CN114452255A - Agomelatine microemulsion, microemulsion gel and preparation method thereof - Google Patents

Agomelatine microemulsion, microemulsion gel and preparation method thereof Download PDF

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CN114452255A
CN114452255A CN202111269142.4A CN202111269142A CN114452255A CN 114452255 A CN114452255 A CN 114452255A CN 202111269142 A CN202111269142 A CN 202111269142A CN 114452255 A CN114452255 A CN 114452255A
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agomelatine
microemulsion
glyceride
emulsifier
gel
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赵娜
韩德强
王钰
张震
李艳芬
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Changzhou Hengbang Pharmaceutical Co ltd
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Abstract

The invention relates to an agomelatine micro-emulsion and micro-emulsion gel and a preparation method thereof, belonging to the field of pharmaceutical formulation. The agomelatine micro-emulsion contains agomelatine and a drug carrier, wherein the drug carrier comprises an emulsifier, an auxiliary emulsifier, an oil phase and a water phase; an agomelatine microemulsion gel comprises an agomelatine microemulsion and a gel matrix. The agomelatine micro-emulsion and the micro-emulsion gel have the advantages of good stability, high bioavailability, good clinical safety, simple preparation process and easy industrial scale-up production.

Description

Agomelatine microemulsion, microemulsion gel and preparation method thereof
Technical Field
The invention relates to an agomelatine micro-emulsion and micro-emulsion gel and a preparation method thereof, belonging to the field of pharmaceutical formulation.
Background
Depression is an affective disorder disease which is mainly characterized by low mood, reduced interest, thought retardation and cognitive function damage, has the characteristics of high morbidity, high disability rate, high recurrence rate, high suicide rate and the like, in recent years, along with the increase of social pressure, the prevalence rate of depressive disorder is increased year by year, becomes one of common serious chronic diseases harmful to human health, and according to the estimation of Chinese disease prevention control center, the prevalence rate of depression in China is increased to 7.3 percent in 2020. 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 drug, is the first melatonin antidepressant drug in the world, is a melatonin receptor agonist and a serotonin 2C (5-HT2C) receptor antagonist, and has the pharmacological action of combining the activity of the melatonin receptor agonist and the performance of the 5-HT2C receptor antagonist, so that depression can be effectively treated, sleep parameters and maintenance functions are improved, and the agomelatine is effective for all types of depression. Agomelatine is a naphthalene derivative of melatonin, in which an indole ring is substituted with a naphthalene core, so that agomelatine is more metabolically stable than melatonin. It is a selective and specific agonist of the hypothalamic melatonin receptor, combined with a weak agonistShows a novel pharmacological property of dual action of melatonin receptor agonist and 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 chemical name of N- [2- (7-methoxynaphthalene-1-yl) ethyl]Acetamide of formula C15H17NO2Molecular weight 243.3, chemical structural formula:
Figure BDA0003328049190000011
the existing marketed dosage form of agomelatine is only oral tablets, is developed by France Schvea company, is approved to be marketed in European Union 2.24.2009, is approved to be marketed in 2011 by CFDA, and has a new trade name. The specification of the agomelatine tablets is 25mg, the agomelatine tablets are orally taken once before sleep every day, although the agomelatine tablets are quickly absorbed and have higher absorption rate, the medicine has large liver first-pass effect and low bioavailability which is only 3-4%; and the biological differences between individuals and within individuals are quite large, with a high degree of variability. Therefore, it is necessary to improve the oral tablet and prepare the administration form with low hepatotoxicity and high bioavailability.
Transdermal Drug Delivery Systems (TDDS) refer to a Transdermal preparation applied to the skin, where the Drug permeates the skin, is absorbed by the capillary vessels into the systemic blood circulation to reach an effective blood concentration and is transferred to various tissues or diseased regions for treating or preventing diseases. The transdermal administration mode can avoid the liver first pass effect and gastrointestinal inactivation which can happen in oral administration; maintaining a constant optimal blood level or physiological effect, reducing the side effects of gastrointestinal administration; the effective acting time is prolonged, and the medicine taking times are reduced; the administration dosage is adjusted by changing the administration area, so that individual difference is reduced, and the patient can independently take the medicine or stop taking the medicine at any time.
The Microemulsion (ME) is a homogeneous, transparent, thermodynamically and kinetically stable multiphase system, and is composed of oil, water, emulsifier and auxiliary emulsifier, and the particle size is 10-100 nm. Microemulsions have a number of advantages in transdermal delivery systems (TDDS), such as: can remarkably increase the solubility of the medicine, maintain higher medicine concentration, improve the medicine concentration gradient between the microemulsion and the skin, increase the transdermal speed, increase the fluidity of stratum corneum lipid bilayer, improve the transdermal capacity of the medicine and improve the bioavailability.
Microemulsion-based gels (MBGs) are prepared by adding a microemulsion into a gel matrix composed of high-molecular materials such as natural high-molecular polymers, cellulose derivatives, block polymers and the like to form a transparent, homogeneous and stable gel network structure, wherein the network structure contains microemulsion droplets; the microemulsion gel is used as a novel transdermal drug delivery carrier and has the double advantages of microemulsion and gel. The microemulsion gel improves the solubility of the drug through microemulsion, reduces the diffusion barrier of the skin, increases the transdermal capacity of the drug and improves the transdermal rate; the gel can improve the viscosity of the microemulsion, improve the adhesiveness and spreadability of the microemulsion and skin, reduce the irritation of the medicine, achieve the functions of transdermal penetration and improving the bioavailability. The microemulsion gel is used as a transdermal drug delivery carrier, can avoid the first-pass clearing effect of the liver, reduce the stimulation of the drug to the gastrointestinal tract, reduce the toxic and side effects, is easy to coat, is convenient for patients to take, and has good stability.
