TW202325285A - Powder drug formulation - Google Patents

Abstract

The present invention pertains to a powder drug formulation that improves the solubility of an antidepressant which is a tricyclic or tetracyclic antidepressant or a triazolopyridine-based antidepressant. In more detail, the present invention pertains to a powder drug formulation that includes particles containing an excipient together with an antidepressant which is a tricyclic or tetracyclic antidepressant or a triazolopyridine-based antidepressant.

Description

powder preparation

The present invention relates to a powder preparation comprising antidepressants, more specifically, the present invention relates to a powder preparation comprising particles containing antidepressants and excipients.

This patent application claims priority based on the previously filed Japanese patent application, namely Japanese Patent Application No. 2021-169147 (filing date: October 14, 2021). The entire disclosure of this prior patent application is hereby incorporated by reference as part of the disclosure of the present invention.

Delirium is a transient disturbance of consciousness or a decrease in cognitive function caused by various factors such as physical illness or drug treatment, surgery or hospitalization, regardless of gender, age or age. It is a symptom commonly seen in elderly patients during hospitalization and after surgery. The onset of delirium is detrimental to patients due to reduced therapeutic effects and increased risk of falls, and it can lead to prolonged hospital stays and burdens on the medical field due to concerns about medical treatment, so the development of therapeutic drugs is expected. Also, if the delirium state of patients undergoing home treatment can be controlled by drug therapy, it can be expected to contribute to the reduction of the burden of care in modern society where the burden of care is increasing due to aging.

It is proposed that Mirtazapine, which is a tetracyclic antidepressant and classified into norepinephrine functional and specific serotonin functional antidepressants, has a therapeutic effect on delirium. Patent Document 1). However, it is difficult for patients who are elderly and delirium showing symptoms of hyperactivity or dementia to take this oral drug, and it takes time until the drug is absorbed in the digestive tract after oral administration and the drug is effective. Therefore, it is expected to develop a usable A novel formulation that is excellent and can be expected to act quickly.

Furthermore, it is known that Moyouping is also useful for the treatment of phantom limb pain (Non-Patent Document 2).

In addition, not only delirium or phantom limb pain, but also patients who need drugs that act on the psychiatric system such as antidepressants, the number of patients who have difficulty in taking oral administration preparations is quite large. Compared with injections, etc., the number of patients Nasal preparations that are less burdensome and easy to administer are more necessary at the clinical site.

Since the capillary network in the nasal cavity is developed, when a fat-soluble low-molecular drug with good membrane penetration is in a dissolved state, it can be expected to absorb the drug rapidly through nasal administration. Furthermore, nasal administration using a dedicated nebulizer is a relatively easy method by which a medical practitioner or caregiver can administer the agent to a delirium patient. On the other hand, it is known that due to the presence of mucociliary clearance function in the nasal cavity, the administered preparation is quickly eliminated from the respiratory part, which is the main site of drug absorption, toward the throat. By administering in the form of a nasal solution, the removal of undissolved drugs can be avoided, but Moyouping antidepressants are unstable to light, and the photodecomposition of the compound is usually further promoted in the solution state compared to the solid state. Therefore, in order to suppress the risk of photodecomposition of Moyouping and avoid the mucociliary clearance function in the nasal cavity, it is required to develop a technical means for rapid dissolution after administration. [Prior Art Literature] [Non-patent literature]

[Non-Patent Document 1] Zhanghong Jinzhong et al., Psychiatry, 2011, 53(11), p.1123-1125. [Non-Patent Document 2] Todd A. Kuiken et al., Pain Practice, 2005, Vol. 5, Issue 4, pp.356-360.

The inventors of the present invention have found that the solubility of Moyouping antidepressants can be improved by using powder preparations containing antidepressants as tricyclic or tetracyclic antidepressants or triazolopyridine antidepressants. Antidepressants and excipients for depression drugs.

Therefore, the present invention provides a powder formulation containing the above-mentioned antidepressant having improved solubility of a tricyclic or tetracyclic antidepressant or a triazolopyridine antidepressant.

The following inventions are included in the present invention. [1] A powder preparation comprising granules containing: (a) an antidepressant that is a tricyclic or tetracyclic antidepressant, or a triazolopyridine antidepressant; (b) an excipient agent. [2] The powder preparation as described in [1], wherein the particles further contain (c) acid. [3] The powder preparation as described in [1] or [2], wherein the aforementioned (a) tricyclic or tetracyclic antidepressant is a tricyclic or tetracyclic nitrogen-containing heterocyclic compound or a salt thereof. [4] The powder preparation according to any one of [1] to [3], wherein the aforementioned (a) tetracyclic antidepressant is a compound represented by the following formula (1) or a salt thereof. [In formula (1), R ₁ represents an alkyl group with 1 to 4 carbons or hydrogen. _R2 represents carbon or nitrogen, and dashed lines indicate the presence or absence of a bond. When R ₂ is carbon, it means that there is a bond, and when R ₂ is nitrogen, the dotted line means that there is no bond. R ₃ represents carbon or nitrogen. ] [5] The powder preparation as described in [1] or [2], wherein the aforementioned (a) tricyclic or tetracyclic antidepressants are selected from Moyouping, Mianserin, Sipro A group consisting of Setiptiline, Amitriptyline, salts thereof, and combinations thereof. [6] The powder preparation as described in any one of [1] to [5], wherein the aforementioned (a) triazolopyridine-based antidepressant is selected from the group consisting of Trazodone and its salts, and the like. The group formed by the combination. [7] The powder preparation as described in any one of [1] to [6], wherein the excipient (b) is selected from the group consisting of sugars, sugar alcohols, and cellulose derivatives, and combinations thereof of the group. [8] The powder preparation according to any one of [2] to [7], wherein the acid (c) is an organic acid. [9] The powder preparation as described in any one of [2] to [8], wherein the aforementioned (c) acid is selected from the group consisting of monocarboxylic acid, dicarboxylic acid, sulfonic acid, and combinations thereof Group. [10] The powder preparation as described in [9], wherein the dicarboxylic acid is selected from glutamic acid, aspartic acid, tartaric acid, maleic acid, malic acid, succinic acid, citric acid, fumaric acid, At least one selected from the group consisting of acid and adipic acid. [11] The powder preparation as described in any one of [1] to [10], wherein the mass ratio of (a) antidepressant to (b) excipient ((a) antidepressant: (b) Excipients) at a ratio of 1:1 to 1:30. [12] The powder preparation as described in any one of [2] to [11], wherein the mass ratio of (a) antidepressant to (c) acid ((a) antidepressant: (c) acid) 1:0.01 to 1:2. [13] The powder preparation according to any one of [1] to [12], wherein the particles are fine particles. [14] The powder formulation as described in [13], further comprising a carrier. [15] The powder preparation according to any one of [1] to [14], wherein the powder preparation is for nasal administration or pulmonary administration. [16] The powder preparation according to any one of [1] to [15], wherein the fine particles are obtained by a jet mill or a spray dryer. [17] The powder preparation as described in any one of [1] to [16], which is used for the treatment or prevention of delirium, phantom limb pain, chronic itching, or depression or a depressive state. [18] A method for producing the powder preparation described in any one of [1] to [17], comprising: mixing the aforementioned (a) antidepressant and (b) excipients and making fine particles step. [19] A method for producing a powder preparation as described in any one of [2] to [17], comprising: mixing the aforementioned (a) antidepressant, (b) excipient, and (c) acid and The step of performing fine particles. [20] The method described in [18] or [19], wherein the fine particle formation is performed by a jet mill, a spray dryer, or a combination thereof.

According to the present invention, the solubility of an antidepressant which is a tricyclic or tetracyclic antidepressant or a triazolopyridine antidepressant can be effectively improved by using the above-mentioned powder preparation. Here, the increase in solubility includes an increase in the solubility of an antidepressant (preferably, supersaturation of the solubility of an antidepressant alone) and/or an increase in the dissolution rate of a drug. For example, the powder formulations of the present invention dissolve rapidly after administration. Also, according to the present invention, the stability of an antidepressant that is a tricyclic or tetracyclic antidepressant or a triazolopyridine antidepressant can be maintained or improved by using the above-mentioned powder preparation. Also, according to the present invention, the bioavailability of the above-mentioned antidepressants can be effectively increased by using the above-mentioned powder preparation. In addition, according to the present invention, the dissolution behavior of the above-mentioned antidepressant in nasal environment can be improved by using the above-mentioned powder preparation.

One of the characteristics of the powder preparation of the present invention is that it comprises particles containing an antidepressant which is a tricyclic or tetracyclic antidepressant or a triazolopyridine antidepressant and an excipient.

[ Antidepressant that is a tricyclic or tetracyclic antidepressant, or a triazolopyridine antidepressant ] Examples of the antidepressant in the present invention include tricyclic or tetracyclic antidepressants, or Triazolopyridines are antidepressants.

The tricyclic or tetracyclic antidepressants are not particularly limited as long as the effect of the present invention can be achieved. For example, tricyclic or tetracyclic nitrogen-containing heterocyclic compounds or salts thereof can be mentioned. Preferable examples of tricyclic antidepressants include amitriptyline, imipramine, doxepin, clomipramine, nortriptyline, amoxapine, trimipramine, lofepa Amitriptyline, dothiapine, protriptyline, didipramine and salts thereof, more preferably amitriptyline.

