CN117338754A - Transdermal drug delivery system of agomelatine and preparation method thereof - Google Patents

Transdermal drug delivery system of agomelatine and preparation method thereof Download PDF

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Publication number
CN117338754A
CN117338754A CN202311479310.1A CN202311479310A CN117338754A CN 117338754 A CN117338754 A CN 117338754A CN 202311479310 A CN202311479310 A CN 202311479310A CN 117338754 A CN117338754 A CN 117338754A
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agomelatine
transdermal
delivery system
duro
tak
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CN202311479310.1A
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Chinese (zh)
Inventor
岳洋
马丹丹
徐壁雄
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Xinwen Biomedical Technology Jiashan Co ltd
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Xinwen Biomedical Technology Jiashan Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Abstract

The invention discloses a transdermal drug delivery system of agomelatine and a preparation method thereof, wherein the system comprises a backing layer, a drug-containing basal layer and a release film anti-adhesive layer which are sequentially arranged from top to bottom; the drug-containing basal layer is a compound of various materials comprising agomelatine, a high polymer framework, a crystallization inhibitor, a transdermal enhancer and an antioxidant; solves the problem of liver toxicity risk in the prior art, can avoid the first pass clearance effect of liver, reduce the irritation of medicine to gastrointestinal tract, reduce toxic and side effects, reduce medicine dosage, improve the compliance of patients and the like through the transdermal administration form of agomelatine. Agomelatine is prepared into a transdermal patch, and the problem of low bioavailability of an oral tablet can be well solved without gastrointestinal damage and liver first pass effect, and the compliance of patients can be improved.

