An agomelatine microemulsion, microemulsion gel and a preparation method thereof

Abstract

This invention relates to an agomelatine microemulsion, a microemulsion gel, and a method for preparing the same, belonging to the field of pharmaceutical formulation. The agomelatine microemulsion comprises agomelatine and a drug carrier, the drug carrier including an emulsifier, a co-emulsifier, an oil phase, and an aqueous phase; the agomelatine microemulsion gel comprises an agomelatine microemulsion and a gel matrix. The agomelatine microemulsion and microemulsion gel of this invention exhibit good stability, high bioavailability, and good clinical safety, and the preparation process is simple and easily scaled up for industrial production.

Description

Technical Field

[0001] This invention relates to an agomelatine microemulsion, a microemulsion gel, and a method for preparing the same, belonging to the field of pharmaceutical formulation. Background Technology

[0002] Depression is an affective disorder characterized by low mood, loss of interest, slowed thinking, and cognitive impairment. It is characterized by high prevalence, high disability rate, high relapse rate, and high suicide rate. In recent years, with increasing social pressure, the prevalence of depressive disorders has been increasing year by year, becoming one of the common and serious chronic diseases threatening human health. According to estimates from the Chinese Center for Disease Control and Prevention, the prevalence of depression in my country will increase to 7.3% in 2020. Based on the findings of pharmacological mechanism research on antidepressants, the hypothesis of abnormal pathological mechanism of monoamine neurotransmitter system function in depression has been proposed. The main mechanism of action of existing antidepressants is the regulation of the monoamine neurotransmitter system. Although new antidepressants have made significant improvements in safety and tolerability, they still have drawbacks such as slow onset of action, poor efficacy in some patients, and potential adverse reactions during long-term treatment, indicating significant room for improvement in treatment.

[0003] Agomelatine is a novel antidepressant, the world's first melatonin-based antidepressant. It is a melatonin receptor agonist and a serotonin 2C (5-HT2c) receptor antagonist. Its pharmacological action combines the activity of a melatonin receptor agonist with the performance of a 5-HT2c receptor antagonist, effectively treating depression, improving sleep parameters, and maintaining sexual function. Agomelatine is effective for all types of depression. Agomelatine is a naphthalene derivative of melatonin, with the indole ring replaced by a naphthalene nucleus, making it more metabolically stable than melatonin. It is a selective and specific agonist of the hypothalamic melatonin receptor, while also possessing weak competitive 5-HT receptor antagonistic activity, exhibiting a novel pharmacological characteristic of dual action as a melatonin receptor agonist and a selective 5-HT antagonist. It mimics the effects of melatonin but has a unique mode of action, making it a promising candidate drug for treating circadian rhythm disorders such as sleep disorders / depression. Agomelatine is a white or off-white crystalline powder, chemically named N-[2-(7-methoxynaphth-1-yl)ethyl]acetamide, with the molecular formula C2. 15 H 17 NO2, molecular weight 243.3, chemical structural formula is:

[0004]

[0005] Agomelatine is currently only available in oral tablet form, developed by Servier in France. It was approved for marketing in the European Union on February 24, 2009, and in China under the brand name Weiduxin after approval by the CFDA in 2011. Agomelatine tablets are 25mg and are taken orally once daily at bedtime. Although asomelatine is rapidly absorbed with a high absorption rate, it suffers from a significant first-pass effect in the liver, resulting in low bioavailability of only 3%–4%. Furthermore, it exhibits considerable inter- and intra-individual biological variability, demonstrating high variability. Therefore, it is necessary to improve the oral tablet form to develop a dosage form with lower hepatotoxicity and higher bioavailability.

[0006] Transdermal drug delivery systems (TDDS) refer to the application of transdermal drug delivery formulations to the skin. The drug penetrates the skin, is absorbed through capillaries into the bloodstream, reaches an effective blood concentration, and is then transported to various tissues or disease sites to exert its therapeutic or preventative effects. Transdermal delivery avoids the first-pass effect and gastrointestinal inactivation that can occur with oral administration; maintains a constant optimal blood drug concentration or physiological effect, reduces the side effects of gastrointestinal administration; prolongs the effective duration of action, reduces the frequency of administration; and allows for dosage adjustment by changing the application area, reducing individual variability. Furthermore, patients can self-medicate and discontinue medication at any time.

[0007] Microemulsions (ME) are homogeneous, transparent, and thermodynamically and kinetically stable multiphase systems composed of oil, water, emulsifiers, and co-emulsifiers, with particle sizes ranging from 10 to 100 nm. Microemulsions offer numerous advantages in transdermal drug delivery systems (TDDS), such as significantly increasing drug solubility, maintaining high drug concentrations, enhancing the drug concentration gradient between the microemulsion and the skin, increasing transdermal permeability, improving the fluidity of the stratum corneum lipid bilayer, and enhancing drug transdermal capacity and bioavailability.