The tetracyclic antidepressant is preferably a compound represented by the following formula (1) or a salt thereof. [Chem 2] [In formula (1), R ₁ represents an alkyl group with 1 to 4 carbons or hydrogen. _R2 represents carbon or nitrogen, and dashed lines indicate the presence or absence of a bond. When R ₂ is carbon, it means that there is a bond, and when R ₂ is nitrogen, the dotted line means that there is no bond. R ₃ represents carbon or nitrogen. ]

In the present invention, the carbon number of the "alkyl group" represented by R ₁ in formula (1) is not particularly limited, but is preferably 1-4. The above-mentioned alkyl group may be linear or branched.

Specific examples of the alkyl represented by _R include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, third butyl, etc., preferably Methyl, ethyl.

According to a preferred embodiment of the present invention, R ₁ represents an alkyl group, R ₂ represents nitrogen, R ₃ represents nitrogen, more preferably R ₁ represents a methyl group, R ₂ represents nitrogen, and R ₃ represents nitrogen.

According to another preferred embodiment of the present invention, R ₁ represents alkyl, R ₂ represents nitrogen, R ₃ represents carbon, more preferably R ₁ represents methyl, R ₂ represents nitrogen, and R ₃ represents carbon.

According to another preferred embodiment of the present invention, R ₁ represents an alkyl group, R ₂ represents a carbon, R ₃ represents a carbon, more preferably R ₁ represents a methyl group, R ₂ represents a carbon, and R ₃ represents a carbon.

Preferable examples of tetracyclic antidepressants include Moyouping, mianserin, sportiline, maprotiline, and their salts; more preferably moyouping, mianserin Lin, sprotiline and salts thereof, and more preferably Moyouping, mianserin and salts thereof.

Preferable examples of triazolopyridine-based antidepressants include trazodone and its salts, and more preferably trazodone.

Furthermore, Moyouping is also known as a norepinephrine functional and specific serotonin functional antidepressant. Therefore, according to another aspect of the present invention, the antidepressants of the present invention can also be norepinephrine functional and specific serotonin functional antidepressants.

In addition, it is known that tricyclic antidepressants or tetracyclic antidepressants have histamine H1 receptor antagonism or serotonin (5-HT _2A/2C ) receptor blocking effects. Helps improve night sleep of elderly patients. Therefore, according to another aspect of the present invention, the antidepressant of the present invention can also be a histamine H1 receptor antagonist and/or a serotonin (5-HT _2A/2C ) receptor blocking drug.

Also, it is known that Moxapine mainly activates 5-HT ₁ receptors, and thus is effective for phantom limb pain. Therefore, according to another aspect of the present invention, the antidepressant of _the present invention can also be an antidepressant with 5- _HT receptor functionality, preferably a tricyclic or Tetracyclic antidepressants or triazolopyridine antidepressants.

The aforementioned antidepressants may be in either free form (eg, free base, etc.) or salt (eg, acid addition salt, etc.). In addition, the aforementioned antidepressants may be racemates or R and S enantiomers. One of these antidepressants may be used alone, or two or more of them may be used in combination if necessary. Preferably a single antidepressant is used.

The aforementioned antidepressants can easily form acid addition salts with pharmaceutically acceptable acids (preferably pharmaceutically acceptable salts). Therefore, as the salt of the above-mentioned antidepressants, for example: salts of inorganic acids such as hydrochloride, sulfate, nitrate, phosphate, hydrobromide; maleate, acetate, p-toluenesulfonate Salts of organic acids such as acid salt, methanesulfonate, oxalate, fumarate, malate, tartrate, citrate, benzoate, etc. These acid addition salts can also be used as active ingredient compounds in the present invention in the same manner as antidepressants in free form.

The content of the antidepressant in the powder preparation of the present invention is not particularly limited as long as it does not hinder the effects of the present invention, and is, for example, 0.01% by mass to 50% by mass relative to the entire preparation, preferably 0.05% by mass % to 30% by mass, more preferably 0.1% to 15% by mass, more preferably 1% to 12% by mass, further preferably 3% to 11% by mass. The content of the antidepressant in the powder preparation of the present invention can be determined by HPLC (High Performance Liquid Chromatograph; High Performance Liquid Chromatography) method, specifically, it can be determined by the HPLC-UV (High Performance Liquid Chromatograph) described in the following examples. Performance Liquid Chromatography-Ultraviolet; high performance liquid chromatography-ultraviolet) method or HPLC-fluorescence method for determination.

[excipient] The excipients used in the present invention are not particularly limited, and include excipients used or to be used in medicine or food in the future.

The excipient of the present invention is not particularly limited as long as the effect of the present invention can be achieved, and it is preferably an excipient effective in improving the solubility of antidepressants and/or reducing the ability of self-aggregation. Therefore, the excipient is preferably a water-soluble excipient, and is preferably an excipient that does not significantly absorb moisture in terms of the properties of the present preparation. Preferred excipients in the present invention include sugars, sugar alcohols, cellulose derivatives and combinations thereof. Examples of the sugars include lactose, glucose, saccharose, and sucrose, preferably lactose. Here, examples of lactose include lactose hydrate (for example, lactose monohydrate) and anhydrous lactose, preferably lactose hydrate. As said sugar alcohol, erythritol, mannitol, sorbitol, trehalose are mentioned, for example, Erythritol is preferable. Examples of the aforementioned cellulose derivatives include crystalline cellulose, methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. The above-mentioned excipients may be used alone, or may be used in combination of two or more, if necessary.

In the preparation of the present invention, the mass ratio of the antidepressant to the excipient ((a) antidepressant: (b) excipient) is not particularly limited, as long as it does not hinder the effect of the present invention, preferably It is in the range of 1:0.1 to 1:100, more preferably in the range of 1:1 to 1:30, and more preferably in the range of 1:2 to 1:15. Also, when the preparation of the present invention includes the carrier mentioned later, the mass ratio of the antidepressant and the excipient is preferably in the range of 1:0.1 to 1:10, more preferably 1:0.2 to 1:5 scope. By setting this range, the uniformity of the content of the antidepressant is improved, the variation in the content of each administration is reduced, and the change in the blood concentration transition of the antidepressant is reduced for each administration. Therefore, further consistency can be expected. Effect.

[carrier] According to an embodiment of the present invention, the above-mentioned powder preparation may contain particles (preferably fine particles) containing an antidepressant, excipients, and an acid if necessary, and a carrier. In the above-mentioned powder preparation, it is preferable to mix the above-mentioned particles with a carrier.

The carrier used in the present invention is not particularly limited, and includes carriers used or will be used in the future for medicines or foods.

The carrier of the present invention is not particularly limited as long as the effect of the present invention is achieved. It is preferable to prevent aggregation or adhesion of particles containing antidepressants before administering the powder preparation, and to use an inhaler or A carrier that is efficiently separated during inhalation or nebulization by a nebulizer to improve absorption efficiency. Preferred carriers in the present invention include sugars, sugar alcohols, calcium sulfate, calcium carbonate, talc, titanium oxide, and combinations thereof. Examples of the sugars include lactose, glucose, fructose, sucrose, maltose, and dextrins, and lactose is preferred. Here, examples of lactose include lactose hydrate (for example, lactose monohydrate) and anhydrous lactose, preferably lactose hydrate. The above-mentioned carriers may be used alone, or may be used in combination of two or more kinds as necessary. When better conditions are required, it is ideal to select raw materials considering the suitability of excipients mixed with antidepressants. The carrier of the same material as the agent.

The powder formulation of the present invention is preferably administered using a nebulizer or an inhaler, therefore, the carrier preferably has an aerodynamically acceptable particle size. By using a carrier, fine particles can be attached to the surface of the carrier, thereby suppressing aggregation between fine particles. Therefore, the particle size of the carrier is preferably larger than that of the fine particles. Specifically, the median particle size of the carrier is preferably in the range of 10 μm to 200 μm, more preferably in the range of 40 μm to 150 μm. Including the examples, the median diameter of the carrier can be measured by laser diffraction and scattering methods. As a laser diffraction scattering type particle size distribution measuring device, for example, Microtrac MT3000II (MicrotracBEL Inc.) can be used.

The mass ratio of particles (preferably fine particles) containing antidepressants, excipients and acids as needed to the carrier can be appropriately set according to the dosage, the type of inhaler or nebulizer, the applied disease, etc., preferably It is in the range of 1:1 to 1:100, more preferably in the range of 1:2 to 1:10. By setting this range, the uniformity of the content of the antidepressant is improved, the difference in the content of each administration is reduced, and the variation of the blood concentration change of the antidepressant is reduced for each administration. Therefore, it is possible to further expect consistent Effect. Furthermore, by setting it as this range, a fine particle will adhere to a carrier surface further, and it can be expected that the aggregation between fine particles will be further suppressed.