Description

Transdermal drug delivery system of agomelatine and preparation method thereof
Technical Field
The invention relates to the technical field of medicaments, in particular to a percutaneous administration system of agomelatine and a preparation method thereof.
Background
Agomelatine is an analogue of melatonin as an antidepressant for the treatment of major depressive and mood disorders in depression. Agomelatine is pharmacologically a melatonin MT 1 and MT2 receptor agonist and a 5-hydroxytryptamine 5-HT 2C receptor antagonist and increases dopamine and norepinephrine levels in brain regions involved in mood control. Agomelatine has significant benefits on other antidepressants such as paroxetine, venlafaxine and sternum, including: (1) reduced side effects; (2) improved sleep quality; (3) uninterrupted syndrome; and (4) is generally weight neutral. Oral dosage forms (tablets) of agomelatine have been approved in europe under the trade names Valdoxan, melier and thymaax. Each tablet contains 25mg of agomelatine, which is taken at bedtime at an initial dose of 1 tablet, which can be increased to 2 tablets (50 mg) as required. Oral agomelatine is well absorbed.
However, oral bioavailability is only 5% with large variation. The limited bioavailability is due to the heavy first liver metabolism, mainly cytochrome CYP1a2 of the P450 isoenzyme system, which results in conjugated metabolites of hydroxylated and demethylated agomelatine. The drug was conjugated to plasma proteins but rapidly eliminated with plasma half-life for 1-2 hours. Agomelatine oral tablet products produced a human plasma concentration-time Pharmacokinetic (PK) profile with a Cmax of about 6ng/ml, followed by a tm decrease of less than 2 hours. Because of this heavy first liver metabolism, the dose-related risk of hepatotoxicity of agomelatine has led to warning updates and monitoring guidance that agomelatine may also cause an increase in serum liver transferase, up to three times the upper limit of the normal range, up to 1% of individuals. Drugs that inhibit cytochrome CYP1A2 (e.g., fluvoxamine, estrogen, propranolol) can slow down the metabolism of agomelatine, resulting in increased and variable levels of agomelatine.
Disclosure of Invention
The invention provides a transdermal drug delivery system of agomelatine and a preparation method thereof, which solve the problem of liver toxicity risk in the prior art, and can avoid the first pass clearance effect of liver, reduce the irritation of drugs to gastrointestinal tracts, reduce toxic and side effects, reduce drug dosage, improve the compliance of patients and the like through the transdermal drug delivery mode of agomelatine in application. Agomelatine is prepared into a transdermal patch, and the problem of low bioavailability of an oral tablet can be well solved without gastrointestinal damage and liver first pass effect, and the compliance of patients can be improved.
In order to solve the technical problem, the invention provides the following technical scheme:
the transdermal drug delivery system of agomelatine comprises a backing layer, a drug-containing basal layer and a release film anti-adhesive layer which are sequentially arranged from top to bottom; the drug-containing basal layer comprises the following components in percentage by mass:
(1) 3% -10% of agomelatine;
(2) 50% -80% of high polymer framework;
(3) 1 to 10 percent of dimethyl sulfoxide and 1 to 20 percent of polyvinylpyrrolidone;
(4) 1% -10% of a transdermal enhancer;
(5) 0.1 to 5 percent of antioxidant. .
Preferably, the backing layer is selected from any one of polyethylene, polyvinyl acetate, polyurethane, aluminum plastic composite film, nylon or non-woven fabric.
Preferably, the release film anti-adhesive layer is a PET film with a surface subjected to siliconizing or fluoridation treatment.
Preferably, the antioxidant is selected from any one or more of vitamin C, vitamin E, sodium metabisulfite, and dibutyl hydroxy toluene.
Preferably, the high polymer skeleton is selected from any one or more of polyacrylate, polyisobutylene and silicone pressure sensitive adhesive.
Preferably, the polyacrylate is selected from one or more of Duro-TAK 2287, duro-TAK 4287, duro-TAK 2052, duro-TAK 9301, duro-TAK 4098, duro-TAK 2510, duro-TAK 2353, duro-TAK 2051 or Duro-TAK 2054; the polyisobutene is selected from one or more of BASF PIB B12, B50, N100, N150 or N200; the silicone pressure sensitive adhesive is selected from one or more of dakangnin 4302, 4301, 4202 or 4201
Preferably, the dermal penetration enhancer is selected from any one or more of tartaric acid, lactic acid, benzyl alcohol, lauric acid, lactic acid esters, isopropyl myristate, glycerol monooleate, levulinic acid, N-oleoyl sarcosine, N-lauroyl sarcosine, oleic acid, glycerol triacetate or propylene glycol.
Preferably, the antioxidant combination is selected from any one or more of vitamin C, vitamin E, sodium metabisulfite, and dibutyl hydroxy toluene.
Compared with the prior art, the invention has the following advantages:
according to the invention, a unique transdermal enhancer combination technology and a crystallization inhibition technology are adopted, and the agomelatine is efficiently and stably conveyed by the product within more than 24 hours. Meanwhile, the product has good stability, and keeps a stable state for 12 months under the acceleration condition of 40 ℃.
Drawings
The accompanying drawings, which are included to provide a further understanding of embodiments of the invention and are incorporated in and constitute a part of this application, illustrate embodiments of the invention. In the drawings:
FIG. 1 is a graph showing the results of the transmission test in example 1;
FIG. 2 is a graph showing the results of the transmission test in example 2;
FIG. 3 is a graph showing the results of the transmission test in example 3;
FIG. 4 is a graph showing the results of the transmission test in example 4;
FIG. 5 is a graph showing the results of the transmission test in example 5;
FIG. 6 is a schematic representation of the average drug time in example 5;
FIG. 7 is a schematic illustration of the oral results of example 5;
FIG. 8 is a schematic diagram of the patch result in example 5;
FIG. 9 is a graph showing the results of the transmission test in example 6;
FIG. 10 is a schematic diagram showing the crystallization case in example 6;
FIG. 11 is a graph showing the results of the transmission test in example 7;
FIG. 12 is a schematic diagram showing the crystallization condition in example 7.
Detailed Description
The present invention will be described in further detail with reference to the following examples, for the purpose of making the objects, technical solutions and advantages of the present invention more apparent, and the description thereof is merely illustrative of the present invention and not intended to be limiting.
Example 1
The drug-containing basal layer was prepared according to the following formulation in table 1:
TABLE 1
Sequentially weighing the agomelatine, the antioxidant, the permeation enhancer and the pressure-sensitive adhesive into a container, adding a solvent, using a stirring mode of rotating and shaking uniformly, coating the container onto a 3M backing film by using a coating scraper until the agomelatine, the antioxidant, the permeation enhancer and the pressure-sensitive adhesive are completely dissolved, and finally covering a PET release film and drying. The specific preparation parameters are shown in Table 2 below:
TABLE 2
The prepared drug delivery system is characterized by transdermal diffusion by adopting an in-vitro model, and the conditions of the in-vitro transdermal diffusion are shown in the following table 3:
TABLE 3 Table 3
Example 1 characterization of transdermal diffusion in vitro results are shown in fig. 1 and table 4 below.
The transdermal drug delivery system has the advantages that the transmission efficiency of the developed transdermal drug delivery system is greatly improved, the total transmission capacity of the transdermal drug delivery system can be improved by more than 70% about 24 hours, meanwhile, the stability is obviously improved, and no crystallization is separated out in 6 months.
TABLE 4 Table 4
Group of Crystallization for 0 day 6 month crystallization Phase separation