[0008] Microemulsion-based gels (MBGs) are formed by incorporating microemulsions into a gel matrix composed of natural polymers, cellulose derivatives, block polymers, and other polymeric materials, creating a transparent, homogeneous, and stable gel network structure containing microemulsion droplets. As a novel transdermal drug delivery carrier, microemulsion gels offer the dual advantages of both microemulsions and gels. Microemulsions enhance drug solubility, reduce the skin's diffusion barrier, and increase transdermal penetration, thus improving the transdermal rate. Conversely, gels increase the viscosity of the microemulsion, improving its adhesion and spreadability to the skin, reducing drug irritation, and ultimately achieving transdermal delivery and improved bioavailability. As a transdermal drug delivery carrier, microemulsion gels avoid the first-pass clearance effect in the liver, reduce gastrointestinal irritation, decrease toxic side effects, are easy to apply, convenient for patient administration, and exhibit good stability. Summary of the Invention

[0009] To address the shortcomings of existing dosage forms, this invention provides an agomela microemulsion and microemulsion gel with good stability and penetration-enhancing effects.

[0010] The technical solution of the present invention to solve the above problems is as follows: an agomelatine microemulsion, comprising a pharmaceutically active ingredient and a drug carrier, wherein the pharmaceutically active ingredient is agomelatine, and the drug carrier comprises an emulsifier, a co-emulsifier, an oil phase and an aqueous phase.

[0011] In a preferred embodiment of the present invention, the agomelatine microemulsion is an oil-in-water microemulsion.

[0012] In a preferred embodiment of the present invention, the oil phase is selected from one or more of fatty acid glycerides, polyethylene glycol glycerides, carboxylic acid esters, and propylene glycol esters; preferably, the fatty acid glycerides are selected from one or more of medium-chain triglycerides, ethyl oleate, ethyl linoleate, monolinoleic acid glycerides, triacetic acid glycerides, caprylic / capric triglycerides, monostearate glycerides, and monooleic glycerides; and the polyethylene glycol glycerides are selected from polyethylene glycol oleate, polyethylene glycol lauryl glyceride, caprylic / capric triglyceride, lauric glycol glyceride, and polyethylene glycol glyceride. Glyceryl decanoate, polyethylene glycol stearate, and polyethylene glycol isostearate are selected from one or more of the following: the carboxylic acid ester is selected from one or more of the following: isopropyl palmitate, lauryl lactate, isopropyl myristate, diisopropyl adipate, dibutyl adipate, and diethyl sebacate; the propylene glycol ester is selected from one or more of the following: propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol oleate, propylene glycol myristate, and propylene glycol dicaprylate; more preferably, at least one of propylene glycol monocaprylate and propylene glycol monolaurate.

[0013] In a preferred embodiment of the present invention, the emulsifier is selected from one or more of polysorbate, polyoxyethylene oil and its derivatives, and polyethylene glycol glycerol; preferably, the polysorbate is selected from one or more of Tween 20, Tween 40, Tween 60, Tween 80, and Tween 85; the polyoxyethylene oil and its derivatives are selected from one or more of polyoxyethylene castor oil, polyoxyethylene triglycerides, and polyoxyethylene hydrogenated castor oil; the polyethylene glycol glycerol is selected from one or more of polyethylene glycol decanoate, polyethylene glycol laurate, polyethylene glycol lauryl glyceride, polyethylene glycol decanoate, polyethylene glycol stearate, and polyethylene glycol isostearate; more preferably, at least one of polyethylene glycol glycerol caprylate and polyoxyethylene hydrogenated castor oil.

[0014] The polyoxyethylene hydrogenated castor oil includes one or more of polyoxyethylene 30 hydrogenated castor oil, polyoxyethylene 35 hydrogenated castor oil, polyoxyethylene 40 hydrogenated castor oil, and polyoxyethylene 60 hydrogenated castor oil; preferably, polyoxyethylene 40 hydrogenated castor oil.

[0015] In a preferred embodiment of the present invention, the co-emulsifier is selected from one or more of alcohols, polyethylene glycol, and ethers; preferably, the alcohol is selected from one or more of anhydrous ethanol, ethylene glycol, propylene glycol, n-propanol, isopropanol, glycerol, n-butanol, and n-octanol; the polyethylene glycol is selected from one or more of polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, and polyethylene glycol 800; and the ether is selected from one or more of diethylene glycol monoethyl ether, cetearyl alcohol polyether, stearyl alcohol polyether, cetearyl alcohol polyoxyethylene ether, and lauryl polyoxyethylene ether; more preferably, at least one of diethylene glycol monoethyl ether and anhydrous ethanol.

[0016] In a preferred embodiment of the present invention, the aqueous phase is selected from deionized water, distilled water, water for injection, high-purity water, or ultrapure water.

[0017] In a preferred embodiment of the present invention, the agomelatine microemulsion further includes pharmaceutically acceptable excipients, said excipients including one or more of humectants, osmotic pressure regulators, fragrances, preservatives, antioxidants, and penetration enhancers.

[0018] Moisturizers include one or more of glycerin, paraffin oil, sorbitol, propylene glycol, isopropanol, ethanol, butylene glycol, and hyaluronic acid.

[0019] Osmotic pressure regulators include one or more of glycerol, borax, glucose, mannitol, propylene glycol, sorbitol, and sodium chloride.

[0020] The fragrance includes one or more of lavender essential oil, orange essence, strawberry essence, chocolate essence, peppermint essence, and milk essence; preferably lavender essential oil; more preferably, in this invention, the fragrance accounts for 0 to 2% of the total weight of the prescription; preferably 0 to 1%; more preferably 0.01 to 0.5%; and even more preferably 0.01 to 0.35%.