Disclosure of Invention
Aiming at the defects of the existing preparation formulation, the invention provides the agomelatine micro-emulsion and the micro-emulsion gel which have good stability and the function of permeation promotion.
The technical scheme for solving the problems is as follows: an agomelatine microemulsion comprises a pharmaceutical active ingredient and a pharmaceutical carrier, wherein the pharmaceutical active ingredient is agomelatine, and the pharmaceutical carrier comprises an emulsifier, an auxiliary emulsifier, an oil phase and a water phase.
In a preferred embodiment of the invention, the agomelatine microemulsion is an oil-in-water microemulsion.
In a preferred embodiment of the present invention, the oil phase is selected from one or more of fatty acid glyceride, macrogol glyceride, carboxylic ester and propylene glycol ester; preferably, the fatty glyceride is selected from one or more of medium chain triglyceride, ethyl oleate, ethyl linoleate, glycerol monolinoleate, glycerol triacetate, caprylic/capric triglyceride, glycerol monostearate and glycerol monooleate, the polyethylene glycol glyceride is selected from polyethylene glycol glyceride oleate, polyethylene glycol lauryl glyceride and polyethylene glycol glyceride caprylic/capric acid, one or more of macrogol glyceride laurate, macrogol glyceryl caprate, macrogol glyceryl stearate and macrogol glyceryl isostearate, the carboxylic acid ester is selected from one or more of isopropyl palmitate, lauryl lactate, isopropyl myristate, diisopropyl adipate, di-n-butyl adipate and diethyl sebacate, and the propylene glycol ester is selected from one or more of propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol oleate, propylene glycol myristate and propylene glycol dicaprylate dicaprate; more preferably at least one of propylene glycol monocaprylate and propylene glycol monolaurate.
In a preferred embodiment of the present invention, the emulsifier is selected from one or more of polysorbate, polyoxyethylene oil and its derivatives, polyglycolyzed glyceride; 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 triacylglycerol and polyoxyethylene hydrogenated castor oil; the macrogol glyceride is one or more selected from acid capric acid macrogol glyceride, macrogol lauric glyceride, macrogol lauryl glyceride, macrogol capric glyceride, macrogol stearic glyceride and macrogol isostearic glyceride; more preferably at least one of caprylic capric acid polyethylene glycol glyceride and polyoxyethylene hydrogenated castor oil.
The polyoxyethylene hydrogenated castor oil comprises 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; polyoxyethylene 40 hydrogenated castor oil is preferred.
In a preferred embodiment of the present invention, the co-emulsifier is selected from one or more of alcohol, polyethylene glycol and ether; preferably, the alcohol is selected from one or more of absolute ethyl alcohol, 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, ceteareth, steareth, ceteth and laureth; more preferably at least one of diethylene glycol monoethyl ether and anhydrous ethanol.
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.
In a preferred embodiment of the invention, the agomelatine microemulsion further comprises pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials comprise one or more of a humectant, an osmotic pressure regulator, an aromatic, a preservative, an antioxidant and a penetration enhancer.
The humectant comprises one or more of glycerin, paraffin oil, sorbitol, propylene glycol, isopropanol, ethanol, butylene glycol, and hyaluronic acid.
The osmotic pressure regulator comprises one or more of glycerol, borax, glucose, mannitol, propylene glycol, sorbitol and sodium chloride.
The aromatic comprises one or more of lavender essential oil, fructus Citri Tangerinae essence, strawberry essence, chocolate essence, herba Menthae essence and milk essence; preferably lavender essential oil; more preferably, in the invention, the weight percentage of the aromatic is 0-2% based on the total weight of the prescription; preferably 0-1%; more preferably 0.01 to 0.5%; further preferably 0.01 to 0.35%.
The antiseptic comprises one or more of methyl paraben, ethyl paraben, propyl paraben, sodium methyl paraben, sodium ethyl paraben, sodium propyl paraben, sorbic acid, potassium sorbate, sodium benzoate, chlorobutanol and benzalkonium bromide.
The antioxidant includes synthetic antioxidants such as BHA (butylhydroxyanisole), BHT (dibutylhydroxytoluene), TBHQ (tert-butylhydroquinone), PG (propyl gallate), AP (L-ascorbyl palmitate), EQ (ethoxyquinoline), sodium metabisulfite, DLTP (dilauryl thiodipropionate), and natural antioxidants such as tea polyphenol, tocopherol, and grape seed extract.
The penetration enhancer comprises one or more of oleic acid, stearic acid, isostearic acid, lactic acid, lauric acid, polyethylene glycol, isopropyl myristate, isopropyl palmitate, dimethylacetamide, triglyceride, menthol, propylene glycol, borneol, cnidium oil, azone, sodium tetradecyl sulfate, geraniol, anethole and decyl methyl sulfoxide.
In the preferable scheme of the invention, the weight percentage of the agomelatine is 0.1-20% based on the total weight of the prescription; preferably 0.1-15%; more preferably 0.5-10%; further preferably 1-5%; further preferably 1-3%; for example, 1 to 2.5%, 1.5 to 2.5%, 2%, 1%, etc.
In the preferable scheme of the invention, the weight percentage of the oil phase is 1-35% based on the total weight of the prescription; preferably 1-25%; more preferably 1-15%; further preferably 3 to 10%, for example 5%, 9.5%; further preferably 4 to 8%.
In a preferable scheme of the 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%; further preferably 6-12%; for example, 10 to 12%, 10.8%, etc.
