Transdermal drug delivery system of polymer-based adhesive membrane preparation, preparation and application

Abstract

The invention relates to a transdermal drug delivery system of a polymer-based adhesive membrane preparation, the preparation and application. The transdermal drug delivery system of the polymer-based adhesive membrane preparation is prepared from the following components in percentage by mass: 0.1 to 70 percent of an ionic liquid-containing system and 30 to 99.9 percent of a polymer framework material. The transdermal drug delivery system can avoid the use of traditional plasticizers, and can endow the membrane preparation with good physical and mechanical properties.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical preparations, and particularly to a transdermal drug delivery system, a preparation and an application of a polymer-based adhesive film preparation. Background Art

[0002] A transdermal drug delivery preparation is a preparation in which an active drug acts through the skin, either locally on the skin or through skin absorption into the systemic blood circulation. In order to allow the active drug to adhere to the skin for a longer time to fully exert its efficacy and extend the action time, preparations with a phase transition and adhesiveness are usually used as the drug dosage form, such as a film preparation attached to the skin for local action, a transdermal patch / film attached to the skin for systemic action, etc. The composition of these adhesive film preparations usually includes an active ingredient, excipients, and a polymer-based skeleton carrier.

[0003] However, excipient components such as penetration enhancers, antioxidants, and bacteriostatic agents commonly used in the formulation of adhesive film preparations will seriously affect the physical and mechanical properties of the film preparation; for some preparations with high dosage requirements and a large amount of active ingredient added, it will also seriously affect the physical and mechanical properties of the film preparation; for some active ingredients or excipients that are oily substances, it will further weaken the strength and toughness of the adhesive film preparation, easily causing film rupture, adhesive film / patch wire drawing, cold flow, collapse, aging, etc., which not only affect the appearance of the preparation, but also affect the release and transdermal behavior of the active ingredient in the preparation. At the same time, it also affects the adhesive performance of the preparation, making it easy to cause shedding, black circles, etc. when applied to the skin.

[0004] To address the above physical and mechanical property problems of the adhesive film preparation, plasticizers are usually added for improvement. Currently, plasticizers are mostly small molecule esters, such as phthalic acid esters and other esters. Such plasticizers have potential carcinogenicity and are prone to migration or evaporation from the film material; at the same time, when applied to the skin, they are not only prone to adverse reactions such as skin allergy and itching, but also easily penetrate the skin and enter the blood. Research shows that long-term exposure to certain phthalic acid esters will have an inhibitory and paralytic effect on the human central nervous system, and may even damage organs such as reproduction, liver, and kidneys, seriously threatening human health.

[0005] Therefore, how to improve the physical and mechanical properties of the adhesive film preparation while avoiding the use of traditional plasticizers is an urgent problem to be solved. Summary of the Invention

[0006] Based on this, the present application provides a transdermal drug delivery system of a polymer-based adhesive film preparation that can avoid the use of traditional plasticizers and at the same time endow the film preparation with good physical and mechanical properties, a polymer-based adhesive film preparation containing the transdermal drug delivery system, and the applications of the two in the preparation of drugs for treating mental and emotional diseases.

[0007] In the first aspect of the present application, a transdermal drug delivery system of a polymer-based adhesive film preparation is provided, which comprises the following components by mass percentage:

[0008] System containing ionic liquid 0.1% - 70%, and

[0009] Polymer matrix material 30% - 99.9%.

[0010] In some embodiments, for the transdermal drug delivery system of the polymer-based adhesive film preparation, by mass percentage, the system containing ionic liquid in the transdermal drug delivery system is 0.1% - 30%; and / or

[0011] The polymer matrix material is 30% - 90%.

[0012] In some embodiments, by mass percentage, the system containing ionic liquid comprises the following components:

[0013] Ionic liquid 0.1% - 99.9%, and

[0014] Dispersant 0.1% - 99.9%;

[0015] Optionally, by mass percentage, the system containing ionic liquid comprises the following components:

[0016] Ionic liquid 2% - 80%, and

[0017] Dispersant 20% - 98%.

[0018] In some embodiments, the dispersant includes one or more of water, methanol, acetone, ethyl acetate, chloroform, isopropanol, ethanol, propylene glycol, glycerol, n-octanol, n-dodecanol, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dichloromethane (DCM), and tetrahydrofuran (THF).