[acid] According to a preferred embodiment of the present invention, the particles in the above-mentioned powder formulation contain antidepressants, excipients, and may further contain acids. The acid used in the present invention is not particularly limited, and includes acids that are used or will be used in medicine or food in the future.

Examples of the acid include organic acids such as carboxylic acid and sulfonic acid from the viewpoint of improving solubility and/or stability by increasing the degree of supersaturation of the antidepressant. Here, the acid may be any acid as long as it has the properties of an acid, and zwitterions which are acids and have properties of a base are also included. As a carboxylic acid, a monocarboxylic acid, a dicarboxylic acid, etc. are mentioned. Examples of the dicarboxylic acid include glutamic acid, aspartic acid, tartaric acid, maleic acid, malic acid, succinic acid, citric acid, fumaric acid, adipic acid, and combinations thereof. Preferred are glutamic acid, aspartic acid, tartaric acid, maleic acid, malic acid, and citric acid. As the sulfonic acid, preferably toluenesulfonic acid is used. These acids may be used alone or in combination of two or more.

According to a preferred embodiment of the present invention, the particles in the above-mentioned powder preparation contain an antidepressant, an excipient and an acid, and the antidepressant is Mozapine or a salt thereof. As the acid, aspartic acid, A combination of glutamic acid, maleic acid, tartaric acid, toluenesulfonic acid or the like, preferably a combination of glutamic acid, maleic acid, tartaric acid or the like, more preferably glutamic acid and/or tartaric acid.

According to a preferred embodiment of the present invention, the particles in the above-mentioned powder preparation contain an antidepressant, an excipient, and an acid, and the antidepressant is mianserin or a salt thereof, and examples of the acid include adipic acid, lemon acid, aspartic acid, glutamic acid, maleic acid, malic acid, tartaric acid, toluenesulfonic acid or combinations thereof, preferably citric acid, malic acid, tartaric acid or combinations thereof, more preferably Malic acid and/or tartaric acid.

The content of the acid in the powder preparation of the present invention is not particularly limited as long as it does not hinder the effects of the present invention, and is, for example, 0.1% by mass to 20% by mass relative to the entire preparation, preferably 0.5% by mass. to 5% by mass, more preferably 0.8% to 3% by mass.

The mass ratio of the antidepressant to the acid (antidepressant:acid) in the powder preparation of the present invention is not particularly limited, as long as it does not hinder the effect of the present invention, for example, it can be set to 1:0.01 to 1:2, relatively Preferably it is 1:0.05 to 1:1, more preferably 1:0.1 to 1:0.5.

The mass ratio of the excipient to the acid (excipient:acid) in the powder preparation of the present invention is not particularly limited, as long as it does not hinder the effect of the present invention, for example, it can be set to 1:0.001 to 1:2, relatively Preferably it is 1:0.005 to 1:1, more preferably 1:0.01 to 1:0.8.

[particle] According to an embodiment of the present invention, the particles in the above-mentioned powder preparation may include an antidepressant and an excipient, preferably an antidepressant, an excipient, and an acid.

According to a preferred embodiment of the present invention, the crystallinity of the antidepressant, excipients, and carrier in the above-mentioned powder preparation is preferably not changed before and after the preparation and mixing of the powder preparation. Crystallinity evaluation of antidepressants, excipients, and carriers can be analyzed by differential scanning calorimetry analysis (DSC analysis) and/or powder X-ray diffraction analysis.

According to another preferred embodiment of the present invention, the particles containing the antidepressant, excipients and acid if necessary in the above powder preparation are preferably fine particles.

According to an embodiment of the present invention, the average particle size of the fine particles is not particularly limited as long as it does not hinder the effect of the present invention, preferably 0.1 μm to 15 μm, more preferably 0.5 μm to 10 μm. The average particle diameter of the fine particles is calculated by selecting random 50 particles from the image obtained by observation using a known device such as a scanning electron microscope described later, and calculating it as the average value of the length in a fixed direction, that is, the orientation diameter. Here, the orientation diameter is the Feret diameter.

[Powder formulation] Furthermore, the powder preparation of the present invention contains pharmaceutically or orally acceptable additives as necessary. The additives are not particularly limited, and include bases, dissolution aids, isotonic agents, stabilizers, preservatives, preservatives, surfactants, regulators, chelating agents, buffers, thickeners, and colorants , aromatics, fragrances, antioxidants, dispersants, disintegrants, plasticizers, emulsifiers, cosolvents, reducing agents, sweeteners, flavoring agents, binders, etc., can be used within the scope of not impairing the effect of the present invention Formulated in the powder preparation of the present invention.

The powder preparation of the present invention can be administered to patients by transmucosal administration such as pulmonary administration and nasal administration. The powder preparation of the present invention is preferably a powder preparation for nasal administration (hereinafter also referred to as a nasal powder preparation) from the viewpoint of ease of administration as described below. Nasal powder preparations can be sprayed from a nebulizer by compressed air, etc., and medical staff or nurses can more easily administer them to patients in delirium who are elderly and exhibit symptoms of hyperactivity or dementia, etc., who exhibit severe pain Patients with phantom limb pain. Therefore, as the aging process progresses and the number of elderly patients undergoing home treatment increases, the nasal powder preparation is also preferable as a preparation capable of home treatment.

In the case of pulmonary administration or nasal administration of the powder preparation of the present invention, various inhalers or nebulizers used in the field may be used. Examples of inhalers for pulmonary administration include Jethaler (registered trademark) and the like. Moreover, Jetlizer etc. are mentioned as a nebulizer for nasal administration.

According to another embodiment of the present invention, the powder preparation of the present invention can be used for the treatment or prevention of delirium and the like as described below. Delirium is a common symptom in elderly patients, so if it is taken orally, it may cause difficulty for patients to swallow. Also, in the case of hyperactivity, it is difficult to say that oral administration, rectal administration, and administration in the form of injection are appropriate administration forms from the viewpoint of the safety of medical personnel, nurses, or patients. Therefore, a nasal powder preparation is advantageous as an administration form of the Moyouping antidepressant intended to be applied to the treatment of delirium and the like.

[Method for Manufacturing Powder Preparation ] According to another aspect of the present invention, there is provided a method for manufacturing the powder preparation of the present invention. The method includes a step of preparing fine particles. As a preparation step of the fine particles, a step of mixing the above-mentioned (a) antidepressant, (b) excipient, and if necessary (c) acid to fine particles is exemplified. Here, the above-mentioned step of mixing and making fine particles may be a step of making fine particles after mixing, or may be a step of mixing and making fine particles.

[Manufacturing method of fine particles] According to an embodiment of the present invention, the preparation step of the fine particles in the method of producing the powder preparation of the present invention is not particularly limited, and a method generally used by the industry can be suitably used. Specifically, dry pulverization such as aerodynamic pulverization, a spray dry method, and a method using a supercritical fluid are exemplified. Here, as a method of using a supercritical fluid, a PCA method (precipitation with compressed antisolvent; compression antisolvent precipitation method), a rapid expansion method (rapid expansion of supercritical fluid solutions; RESS) and a GAS method (Gas antisolvent; gas- anti-solvent), etc.

According to a preferred embodiment of the present invention, the spray-drying method can be mentioned as the preparation step of the fine particles in the method of producing the powder preparation of the present invention. As this method, for example, a method of spray-drying a solution or a suspension obtained by adding a solvent to an antidepressant, (b) excipient, and optionally (c) acid is exemplified. The spray drying method is a better method in terms of drying efficiency, powder recovery rate, economical efficiency, and production scale expansion.

The solvent used to prepare the above-mentioned solution or suspension is not particularly limited, and includes solvents used or will be used in medicine or food in the future. Specifically, the above-mentioned solvents can include water, alcohols (such as methanol, ethanol, propanol, etc.), ketones (such as acetone, methyl ethyl ketone, etc.), or their mixed solvents, preferably water, ethanol, or their mixed solvents.

According to another preferred embodiment of the present invention, dry pulverization, preferably aerodynamic pulverization can be mentioned as the preparation step of the fine particles in the method of manufacturing the powder preparation of the present invention. In the present invention, ordinary dry pulverization can be used for the preparation of fine particles, but an aerodynamic pulverizer is preferably used. Specifically, as a common dry pulverizer, a laboratory-use mortar or ball mill, etc., can be used to pulverize a small amount of raw materials efficiently. Examples of the ball mill include a rolling ball mill, a centrifugal ball mill, a vibration ball mill, and a planetary ball mill. Examples of industrial use include media agitation mills, high-speed rotary mills/impact mills, jet mills, and other devices aimed at efficiently pulverizing a large amount of raw materials. Examples of high-speed rotary grinding mills include disc mills and roller mills, high-speed rotary impact grinders, shredders (cutters), hammer mills (sprayers), pin mills, sieve mills, etc. In addition to those crushed by rotational impact, those crushed by shearing force can also be mentioned. As an aerodynamic pulverizer, a jet mill can be cited. Jet mills mainly perform pulverization by impact, and the types thereof include particle-particle collision type, particle-collision plate collision type, and nozzle suction (blow-out) type. As the preparation step of the fine particles of the present invention, it is preferable to use a jet mill.

