CN113876740A

CN113876740A - Agomelatine transdermal patch

Info

Publication number: CN113876740A
Application number: CN202110748528.7A
Authority: CN
Inventors: 韩德强; 赵娜; 范录云
Original assignee: Changzhou Hengbang Pharmaceutical Co ltd
Current assignee: Changzhou Hengbang Pharmaceutical Co ltd
Priority date: 2020-07-02
Filing date: 2021-07-02
Publication date: 2022-01-04

Abstract

The invention provides an agomelatine transdermal patch and a preparation method thereof. Specifically, the agomelatine transdermal patch comprises (a) a backing layer, (b) an adhesive matrix layer and (c) a protective layer, wherein the adhesive matrix layer contains agomelatine and the adhesive matrix, and optionally a penetration enhancer. The agomelatine prepared by the invention has the characteristics of high transdermal absorption rate, high transdermal absorption amount, stability, high efficiency, good uniformity and low irritation, and the preparation method is simple.

Description

Agomelatine transdermal patch

Technical Field

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

Background

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

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

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

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

Patent CN103830206A discloses a transdermal drug delivery preparation with agomelatine three-dimensional net stereo configuration and a preparation method thereof, which comprises a back lining layer, a drug-loaded three-dimensional net stereo configuration system coated on the back lining layer and an anti-sticking layer compounded on the back lining layer. The invention not only can effectively realize the continuous transdermal of the drug for a longer time and maintain the constant blood concentration, but also has the characteristics of high transdermal absorption rate, high transdermal absorption amount, stability and high efficiency. However, the technology needs to take nano silicon dioxide as a medicine carrier to form a three-dimensional net-shaped three-dimensional structure, and then the three-dimensional net-shaped three-dimensional structure system is used for preparing the transdermal patch. The method is too complicated and reproducibility is difficult to ensure.

Patent CN110151735A discloses an agomelatine transdermal patch and a preparation method thereof, and the preparation method comprises the following steps: micronizing the agomelatine crystal with a specific crystal form; dispersed in a mixture of fucosterol, octanol, 2-pyrrolidone, and isopropanol; coating on a polymer pressure-sensitive adhesive to obtain the patch. The agomelatine transdermal patch has the advantages of high transdermal absorption rate, high transdermal absorption amount, stability, high efficiency, good uniformity and low irritation, and is favorable for wide clinical application. However, this technique requires micronization of the API, which may degrade the API to produce impurities. Moreover, the yield of micronization operation is not high, and the economic effect is low.

Patent WO2016109483a1 discloses a composition comprising agomelatine, delivered through an enhancer selected from the group consisting of isopropanol and ethanol. The reservoir type transdermal patch prepared by the technology has the problems of poor stability, poor reproducibility and uniformity, dose leakage risk and high industrialization difficulty.

The transdermal patch has the advantages of avoiding the first-pass clearing effect of liver, reducing the stimulation of medicine to gastrointestinal tract, reducing toxic and side effects, reducing the medicine dosage, improving the use compliance of patients, and the like. The agomelatine is prepared into the transdermal patch, the problem of low bioavailability of the oral tablet can be well solved without gastrointestinal tract damage and liver first pass effect, and the compliance of a patient can be improved. However, the existing preparation or process is complex and difficult to reproduce, or the preparation has poor stability, which affects the safety of medication. Therefore, the agomelatine transdermal patch with good reproducibility and safety and effectiveness is needed clinically.

Disclosure of Invention

The invention aims to provide an agomelatine transdermal patch with stable drug release performance, which comprises (a) a back lining layer, (b) an adhesive matrix layer and (c) a protective layer, wherein the agomelatine and the adhesive matrix are contained in the (b) adhesive matrix layer.

In a preferable embodiment of the present invention, in the (b) adhesive matrix layer, the content of the pharmaceutical active ingredient agomelatine is 1-15% by weight and the content of the adhesive matrix is 75-95% by weight, based on the total weight of the adhesive matrix layer.

In a more preferred embodiment of the present invention, agomelatine is dissolved and mixed in the adhesive layer in an amount of 5 to 15%, preferably 10 to 15%, 8 to 12%, and more preferably 10 to 12% of the total weight of the adhesive matrix layer (b).

In a more preferred embodiment of the invention, the adhesive matrix is present in an amount of 75 to 95% by weight, preferably 80 to 90% by weight, based on the total weight of the adhesive matrix layer.

In a preferred embodiment of the invention, the adhesive matrix is a non-aqueous adhesive.

In a more preferred embodiment of the present invention, the adhesive matrix used in the adhesive matrix layer of the patch of the present invention is one or more selected from polyisobutylene, silicone, acrylic, polyurethane, natural rubber and synthetic rubber, preferably one or more selected from styrene-isoprene-styrene block copolymer (SIS), polyamide, polyurethane, polyisobutylene pressure sensitive adhesive, silicone pressure sensitive adhesive, acrylate pressure sensitive adhesive and hot melt pressure sensitive adhesive, more preferably acrylate pressure sensitive adhesive and/or styrene-isoprene-styrene block copolymer.

