CN114917213A

CN114917213A - Remedies for mental diseases containing amitriptyline and method for treating mental diseases

Info

Publication number: CN114917213A
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: 2022-08-19
Anticipated expiration: 2042-07-05
Also published as: CN114917213B

Abstract

The present invention relates to a therapeutic agent for mental diseases comprising amitriptyline and a method for treating mental diseases. In one aspect, the present invention relates to a pharmaceutical composition comprising: 25 parts of amitriptyline hydrochloride and 0-200 parts of solid pharmaceutic adjuvant by weight, wherein the pharmaceutical composition is a solid preparation, in particular a tablet preparation. The solid pharmaceutic adjuvant comprises one or more types selected from the following materials: diluent, disintegrant, adhesive, glidant and lubricant. Also relates to the use of the pharmaceutical composition for the treatment of psychiatric disorders. The composition of the present invention exhibits excellent effects as described in the present invention, and exerts excellent biological effects particularly when used for the treatment of mental diseases such as various depression, particularly anxiety-type or agitation-type depression.

Description

Remedies for mental diseases containing amitriptyline and method for treating mental diseases

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 psychiatric disorder is various depression. In particular, the active agent used in the method of treating a psychiatric disorder of the present invention is amitriptyline or a pharmaceutically acceptable salt thereof. The active drug amitriptyline can be used in particular for the treatment of anxiety or agitated depression, since it has a strong sedative effect. The compositions of the present invention exhibit superior efficacy as described herein and are therefore believed to exert superior biological efficacy when used in the treatment of psychiatric disorders, for example in the treatment of various depressive disorders, and in particular in the treatment of anxiety or agitation depressive disorders.

Background

Depression (depression) is currently the most common psychological disorder, with continuous and long-term depression as the major clinical feature, the most important type of psychological disorder in modern people, and 3.22 million people worldwide are believed to suffer from varying degrees of depression.

The etiology of depression is not well understood, 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 the aspects of heredity, neurobiochemistry, neuroendocrine, nerve regeneration and the like; psychological predisposition closely associated with depression is a pre-pathological trait, such as depressive temperament. The exposure to stressful life events in adulthood is an important trigger for the occurrence of clinically significant depressive episodes. However, these factors do not work alone, emphasizing the interaction between genetics and the environment or stressors, and the point at which such interactions occur, has a significant impact on the development of depression.

Depression can be manifested as a single or repeated depressive episode, and the clinical manifestations of depression are mainly: mood depression, mainly manifested as marked and persistent emotional depression, depressive pessimism; slow thinking, slow thinking association speed, slow response and blocked thinking; will move about and decline, patient will move about and show the lasting inhibition of will obviously; impairment of cognitive function is mainly manifested by hypomnesis, attention deficit, prolonged response time, increased alertness, poor abstract thinking ability, difficulty in learning, poor language fluency, spatial perception, eye-hand coordination, and decreased thinking ability. Impairment of cognitive function leads to social dysfunction in the patient and affects the patient's prognosis; the physical symptoms mainly include sleep disorder, hypodynamia, anorexia, weight loss, constipation and pain of any part of the body.

The diagnosis of depression should be based primarily on medical history, clinical symptoms, course of disease, physical examination and laboratory examination, and diagnosis in typical cases is generally not difficult. International diagnostic standards in general are ICD-10 and DSM-IV. ICD-10 is mainly adopted in China, and refers to the first-onset depression and recurrent depression, but does not include bipolar depression. Patients often have typical symptoms of depressed mood, loss of interest and pleasure, loss of energy or fatigue.

Treatment of depressive episodes achieves three goals: the clinical cure rate is improved, the disease and disability rate is reduced to the maximum extent, and the key point is to thoroughly eliminate clinical symptoms; secondly, the living quality is improved; preventing recurrence. The therapeutic principles for depression mainly include: individualized treatment; the dosage is gradually increased, the minimum effective dose is adopted as far as possible, and adverse reactions are reduced to the minimum, so that the medication compliance is improved; thirdly, sufficient pedicure course treatment; fourthly, the medicine is used singly as far as possible, if the curative effect is not good, the conversion treatment, the synergistic treatment or the combination treatment can be considered, but the mutual effect of the medicines needs to be paid attention; informing before treatment; closely observing the change of illness state and adverse reaction during the treatment period and timely treating; seventhly, the treatment effect can be enhanced by combining psychological treatment; actively treat other body diseases, substance dependence, anxiety disorder and the like which are commonly suffered from depression.

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

Amitriptyline Hydrochloride, molecular formula C20H 23N. HCl, molecular weight 313.87, chemical name: n, N-dimethyl-3- [10, 11-dihydro-5H-dibenzo (a, d) cycloheptatrien-5-ylidene ] -1-propanamine hydrochloride having the chemical structure:

amitriptyline hydrochloride is one of antidepressant drugs used for primary insomnia at present, belongs to tricyclic antidepressant drugs, mainly plays a role by blocking reabsorption of norepinephrine and 5-hydroxytryptamine, and can also block neurotransmitters such as acetylcholine and histamine. 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 may be used in pediatric therapy for the treatment of childhood hyperkinetic syndrome. The clinical application method is that the daily dosage of an adult is 25mg once and 2-3 times a day, and then gradually increases to 150-250 mg a day and 3 times a day according to the disease condition and tolerance condition, the high dose does not exceed 300mg a day, and the maintenance dose is 50-150 mg a day.

