CN114306233A

CN114306233A - Agomelatine self-microemulsion preparation

Info

Publication number: CN114306233A
Application number: CN202111135102.0A
Authority: CN
Inventors: 范录云; 韩德强; 赵娜
Original assignee: Changzhou Hengbang Pharmaceutical Co ltd; Jiangsu Hansoh Pharmaceutical Group Co Ltd
Current assignee: Changzhou Hengbang Pharmaceutical Co ltd; Jiangsu Hansoh Pharmaceutical Group Co Ltd
Priority date: 2020-09-27
Filing date: 2021-09-27
Publication date: 2022-04-12

Abstract

The invention discloses an agomelatine self-microemulsion preparation which comprises an oil phase, an emulsifier and an auxiliary emulsifier, wherein the agomelatine is distributed in the oil phase. The agomelatine self-microemulsion preparation prepared by the invention has the advantages of simple preparation process, good stability, high bioavailability and good clinical safety.

Description

Agomelatine self-microemulsion preparation

Technical Field

The invention belongs to the field of medical preparations, and mainly relates to an agomelatine-containing self-microemulsion preparation, and medical application and a preparation method thereof.

Background

Depression is a common, easily recurring and highly disabling mental disorder. Based on the discovery of the research of the pharmacological mechanism of the antidepressant, the pathological mechanism hypothesis of dysfunction of the monoamine transmitter system of depression is provided, and the main action mechanism of the existing antidepressant is to regulate the monoamine transmitter system. Although the novel antidepressant drug has great improvement on safety and tolerance, the novel antidepressant drug still has the advantages of slow response, poor curative effect of part of patients, possible adverse reactions in long-term treatment and the like, and has great improvement space in treatment.

Agomelatine is a novel antidepressant, is a melatonin receptor agonist and a serotonin 2C (5-HT2C) receptor antagonist, is the first melatonin antidepressant in the world, is a naphthalene derivative of melatonin, and has better metabolic stability than melatonin because an indole ring is replaced by a naphthalene core. It is a selective and specific agonist of the hypothalamic melatonin receptor, has weak competitive antagonistic activity of 5-HT receptor, and shows a novel pharmacological property of dual action of the melatonin receptor agonist and the selective 5-HT antagonist. It can simulate the action of melatonin, has unique action mode, and is a promising candidate drug for treating circadian rhythm disorder diseases (such as sleep disorder/depression).

Agomelatine (Agomelatine) is white or off-white crystalline powder with the chemical name of N- [2- (7-methoxynaphthalene-1-yl) ethyl]Acetamide of formula C₁₅H₁₇NO₂Molecular weight 243.3, chemical structural formula:

the existing dosage form of agomelatine on the market only comprises oral tablets, and the agomelatine is orally taken once a day before sleep. Agomelatine administered by the oral route, however, has low bioavailability in humans and varies considerably between and within individuals. Because the dosage form of the agomelatine is single, the agomelatine has very obvious liver first pass effect and gastrointestinal tract damage, and the final human bioavailability of the oral tablet is only 3 to 4 percent. Therefore, it is necessary to improve the oral tablet and prepare a drug delivery form with low hepatotoxicity and high bioavailability.

Agomelatine regulates the circadian rhythm of depression patients by acting on melatonin receptors and serotonin 2C (5-HT2C) receptors. Melatonin secretion has circadian rhythm, and the half-life period of agomelatine in vivo is short, so that agomelatine must be administrated before sleep, and the maximum blood concentration needs to be reached after a period of time for effectiveness. Thus, the improved dosage form must be capable of rapid release and rapid onset of action.

Patent CN103830206A discloses a transdermal drug delivery preparation with agomelatine three-dimensional net stereo configuration and a preparation method thereof, which comprises a back lining layer, a drug-loaded three-dimensional net stereo configuration system coated on the back lining layer and an anti-sticking layer compounded on the back lining layer. The invention not only can effectively realize the continuous transdermal of the drug for a longer time and maintain the constant blood concentration, but also has the characteristics of high transdermal absorption rate, high transdermal absorption amount, stability, high efficiency and safety. The preparation has the disadvantages of rapid release, rapid action, and no effect of regulating circadian rhythm disorder of depression patients.

Patent CN105193764A discloses an agomelatine solid dispersion and a preparation method thereof, the agomelatine solid dispersion comprises drug agomelatine and a carrier, wherein the carrier is a hydrophilic polymer carrier. The agomelatine solid dispersion has the advantages of improving water solubility and increasing the dissolution rate of the medicine. However, the preparation still has great hepatotoxicity and limited improvement of bioavailability.

The self-microemulsion consists of an oil phase, an emulsifier and an auxiliary emulsifier, and can spontaneously form 10-100 nm oil-in-water microemulsion in gastrointestinal tracts after being taken orally. The self-microemulsion can improve the solubility of the slightly soluble medicament and improve the dissolution so as to improve the bioavailability of the medicament. The medicine is dispersed to form emulsion with smaller particle size under the dilution of gastrointestinal fluid, has larger surface area, is easy to pass through a hydration layer of a gastrointestinal wall, and can be directly contacted with epithelial cells of the gastrointestinal tract, thereby promoting the absorption of the medicine; can also enter into systemic circulation via lymphatic system to overcome first pass effect of medicine.

However, the existing agomelatine preparation has complex process and is difficult to reproduce, or the preparation has poor stability or low bioavailability, so that the medication safety is influenced. Therefore, a good-reproducibility, safe and effective agomelatine self-microemulsion preparation is needed clinically.

Disclosure of Invention

The invention provides a self-microemulsion preparation of agomelatine, which can obviously make up for the defects of the prior art.

In order to achieve the above object, the present invention provides the following technical solutions:

an agomelatine self-microemulsion comprising an oil phase, an emulsifier and a co-emulsifier, wherein the agomelatine is distributed in the oil phase.