In a preferred embodiment of the invention, the adhesive matrix layer has a thickness of 10 to 150. mu.m, preferably 20 to 80 μm, more preferably 40 to 65 μm.

In a preferred embodiment of the present invention, the adhesive matrix layer may further comprise one or more other pharmaceutically acceptable excipients such as penetration enhancer, antioxidant, surfactant, filler, flavoring agent, colorant, etc.

In a more preferred embodiment of the invention, the sum of the percentages by weight of the other pharmaceutically acceptable excipients does not exceed 15%.

The penetration enhancer adopted by the invention can be one or more of sulfoxides, pyrrolidones, amides, fatty acids and esters thereof, surfactants, alcohols, polyols, terpenes and phospholipids, such as propylene glycol, oleic acid, stearic acid, isostearic acid, lactic acid, lauric acid, polyethylene glycol, isopropyl myristate, isopropyl palmitate, decyl methyl sulfoxide, dimethylacetamide and triglyceride, and the content of the penetration enhancer is 0-15% (by weight), preferably 1-8% (by weight), more preferably 2-6% (by weight) based on the total weight of the adhesive matrix layer.

The antioxidant used in the invention is selected from dibutyl hydroxy toluene, tert-butyl p-hydroxy anisole, propyl gallate, ascorbic acid and sodium metabisulfite, and the content of the antioxidant is 0-2% (weight ratio), preferably 0-1% (weight ratio) based on the total weight of the adhesive matrix layer.

The filler adopted in the invention can be selected from silicon dioxide, titanium dioxide, metal stearate, calcium carbonate, polyvidone and acrylic resin, and the content of the filler is 0-1% (weight ratio) based on the total weight of the adhesive matrix layer.

In a more preferred embodiment of the invention, when the adhesive matrix is selected from silicones, silicone pressure-sensitive adhesives are preferred, and further preferably, the agomelatine is present in an amount of 5-15% by weight and the adhesive is present in an amount of 85% -95% by weight, based on the total weight of the adhesive matrix layer.

In a more preferred embodiment of the invention, when the adhesive matrix is selected from the group consisting of acrylics, acrylate pressure sensitive adhesives are preferred; more preferably, the weight percentage of the agomelatine is 5-15%, the weight percentage of the adhesive matrix is 75-87%, the weight percentage of the penetration enhancer is 2-10%, and the weight percentage of the antioxidant is 0-2%; further preferably, the weight percentage of the agomelatine is 10-15%, the weight percentage of the adhesive is 75% -90%, the weight percentage of the penetration enhancer is 2-8%, and the weight percentage of the antioxidant is 1-2% based on the total weight of the adhesive matrix layer; more preferably, the weight percentage of the agomelatine is 10-15%, the weight percentage of the acrylate pressure-sensitive adhesive is 75-85%, the weight percentage of the isopropyl myristate is 2-4%, the weight percentage of the polyethylene glycol is 0-2%, the weight percentage of the lactic acid is 1-3%, the weight percentage of the oleic acid is 1-2%, and the weight percentage of the dimethylacetamide is 1-2% based on the total weight of the adhesive matrix layer.

In a more preferred embodiment of the invention, the acrylate pressure sensitive adhesive is selected from 2-ethylhexyl acrylate containing copolymers, preferably one or more of DURO-TAK 2287, DURO-TAK 4098, DURO-TAK 2510, DURO-TAK 2516, DURO-TAK 2074, and DURO-TAK 2677; more preferably one or more of DURO-TAK 387-2287, DURO-TAK 87-4098, DURO-TAK 387-2516, DURO-TAK 87-2074, DURO-TAK 87-2677, DURO-TAK 387-2510 or DURO-TAK 87-2510; further preferably at least DURO-TAK 2287, optionally also DURO-TAK 4098, DURO-TAK 2510, DURO-TAK 2516, DURO-TAK 2074 and/or DURO-TAK 2677; further preferably at least DURO-TAK 4098, optionally also DURO-TAK 2287, DURO-TAK 2510, DURO-TAK 2516, DURO-TAK 2074 and/or DURO-TAK 2677; further preferably at least DURO-TAK 2516, optionally also DURO-TAK 2287, DURO-TAK 2510, DURO-TAK 4098, DURO-TAK 2074 and/or DURO-TAK 2677; further preferably at least DURO-TAK 2074, optionally also DURO-TAK 2287, DURO-TAK 2510, DURO-TAK 4098, DURO-TAK 2516 and/or DURO-TAK 2677; most preferred is the combination of DURO-TAK 2287 with DURO-TAK 4098 or the combination of DURO-TAK 2516 with DURO-TAK 2074.