In the preferable scheme of the invention, the weight percentage of the co-emulsifier is 1-30% based on the total weight of the prescription; preferably 1-25%; more preferably 5-25%; further preferably 5-20%; further preferably 5 to 15%, for example 5 to 8%, 7.4%, etc.; or, preferably 10-25%; more preferably 15 to 22%.
In the preferable scheme of the invention, the weight percentage of the water phase is 10-90% based on the total weight of the prescription; preferably 40-85%; more preferably 50-80%; further preferably 55 to 75%, for example 62%, 64%, 70.3%; further preferably 60 to 70% or 62 to 72%.
In a preferred embodiment of the present invention, the weight ratio of the emulsifier to the co-emulsifier to the total weight of the formulation is preferably less than 30%, more preferably less than 20%;
in a preferred embodiment of the invention, the weight percentages of the components based on the total weight of the prescription are as follows:
components Percentage of
Agomelatine 0.1～20％
Oil phase 1～40％
Emulsifier 1～60％
Auxiliary emulsifier 1～30％
Aqueous phase 5～90％
；
Alternatively, the first and second electrodes may be,
components Percentage of
Agomelatine 0.1～15％
Oil phase 1～35％
Emulsifier 1～50％
Auxiliary emulsifier 1～30％
Aromatic agent 0～2％
Aqueous phase 10～90％
；
Alternatively, the first and second electrodes may be,
components Percentage of
Agomelatine 0.5～10％
Oil phase 1～25％
Emulsifier 1～35％
Auxiliary emulsifier 1～25％
Aromatic agent 0～2％
Aqueous phase 40～85％
；
Alternatively, the first and second electrodes may be,
components Percentage of
Agomelatine 1～5％
Oil phase 1～15％
Emulsifier 5～25％
Auxiliary emulsifier 5～25％
Aromatic agent 0～1％
Aqueous phase 50～80％
；
Alternatively, the first and second electrodes may be,
components Percentage of
Agomelatine 1～5％
Oil phase 3～15％
Emulsifying agent 5～15％
Auxiliary emulsifier 5～25％
Aromatic agent 0～0.5％
Aqueous phase 55～75％
；
Alternatively, the first and second electrodes may be,
components Percentage of
Agomelatine 1～5％
Oil phase 3～15％
Emulsifier 5～15％
Auxiliary emulsifier 5～15％
Aromatic agent 0～0.5％
Aqueous phase 55～75％
。
In a preferred scheme of the invention, when the oil phase is propylene glycol monocaprylate, the weight percentages of the components are as follows based on the total weight of the prescription:
Figure BDA0003328049190000061
Figure BDA0003328049190000072
alternatively, the first and second liquid crystal display panels may be,
components Percentage of
Agomelatine 1～5％
Propylene glycol monocaprylate 3～15％
Emulsifying agent 5～15％
Auxiliary emulsifier 5～25％
Aromatic agent 0～0.5％
Water (W) 55～75％
；
Alternatively, the first and second electrodes may be,
components Percentage of
Agomelatine 1～5％
Propylene glycol monocaprylate 3～15％
Emulsifier 5～15％
Auxiliary emulsifier 5～25％
Aromatic agent 0～0.5％
Water (W) 55～75％
；
Alternatively, the first and second electrodes may be,
Figure BDA0003328049190000071
Figure BDA0003328049190000081
alternatively, the first and second electrodes may be,
components Percentage of
Agomelatine 1～5％
Propylene glycol monocaprylate 3～15％
Polyoxyethylene Castor oil 5～15％
Diethylene glycol monoethyl ether 5～25％
Aromatic agent 0～0.5％
Water (W) 55～75％
；
Alternatively, the first and second electrodes may be,
components Percentage of
Agomelatine 1～5％
Propylene glycol monocaprylate 3～10％
Polyoxyethylene Castor oil 5～15％
Diethylene glycol monoethyl ether 10～25％
Lavender essential oil 0～0.5％
Water (W) 55～75％
；
Alternatively, the first and second electrodes may be,
Figure BDA0003328049190000082
Figure BDA0003328049190000091
alternatively, the first and second electrodes may be,
components Percentage of
Agomelatine 1～5％
Propylene glycol monocaprylate 3～15％
Polyoxyethylene hydrogenated castor oil 5～15％
Diethylene glycol monoethyl radicalEther compounds 5～25％
Water (I) 55～75％
Alternatively, the first and second liquid crystal display panels may be,
components Percentage of
Agomelatine 1～2.5％
Propylene glycol monocaprylate 5～10％
Polyoxyethylene hydrogenated castor oil 10～12％
Diethylene glycol monoethyl ether 5～20％
Water (W) 62～75％
Alternatively, the first and second electrodes may be,
components Percentage of
Agomelatine 2％
Propylene glycol monocaprylate 9.5％
Polyoxyethylene hydrogenated castor oil 10.8％
Diethylene glycol monoethyl ether 7.4％
Water (W) 70.3％
Alternatively, the first and second electrodes may be,
Figure BDA0003328049190000092
Figure BDA0003328049190000101
in a preferred embodiment of the invention, the oil phase is propylene glycol monolaurate, and the weight percentages of the components based on the total weight of the prescription are as follows:
components Percentage of
Agomelatine 0.5～10％
Propylene glycol monolaurate 1～25％
Emulsifier 1～35％
Auxiliary emulsifier 1～25％
Aromatic agent 0～2％
Water (W) 40～85％
；
Alternatively, the first and second electrodes may be,
components Percentage of
Agomelatine 1～5％
Propylene glycol monolaurate 3～15％
Emulsifier 5～15％
Auxiliary emulsifier 5～25％
Aromatic agent 0～0.5％
Water (W) 55～75％
；
Alternatively, the first and second electrodes may be,
Figure BDA0003328049190000102
Figure BDA0003328049190000111
alternatively, the first and second electrodes may be,
components Percentage of
Agomelatine 1～5％
Propylene glycol monolaurate 3～15％
Polyoxyethylene Castor oil 5～15％
Diethylene glycol monoethyl ether 5～25％
Aromatic agent 0～0.5％
Water (W) 55～75％
；
Alternatively, the first and second electrodes may be,
components Percentage of
Agomelatine 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 (W) 55～75％