[Step of Mixing Carrier and Fine Particles ] The fine particles obtained in the above-mentioned fine particle preparation step may also be mixed with a carrier next. By mixing the fine particles and the carrier, a stable complex can be formed until the time of administration. A generally known mixer can be used for mixing the carrier and the fine particles. The mixer mainly includes a batch type and a continuous type, and the batch type further includes two types of a rotary type and a stationary type. Rotary type includes horizontal cylinder type mixer, V type type mixer, double cone type type type mixer, cube type type type mixer, fixed type includes spiral type (vertical, horizontal) type type mixer, rotary screw type type type mixer, belt (ribbon) type (vertical, horizontal) mixers. The continuous type is still divided into two types: rotary type and fixed type. It is known that the rotary type includes horizontal cylindrical mixer and horizontal conical mixer, and the fixed type includes spiral (vertical, horizontal) mixer, belt type ( Vertical, horizontal) mixers, rotary disc mixers. In addition, more uniform mixed preparations can be made by using aerodynamic pulverizers such as medium-stirred mills, high-speed rotary mills/impact mills, and jet mills, or nylon or quasi-nylon properties can be used. The resulting bag is then agitated, thereby producing a more uniform blended formulation.

According to one aspect of the present invention, the powder preparation comprising the antidepressant of the present invention can achieve the therapeutic or preventive effect on delirium. Therefore, according to an aspect of the present invention, the powder preparation of the present invention is provided as a powder preparation for the treatment or prevention of delirium, preferably as a powder preparation for the treatment of delirium.

According to another aspect of the present invention, the powder preparation comprising the antidepressant of the present invention can realize the treatment or prevention of phantom limb pain. Therefore, according to another aspect of the present invention, the powder preparation of the present invention is provided as a powder preparation for the treatment or prevention of phantom limb pain, preferably as a powder preparation for the treatment of phantom limb pain.

It is known that the antidepressants of the present invention can exert therapeutic or preventive effects on chronic itching (G Yoshipovitch, et al., The New England Journal of Medicine, 2013, 368, pp.1625-1634.). The above-mentioned chronic itching is caused, for example, by ectopia, chronic kidney disease, psoriasis, lichen planus, or mange. Therefore, according to another aspect of the present invention, the powder preparation containing the antidepressant of the present invention can exert therapeutic or preventive effects on chronic itching. Therefore, according to another aspect of the present invention, the powder preparation of the present invention is provided as a powder preparation for the treatment or prevention of chronic itching, preferably as a powder preparation for the treatment of chronic itching.

The powder preparation containing the antidepressant of the present invention can exert therapeutic or preventive effects on depression or depressive state. Therefore, according to another aspect of the present invention, the powder formulation of the present invention is provided as a powder formulation for the treatment or prevention of depression or a depressive state, preferably as a powder for the treatment of depression or a depressive state preparations are provided.

According to an embodiment of the present invention, the powder preparation of the present invention can also be used as a medicine or quasi-drug for humans or animals. In addition, the powder preparation of the present invention may be used in combination with other pharmaceuticals and quasi-drugs commonly used in this technical field as needed.

According to an embodiment of the present invention, the powder preparation of the present invention can be used as an object, for example, animals, preferably mammals, birds, reptiles, amphibians, fish, etc., more preferably humans. The above-mentioned subjects can be healthy people (healthy animals) or patients (sick animals).

In addition, according to another embodiment of the present invention, there is provided a treatment or prevention method for delirium, phantom limb pain, chronic itching, or depression or depressive state of the subject, which includes a drug containing an effective amount of an antidepressant The step of administering the powder preparation of the invention to a subject is preferably a method of treatment. According to yet another embodiment of the present invention, the above-mentioned preventive method for delirium, phantom limb pain, chronic itching, or depression or depressive state is a non-therapeutic method when the subject is a healthy person. Here, the above-mentioned non-therapeutic meaning does not include the concept of medical behavior, that is, it does not include the concept of methods of performing surgery, treatment or diagnosis on people, and more specifically, it does not include the concept of performing on people by a doctor or a person instructed by a doctor. Concept of methods of surgery, treatment or diagnosis. The method of treatment or prevention of delirium, phantom limb pain, or chronic itching that is the subject of the present invention can be implemented in accordance with the contents described in this specification regarding the powder preparation of the present invention.

In addition, the effective dose of the antidepressant of the present invention and the frequency of administration of the powder preparation of the present invention are not particularly limited, and may be determined by the practitioner according to the type, purity, type, nature, sex, age, and symptoms of the antidepressant. Decide. For example, the effective dose of an antidepressant is 0.01 mg/kg to 1000 mg/kg body weight, preferably 0.05 mg/kg to 500 mg/kg body weight. The frequency of administration is, for example, 1 to 5 times per day.

Also, according to another aspect of the present invention, there is provided a use of particles, which are used for the manufacture of powder preparations, the particles containing tricyclic or tetracyclic antidepressants, or triazolopyridine antidepressants Antidepressants and excipients. The aforementioned particles preferably further contain an acid. Moreover, according to another preferred embodiment of the present invention, the above-mentioned powder preparation is used for the treatment or prevention of delirium, phantom limb pain, chronic itching, or depression or depressive state.

Moreover, according to another aspect of the present invention, there is provided a use of a powder preparation, which is used for the treatment or prevention of delirium, phantom limb pain, chronic itching, or depression or depressive state. It is made of particles of antidepressants and excipients of tetracyclic antidepressants or triazolopyridine antidepressants. The aforementioned particles preferably further contain an acid.

Moreover, according to another aspect of the present invention, there is provided a use of particles as a composition for the treatment or prevention of delirium, phantom limb pain, chronic itching, or depression or depressive states, the aforementioned particles containing three Antidepressants and excipients of cyclic or tetracyclic antidepressants, or triazolopyridine antidepressants. The aforementioned particles preferably further contain an acid.

Moreover, according to another aspect of the present invention, there is provided a use of a particle, which is used for the treatment or prevention of delirium, phantom limb pain, chronic itching, or depression or depressive state. An antidepressant of a cyclic antidepressant, or a triazolopyridine antidepressant, and an excipient. The aforementioned particles preferably further contain an acid.

Also, according to another aspect of the present invention, a particle is provided, which is used for the treatment or prevention of delirium, phantom limb pain, chronic itching, or depression or depressive state. A depressant, or an antidepressant of a triazolopyridine-based antidepressant, and an excipient. The aforementioned particles preferably further contain an acid.

The above-mentioned uses and aspects of particles can be implemented according to the description related to the powder preparation or method of the present invention. [Example]

Hereinafter, the present invention will be more specifically described with reference to test examples and reference examples, but the technical scope of the present invention is not limited to these examples. Furthermore, unless otherwise specified, all percentages or ratios used in the present invention are based on mass. In addition, unless otherwise specified, the units and measurement methods described in this specification are based on JIS standards.

Quantification of the concentration of moxapine in the following preparation examples 1 to 4, and test example 1, test example 2, test example 4, test example 6 and test example 7 was performed using HPLC-UV. After weighing the nasal powder preparation and powder preparation samples obtained in Preparation Example 1 to Preparation Example 4, and Test Example 2 and Test Example 4, they were dissolved in the mobile phase (0.1% formic acid:methanol=45:55) to prepare Quantitative samples were obtained and supplied to HPLC-UV. The quantitative samples in Test Example 1, Test Example 6, and Test Example 7 were prepared as described in Test Example 1, Test Example 6, and Test Example 7. In addition, HPLC-UV was performed under the following conditions. (HPLC-UV analysis conditions) Column used: InertSustain AQ-C18 HP 3μm, 4.6I.D.×100mm (GL Science Inc.) Detector: SPD-M10Avp diode array detector (Shimadzu Corporation) Pump: LC-10ADvp (Shimadzu Corporation) Mobile phase flow rate: 1mL/min Mobile phase: A: 0.1% formic acid, B: methanol, A: B=45:55 Column temperature: 40°C Hold time: 2.7min

[Preparation Example 1: Preparation of Nasal Powder Preparation 1 Containing Moyouping ] About 500 mg of (a) Moyouping crystal (M2151 (product code): Tokyo Chemical Industry Co., Ltd.) was mixed with (b) in an agate mortar About 500 mg of lactose hydrate (Respitose (registered trademark) SV010 (DFE Pharma GmbH & Co.KG)) was mixed, and co-pulverization was performed using a jet mill under the following conditions to prepare fine particles. The obtained fine particles were recovered in a Falcon (trademark) 50 mL conical tube, and lactose hydrate (median particle size 53 μm to 66 μm, Respitose (registered trademark) SV003 (DFE Pharma GmbH & Co. KG)) (hereinafter, also referred to as carrier or lactose carrier), was mixed by vibrating the conical tube, whereby nasal powder preparation 1 was obtained. (Grinding conditions) Machine used: AO-Jet Mill (SEISHIN company) Raw material supply method: Automatic feeder Supply air pressure: 6.0kg/cm ² G Grinding air pressure: 6.5kg/cm ² G Dust collection method: Exhaust bag ( The content of Moyoupine in the obtained nasal powder preparation 1 was about 8.3% by mass.