[0019] In some embodiments, the ionic liquid includes a hydrogen bond acceptor anion and a hydrogen bond donor cation;

[0020] Optionally, the hydrogen bond acceptor anion includes one or more of betaine, choline, basic amino acids, imidazole or its derivatives, and pyridine or its derivatives; further optionally, the basic amino acids include one or more of lysine, arginine, and histidine;

[0021] Optionally, the hydrogen bond donor cation includes one or more of citric acid, geranic acid, maleic acid, tartaric acid, capric acid, phosphoric acid, boric acid, acetic acid, hydrochloric acid, and sulfonic acid.

[0022] In some of these embodiments, the ionic liquid includes one or more of betaine citrate, betaine geranate, betaine maleate, betaine decanoate, choline geranate, choline citrate, choline maleate, lysine citrate, arginine citrate, histidine citrate, 1-ethyl-3-methylimidazolium acetate, 1-butyl-3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium hexafluorophosphate, 1-ethylpyridinium hydrochloride, and 1-butylpyridinium trifluoromethanesulfonate.

[0023] In some of these embodiments, the polymer backbone material includes one or both of a gel backbone material and a pressure-sensitive adhesive;

[0024] Optionally, by weight parts, the gel backbone material includes:

[0025] 1 part of a gel material, and

[0026] 0 to 50 parts of an adhesive;

[0027] Further optionally, the gel material includes one or more of polyacrylate copolymers, povidone, and cellulose-based materials; even further optionally, the cellulose-based materials include one or more of methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and cellulose acetate;

[0028] Further optionally, the adhesive includes one or more of hydrophobic polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / acrylic ester copolymer, ethylene / vinyl acetate copolymer, polyisobutylene, butyl rubber, polyisoprene, polyacrylate, silicone copolymer, styrene-isoprene-styrene triblock copolymer, ethylene-butadiene-styrene triblock copolymer, hydrogenated styrene-butadiene-styrene block copolymer (hydrogenated SBS), and polyurethane;

[0029] Optionally, the pressure-sensitive adhesive includes one or more of polyacrylate pressure-sensitive adhesives, silicone pressure-sensitive adhesives, polyisoprene pressure-sensitive adhesives, and rubber pressure-sensitive adhesives.

[0030] In some of these embodiments, the transdermal drug delivery system of the polymer-based adhesive film preparation further includes one or more of a penetration enhancer, an antioxidant, and an antibacterial agent;

[0031] Optionally, the penetration enhancer includes one or more of terpenes, amines, phospholipids, laurocapram, poloxamer, sodium lauryl sulfate, fatty acids, and fatty acid esters;

[0032] Optionally, the antioxidant includes one or more of sulfites, vitamin C or its derivatives, sulfur compounds, amino acids, organic acids, phenols, amines, oil-soluble antioxidants, and chelating agents;

[0033] Optionally, the bacteriostatic agent includes one or more of phenol, cresol, parabens, phenoxyethanol, chlorobutanol, benzyl alcohol, and benzalkonium chloride.

[0034] In some embodiments, the transdermal drug delivery system of the polymer-based adhesive film preparation includes the following components by mass percentage:

[0035] Ionic liquid-containing system 0.1% - 30%,

[0036] Polymer matrix material 30% - 90%,

[0037] Penetration enhancer 0.05% - 30%,

[0038] Antioxidant 0.05% - 30%, and

[0039] Bacteriostatic agent 0% - 10%.

[0040] In a second aspect of the present application, there is provided a polymer-based adhesive film preparation, including the transdermal drug delivery system of the polymer-based adhesive film preparation described in the first aspect, and a drug active ingredient;

[0041] Optionally, the drug active ingredient includes an active ingredient for treating mental and emotional diseases.

[0042] In some embodiments, in the polymer-based adhesive film preparation, the mass percentage of the drug active ingredient is 0.1% - 95%;

[0043] Optionally, in the polymer-based adhesive film preparation, the mass percentage of the drug active ingredient is 0.1% - 60%.

