An agomelatine self-microemulsion formulation

Abstract

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

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and mainly relates to a self-microemulsion preparation containing agomelatine and a medical use and a preparation method thereof. BACKGROUND

[0002] Depression is a common, recurrent and high-disability mental illness. Based on the discovery of the pharmacological mechanism of antidepressants, the hypothesis of the pathological mechanism of monoamine neurotransmitter system dysfunction of depression is proposed, and the main mechanism of the existing antidepressants is to regulate the monoamine neurotransmitter system. Although new antidepressants have been greatly improved in safety and tolerability, there are still slow onset, poor efficacy in some patients, and adverse reactions in long-term treatment, and there is still a lot of room for improvement in treatment.

[0003] Agomelatine is a new antidepressant, which is a melatonin receptor agonist and a serotonin 2C (5-HT2C) receptor antagonist. It is the first melatonin-based antidepressant in the world, which is a naphthalene derivative of melatonin. The indole ring is replaced by a naphthalene nucleus, which makes it more metabolically stable than melatonin. It is a selective and specific agonist of hypothalamic melatonin receptors, and also has weak 5-HT receptor competitive antagonistic activity, showing a new pharmacological property of dual action of melatonin receptor agonist and selective 5-HT antagonist. It can mimic the action of melatonin and has a unique mode of action, and is a promising candidate drug for the treatment of physiological rhythm disorder diseases (such as sleep disorders / depression).

[0004] Agomelatine is a white or white crystalline powder, the chemical name is N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide, the molecular formula is C 15 H 17 NO2, the molecular weight is 243.3, and the chemical structural formula is:

[0005]

[0006] The existing marketed dosage form of agomelatine is only oral tablets, which are administered once a day before sleep. However, the bioavailability of agomelatine administered by oral route in the human body is low, and the inter-individual and intra-individual biological differences are quite large. Due to the single dosage form of agomelatine, there is a very obvious liver first-pass effect and gastrointestinal destruction, and the final human bioavailability of oral tablets is only 3% to 4%. Therefore, it is necessary to improve the oral tablets to prepare a drug dosage form with small liver toxicity and high bioavailability.

[0007] Agomelatine regulates the physiological rhythm of patients with depression by acting on the melatonin receptor and the serotonin 2C (5-HT2C) receptor. Melatonin secretion has circadian rhythm, and the short in vivo half-life of agomelatine leads to the fact that agomelatine must be administered before sleep, and a maximum blood concentration needs to be reached after a period of time to take effect. Therefore, the modified dosage form must be capable of rapid release and rapid onset of action.

[0008] Patent CN103830206A discloses a kind of agomelatine three-dimensional net stereoscopic configuration of transdermal drug delivery preparation and preparation method, by backing layer, drug-loaded three-dimensional net stereoscopic configuration system coated on the backing layer and composite on it The anti-sticking layer is formed. The application not only can effectively realize the sustained transdermal of drug for a long time, maintain constant blood concentration, and the preparation transdermal absorption rate is fast, transdermal absorption amount is high, with the characteristics of stable, efficient, safe. The disadvantage of this dosage form is that it cannot be quickly released, quickly take effect, and cannot achieve the effect of regulating the physiological rhythm disorder of patients with depression.

[0009] Patent CN105193764A discloses a kind of agomelatine solid dispersion and preparation method thereof, agomelatine solid dispersion includes drug agomelatine and carrier, wherein, carrier is hydrophilic polymer carrier. The agomelatine solid dispersion of the application has the advantages of improving water solubility and improving the dissolution rate of the drug. However, the liver toxicity of this dosage form is still very large, and the improvement of bioavailability is also limited.

[0010] Self-microemulsion is composed of oil phase, emulsifier and co-emulsifier, and can spontaneously form 10-100 nm oil-in-water microemulsion in the gastrointestinal tract after oral administration. Self-microemulsion can improve the solubility of poorly soluble drugs and improve the dissolution to improve the bioavailability of drugs. The drug is dispersed to form a smaller emulsion under the dilution of gastrointestinal fluid, has a larger surface area, is easy to pass through the hydration layer of the gastrointestinal wall, and can directly contact the epithelial cells of the gastrointestinal tract, thereby promoting drug absorption; it can also enter the systemic circulation through the lymphatic system, overcoming the first-pass effect of drugs.

[0011] However, the existing agomelatine preparation or process is complex and difficult to reproduce, or the preparation stability is poor, or the bioavailability is low, which affects the safety of drug use. Therefore, there is an urgent need for a safe and effective agomelatine self-microemulsion preparation in clinical practice. SUMMARY

[0012] The present application provides a kind of agomelatine self-microemulsion preparation, which can significantly make up for the deficiencies of prior art.