At present, the dosage form of amitriptyline hydrochloride is mainly 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 of the tablet is: 1) weighing raw materials according to a proportion, uniformly mixing amitriptyline hydrochloride, corn starch, dextrin, pregelatinized starch, calcium hydrophosphate, sucrose, hydroxypropyl methyl cellulose and low-substituted hydroxypropyl cellulose, then crushing, and sieving with a 100-mesh sieve to obtain a mixture; 2) adding silicon dioxide and fructus amomi powder into the mixture, uniformly mixing, putting into a granulator, boiling and mixing for 5 minutes, then spraying absolute ethyl alcohol accounting for 20 percent of the total mass of the mixture, drying by starting steam after spraying, controlling the air inlet temperature to be 100 ℃, controlling the air outlet temperature to be 40 ℃, and drying for 10 minutes to obtain granules with the water content of 1-2 percent; 3) adding magnesium stearate and carboxymethyl starch sodium into the dried granules in sequence, granulating by using a granulator with a 10-mesh sieve, putting into a lifting hopper mixer, mixing at the rotating speed of 10 revolutions per minute for 15 minutes, uniformly mixing, and tabletting by using a tabletting machine 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 new useful drugs such as pharmaceutical compositions for realizing such treatment methods.

Disclosure of Invention

The present invention aims to provide a novel method for treating mental diseases, or the present invention aims to provide a novel beneficial drug, such as a pharmaceutical composition, for realizing the treatment method, or the present invention aims to provide a novel pharmaceutical composition with amitriptyline hydrochloride as an active ingredient. It has been surprisingly found that pharmaceutical compositions comprising amitriptyline hydrochloride prepared by the process of the invention exhibit one or more advantageous effects, and the 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 by weight of amitriptyline hydrochloride,

8-12 parts by weight of glyceryl behenate,

4-6 parts by weight of arginine,

0 to 200 parts by weight of a solid pharmaceutical excipient, 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 present invention, which is a formulation in solid form.

The pharmaceutical composition according to the first aspect of the invention, which 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 excipient comprises one or more types selected from the group consisting of: diluent, disintegrant, adhesive, glidant and lubricant. The solid pharmaceutic adjuvants are common adjuvants for solid preparations, and the selection, the addition amount and the addition mode of the solid pharmaceutic adjuvants are well known by a person skilled in the preparation field. For example, diluents to make solid formulations, especially tablets, of suitable size or volume for oral administration, typical diluents are, for example, but not limited to, corn starch, dextrin, pregelatinized starch, dibasic calcium phosphate, sucrose. For example, when formulated into tablets, it may be beneficial to add an appropriate amount of disintegrant, typically from 1 to 10%, such as from 2 to 8%, typically a disintegrant such as, but not limited to, low substituted hydroxypropylcellulose, sodium starch glycolate, and the like. For example, it may be beneficial to add a suitable amount of binder when the composition is granulated or even further granulated into tablets, which may be 0-10%, such as 0-8%, typical binders such as but not limited to hydroxypropyl methylcellulose, or the material may be granulated by wetting it with a wetting agent such as water, ethanol or an ethanol solution instead of a binder, which is removed in the final pharmaceutical composition of the invention (residual traces or pharmaceutically acceptable amounts of wetting agent are unavoidable), which may especially contribute to the increased stickiness of the overall material by excipients in the material that are not formulated into a binder solution, such as the above mentioned hydroxypropyl methylcellulose. For example, to aid in the processing of solid formulations in the granular state, it may be beneficial to enhance the flowability of the granules by adding a glidant, typically in an amount of 0 to 5%, for example 0.5 to 4% of the granule mass, typical glidants such as, but not limited to, silicon dioxide. For tablets, to avoid material sticking, it is beneficial to add a lubricant, typically in an amount of 0-5%, such as 0.5-3% of the final blend material, typically a lubricant such as, but not limited to, magnesium stearate.

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

(1) mixing amitriptyline hydrochloride and arginine, then crushing into powder of 120 meshes, uniformly mixing the mixed powder and powdered glyceryl behenate (60 meshes), heating the mixing container to 85 ℃ under stirring, keeping the temperature and stirring for 25-30 min, and cooling at room temperature to obtain a powdered pharmaceutical composition (80 meshes for example); and, optionally,

(2) and (2) mixing the powdery pharmaceutical composition obtained in the step (1) with solid pharmaceutic adjuvants to prepare a solid pharmaceutical preparation.

It has been surprisingly found that the combination of the active drug mixed with arginine and glyceryl behenate by the above process exhibits enhanced bioavailability.