In a preferred embodiment of the present invention, the oil phase is selected from one or more of oils, esters, fatty acids, and fatty alcohols; esters are preferred; more preferably, the oil phase is selected from esters, preferably one or more of medium or long chain fatty acid glycerides, polyethylene glycol fatty acid glycerides, carboxylic acid esters and propylene glycol esters.

In a preferred embodiment of the invention, the oily phase is selected from oils, preferably one or more of vegetable oils, hydrogenated vegetable oils or animal oils; more preferably, the vegetable oil is selected from one or more of soybean oil, almond oil, garlic oil, peppermint oil, coconut oil, cotton oil, corn oil, castor oil, peanut oil, olive oil, palm kernel oil and grape seed oil; preferably one or more of soybean oil, castor oil, peanut oil and palm kernel oil; more preferably soybean oil; the hydrogenated vegetable oil is selected from one or more of hydrogenated peanut oil, hydrogenated palm kernel oil, hydrogenated soybean oil, hydrogenated castor oil and hydrogenated coconut oil; the animal oil is selected from one or more of adeps medulla bovis Seu Bubali, adeps Sus Domestica, fish oil, lanolin, mink oil, squalene and squalane.

In a preferred embodiment of the invention, the oily phase is selected from fatty acids, preferably one or more of caproic acid, caprylic acid, lauric acid, undecanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid and linoleic acid.

In a preferred embodiment of the invention, the oily phase is selected from medium or long chain fatty acid glycerides, preferably one or more of medium chain triglycerides, ethyl oleate, ethyl linoleate, glycerol monolinoleate, glycerol triacetate, glycerol monostearate, glycerol monooleate; more preferably one or more of medium chain triglycerides, ethyl oleate and glycerol monolinoleate; further preferred are medium chain triglycerides including Capterx300, Capterx355, GTCC, labrafac cc, MCT oil, Miglyol 812, Miglyol 810, Miglyol 818, Miglyol 829, Miglyol 840, neobee m5, and further preferred are medium chain triglycerides.

In a preferred embodiment of the present invention, the oil phase is selected from polyethylene glycol fatty acid glycerides, preferably one or more of oleic acid polyethylene glycol glyceride, polyethylene glycol lauryl glyceride, caprylic/capric polyethylene glycol glyceride, lauric acid polyethylene glycol glyceride, polyethylene glycol capric glyceride, polyethylene glycol stearic glyceride and polyethylene glycol isostearic glyceride.

In a preferred embodiment of the invention, the oily phase is selected from carboxylic acid esters, preferably one or more of isopropyl palmitate, lauryl lactate, diisopropyl adipate, di-n-butyl adipate and diethyl sebacate.

In a preferred embodiment of the invention, the oily phase is selected from propylene glycol esters, preferably one or more of propylene glycol caprylate, propylene glycol monolaurate, propylene glycol oleate, propylene glycol myristate, propylene glycol dicaprylate dicaprate, more preferably propylene glycol caprylate.

In a preferred embodiment of the invention, the oily phase is selected from fatty alcohols, preferably one or more of lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, linoleyl alcohol, benzil alcohol, octyldodecanol; more preferably one or more of lauryl alcohol, myristyl alcohol, octyldodecanol; further, octyldodecanol is more preferred.

In a preferred embodiment of the present invention, the emulsifier is selected from one or more of phospholipids, polysorbates, polyoxyethylene oils and their derivatives, polyglycolycerides.

In a preferred embodiment of the invention, the emulsifier is selected from phospholipids, preferably one or two of egg yolk lecithin, cephalin, hydrogenated phospholipids, inositol phospholipids and soybean lecithin.

In a preferred embodiment of the present invention, the emulsifier is selected from polysorbate, preferably one or more of tween 20, tween 40, tween 60, tween 80 and tween 85, more preferably tween 80.

In a preferred embodiment of the invention, the emulsifier is selected from the group consisting of polyoxyethylene oils and derivatives thereof, preferably one or more of polyoxyethylene castor oil, polyoxyethylene triacylglycerols, polyoxyethylene hydrogenated castor oil, more preferably one or more of polyoxyethylene 40-hydrogenated castor oil, polyoxyethylene 50-hydrogenated castor oil, polyoxyethylene 60-hydrogenated castor oil, and polyoxyethylene 90-hydrogenated castor oil; further preferred is polyoxyethylene 40-hydrogenated castor oil.

In a preferred embodiment of the present invention, the emulsifier is selected from one or more of polyglycolyzed glyceride, preferably polyethylene glycol-8-glyceryl caprylate/caprate, polyethylene glycol lauric glyceride, polyethylene glycol lauryl glyceride, polyethylene glycol capric glyceride, polyethylene glycol stearic glyceride, polyethylene glycol isostearic glyceride, coconut oil polyglycolyzed glyceride and almond oil oleic polyglycolyzed glyceride.

In a preferred scheme of the invention, the co-emulsifier is selected from one or more of alcohols, polyethylene glycols, ethers and glycerides; the auxiliary emulsifier is selected from alcohols, preferably C1-C6 fatty alcohol; more preferably one or more of propylene glycol, n-butanol, isobutanol, sec-butanol, isopropanol and ethanol; the auxiliary emulsifier is selected from polyethylene glycol, preferably one or more of polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600 and polyethylene glycol 800; more preferably polyethylene glycol 400; the emulsifier is selected from ethers, preferably one or more of diethylene glycol monoethyl ether, ceteareth, steareth, ceteth and laureth; more preferably diethylene glycol monoethyl ether; the emulsifier is selected from glycerides, preferably one or more of glyceryl monooleate, glyceryl triacetate and polyglycerol fatty acid ester; more preferably glycerol monooleate.

In a preferred embodiment of the present invention, the weight percentage of the oil phase is 5 to 60%, preferably 10% to 50%, more preferably 15% to 45%, further preferably 20% to 40%, and further preferably 25 to 35% based on the total weight of the formula.