[0021] Preservatives include one or more of methylparaben, ethylparaben, propylparaben, sodium methylparaben, sodium ethylparaben, sodium propylparaben, sorbic acid, potassium sorbate, sodium benzoate, chlorobutanol, and benzalkonium bromide.

[0022] Antioxidants include synthetic antioxidants such as BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), TBHQ (tert-butylhydroquinone), PG (propyl gallate), AP (L-ascorbyl palmitate), EQ (ethoxyquinoline), sodium metabisulfite, and DLTP (dilauryl thiodipropionate), as well as natural antioxidants such as tea polyphenols, tocopherols, and grape seed extract.

[0023] Penetration enhancers include one or more of the following: oleic acid, stearic acid, isostearic acid, lactic acid, lauric acid, polyethylene glycol, isopropyl myristate, isopropyl palmitate, dimethylacetamide, triglycerides, menthol, menthol, propylene glycol, borneol, Cnidium monnieri oil, azone, sodium tetradecyl sulfate, geraniol, anethole, and decyl methyl sulfoxide.

[0024] In a preferred embodiment of the present invention, the weight percentage of agomelatine, based on the total weight of the prescription, is 0.1-20%; preferably 0.1-15%; more preferably 0.5-10%; further preferably 1-5%; even more preferably 1-3%; for example, 1-2.5%, 1.5-2.5%, 2%, 1%, etc.

[0025] In a preferred embodiment of the present invention, the oil phase comprises 1-35% by weight of the total formulation; preferably 1-25%; more preferably 1-15%; further preferably 3-10%, for example 5% or 9.5%; and even more preferably 4-8%.

[0026] In a preferred embodiment of the present invention, the weight percentage of the emulsifier is 1-50% based on the total weight of the prescription; preferably 1-35%; more preferably 5-25%; further preferably 5-15%; even more preferably 6-12%; for example 10-12%, 10.8%, etc.

[0027] In a preferred embodiment of the present invention, the weight percentage of the co-emulsifier, based on the total weight of the prescription, is 1-30%; preferably 1-25%; more preferably 5-25%; further preferably 5-20%; even more preferably 5-15%, for example 5-8%, 7.4%, etc.; or, preferably 10-25%; more preferably 15-22%.

[0028] In a preferred embodiment of the present invention, the weight percentage of the aqueous phase, based on the total weight of the formulation, is 10-90%; preferably 40-85%; more preferably 50-80%; further preferably 55-75%, for example 62%, 64%, 70.3%; and even more preferably 60-70% or 62-72%.

[0029] In a preferred embodiment of the present invention, the weight of the emulsifier and the co-emulsifier, based on the total weight of the prescription, is preferably less than 30%, more preferably less than 20%;

[0030] In a preferred embodiment of the present invention, the weight percentages of each component, based on the total weight of the prescription, are as follows:

[0031] Components percentage Agomelatin 0.1～20％ oil phase 1～40％ emulsifier 1～60％ co-emulsifier 1～30％ Aqueous phase 5～90％ ;

[0033] or,

[0034] Components percentage Agomelatin 0.1～15％ oil phase 1～35％ emulsifier 1～50％ co-emulsifier 1～30％ Fragrance 0～2％ Aqueous phase 10～90％ ;

[0036] or,

[0037] Components percentage Agomelatin 0.5～10％ oil phase 1～25％ emulsifier 1～35％ co-emulsifier 1～25％ Fragrance 0～2％ Aqueous phase 40～85％ ;

[0039] or,

[0040] Components percentage Agomelatin 1～5％ oil phase 1～15％ emulsifier 5～25％ co-emulsifier 5～25％ Fragrance 0～1％ Aqueous phase 50～80％ ;

[0042] or,

[0043] Components percentage Agomelatin 1～5％ oil phase 3～15％ emulsifier 5～15％ co-emulsifier 5～25％ Fragrance 0～0.5％ Aqueous phase 55～75％ ;

[0045] or,

[0046] Components percentage Agomelatin 1～5％ oil phase 3～15％ emulsifier 5～15％ co-emulsifier 5～15％ Fragrance 0～0.5％ Aqueous phase 55～75％

[0047] In a preferred embodiment of the present invention, when the oil phase is propylene glycol monooctanoate, the weight percentages of each component, based on the total weight of the formulation, are as follows:

[0048]

[0049]

[0050] or,

[0051] Components percentage Agomelatin 1～5％ Propylene glycol monooctanoate 3～15％ emulsifier 5～15％ co-emulsifier 5～25％ Fragrance 0～0.5％ water 55～75％ ;

[0053] or,

[0054] Components percentage Agomelatin 1～5％ Propylene glycol monooctanoate 3～15％ emulsifier 5～15％ co-emulsifier 5～25％ Fragrance 0～0.5％ water 55～75％ ;

[0056] or,

[0057]

[0058]

[0059] or,

[0060] Components percentage Agomelatin 1～5％ Propylene glycol monooctanoate 3～15％ Polyoxyethylene castor oil 5～15％ Diethylene glycol monoethyl ether 5～25％ Fragrance 0～0.5％ water 55～75％ ;