The pharmaceutical composition according to the first aspect of the present invention, wherein the solid pharmaceutical excipient comprises:

diluent (b): corn starch, dextrin, pregelatinized starch, calcium hydrogen phosphate, sucrose,

Adhesive: hydroxypropyl methylcellulose (e.g. 60RT50 type),

Disintegrating agent: low substituted hydroxypropyl cellulose, sodium carboxymethyl starch (such as Suqiang),

Glidant: silicon dioxide,

Lubricant: magnesium stearate.

According to the pharmaceutical composition of the first aspect of the invention, the solid pharmaceutic adjuvant comprises, 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, for example, 1.4 parts by weight of low-substituted hydroxypropylcellulose, 0.2 to 0.5 part by weight, for example, 0.36 part by weight of sodium starch glycolate (for example, Queen rapidly disintegrating),

0.5 to 1 part by weight, for example, 0.7 part by weight of silicon dioxide, and 0.5 to 1 part by weight, for example, 0.7 part by weight of magnesium stearate.

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

(2a) crushing each solid pharmaceutic adjuvant into powder which can pass through a 100-mesh sieve;

(2b) mixing the powdered pharmaceutical composition obtained in step (1) with diluent (such as corn starch, dextrin, pregelatinized starch, calcium hydrogen phosphate, sucrose), binder (such as hydroxypropyl methylcellulose), disintegrant (such as low-substituted hydroxypropyl cellulose), and glidant (such as silicon dioxide) to obtain mixture;

(2c) mixing the mixture in a boiling type granulator for 5 minutes, then spraying absolute ethyl alcohol accounting for 15-25% of the total weight of the mixture, for example 20%, boiling and drying after spraying till the moisture content of the granules is 1-2%;

(2d) adding disintegrant (such as carboxymethyl starch sodium) and lubricant (such as magnesium stearate) into the above dried granules, mixing, grading (such as with 10 mesh sieve) to obtain final mixed granule, and tabletting to obtain tablet.

The pharmaceutical composition according to the first aspect of the present invention, wherein the solid pharmaceutical preparation 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 weight of the coating material is 1-4%, such as 1-3% of the weight of the tablet core.

The pharmaceutical composition according to the first aspect of the present invention is a coated tablet, and the material formulation thereof is as follows:

25 parts by weight of amitriptyline hydrochloride,

8-12 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,

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

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

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

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

0.2-0.5 parts by weight of sodium starch glycolate (such as Queen quickly disintegrating tablet), such as 0.36 parts by weight,

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

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

The coating material is 1-4% by weight of the core, for example 1-3%.

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

(1) mixing amitriptyline hydrochloride and arginine, then crushing into powder of 120 meshes, uniformly mixing the mixed powder and powdered glyceryl behenate (60 meshes), heating the mixing container to 85 ℃ under stirring, keeping the temperature and stirring for 25-30 min, and cooling at room temperature to obtain a powdered pharmaceutical composition (80 meshes for example);

(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 disintegrant (such as low-substituted hydroxypropyl cellulose) and a glidant (such as silicon dioxide) to obtain a mixture;

(2c) mixing the mixture in a boiling type granulator for 5 minutes, then 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 moisture content of the granules is 1-2%;

(3) And (3) taking the tablets obtained in the step (2d) as tablet cores, and performing tablet coating to obtain coated tablets.

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

25 parts by weight of amitriptyline hydrochloride,

8-12 parts by weight of glyceryl behenate,

4-6 parts by weight of arginine,

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

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

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

The method according to the second aspect of the present 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 excipient comprises one or more types selected from the group consisting of: diluent, disintegrant, adhesive, glidant and lubricant. The solid pharmaceutic adjuvants are common adjuvants for solid preparations, and the selection, the addition amount and the addition mode of the solid pharmaceutic adjuvants are well known by a person skilled in the preparation field. For example, diluents to make solid formulations, especially tablets, of suitable size or volume for oral administration, typical diluents are, for example, but not limited to, corn starch, dextrin, pregelatinized starch, dibasic calcium phosphate, sucrose. For example, when formulated into tablets, it may be beneficial to add an appropriate amount of disintegrant, typically from 1 to 10%, such as from 2 to 8%, typically a disintegrant such as, but not limited to, low substituted hydroxypropylcellulose, sodium starch glycolate, and the like. For example, it may be beneficial to add a suitable amount of binder when the composition is granulated or even further granulated into tablets, which may be 0-10%, such as 0-8%, typical binders such as but not limited to hydroxypropyl methylcellulose, or the material may be granulated by wetting it with a wetting agent such as water, ethanol or an ethanol solution instead of a binder, which is removed in the final pharmaceutical composition of the invention (residual traces or pharmaceutically acceptable amounts of wetting agent are unavoidable), which may especially contribute to the increased stickiness of the overall material by excipients in the material that are not formulated into a binder solution, such as the above mentioned hydroxypropyl methylcellulose. For example, to facilitate processing of solid formulations in the granular state, it may be beneficial to improve the flowability of the granules by adding a glidant, typically in an amount of 0 to 5%, for example 0.5 to 4% of the granular material, a typical glidant being for example but not limited to silicon dioxide. For tablets, to avoid material sticking, it is beneficial to add a lubricant, typically in an amount of 0-5%, such as 0.5-3% of the final blend material, typically a lubricant such as, but not limited to, magnesium stearate.