In a preferred scheme of the invention, the weight percentage of the agomelatine is 0.1-5%, preferably 0.5-4%, more preferably 1-3%, and further preferably 1.2-2.8% based on the total weight of the prescription; more preferably 1.5 to 2.5%.

In a preferred embodiment of the present invention, the weight percentage of the emulsifier is 20% to 70%, preferably 30% to 65%, more preferably 35% to 60%, further preferably 40% to 58%, and further preferably 45% to 55% based on the total weight of the formula.

In a preferred embodiment of the present invention, the weight percentage of the co-emulsifier is 1 to 40%, preferably 5 to 35%, more preferably 10 to 35%, and further preferably 12 to 30% based on the total weight of the formula; more preferably 15% to 25%.

In a preferred embodiment of the invention, the weight ratio of agomelatine to the oil phase is 1: 5-30; preferably 1: 5-25; more preferably 1: 6-20; further preferably 1: 10 to 18 parts; still more preferably 1: 12 to 18.

In a preferable scheme of the invention, the weight ratio of the emulsifier to the co-emulsifier is 20-1: 1-20; preferably 15-1: 1-15; more preferably 10 to 1: 1-10; further preferably 5 to 1: 1-5; more preferably 3 to 1: 1: 3; particularly preferably 3 to 1.5: 1.

in a preferred embodiment of the invention, the agomelatine self-microemulsion preparation comprises the following components:

an oil phase selected from: one or more of oils, esters, fatty acids and fatty alcohols;

an emulsifier selected from the group consisting of: one or more of phospholipid, polysorbate, polyoxyethylene oil and its derivatives, and polyethylene glycol glyceride;

a co-emulsifier selected from: one or more of alcohols, polyethylene glycols, ethers and glycerides;

optionally further comprising other pharmaceutically compatible excipients.

In a preferred embodiment of the present invention, the other pharmaceutically compatible excipients may be any conventional excipient in the art, such as pharmaceutically acceptable antioxidants, flavoring agents, preservatives, tonicity adjusting agents, viscosity adjusting agents, and the like; the antioxidant can improve product stability, such as sodium sulfite, sodium bisulfite, sodium metabisulfite, alpha-tocopherol, ascorbic acid, sodium ascorbate, ascorbyl palmitate, glutathione, malic acid, citric acid, tartaric acid, succinic acid, gallic acid, propyl gallate, p-hydroxy-tert-butyl anisole (BHA), di-tert-butyl-p-cresol (BHT), disodium edetate, etc.; the flavoring agent can improve product taste, and comprises natural or synthetic sweetener, natural or synthetic aromatic, mucilage, effervescent, such as menthol, oleum Menthae Dementholatum, eugenol, mandarin oil, citral, lemon ester, essence, sorbitol, xylitol, syrup, etc.; the preservative can improve the stability of the drug, prevent the increase of impurities, and prolong the shelf life, such as methyl paraben, ethyl paraben, propyl paraben, isopropanol, isoascorbic acid, sodium erythorbate, cinnamyl alcohol, lactic acid, sodium salicylate, acetic acid, sorbic acid, potassium sorbate, sodium benzoate, etc.; the osmotic pressure regulator is used for regulating the osmotic pressure of emulsion preparations, such as sodium chloride, glucose, mannitol, glycerol, sorbitol, etc.; the viscosity regulator is used for regulating the viscosity of the preparation, such as saccharides, xanthan gum, cellulose and derivatives thereof, polyvinyl alcohol, magnesium aluminum silicate and the like; the anti-freezing agent also comprises other pharmaceutically acceptable auxiliary materials such as an anti-freezing agent, a stabilizing agent, a filling agent and the like, and can be selected by a person skilled in the art according to the preparation requirement, wherein the addition amount of the additive can be 0.001-20% of the total amount; preferably 0.001-10%; more preferably 0.001 to 5%; further preferably 0.001-5%; further preferably 0.001 to 1%; further preferably 0.001 to 0.5%; .

In a preferred embodiment of the invention, the oil phase comprises at least fatty acids; preferably, at least medium or long chain fatty acid glycerides; more preferably, at least medium chain triglycerides; further preferably, the weight percentage of the medium chain triglycerides is 10-50%, preferably 15-45%, more preferably 20-40%, further preferably 25-35% based on the total weight of the formula.

In a preferred embodiment of the invention, the oil phase comprises at least ethyl oleate; preferably, the weight percentage of the ethyl oleate is 10% -50%, preferably 15% -45%, more preferably 20% -40%, and further preferably 25% -35% of the total weight of the prescription.

In a preferred embodiment of the present invention, the emulsifier comprises at least polyoxyethylene oil and its derivatives; preferably, at least polyoxyethylene hydrogenated castor oil; more preferably, at least polyoxyethylene 40-hydrogenated castor oil; further preferably, the weight percentage of polyoxyethylene 40-hydrogenated castor oil is 30% to 65%, preferably 35% to 60%, more preferably 40% to 58%, further preferably 45% to 55% based on the total weight of the formulation.

In a preferred embodiment of the invention, the emulsifier comprises at least a polysorbate; preferably, at least tween 80 is included; more preferably, the weight percentage of tween 80 is 30% to 65%, preferably 35% to 60%, more preferably 40% to 58%, and even more preferably 45% to 55%, based on the total weight of the prescription.