；
Alternatively, the first and second electrodes may be,
components Percentage of
Agomelatine 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 (W) 55～75％
。
Alternatively, the first and second electrodes may be,
components Percentage of
Agomelatine 1～5％
Propylene glycol monolaurate 3～15％
Polyoxyethylene hydrogenated castor oil 5～15％
Diethylene glycol monoethyl ether 5～25％
Water (W) 55～75％
Alternatively, the first and second electrodes may be,
components Percentage of
Agomelatine 1.5～2.5％
Propylene glycol monolaurate 8～10％
Polyoxyethylene hydrogenated castor oil 10～12％
Diethylene glycol monoethyl ether 5～8％
Water (W) 62～75％
Alternatively, the first and second electrodes may be,
components Percentage of
Agomelatine 2％
Propylene glycol monolaurate 9.5％
Polyoxyethylene hydrogenated castor oil 10.8％
Diethylene glycol monoethyl ether 7.4％
Water (W) 70.3％
In a preferable scheme of the invention, the grain diameter of the agomelatine micro-emulsion 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.
In a preferred embodiment of the invention, the agomelatine microemulsion can be directly applied to the affected part, and can also be prepared into other pharmaceutical dosage forms, such as spray, film, ointment, cream, gel, patch, cataplasm and the like, wherein the preferred pharmaceutical dosage form is gel or patch.
The preparation method of the agomelatine micro emulsion comprises the following steps:
1) weighing the agomelatine, the oil phase, the emulsifier and the co-emulsifier in the weight ratio, and uniformly mixing the agomelatine, the oil phase, the emulsifier and the co-emulsifier under magnetic stirring; or weighing the emulsifier, the co-emulsifier and the oil phase according to the weight ratio, uniformly mixing under magnetic stirring, and dissolving the agomelatine in the mixture;
2) adding the water phase into the mixed solution obtained in the step 1), and uniformly mixing under magnetic stirring to obtain the agomelatine microemulsion.
The invention also provides an agomelatine micro-emulsion gel, which comprises an agomelatine micro-emulsion and a gel matrix.
In a preferred embodiment of the invention, the gel matrix comprises one or more of carbomer, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, xanthan gum, acacia, sodium alginate and poloxamer; carbomers are preferred.
Carbomers that may be used in the present invention include carbomer 980, carbomer 934, carbomer 940, carbomer 941, carbomer 971, carbomer 974, carbomer 981, carbomer ETD 2020, carbomer Ultrez 21.
In the preferable scheme of the invention, the addition amount of the gel matrix is 0.1-3% of the total weight of the agomelatine microemulsion; preferably 0.1 to 1.5 percent; more preferably 0.3% to 1.0%; more preferably 0.5% to 0.7%.
In the preferable scheme of the invention, the microemulsion gel further comprises a pH regulator, and the pH regulator is preferably used for regulating the pH to 3.0-10.0; preferably 4.0-8.0; more preferably 5.0 to 6.5; the pH regulator comprises one or more of hydrochloric acid, sodium hydroxide, phosphate, boric acid, borate, tris (hydroxymethyl) aminomethane, citric acid, citrate, and triethanolamine; triethanolamine is preferred.
The preparation method of the agomelatine micro-emulsion gel comprises the steps of adding a gel matrix into the agomelatine micro-emulsion, swelling, uniformly stirring, adding a pH regulator to regulate the pH value, and preparing a uniform transparent semisolid preparation, namely the agomelatine micro-emulsion gel.
The agomelatine microemulsion and agomelatine microemulsion gel provided by the invention are applied to preparation of medicines for treating mental diseases, preferably, the mental diseases refer to depression, and more preferably, the mental diseases refer to severe depression.
The oil phase, the emulsifier and the co-emulsifier of the microemulsion prepared by the invention sometimes play a role of a medicinal penetration enhancer. It can be seen that the microemulsion may promote transdermal absorption of the drug as a drug carrier. The microemulsion is used as a carrier of an active ingredient agomelatine of a medicament, and the key point for preparing the microemulsion is the selection of the components and the design of the proportion of the components.
According to the invention, a high-molecular gel material is added into the microemulsion to form a transparent and stable network structure, microemulsion liquid drops are contained in the network, the microemulsion gel is called, and the stable three-dimensional network structure of the gel can prevent the precipitation of drug precipitates, which is very significant for the administration of agomelatine with a polycrystalline phenomenon. And (3) investigating the influence of different gel matrixes and different concentrations of the same matrix on the formation of the microemulsion gel, thereby obtaining the agomelatine microemulsion gel preparation with high permeability. The gel of the invention has good compatibility and small irritation to skin.
The speed-limiting steps of the drug microemulsion gel transdermal drug delivery are mainly two, namely the process of releasing the drug from the matrix and the process of permeating the drug through the skin. The design of the microemulsion composition can affect both steps. Provides possibility for controlling the percutaneous absorption of the drug by adjusting the composition formula of the microemulsion.