The method according to the second aspect of the invention, wherein the solid pharmaceutical excipient comprises:

diluent (b): corn starch, dextrin, pregelatinized starch, calcium hydrophosphate, sucrose,

Adhesive: hydroxypropyl methylcellulose (e.g. 60RT50 type),

Disintegrating agent: low substituted hydroxypropyl cellulose, sodium starch glycolate (such as Quejia),

Glidant: silicon dioxide,

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:

1 to 2 parts by weight, for example, 1.4 parts by weight of low-substituted hydroxypropylcellulose, 0.2 to 0.5 part by weight, for example, 0.36 part by weight of sodium starch glycolate (for example, Quikuowang),

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 preparation in the form 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 preparation comprises the steps of:

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

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

The method according to the second aspect of the present invention, wherein the pharmaceutical composition is a coated tablet, the formulation of which is as follows:

25 parts by weight of amitriptyline hydrochloride,

8-12 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,

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,

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

0.2-0.5 parts by weight of sodium starch glycolate (such as Queen rapidly disintegrating tablet), such as 0.36 parts by weight,

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

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

The coating material is 1-4% by weight of the core, for example 1-3%.

The method according to the second aspect of the invention, comprising the steps of:

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

Further, the third aspect of the present invention provides a use of the pharmaceutical composition of any one of the first aspect of the present invention or the pharmaceutical composition prepared by the method of any one of the embodiments of the second aspect of the present invention in the preparation of a medicament for treating and/or preventing mental disorders.

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

The use according to the third aspect of the invention, wherein the psychiatric disorder is anxiety or agitated depression.

Further, the fourth aspect of the present invention provides a method for treating and/or preventing a psychiatric 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 aspects of the present invention or a pharmaceutical composition prepared by a method according to any of the embodiments of the second aspects of the present invention.

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

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

In the above-described steps of the preparation method of the present invention, although the specific steps described therein are distinguished in some detail or in language description from the steps described in the preparation examples of the detailed embodiments below, those skilled in the art can fully summarize the above-described method steps in light of the detailed disclosure throughout the present disclosure.

Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict. The invention is further described below.

All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.

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 mechanisms responsible for the uptake of noradrenaline and serotonin in adrenergic and serotonergic neurons. Pharmacologically, this effect may enhance or prolong neuronal activity, since the reuptake of these biogenic amines is of physiological importance in terminating transmission activity. Some believe that this interference with the reuptake of norepinephrine and/or serotonin underlies the antidepressant activity of amitriptyline.

Amitriptyline hydrochloride has the strongest sedative effect in tricyclic antidepressants, can obviously improve the mood of depressed patients, and is suitable for treating anxiety or agitation type depression. The anti-depression effect of amitriptyline hydrochloride can improve the mood of various depression patients and improve the symptoms of slow thinking, slow behavior, inappetence and the like. Generally, the medicine can produce obvious curative effect after being taken for 7-10 days. Amitriptyline hydrochloride has strong sedative and hypnotic effects. Amitriptyline hydrochloride is suitable for various depression types, such as endogenous depression, climacteric depression, reactive depression and the like. The curative effect of the composition is superior to that of imipramine on patients with anxiety and depression symptoms. In addition, amitriptyline hydrochloride has certain curative effect on functional enuresis.

In addition, it has been found that amitriptyline, which is widely used as an antidepressant and an analgesic, directly stimulates the growth of brain nerve cells, thereby promoting brain development. Experiments show that amitriptyline can directly promote the development of nerve growth factor in the brain, maintain the oxygen content and the glucose content in nerve cells, and stimulate the nerve cells to extend neurites outwards so as to connect other nerve cells. In addition, amitriptyline also inhibits the production of the neurotoxin kainic acid. This shows that it is different from the pharmacodynamic mechanism of many antidepressant drugs. Amitriptyline is a tricyclic antidepressant that is currently widely used for the treatment of migraine and neurological disorders 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: chromatogram of blank plasma, amitriptyline and internal standard two controls (t: 7.907min is amitriptyline peak, t: 10.034min is clomipramine peak).

Detailed Description

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

The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. It will be apparent to those skilled in the art that the materials and methods of operation used in the present invention are well known in the art, unless otherwise specified.

In the following preparation of the composition, each charge is not less than 250 g as active ingredient, when the charge ratio is expressed in terms of parts by weight. In various examples of the present invention for preparing tablets, compression was performed at a specification comprising 25mg amitriptyline hydrochloride per tablet, if not otherwise specified.