[0062] or,

[0063] Components percentage Agomelatin 1～5％ Propylene glycol monooctanoate 3～10％ Polyoxyethylene castor oil 5～15％ Diethylene glycol monoethyl ether 10～25％ Lavender essential oil 0～0.5％ water 55～75％ ;

[0065] or,

[0066]

[0067]

[0068] or,

[0069] Components percentage Agomelatin 1～5％ Propylene glycol monooctanoate 3～15％ Polyoxyethylene hydrogenated castor oil 5～15％ Diethylene glycol monoethyl ether 5～25％ water 55～75％

[0070] or,

[0071] Components percentage Agomelatin 1～2.5％ Propylene glycol monooctanoate 5～10％ Polyoxyethylene hydrogenated castor oil 10～12％ Diethylene glycol monoethyl ether 5～20％ water 62～75％

[0072] or,

[0073] Components percentage Agomelatin 2％ Propylene glycol monooctanoate 9.5％ Polyoxyethylene hydrogenated castor oil 10.8％ Diethylene glycol monoethyl ether 7.4％ water 70.3％

[0074] or,

[0075]

[0076]

[0077] In a preferred embodiment of the present invention, the oil phase is propylene glycol monolaurate, and the weight percentages of each component based on the total weight of the formulation are as follows:

[0078] Components percentage Agomelatin 0.5～10％ Propylene glycol monolaurate 1～25％ emulsifier 1～35％ co-emulsifier 1～25％ Fragrance 0～2％ water 40～85％ ;

[0080] or,

[0081] Components percentage Agomelatin 1～5％ Propylene glycol monolaurate 3～15％ emulsifier 5～15％ co-emulsifier 5～25％ Fragrance 0～0.5％ water 55～75％ ;

[0083] or,

[0084]

[0085]

[0086] or,

[0087] Components percentage Agomelatin 1～5％ Propylene glycol monolaurate 3～15％ Polyoxyethylene castor oil 5～15％ Diethylene glycol monoethyl ether 5～25％ Fragrance 0～0.5％ water 55～75％ ;

[0089] or,

[0090] Components percentage Agomelatin 1～5％ Propylene glycol monolaurate 3～10％ Polyoxyethylene castor oil 5～15％ Diethylene glycol monoethyl ether 10～25％ Lavender essential oil 0～0.5％ water 55～75％ ;

[0092] or,

[0093] Components percentage Agomelatin 1～5％ Propylene glycol monolaurate 3～15％ Polyoxyethylene castor oil 5～15％ Diethylene glycol monoethyl ether 5～25％ Lavender essential oil 0～0.5％ water 55～75％

[0094] or,

[0095] Components percentage Agomelatin 1～5％ Propylene glycol monolaurate 3～15％ Polyoxyethylene hydrogenated castor oil 5～15％ Diethylene glycol monoethyl ether 5～25％ water 55～75％

[0096] or,

[0097] Components percentage Agomelatin 1.5～2.5％ Propylene glycol monolaurate 8～10％ Polyoxyethylene hydrogenated castor oil 10～12％ Diethylene glycol monoethyl ether 5～8％ water 62～75％

[0098] or,

[0099] Components percentage Agomelatin 2％ Propylene glycol monolaurate 9.5％ Polyoxyethylene hydrogenated castor oil 10.8％ Diethylene glycol monoethyl ether 7.4％ water 70.3％

[0100] In a preferred embodiment of the present invention, the particle size of the agomelatine microemulsion is 10-100 nm; preferably, the particle size can be 10-90 nm, or 30-100 nm, or 40-80 nm, or 50-80 nm, or 50-65 nm.

[0101] In a preferred embodiment of the present invention, the above-mentioned agomelatine microemulsion can be applied directly to the affected area, or it can be prepared into other drug dosage forms, such as sprays, films, ointments, creams, gels, patches, poultices, etc., with the preferred drug dosage form being a gel or patch.

[0102] The preparation method of agomelatine microemulsion according to the present invention includes the following steps:

[0103] 1) Weigh out the specified weight ratio of agomelatine, oil phase, emulsifier, and co-emulsifier, and mix them evenly under magnetic stirring; or, weigh out the specified weight ratio of emulsifier, co-emulsifier, and oil phase, mix them evenly under magnetic stirring, and then dissolve agomelatine in the mixture.

[0104] 2) Add the aqueous phase to the mixed solution obtained in step 1) and mix evenly under magnetic stirring to obtain agomelatine microemulsion.

[0105] The present invention also provides an agomelatine microemulsion gel, comprising an agomelatine microemulsion and a gel matrix.

[0106] In a preferred embodiment of the present invention, the gel matrix includes one or more of carbomer, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, xanthan gum, gum arabic, sodium alginate, and poloxamer; carbomer is preferred.

[0107] The carbomers that can be used in this invention include carbomer 980, carbomer 934, carbomer 940, carbomer 941, carbomer 971, carbomer 974, carbomer 981, carbomer ETD 2020, and carbomer Ultraz 21.

[0108] In a preferred embodiment of the present invention, the amount of gel matrix added is 0.1% to 3% of the total weight of agomelatine microemulsion; preferably 0.1% to 1.5%; more preferably 0.3% to 1.0%; and even more preferably 0.5% to 0.7%.