[0013] In order to achieve the above-mentioned purpose of the application, the following technical solutions are provided:

[0014] A kind of agomelatine self-microemulsion, which comprises an oil phase, an emulsifier and a co-emulsifier, and the agomelatine is distributed in the oil phase.

[0015] In preferred embodiments of the application, the oil phase is selected from one or more of oils, esters, fatty acids, fatty alcohols; preferably esters; more preferably, the oil phase is selected from one or more of esters, preferably medium or long chain fatty acid glycerides, polyethylene glycol fatty acid glycerides, carboxylic acid esters and propylene glycol esters.

[0016] In preferred embodiments of the application, the oil phase is selected from one or more of oils, preferably 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, mint 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, 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 beef tallow, lard, fish oil, lanolin, mink oil, squalene and squalane.

[0017] In preferred embodiments of the application, the oil phase is selected from one or more of fatty acids, preferably hexanoic acid, octanoic acid, lauric acid, undecanoic acid, myristic acid, palmitic acid, stearic acid, oleic acid and linoleic acid.

[0018] In preferred embodiments of the application, the oil phase is selected from one or more of medium or long chain fatty acid glycerides, preferably medium chain triglycerides, ethyl oleate, ethyl linoleate, monolinolein, triacetin, monostearin, monoolein; more preferably one or more of medium chain triglycerides, ethyl oleate and monolinolein; further preferably one or both of medium chain triglycerides and ethyl oleate, more further preferably medium chain triglycerides, wherein the medium chain triglycerides include Capterx 300, Capterx 355, GTCC, Labrafac CC, MCT oil, Miglyol 812, Miglyol 810, Miglyol 818, Miglyol 829, Miglyol 840, Neobee M5.

[0019] In preferred embodiments of the application, the oil phase is selected from one or more of polyethylene glycol fatty acid glycerides, preferably oleth-20, lauryl macrogol glycereth, caprylocaproyl macrogol glycerides, lauryl macrogol glycerides, macrogol caprate, macrogol stearate and macrogol isostearate.

[0020] In preferred embodiments of the application, the oil phase is selected from one or more of carboxylic acid esters, preferably isopropyl palmitate, lauryl lactate, diisopropyl adipate, di-n-butyl adipate and diethyl sebacate.

[0021] In a preferred embodiment of the application, the oil 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 dicaprylocaprate, more preferably propylene glycol caprylate.

[0022] In a preferred embodiment of the application, the oil phase is selected from fatty alcohols, preferably one or more of lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, linoleyl alcohol, biphenyl alcohol, octyldodecanol; more preferably one or more of lauryl alcohol, myristyl alcohol, octyldodecanol; further preferably octyldodecanol.

[0023] In a preferred embodiment of the application, the emulsifier is selected from one or more of phospholipids, polysorbate esters, polyoxyethylene oils and derivatives thereof, polyethylene glycol glycerol esters.

[0024] In a preferred embodiment of the application, the emulsifier is selected from phospholipids, preferably one or two of egg yolk lecithin, brain phospholipid, hydrogenated phospholipid, inositol phospholipid and soybean lecithin.

[0025] In a preferred embodiment of the application, the emulsifier is selected from polysorbate esters, preferably one or more of Tween 20, Tween 40, Tween 60, Tween 80, Tween 85, more preferably Tween 80.

[0026] In a preferred embodiment of the application, the emulsifier is selected from polyoxyethylene oils and derivatives thereof, preferably one or more of polyoxyethylene castor oil, polyoxyethylene triacylglycerol, 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 preferably polyoxyethylene 40-hydrogenated castor oil.

[0027] In a preferred embodiment of the application, the emulsifier is selected from polyethylene glycol glycerol esters, preferably one or more of polyethylene glycol-8-glycerol caprylate / caprate, polyethylene glycol glyceryl laurate, polyethylene glycol glyceryl laurate, polyethylene glycol glyceryl caprate, polyethylene glycol glyceryl stearate, polyethylene glycol glyceryl isostearate, coconut oil polyethylene glycol glycerol ester and almond oil polyethylene glycol glycerol oleate.

[0028] In a preferred embodiment of the present application, the co-emulsifier is selected from one or more of the group consisting of alcohols, polyethylene glycols, ethers, glycerides; the co-emulsifier is selected from alcohols, preferably C1-C6 fatty alcohols; more preferably one or more of propylene glycol, n-butanol, isobutyl alcohol, sec-butyl alcohol, isopropyl alcohol and ethanol; the co-emulsifier is selected from polyethylene glycols, 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, cetostearyl alcohol polyether, stearyl alcohol polyether, cetyl alcohol polyoxyethylene ether and lauryl polyoxyethylene ether; more preferably diethylene glycol monoethyl ether; the emulsifier is selected from glycerides, preferably one or more of glyceryl monooleate, glyceryl triacetate, polyglyceryl fatty acid ester; more preferably glyceryl monooleate.

