolve and dilute the amitriptyline hydrochloride reference substance to prepare a solution containing about 0.02mg per 1ml as a reference substance solution; precisely measuring 10 mu l of each of the sample solution and the reference solution, respectively injecting into a liquid chromatograph, recording the chromatograms, and calculating the percentage of amitriptyline hydrochloride in each tablet relative to the marked amount thereof according to the peak area by an external standard method to obtain the percentage content.

Using the above-mentioned methods, the content of each of the 6 coated tablets (25 mg/tablet) obtained in examples 1 to 3 and examples 11 to 13 was measured, and as a result, the content of each of the tablets was in the range of 99.2 to 101.6%, for example, the content of the tablet of example 1 was 100.6%.

Test example 4: inspection of substances of interest

The test examples were conducted by referring to examination items of substances under the amitriptyline hydrochloride tablet variety item carried on page 1183 of the second edition of the pharmacopoeia 2020, and the substances of 6 coated tablets prepared in examples 1 to 3 and examples 11 to 13 were measured.

Results: the individual impurities of the 6 coated tablets prepared in examples 1 to 3 and examples 11 to 13 were all less than 0.16%, for example the maximum individual impurity of the tablet of example 1 was 0.09%,

the total amount of each impurity in the 6 coated tablets prepared in examples 1 to 3 and examples 11 to 13 was less than 1.0%, for example, the total amount of each impurity in the tablet of example 1 was 0.28%.

According to the results of the above test examples 2 to 4, it was shown that each of the tablets prepared according to the present invention meets the current standard specifications.

Test example 5: stability investigation

The coated tablets obtained in examples 1 to 3 were sealed in a light-shielding simulated market package, placed in a 40℃incubator for 6 months, and the dissolution rate, content and related substances of the tablets were measured at 6 months according to the above test examples 2 to 4. Results:

The dissolution rates of the 3 coated tablets of examples 1 to 3 were respectively: 91.7%, 92.3%, 90.8%;

the contents of the 3 coated tablets of examples 1 to 3 were respectively: 99.7%, 100.3%, 99.4%;

the largest individual impurity for the 3 coated tablets of examples 1-3 were: 0.11%, 0.13%, 0.09%, and the total amount of each impurity was 0.34%, 0.29%, 0.37%, respectively.

The above results indicate that some of the tablets prepared according to the present invention have excellent stability.

The present invention is described in detail by the above examples, but the present invention is not limited to the above detailed methods, i.e., it does not mean that the present invention must be practiced depending on the above detailed methods. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.

Claims

1. A pharmaceutical composition in the form of a tablet, consisting of the following components in proportions: 25 parts of amitriptyline hydrochloride, 8-12 parts of glyceryl behenate, 4-6 parts of arginine and the following solid pharmaceutical excipients: 15-25 parts of corn starch, 4-7 parts of dextrin, 2-5 parts of pregelatinized starch, 4-7 parts of calcium hydrophosphate, 3-6 parts of sucrose, 0.2-0.5 part of hydroxypropyl methyl cellulose, 1-2 parts of low-substituted hydroxypropyl cellulose, 0.2-0.5 part of carboxymethyl starch sodium, 0.5-1 part of silicon dioxide and 0.5-1 part of magnesium stearate; the pharmaceutical composition is prepared by the following process:

(1) Mixing amitriptyline hydrochloride and arginine, crushing into powder capable of passing through 120 meshes, uniformly mixing the mixed powder and 60 meshes of glyceryl behenate, heating a mixing container to 85 ℃ under a stirring state, preserving heat, stirring for 25-30 min, and cooling at room temperature to obtain a powdery pharmaceutical composition;

(2) Mixing the powdery pharmaceutical composition obtained in the step (1) with solid pharmaceutical excipients to prepare a pharmaceutical composition in the form of a tablet, comprising the following steps:

(2b) Uniformly mixing the powdery pharmaceutical composition obtained in the step (1) with diluents such as corn starch, dextrin, pregelatinized starch, calcium hydrophosphate, sucrose, adhesive hydroxypropyl methylcellulose, disintegrant low-substituted hydroxypropyl cellulose and glidant silicon dioxide to obtain a mixture;

(2c) Placing the mixture into a boiling granulator for mixing for 5 minutes, then spraying absolute ethyl alcohol accounting for 15-25% of the total weight of the mixture, and boiling and drying after spraying until the moisture content of particles is 1-2%;

(2d) Adding sodium carboxymethyl starch as a disintegrating agent and magnesium stearate as a lubricant into the dry granules, mixing, sieving with a 10-mesh sieve, granulating to obtain final mixed granules, and tabletting with a tablet press to obtain the pharmaceutical composition in the form of tablet.

2. The pharmaceutical composition according to claim 1, wherein the hydroxypropyl methylcellulose is model 60RT 50.

3. The pharmaceutical composition according to claim 1, wherein the sodium carboxymethyl starch is rapidly disintegrating king.

4. The pharmaceutical composition according to claim 1, wherein the corn starch is 21 parts by weight per 25 parts by weight amitriptyline hydrochloride.

5. The pharmaceutical composition according to claim 1, wherein the dextrin is 5.7 parts by weight per 25 parts by weight amitriptyline hydrochloride.