[0109] In a preferred embodiment of the present invention, the microemulsion gel further includes a pH adjuster, preferably the pH adjuster to 3.0–10.0; more preferably 4.0–8.0; more preferably 5.0–6.5; the pH adjuster includes one or more of hydrochloric acid, sodium hydroxide, phosphate, boric acid, borate, tris(hydroxymethyl)aminomethane, citric acid, citrate, and triethanolamine; preferably triethanolamine.

[0110] The method for preparing agomelatine microemulsion gel according to the present invention includes adding a gel matrix to agomelatine microemulsion, swelling and stirring until homogeneous, and then adding a pH adjuster to adjust the pH value to obtain a homogeneous and transparent semi-solid formulation, which is agomelatine microemulsion gel.

[0111] In the application of the agomelatine microemulsion and agomelatine microemulsion gel described in this invention in the preparation of drugs for treating mental illnesses, preferably, the mental illness refers to depression, and more preferably, the mental illness refers to major depressive disorder.

[0112] The oil phase, emulsifier, and co-emulsifier in this invention for preparing microemulsions sometimes also act as drug penetration enhancers. Therefore, microemulsions, as drug carriers, may promote transdermal drug absorption. The key to preparing microemulsions as carriers for the active pharmaceutical ingredient agomelatine lies in the selection of components and the design of their proportions.

[0113] This invention involves adding a polymeric gel material to a microemulsion, which forms a transparent and stable network structure containing microemulsion droplets, termed a microemulsion gel. The stable three-dimensional network structure of the gel prevents drug precipitation, which is particularly significant for the administration of agomelatine, a polycrystalline drug. The effects of different gel matrices and different concentrations of the same matrice on microemulsion gel formation were investigated, resulting in a highly permeable agomelatine microemulsion gel formulation. The gel of this invention exhibits excellent biocompatibility and low skin irritation.

[0114] The rate-limiting steps in transdermal drug delivery via microemulsion gels are primarily two: the release of the drug from the matrix and the penetration of the drug through the skin. The design of the microemulsion composition can influence both of these steps, making it possible to control transdermal drug absorption by adjusting the microemulsion formulation.

[0115] This invention combines agomelatine, a transdermal drug delivery system, microemulsions, and microemulsion gels to create an antidepressant with low toxicity, good stability, and high efficacy. Currently, there are no publicly reported transdermal formulations of agomelatine microemulsions and microemulsion gels. This invention, using microemulsions and microemulsion gels, significantly improves drug loading capacity, requires less emulsifier and co-emulsifying agent, and significantly enhances agomelatine's ability to penetrate the skin, resulting in a rapid onset of action, increased cumulative permeation per unit area, and thus improved bioavailability and convenient administration. Furthermore, the preparation process of this invention is simple and easy to implement, suitable for industrial production, and yields a product with stable quality that is easy to store and transport. Detailed Implementation

[0116] The principles and features of the present invention are described below. The examples given are only for explaining the present invention and are not intended to limit the scope of the present invention.

[0117] Example 1: Preparation of agomelatine microemulsion with a total weight of 100g

[0118] Example 1.1

[0119] Components Material Name Prescription dosage (g) Active ingredients Agomelatin 0.5 oil phase monolinoleic glycerides 3.0 emulsifier Twain 80 13.4 co-emulsifier Anhydrous ethanol 5.3 Aqueous phase water 77.8

[0120] The oil phase, emulsifier, co-emulsifier, and agomelatine of the above weight are thoroughly mixed. The water of the above weight is added dropwise under room temperature and magnetic stirring conditions, and stirring is continued for 30 minutes to obtain the agomelatine microemulsion.

[0121] Example 1.2

[0122] Components Material Name Prescription dosage (g) Active ingredients Agomelatin 0.5 oil phase Propylene glycol monooctanoate 3.0 emulsifier Polyoxyethylene castor oil 7.2 co-emulsifier Propylene glycol 9.5 Aqueous phase water 79.8

[0123] The preparation method is the same as in Example 1.1.

[0124] Example 1.3

[0125]

[0126]

[0127] The preparation method is the same as in Example 1.1.

[0128] Example 1.4

[0129] Components Material Name Prescription dosage (g) Active ingredients Agomelatin 5.0 oil phase Ethyl oleate 13.8 emulsifier Polyoxyethylene hydrogenated castor oil 25.5 co-emulsifier Diethylene glycol monoethyl ether 10.8 Aqueous phase water 44.9

[0130] The preparation method is the same as in Example 1.1.

[0131] Example 1.5

[0132] Components Material Name Prescription dosage (g) Active ingredients Agomelatin 3.0 oil phase monolinoleic glycerides 9.8 emulsifier Polyoxyethylene hydrogenated castor oil 30.6 co-emulsifier Polyethylene glycol 400 3.5 Aqueous phase water 53.1

[0133] The preparation method is the same as in Example 1.1.

[0134] Example 1.6

[0135] Components Material Name Prescription dosage (g) Active ingredients Agomelatin 2.0 oil phase Propylene glycol monolaurate 8 emulsifier Caprylic / Capric ... 18.5 co-emulsifier Glycerol 3.0 Aqueous phase water 68.5

[0136] The preparation method is the same as in Example 1.1.

[0137] Example 1.7

[0138]

[0139]

[0140] The preparation method is the same as in Example 1.1.