[0044] In a third aspect of the present application, there is provided the use of the transdermal drug delivery system of the polymer-based adhesive film preparation described in the first aspect or the polymer-based adhesive film preparation described in the second aspect in the preparation of a drug for treating mental and emotional diseases.

[0045] In a fourth aspect of the present application, there is provided the use of an ionic liquid as a plasticizer, toughening agent, or tackifier in the preparation of a transdermal drug delivery film preparation.

[0046] In some embodiments, the transdermal drug delivery film is a polymer-based adhesive film preparation.

[0047] In some embodiments, the ionic liquid includes a hydrogen bond acceptor anion and a hydrogen bond donor cation;

[0048] Optionally, the hydrogen bond acceptor anion includes one or more of betaine, choline, basic amino acids, imidazole or its derivatives, and pyridine or its derivatives; Further optionally, the basic amino acids include one or more of lysine, arginine, and histidine;

[0049] Optionally, the hydrogen bond donor cation includes one or more of citric acid, geranic acid, maleic acid, tartaric acid, capric acid, phosphoric acid, boric acid, acetic acid, hydrochloric acid, and sulfonic acid;

[0050] Further optionally, the ionic liquid includes one or more of betaine citrate, betaine geranate, betaine maleate, betaine capric acid, choline geranate, choline citrate, choline maleate, lysine citrate, arginine citrate, histidine citrate, 1-ethyl-3-methylimidazolium acetate, 1-butyl-3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium hexafluorophosphate, 1-ethylpyridine hydrochloride, and 1-butylpyridine trifluoromethanesulfonate.

[0051] It has been found that introducing an ionic liquid on the basis of a polymer matrix material can achieve good toughening, plasticizing, and tackifying effects, enabling the transdermal drug delivery system of the obtained polymer-based adhesive film preparation to achieve excellent film plasticity, strength, and adhesion without using traditional plasticizers. Without limitation, the possible principle is as follows:

[0052] (1) In terms of plasticizing modification, it has been found that ionic liquids can improve the physical and mechanical properties of polymer-based adhesive film materials because: the ionic liquid increases the distance between polymer molecules; the interaction between the ionic liquid and the polar groups of the polymer weakens the intermolecular forces of the polymer; and the lubricating effect of the ionic liquid itself. These three factors together increase the plasticity of the polymer-based adhesive film materials;

[0053] (2) The introduction of ionic liquids can weaken the erosion of the adhesiveness of polymer matrix materials by excipients such as oily drugs and oily penetration enhancers, which leads to the destruction of the adhesion film strength and cohesion, thereby increasing the plasticity and strength of the polymer-based adhesive film materials;

[0054] (3) In terms of tackifying modification, it has been found that ionic liquids can enhance the adhesion function of polymer-based adhesive film materials. This is because the ionic liquids can migrate into the amorphous region of the polymer after encountering a dispersant such as water, and hydrogen bonds can be regenerated between the molecular chains of the film material, enhancing the intermolecular force, improving the film strength and adhesion, and effectively solving the drawback that the adhesion of traditional polymer skeleton materials suddenly decreases when exposed to water. Especially for long-acting preparations that need to be attached for 1 to 7 days, when the patient exercises frequently, sweats, takes a shower, etc., the adhesion of the adhesive film is likely to decrease when exposed to water, and the preparation may slip due to the traction of the body part. Due to the tackifying modification of the ionic liquid in this application, the adhesion performance of the preparation can be significantly improved, thus avoiding the occurrence of the above defects.

[0055] In addition, during the research process, it has been found that the transdermal drug delivery system of the polymer-based adhesive film preparation provided in this application also has the following advantages:

[0056] (1) It can inhibit drug crystallization. Especially for long-acting preparations, due to the large drug reservoir, it is easy to cause supersaturation, and the particles are prone to aggregation, accelerating drug crystallization, which affects the appearance and percutaneous absorption efficiency of the preparation. It has been found that ionic liquids can enter the spatial network structure of the polymer material, causing its originally entangled molecular long chains to unfold. The space and compartments inside the expanded network structure are more orderly, and the drugs that are prone to aggregation can enter the internal compartments in an orderly and regular manner, avoiding the random aggregation of drug particles, significantly reducing drug crystallization, and thus dispersing the drugs in the polymer skeleton system in an orderly and uniform manner to achieve stable drug release;