In a preferred embodiment of the invention, when the oil phase is a medium chain triglyceride, it comprises the following components:

components	Material(s)
		Agomelatine	Agomelatine
Oil phase	Medium chain triglycerides
		Emulsifier	Polyoxyethylene 40-hydrogenated castor oil
Auxiliary emulsifier	Polyethylene glycol 400

；

Or,

components	Material(s)
		Agomelatine	Agomelatine
Oil phase	Medium chain triglycerides
		Emulsifier	Polyoxyethylene 40-hydrogenated castor oil
Auxiliary emulsifier	Glyceryl monooleate

；

Or,

components	Material(s)
		Agomelatine	Agomelatine
Oil phase	Medium chain triglycerides
		Emulsifier	Polyoxyethylene 40-hydrogenated castor oil
Auxiliary emulsifier	Diethylene glycol monoethyl ether

；

Or,

components	Material(s)
		Agomelatine	Agomelatine
Oil phase	Medium chain triglycerides
		Emulsifier	Tween 80
Auxiliary emulsifier	Diethylene glycol monoethyl ether

；

Or,

components	Material(s)
		Agomelatine	Agomelatine
Oil phase	Medium chain triglycerides
		Emulsifier	Tween 80
Auxiliary emulsifier	Glyceryl monooleate

；

Or,

components	Material(s)
		Agomelatine	Agomelatine
Oil phase	Medium chain triglycerides
		Emulsifier	Tween 80
Auxiliary emulsifier	Polyethylene glycol 400

In a preferred embodiment of the present invention, when the oil phase is ethyl oleate, the oil phase comprises the following components:

components	Material(s)
		Agomelatine	Agomelatine
Oil phase	Oleic acid ethyl ester
		Emulsifier	Polyoxyethylene 40-hydrogenated castor oil
Auxiliary emulsifier	Polyethylene glycol 400

；

Or,

components	Material(s)
		Agomelatine	Agomelatine
Oil phase	Oleic acid ethyl ester
		Emulsifier	Polyoxyethylene 40-hydrogenated castor oil
Auxiliary emulsifier	Glyceryl monooleate

；

Or,

or,

components	Material(s)
		Agomelatine	Agomelatine
Oil phase	Oleic acid ethyl ester
		Emulsifier	Tween 80
Auxiliary emulsifier	Diethylene glycol monoethyl ether

；

Or,

components	Material(s)
		Agomelatine	Agomelatine
Oil phase	Oleic acid ethyl ester
		Emulsifier	Tween 80
Auxiliary emulsifier	Glyceryl monooleate

；

Or,

components	Material(s)
		Agomelatine	Agomelatine
Oil phase	Oleic acid ethyl ester
		Emulsifier	Tween 80
Auxiliary emulsifier	Polyethylene glycol 400

In the preferred scheme of the invention, the weight percentages of the components in the self-microemulsion are as follows:

or,

material(s)	Percent (%)
		Agomelatine	0.5％-4％
Oil phase	10％-50％
		Emulsifier	30％-65％
Auxiliary emulsifier	5％-35％

；

Or,

material(s)	Percent (%)
		Agomelatine	1％-3％
Oil phase	15％-45％
		Emulsifier	35％-60％
Auxiliary emulsifier	10％-35％

；

Or,

material(s)	Percent (%)
		Agomelatine	1.2％-2.8％
Oil phase	20％-40％
		Emulsifier	40％-58％
Auxiliary emulsifier	12％-30％

；

Or,

material(s)	Percent (%)
		Agomelatine	1.5％-2.5％
Medium chain triglycerides	25％-35％
		Emulsifier	45％-55％
Auxiliary emulsifier	15％-25％

；

Or,

material(s)	Percent (%)
		Agomelatine	1.5％-2.5％
Oleic acid ethyl ester	25％-35％
		Emulsifier	45％-55％
Auxiliary emulsifier	15％-25％

；

Or,

material(s)	Percent (%)
		Agomelatine	1.5％-2.5％
Medium chain triglycerides	25％-35％
		Polyoxyethylene 40-hydrogenated castor oil	45％-55％
Auxiliary emulsifier	15％-25％

；

Or,

material(s)	Percent (%)
		Agomelatine	1.5％-2.5％
Medium chain triglycerides	25％-35％
		Tween 80	45％-55％
Auxiliary emulsifier	15％-25％

；

Or,

material(s)	Percent (%)
		Agomelatine	1.5％-2.5％
Oleic acid ethyl ester	25％-35％
		Polyoxyethylene 40-hydrogenated castor oil	45％-55％
Auxiliary emulsifier	15％-25％

；

Or,

material(s)	Percent (%)
		Agomelatine	1.5％-2.5％
Oleic acid ethyl ester	25％-35％
		Tween 80	45％-55％
Auxiliary emulsifier	15％-25％

material(s)	Percent (%)
		Agomelatine	1.5％-2.5％
Medium chain triglycerides	25％-35％
		Polyoxyethylene 40-hydrogenated castor oil	45％-55％
Polyethylene glycol 400	15％-25％

；

Or,

material(s)	Percent (%)
		Agomelatine	1.5％-2.5％
Oleic acid ethyl ester	25％-35％
		Polyoxyethylene 40-hydrogenated castor oil	45％-55％
Polyethylene glycol 400	15％-25％

；

Or,

or,

material(s)	Percent (%)
		Agomelatine	1.5％-2.5％
Medium chain triglycerides	25％-35％
		Polyoxyethylene 40-hydrogenated castor oil	45％-55％
Glyceryl monooleate	15％-25％

；

Or,

material(s)	Percent (%)
		Agomelatine	1.5％-2.5％
Medium chain triglycerides	25％-35％
		Polyoxyethylene 40-hydrogenated castor oil	45％-55％
Diethylene glycol monoethyl ether	15％-25％

。

The dosage form of the self-microemulsion can be capsules or oral solution, wherein the capsules comprise various suitable capsule dosage forms such as soft capsules, liquid-filled hard capsules, sustained and controlled release capsules, osmotic pump capsules and the like.

The self-microemulsion preparation can be solidified after being added with proper absorbent according to the requirement, thereby obtaining solid medicinal preparations in various forms such as common tablets, dispersible tablets, double-layer tablets, multilayer tablets, sustained-release tablets, micro-pills and the like.