[0141] Example 1.8

[0142] Components Material Name Prescription dosage (g) Active ingredients Agomelatin 3.0 oil phase Propylene glycol monolaurate 9.8 emulsifier Polyoxyethylene castor oil 18.6 co-emulsifier Diethylene glycol monoethyl ether 10.2 co-emulsifier Anhydrous ethanol 4.2 Aqueous phase water 54.2

[0143] The preparation method is the same as in Example 1.1.

[0144] Example 1.9

[0145] Components Material Name Prescription dosage (g) Active ingredients Agomelatin 2.0 oil phase Propylene glycol monooctanoate 9.5 emulsifier Polyoxyethylene hydrogenated castor oil 10.8 co-emulsifier Diethylene glycol monoethyl ether 7.4 Aqueous phase water 70.3

[0146] The preparation method is the same as in Example 1.1.

[0147] Example 1.10

[0148] Components Material Name Prescription dosage (g) Active ingredients Agomelatin 2.0 oil phase monolinoleic glycerides 9.5 emulsifier Polyoxyethylene hydrogenated castor oil 10.8 co-emulsifier Diethylene glycol monoethyl ether 7.4 Aqueous phase water 70.3

[0149] The preparation method is the same as in Example 1.1.

[0150] Example 1.11

[0151]

[0152]

[0153] The preparation method is the same as in Example 1.1.

[0154] Example 1.12

[0155] Components Material Name Prescription dosage (g) Active ingredients Agomelatin 2.0 oil phase Propylene glycol monooctanoate 6.0 emulsifier Polyoxyethylene hydrogenated castor oil 9.0 co-emulsifier Diethylene glycol monoethyl ether 17.9 Fragrance Lavender essential oil 0.1 Aqueous phase water 65.0

[0156] The oil phase, emulsifier, co-emulsifier, fragrance, and agomelatine of the above weight are thoroughly mixed. The water of the above weight is added dropwise under room temperature and magnetic stirring conditions, and stirring is continued for 30 minutes to obtain the agomelatine microemulsion.

[0157] Example 1.13

[0158] Components Material Name Prescription dosage (g) Active ingredients Agomelatin 2.0 oil phase Propylene glycol monooctanoate 6.0 emulsifier Polyoxyethylene hydrogenated castor oil 9.0 co-emulsifier Diethylene glycol monoethyl ether 17.9 preservative Methylparaben 0.1 Aqueous phase water 65.0

[0159] The oil phase, emulsifier, co-emulsifier, preservative and agomelatine of the above weight are thoroughly mixed. The water of the above weight is added dropwise under room temperature and magnetic stirring conditions. Stirring is continued for 30 minutes to obtain agomelatine microemulsion.

[0160] Example 1.14

[0161]

[0162]

[0163] The oil phase, emulsifier, co-emulsifier, fragrance, preservative and agomelatine of the above weight are thoroughly mixed. The water of the above weight is added dropwise under room temperature and magnetic stirring conditions. Stirring is continued for 30 minutes to obtain agomelatine microemulsion.

[0164] Example 1.15

[0165] Components Material Name Prescription dosage (g) Active ingredients Agomelatin 1.0 oil phase Propylene glycol monooctanoate 4.95 emulsifier Polyoxyethylene hydrogenated castor oil 14.85 co-emulsifier Diethylene glycol monoethyl ether 29.7 Aqueous phase water 49.5

[0166] Mix the emulsifier, co-emulsifier and oil phase of the above weight evenly, then dissolve agomelatine in the mixture, add water of the above weight dropwise under room temperature and magnetic stirring conditions, and continue stirring for 30 minutes to obtain agomelatine microemulsion.

[0167] Example 1.16

[0168] Components Material Name Prescription dosage (g) Active ingredients Agomelatin 1.0 oil phase Propylene glycol monooctanoate 5.0 emulsifier Polyoxyethylene hydrogenated castor oil 10.0 co-emulsifier Diethylene glycol monoethyl ether 20.0 Aqueous phase water 64

[0169] The preparation method is the same as in Example 1.1.

[0170] Example 1.17

[0171] Components Material Name Prescription dosage (g) Active ingredients Agomelatin 2.0 oil phase Propylene glycol monolaurate 9.5 emulsifier Polyoxyethylene hydrogenated castor oil 10.8 co-emulsifier Diethylene glycol monoethyl ether 7.4 Aqueous phase water 70.3

[0172] The preparation method is the same as in Example 1.1.

[0173] Compare with Example 1.1

[0174] Components Material Name Prescription dosage (g) Active ingredients Agomelatin 2.0 solvent Diethylene glycol monoethyl ether 46.8 Penetration enhancer Propylene glycol 5.2 Aqueous phase water 46.0

[0175] Mix the solvent, penetration enhancer, and agomelatine by weight as described above thoroughly. Add the water by weight as described above dropwise at room temperature with magnetic stirring. Continue stirring for 30 minutes to obtain the agomelatine solution.

[0176] Compare with Example 1.2

[0177] Components Material Name Prescription dosage (g) Active ingredients Agomelatin 5.0 solvent Diethylene glycol monoethyl ether 46.8 Penetration enhancer Propylene glycol 5.2 Aqueous phase water 43.0

[0178] The preparation method is the same as that of Control Example 1.1

[0179] The agomelatine microemulsions prepared in Examples 1.1-1.17 above, as well as Control Examples 1.1 and 1.2, were tested. The determination methods and results are as follows:

[0180] 1. Agomelatine microemulsion particle size detection

[0181] Instrument: Zetasizer potentiometric particle size analyzer (Malvin, UK), temperature 25℃. Particle size measurement results are shown in Table 1.