The agomelatine, the transdermal drug delivery system, the microemulsion and the microemulsion gel are combined to prepare the antidepressant drug with small toxic and side effect, good stability and high curative effect. At present, no agomelatine microemulsion and microemulsion gel transdermal preparation is disclosed, the microemulsion and microemulsion gel transdermal preparation adopted by the invention can obviously improve the drug loading capacity, the required emulsifier and auxiliary emulsifier are few, the agomelatine transdermal capacity can be obviously enhanced, the onset time is fast, the unit area accumulated permeation quantity is increased, the bioavailability is further improved, and the administration is convenient. In addition, the preparation process is simple and feasible, industrial production can be realized, and the prepared product has stable quality and is convenient to store and transport.
Detailed Description
The principles and features of this invention are described below in conjunction with examples which are set forth to illustrate, but are not to be construed to limit the scope of the invention.
Example 1 preparation of Agomelatine microemulsion with a Total weight of 100g
Example 1.1
Components Name of material Prescription amount (g)
Active ingredient Agomelatine 0.5
Oil phase Monolinolic acid glyceride 3.0
Emulsifier Tween 80 13.4
Auxiliary emulsifier Anhydrous ethanol 5.3
Aqueous phase Water (W) 77.8
And (3) fully and uniformly mixing the oil phase, the emulsifier, the co-emulsifier and the agomelatine, dropwise adding the water with the weight under the magnetic stirring condition at room temperature, and continuously stirring for 30 minutes to obtain the agomelatine micro emulsion.
Example 1.2
Components Name of material Prescription amount (g)
Active ingredient Agomelatine 0.5
Oil phase Propylene glycol monocaprylate 3.0
Emulsifying agent Polyoxyethylene Castor oil 7.2
Auxiliary emulsifier Propylene glycol 9.5
Aqueous phase Water (W) 79.8
The preparation method is the same as example 1.1.
Example 1.3
Figure BDA0003328049190000141
Figure BDA0003328049190000151
The preparation method is the same as example 1.1.
Example 1.4
Components Name of material Prescription amount (g)
Active ingredient Agomelatine 5.0
Oil phase Oleic acid ethyl ester 13.8
Emulsifier Polyoxyethylene hydrogenated castor oil 25.5
Auxiliary emulsifier Diethylene glycol monoethyl ether 10.8
Aqueous phase Water (W) 44.9
The preparation method is the same as example 1.1.
Example 1.5
Components Name of material Prescription dose (g)
Active ingredient Agomelatine 3.0
Oil phase Monolinolic acid glyceride 9.8
Emulsifier Polyoxyethylene hydrogenated castor oil 30.6
Auxiliary emulsifier Polyethylene glycol 400 3.5
Aqueous phase Water (W) 53.1
The preparation method is the same as example 1.1.
Example 1.6
Components Name of material Prescription amount (g)
Active ingredient Agomelatine 2.0
Oil phase Propylene glycol monolaurate 8
Emulsifier Caprylic capric acid polyethylene glycol glyceride 18.5
Auxiliary emulsifier Glycerol 3.0
Aqueous phase Water (W) 68.5
The preparation method is the same as example 1.1.
Example 1.7
Figure BDA0003328049190000152
Figure BDA0003328049190000161
The preparation method is the same as example 1.1.
Example 1.8
Components Name of material Prescription amount (g)
Active ingredient Agomelatine 3.0
Oil phase Propylene glycol monolaurate 9.8
Emulsifier Polyoxyethylene Castor oil 18.6
Auxiliary emulsifier Diethylene glycol monoethyl ether 10.2
Auxiliary emulsifier Anhydrous ethanol 4.2
Aqueous phase Water (W) 54.2
The preparation method is the same as example 1.1.
Example 1.9
Components Name of material Prescription amount (g)
Active ingredient Agomelatine 2.0
Oil phase Propylene glycol monocaprylate 9.5
Emulsifier Polyoxyethylene hydrogenated castor oil 10.8
Auxiliary emulsifier Diethylene glycol monoethyl ether 7.4
Aqueous phase Water (W) 70.3
The preparation method is the same as example 1.1.
Example 1.10
Components Name of material Prescription amount (g)
Active ingredient Agomelatine 2.0
Oil phase Monolinolic acid glyceride 9.5
Emulsifying agent Polyoxyethylene hydrogenated castor oil 10.8
Auxiliary emulsifier Diethylene glycol monoethyl ether 7.4
Aqueous phase Water (W) 70.3
The preparation method is the same as example 1.1.
Example 1.11
Figure BDA0003328049190000162
Figure BDA0003328049190000171
The preparation method is the same as example 1.1.
Example 1.12
Components Name of material Prescription amount (g)
Active ingredient Agomelatine 2.0
Oil phase Propylene glycol monocaprylate 6.0
Emulsifier Polyoxyethylene hydrogenated castor oil 9.0
Auxiliary emulsifier Diethylene glycol monoethyl ether 17.9
Aromatic agent Lavender essential oil 0.1
Aqueous phase Water (W) 65.0
And (3) fully and uniformly mixing the oil phase, the emulsifier, the co-emulsifier, the aromatic and the agomelatine, dropwise adding the water with the weight under the condition of magnetic stirring at room temperature, and continuously stirring for 30 minutes to obtain the agomelatine micro-emulsion.