[0029] In a preferred embodiment of the present application, the weight percentage of the oil phase is 5-60%, preferably 10%-50%, more preferably 15%-45%, further preferably 20%-40%, more further preferably 25-35%, based on the total weight of the prescription.

[0030] In a preferred embodiment of the present application, the weight percentage of agomelatine is 0.1%-5%, preferably 0.5%-4%, more preferably 1%-3%, further preferably 1.2-2.8%; more further preferably 1.5-2.5%, based on the total weight of the prescription.

[0031] In a preferred embodiment of the present application, the weight percentage of the emulsifier is 20%-70%, preferably 30%-65%, more preferably 35%-60%, further preferably 40%-58%, more further preferably 45%-55%, based on the total weight of the prescription.

[0032] In a preferred embodiment of the present application, the weight percentage of the co-emulsifier is 1-40%, preferably 5%-35%, more preferably 10%-35%, further preferably 12-30%; more further preferably 15%-25%, based on the total weight of the prescription.

[0033] In a preferred embodiment of the present application, the weight ratio of agomelatine to the oil phase is 1:5-30; preferably 1:5-25; more preferably 1:6-20; further preferably 1:10-18; more further preferably 1:12-18.

[0034] In a preferred embodiment of the present application, the weight ratio of the emulsifier to the co-emulsifier is 20-1:1-20; preferably 15-1:1-15; more preferably 10-1:1-10; further preferably 5-1:1-5; more further preferably 3-1:1:3; particularly preferably 3-1.5:1.

[0035] In a preferred embodiment of the present application, the agomelatine self-microemulsion preparation comprises the following components:

[0036] an oil phase selected from the group consisting of one or more of oils, esters, fatty acids and fatty alcohols;

[0037] an emulsifier selected from the group consisting of one or more of phospholipids, polysorbates, polyoxyethylene oils and their derivatives, polyglycolized glycerides;

[0038] a co-emulsifier selected from the group consisting of one or more of alcohols, polyethylene glycols, ethers, glycerides;

[0039] optionally further comprising other pharmaceutically compatible adjuvants.

[0040] In the preferred embodiments of the present application, the other pharmaceutically compatible adjuvants can be any conventional adjuvants in the art, such as pharmaceutically acceptable antioxidants, flavoring agents, preservatives, osmotic pressure adjusting agents, viscosity adjusting agents, etc.; the antioxidants can improve the stability of the product, such as sodium sulfite, sodium bisulfite, sodium metabisulfite, a-tocopherol, ascorbic acid, sodium ascorbate, ascorbyl palmitate, glutathione, malic acid, citric acid, tartaric acid, succinic acid, gallic acid, propyl gallate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), disodium ethylenediaminetetraacetate, etc.; the flavoring agents can improve the taste of the product, including natural or synthetic sweeteners, natural or synthetic fragrances, gum agents, effervescent agents, commonly used such as menthol, peppermint oil, eugenol, orange oil, citral, lemon ester, essence, sorbitol, xylitol, sugar syrup, etc.; the preservatives can improve the stability of the drug, prevent the growth of impurities, and prolong the shelf life, such as methyl paraben, ethyl paraben, propyl paraben, isopropyl alcohol, erythorbic acid, sodium erythorbate, cinnamic alcohol, lactic acid, sodium salicylate, acetic acid, sorbic acid, potassium sorbate, sodium benzoate, etc.; the osmotic pressure adjusting agents are used to adjust the osmotic pressure of the emulsion preparation, such as sodium chloride, glucose, mannitol, glycerol, sorbitol, etc.; the viscosity adjusting agents are used to adjust the viscosity of the preparation, such as sugars, xanthan gum, cellulose and its derivatives, polyvinyl alcohol, magnesium aluminum silicate, etc.; other pharmaceutically acceptable adjuvants such as antifreeze agents, stabilizers, fillers, etc. are also included, and the skilled person in the art can select them according to the preparation needs, and the amount of additives added can be 0.001-20% of the total amount; preferably 0.001-10%; more preferably 0.001-5%; further preferably 0.001-5%; more preferably 0.001-1%; further preferably 0.001-0.5%.

[0041] In a preferred embodiment of the present application, 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 medium chain triglycerides is 10% to 50%, preferably 15% to 45%, more preferably 20% to 40%, further preferably 25 to 35%, based on the total weight of the formulation.