6. The pharmaceutical composition according to claim 1, wherein the pregelatinized starch is 3.6 parts by weight per 25 parts by weight amitriptyline hydrochloride.

7. The pharmaceutical composition according to claim 1, wherein the dibasic calcium phosphate is 5.7 parts by weight per 25 parts by weight amitriptyline hydrochloride.

8. The pharmaceutical composition according to claim 1, wherein the sucrose is 4.3 parts by weight per 25 parts by weight amitriptyline hydrochloride.

9. The pharmaceutical composition according to claim 1, hydroxypropyl methylcellulose is 0.36 parts by weight per 25 parts by weight amitriptyline hydrochloride.

10. The pharmaceutical composition according to claim 1, wherein the low-substituted hydroxypropylcellulose is 1.4 parts by weight per 25 parts by weight of amitriptyline hydrochloride.

11. The pharmaceutical composition according to claim 1, wherein the sodium carboxymethyl starch is 0.36 parts by weight per 25 parts by weight amitriptyline hydrochloride.

12. The pharmaceutical composition according to claim 1, wherein the silica is 0.7 parts by weight per 25 parts by weight amitriptyline hydrochloride.

13. The pharmaceutical composition according to claim 1, wherein the magnesium stearate is 0.7 parts by weight per 25 parts by weight amitriptyline hydrochloride.

14. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition in the form of a tablet is further coated.

15. The pharmaceutical composition according to claim 14, wherein the coating is a gastric-soluble coating material.

16. The pharmaceutical composition according to claim 15, wherein the weight of the coating material is 1-4% of the weight of the tablet core.

17. The pharmaceutical composition according to claim 1, which is a coated tablet having the following formulation:

25 parts of amitriptyline hydrochloride, 8-12 parts of glyceryl behenate and 4-6 parts of arginine;

the following solid pharmaceutical excipients: 15-25 parts of corn starch, 4-7 parts of dextrin, 2-5 parts of pregelatinized starch, 4-7 parts of calcium hydrophosphate, 3-6 parts of sucrose, 0.2-0.5 part of hydroxypropyl methyl cellulose, 1-2 parts of low-substituted hydroxypropyl cellulose, 0.2-0.5 part of carboxymethyl starch sodium, 0.5-1 part of silicon dioxide, 0.5-1 part of magnesium stearate and 1-4% of coating material by weight of tablet core;

The preparation method comprises the following steps:

(2d) Adding sodium carboxymethyl starch as a disintegrating agent and magnesium stearate as a lubricating agent into the dry granules, mixing, sieving with a 10-mesh sieve, granulating to obtain final mixed granules, and pressing the final mixed granules into tablets by a tablet press to obtain a tablet-shaped pharmaceutical composition;

18. The pharmaceutical composition according to claim 1, which is formulated as:

25 parts of amitriptyline hydrochloride, 10 parts of glyceryl behenate and 5 parts of arginine,

solid pharmaceutical excipients: 21 parts of corn starch, 5.7 parts of dextrin, 3.6 parts of pregelatinized starch, 5.7 parts of calcium hydrophosphate, 4.3 parts of sucrose, 0.36 part of hydroxypropyl methylcellulose 60RT50 type, 1.4 parts of low-substituted hydroxypropyl cellulose, 0.36 part of carboxymethyl starch sodium fast disintegrating agent, 0.7 part of silicon dioxide and 0.7 part of magnesium stearate,

coating material: the eudragit gastric solubility coating premix is 2% of the tablet core weight;

the preparation method of the pharmaceutical composition comprises the following steps:

(1) Mixing amitriptyline hydrochloride and arginine, crushing into powder which can pass through 120 meshes, uniformly mixing the mixed powder with 60 meshes of glyceryl behenate, heating a mixing container to 85 ℃ under a stirring state, preserving heat, stirring for 25-30 min, and cooling at room temperature to obtain a powdery pharmaceutical composition;

(2b) Uniformly mixing the powdery pharmaceutical composition obtained in the step (1) with corn starch, dextrin, pregelatinized starch, calcium hydrophosphate, sucrose, hydroxypropyl methylcellulose as an adhesive and low-substituted hydroxypropyl cellulose as a disintegrating agent and silicon dioxide as a glidant to obtain a mixture;

(2c) Mixing the mixture in a boiling granulator for 5 minutes, spraying absolute ethyl alcohol accounting for 20% of the total weight of the mixture, and boiling and drying after spraying until the water content of the particles is 1-2%;

19. A method of preparing the pharmaceutical composition of claim 1, comprising the steps of:

(2d) Adding sodium carboxymethyl starch as a disintegrating agent and magnesium stearate as a lubricant into the dry granules, mixing, sieving with a 10-mesh sieve, granulating to obtain final mixed granules, and tabletting with a tablet press to obtain the tablet-shaped pharmaceutical composition.

20. Use of a pharmaceutical composition according to any one of claims 1 to 18 for the manufacture of a medicament for the treatment and/or prophylaxis of psychotic disorders, which is depression.

21. The use according to claim 20, wherein the psychotic disorder is anxiety or agitation depression.