The invention also provides a preparation method of the agomelatine self-microemulsion preparation, which comprises the steps of weighing the agomelatine, the oil phase, the emulsifier and the auxiliary emulsifier according to the prescription amount, uniformly mixing, optionally adding other pharmaceutically compatible auxiliary materials, and uniformly mixing to obtain the agomelatine self-microemulsion preparation.

The agomelatine self-microemulsion preparation can be applied to preparation of related medicines for treating mental diseases, preferably, the mental diseases refer to depression, and more preferably, the mental diseases refer to major depression.

The agomelatine self-microemulsion preparation provided by the invention has the following advantages:

(1) the preparation process is simple, the reproducibility is good, and the large-scale production is very easy;

(2) the solubility of the medicine is improved, so that the oral bioavailability of the medicine is greatly improved;

(3) good stability and high safety, and can meet the requirements of clinical use.

Detailed Description

To better illustrate the embodiments and effects achieved by the present invention, the following examples are further described.

Example 1

The self-microemulsion formula comprises:

material(s)	Addition amount (g)	Percent (%)
			Agomelatine	2	1.96
Medium chain triglycerides	30	29.41
			Polyoxyethylene 40-hydrogenated castor oil	50	49.02
Polyethylene glycol 400	20	19.61

The preparation method comprises the following steps: weighing agomelatine, medium-chain triglyceride, polyoxyethylene 40-castor oil and polyethylene glycol 400 in a formula amount into a beaker, and stirring to completely dissolve the agomelatine, the medium-chain triglyceride, the polyoxyethylene 40-castor oil and the polyethylene glycol to obtain a clear transparent solution, namely the self-microemulsion. Finally, the self-microemulsion is prepared into capsules.

Example 2

The self-microemulsion formula comprises:

material(s)	Addition amount (g)	Percent (%)
			Agomelatine	2	1.96
Soybean oil	30	29.41
			Polyoxyethylene 40-hydrogenated castor oil	50	49.02
Polyethylene glycol 400	20	19.61

The preparation method comprises the following steps: weighing agomelatine, soybean oil, polyoxyethylene 40-castor oil and polyethylene glycol 400 in the formula amount into a beaker, and stirring to completely dissolve the agomelatine, the soybean oil, the polyoxyethylene 40-castor oil and the polyethylene glycol to obtain a clear transparent solution, namely the self-microemulsion. Finally, the self-microemulsion is prepared into capsules.

Example 3

The self-microemulsion formula comprises:

the preparation method comprises the following steps: weighing agomelatine, ethyl oleate, polyoxyethylene 40-castor oil and polyethylene glycol 400 in the formula amount into a beaker, and stirring to completely dissolve the agomelatine, the ethyl oleate, the polyoxyethylene 40-castor oil and the polyethylene glycol 400 to obtain a clear transparent solution, namely the self-microemulsion. Finally, the self-microemulsion is prepared into capsules.

Example 4

The self-microemulsion formula comprises:

material(s)	Addition amount (g)	Percent (%)
			Agomelatine	2	1.96
Medium chain triglycerides	30	29.41
			Tween 80	50	49.02
Polyethylene glycol 400	20	19.61

The preparation method comprises the following steps: weighing agomelatine, medium-chain triglyceride, tween 80 and polyethylene glycol 400 in the prescribed amount into a beaker, and stirring to completely dissolve the agomelatine, the medium-chain triglyceride, the tween 80 and the polyethylene glycol 400 to obtain a clear and transparent solution, namely the self-microemulsion. Finally, the self-microemulsion is prepared into capsules.

Example 5

The self-microemulsion formula comprises:

material(s)	Addition amount (g)	Percent (%)
			Agomelatine	2	1.96
Medium chain triglycerides	30	29.41
			Egg yolk lecithin	50	49.02
Polyethylene glycol 400	20	19.61

The preparation method comprises the following steps: weighing agomelatine, medium-chain triglyceride, egg yolk lecithin and polyethylene glycol 400 in the formula amount into a beaker, and stirring to completely dissolve the agomelatine, the medium-chain triglyceride, the egg yolk lecithin and the polyethylene glycol to obtain a clear and transparent solution, namely the self-microemulsion. Finally, the self-microemulsion is prepared into capsules.

Example 6

The self-microemulsion formula comprises:

material(s)	Addition amount (g)	Percent (%)
			Agomelatine	2	1.96
Medium chain triglycerides	30	29.41
			Soybean lecithin	50	49.02
Polyethylene glycol 400	20	19.61

The preparation method comprises the following steps: weighing agomelatine, medium-chain triglyceride, soybean lecithin and polyethylene glycol 400 in the prescribed amount into a beaker, and stirring to completely dissolve the agomelatine, the medium-chain triglyceride, the soybean lecithin and the polyethylene glycol to obtain a clear and transparent solution, namely the self-microemulsion. Finally, the self-microemulsion is prepared into capsules.

Example 7

The self-microemulsion formula comprises:

material(s)	Addition amount (g)	Percent (%)
			Agomelatine	2	1.96
Medium chain triglycerides	30	29.41
			Polyoxyethylene 40-hydrogenated castor oil	50	49.02
Glyceryl monooleate	20	19.61

The preparation method comprises the following steps: weighing agomelatine, medium-chain triglyceride, polyoxyethylene 40-hydrogenated castor oil and glyceryl monooleate in the formula amount into a beaker, and stirring to completely dissolve the agomelatine, the medium-chain triglyceride, the polyoxyethylene 40-hydrogenated castor oil and the glyceryl monooleate to obtain a clear transparent solution, namely the self-microemulsion. Finally, the self-microemulsion is prepared into capsules.