In a more preferred embodiment of the invention, the penetration enhancer is selected from the group consisting of isopropyl myristate, lactic acid, a two-component combination of isopropyl myristate and lactic acid, a two-component combination of triglyceride and lactic acid, a three-component combination of isopropyl myristate, lactic acid and dimethylacetamide, a three-component combination of isopropyl myristate, lactic acid and polyethylene glycol, isopropyl myristate, oleic acid, a four-component combination of lactic acid and dimethylacetamide, or a five-component combination of isopropyl myristate, oleic acid, lactic acid, polyethylene glycol and dimethylacetamide.

In a more preferred embodiment of the present invention, the adhesive matrix layer of the patch comprises the following components in percentage by weight:

material(s)	Percent (%)
		Agomelatine	10％-15％
Acrylate pressure-sensitive adhesive	75％-85％
		Aminoalkyl methacrylate copolymers	1％-5％
Penetration enhancer	2％-10％

，

Preferably, the adhesive matrix layer of the patch comprises the following components in percentage by weight:

material(s)	Percent (%)
		Agomelatine	10％-15％
Acrylate pressure-sensitive adhesive	70％-85％
		Aminoalkyl methacrylate copolymers	1％-3％
Myristic acid isopropyl ester	2％-4％
		Polyethylene glycol	0-2％
Lactic acid	1％-3％
		Oleic acid	1％-2％
Dimethylacetamide	1％-2％

，

material(s)	Percent (%)
		Agomelatine	5％-15％
DURO-TAK 387-2287	70％-80％
		DURO-TAK 87-4098	5％-15％
Myristic acid isopropyl ester	2％-4％
		Dimethylacetamide	1％-2％
Lactic acid	1％-2％

。

material(s)	Percent (%)
		Agomelatine	5％-15％
DURO-TAK 387-2516	70％-80％
		DURO-TAK 87-2074	5％-15％
Myristic acid isopropyl ester	2％-4％
		Dimethylacetamide	1％-2％
Lactic acid	1％-2％

。

。

material(s)	Percent (%)
		Agomelatine	10％-15％
DURO-TAK 387-2287	70％-80％
		DURO-TAK 87-4098	0-5％
Aminoalkyl methacrylate copolymers	1％-3％
		Myristic acid isopropyl ester	2％-4％
Polyethylene glycol	0-2％
		Lactic acid	1％-3％
Oleic acid	1％-2％
		Dimethylacetamide	1％-2％

。

In a more preferred embodiment of the present invention, when the adhesive matrix is selected from synthetic rubbers, it is preferably a styrene-isoprene-styrene block copolymer, and further, it further comprises a tackifier and a softener together as the adhesive matrix, and the content of the tackifier and the softener is 75 to 95% by weight, and more preferably 80 to 90% by weight, based on the total weight of the adhesive matrix.

In a more preferable embodiment of the present invention, the weight percentage of the synthetic rubber is 10 to 30%, the weight percentage of the tackifier is 30 to 65%, and the weight percentage of the softener is 10 to 30% based on the weight of the adhesive matrix.

In a more preferred embodiment of the present invention, the emollient is selected from one or more of paraffin oil, silicone oil, higher fatty acid, and vegetable oil, preferably one or more of liquid paraffin, white oil, naphthenic oil, squalane, squalene, silicone oil, vaseline, and lanolin; more preferably liquid paraffin.

In a more preferred embodiment of the present invention, the tackifier is one or more selected from terpene resin, petroleum resin, hydrogenated rosin glyceride, alicyclic saturated hydrocarbon resin, high molecular polyisobutylene, and low molecular polyisobutylene; preferably one or more of hydrogenated rosin glyceride, alicyclic saturated hydrocarbon resin, high molecular polyisobutylene and low molecular polyisobutylene.

In a more preferable scheme of the invention, the weight percentage of the agomelatine is 5-15%, the weight percentage of the adhesive matrix is 75-87%, the weight percentage of the penetration enhancer is 2-10%, and the weight percentage of the antioxidant is 0-2%; further preferably, the weight percentage of the agomelatine is 10-15%, the weight percentage of the adhesive is 75% -90%, the weight percentage of the penetration enhancer is 2-8%, and the weight percentage of the antioxidant is 1-2%, based on the total weight of the adhesive matrix layer.

In a more preferred embodiment of the present invention, when the adhesive matrix is selected from the group consisting of silicones and acrylics, it is further preferred that the agomelatine is present in an amount of 5-15% by weight, the adhesive is present in an amount of 85-95% by weight, and the penetration enhancer is present in an amount of 1-3% by weight, based on the total weight of the adhesive matrix.

In a more preferred embodiment of the present invention, agomelatine is contained in the adhesive matrix layer in a dissolved state.

The back lining layer of the patch used in the invention is used for supporting the adhesive matrix layer, has certain sealing property and flexibility, and can be selected from polypropylene, polyethylene, polyvinyl chloride, polyethylene terephthalate, composite aluminum foil, polyester and non-woven fabric composite PE film.

The protective layer material of the patch can be selected from polyethylene, polyethylene terephthalate, polypropylene, polystyrene, polycarbonate or fluorine-containing materials treated with paraffin or organic silicon release agent, such as silicon-treated polyethylene terephthalate, etc.