[Preparation Example 2: Preparation of Nasal Powder Preparation 2 Containing Moyoupine ] Dissolve (a) about 315 mg of Moyoupine crystals and (b) about 3.44 g of lactose hydrate (Respitose (registered trademark) SV010) in 30v/ After soaking in v% ethanol, spray-dry under the following conditions to prepare fine particles and obtain nasal powder preparation 2. (Drying conditions) Machine used: Yamato Pulvis GB-22 Lab Spray Dryer (Yamato Scientific) Inlet temperature: 180°C Outlet temperature: 80°C Liquid delivery pump flow rate: 2.5mL/min Solvent composition: methanol: water = 3:7 solids Concentration: 3.75w/v% The content of Moyouping in the obtained nasal powder preparation 2 is about 1.8% by mass.

[Test Example 1: Determination of supersaturation of Moyoupine by adding acid ] (a) Moyoupine crystals (about 25 mg), (c) various acids (about 5 mg), and (b) lactose hydrate (Respitose ( Registered trademark) SV010) (approximately 270 mg) was put into a mortar, and pulverized and mixed with a pestle, whereby the following powder preparation samples were obtained. Add each powder preparation sample to pH 5.6 phosphate buffer solution (dissolve 9.07 mg of potassium dihydrogen phosphate in 750 mL of water, adjust the pH to 5.6 with potassium hydroxide test solution, then add water to make the total amount 1000 mL) , after stirring for a few seconds, centrifuge to remove insoluble matter. In order to prevent the precipitation of Moyouping during the analysis, the supernatant was diluted with methanol to prepare a quantitative sample. Quantification of Moyoupine in samples was quantified using HPLC-UV. Powder preparation sample D (acid: aspartic acid: Aspartic acid) powder preparation sample E (acid: glutamic acid: Glutamic acid) powder preparation sample MAL (acid: maleic acid: Maleic acid) powder preparation sample TA (acid : Tartaric acid: Tartaric acid) powder preparation sample TS (acid: toluenesulfonic acid: Toluenesulfonic acid)

As shown in Figure 1 , supersaturation was confirmed in all powder formulation samples of acid and moxapine. Here, the so-called supersaturation refers to the situation where the solubility (2.3 mg/mL) after adding Moyouping crystals to the phosphate buffer solution of pH 5.6 and vortex stirring for 24 hours is set as the saturated solubility, and becomes above the saturated solubility . In particular, powder preparation sample E, powder preparation sample MAL, and powder preparation sample TA showed a high supersaturation degree of 8.7 times or more relative to the saturation solubility.

[Test Example 2: Stability Evaluation of Moyoupine in the Presence of Acid] The powder preparation sample E, Moyoupine crystals, and Moyoupine aqueous solution (0.1 mg/mL ) for photostability evaluation. Using Suntest CPS plus (registered trademark) (Atlas, USA, Xe lamp uses UV (Ultraviolet) filter), the residual rate of each sample after 45 minutes of UV (250 W/m ² , 25° C.) irradiation was measured. The quantitative system of Moyouping uses HPLC-UV. As a result, reduction in the survival rate was confirmed in all samples. Usually photodecomposition is easier in the solution state, even in this test, the residual rate in the aqueous solution of Mozapine is the lowest value of about 30%. On the other hand, powder preparation sample E had a significantly higher residual rate of about 59% compared with the aqueous solution of Moyoupine (P<0.05 vs the aqueous solution of Moyoupine (Student's t-test)). In addition, the residual rate of Moyouping crystals was also at the same level as that of the powder preparation sample E.

In addition, the stability of powder preparation sample E, powder preparation sample MAL, powder preparation sample TA and moxapine crystals stored at 40° C., 75% RH (accelerated test) for 2 weeks was evaluated. As a result, as shown in FIG. 2 , the residual rate of Moyouping in any of the powder preparation samples was approximately 100%, which was equivalent to that of Moyouping crystals, and had good stability. The quantitative system of Moyouping uses HPLC-UV.

[Preparation Example 3: Preparation of Nasal Powder Preparation Containing Moyoupine and Acid (Nasal Powder Preparation 3 Containing Moyoupine]] Dissolve (a) about 315 mg of Moyouping crystals, (c) about 63 mg of acid (glutamic acid), and (b) about 3.37 g of lactose hydrate (Respitose (registered trademark) SV010) in 30v/v% ethanol , spray-dried under the same conditions as in Preparation Example 2, thereby preparing fine particles and obtaining an acid-containing nasal powder preparation. Hereinafter, a nasal powder preparation containing glutamic acid as an acid is referred to as nasal powder preparation 3. The content of moxapine in the obtained nasal powder preparation 3 was about 4.1% by mass.

[Preparation Example 4: Preparation of Nasal Powder Preparation Containing Moyouping and Acid (Nasal Powder Preparation 4 Containing Moyoupine]] Mix (a) about 400 mg of Moyouping crystals, (c) about 80 mg of acid (glutamic acid), and (b) about 160 mg of lactose hydrate (Respitose (registered trademark) SV010) in an agate mortar, and prepare Under the same conditions as in Example 1, co-pulverization was performed using a jet mill to prepare fine particles. In the same manner as Preparation Example 1, lactose hydrate (median particle size 53 μm to 66 μm, Respitose (registered trademark) SV003) was mixed in an amount 5 times the mass ratio of the obtained fine particles, thereby obtaining nasal Powder formulation4. The content of Moyoupine in the obtained nasal powder preparation 4 was about 8.1% by mass.

[Test Example 3: Observation of Particle Morphology of Nasal Powder Preparation] For nasal powder preparation 1, nasal powder preparation 2, nasal powder preparation 3, nasal powder preparation 4, and Moyouping crystals, the morphology was observed using a scanning electron microscope (TM-3030, Hitachi). Specifically, first, the above-mentioned nasal powder preparation and the like were fixed to an aluminum sample holder with a carbon double-sided adhesive tape for a scanning electron microscope, and a magnetron sputtering device MSP-1S (VACUUM DEVICE Co., Ltd.) coating. Thereafter, the surface morphology was observed with a voltage of 15 kV using a scanning electron microscope. The average particle diameter was calculated by selecting arbitrary 50 particles from the observation image obtained by a scanning electron microscope, and taking the length in a fixed direction, that is, the average value of the orientation diameter. Here, the directional diameter refers to the Feret diameter. As a result, as shown in Figure 3, the fine particles in nasal powder preparation 1 and nasal powder preparation 4 prepared by jet mill and nasal powder preparation 2 and nasal powder preparation 3 prepared by spray drying Compared with Moyouping crystals, its particle size was significantly reduced. The average particle sizes of the fine particles in nasal powder formulation 1 and nasal powder formulation 4 were about 6 μm and about 4 μm, respectively. The average particle diameters of the powder formulations 3 were all about 2 μm. Nasal powder preparation 1 and nasal powder preparation 4 prepared by a jet mill are micronized by the collision of particles, so they have an oblate surface shape, but by adding coarse lactose hydrate as a carrier, the Fine particles adhere to the surface of the carrier to inhibit aggregation. The fine particles in the nasal powder preparation 2 and the nasal powder preparation 3 prepared by spray drying were spherical, and no significant aggregation was confirmed even when no carrier was added during storage at room temperature in a vacuum desiccator. After storage at 40° C. and 75% RH for one week, no morphological change was observed in nasal powder preparation 1 and nasal powder preparation 4 .

[Test Example 4: Stability Evaluation of Nasal Powder Preparation] In the same method as Test Example 2, nasal powder preparation 1, nasal powder preparation 2, nasal powder preparation 3, nasal powder preparation 4, Moyouping Evaluation of crystallization and photostability of aqueous solution (0.1 mg/mL) of Mozapine. As a result, it was visually confirmed that the nasal powder preparations and moxapine crystals, which were white before UV irradiation, and the moxapine solution, which was a transparent liquid, changed in color to light yellow or light yellow brown after irradiation. Also, as shown in Figure 4, after 45 minutes of UV irradiation, the residual rate of Moyouping in the Moyouping solution was significantly lower than that of Moyouping crystals (*: P<0.05 v.s. Moyouping crystals (Student's t- test)). On the other hand, the residual rate of Moyouping in nasal powder preparation 1, nasal powder preparation 2, nasal powder preparation 3 and nasal powder preparation 4 was equal to or increased compared with Moyouping crystal. In addition, the stability of 4 types of nasal powder preparations and 2 types of moyoupine crystals stored at 40° C. and 75% RH for 2 weeks was evaluated. As a result, there was no difference in the residual rate of Moyouping in any of the samples, and had good stability.

[Test Example 5: Crystallinity Evaluation of Nasal Powder Preparation] For nasal powder preparation 1, Moyouping crystals, lactose hydrate (excipient) (Respitose (registered trademark) SV010) for co-crushing, and lactose hydrate (Respitose (registered trademark) SV003) added as a carrier ) for crystallinity evaluation. Differential scanning calorimeter analysis (DSC analysis) and powder X-ray diffraction analysis were performed as crystallinity evaluation.