[0042] In a preferred embodiment of the present application, the oil phase comprises at least ethyl oleate; preferably, the weight percentage of ethyl oleate is 10% to 50%, preferably 15% to 45%, more preferably 20% to 40%, further preferably 25 to 35%, based on the total weight of the formulation.

[0043] In a preferred embodiment of the present application, 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.

[0044] In a preferred embodiment of the present application, the emulsifier comprises at least polysorbate; preferably, at least Tween 80; more preferably, the weight percentage of Tween 80 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.

[0045] In a preferred embodiment of the present application, when the oil phase is medium chain triglycerides, it comprises the following components:

[0046] Component Material Agomelatine Agomelatine Oil phase Medium chain triglyceride Emulsifier Polyoxyl 40-hydrogenated castor oil Co-emulsifier Polyethylene glycol 400 ;

[0048] or,

[0049] Component Material Agomelatine Agomelatine Oil phase Medium chain triglyceride Emulsifier Polyoxyl 40-hydrogenated castor oil Co-emulsifier Glyceryl monooleate ;

[0051] or,

[0052] Component Material Agomelatine Agomelatine Oil phase Medium chain triglyceride Emulsifier Polyoxyl 40-hydrogenated castor oil Co-emulsifier Diethylene glycol monoethyl ether ;

[0054] or,

[0055] Component Material Agomelatine Agomelatine Oil phase Medium chain triglyceride Emulsifier Tween 80 Co-emulsifier Diethylene glycol monoethyl ether ;

[0057] or,

[0058] Component Material Agomelatine Agomelatine Oil phase Medium chain triglyceride Emulsifier Tween 80 Co-emulsifier Glyceryl monooleate ;

[0060] or

[0061] Component Material Agomelatine Agomelatine Oil phase Medium chain triglyceride Emulsifier Tween 80 Co-emulsifier Polyethylene glycol 400

[0062] In a preferred embodiment of the application, when the oil phase is ethyl oleate, it comprises the following components:

[0063] Component Material Agomelatine Agomelatine Oil phase Ethyl oleate Emulsifier Polyoxyl 40-hydrogenated castor oil Co-emulsifier Polyethylene glycol 400

[0065] or

[0066] Component Material Agomelatine Agomelatine Oil phase Ethyl oleate Emulsifier Polyoxyl 40-hydrogenated castor oil Co-emulsifier Glyceryl monooleate

[0068] or

[0069]

[0070]

[0071] or

[0072] Component Material Agomelatine Agomelatine Oil phase Ethyl oleate Emulsifier Tween 80 Co-emulsifier Diethylene glycol monoethyl ether

[0074] or

[0075] Component Material Agomelatine Agomelatine Oil phase Ethyl oleate Emulsifier Tween 80 Co-emulsifier Glyceryl monooleate

[0077] or

[0078] Component Material Agomelatine Agomelatine Oil phase Ethyl oleate Emulsifier Tween 80 Co-emulsifier Polyethylene glycol 400

[0079] In a preferred embodiment of the application, the weight percentages of the components in the self-microemulsion are as follows:

[0080]

[0081]

[0082] or

[0083] Material Percent (%) Agomelatine 0.5％-4％ Oil phase 10％-50％ Emulsifier 30％-65％ Co-emulsifier 5％-35％

[0085] or

[0086] Material Percent (%) Agomelatine 1％-3％ Oil phase 15％-45％ Emulsifier 35％-60％ Co-emulsifier 10％-35％

[0088] or

[0089] Material Percent (%) Agomelatine 1.2％-2.8％ Oil phase 20％-40％ Emulsifier 40％-58％ Co-emulsifier 12％-30％

[0091] or ​​​​​​​

[0092]

[0093]

[0094] In a preferred embodiment of the application, the weight percentages of the components in the self-microemulsion are as follows:

[0095] Material Percent (%) Agomelatine 1.5％-2.5％ Medium chain triglyceride 25％-35％ Emulsifier 45％-55％ Co-emulsifier 15％-25％ ;

[0097] or,

[0098] Material Percent (%) Agomelatine 1.5％-2.5％ Ethyl oleate 25％-35％ Emulsifier 45％-55％ Co-emulsifier 15％-25％ ;

[0100] or,

[0101] Material Percent (%) Agomelatine 1.5％-2.5％ Medium chain triglyceride 25％-35％ Polyoxyl 40-hydrogenated castor oil 45％-55％ Co-emulsifier 15％-25％ ;

[0103] or,

[0104] Material Percent (%) Agomelatine 1.5％-2.5％ Medium chain triglyceride 25％-35％ Tween 80 45％-55％ Co-emulsifier 15％-25％ ;

[0106] or,

[0107] Material Percent (%) Agomelatine 1.5％-2.5％ Ethyl oleate 25％-35％ Polyoxyl 40-hydrogenated castor oil 45％-55％ Co-emulsifier 15％-25％ ;