Example 1.13
Components Name of material Prescription amount (g)
Active ingredient Agomelatine 2.0
Oil phase Propylene glycol monocaprylate 6.0
Emulsifier Polyoxyethylene hydrogenated castor oil 9.0
Auxiliary emulsifier Diethylene glycol monoethyl ether 17.9
Preservative Nipagin methyl ester 0.1
Aqueous phase Water (W) 65.0
And (3) fully and uniformly mixing the oil phase, the emulsifier, the co-emulsifier, the preservative and the agomelatine, dropwise adding the water with the weight under the condition of magnetic stirring at room temperature, and continuously stirring for 30 minutes to obtain the agomelatine micro-emulsion.
Example 1.14
Figure BDA0003328049190000172
Figure BDA0003328049190000181
And (3) fully and uniformly mixing the oil phase, the emulsifier, the co-emulsifier, the aromatic, the preservative and the agomelatine, dropwise adding the water with the weight under the condition of magnetic stirring at room temperature, and continuously stirring for 30 minutes to obtain the agomelatine microemulsion.
Example 1.15
Components Name of material Prescription amount (g)
Active ingredient Agomelatine 1.0
Oil phase Propylene glycol monocaprylate 4.95
Emulsifier Polyoxyethylene hydrogenated castor oil 14.85
Auxiliary emulsifier Diethylene glycol monoethyl ether 29.7
Aqueous phase Water (W) 49.5
And (3) uniformly mixing the emulsifier, the co-emulsifier and the oil phase, dissolving the agomelatine in the mixture, dropwise adding the water with the weight under the conditions of room temperature and magnetic stirring, and continuously stirring for 30 minutes to obtain the agomelatine micro-emulsion.
Example 1.16
Components Name of material Prescription amount (g)
Active ingredient Agomelatine 1.0
Oil phase Propylene glycol monocaprylate 5.0
Emulsifier Polyoxyethylene hydrogenated castor oil 10.0
Auxiliary emulsifier Diethylene glycol monoethyl ether 20.0
Aqueous phase Water (W) 64
The preparation method is the same as example 1.1.
Example 1.17
Components Name of material Prescription amount (g)
Active ingredient Agomelatine 2.0
Oil phase Propylene glycol monolaurate 9.5
Emulsifier Polyoxyethylene hydrogenated castor oil 10.8
Auxiliary emulsifier Diethylene glycol monoethyl ether 7.4
Aqueous phase Water (W) 70.3
The preparation method is the same as example 1.1.
Comparative example 1.1
Components Name of material Prescription amount (g)
Active ingredient Agomelatine 2.0
Solvent(s) Diethylene glycol monoethyl ether 46.8
Penetration enhancer Propylene glycol 5.2
Aqueous phase Water (W) 46.0
And (3) fully and uniformly mixing the solvent, the penetration enhancer and the agomelatine by weight, dropwise adding the water by weight under the condition of magnetic stirring at room temperature, and continuously stirring for 30 minutes to obtain an agomelatine solution.
Comparative example 1.2
Components Name of material Prescription amount (g)
Active ingredient Agomelatine 5.0
Solvent(s) Diethylene glycol monoethyl ether 46.8
Penetration enhancer Propylene glycol 5.2
Aqueous phase Water (W) 43.0
Preparation method is the same as comparative example 1.1
The agomelatine microemulsions prepared in the above examples 1.1 to 1.17 and the comparative examples 1.1 and 1.2 were tested, and the measurement methods and results were as follows:
1. detection of grain size of agomelatine microemulsion
The instrument comprises the following steps: the Zetasizer potential-particle size analyzer (British Marvin) temperature was 25 ℃. The results of the particle size measurements are shown in Table 1.
2. Agomelatine microemulsion in-vitro permeation test detection
Carefully removing the hair on the abdomen of the rat by using a shaver, peeling off the skin on the abdomen, carefully removing subcutaneous tissues and adhesion substances, cleaning by using normal saline, and sucking water by using filter paper. Franz diffusion cells (effective area 1.76 cm) were assembled2) The rat skin is positioned between the delivery chamber and the receiving chamber with the stratum corneum facing the delivery chamber and the dermis facing the receiving chamber, and secured. The Franz diffusion cell was placed on a constant temperature heating magnetic stirrer at 32 + -0.5 deg.C and rotated at 350 rpm. Adding agomelatine microemulsion (equivalent to agomelatine 10mg) into a supply chamber, taking 30% ethanol-physiological saline as a receiving medium, sampling 3ml at 0.5, 1, 2, 3, 4 and 6 hours respectively, supplementing blank receiving medium with the same volume each time and removing bubbles, filtering the obtained liquid by a 0.45 mu m microporous filter membrane, detecting the content of agomelatine in the sample by an HPLC method, and calculating the cumulative permeation amount (mu g/cm) of a corresponding point2). The results are shown in Table 1.
TABLE 1 Agomelatine microemulsion granularity and in vitro penetration test detection table
Figure BDA0003328049190000191
Figure BDA0003328049190000201
Example 2 preparation of Agomelatine microemulsion gel
Example 2.1
100g of the agomelatine microemulsion prepared in the example 1.7 is mixed with 0.5g of carbomer, the mixture is fully swelled, a triethanolamine solution is added, and the pH is adjusted to 5.0-6.5, so that agomelatine microemulsion gel is obtained. Wherein the sufficient swelling refers to swelling at room temperature overnight or swelling at 40 deg.C for more than 2 hr. The microemulsion gel swelling process includes, but is not limited to, the listed temperature and time, and finally, the swelling purpose is achieved.
The agomelatine micro emulsion or the agomelatine micro emulsion gel can also be added with preservative, antioxidant, water retention agent and other components.
Example 2.2
100g of the agomelatine microemulsion prepared in example 1.8 is mixed with 0.5g of carbomer, the mixture is fully swelled, a triethanolamine solution is added, and the pH is adjusted to 5.0-6.5, so that agomelatine microemulsion gel is obtained.