The patch of the invention can be cut into different specifications according to different clinical requirements, such as 45mm multiplied by 45mm, 55mm multiplied by 55mm, 65mm multiplied by 65mm and the like, and the content of the patch is different correspondingly due to different specifications of the patch, and the drug content of the patch is 5-15%, and is more preferably 8-12%.

The inventors of the present application have found, through extensive studies, that a patch prepared by including agomelatine in a pressure-sensitive adhesive layer at a supersaturated concentration shows: the ability to deliver therapeutically effective amounts of drug to the patient, release and easily control the drug, and release the form of the formulation is desirable, and has the necessary physical properties, such as adhesion and peel, and a simple method of preparation. In addition, the agomelatine patch of the invention is also excellent in safety.

Detailed Description

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

Example 1

The adhesive matrix layer formula comprises:

the preparation method comprises the following steps: stirring and dissolving DURO-TAK 387-2287, DURO-TAK 87-4098, isopropyl myristate, dimethylacetamide, lactic acid and ethyl acetate according to the prescription amount, adding agomelatine, stirring uniformly, uniformly coating the obtained medicine-containing ointment on a protective layer, drying to remove the solvent, attaching the medicine-containing ointment to a back lining layer serving as a preparation, and cutting into a set size and a set shape to obtain the external patch.

Example 2

The adhesive matrix layer formula comprises:

Example 3

The adhesive matrix layer formula comprises:

Example 4

The adhesive matrix layer formula comprises:

the preparation method comprises the following steps: mixing DURO-TAK 387-2516, DURO-TAK 87-2074, isopropyl myristate, dimethylacetamide and lactic acid according to the prescription dose, stirring and dissolving, adding agomelatine, stirring uniformly, uniformly coating the obtained medicine-containing ointment on a protective layer, drying to remove the solvent, attaching the medicine-containing ointment to a back lining layer, and cutting into a set size and a set shape to obtain the external patch.

Example 5

The adhesive matrix layer formula comprises:

the preparation method comprises the following steps: stirring and dissolving DURO-TAK 387-2287, DURO-TAK 87-4098, isopropyl myristate, polyethylene glycol 400 and lactic acid according to the prescription amount, adding agomelatine, stirring uniformly, uniformly coating the obtained medicine-containing ointment on a protective layer, drying to remove the solvent, attaching the medicine-containing ointment to a back lining layer serving as a preparation, and cutting into a set size and a set shape to obtain the external patch.

Example 6

The adhesive matrix layer formula comprises:

the preparation method comprises the following steps: stirring and dissolving DURO-TAK 387-2516, DURO-TAK 87-2074, isopropyl myristate, polyethylene glycol 400 and lactic acid according to the prescription amount, adding agomelatine, stirring uniformly, uniformly coating the obtained medicine-containing paste on the protective layer, drying to remove the solvent, attaching the medicine-containing paste to the backing layer, and cutting into a set size and a set shape to obtain the external patch.

Example 7

The adhesive matrix layer formula comprises:

the preparation method comprises the following steps: mixing DURO-TAK 387-2516, DURO-TAK 87-2074, d-limonene, lactic acid, Eudragit E100 and ethyl acetate according to the prescription dose, stirring and dissolving, adding agomelatine, uniformly stirring, uniformly coating the obtained medicine-containing paste on the protective layer, drying to remove the solvent, attaching the medicine-containing paste to the backing layer, and cutting into a set size and a set shape to obtain the external patch.

Example 8

The adhesive matrix layer formula comprises:

the preparation method comprises the following steps: mixing DURO-TAK 387-2516, DURO-TAK 87-2074, triglyceride, lactic acid, Eudragit E100 and ethyl acetate according to the prescription dose, stirring and dissolving, adding agomelatine, stirring uniformly, uniformly coating the obtained medicine-containing paste on the protective layer, drying to remove the solvent, bonding with the back lining layer, and cutting into the set size and shape to obtain the external patch of the invention.

Example 9

The adhesive matrix layer formula comprises:

the preparation method comprises the following steps: DURO-TAK 387-2516, DURO-TAK 87-2074, dimethylacetamide, lactic acid, Eudragit E100 and ethyl acetate are stirred and dissolved, agomelatine is added and stirred uniformly, the obtained medicine-containing paste is uniformly coated on the protective layer, the solvent is removed by drying, the medicine-containing paste is attached to the backing layer and then cut into a set size and shape, and the external patch of the invention can be obtained.

Example 10

The adhesive matrix layer formula comprises:

the preparation method comprises the following steps: mixing DURO-TAK 387-2516, DURO-TAK 87-2074, isopropyl myristate, lactic acid, Eudragit E100 and ethyl acetate according to the prescription dose, stirring and dissolving, adding agomelatine, stirring uniformly, uniformly coating the obtained medicine-containing paste on a protective layer, drying to remove the solvent, attaching the medicine-containing paste to a back lining layer, and cutting into a set size and a set shape to obtain the external patch.