Example 8

The self-microemulsion formula comprises:

material(s)	Addition amount (g)	Percent (%)
			Agomelatine	2	1.96
Medium chain triglycerides	30	29.41
			Polyoxyethylene 40-hydrogenated castor oil	50	49.02
Diethylene glycol monoethyl ether	20	19.61

The preparation method comprises the following steps: weighing agomelatine, medium-chain triglyceride, polyoxyethylene 40-hydrogenated castor oil and diethylene glycol monoethyl ether in the formula amount into a beaker, and stirring to completely dissolve the agomelatine, the medium-chain triglyceride, the polyoxyethylene 40-hydrogenated castor oil and the diethylene glycol monoethyl ether to obtain a clear and transparent solution, namely the self-microemulsion. Finally, the self-microemulsion is prepared into capsules.

Example 9

The self-microemulsion formula comprises:

material(s)	Addition amount (g)	Percent (%)
			Agomelatine	2	2
Medium chain triglycerides	44.6	44.6
			Polyoxyethylene 40-hydrogenated castor oil	39.4	39.4
Polyethylene glycol 400	14	14

The preparation method comprises the following steps: weighing agomelatine, medium-chain triglyceride, polyoxyethylene 40-hydrogenated castor oil and polyethylene glycol 400 in the formula amount into a beaker, and stirring to completely dissolve the agomelatine, the medium-chain triglyceride, the polyoxyethylene 40-hydrogenated castor oil and the polyethylene glycol to obtain a clear transparent solution, namely the self-microemulsion. Finally, the self-microemulsion is prepared into capsules.

Example 10

The self-microemulsion formula comprises:

material(s)	Addition amount (g)	Percent (%)
			Agomelatine	2	2
Medium chain triglycerides	34	34
			Polyoxyethylene 40-hydrogenated castor oil	47	47
Polyethylene glycol 400	17	17

Example 11

The self-microemulsion formula comprises:

material(s)	Addition amount (g)	Percent (%)
			Agomelatine	1.55	1.52
Medium chain triglycerides	30	29.54
			Polyoxyethylene 40-hydrogenated castor oil	50	49.24
Polyethylene glycol 400	20	19.69

Example 12

The self-microemulsion formula comprises:

material(s)	Addition amount (g)	Percent (%)
			Agomelatine	2.55	2.49
Medium chain triglycerides	30	29.25
			Polyoxyethylene 40-hydrogenated castor oil	50	48.76
Polyethylene glycol 400	20	19.5

Example 13

The self-microemulsion formula comprises:

material(s)	Addition amount (g)	Percent (%)
			Agomelatine	2	1.96
Medium chain triglycerides	25	24.51
			Polyoxyethylene 40-hydrogenated castor oil	55	53.92
Polyethylene glycol 400	20	19.61

Example 14

The self-microemulsion formula comprises:

material(s)	Addition amount (g)	Percent (%)
			Agomelatine	2	1.96
Medium chain triglycerides	35	34.31
			Polyoxyethylene 40-hydrogenated castor oil	45	44.12
Polyethylene glycol 400	20	19.61

Example 15

The self-microemulsion formula comprises:

material(s)	Addition amount (g)	Percent (%)
			Agomelatine	2.8	2.75
Medium chain triglycerides	27.5	26.96
			Polyoxyethylene 40-hydrogenated castor oil	45.5	44.61
Polyethylene glycol 400	26.2	25.69

Example 16

The self-microemulsion formula comprises:

material(s)	Addition amount (g)	Percent (%)
			Agomelatine	2.8	2.75
Medium chain triglycerides	25.7	25.2
			Polyoxyethylene 40-hydrogenated castor oil	43.3	42.45
Polyethylene glycol 400	30.2	29.61

Example 17

The self-microemulsion formula comprises:

material(s)	Addition amount (g)	Percent (%)
			Agomelatine	2	2
Medium chain triglycerides	38.2	38.2
			Tween 80	42.1	42.1
Glyceryl monooleate	17.7	17.7

The preparation method comprises the following steps: weighing agomelatine, medium-chain triglyceride, tween 80 and glyceryl monooleate in the formula amount into a beaker, and stirring to completely dissolve the agomelatine, the medium-chain triglyceride, the tween 80 and the glyceryl monooleate to obtain a clear transparent solution, namely the self-microemulsion. Finally, the self-microemulsion is prepared into capsules.

Example 18

The self-microemulsion formula comprises:

material(s)	Addition amount (g)	Percent (%)
			Agomelatine	2	2
Oleic acid ethyl ester	44.6	44.6
			Tween 80	39.4	39.4
Polyethylene glycol 400	14	14

The preparation method comprises the following steps: weighing agomelatine, ethyl oleate, Tween 80 and polyethylene glycol 400 in the prescribed amount into a beaker, and stirring to completely dissolve the agomelatine, the ethyl oleate, the Tween 80 and the polyethylene glycol 400 to obtain a clear transparent solution, namely the self-microemulsion. Finally, the self-microemulsion is prepared into capsules.

Experimental example 1 investigation of oil phase type

Different oil phases (soybean oil, medium chain triglycerides and ethyl oleate) were prepared from the microemulsions and the effect of the oil on the quality of the samples was examined.

TABLE 1 investigation results of oil phase species

The result shows that the self-microemulsion surface floating oil prepared by taking the soybean oil as the oil phase is turbid after emulsification and has larger particle size. The self-microemulsion prepared by taking the medium-chain triglyceride and the ethyl oleate as oil phases is a clear and transparent solution, and the emulsified solution is clear and transparent, has light blue opalescence and small particle size. Thus, medium chain triglycerides or ethyl oleate may be selected as the oil phase to prepare self-microemulsions, with medium chain triglycerides being preferred.

Experimental example 2 examination of emulsifier types

Different emulsifiers (polyoxyethylene 40-hydrogenated castor oil, tween 80, egg yolk lecithin and soybean lecithin) were prepared from the microemulsions and the effect of the emulsifiers on the sample quality was investigated.