Example 2.3
100g of the agomelatine microemulsion prepared in example 1.9 is mixed with 0.5g of carbomer, the mixture is fully swelled, a triethanolamine solution is added, and the pH is adjusted to 5.0-6.5, so that agomelatine microemulsion gel is obtained.
Example 2.4
100g of the agomelatine microemulsion prepared in example 1.10 is mixed with 0.3g of carbomer, the mixture is fully swelled, a triethanolamine solution is added, and the pH is adjusted to 5.0-6.5, so that agomelatine microemulsion gel is obtained.
Example 2.5
100g of the agomelatine microemulsion prepared in example 1.10 is mixed with 0.5g of carbomer, the mixture is fully swelled, a triethanolamine solution is added, and the pH is adjusted to 5.0-6.5, so that agomelatine microemulsion gel is obtained.
Example 2.6
100g of the agomelatine microemulsion prepared in example 1.10 is mixed with 0.8g of carbomer, the mixture is fully swelled, a triethanolamine solution is added, and the pH is adjusted to 5.0-6.5, so that agomelatine microemulsion gel is obtained.
Example 2.7
100g of the agomelatine microemulsion prepared in example 1.10 is mixed with 1.0g of carbomer, the mixture is fully swelled, a triethanolamine solution is added, and the pH is adjusted to 5.0-6.5, so that agomelatine microemulsion gel is obtained.
Comparative example 2.1
100g of the agomelatine solution prepared in the comparative example 1.1 is mixed with 0.4g of carbomer, the mixture is fully swelled, triethanolamine solution is added, and the pH is adjusted to 5.0-6.5, so that agomelatine gel is obtained.
Comparative example 2.2
100g of the agomelatine solution prepared in the comparative example 1.2 is mixed with 0.4g of carbomer, the mixture is fully swelled, triethanolamine solution is added, and the pH is adjusted to 5.0-6.5, so that agomelatine gel is obtained.
The agomelatine microemulsion gels prepared in the above examples 2.1 to 2.7 were tested, and the determination method and results were as follows:
1. determination of agomelatine microemulsion gel viscosity
The viscosity of the microemulsion gel was measured with a viscometer at 25 ℃. The viscosity measurements are shown in Table 2.
2. In vitro transdermal penetration test of agomelatine microemulsion gel
The skin obtaining method, the Franz diffusion cell assembly and the determination method are the same as the in-vitro transdermal penetration test of the agomelatine microemulsion. 300mg of the agomelatine microemulsion gel of example 2.1-2.7 was added to the feeding reservoir. The results of the in vitro transdermal penetration test are shown in table 2.
TABLE 2 Agomelatine microemulsion gel viscosity and in vitro transdermal penetration test detection table
Viscosity (mPa.s) Q6(μg/cm2)
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
Comparative example 2.1 28431±386 18.58±3.22
Comparative example 2.2 27652±427 33.36±2.56
3. Skin irritation study
White male rabbits (n ═ 3) were used as test animals. The rabbit hairs on the back side were shaved off with an electric razor, and approximately 50mg of the samples of example 2.2 and comparative example 2.2 were applied to two sites (corresponding sites) of each rabbit, respectively, in an area of approximately 10cm2. The rabbits were returned to their cages. After 24 hours of administration, the test site was wiped with tap water to remove residual gel. Observing the condition of erythema/edema of rabbit skin by naked eyes for 3 days, and marking according to tables 3 and 4Scoring and evaluation are performed.
TABLE 3 skin irritation response score
Erythema Scoring
No erythema 0
Can be barely seen 1
Obvious erythema 2
Moderate to severe erythema 3
Purplish red erythema with eschar formation 4
Edema (edema) /
Without edema 0
Can be barely seen 1
Skin doming contour definition 2
Edema and swelling1mm 3
Edema with swelling exceeding 1mm and enlarged range 4
Total score 8
TABLE 4 evaluation of skin irritation Strength
Strength of Score value
Has no irritation 0～0.4
Light irritation 0.5～2.9
Moderate irritation 3.0～5.9
Strong irritation 6.0～8.0
Results no erythema/edema was observed in both groups, and a score of 0 was obtained. Therefore, the agomelatine microemulsion gel has no irritation to the skin.
4. Stability test
Placing the agomelatine microemulsion gel prepared in the example 2.3-2.4 at 30 +/-2 ℃; RH 65% + -5%. Samples were taken at the end of 0, 1, 2, 3, 6 months to observe the gel, and the results of the formula are shown in Table 5. The result shows that the agomelatine micro-emulsion gel has good stability.