[0057] (2) It can increase the drug loading capacity. It has been found that ionic liquids can enter the spatial network structure of the polymer material, causing its originally entangled molecular long chains to unfold, significantly expanding its internal space, having a larger internal surface area, showing a great loading capacity, and being able to uniformly load the drugs into the spatial network structure. Therefore, the drug loading capacity is greatly increased;

[0058] (3) In terms of stability, it has been found that ionic liquids can improve the stability of polymer-based adhesive film materials. The good thermal stability of ionic liquids helps to improve the thermal stability of the polymer, enabling it to have a wider range of use temperatures and mechanical properties, thus effectively reducing the aging, denaturation, etc. of the polymer-based material, achieving the purpose of anti-thermal aging and increasing the drug stability;

[0059] (4) It can meet the requirements of local target organ treatment of the skin, ensure that the drug remains inside and outside the skin for a certain period of time, and maintain a stable drug release demand, so as to actively exert the drug effect; in some embodiments, it can continuously release and transdermally deliver the drug for more than 24 hours; in this drug delivery system, the drug is released into the human body through the skin to exert the drug effect, and at the same time, it can maintain a stable blood drug concentration, reduce the dosing frequency, increase the compliance and compliance of patients; at the same time, the transdermal route avoids the first-pass effect of the drug through oral administration via the gastrointestinal tract and the liver, has a higher bioavailability, has obvious advantages in medical applications, and the preparation has a fast transdermal absorption rate and a high transdermal absorption amount, and has the characteristics of stability and high efficiency. Detailed implementation manners

[0060] The following further describes in detail the transdermal drug delivery system, the preparation and the application of the polymer-based adhesive film preparation of the present application in combination with specific embodiments. The present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosed content of the present application more thorough and comprehensive.

[0061] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which this application belongs. The terms used in the description of this application herein are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0062] As used herein, "one or more" refers to any one, any two, or any two or more of the listed items.

[0063] In this application, "the first aspect", "the second aspect", "the third aspect", "the fourth aspect", etc. are only for descriptive purposes and should not be construed as indicating or implying relative importance or quantity, nor should they be construed as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "the first", "the second", "the third", "the fourth", etc. only serve the purpose of non-exhaustive listing and description and should be understood not to constitute a closed limitation on quantity.

[0064] In this application, among the technical features described in an open-ended manner, there are included closed technical solutions composed of the listed features, as well as open technical solutions including the listed features.

[0065] In this application, when it comes to numerical ranges, unless otherwise specified, the above numerical ranges are considered continuous and include the minimum and maximum values of the range, as well as each value between such minimum and maximum values. Further, when the range refers to an integer, it includes each integer between the minimum and maximum values of the range. In addition, when providing multiple ranges to describe features or characteristics, these ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0066] In this application, the percentage content involved, unless otherwise specified, refers to the mass percentage for solid-liquid mixing and solid-solid mixing, and refers to the volume percentage for liquid-liquid mixing.

[0067] In this application, the percentage concentration involved, unless otherwise specified, refers to the final concentration. The final concentration refers to the proportion of the added component in the system after adding the component.

[0068] In this application, the temperature parameter, unless otherwise specified, allows both isothermal treatment and treatment within a certain temperature range. The isothermal treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument.

[0069] The room temperature in this application generally refers to 4°C to 30°C, preferably 20 ± 5°C.

[0070] Due to the negative effects of traditional plasticizers, in recent years, the main challenges in industrial and academic research have been to develop new polymer-based materials with unique and adjustable properties, and ionic liquids (ILs) have emerged as a result. The applications of ionic liquids in life sciences mainly focus on the extraction and separation of plant components, etc., and the applications in polymer-based plasticizing modification mainly focus on daily chemical materials. The applications and research of ionic liquids in pharmaceutical preparations, especially in drug carriers, drug delivery, drug excipients, etc., are very few. There is no report yet on the application for improving the performance of preparations, especially for skin route drug delivery preparations, to overcome the defects of traditional polymer-based adhesive film preparations and meet the needs of clinical applications.