Example 11

The adhesive matrix layer formula comprises:

the preparation method comprises the following steps: heating and dissolving SIS, alicyclic saturated hydrocarbon resin, hydrogenated rosin glyceride, partial liquid paraffin, polybutene, polyethylene glycol 6000 and dibutyl hydroxy toluene in the formula amount, and uniformly mixing; adding the rest liquid paraffin, isopropyl myristate and isostearic acid into the solution, and mixing uniformly; after the paste body is cooled, adding agomelatine with the prescription amount into the paste body, uniformly stirring, uniformly coating the obtained paste body containing the medicine on the protective layer, attaching the paste body containing the medicine to the back lining layer, and cutting the paste body into a set size and a set shape to obtain the external patch.

Example 12

Material(s)	Addition amount (g)	Percent (%)
			Agomelatine	12.5	5.0
SIS	46.75	18.7
			Alicyclic saturated hydrocarbon resin	67.5	27.0
Hydrogenated rosin glycerol ester	25.0	10.0
			Liquid paraffin	45.0	18.0
Low molecular weight polyisobutylene	25.0	10.0
			Myristic acid isopropyl ester	4.5	1.8
Polyethylene glycol 6000	11.25	4.5
			Isostearic acid	10.0	4.0
Dibutylhydroxytoluene	2.5	1.0
			Toluene (solvent, final removal)	120.0	——

The preparation method comprises the following steps: heating and dissolving SIS, alicyclic saturated hydrocarbon resin, hydrogenated rosin glyceride, toluene, liquid paraffin, polybutylene, polyethylene glycol 6000 and dibutyl hydroxy toluene according to the formula amount, and uniformly mixing; adding isopropyl myristate and isostearic acid into the solution, and uniformly mixing; after the paste body is cooled, adding agomelatine with the prescription amount into the paste body, uniformly stirring, uniformly coating the obtained paste body containing the medicine on the protective layer, drying to remove the solvent, attaching the paste body to the back lining layer, and cutting the back lining layer into a set size and a set shape to obtain the external patch.

Example 13

The preparation method comprises the following steps: heating and dissolving prescription amounts of SIS, hydrogenated rosin glyceride, liquid paraffin, high molecular weight polyisobutylene, low molecular weight polyisobutylene and dibutyl hydroxy toluene, and uniformly mixing; adding isopropyl myristate and isostearic acid into the solution, and uniformly mixing; after the paste body is cooled, adding agomelatine with the prescription amount into the paste body, uniformly stirring, uniformly coating the obtained paste body containing the medicine on the protective layer, attaching the paste body containing the medicine to the back lining layer, and cutting the paste body into a set size and a set shape to obtain the external patch.

Example 14

The preparation method comprises the following steps: stirring and dissolving the high molecular weight polyisobutylene, the low molecular weight polyisobutylene, the hydrogenated rosin glyceride, the cyclohexane and the isopropyl myristate; adding agomelatine, uniformly stirring, uniformly coating the obtained ointment-containing body on the protective layer, attaching the ointment-containing body to the back lining layer, and cutting the back lining layer into a set size and a set shape to obtain the external patch.

Example 15

Example 16

Material(s)	Addition amount (g)	Percent (%)
			Agomelatine	25	10.5
Dow Corning T4500	106.5	44.75
			Dow Corning T4200	106.5	44.75
Heptane (solvent, final removal)	32.5	——

The preparation method comprises the following steps: the patch of the present invention can be obtained by dissolving the prescribed amounts of Dow Corning T4500, Dow Corning T4200 and heptane with stirring, adding agomelatine, stirring uniformly, coating the resulting drug-containing paste uniformly on the protective layer, drying to remove the solvent, attaching to the backing layer, and cutting into a predetermined size and shape.

Example 17

Material(s)	Addition amount (g)	Percent (%)
			Agomelatine	12.5	5.0
Dow Corning T4500	118.75	47.5
			Dow Corning T4200	118.75	47.5
Heptane (solvent, final removal)	85	——

Example 18

The preparation method comprises the following steps: dow Corning T4200, DURO-TAK 87-2196 and heptane in the prescribed amounts are stirred and dissolved, isopropyl myristate and agomelatine are added and stirred uniformly, the obtained drug-containing ointment is uniformly coated on the protective layer, the solvent is removed by drying, the drug-containing ointment is attached to the back lining layer and then the drug-containing ointment is cut into a set size and a set shape, and the external patch of the invention is obtained.

Experimental example 1 determination of drug content

The patches with different drug concentrations were prepared, the devitrification on the patch surface was examined, and the effect of concentration on drug release was examined.

The results show that the adhesive patch of the present invention has no drug crystals precipitated on the surface thereof at drug contents of 6%, 8% and 10%, even if the drug is present in the adhesive layer in a supersaturated state and no crystals are precipitated.

TABLE 1 Effect of different drug concentrations on Release

And (4) conclusion: the higher the drug concentration of the transdermal patch, the faster the drug release. Under the content range of the agomelatine patch, the medicine in the agomelatine patch can be well released.