For differential scanning calorimeter analysis, a differential scanning calorimeter (DSC7020, Hitachi) was used, and 3 mg of each sample was heated from 50°C to 190°C at 5°C/min to measure the heat. The results are shown in Figure 5A. As shown in Figure 5A, the endothermic peak of the nasal powder preparation is consistent with the peaks of Moyoupin crystals and lactose hydrates, and no crystallinity was confirmed during the process of preparing fine particles by jet mill and mixing with lactose carrier change.

The powder X-ray diffraction analysis system uses a powder X-ray diffraction device (MiniFlexII, RIGAKU), X-ray source: Cu-Kα, tube voltage: 30kV, tube current: 15mA, measurement temperature: room temperature, 2θ: 3° to The conditions of 40° and step angle: 0.02° are implemented. The results are shown in Figure 5B. As shown in FIG. 5B , the diffraction peaks originating from Moxapine contained in the nasal powder preparation were consistent with those of Moxapine crystals. This result indicates that Moyouping in the nasal powder preparation 1 exists in the same crystalline state as the raw drug (Moyouping crystal).

[Test Example 6: Evaluation of Dissolution Behavior of Nasal Powder Preparation] For nasal powder preparation 1, nasal powder preparation 4 and Moyouping crystals, the dissolution test was carried out by paddle method under the following conditions under the condition of simulating the pH environment in the nasal cavity (phosphate buffer solution, pH 5.6). In the following sample collection, samples were collected using a syringe equipped with an injection needle, and insoluble matter was removed by centrifugation. Thereafter, in order to prevent the precipitation of moxapine during the analysis, the same amount of methanol as the supernatant was mixed to prepare a quantitative sample. Quantification of Moyoupine in samples was quantified using HPLC-UV.

(dissolution test method) Device: NTR-6100A (Toyama Sangyo Co., Ltd.) Test solution: phosphate buffer, pH5.6 Test liquid volume: 50mL Stirring speed: 50rpm Temperature: 37°C Sample collection: 1 minute, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes (200μL) Centrifugation conditions: 25°C, 15,000×g, 5 minutes

As shown in Figure 6, the nasal powder preparation 1 has a higher dissolution rate than Moyouping crystals, and the dissolution rate reaches 100% 10 minutes after the start of the test. It is considered that the effect is due to the fact that the surface area is increased by micronization of Moxapine using a jet mill, and the wettability of the particles is high due to co-pulverization with lactose hydrate. Also, about 90% of the nasal powder preparation 4 was eluted 1 minute after the start of the test, and completely eluted 5 minutes later. The reason for this is presumed to be that, in addition to finer particles and improved particle wettability, the drop in pH in the microenvironment near the preparation promotes the elution of Moxapine, which is a basic drug. The dissolution rates of the nasal powder preparation 1 and the nasal powder preparation 4 were about 80 times and about 200 times higher than that of Moyoupin crystalline, respectively, and rapid drug absorption after intranasal administration can be expected. In addition, there is a clearing mechanism called mucociliary clearing function in the nasal cavity. Compared with Moyouping crystals, the nasal powder preparation has an increased dissolution rate, and the standard for foreign matter attached to the front of the nasal mucosa to be cleared from the nasal cavity is also That is, it shows 100% dissolution within 10 minutes to 15 minutes. Therefore, the nasal powder preparation can avoid the elimination of undissolved drug by rapid dissolution, and thus a high absorption rate can be expected.

[Test Example 7: Evaluation of the Release Rate of Moyoupine from Capsules Filled with Nasal Powder Preparation] Nasal powder preparation 1, nasal powder preparation 2, nasal powder preparation 3, and nasal powder preparation 4 are filled into Japanese Pharmacopoeia No. 2 capsules, set in a Jetlizer (Tokico System Solutions, Ltd.), and the The drug release rate from the capsule was evaluated when the compressed air generated by the pump was sprayed three times in total. The specific quantitative method of Moyouping is as follows. Put the sprayed capsules into a Falcon (trademark) 15mL conical tube, add 10mL of 0.1% formic acid: methanol = 1:1 solution, and dissolve the capsules and the remaining Moyouping in the capsules. Thereafter, the above solution was diluted 10 times, and the concentration of Moxapine in the solution was measured by HPLC-UV. As a result, as shown in FIG. 7 , any nasal powder formulation released more than 80% of Moxapine from the capsule.

[Test Example 8: In vivo dynamic evaluation of Moyouping] Under isoflurane inhalation anesthesia, nasal powder preparation 1 and nasal powder preparation 4 were intranasally administered to male rabbits (Japanese white species, 17 to 18 weeks old) at a dose of 300 μg Moyouping/kg . As a comparison group, the crushed tablets of one type of moxapine which was already on the market were suspended in water, and the dosage of 3 mg moxapine/kg was orally administered to male rabbits. Also, in order to calculate the bioavailability, an aqueous solution of Moxapine was administered to male rabbits intravenously through the pinna at an amount of 300 μg Moxapine/kg. After administration of each sample, 300 μL of blood was collected from the auricular vein at 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hour, 2 hours, 4 hours, and 6 hours, and the plasma samples obtained by centrifugation were depleted. Protein processing, thereby making quantitative samples. Quantification of Moyoupine in samples was quantified using HPLC-fluorescence.

(Sample processing method) Separate 100 μL of plasma sample into a brown co-embedded test tube, add 50 μL of 1N sodium hydroxide aqueous solution, 50 μL of methanol solution containing melanin (500 ng/mL) as an internal standard substance, and mix with hexane:ethyl acetate=9:1 After adding 1.4 mL of solvent, shake for 15 minutes. After shaking, it was centrifuged at 3,500 rpm for 10 minutes, and the supernatant was evaporated to dryness in a nitrogen stream. The residue was redissolved in 200 µL of methanol to prepare a quantitative sample.

(HPLC-fluorescence analysis conditions) Column used: InertSustain AQ-C18 HP 3μm, 4.6I.D.×100mm (GL Science Inc.) Detector: Fluorescence detector RF-20A (Shimadzu Corporation) Pump: LC-10ADvp (Shimadzu Corporation) Mobile phase flow rate: 1mL/min Mobile phase: A: 0.1% formic acid, B: methanol 0 minutes-2 minutes: A65% 2 minutes-8 minutes: A65-25% 8 minutes-15 minutes: A5% Column temperature: 40°C

The results are shown in FIG. 8 . The pharmacokinetic parameters after administration of each Mozapine sample are shown in Table 1 below.

[Table 1] sample C _max (ng/mL) T _max (min) t _1/2 (h) BA(%) Nasal powder preparation 1, intranasal administration (300μg Moyouping/kg) 77±31 12±6 1.1±0.0 85 Nasal powder preparation 4, intranasal administration (300μg Moyouping/kg) 83±10 5±0 0.9±0.4 93 Moyouping ingot crushed, orally administered (3mg Moyouping/kg) 18±10 72±30 - 10 In Table 1, each pharmacokinetic parameter is represented by mean ± standard error (n=4).

The concentration of moxapine in the blood within 5 minutes after the intravenous administration of the aqueous solution of moxapine was 105 ng/mL, and the half-life of disappearance (half-lifE: t _1/2 ) was 1 hour. After oral administration of broken tablets of Moyoupine, the maximum plasma concentration (Cmax) in blood is 18ng/mL, and the biological availability (bioavailability; BA) is 10%. Furthermore, in this test example, the bioavailability is calculated by the area under the concentration curve ( AUC) was divided by the AUC calculated when the same amount of auricular vein was administered. Moyouping is known to be metabolized by the liver, and it is considered that after oral administration, BA decreases due to the hepatic primary passage effect. On the other hand, after intranasal administration of nasal powder preparation 1, the C _max was 77 ng/mL, the time to maximum concentration in blood (the time to maximum concentration; T _max ) was 12 minutes, and the BA was 85%. Absorbed by nasal mucosa. The reason for this is considered to be that Moyouping in the nasal powder preparation 1 dissolves rapidly in the mucus in the nasal cavity, and because it is a low-molecular and fat-soluble drug, it quickly penetrates the membrane. In addition, it is believed that the developed capillary network in the nasal cavity or the absence of hepatic first-pass effect during absorption will promote the absorption of Moyouping through the nasal mucosa. After intranasal administration of nasal powder preparation 4 containing glutamic acid, the C _max was 83 ng/mL, almost unchanged from nasal powder preparation 1, but T _max was shortened to 5 minutes, and BA was 93%. It is believed that because Moyouping is a fat-soluble low-molecular drug with good membrane penetration, the absorption rate of nasal mucosa will increase due to the further increase of dissolution rate. In addition, it is known that undissolved drugs in the nasal cavity will be excreted toward the throat through mucociliary clearance (MCC), and the nasal powder preparation 4 that dissolves rapidly in the nasal cavity avoids this MCC, so it is believed that it promotes nasal mucosal clearance. absorb. It is speculated that the addition of acid contributes more significantly to the improvement of nasal mucosal absorption when administered at a high dosage. It is considered that the administration of nasal powder preparation 1 and nasal powder preparation 4 quickly reaches the highest blood concentration and then disappears quickly, which is useful for rapid drug efficacy and avoidance of side effects caused by excessive drug efficacy.