TABLE 5 Agomelatine microemulsion gel stability test results
Figure BDA0003328049190000221
Figure BDA0003328049190000231

Claims (10)

1. An agomelatine microemulsion comprises agomelatine and a drug carrier, and is characterized in that the drug carrier comprises an emulsifier, an auxiliary emulsifier, an oil phase and a water phase;
the oil phase is selected from one or more of fatty glyceride, macrogol glyceride, carboxylic ester and propylene glycol ester; preferably, the fatty glyceride is selected from one or more of medium chain triglyceride, ethyl oleate, ethyl linoleate, glycerol monolinoleate, glycerol triacetate, caprylic/capric triglyceride, glycerol monostearate and glycerol monooleate, the polyethylene glycol glyceride is selected from polyethylene glycol glyceride oleate, polyethylene glycol lauryl glyceride and polyethylene glycol glyceride caprylic/capric acid, one or more of macrogol glyceride laurate, macrogol glyceryl caprate, macrogol glyceryl stearate and macrogol glyceryl isostearate, the carboxylic acid ester is selected from one or more of isopropyl palmitate, lauryl lactate, isopropyl myristate, diisopropyl adipate, di-n-butyl adipate and diethyl sebacate, and the propylene glycol ester is selected from one or more of propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol oleate, propylene glycol myristate and propylene glycol dicaprylate dicaprate; more preferably at least one of propylene glycol monocaprylate and propylene glycol monolaurate;
the emulsifier is one or more selected from polysorbate, polyoxyethylene oil and its derivatives, and polyglycolyzed glyceride; 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 triacylglycerol and polyoxyethylene hydrogenated castor oil; the macrogol glyceride is one or more selected from caprylic capric acid macrogol glyceride, macrogol lauric glyceride, macrogol lauryl glyceride, macrogol capric glyceride, macrogol stearic glyceride and macrogol isostearic glyceride; more preferably at least one of caprylic capric acid polyethylene glycol glyceride and polyoxyethylene hydrogenated castor oil;
the auxiliary emulsifier is selected from one or more of alcohol, polyethylene glycol and ether; preferably, the alcohol is selected from one or more of absolute ethyl alcohol, 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, ceteareth, steareth, ceteth and laureth; more preferably at least one of diethylene glycol monoethyl ether and absolute ethanol;
preferably, the agomelatine microemulsion is an oil-in-water microemulsion;
preferably, the aqueous phase is selected from deionized water, distilled water, water for injection, high purity water or ultrapure water.
2. The agomelatine microemulsion according to claim 1, further comprising one or more of a humectant, an osmotic pressure regulator, a fragrance, a preservative, an antioxidant and a penetration enhancer;
preferably, the aromatic is selected from one or more of lavender essential oil, orange essence, strawberry essence, chocolate essence, mint essence and milk essence; more preferably lavender essential oil;
preferably, the preservative comprises one or more of methyl paraben, ethyl paraben, propyl paraben, sodium methyl paraben, sodium ethyl paraben, sodium propyl paraben, sorbic acid, potassium sorbate, sodium benzoate, chlorobutanol and benzalkonium bromide.
3. An agomelatine microemulsion according to any one of claims 1 to 2, wherein the weight percentage of agomelatine is 0.1 to 20% based on the total weight of the formulation; preferably 0.1-15%; more preferably 0.5-10%; further preferably 1-5%;
alternatively, the first and second electrodes may be,
based on the total weight of the prescription, the weight percentage of the oil phase is 1-35%; preferably 1-25%; more preferably 1-15%; further preferably 3-10%;
alternatively, the first and second electrodes may be,
based on the total weight of the prescription, the weight percentage of the emulsifier is 1-50%; preferably 1-35%; more preferably 5-25%; further preferably 5-15%;
alternatively, the first and second electrodes may be,
the weight percentage of the co-emulsifier is 1-30% based on the total weight of the prescription; preferably 1-25%; more preferably 5-25%; further preferably 5-20%;
alternatively, the first and second electrodes may be,
the weight percentage of the water phase is 10-90% based on the total weight of the prescription; preferably 40-85%; more preferably 50-80%; further preferably 55 to 75%.
4. An agomelatine microemulsion according to any one of claims 1 to 3, wherein the particle size of the agomelatine microemulsion is 10 to 100 nm.
5. Use of an agomelatine microemulsion according to any one of claims 1 to 4 for the preparation of a spray, film, ointment, cream, gel, patch or cataplasm.
6. A method for preparing an agomelatine microemulsion according to any one of claims 1 to 5, which comprises the following steps:
1) weighing the agomelatine, the oil phase, the emulsifier and the co-emulsifier in the weight ratio, and uniformly mixing the agomelatine, the oil phase, the emulsifier and the co-emulsifier under magnetic stirring;
2) adding the water phase into the mixed solution obtained in the step 1), and uniformly mixing under magnetic stirring to obtain the agomelatine microemulsion.
7. An agomelatine microemulsion gel comprising the agomelatine microemulsion according to any one of claims 1 to 5, further comprising a gel base;
the gel matrix is one or more selected from carbomer, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, xanthan gum, acacia, sodium alginate and poloxamer; more preferably carbomer;
the addition amount of the gel matrix is 0.1-3% of the total weight of the agomelatine microemulsion; preferably 0.1 to 1.5 percent; more preferably 0.3% to 1.0%; more preferably 0.5% to 0.7%.
8. The microemulsion gel as claimed in claim 7, further comprising a pH regulator, preferably a pH regulator for regulating pH to 3.0-10.0; more preferably 4.0 to 8.0; further preferably 5.0 to 6.5; the pH regulator is selected from one or more of hydrochloric acid, sodium hydroxide, phosphate, boric acid, borate, tris (hydroxymethyl) aminomethane, citric acid, citrate and triethanolamine; triethanolamine is preferred.
9. A preparation method of an agomelatine microemulsion gel according to any one of claims 7 to 8, characterized in that the agomelatine microemulsion gel is prepared by adding a gel matrix into the agomelatine microemulsion according to any one of claims 1 to 5, swelling the gel matrix, uniformly stirring the gel matrix, and adding a pH regulator.
10. Use of an agomelatine microemulsion according to any one of claims 1 to 5 and an agomelatine microemulsion gel according to any one of claims 7 to 8 for the preparation of a medicament for the treatment of psychiatric disorders; preferably, the psychiatric disorder is depression, more preferably major depression.
CN202111269142.4A 2020-10-30 2021-10-29 Agomelatine microemulsion, microemulsion gel and preparation method thereof Pending CN114452255A (en)

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