Experimental example 2 Effect of gel layer thickness on drug Release

Samples with the same concentration and different dry glue layer thicknesses are prepared, and the influence of the glue layer thickness on the drug release is inspected.

The result shows that under the same drug concentration, the drug release is gradually prolonged along with the increase of the thickness of the drug layer, and the effect of slow release is achieved.

Experimental example 3 Agomelatine external patch Release test and skin permeation test

Using the agomelatine external patches of example 3, example 4 and example 11, the following test methods were used to evaluate the release properties and skin permeability of the agomelatine external patches.

1) Method for release testing

According to 0931 of the fourth general rule of the four parts of the 'Chinese pharmacopoeia' 2015 edition, the fourth method of dissolution and release degree measurement, namely the paddle-disk method, 900mL of phosphate buffer solution with pH6.8 is used as a release medium, the rotating speed is 50 revolutions per minute, the transdermal patch is fixed on a net disk according to the method, the medicine-containing surface faces upwards, and the transdermal patch is kept as flat as possible. Then the mesh plate is horizontally placed at the lower part of the dissolution cup, the mesh plate is parallel to the rotating surface of the paddle bottom, the distance between the mesh plate and the rotating surface of the paddle bottom is 25mm +/-2 mm, and the device is started to sample 10ml at 0.5h, 1h, 2h, 4h, 6h and 8h respectively to be used as a test solution. And taking about 10mg of agomelatine as a reference substance, precisely weighing, putting into a 1000mL volumetric flask, adding a proper amount of release medium, shaking to completely dissolve, adding the release medium to a scale, and shaking uniformly to obtain a reference substance solution. Precisely measuring 20 μ L of each of the reference solution and the sample solution, respectively injecting into a liquid chromatograph, and recording chromatogram. The amount released at different times for each tablet was calculated.

2) Skin permeability test method

Treatment of skin of nude mice: two-week-old nude mice were sacrificed by cervical dislocation, skin was peeled off, subcutaneous fat was carefully removed, and the mice were refrigerated at-30 ℃ for future use. Before use, the mixture is thawed and washed with physiological saline.

The test method comprises the following steps: transdermal tests were carried out using a Franz transdermal diffusion cell with a water bath temperature of 32 ℃. Stirring speed 300rpm, transdermal area 1.76cm²The volume of the receiving pool is 7ml, and the receiving solution is 20% ethanol-physiological saline solution. The patches of the samples of examples 3, 4 and 11 were attached to the stratum corneum of the skin, the dermis of the skin was brought into close contact with the receptor medium, and the patches were fixed to a receiving cell, sampled at regular intervals of 5mL, and supplemented with blank receptor solution maintained at a constant temperature of 32 ℃. The samples were analyzed by high performance liquid chromatography.

The result shows that the agomelatine external patch prepared by the invention has stable release amount and good permeability.

Experimental example 4 skin irritation test

1. The test method comprises the following steps: 6 rabbits were divided into 2 groups on average, namely, an intact skin group and a damaged skin group, and the backs of the animals were depilated 24 hours before administration. The test (patch of example 1) and control (blank patch) were attached to 5 separate test and control areas (45 cm) on the back of the animal²) Applied 1 time daily for 7 consecutive days. The residues are removed by warm water and normal saline 24 hours after the last administration, the condition of erythema and edema of the application parts of the test objects 1, 24, 48 and 72 hours after the removal and the recovery condition and time of the change are observed, and the stimulation response scoring and the stimulation intensity evaluation are carried out on the experimental results of each animal according to the guiding principle of the preclinical study of the new medicine.

2. And (3) test results: the product has no irritation reaction in intact skin group and damaged skin group.

3. And (4) conclusion: the product is irritated by rabbit skin, and has no irritation.

Experimental example 5 stability test results

The patches of examples 1 to 7 were subjected to an accelerated condition test (60 ℃ C., RH 75%) and a stability test for two months of storage, and the residual drug amount was measured. The result shows that the agomelatine external patch has small loss of the drug content and no crystallization phenomenon by testing the drug content of the agomelatine through an accelerated condition by HPLC, has better stability and ensures that the drug administration of a patient is safer.

Claims

1. An agomelatine transdermal patch is characterized by comprising (a) a back lining layer, (b) an adhesive matrix layer and (c) a protective layer, wherein the adhesive matrix layer contains agomelatine and the adhesive matrix.

2. The agomelatine transdermal patch according to claim 1, wherein the adhesive matrix layer contains agomelatine in an amount of 1 to 15 wt%, preferably 5 to 15 wt%, more preferably 8 to 12 wt%, and still more preferably 10 to 12 wt%, based on the total weight of the adhesive matrix layer.

3. Agomelatine transdermal patch according to claim 1, characterized in that the adhesive matrix layer contains 75-95% by weight of adhesive matrix, preferably 80-90% by weight of adhesive matrix, based on the total weight of the adhesive matrix layer.