[0109] or,

[0110] Material Percent (%) Agomelatine 1.5％-2.5％ Ethyl oleate 25％-35％ Tween 80 45％-55％ Co-emulsifier 15％-25％

[0111] In a preferred embodiment of the application, the weight percentages of the components in the self-microemulsion are as follows:

[0112] Material Percent (%) Agomelatine 1.5％-2.5％ Medium chain triglyceride 25％-35％ Polyoxyl 40-hydrogenated castor oil 45％-55％ Polyethylene glycol 400 15％-25％ ;

[0114] or,

[0115] Material Percent (%) Agomelatine 1.5％-2.5％ Ethyl oleate 25％-35％ Polyoxyl 40-hydrogenated castor oil 45％-55％ Polyethylene glycol 400 15％-25％ ;

[0117] or,

[0118]

[0119]

[0120] or,

[0121] Material Percent (%) Agomelatine 1.5％-2.5％ Medium chain triglyceride 25％-35％ Polyoxyl 40-hydrogenated castor oil 45％-55％ Glyceryl monooleate 15％-25％ ;

[0123] or,

[0124] Material Percent (%) Agomelatine 1.5％-2.5％ Medium chain triglyceride 25％-35％ Polyoxyl 40-hydrogenated castor oil 45％-55％ Diethylene glycol monoethyl ether 15％-25％

[0125] The self-microemulsion dosage form of the present application can be a capsule or an oral solution, wherein the capsule includes soft capsules, hard capsules filled with liquid, controlled-release capsules, and osmotic pump capsules, and various suitable capsule dosage forms.

[0126] The self-microemulsion preparation of the present application can also be solidified by adding a suitable absorbent as needed, thereby obtaining various forms of solid pharmaceutical preparations such as ordinary tablets, dispersible tablets, double-layer tablets, multi-layer tablets, controlled-release tablets, and pellets.

[0127] The present application also provides a preparation method of the agomelatine self-microemulsion preparation, which comprises weighing the prescribed amount of agomelatine, an oil phase, an emulsifier, and a co-emulsifier, mixing them uniformly, and optionally adding other pharmaceutically compatible excipients and mixing them uniformly.

[0128] The agomelatine self-microemulsion preparation of the present application can be applied to the preparation of a drug for treating a mental disease, preferably depression, and more preferably major depressive disorder.

[0129] The agomelatine self-microemulsion preparation of the present application has the following advantages:

[0130] (1) The preparation process is simple, reproducible, and very easy to scale up;

[0131] (2) The solubility of the drug is improved, thereby greatly improving the oral bioavailability of the drug;

[0132] (3) The stability is good, the safety is high, and the needs of clinical use are met. DETAILED DESCRIPTION

[0133] In order to better demonstrate the specific embodiments of the present application and the effects achieved, further description will be made in combination with specific examples.

[0134] Example 1

[0135] Self-microemulsion prescription composition:

[0136] Material Amount added (g) Percent (%) Agomelatine 2 1.96 Medium chain triglyceride 30 29.41 Polyoxyl 40-hydrogenated castor oil 50 49.02 Polyethylene glycol 400 20 19.61

[0137] Preparation method: weigh the prescribed amount of agomelatine, medium-chain triglyceride, polyoxyethylene 40-castor oil, and polyethylene glycol 400 into a beaker, stir to completely dissolve, and obtain a clear and transparent solution, i.e., a self-microemulsion. Finally, the self-microemulsion is made into a capsule.

[0138] Example 2

[0139] Self-microemulsion prescription composition:

[0140] Material Amount added (g) Percent (%) Agomelatine 2 1.96 Soybean oil 30 29.41 Polyoxyl 40-hydrogenated castor oil 50 49.02 Polyethylene glycol 400 20 19.61

[0141] Preparation method: Take the prescribed amount of agomelatine, soybean oil, polyoxyethylene 40-castor oil and polyethylene glycol 400 into a beaker, stir to completely dissolved, get clear transparent solution, namely self-microemulsion. Finally the self-microemulsion into capsules.

[0142] Example 3

[0143] Self-microemulsion prescription composition:

[0144]

[0145]

[0146] Preparation method: Take the prescribed amount of agomelatine, ethyl oleate, polyoxyethylene 40-castor oil and polyethylene glycol 400 into a beaker, stir to completely dissolved, get clear transparent solution, namely self-microemulsion. Finally the self-microemulsion into capsules.