Example 1: preparation of pharmaceutical composition

Prescription:

25 parts by weight of amitriptyline hydrochloride,

10 parts by weight of glyceryl behenate,

5 parts by weight of arginine,

solid pharmaceutic adjuvant:

21 parts of corn starch,

5.7 parts of dextrin,

Pregelatinized starch 3.6 parts by weight,

5.7 parts by weight of calcium hydrophosphate,

4.3 parts of cane sugar,

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

1.4 parts of low-substituted hydroxypropyl cellulose,

0.36 weight portion of sodium carboxymethyl starch (quick disintegrating king),

0.7 part by weight of silica,

0.7 part by weight of magnesium stearate,

coating materials:

opadry gastric-soluble coating premix which is 2% of the tablet core weight.

The preparation method comprises the following steps:

(1) mixing amitriptyline hydrochloride and arginine, then crushing into powder capable of passing through 120 meshes, uniformly mixing the mixed powder and powdered glyceryl behenate (passing through 60 meshes), then heating the mixing container to 85 ℃ under the stirring state, keeping the temperature and stirring for 25-30 min, and cooling at room temperature to obtain a powdered 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 type granulator for 5 minutes, then spraying absolute ethyl alcohol accounting for 20% of the total weight of the mixture, and boiling and drying after spraying until the moisture content of the granules is 1-2%;

(2d) adding disintegrating agent (carboxymethyl starch sodium) and lubricant (magnesium stearate) into the above dried granules, mixing, grading (with 10 mesh sieve), to obtain final mixed granule, and tabletting to obtain tablet.

(3) And (5) taking the tablet obtained in the step (2d) as a tablet core, and performing tablet coating to obtain a coated tablet.

The parameters of each step refer to CN109157525A (chinese patent application No. 201811245265.2, dongting) in example 1, for example: the boiling granulator is produced by Changzhou Lima drying engineering Limited company, and the water content of the obtained granules can be reduced to 1-2% by starting steam drying after the lubricant is sprayed, controlling the air inlet temperature to be 100 ℃, controlling the air outlet temperature to be 40 ℃ and drying for 10 minutes; the granulator is YK-160 granulator of Zhongcheng pharmaceutical machinery factory in Hunan; the tablet press is a ZP-5B/9B/7B tablet press of Guangzhou morning-carving mechanical equipment Limited company, and the hardness of the tablets is kept within the range of 5-6 kg; the Opadry gastric-soluble coating powder is added with water and suspended to form a coating solution with the concentration of 5-10%, and the amitriptyline hydrochloride tablets are coated in a high-efficiency coating machine, the rotation speed of a pan is 5 r/min when the coating solution is sprayed, the air inlet temperature is 80 ℃, and the air outlet temperature is 55 ℃. Although the process for preparing tablets is well known in the art, the process parameters in other embodiments of the present invention for preparing compositions are the same as those described above unless otherwise specified.

Example 2: preparation of pharmaceutical composition

Prescription:

25 parts by weight of amitriptyline hydrochloride,

12 parts by weight of glyceryl behenate,

4 parts by weight of arginine,

solid pharmaceutic adjuvant:

15 parts 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 of cane sugar,

0.5 part by weight of hydroxypropylmethylcellulose (60RT50 type),

1 part by weight of low-substituted hydroxypropyl cellulose,

0.5 weight portion of carboxymethyl starch sodium (quick disintegrating king),

0.5 part by weight of silica,

1 part by weight of magnesium stearate,

coating materials:

opadry gastric soluble coating premix which is 1% of the tablet core weight.

The preparation method comprises the following steps:

(1) mixing amitriptyline hydrochloride and arginine, then crushing into powder capable of passing through 120 meshes, uniformly mixing the mixed powder with powdery glyceryl behenate (passing through 60 meshes), then heating the mixing container to 85 ℃ under a stirring state, keeping the temperature, 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 hydrogen phosphate and sucrose), binders (hydroxypropyl methyl cellulose), disintegrants (low-substituted hydroxypropyl cellulose) and glidants (silicon dioxide) to obtain a mixture;

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

Example 3: preparation of pharmaceutical composition

Prescription:

25 parts by weight of amitriptyline hydrochloride,

8 parts by weight of glyceryl behenate,

6 parts by weight of arginine,

solid pharmaceutic adjuvant:

25 parts of corn starch,

4 parts of dextrin,

5 parts by weight of pregelatinized starch,

4 parts of calcium hydrophosphate,

6 parts of cane sugar,

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

2 parts by weight of low-substituted hydroxypropyl cellulose,

0.2 weight portion of sodium carboxymethyl starch (quick disintegrating king),

1 part by weight of silicon dioxide,

0.5 part by weight of magnesium stearate,

coating materials:

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

The preparation method comprises the following steps:

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

Example 11: preparation of pharmaceutical composition

Reference example 1 formulation and preparation, except arginine was not added.