4. The agomelatine transdermal patch according to claim 1, characterized in that the adhesive matrix is a non-aqueous adhesive.

5. Agomelatine transdermal patch according to claim 1, characterized in that the adhesive matrix is selected from one or more of polyisobutylene, silicones, acrylics, polyurethanes, natural rubber, synthetic rubber, preferably one or more combinations of styrene-isoprene-styrene block copolymer, polyamide, polyurethane, polyisobutylene pressure sensitive adhesive, silicone pressure sensitive adhesive, acrylate pressure sensitive adhesive, hot melt pressure sensitive adhesive, more preferably acrylate pressure sensitive adhesive and/or styrene-isoprene-styrene block copolymer.

6. Agomelatine transdermal patch according to claim 1, characterized in that the thickness of the adhesive matrix layer is 10-150 μm, preferably 20-80 μm, more preferably 40-65 μm.

7. Agomelatine transdermal patch according to any of claims 1 to 6, characterized in that the adhesive matrix layer also comprises other pharmaceutically acceptable excipients selected from penetration enhancers, antioxidants, surfactants, fillers or flavoring agents, preferably, the sum of the weight percentages of the other pharmaceutically acceptable excipients is not more than 15% based on the total weight of the adhesive matrix layer.

8. The agomelatine transdermal patch according to claim 7, characterized in that the penetration enhancer is selected from one or more of sulfoxides, pyrrolidones, amides, fatty acids and esters thereof, surfactants, alcohols, polyols, terpenes, phospholipids, preferably one or more of propylene glycol, oleic acid, stearic acid, isostearic acid, lactic acid, lauric acid, polyethylene glycol, isopropyl myristate, isopropyl palmitate, decyl methyl sulfoxide, dimethylacetamide, triglycerides; more preferably, the content of the adhesive matrix layer is 0 to 15 wt%, further preferably 1 to 8 wt%, and further preferably 2 to 6 wt%, based on the total weight of the adhesive matrix layer.

9. The agomelatine transdermal patch according to claim 7, wherein the antioxidant is selected from one or more of dibutylhydroxytoluene, tert-butyl p-hydroxyanisole, propyl gallate, ascorbic acid and sodium metabisulfite; preferably, the content of the antioxidant is 0-2% by weight, more preferably 0.5-2% by weight, and further preferably 1-2% by weight, based on the total weight of the adhesive matrix layer.

10. The agomelatine transdermal patch according to claim 7, wherein the filler is one or more selected from the group consisting of silicon dioxide, titanium dioxide, metal stearate, calcium carbonate, povidone, and acrylic resin; preferably, the content of the adhesive matrix layer is 0-1% by weight based on the total weight of the adhesive matrix layer.

11. Agomelatine transdermal patch according to claim 5, characterized in that when the adhesive matrix is selected from the silicones, preferably silicone pressure sensitive adhesive, further preferably the agomelatine is present in an amount of 5-15% by weight and the adhesive is present in an amount of 85-95% by weight, based on the total weight of the adhesive matrix.

12. Agomelatine transdermal patch according to claim 7, characterized in that the adhesive matrix is selected from the group consisting of acrylic, preferably acrylate pressure-sensitive adhesives;

more preferably, the weight percentage of the agomelatine is 5-15%, the weight percentage of the adhesive matrix is 75% -90%, the weight percentage of the penetration enhancer is 2-10%, and the weight percentage of the antioxidant is 0-2%;

further preferably, the weight percentage of the agomelatine is 10-15%, the weight percentage of the adhesive matrix is 75-87%, the weight percentage of the penetration enhancer is 3-8%, and the weight percentage of the antioxidant is 0-2% based on the total weight of the adhesive matrix layer;

more preferably, the weight percentage of the agomelatine is 10-15%, the weight percentage of the acrylate pressure-sensitive adhesive is 75-85%, the weight percentage of the isopropyl myristate is 2-4%, the weight percentage of the polyethylene glycol is 0-2%, the weight percentage of the lactic acid is 1-3%, the weight percentage of the oleic acid is 1-2%, and the weight percentage of the dimethylacetamide is 1-2% based on the total weight of the adhesive matrix layer.

13. An agomelatine transdermal patch according to claim 12, characterized in that the acrylate pressure-sensitive adhesive is selected from the group consisting of 2-ethylhexyl acrylate-containing copolymers; preferably one or more of DURO-TAK 2287, DURO-TAK 4098, DURO-TAK 2510, DURO-TAK 2516, DURO-TAK 2074, DURO-TAK 2677; more preferably one or more of DURO-TAK 387-2287, DURO-TAK 87-4098, DURO-TAK 387-2516, DURO-TAK 87-2074, DURO-TAK 87-2677, DURO-TAK 387-2510 or DURO-TAK 87-2510; further preferably at least DURO-TAK 2287, optionally also DURO-TAK 4098, DURO-TAK 2510, DURO-TAK 2516, DURO-TAK 2074 and/or DURO-TAK 2677; further preferably at least DURO-TAK 4098, optionally also DURO-TAK 2287, DURO-TAK 2510, DURO-TAK 2516, DURO-TAK 2074 and/or DURO-TAK 2677; further preferably at least DURO-TAK 2516, optionally also DURO-TAK 2287, DURO-TAK 2510, DURO-TAK 4098, DURO-TAK 2074 and/or DURO-TAK 2677; further preferably at least DURO-TAK 2074, optionally also DURO-TAK 2287, DURO-TAK 2510, DURO-TAK 4098, DURO-TAK 2516 and/or DURO-TAK 2677; most preferred is the combination of DURO-TAK 2287 with DURO-TAK 4098 or the combination of DURO-TAK 2516 with DURO-TAK 2074.