[0147] Example 4

[0148] Self-microemulsion prescription composition:

[0149] Material Amount added (g) Percent (%) Agomelatine 2 1.96 Medium chain triglyceride 30 29.41 Tween 80 50 49.02 Polyethylene glycol 400 20 19.61

[0150] Preparation method: Take the prescribed amount of agomelatine, medium-chain triglyceride, Tween 80 and polyethylene glycol 400 into a beaker, stir to completely dissolved, get clear transparent solution, namely self-microemulsion. Finally the self-microemulsion into capsules.

[0151] Example 5

[0152] Self-microemulsion prescription composition:

[0153] Material Amount added (g) Percent (%) Agomelatine 2 1.96 Medium chain triglyceride 30 29.41 Egg yolk lecithin 50 49.02 Polyethylene glycol 400 20 19.61

[0154] Preparation method: Take the prescribed amount of agomelatine, medium-chain triglyceride, egg yolk lecithin and polyethylene glycol 400 into a beaker, stir to completely dissolved, get clear transparent solution, namely self-microemulsion. Finally the self-microemulsion into capsules.

[0155] Example 6

[0156] Self-microemulsion prescription composition:

[0157] materials Amount added (g) percentage(%) Agomelatin 2 1.96 medium-chain triglycerides 30 29.41 Soy lecithin 50 49.02 Polyethylene glycol 400 20 19.61

[0158] Preparation method: Take the prescribed amount of agomelatine, medium-chain triglyceride, soybean lecithin and polyethylene glycol 400 into a beaker, stir to completely dissolved, get clear transparent solution, namely self-microemulsion. Finally the self-microemulsion into capsules.

[0159] Example 7

[0160] Self-microemulsion formulation:

[0161] materials Amount added (g) percentage(%) Agomelatin 2 1.96 medium-chain triglycerides 30 29.41 Polyoxyethylene 40-hydrogenated castor oil 50 49.02 Glyceryl monooleate 20 19.61

[0162] Preparation method: Take the prescribed amount of agomelatine, medium-chain triglyceride, polyoxyethylene 40-hydrogenated castor oil and glyceryl monooleate into a beaker, stir to completely dissolve, get a clear transparent solution, namely self-microemulsion. Finally, the self-microemulsion is made into a capsule.

[0163] Example 8

[0164] Self-microemulsion formulation:

[0165] materials Amount added (g) percentage(%) Agomelatin 2 1.96 medium-chain triglycerides 30 29.41 Polyoxyethylene 40-hydrogenated castor oil 50 49.02 Diethylene glycol monoethyl ether 20 19.61

[0166] Preparation method: Take the prescribed amount of agomelatine, medium-chain triglyceride, polyoxyethylene 40-hydrogenated castor oil and diethylene glycol monoethyl ether into a beaker, stir to completely dissolve, get a clear transparent solution, namely self-microemulsion. Finally, the self-microemulsion is made into a capsule.

[0167] Example 9

[0168] Self-microemulsion formulation:

[0169] materials Amount added (g) percentage(%) Agomelatin 2 2 medium-chain triglycerides 44.6 44.6 Polyoxyethylene 40-hydrogenated castor oil 39.4 39.4 Polyethylene glycol 400 14 14

[0170] Preparation method: Take the prescribed amount of agomelatine, medium-chain triglyceride, polyoxyethylene 40-hydrogenated castor oil and polyethylene glycol 400 into a beaker, stir to completely dissolve, get a clear transparent solution, namely self-microemulsion. Finally, the self-microemulsion is made into a capsule.

[0171] Example 10

[0172] Self-microemulsion formulation:

[0173] materials Amount added (g) percentage(%) Agomelatin 2 2 medium-chain triglycerides 34 34 Polyoxyethylene 40-hydrogenated castor oil 47 47 Polyethylene glycol 400 17 17

[0174] Preparation method: Take the prescribed amount of agomelatine, medium-chain triglyceride, polyoxyethylene 40-hydrogenated castor oil and polyethylene glycol 400 into a beaker, stir to completely dissolve, get a clear transparent solution, namely self-microemulsion. Finally, the self-microemulsion is made into a capsule.

[0175] Example 11

[0176] Self-microemulsion formulation:

[0177] materials Amount added (g) percentage(%) Agomelatin 1.55 1.52 medium-chain triglycerides 30 29.54 Polyoxyethylene 40-hydrogenated castor oil 50 49.24 Polyethylene glycol 400 20 19.69

[0178] Preparation method: Take the prescribed amount of agomelatine, medium chain triglyceride, polyoxyethylene 40-hydrogenated castor oil and polyethylene glycol 400 into a beaker, stir to completely dissolve, get a clear transparent solution, that is, a self-microemulsion. Finally, the self-microemulsion is made into a capsule.