Example 12: preparation of pharmaceutical composition

Reference is made to the formulation and preparation of example 1, except that no glyceryl behenate is added and step (1) is 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 compositionsArticle (A)

Referring to the formulation and preparation of example 1, except that arginine and glyceryl behenate were not added and step (1) was changed to: and (3) pulverizing amitriptyline hydrochloride into powder capable of passing through 120 meshes to obtain the amitriptyline hydrochloride (the amitriptyline hydrochloride is essentially the raw material medicine and is used for mixing with a diluent and the like in the step (2 b)). This example 13 is substantially the same as example 1 of CN109157525A (Chinese patent application No. 201811245265.2, Dongting) except that no fructus Amomi powder is added, and the preparation process is not substantially different.

Test example 1: pharmacokinetic study of amitriptyline

In this test example, the pharmacokinetic study of the composition prepared according to the present invention was conducted with reference to Shen Yuan literature (Shen Yuan, et al, reverse phase high performance liquid chromatography for measuring the concentration of amitriptyline in rat plasma, Zhongnan pharmacology, 2009, 7 (2): 88), etc.

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 3 workstation; the remaining equipment was commercially available conventional equipment.

Amitriptyline hydrochloride reference substance (provided by the department of examination of the applicant, batch number 200603, content > 98%), internal standard clomipramine hydrochloride (provided by the department of examination of the applicant, batch number 200816, content > 98%), acetonitrile and other reagents are chromatographically pure, triethylamine and other reagents are analytically pure; the experimental water was double distilled water.

Male SD rats, weighing 180-200 g, provided by university of traditional Chinese medicine in Hunan, SYXK (Hunan) 2019-.

2. Chromatographic conditions

C18 column (Inspire, 4.6X 250mm, 5 μm), C18 guard column (phenomene x),

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

flow rate: 1.0mL/min of the water-soluble polymer,

detection wavelength: the particle size of the nano-particles is 240nm,

column temperature: at 40 ℃.

Sample introduction amount: 20 μ l.

3. Methodology investigation

3.1. Preparation of control solution

20.0mg of amitriptyline hydrochloride reference substance is precisely weighed, and acetonitrile is used for preparing reference substance stock solution with the concentration of 200 mug/mL, and then the reference substance stock solution is diluted by a mobile phase to prepare reference substance series working solution with the concentrations of 0.5, 1.0, 2.5, 5.0, 10.0, 25.0 and 50.0 mug/mL respectively, and the reference substance series working solution is stored at 4 ℃.

3.2. Internal standard solution

The reference substance of clomipramine hydrochloride is weighed up 15mg precisely. Preparing an internal standard stock solution with the concentration of 150 mu g/mL by using methanol, diluting the stock solution into an internal standard solution with the concentration of 15 mu g/mL by using water, and storing at 4 ℃.

3.3. Plasma sample processing

Putting 200 mu L of rat blank plasma or drug-containing plasma into a 10mL centrifuge tube, precisely adding 50 mu L of internal standard clomipramine hydrochloride solution, vortexing for 30s, adding 50 mu L of 0.5mol/L sodium hydroxide, vortexing for 30s, adding 2mL of tert-butyl methyl ether, vortexing for 1min, centrifuging for 5min at 3000r/min, taking an upper organic phase, drying by drying in water bath nitrogen at 40 ℃, dissolving residues by using 100 mu L of mobile phase, and carrying out sample injection detection.

3.4. Preparation of Standard Curve

180 mu L of rat blank plasma is precisely added with 20 mu L of amitriptyline hydrochloride control strain working solution to ensure that the drug concentration of the plasma is respectively 0.05, 0.10, 0.25, 0.50, 1.0, 2.5 and 5.0 mu g/mL. And precisely adding 50 mu L of internal standard clomipramine hydrochloride solution into each tube, processing according to the plasma sample processing method, and carrying out sample injection detection. Taking the peak area ratio A of amitriptyline hydrochloride and an internal standard substance as a vertical coordinate, taking the concentration C (mu g/mL) of a substance to be detected as a horizontal coordinate, and performing linear regression, wherein the regression equation is as follows: and A is 1427.28C +11.36, r is 0.9998, and the linear range is 0.05-5.0 mu g/mL.

3.5. Specificity of the method

Respectively processing blank plasma, reference substance, and plasma sample by the above method, and injecting into liquid chromatograph. The retention time of amitriptyline was about 8min and the retention time of the internal standard was about 10 min. Endogenous impurities do not interfere with the isolation assay of the test agent. Typical chromatograms for the two controls, blank plasma plus amitriptyline and internal standard, are shown in figure 1.

3.6. Recovery and precision tests

Preparing high, medium and low concentration quality control samples according to the method under the item of '3.4. standard curve preparation', preparing reference substance plasma with the concentration of the substance to be detected being 0.05, 0.5 and 5.0 mug/mL, injecting sample to detect the peak area of the reference substance after extraction treatment by the method, and calculating the extraction recovery rate according to the ratio of the peak area measured by directly injecting sample without extraction to the reference substance solution with corresponding concentration. The recovery rate and the precision in and during the day were also examined (see Table 1).