[0182] 2. Agomelatine microemulsion in vitro permeation test

[0183] Carefully remove the fur from the rat's abdomen with a razor, peel off the abdominal skin, carefully remove subcutaneous tissue and adhesions, rinse thoroughly with physiological saline, and blot dry with filter paper. Assemble the Franz diffusion cell (effective area 1.76 cm²). 2 A mouse skin was placed between the supply chamber and the receiving chamber, with the stratum corneum facing the supply chamber and the dermis facing the receiving chamber, and fixed in place. A Franz diffusion cell was placed on a magnetic stirrer heated to 32℃±0.5℃ at 350 rpm. Agomelatine microemulsion (equivalent to 10 mg of agomelatine) was added to the supply chamber, using 30% ethanol-physiological saline as the receiving medium. 3 ml samples were taken at 0.5, 1, 2, 3, 4, and 6 hours, with the same volume of blank receiving medium added each time and air bubbles removed. The collected liquid was filtered through a 0.45 μm microporous membrane, and the content of agomelatine in the sample was determined by HPLC. The cumulative permeate (μg / cm³) at the corresponding points was calculated. 2 The results are shown in Table 1.

[0184] Table 1. Agomelatine Microemulsion Particle Size and In Vitro Permeability Test Table

[0185]

[0186]

[0187] Example 2. Preparation of agomelatine microemulsion gel

[0188] Example 2.1

[0189] 100g of agomelatine microemulsion prepared in Example 1.7 was mixed with 0.5g of carbomer and allowed to swell completely. Triethanolamine solution was then added to adjust the pH to 5.0–6.5, yielding the agomelatine microemulsion gel. Complete swelling refers to swelling overnight at room temperature or for at least 2 hours at 40°C. The swelling process of the microemulsion gel described above includes, but is not limited to, the listed temperatures and times, and the final determination is based on achieving the desired swelling.

[0190] The above-mentioned agomelatine microemulsions or agomelatine microemulsion gels may also contain preservatives, antioxidants, water-retaining agents, and other ingredients.

[0191] Example 2.2

[0192] 100g of agomelatine microemulsion prepared in Example 1.8 was mixed with 0.5g of carbomer, allowed to swell fully, and then triethanolamine solution was added to adjust the pH to 5.0-6.5 to obtain agomelatine microemulsion gel.

[0193] Example 2.3

[0194] 100g of agomelatine microemulsion prepared in Example 1.9 was mixed with 0.5g of carbomer, allowed to swell fully, and then triethanolamine solution was added to adjust the pH to 5.0-6.5 to obtain agomelatine microemulsion gel.

[0195] Example 2.4

[0196] 100g of agomelatine microemulsion prepared in Example 1.10 was mixed with 0.3g of carbomer, allowed to swell fully, and then triethanolamine solution was added to adjust the pH to 5.0-6.5 to obtain agomelatine microemulsion gel.

[0197] Example 2.5

[0198] 100g of agomelatine microemulsion prepared in Example 1.10 was mixed with 0.5g of carbomer and allowed to swell completely. Triethanolamine solution was added and the pH was adjusted to 5.0-6.5 to obtain agomelatine microemulsion gel.

[0199] Example 2.6

[0200] 100g of agomelatine microemulsion prepared in Example 1.10 was mixed with 0.8g of carbomer and allowed to swell completely. Triethanolamine solution was added and the pH was adjusted to 5.0-6.5 to obtain agomelatine microemulsion gel.

[0201] Example 2.7

[0202] 100g of agomelatine microemulsion prepared in Example 1.10 was mixed with 1.0g of carbomer, allowed to swell fully, and then triethanolamine solution was added to adjust the pH to 5.0-6.5 to obtain agomelatine microemulsion gel.

[0203] Compare with Example 2.1

[0204] 100g of agomelatine solution prepared in Comparative Example 1.1 was mixed with 0.4g of carbomer and allowed to swell completely. Triethanolamine solution was then added and the pH was adjusted to 5.0–6.5 to obtain agomelatine gel.

[0205] Compare with Example 2.2

[0206] 100g of agomelatine solution prepared in Comparative Example 1.2 was mixed with 0.4g of carbomer and allowed to swell completely. Triethanolamine solution was then added and the pH was adjusted to 5.0–6.5 to obtain agomelatine gel.

[0207] The agomelatine microemulsion gels prepared in Examples 2.1-2.7 above were tested, and the determination methods and results are as follows:

[0208] 1. Determination of the viscosity of agomelatine microemulsion gel

[0209] The viscosity of the microemulsion gel was measured using a viscometer at 25°C. The viscosity measurement results are shown in Table 2.

[0210] 2. In vitro transdermal permeation test of agomelatine microemulsion gel

[0211] The skin acquisition method, the assembly of the Franz diffusion cell, and the measurement method were the same as in the "In Vitro Transdermal Permeation Test of Agomelatine Microemulsion". 300 mg of agomelatine microemulsion gel from Examples 2.1-2.7 was added to the supply cell. The results of the in vitro transdermal permeation test are shown in Table 2.