[0179] Example 12

[0180] Self-microemulsion prescription composition:

[0181] materials Amount added (g) percentage(%) Agomelatin 2.55 2.49 medium-chain triglycerides 30 29.25 Polyoxyethylene 40-hydrogenated castor oil 50 48.76 Polyethylene glycol 400 20 19.5

[0182] Preparation method: Take the prescribed amount of agomelatine, medium chain triglyceride, polyoxyethylene 40-hydrogenated castor oil and polyethylene glycol 400 into a beaker, stir to completely dissolve, get a clear transparent solution, that is, a self-microemulsion. Finally, the self-microemulsion is made into a capsule.

[0183] Example 13

[0184] Self-microemulsion prescription composition:

[0185] materials Amount added (g) percentage(%) Agomelatin 2 1.96 medium-chain triglycerides 25 24.51 Polyoxyethylene 40-hydrogenated castor oil 55 53.92 Polyethylene glycol 400 20 19.61

[0186] Preparation method: Take the prescribed amount of agomelatine, medium chain triglyceride, polyoxyethylene 40-hydrogenated castor oil and polyethylene glycol 400 into a beaker, stir to completely dissolve, get a clear transparent solution, that is, a self-microemulsion. Finally, the self-microemulsion is made into a capsule.

[0187] Example 14

[0188] Self-microemulsion prescription composition:

[0189] materials Amount added (g) percentage(%) Agomelatin 2 1.96 medium-chain triglycerides 35 34.31 Polyoxyethylene 40-hydrogenated castor oil 45 44.12 Polyethylene glycol 400 20 19.61

[0190] Preparation method: Take the prescribed amount of agomelatine, medium chain triglyceride, polyoxyethylene 40-hydrogenated castor oil and polyethylene glycol 400 into a beaker, stir to completely dissolve, get a clear transparent solution, that is, a self-microemulsion. Finally, the self-microemulsion is made into a capsule.

[0191] Example 15

[0192] Self-microemulsion prescription composition:

[0193] materials Amount added (g) percentage(%) Agomelatin 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

[0194] Preparation method: Take the prescribed amount of agomelatine, medium chain triglyceride, polyoxyethylene 40-hydrogenated castor oil and polyethylene glycol 400 into a beaker, stir to completely dissolve, get a clear transparent solution, that is, a self-microemulsion. Finally, the self-microemulsion is made into a capsule.

[0195] Example 16

[0196] Self-microemulsion prescription composition:

[0197] materials Amount added (g) percentage(%) Agomelatin 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

[0198] Preparation method: Take the prescribed amount of agomelatine, medium-chain triglyceride, polyoxyethylene 40-hydrogenated castor oil and polyethylene glycol 400 into a beaker, stir to completely dissolve, get a clear transparent solution, that is, a self-microemulsion. Finally, the self-microemulsion is made into a capsule.

[0199] Example 17

[0200] Self-microemulsion prescription composition:

[0201] materials Amount added (g) percentage(%) Agomelatin 2 2 medium-chain triglycerides 38.2 38.2 Twain 80 42.1 42.1 Glyceryl monooleate 17.7 17.7

[0202] Preparation method: Take the prescribed amount of agomelatine, medium-chain triglyceride, Tween 80 and glycerol monooleate into a beaker, stir to completely dissolve, get a clear transparent solution, that is, a self-microemulsion. Finally, the self-microemulsion is made into a capsule.

[0203] Example 18

[0204] Self-microemulsion prescription composition:

[0205] materials Amount added (g) percentage(%) Agomelatin 2 2 Ethyl oleate 44.6 44.6 Twain 80 39.4 39.4 Polyethylene glycol 400 14 14

[0206] Preparation method: Take the prescribed amount of agomelatine, ethyl oleate, Tween 80 and polyethylene glycol 400 into a beaker, stir to completely dissolve, get a clear transparent solution, that is, a self-microemulsion. Finally, the self-microemulsion is made into a capsule.

[0207] Experimental example 1 oil phase type investigation

[0208] Self-microemulsions were prepared with different oil phases (soybean oil, medium-chain triglyceride and ethyl oleate) to investigate the influence of oil phase on sample quality.

[0209] Table 1 Oil phase type investigation results

[0210]

[0211] The results show that the self-microemulsion prepared with soybean oil as the oil phase has surface oil, the emulsified solution is slightly turbid, and the particle size is large. The self-microemulsion prepared with medium-chain triglyceride and ethyl oleate as the oil phase is a clear transparent solution, the emulsified solution is clear and transparent, with a light blue opalescence, and the particle size is small. Therefore, medium-chain triglyceride or ethyl oleate can be selected as the oil phase to prepare the self-microemulsion, and medium-chain triglyceride is preferred.