Table 2 emulsifier species investigation results

The results show that the self-microemulsions prepared with the different emulsifiers are clear and transparent solutions. The self-microemulsion prepared from the medium-chain triglyceride or the Tween 80 is a clear and transparent solution with pale blue opalescence after emulsification, and has smaller particle size. The self-microemulsion prepared by using the egg yolk lecithin or the soybean oil lecithin as the emulsifier is a clear and semitransparent solution after emulsification, and has larger particle size. Therefore, polyoxyethylene 40-hydrogenated castor oil or tween 80 can be selected as the emulsifier to prepare the self-microemulsion, and polyoxyethylene 40-hydrogenated castor oil is preferred.

Experimental example 3 examination of the kind of co-emulsifier

Different co-emulsifiers (polyethylene glycol 400, glyceryl monooleate and diethylene glycol monoethyl ether) are prepared into the self-microemulsion, and the influence of the co-emulsifiers on the quality of a sample is investigated.

TABLE 3 examination of the type of co-emulsifier

The result shows that the difference between the self-microemulsion prepared by different co-emulsifiers is relatively small before and after emulsification, and polyethylene glycol 400, glyceryl monooleate and diethylene glycol monoethyl ether can be used as the co-emulsifiers for preparing the self-microemulsion, but the polyethylene glycol 400 is preferred.

Experimental example 4 stability test results

The self-microemulsion of example 1 was subjected to accelerated condition test (40 ℃ C., RH 75%) and long-term condition test (25 ℃ C., RH 60%) and left for 2 weeks to examine properties, contents, related substances and particle diameters. The result shows that the self-microemulsion prepared in the embodiment 1 has no obvious change in the detection result compared with 0 day through the accelerated condition test and the long-term condition test, and the self-microemulsion has better stability.

Experimental example 5 pharmacokinetics in rats

To investigate the pharmacokinetics of the formulation of the present invention in vivo, rat in vivo pharmacokinetic studies were performed using agomelatine self-microemulsion and an aqueous solution of agomelatine in example 1.

Preparing an agomelatine aqueous solution: and adding 10ml of purified water into 10mg of agomelatine, and uniformly stirring to obtain the agomelatine. Before animal experiment, the medicine is administered after being stirred uniformly again.

6 healthy rats were divided into two groups, the first group being self-microemulsion formulations of agomelatine (n-3) intubated with a single dose of 2.5mg/kg of oesophagus, and the second group being intubated with a single dose of 10mg/kg of aqueous agomelatine solution (n-3). After administration, sampling at 0min, 5min, 15min, 30min, 1h, 2h, 4h, 8h and 24h, and LC-MS-MS determining blood concentration. Animal experimental experiments show that the Cmax, Tmax and AUC of the two groups of data are not obviously different, and the blood concentration-time curves of the agomelatine self-microemulsion and the agomelatine aqueous solution are basically consistent. The agomelatine self-microemulsion can effectively improve the solubility and bioavailability of the medicine.

Claims

1. The agomelatine self-microemulsion preparation is characterized by comprising an oil phase, an emulsifier and an auxiliary emulsifier, wherein the agomelatine is distributed in the oil phase;

the oil phase is selected from one or more of oils, esters, fatty acids and fatty alcohols; esters are preferred; more preferably one or more of medium or long-chain fatty acid glycerides, polyethylene glycol fatty acid glycerides, carboxylic acid esters and propylene glycol esters;

the emulsifier is selected from one or more of phospholipid, polysorbate, polyoxyethylene oil and its derivatives, and macrogol glyceride;

the auxiliary emulsifier is selected from one or more of alcohols, polyethylene glycols, ethers and glycerides; the coemulsifier is selected from alcohols, preferably C₁-C₆A fatty alcohol; more preferred are propylene glycol, n-butanol, isobutanol, sec-butanol, isopropanol, n-hexanolAnd one or more of ethanol; the auxiliary emulsifier is selected from polyethylene glycol, preferably one or more of polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600 and polyethylene glycol 800; more preferably polyethylene glycol 400; the emulsifier is selected from ethers, preferably one or more of diethylene glycol monoethyl ether, ceteareth, steareth, ceteth and laureth; more preferably diethylene glycol monoethyl ether; the emulsifier is selected from glycerides, preferably one or more of glyceryl monooleate, glyceryl triacetate and polyglycerol fatty acid ester; more preferably glycerol monooleate.

2. The agomelatine self-microemulsion formulation according to claim 1, wherein,

the oil phase is selected from medium-chain or long-chain fatty acid glycerides, preferably one or more of medium-chain triglyceride, ethyl oleate, ethyl linoleate, glycerol monolinoleate, glycerol triacetate, glycerol monostearate and glycerol monooleate; more preferably one or more of medium chain triglyceride, ethyl oleate and glycerol monolinoleate; further preferably one or more of medium chain triglyceride and ethyl oleate; still further preferred are medium chain triglycerides;

and/or the presence of a gas in the gas,

the emulsifier is selected from polysorbate, preferably one or more of Tween 20, Tween 40, Tween 60, Tween 80, and Tween 85, more preferably Tween 80;

and/or the presence of a gas in the gas,

the emulsifier is selected from polyoxyethylene oil and its derivatives, preferably one or more of polyoxyethylene castor oil, polyoxyethylene triacylglycerol, and polyoxyethylene hydrogenated castor oil; more preferably polyoxyethylene hydrogenated castor oil; further preferred is one or more selected from polyoxyethylene 40-hydrogenated castor oil, polyoxyethylene 50-hydrogenated castor oil, polyoxyethylene 60-hydrogenated castor oil and polyoxyethylene 90-hydrogenated castor oil, and further preferred is polyoxyethylene 40-hydrogenated castor oil.