Considering the above-mentioned results of the dissolution test and the stability test, it is more desirable to select a powder preparation instead of a liquid preparation as a preparation for nasal administration of the Moyouping antidepressant. Nasal powder preparations with acids added as excipients in addition to antidepressants and lactose showed supersaturation in the test solution (phosphate buffer at pH 5.6) that simulated the pH environment in the nasal cavity, such as glutamic acid In the case of an acid, about 11-fold supersaturation was achieved with respect to the solubility. Also, regarding the antidepressant content of the nasal powder preparations after light irradiation and storage under heat and humidity conditions, there was no statistical difference between the nasal powder preparations containing acid and the nasal powder preparations not containing acid Significant differences. Therefore, the acid-containing nasal powder formulation can become a formulation with better stability and functionality.

Powder X-ray diffraction analysis was performed in the same manner as in Experimental Example 5 on the recovered product obtained by desalting mianserin hydrochloride (M2623 (product code): Tokyo Chemical Industry Co., Ltd.). As a result, the powder X-ray diffraction pattern suggested that mianserin in the recovered product was in a crystalline state. Hereinafter, the recovered product obtained by desalination of mianserin hydrochloride is referred to as mianserin crystals.

Quantification of the concentration of mianserin in the following Preparation Examples 5 to 7, and Test Example 9, Test Example 10, Test Example 11, and Test Example 13 was performed using HPLC-UV. In Preparation Example 5 to Preparation Example 7 and Test Example 10, nasal powder preparation and powder preparation samples were weighed and dissolved in a solution of 0.1% formic acid:methanol=40:60 to prepare quantitative samples and supplied to HPLC-UV . The quantitative samples in Test Example 9, Test Example 11, and Test Example 13 were prepared as described in Test Example 9, Test Example 11, and Test Example 13. HPLC-UV was carried out under the following conditions. (HPLC-UV analysis conditions) Column used: InertSustain AQ-C18 HP 3μm, 4.6I.D.×100mm (GL Science Inc.) Detector: SPD-M10Avp diode array detector (Shimadzu Corporation) Pump: LC-10ADvp (Shimadzu Corporation) Mobile phase flow rate: 1mL/min Mobile phase: A: 0.1% formic acid, B: methanol, A: B=40:60 Column temperature: 40°C Hold time: 2.4min

[Test Example 9: Determination of Supersaturation of Mianserin by Adding Acid] Except for using mianserin crystals instead of moxanopin crystals, and using the following acids as various acids, powder preparation samples were prepared in the same manner as in Test Example 1, and supersaturation was measured. Powder preparation sample AA' (acid: adipic acid, Adipic acid) Powder preparation sample CA' (acid: citric acid, Citric acid) Powder preparation sample D' (acid: aspartic acid: Aspartic acid) Powder preparation sample E' (acid: glutamic acid: Glutamic acid) Powder preparation sample MAL' (acid: maleic acid: Maleic acid) Powder preparation sample MLI' (acid: malic acid: Malic acid) Powder preparation sample TA' (acid: tartaric acid: Tartaric acid) Powder preparation sample TS' (acid: toluenesulfonic acid: Toluenesulfonic acid)

It was confirmed that the solubility of mianserin crystals increased by adding various acids. In particular, as shown in FIG. 9 , the powder preparation sample CA', the powder preparation sample MLI', and the powder preparation sample TA' showed a supersaturation degree 5 times higher than the saturation solubility. Similar to the supersaturation of moxapine in Test Example 1, it was confirmed that supersaturation was achieved by adding acid in mianserin.

[Test Example 10: Stability evaluation of mianserin in the presence of acid] For powder preparation sample CA', powder preparation sample MLI', powder preparation sample TA', mianserin crystals, mianserin solution (0.1mg/mL, 20v /v% methanol solution) and the stability after storage at 40°C and 75%RH for 2 weeks were evaluated. The photostability and the stability after storage for 2 weeks were evaluated in the same manner as in Test Example 2 except that mianserin was used instead of moxapin. As shown in Figure 10A, it was confirmed that in the mianserin solution, the residual rate was significantly lower than that of mianserin crystals (*: P<0.05 v.s. mianserin crystals (Student's t-test)). Due to the risk of photodecomposition during manufacture or storage, it is preferable to develop a nasal powder preparation instead of a nasal liquid preparation. Powder preparation sample CA', powder preparation sample MLI', and powder preparation sample TA showed the same degree of photostability as mianserin crystals. In addition, after storing each powder preparation sample at 40° C. and 75% RH for 2 weeks, as shown in FIG. The residual rate of mianserin is approximately 100%, and has good stability.

[Test Example 11: Evaluation of Dissolution Behavior of Mianserin Nasal Powder Preparation Samples Containing Acid] Put mianserin crystals, acid, and lactose hydrate (Respitose (registered trademark) SV010) in an agate mortar at a mass ratio of 5:1:4, crush and mix with a pestle, and make mianserin sutra easily Nasal powder formulation samples. Among the mianserin nasal powder preparation samples prepared this time, the sample using citric acid as the acid is referred to as the nasal powder preparation sample CA', and the sample using malic acid as the acid is referred to as the nasal powder preparation sample MLI', A sample using tartaric acid as an acid was referred to as a nasal powder preparation sample TA'. Furthermore, mianserin crystals were put into an agate mortar and crushed with a pestle to obtain mianserin fine particles. Dissolution behavior was evaluated in the same manner as in Test Example 6 for mianserin crystals, mianserin fine particles, and the three nasal powder preparation samples described above. Quantification of mianserin in samples was performed using HPLC-UV.

As shown in FIG. 11 , the dissolution rate of mianserin crystals was about 50% 60 minutes after the start of the dissolution test, showing slow dissolution. Similar to the Moyouping nasal powder preparation of Test Example 6, the micronized mianserin crystals showed an increase in the surface area accompanied by an increase in the dissolution rate according to the Noyes-Whitney formula. In addition, the dissolution rate of mianserin nasal powder preparation samples containing citric acid, malic acid, and tartaric acid was increased compared with mianserin fine particles not containing acid, especially mianserin nasal powder preparation Sample MLI' and mianserin nasal powder preparation sample TA' increased about 6.7 times and 7.8 times, respectively. The solubility of mianserin in water and phosphate buffer (pH 5.6) simulating the nasal cavity environment is insufficient compared with that of Moyouping, so it can be expected that the dissolution rate brought about by adding acid when considering the mucociliary clearance function The increase is the same as the situation of Moyouping, or more helpful to improve the absorption of nasal mucosa than the situation of Moyouping.

[Preparation Example 5: Preparation of nasal powder preparation containing mianserin (nasal powder preparation 5 containing mianserin]] After mixing about 50 mg of (a) mianserin crystals and about 100 mg of (b) lactose hydrate (Respitose (registered trademark) SV010), they were co-pulverized with a jet mill under the same conditions as in Preparation Example 1 to prepare fine particles. Nasal powder preparation 5 was obtained by mixing with lactose hydrate (median particle size 53 μm to 66 μm, Respitose (registered trademark) SV003) in an amount 5 times the mass ratio of the obtained fine particles. The mianserin content of the obtained nasal powder formulation 5 was about 1.2% by mass.

[Preparation Example 6, Preparation Example 7: Preparation of nasal powder preparations containing mianserin and acid (nasal powder preparation 6 containing mianserin, nasal powder preparation 7)] After mixing about 200 mg of (a) mianserin crystals, about 40 mg of (c) acid (malic acid or tartaric acid), and about 480 mg of lactose hydrate (Respitose (registered trademark) SV010), the same conditions as in Preparation Example 1 were mixed. Co-pulverization is performed by a jet mill to prepare fine particles. A nasal powder preparation was obtained by mixing lactose hydrate (median particle size 53 μm to 66 μm, Respitose (registered trademark) SV003) in an amount 5 times the mass ratio of the obtained fine particles. Hereinafter, the mianserin-containing nasal powder preparation containing malic acid as an acid is referred to as nasal powder preparation 6, and the mianserin-containing nasal powder preparation containing tartaric acid as an acid is referred to as nasal powder preparation 7 . The mianserin content in the obtained nasal powder preparation 6 and nasal powder preparation 7 were both about 4.5% by mass.

[Test Example 12: Observation of Particle Morphology of Nasal Powder Preparation] Morphological observations of nasal powder formulation 5, nasal powder formulation 6, nasal powder formulation 7, and mianserin crystals were performed in the same manner as in Test Example 3. As shown in Figure 12, mianserin crystals are very large plate-shaped crystals, and the fine particles in nasal powder formulation 5, nasal powder formulation 6, and nasal powder formulation 7 were pulverized by using a jet mill It is miniaturized to an average particle size of about 5 μm. In addition, fine particles in any of the nasal powder preparations were dispersed and adhered to the surface of the lactose carrier, and significant aggregation was not confirmed.

[Test Example 13: Evaluation of Release Rate of Mianserin from Capsules Filled with Nasal Powder Preparation] For nasal powder preparation 5, nasal powder preparation 6, and nasal powder preparation 7, the release rate of mianserin from capsules was evaluated in the same manner as in Test Example 7, except that quantitative samples were prepared in the following manner . As a quantitative sample preparation, the capsule and the mianserin remaining in the capsule were dissolved in a solution of 0.1% formic acid:methanol=40:60, and further diluted 10 times to prepare a quantitative sample for HPLC-UV. As a result, as shown in Figure 13, in any nasal powder formulation, more than 90% of mianserin was released from the capsule.