[0212] Experimental example 2 emulsifier type investigation

[0213] Self-microemulsions were prepared with different emulsifiers (polyoxyethylene 40-hydrogenated castor oil, Tween 80, egg yolk lecithin and soybean lecithin) to investigate the influence of emulsifier on sample quality.

[0214] Table 2 Results of emulsifier type investigation

[0215]

[0216] The results show that the self-microemulsions prepared with different emulsifiers are all clear and transparent solutions. The self-microemulsions prepared with medium-chain triglyceride or Tween 80 are clear and transparent after emulsification, with a light blue luster and small particle size. The self-microemulsions prepared with egg yolk lecithin or soybean oil lecithin are all clear and translucent after emulsification, with a large particle size. Therefore, polyoxyethylene 40-hydrogenated castor oil or Tween 80 can be selected as the emulsifier for preparing the self-microemulsion, and polyoxyethylene 40-hydrogenated castor oil is preferred.

[0217] Experimental Example 3 Investigation of co-emulsifier type

[0218] The self-microemulsions were prepared with different co-emulsifiers (polyethylene glycol 400, glycerol monooleate and diethylene glycol monoethyl ether) to investigate the influence of the co-emulsifier on the quality of the sample.

[0219] Table 3 Results of co-emulsifier type investigation

[0220]

[0221] The results show that the self-microemulsions prepared with different co-emulsifiers have relatively small differences before and after emulsification, and polyethylene glycol 400, glycerol monooleate and diethylene glycol monoethyl ether can all be used as the co-emulsifier for preparing the self-microemulsion, but polyethylene glycol 400 is preferred.

[0222] Experimental Example 4 Stability test results

[0223] The self-microemulsion in Example 1 was subjected to accelerated condition test (40°C, RH 75%) and long-term condition test (25°C, RH 60%) for 2 weeks, and the properties, content, related substances and particle size were detected. The results show that the self-microemulsion prepared in this example has no obvious change in the detection results compared with those at 0 day after the accelerated condition test and the long-term condition test, and the self-microemulsion has good stability.

[0224] Experimental Example 5 Rat in vivo pharmacokinetics

[0225] In order to investigate the in vivo pharmacokinetics of the preparation of the application, the rat in vivo pharmacokinetics was studied using the agomelatine self-microemulsion in Example 1 and the aqueous solution of agomelatine.

[0226] Preparation of the aqueous solution of agomelatine: 10 mg of agomelatine was added to 10 ml of purified water, and stirred to obtain the solution. Before the animal experiment, the solution was stirred again to be uniform, and then administered.

[0227] 6 healthy rats were divided into two groups, the first group was given agomelatine self-microemulsifying drug delivery system by esophageal intubation at a single dose of 2.5 mg / kg (n=3), the second group was given agomelatine aqueous solution by esophageal intubation at a single dose of 10 mg / kg (n=3). After administration, samples were taken at 0 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, and the plasma concentration was determined by LC-MS-MS. The animal experiment showed that there was no significant difference in Cmax, Tmax and AUC between the two groups, and the plasma concentration-time curves of agomelatine self-microemulsion and agomelatine aqueous solution were basically consistent. It is proved that agomelatine self-microemulsion can effectively improve the solubility and bioavailability of the drug.

Claims

1. An agomelatine self-microemulsifying formulation characterized in that, The self-microemulsion preparation comprises an oil phase, an emulsifier and a co-emulsifier, and the agomelatine is distributed in the oil phase; the weight percentage of agomelatine is 1.5-2.5% based on the total weight of the prescription; The oil phase is medium-chain triglyceride; the weight percentage of the oil phase is 25-35% based on the total weight of the prescription; The emulsifier is polyoxyethylene 40-hydrogenated castor oil; the weight percentage of the emulsifier is 45-55% based on the total weight of the prescription; The co-emulsifier is polyethylene glycol 400; the weight percentage of the co-emulsifier is 15-25% based on the total weight of the prescription.

2. The agomelatine self-microemulsifying formulation according to claim 1, characterized in that, The dosage form of the self-microemulsion preparation is capsule or oral solution, wherein the capsule includes soft capsule, hard capsule filled with liquid, sustained-release and controlled-release capsule and osmotic pump capsule.

3. The agomelatine self-microemulsifying formulation according to claim 1, characterized in that, The self-microemulsion preparation can be solidified into common tablet, dispersible tablet, double-layer tablet, multi-layer tablet, sustained-release and controlled-release tablet or pellet by adding appropriate absorbent as needed.

4. Use of the agomelatine self-microemulsion preparation according to any one of claims 1-3 in the preparation of a medicament for treating mental disease.

5. Use according to claim 4, characterized in that, The mental disease refers to depression.

6. Use according to claim 4, characterized in that, The mental disease refers to major depressive disorder.

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