Table 1: determination of the recovery and precision of amitriptyline in plasma by HPLC (n ═ 6)

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

4. Administration of drugs

Reagent preparation: the four coated tablets obtained in the step (3) of the four examples of example 1, example 11, example 12 and example 13 were ground into fine powder and administered in terms of the amount of the active ingredient, and were suspended in 1% sodium carboxymethylcellulose and prepared into a concentration of about 1ml of a liquid medicine to be orally administered to each animal.

SD rats fasted for 8 hours were randomly divided into four groups of 6 animals, and the drugs of examples 1, 11, 12 and 13 were orally gavaged with a dose of 60mg/kg animal body weight as amitriptyline hydrochloride, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h and 48h before (0min) and after administration, respectively, in the retroorbital venous plexus, 0.5mL of heparin was anticoagulated, plasma was aliquoted, treated as "3.3. plasma sample treatment", and the plasma concentration at each time point was measured and calculated using HPLC method. Animals were fed ad libitum 2 hours after dosing, with no water deprivation during the test period.

Next, pharmacokinetic parameters were calculated for each group of animals using a non-compartmental model analysis method according to the plasma concentration-time curve using DAS 2.0 pharmacokinetic processing analysis software. AUC0 → 48h was calculated as the blood concentration at each time point by the trapezoidal method; AUC0 → ∞ is calculated as follows: AUC0 → ∞ AUC0 → 48h + C48h/λ, where C48h is the blood concentration at the last point and λ is the terminal elimination rate constant; lambda is obtained by the slope of the straight line part at the tail end of the logarithmic blood concentration-time curve, and t1/2 is 0.714/lambda; CL/F is the apparent clearance; MRT is the mean residence time. Pharmacokinetic parameters between groups were t-tested using SPSS22.0 statistical software. See table 2.

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

P <0.05 compared to the example 1 group.

As can be seen from the above table results, of the important parameters Cmax, AUC0 → 48h, AUC0 → ∞ which are extremely correlated with bioavailability, example 1 group is significantly higher than the other groups, indicating that the bioavailability of the example 1 composition is significantly higher.

In supplementary tests, the applicant also referred to the above "test example 1: amitriptyline pharmacokinetics study "was conducted in example 1, step (1), using a powdered pharmaceutical composition, also administered at a dose of 60mg/kg animal body weight, calculated as amitriptyline hydrochloride, and the results were obtained (n ═ 6): tmax (min) ═ 62.25 ± 22.36, Cmax (μ g/L) ═ 109.27 ± 22.83, t1/2(min) ═ 278.56 ± 59.51, AUC0 → 48h (μ g/L · min) ═ 18184.53 ± 1895.33, AUC0 → ∞ (μ g/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 indicate that the powdered pharmaceutical composition obtained in step (1) can impart higher bioavailability to the final tablet.

Test example 2: dissolution study

Taking a test sample, and measuring according to a dissolution rate and release rate measuring method (0931 first method of the four general rules of the 2020 edition of Chinese pharmacopoeia); using hydrochloric acid solution (9 → 1000)900ml as dissolution medium, rotating speed is 100 rpm, operating according to law, taking 10ml of solution after 45 minutes, filtering; accurately measuring 5ml of the subsequent filtrate, placing in a 10ml measuring flask, diluting to scale with dissolution medium, and shaking; measuring absorbance at 239mn wavelength by ultraviolet-visible spectrophotometry (four parts general rule 0401 of Chinese pharmacopoeia 2020 edition) according to absorption coefficient of C20H 23N. HC1

The elution amount for each test article was calculated for 444.

Under the above conditions, the dissolution rate of the amitriptyline hydrochloride tablet of 25 mg/tablet is more than 75% of the marked amount according to the general pharmaceutical standard.

Dissolution rate measurements were carried out on 6 coated tablets (25 mg/tablet) obtained in examples 1 to 3 and examples 11 to 13 using the above measurement method, and the results were (percentage relative to the indicated amount): 92.1%, 89.8%, 91.6%, 92.8%, 89.2% and 90.3%, the results show that the determination results of the 6 coated tablets under the pharmacopoeia dissolution determination conditions are not obviously different and are all between 89% and 93%, and the difference between the results and the above bioavailability results show that the in vitro dissolution rate and the absorption percentage of the tablet have no direct correlation with respect to the formula/process difference of each embodiment of the invention.

Further, the final blend granules obtained in step (2d) of examples 1 to 3 and examples 11 to 13 were filled into gelatin empty capsules of an appropriate size, each granule being filled in an amount corresponding to a granule containing 25mg of amitriptyline hydrochloride, to obtain 6 capsules; according to the dissolution rate measuring method, the dissolution rate of each capsule is measured, and the result is between 90 and 93 percent, for example, the dissolution rate of the capsule in example 1 is 91.3 percent, and the result is basically not different from the result of a tablet.

Test example 3: determination of content

The test example refers to the pharmacopoeia method to determine the content of active ingredient in the tablet.

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

The content of 6 coated tablets (25 mg/tablet) obtained in examples 1 to 3 and examples 11 to 13 was measured by the above method, and was in the range of 99.2 to 101.6%, for example, the content of the tablet in example 1 was 100.6%.