[0071] Some examples of this application provide a transdermal drug delivery system of a polymer-based adhesive film preparation, which, calculated by mass percentage, includes the following components:

[0072] The ionic liquid-containing system 0.1% - 70%, and

[0073] The polymer skeleton material 30% - 99.9%.

[0074] Specifically, the mass percentage of the ionic liquid-containing system includes but is not limited to: 0.1%, 0.5%, 1%, 3%, 8%, 10%, 12%, 15%, 16%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% or the range between any two of the foregoing.

[0075] Specifically, the mass percentage of the polymer skeleton material includes but is not limited to: 30%, 35%, 40%, 45%, 50%, 53.5%, 55.4%, 57%, 57.4%, 57.8%, 58.8%, 59.6%, 60%, 60.5%, 61.5%, 62.5%, 66.2%, 70%, 75%, 80%, 82%, 90%, 95%, 99.9% or the range between any two of the foregoing.

[0076] Further, in the transdermal drug delivery system of the polymer-based adhesive film preparation, based on mass percentage, the system containing ionic liquid in the transdermal drug delivery system is 0.1% - 30%.

[0077] Further, in the transdermal drug delivery system of the polymer-based adhesive film preparation, based on mass percentage, the polymer skeleton material is 30% - 90%.

[0078] In some of the examples, in the system containing ionic liquid, the mass percentage of the ionic liquid is 0.1% - 99.9%. Specifically, the mass percentage of the ionic liquid includes but is not limited to: 0.1%, 2%, 6%, 7%, 10%, 12%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 58%, 60%, 65%, 70%, 78%, 80%, 85%, 90%, 95%, 99.9% or the range between any two of the foregoing.

[0079] In some of the examples, based on mass percentage, the system containing ionic liquid includes the following components:

[0080] Ionic liquid 0.1% - 99.9%, and

[0081] Dispersant 0.1% - 99.9%.

[0082] Specifically, the mass percentage of the dispersant includes but is not limited to: 0.1%, 1%, 5%, 10%, 15%, 20%, 22%, 30%, 35%, 42%, 46%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 93%, 94%, 98%, 99.9% or the range between any two of the foregoing.

[0083] In some of the examples, based on mass percentage, the system containing ionic liquid includes the following components:

[0084] Ionic liquid 2% - 80%, and

[0085] Dispersant 20% - 98%.

[0086] In some of these examples, the dispersant includes one or more of water, methanol, acetone, ethyl acetate, chloroform, isopropanol, ethanol, propylene glycol, glycerol, n-octanol, n-dodecanol, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dichloromethane (DCM), and tetrahydrofuran (THF). By using a suitable type of dispersant, it is beneficial to enhance the stability of the ionic liquid and achieve better toughening, plasticizing, and viscosity-increasing effects. Further, the dispersant includes one or more of water, methanol, ethanol, propylene glycol, glycerol, polyethylene glycol 200, polyethylene glycol 400, dimethyl sulfoxide, and dimethylformamide.

[0087] It can be understood that the ionic liquid includes a hydrogen bond acceptor anion and a hydrogen bond donor cation. Further, by using a suitable type of ionic liquid, it is more beneficial to improve the physical and mechanical properties and adhesion properties of the polymer-based adhesive film material.

[0088] In some of these examples, the hydrogen bond acceptor anion includes one or more of betaine, choline, basic amino acids, imidazole or its derivatives, and pyridine or its derivatives. Without limitation, the basic amino acids may include one or more of lysine, arginine, and histidine. Without limitation, the derivatives of imidazole or its derivatives and pyridine or its derivatives may refer to alkyl substitution on the imidazole or pyridine ring, such as C1-C10 alkyl.

[0089] Further, compared with imidazole or its derivatives and pyridine or its derivatives, betaine, choline, and basic amino acids have lower cytotoxicity, so better biocompatibility and safety can be achieved. Therefore, in some of these examples, the hydrogen bond acceptor anion includes one or more of betaine, choline, and basic amino acids.

[0090] In some of these examples, the hydrogen bond donor cation includes one or more of citric acid, geranic acid, maleic acid, tartaric acid, capric acid, phosphoric acid, boric acid, acetic acid, hydrochloric acid, and sulfonic acid.