Group 1 Without any means for Needle-like precipitation Without any means for
Group 2 Without any means for Without any means for Without any means for
Example 2
The drug-containing basal layer was prepared according to the following formulation in table 5:
TABLE 5
The corresponding agomelatine, crystallization inhibitor and pressure-sensitive adhesive are weighed into a container in sequence, a solvent is added, a stirring mode of rotary shaking is adopted, after complete dissolution, a coating scraper is adopted to coat the container onto a 3M backing film, and finally, a PET release film is covered and dried. The process parameters and transdermal diffusion conditions were set as in example 1.
Example 2 in-vitro transdermal diffusion test results using a combination of crystallization inhibitors of PVP and DMSO in a polyacrylate backbone of Duro-Tak 2052 are shown in fig. 2 and table 6 below. When the two groups of samples were left to stand at 40℃for 1 month, a small amount of lumpy crystallization was observed in group 2 and no lumpy crystallization was observed in group 1. The transdermal drug delivery system can obviously improve the stability of the transdermal drug delivery system and reduce the occurrence of crystallization on the premise of not affecting the permeation efficiency.
TABLE 6
Example 3
The drug-containing basal layer was prepared according to the following formulation in table 7:
TABLE 7
Sequentially weighing the agomelatine, the transdermal enhancer and the pressure-sensitive adhesive into a container, adding a solvent, using a stirring mode of rotating and shaking uniformly, coating the container onto a 3M backing film by using a coating scraper until the agomelatine, the transdermal enhancer and the pressure-sensitive adhesive are completely dissolved, and finally covering a PET release film and drying. The process parameters were the same as in example 1.
Example 3 the results of the in vitro transdermal diffusion test are shown in figure 3 below. It can be seen that in the polyisobutylene pressure sensitive adhesive system, different permeation promoters have different improvement on the permeation efficiency of the transdermal drug delivery system, and the total permeation capacity can be improved by more than 200% about 24 hours of maximum effect. The most preferred permeation enhancers are glycerol monooleate and oleic acid.
Example 4
The drug-containing basal layer was prepared according to the following formulation in table 8:
TABLE 8
Sequentially weighing the agomelatine, the antioxidant, the penetration enhancer and the pressure-sensitive adhesive into a container, adding a solvent, stirring in a rotary shaking mode, coating by using a coating scraper, and drying. The process parameters were the same as in example 1.
Example 4 the results of the in vitro transdermal diffusion test are shown in figure 4 below. It can be seen that the transdermal drug delivery system developed in the silicone pressure-sensitive adhesive system has greatly improved permeation efficiency.
Example 5
The medicated substrate layer was prepared according to the following Table 9 formulation
TABLE 9
Sequentially weighing the agomelatine, the antioxidant, the permeation enhancer and the pressure-sensitive adhesive into a container, adding a solvent, using a stirring mode of rotating and shaking uniformly, coating the container onto a 3M backing film by using a coating scraper until the agomelatine, the antioxidant, the permeation enhancer and the pressure-sensitive adhesive are completely dissolved, and finally covering a PET release film and drying. The process parameters were the same as in example 1.
Example 5 the results of the in vitro transdermal diffusion test are shown in figure 5 below. The PK experiments with animals dosed in vivo were performed on pigs of bar Ma Xiaoxiang, 3 animals per group, one patch per animal, and blood concentration was measured after dosing for comparison study. The experimental results are shown in FIG. 6 below. From fig. 5 and 6, the in vivo PK experiment results were consistent with the in vitro permeation experiment.
This example demonstrates that group 2, as a developed transdermal agomelatine diffusion system, has a significant effect of increasing the permeation rate in vivo and in vitro.
Group 2 and oral animals were compared and animals were selected from the group of pigs Ma Xiaoxiang, three. For the patch set, each piglet was patch-coated and agomelatine concentration in the blood was measured over 24 h. The specification of the prepared patch is 1.2mg/5cm per tablet 2 。
As shown in fig. 6 and 7, in vivo experiments of piglets prove that compared with oral preparations, the total transdermal administration dosage is consistent with oral administration within 24 hours, but the administration is very stable, and the administration efficiency and stability are greatly improved.
Example 6
The medicated substrate layer was prepared according to the following Table 11 formulation
TABLE 11
Sequentially weighing the agomelatine, the transdermal enhancer and the pressure-sensitive adhesive into a container, adding a solvent, using a stirring mode of rotating and shaking uniformly, coating the container onto a 3M backing film by using a coating scraper until the agomelatine, the transdermal enhancer and the pressure-sensitive adhesive are completely dissolved, and finally covering a PET release film and drying. The process parameters were the same as in example 1.
Example 6 the results of the in vitro transdermal diffusion test are shown in figure 9 below. The samples were placed in a constant temperature and humidity cabinet and stored at 40 ℃ for 6 months, and the crystallization observations were as follows in table 12:
table 12
Group of Crystallization for 0 day 6 month crystallization Phase separation
Group 1 Without any means for Needle-like precipitation Has the following components
Group 2 Without any means for Precipitation of fine powder Without any means for
Group 3 Without any means for Precipitation of fine powder Without any means for
Group 4 Without any means for Without any means for Without any means for
Group 5 Without any means for Without any means for Without any means for
It can be seen that the stability of the transdermal drug delivery system is greatly improved in the combination of DMSO and PVP, and the transdermal drug delivery system can still be kept stable under the acceleration condition of 40 ℃ for 6 months, and the results of the typical crystallization condition group 1 are shown in figure 10.
Example 7
The medicated substrate layer was prepared according to the following Table 13 formulation
TABLE 13
Group of Agomelatine A PIB/B12/N100 PVP DMSO
Group 1 5％ 85％ 0％ 10％
Group 2 5％ 75％ 10％ 10％
Group 3 5％ 65％ 20％ 10％
Sequentially weighing the agomelatine, the transdermal enhancer and the pressure-sensitive adhesive into a container, adding a solvent, using a stirring mode of rotating and shaking uniformly, coating the container onto a 3M backing film by using a coating scraper until the agomelatine, the transdermal enhancer and the pressure-sensitive adhesive are completely dissolved, and finally covering a PET release film and drying. The process parameters were the same as in example 1.
Example 7 in vitro model transdermal diffusion characterization results are shown in figure 11. The samples were placed in a constant temperature and humidity cabinet and stored at 40 ℃ for 6 months, and the crystallization observations were as shown in table 14 below:
TABLE 14
It can be seen that in the combination of DMSO and PVP, PVP plays a critical role in crystallization inhibition, and the stability of the transdermal delivery system is greatly improved, and remains stable under acceleration conditions of 40 ℃ for 6 months, as shown in fig. 12 for group 1 of typical crystallization conditions.
The foregoing description of the embodiments has been provided for the purpose of illustrating the general principles of the invention, and is not meant to limit the scope of the invention, but to limit the invention to the particular embodiments, and any modifications, equivalents, improvements, etc. that fall within the spirit and principles of the invention are intended to be included within the scope of the invention.