3. The agomelatine self-microemulsion preparation according to any one of claims 1 to 2, wherein the oil phase is present in an amount of 5 to 60% by weight, based on the total weight of the formulation; preferably 10% -50%; more preferably 15% to 45%; further preferably 20% to 40%; further preferably 25-35%;

and/or the presence of a gas in the gas,

the weight percentage of the agomelatine is 0.1 to 5 percent based on the total weight of the prescription; preferably 0.5 to 4 percent; more preferably 1% to 3%; further preferably 1.2-2.8%; further preferably 1.5 to 2.5%;

and/or the presence of a gas in the gas,

based on the total weight of the prescription, the weight percentage of the emulsifier is 20 to 70 percent; preferably 30% -65%; more preferably 35% to 60%; further preferably 40% to 58%; further preferably 45 to 55 percent;

and/or the presence of a gas in the gas,

the weight percentage of the co-emulsifier is 1-40% based on the total weight of the prescription; preferably 5% -35%; more preferably 10% to 35%; further preferably 12-30%; more preferably 15% to 25%.

4. The agomelatine self-microemulsion formulation according to claim 1, wherein the weight ratio of agomelatine to the oil phase is 1: 5-30; preferably 1: 5-25; more preferably 1: 6-20; further preferably 1: 10 to 18 parts; still more preferably 1: 12 to 18;

and/or the presence of a gas in the gas,

the weight ratio of the emulsifier to the co-emulsifier is 20-1: 1-20; preferably 15-1: 1-15; more preferably 10 to 1: 1-10; further preferably 5 to 1: 1-5; more preferably 3 to 1: 1: 3; particularly preferably 3 to 1.5: 1.

5. the agomelatine self-microemulsion formulation according to claim 1, characterized by comprising the following components:

optionally further comprising other pharmaceutically compatible excipients;

preferably, the pharmaceutically compatible auxiliary materials comprise one or more of an antioxidant, a flavoring agent, a preservative, an osmotic pressure regulator and a viscosity regulator.

6. The agomelatine self-microemulsion formulation according to claim 1, characterized in that the oily phase comprises at least fatty acids; preferably at least medium or long chain fatty acid glycerides, more preferably at least medium chain triglycerides; further preferably, the weight percentage of the medium chain triglyceride is 10% -50%, preferably 15% -45%, more preferably 20% -40%, further preferably 25% -35% by total weight of the prescription;

and/or the presence of a gas in the gas,

the oil phase comprises at least ethyl oleate; preferably, the weight percentage of the ethyl oleate is 10% -50% of the total weight of the prescription; preferably 15 to 45 percent; more preferably 20% to 40%; further preferably 25-35%;

and/or the presence of a gas in the gas,

the emulsifier at least comprises polyoxyethylene oil and derivatives thereof; preferably, at least polyoxyethylene hydrogenated castor oil; more preferably, at least polyoxyethylene 40-hydrogenated castor oil; further preferably, the weight percentage of the polyoxyethylene 40-hydrogenated castor oil is 30-65% based on the total weight of the prescription; preferably 35% -60%; more preferably 40% to 58%; further preferably 45% to 55%;

and/or the presence of a gas in the gas,

the emulsifier comprises at least a polysorbate; preferably, at least tween 80 is included; more preferably, the weight percentage of tween 80 is 30% to 65% based on the total weight of the prescription; preferably 35% -60%; more preferably 40% to 58%; further preferably 45% to 55%.

7. The agomelatine self-microemulsion formulation according to claim 1, wherein when the oil phase is a medium chain triglyceride, it comprises the following components:

components Material(s) Agomelatine Agomelatine Oil phase Medium chain glycerol tri-vinegar Emulsifier Polyoxyethylene 40-hydrogenated castor oil Auxiliary emulsifier Polyethylene glycol 400

；

Or,

or,

；

Or,

；

Or,

；

Or,

；

And/or the presence of a gas in the gas,

when the oil phase is ethyl oleate, the oil phase comprises the following components:

；

Or,

；

Or,

components Material(s) Agomelatine Agomelatine Oil phase Oleic acid ethyl ester Emulsifier Polyoxyethylene 40-hydrogenated castor oil Auxiliary emulsifier Diethylene glycol monoethyl ether

；

Or,

；

Or,

；

Or,

。

8. The agomelatine self-microemulsion preparation according to any one of claims 1 to 7, wherein the weight percentages of the components in the self-microemulsion are as follows:

material(s) Percent (%) Agomelatine 0.1％-5％ Oil phase 5％-60％ Emulsifier 20％-70％ Auxiliary emulsifier 1％-40％

；

Or,

or,

；

Or,

；

Or,

material(s) Percent (%) Agomelatine 1.5％-2.5％ Oil phase 25％-35％ Emulsifier 45％-55％ Auxiliary emulsifier 15％-25％

；

Preferably, the weight percentages of the components in the self-microemulsion are as follows:

material(s) Percent (%) Agomelatine 1.5％-2.5％ Medium chain triglycerides 25％％-35％ Emulsifier 45％-55％ Auxiliary emulsifier 15％-25％

；

Or,

；

Or,

；

Or,

；

Or,

；

Or,

；

More preferably, the weight percentages of the components in the self-microemulsion are as follows:

；

Or,

；

Or,

material(s) Percent (%) Agomelatine 1.5％-2.5％ Medium chain triglycerides 25％-35％ Tween 80 45％-55％ Polyethylene glycol 400 15％-25％

；

Or,

；

Or,

。

9. The agomelatine self-microemulsion formulation according to any one of claims 1 to 8, wherein the dosage form of the self-microemulsion formulation is a capsule or an oral solution, wherein the capsule includes a soft capsule, a hard-filled capsule, a sustained-release capsule and an osmotic pump capsule;

optionally, the self-microemulsion preparation can be solidified after adding a proper absorbent according to needs, so as to obtain a common tablet, a dispersible tablet, a double-layer tablet, a multi-layer tablet, a sustained-release tablet or a pellet.

10. Use of the agomelatine self-microemulsion formulation according to any one of claims 1 to 9 for the preparation of a medicament for the treatment of psychiatric disorders, preferably depression, more preferably major depression.