14. An agomelatine transdermal patch according to claim 12, characterized in that the penetration enhancer is selected from isopropyl myristate, lactic acid, a two-component combination of isopropyl myristate and lactic acid, a two-component combination of triglyceride and lactic acid, a three-component combination of isopropyl myristate, lactic acid and dimethylacetamide, isopropyl myristate, a three-component combination of lactic acid and polyethylene glycol, isopropyl myristate, oleic acid, a four-component combination of lactic acid and dimethylacetamide or a five-component combination of isopropyl myristate, oleic acid, lactic acid, polyethylene glycol and dimethylacetamide.

15. The agomelatine transdermal patch according to claim 12, characterized in that the adhesive matrix layer of the patch comprises the following components in percentage by weight:

，

，

more preferably, the adhesive matrix layer of the patch comprises the following components in percentage by weight:

。

16. The agomelatine transdermal patch according to claim 7, wherein when the adhesive matrix is selected from synthetic rubbers, preferably styrene-isoprene-styrene block copolymers, and further comprising a tackifier and a softener together as an adhesive matrix, the content of the tackifier and the softener is 75 to 95% by weight, and more preferably 80 to 90% by weight, based on the total weight of the adhesive matrix.

17. The agomelatine transdermal patch according to claim 16, wherein the weight percentage of the synthetic rubber is 10 to 30%, the weight percentage of the tackifier is 30 to 65%, and the weight percentage of the softener is 10 to 30%, based on the weight of the adhesive matrix.

18. The agomelatine transdermal patch according to claim 17, characterized in that the emollient is selected from one or more of paraffin oil, silicone oil, higher fatty acid, vegetable oil, preferably one or more of liquid paraffin, white oil, naphthenic oil, squalane, squalene, silicone oil, vaseline or lanolin; more preferably liquid paraffin.

19. The agomelatine transdermal patch according to claim 17, wherein the tackifier is one or more selected from terpene resins, petroleum resins, hydrogenated rosin glycerides, alicyclic saturated hydrocarbon resins, high molecular polyisobutylene, and low molecular polyisobutylene; preferably one or more of hydrogenated rosin glyceride, alicyclic saturated hydrocarbon resin, high molecular polyisobutylene and low molecular polyisobutylene.

20. The agomelatine transdermal patch according to claim 17, wherein the weight percentage of agomelatine is 5-15%, the weight percentage of adhesive matrix is 75-90%, the weight percentage of penetration enhancer is 2-10%, and the weight percentage of antioxidant is 0-2%; further preferably, the weight percentage of the agomelatine is 10-15%, the weight percentage of the adhesive is 75% -87%, the weight percentage of the penetration enhancer is 2-8%, and the weight percentage of the antioxidant is 1-2%, based on the total weight of the adhesive matrix layer.

21. Agomelatine transdermal patch according to claim 7, characterized in that when the adhesive matrix is selected from the group consisting of silicones and acrylics, it is further preferred that the weight percentage of Agomelatine is 3-15%, the weight percentage of adhesive is 85% -95% and the penetration enhancer is 1-3% based on the total weight of the adhesive matrix layer.

22. The agomelatine transdermal patch according to claim 7, wherein when the adhesive matrix is selected from polyisobutylene, a tackifier selected from terpene resins, petroleum resins, hydrogenated rosin glycerides or alicyclic saturated hydrocarbon resins is further included as the adhesive matrix;

preferably, the weight percentage of the agomelatine is 3-15%, the weight percentage of the adhesive is 85% -95%, and the weight percentage of the penetration enhancer is 1-3% based on the total weight of the adhesive matrix layer.

23. The agomelatine transdermal patch according to claim 1, characterized in that the material of the backing layer is selected from polypropylene, polyethylene, polyvinyl chloride, polyethylene terephthalate, composite aluminum foil, polyester, non-woven composite PE film; the protective layer material is selected from polyethylene, polypropylene, polystyrene, polycarbonate or fluorine-containing material treated by paraffin or organic silicon release agent.

24. An agomelatine transdermal patch according to claim 1, characterized in that agomelatine is contained in the adhesive matrix layer in a dissolved state.

25. Use of an agomelatine transdermal patch according to any one of claims 1 to 24 for the preparation of a medicament for the treatment of psychiatric disorders, preferably depression, more preferably major depression.