Claims (8)

1. The transdermal drug delivery system of agomelatine is characterized by comprising a backing layer, a drug-containing basal layer and a release film anti-adhesive layer which are sequentially arranged from top to bottom; the drug-containing basal layer comprises the following components in percentage by mass:
(1) 3% -10% of agomelatine;
(2) 50% -80% of high polymer framework;
(3) 1 to 10 percent of dimethyl sulfoxide and 1 to 20 percent of polyvinylpyrrolidone;
(4) 1% -10% of a transdermal enhancer;
(5) 0.1 to 5 percent of antioxidant.
2. The transdermal drug delivery system of agomelatine according to claim 1, wherein the backing layer is selected from any one of polyethylene, polyvinyl acetate, polyurethane, aluminum plastic composite film, nylon or nonwoven fabric.
3. Transdermal drug delivery system of agomelatine according to claim 1, characterised in that the release film anti-adhesive layer is a surface siliconized or fluorinated PET film.
4. Transdermal agomelatine delivery system according to claim 1, characterised in that the antioxidant is selected from any one or more of vitamin C, vitamin E, sodium metabisulphite, dibutyl hydroxytoluene.
5. Transdermal agomelatine delivery system according to claim 1, characterised in that the polymeric backbone is chosen from any one or more of polyacrylate, polyisobutylene, silicone pressure sensitive adhesive.
6. The transdermal drug delivery system of agomelatine according to claim 1, wherein the polyacrylate is selected from one or more of Duro-TAK 2287, duro-TAK 4287, duro-TAK 2052, duro-TAK 9301, duro-TAK 4098, duro-TAK 2510, duro-TAK 2353, duro-TAK 2051 or Duro-TAK 2054; the polyisobutene is selected from one or more of BASF PIB B12, B50, N100, N150 or N200; the silicone pressure sensitive adhesive is selected from one or more of the dakangnin 4302, 4301, 4202 or 4201.
7. The transdermal drug delivery system of agomelatine according to claim 1, wherein the transdermal enhancer is selected from any one or more of tartaric acid, lactic acid, benzyl alcohol, lauric acid, lactic acid ester, isopropyl myristate, glycerol monooleate, levulinic acid, N-oleoyl sarcosine, N-lauroyl sarcosine, oleic acid, glycerol triacetate or propylene glycol.
8. Transdermal agomelatine delivery system according to claim 1, characterised in that said antioxidant combination is selected from any one or more of vitamin C, vitamin E, sodium metabisulphite, dibutyl hydroxytoluene.
CN202311479310.1A 2023-11-08 2023-11-08 Transdermal drug delivery system of agomelatine and preparation method thereof Pending CN117338754A (en)

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