Test example 4: examination of related substances

In this test example, the relevant substances of 6 kinds of coated tablets prepared in examples 1 to 3 and examples 11 to 13 were measured with reference to the relevant substance examination items in the item of amitriptyline hydrochloride tablet variety carried on the second part 1183 of the 2020 edition of Chinese pharmacopoeia.

As a result: examples 1-3, examples 11-13 all had less than 0.16% of the individual impurities of the 6 coated tablets, e.g., 0.09% of the maximum individual impurity of the tablets of example 1,

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

According to the results of the test examples 2 to 4, it is shown that each tablet prepared by the invention meets the current standard.

Test example 5: stability survey

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

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 types of coated tablets in examples 1 to 3 were: 99.7%, 100.3%, 99.4%;

the maximum individual impurities of the 3 coated tablets of examples 1-3 were: 0.11%, 0.13%, 0.09%, the total amount of each impurity being 0.34%, 0.29%, 0.37%, respectively.

The above results show that some tablets prepared according to the invention have excellent stability.

The present invention is illustrated in detail by the examples described above, but the present invention is not limited to the details described above, i.e., it is not intended that the present invention be implemented by relying on the details described above. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.

Claims

1. A pharmaceutical composition, comprising: 25 parts of amitriptyline hydrochloride, 8-12 parts of glyceryl behenate, 4-6 parts of arginine and 0-200 parts of solid pharmaceutic adjuvant, such as 0-150 parts, such as 0-100 parts.

2. The pharmaceutical composition according to claim 1, which is in the form of a solid formulation, such as a tablet formulation.

3. The pharmaceutical composition according to claim 1, wherein the solid pharmaceutical excipient comprises one or more types selected from the group consisting of: diluents, disintegrants, binders, glidants, lubricants; for example, typical diluents such as, but not limited to, corn starch, dextrin, pregelatinized starch, dibasic calcium phosphate, sucrose; for example, typical disintegrants such as, but not limited to, low substituted hydroxypropyl cellulose, sodium starch glycolate, and the like; for example, typical binders such as, but not limited to, hydroxypropyl methylcellulose or the binder is replaced with a wetting agent such as water, ethanol or ethanol solution; for example, the glidant is selected from silicon dioxide; for example, the lubricant is selected from magnesium stearate; or

The pharmaceutical composition is prepared by the following process:

4. The pharmaceutical composition according to claim 1, wherein the solid pharmaceutical excipient comprises:

Adhesive: hydroxypropyl methylcellulose (e.g. 60RT50 type),

Glidant: silicon dioxide,

Lubricant: magnesium stearate.

5. The pharmaceutical composition according to claim 1, wherein the solid pharmaceutical excipient comprises, per 25 parts by weight amitriptyline hydrochloride:

6. The pharmaceutical composition according to claim 3, which is in the form of a solid pharmaceutical preparation of a tablet, wherein the step (2) of mixing the powdery pharmaceutical composition obtained in the step (1) with a solid pharmaceutical excipient to prepare a solid pharmaceutical preparation comprises the steps of:

7. The pharmaceutical composition according to claim 1, wherein the solid pharmaceutical formulation in tablet form is further coated; for example, the coating is a gastric soluble coating material; for example, the weight of the coating material is 1-4%, such as 1-3% of the weight of the tablet core.

8. The pharmaceutical composition according to claim 1, characterized in that:

the tablet is a coated tablet, and the formula of the material is as follows:

25 parts by weight of amitriptyline hydrochloride,

8-12 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,

4 to 7 parts by weight of dextrin, 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, for example, 0.7 part by weight of silica,

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

A coating material which is 1-4% such as 1-3% of the weight of the tablet core;

alternatively, it is a coated tablet, and the preparation method comprises the following steps:

(2d) adding disintegrant (such as carboxymethyl starch sodium) and lubricant (such as magnesium stearate) into the above dried granules, mixing, grading (such as with 10 mesh sieve) to obtain final mixed granule, and tabletting to obtain tablet;

9. A process for preparing a pharmaceutical composition according to any one of claims 1 to 8, comprising the steps of:

(2) mixing the powdery pharmaceutical composition obtained in the step (1) with solid pharmaceutic adjuvant to prepare a solid pharmaceutical preparation,

for example, the step (2) further comprises the following steps:

(2d) adding disintegrant (such as carboxymethyl starch sodium) and lubricant (such as magnesium stearate) into the above dried granules, mixing, grading (such as with 10 mesh sieve) to obtain final mixed granule, and tabletting the final mixed granule with tabletting machine to obtain tablet dosage form of pharmaceutical composition,

for example, further, solid pharmaceutical preparations in tablet form may be further coated,

for example, it comprises the following steps:

10. Use of a pharmaceutical composition according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment and/or prevention of a psychotic disorder; for example, the psychiatric disorder is depression; for example, the psychiatric disorder is anxiety or agitated depression.