[ Fig. 1 ] is a graph showing the degree of supersaturation of moxapine in a powder formulation sample containing an acid in an amount 1/5 times that of moxapine in terms of mass ratio. D: powder preparation sample D (containing aspartic acid); E: powder preparation sample E (containing glutamic acid); MAL: powder preparation sample MAL (containing maleic acid); TA: powder preparation sample TA (containing tartaric acid); TS: powder formulation sample TS (containing toluenesulfonic acid). Data represent mean±standard deviation (n=3) values. [Fig. 2] is a graph showing the survival rate of Moyouping when stored under accelerated test conditions. MRZ crystal: Moyouping crystal; E: powder preparation sample E; MAL: powder preparation sample MAL; TA: powder preparation sample TA. Data represent mean±standard deviation (n=3) values. [ Fig. 3 ] shows observation images of Moyouping crystals and nasal powder preparations obtained by a scanning electron microscope. Panel 3A shows the observation image of Moyouping crystal. Screen 3B shows the observed image of nasal powder preparation 1. Screen 3C and screen 3D represent the observation image of nasal powder preparation 2. Screens 3E and 3F represent observation images of the nasal powder preparation 3 . Screen 3G represents the observed image of nasal powder preparation 4. The white bar in the figure represents 20 μm, and the black bar represents 10 μm. [Fig. 4] is a graph showing the residual rate of Moyoupine crystals, Moyoupine aqueous solution, and each nasal powder preparation after light irradiation (250W/m ² , 45 minutes). Data represent mean±standard deviation (n=3) values. [ FIG. 5A ] shows a DSC (Differential scanning calorimetry; differential scanning calorimetry) thermogram as an evaluation of the crystallinity of nasal powder preparation 1. [ FIG. In the DSC thermogram, an endothermic peak due to melting appears around 115°C to 117°C, which is the melting point of Mozapine. [ FIG. 5B ] shows an X-ray diffraction pattern as an evaluation of the crystallinity of Nasal Powder Preparation 1. [ FIG. In the X-ray diffraction pattern, specific peaks appeared in the nasal powder formulation 1 as well as in the crystals of Moyoupin. [ Fig. 6 ] shows the dissolution behavior of nasal powder preparation 1, nasal powder preparation 4, and moxapine crystals (MRZ crystals). In order to simulate the pH in the nasal cavity, a phosphate buffer solution (pH 5.6) was used as a test solution, and a dissolution test was performed by the paddle method. The data represent the mean ± standard deviation (n=2-3, wherein n=3 for nasal powder preparation 1 and Moyouping crystal, and n=2 for nasal powder preparation 4). [ Fig. 7 ] is a graph showing the release rate of Moxapine from capsules filled with nasal powder preparations. Jetlizer was used for the nebulizer, Japanese Pharmacopoeia No. 2 capsule was used for the capsule, and 3 sprays were used as 1 test. Data represent mean±standard deviation (n=3) values. [ Fig. 8 ] is a graph showing the change of the concentration in the blood after the administration of each Moyouping sample. Data represent mean±standard error (n=4) values. The samples used were nasal powder preparation 1 and nasal powder preparation 4 (300 μg Moyouping/kg, intranasally administered), Moyouping tablet crushed (MRZ tablet crushed) (3 mg Moyoupine/kg, administered orally). [ Fig. 9 ] shows the degree of supersaturation of mianserin in a powder formulation sample containing acid in an amount 1/5 times the mass ratio of mianserin. AA': powder preparation sample AA' (containing adipic acid); CA': powder preparation sample CA' (containing citric acid); D': powder preparation sample D' (containing aspartic acid); E': powder preparation Sample E' (containing glutamic acid); MAL': powder preparation sample MAL' (containing maleic acid); MLI': powder preparation sample MLI' (containing malic acid); TA': powder preparation sample TA'( containing tartaric acid); TS': powder preparation sample TS' (containing toluenesulfonic acid). [ Fig. 10A ] is a graph showing the residual rate of mianserin of each sample after light irradiation (250 W/m ² , 45 minutes). MIA crystal: mianserin crystal; MIA aqueous solution: mianserin aqueous solution; CA': powder formulation sample CA';MLI': powder formulation sample MLI';TA': powder formulation sample TA'. Data represent mean±standard deviation (n=3) values. *Indicates P<0.05 vs MIA crystals. [ FIG. 10B ] is a graph showing the residual rate of mianserin when stored under accelerated test conditions. MIA crystal: mianserin crystal; MIA aqueous solution: mianserin aqueous solution; CA': powder formulation sample CA';MLI': powder formulation sample MLI';TA': powder formulation sample TA'. Data represent mean±standard deviation (n=3) values. [ Fig. 11 ] shows the dissolution behavior of mianserin crystals and their fine particles, and samples of mianserin nasal powder preparations. In order to simulate the pH in the nasal cavity, a phosphate buffer (pH 5.6) was used as a test solution, and a dissolution test was performed by the paddle method. Data represent mean±standard deviation (n=3) values. Nasal powder preparation sample CA' (black square), nasal powder preparation sample MLI' (black triangle), nasal powder preparation sample TA' (black rhombus), micronized mianserin crystals (white inverted triangle) and mianserin crystals (white circles). [ Fig. 12 ] shows observation images of mianserin crystals and nasal powder preparations obtained by a scanning electron microscope. Screen 12A shows an observed image of mianserin crystals. The screen 12B shows the observed image of the nasal powder preparation 5 . The screen 12C shows the observed image of the nasal powder preparation 6 . The screen 12D shows the observed image of the nasal powder preparation 7 . The white bar in the figure represents 20 μm. [ Fig. 13 ] is a graph showing the release rate of mianserin from capsules filled with each nasal powder preparation. Jetlizer was used for the nebulizer, Japanese Pharmacopoeia No. 2 capsule was used for the capsule, and 3 sprays were used as 1 test. Data represent mean±standard deviation (n=3) values.

Claims (17)

A powder preparation comprising the following particles, the particles containing: (a) antidepressants that are tricyclic or tetracyclic antidepressants, or triazolopyridine antidepressants; and (b) Excipients. The powder preparation as described in claim 1, wherein the particles further contain (c) acid. The powder preparation as described in claim 1 or 2, wherein the aforementioned (a) tricyclic or tetracyclic antidepressant is a tricyclic or tetracyclic nitrogen-containing heterocyclic compound or a salt thereof. The powder preparation as described in claim 1 or 2, wherein the aforementioned (a) tetracyclic antidepressant is a compound represented by the following formula (1) or a salt thereof: In formula (1), R ₁ represents an alkyl group or hydrogen with 1 to 4 carbons; R ₂ represents carbon or nitrogen, and the dotted line represents the presence or absence of a bond; when R ₂ is carbon, it represents the presence of a bond In the case where R ₂ is nitrogen, the dotted line indicates the absence of a bond; R ₃ represents carbon or nitrogen]. The powder preparation as described in Claim 1 or 2, wherein the aforementioned (a) tricyclic or tetracyclic antidepressants are selected from the group consisting of Mozapine, Mianserin, Sprotriptyline, Amitriptyline, and The group formed by their salts and their combinations. The powder preparation as described in claim 1 or 2, wherein the aforementioned (a) triazolopyridine-based antidepressant is selected from the group consisting of trazodone, its salts, and combinations thereof. The powder preparation as described in claim 1 or 2, wherein the excipient (b) is selected from the group consisting of sugars, sugar alcohols, and cellulose derivatives, and combinations thereof. The powder preparation as described in claim 2, wherein the acid (c) is an organic acid. The powder preparation as described in claim 2, wherein the aforementioned (c) acid is selected from the group consisting of monocarboxylic acid, dicarboxylic acid, sulfonic acid, and combinations thereof. The powder preparation as described in Claim 9, wherein the dicarboxylic acid is selected from glutamic acid, aspartic acid, tartaric acid, maleic acid, malic acid, succinic acid, citric acid, fumaric acid, and At least one of the group consisting of adipic acid. The powder preparation as described in claim 1 or 2, wherein the aforementioned particles are fine particles. The powder formulation as described in Claim 11 further includes a carrier. The powder preparation as described in claim 1 or 2, wherein the powder preparation is a powder preparation for nasal administration or pulmonary administration. The powder preparation as described in Claim 1 or 2, which is used for the treatment or prevention of delirium, phantom limb pain, chronic itching, or depression or depressive state. A method for manufacturing a powder preparation as described in claim 1, comprising the following steps: A step of mixing the aforementioned (a) antidepressant and (b) excipient and performing fine particle formation. A method for manufacturing a powder preparation as described in claim 2, comprising the following steps: A step of mixing the aforementioned (a) antidepressant, (b) excipient, and (c) acid to make fine particles. The production method as described in claim 15 or 16, wherein the fine particle formation is performed by a jet mill, a spray dryer, or a combination thereof.