[0212] Table 2. Viscosity and In Vitro Transdermal Permeability Test Results of Agomelatine Microemulsion Gel

[0213] Viscosity (mPa.s) <![CDATA[Q6(μg / cm 2 )]]> Example 2.1 28380±322 45.17±8.23 Example 2.2 25847±545 73.38±2.72 Example 2.3 29053±421 85.85±7.52 Example 2.4 26634±538 53.42±6.88 Example 2.5 31208±365 48.42±6.88 Example 2.6 48425±347 43.58±3.11 Compare with Example 2.1 28431±386 18.58±3.22 Compare with Example 2.2 27652±427 33.36±2.56

[0214] 3. Skin irritation studies

[0215] White male rabbits (n=3) were used as test animals. The fur on the back of the rabbits was shaved off with an electric shaver, and then approximately 50 mg of the sample from Example 2.2 and Control Example 2.2 was applied to two corresponding sites on each rabbit, covering an area of ​​approximately 10 cm². 2Return the rabbit to its cage. 24 hours after administration, wipe the test site with tap water to remove any residual gel. Observe the rabbit's skin erythema / edema visually for 3 consecutive days, and score and evaluate according to the standards in Tables 3 and 4.

[0216] Table 3. Skin Irritation Response Scores

[0217] erythema score No erythema 0 Barely visible 1 Obvious erythema 2 Moderate to severe erythema 3 purplish-red erythema with eschar formation 4 edema / No edema 0 Barely visible 1 The skin is raised and the contours are clear. 2 The edema is about 1mm in size. 3 Edema bulging exceeding 1mm and expanding in area 4 Total Score 8

[0218] Table 4. Evaluation of Skin Irritation Intensity

[0219] strength Score Non-irritating 0～0.4 Mild irritation 0.5～2.9 moderately irritating 3.0～5.9 Strong irritant 6.0～8.0

[0220] No erythema / edema was observed in either group, with a score of 0. Therefore, agomelatine microemulsion gel is non-irritating to the skin.

[0221] 4. Stability test

[0222] The agomelatine microemulsion gels prepared in Examples 2.3-2.4 were placed at 30℃±2℃ and RH 65%±5%. Samples were taken at the end of 0, 1, 2, 3, and 6 months to observe the gel condition. The results are shown in Table 5. The results show that the agomelatine microemulsion gel has good stability.

[0223] Table 5. Results of stability assays for agomelatine microemulsion gels

[0224]

[0225]

Claims

1. An agomelatine microemulsion comprising agomelatine and a drug carrier, characterized in that, Drug carriers include emulsifiers, co-emulsifiers, oil phases, and aqueous phases; The oil phase is selected from propylene glycol monooctanoate or propylene glycol monolaurate; The emulsifier is selected from polyoxyethylene hydrogenated castor oil; The co-emulsifier is selected from diethylene glycol monoethyl ether; The agomelatine microemulsion is an oil-in-water microemulsion. The aqueous phase is selected from deionized water, distilled water, water for injection, high-purity water, or ultrapure water; Based on the total weight of the formulation, agomelatine comprises 1–3% by weight; the oil phase comprises 3–10% by weight; the emulsifier comprises 10–12% by weight; the co-emulsifier comprises 5–8% by weight; and the aqueous phase comprises 62–72% by weight.

2. The agomelatine microemulsion according to claim 1, characterized in that, It also includes one or more of fragrances or preservatives; The fragrance is selected from lavender essential oil; The preservative is selected from methylparaben.

3. The agomelatine microemulsion according to claim 1 or 2, characterized in that, The particle size of agomelatine microemulsion is 10–100 nm.

4. The use of the agomelatine microemulsion according to any one of claims 1 to 3 in the preparation of gels.

5. The method for preparing agomelatine microemulsion according to any one of claims 1 to 4, characterized in that, Includes the following steps: 1) Weigh out the agomelatine, oil phase, emulsifier, and co-emulsifier according to the specified weight ratio, and mix them evenly under magnetic stirring; 2) Add the aqueous phase to the mixed solution obtained in step 1) and mix evenly under magnetic stirring to obtain agomelatine microemulsion.

6. An agomelatine microemulsion gel, comprising the agomelatine microemulsion according to any one of claims 1 to 3, characterized in that, It also includes the gel matrix; The gel matrix is ​​selected from carbomer; The amount of gel matrix added is 0.5% to 0.7% of the total weight of agomelatine microemulsion.

7. The microemulsion gel according to claim 6, characterized in that, It also includes a pH adjuster, which adjusts the pH to 5.0–6.5; the pH adjuster is selected from triethanolamine.

8. The method for preparing agomelatine microemulsion gel according to any one of claims 6 to 7, characterized in that, Adding a gel matrix to the agomelatine microemulsion according to any one of claims 1 to 3, followed by swelling and uniform stirring, and then adding a pH adjuster, yields the agomelatine microemulsion gel.

9. The use of the agomelatine microemulsion according to any one of claims 1 to 3 and the agomelatine microemulsion gel according to any one of claims 6 to 7 in the preparation of a drug for treating mental illness; wherein the mental illness is major depressive disorder.

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