[0091] In some of these examples, the ionic liquid includes one or more of betaine citrate, betaine geranate, betaine maleate, betaine caprate, choline geranate, choline citrate, choline maleate, lysine citrate, arginine citrate, histidine citrate, 1-ethyl-3-methylimidazolium acetate, 1-butyl-3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium hexafluorophosphate, 1-ethylpyridinium hydrochloride, and 1-butylpyridinium trifluoromethanesulfonate.

[0092] Further, the ionic liquid includes one or more of betaine citric acid, betaine geranic acid, betaine maleic acid, betaine decanoic acid, choline geranic acid, choline citric acid, choline maleic acid, lysine citric acid, arginine citric acid, and histidine citric acid. In this way, better biocompatibility and safety can be achieved.

[0093] In some examples, the polymer backbone material includes one or both of a gel backbone material and a pressure-sensitive adhesive;

[0094] In some examples, by weight, the gel backbone material includes:

[0095] 1 part of a gel material, and

[0096] 0 to 50 parts of an adhesive;

[0097] Specifically, the weight parts of the adhesive include, but are not limited to: 0 parts, 1 part, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, or the range between any two of the foregoing.

[0098] Without limitation, the gel material includes one or more of polyacrylate copolymers, povidone, and cellulose-based materials. Optionally, the cellulose-based materials include one or more of methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and cellulose acetate. Among them, the polyacrylate copolymer can include cationic or anionic copolymers obtained by polymerizing dimethylaminoethyl methacrylate, methacrylic acid, and methacrylate in different proportions; the cellulose-based materials include hydroxypropyl cellulose and / or ethylcellulose.

[0099] Without limitation, the adhesive includes one or more of hydrophobic polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / acrylic ester copolymer, ethylene / vinyl acetate copolymer, polyisobutylene, butyl rubber, polyacrylate, ethylene-butadiene-styrene triblock copolymer, hydrogenated styrene-butadiene-styrene block copolymer (hydrogenated SBS), and polyurethane. Further, the adhesive includes polyacrylate and / or silicone copolymer.

[0100] In some of these examples, the pressure-sensitive adhesive includes one or more of polyacrylate pressure-sensitive adhesives, silicone pressure-sensitive adhesives, polyisoprene pressure-sensitive adhesives, and rubber pressure-sensitive adhesives. Without limitation, examples of the pressure-sensitive adhesive may include, but are not limited to, polyacrylate pressure-sensitive adhesive 4098, polyacrylate pressure-sensitive adhesive 2287, polyacrylate pressure-sensitive adhesive 2051, silicone pressure-sensitive adhesive 4202, polyisoprene pressure-sensitive adhesive, polyacrylate pressure-sensitive adhesive 2054, polyacrylate pressure-sensitive adhesive 2852, polyacrylate pressure-sensitive adhesive 2510, silicone pressure-sensitive adhesive 4302, rubber pressure-sensitive adhesive 202A, polyacrylate pressure-sensitive adhesive 4098, and the like.

[0101] Without limitation, the transdermal drug delivery system of the polymer-based adhesive film preparation further includes one or more of a penetration enhancer, an antioxidant, and an antibacterial agent.

[0102] In some of these examples, the penetration enhancer includes one or more of terpenes, amines, phospholipids, azone, poloxamer, sodium lauryl sulfate, fatty acids, and fatty acid esters. By way of example, the terpenes include one or more of eucalyptol, limonene, and nerolidol; the amines include one or more of urea, dodecyl-N, and dimethylaminoethyl ester; the phospholipids include one or more of lecithin, soya lecithin, and phosphatidylglycerol; the fatty acids include one or more of oleic acid and lauric acid; and the fatty acid esters include one or more of lauryl lactate (LA), isopropyl myristate (IPM), propylene glycol dinonanoate, and diethyl sebacate.

[0103] Further, the penetration enhancer includes one or more of isopropyl myristate (IPM), azone, lauryl lactate (LA), and glyceryl acetate.

[0104] In some of these examples, the antioxidant includes one or more of sulfites, vitamin C or its derivatives, sulfur compounds, amino acids, organic acids, phenols, amines, oil-soluble antioxidants, and chelating agents. By way of example, the sulfites include one or more of sodium bisulfite, sodium sulfite, sodium metabisulfite, sodium thiosulfate, and sodium hyposulfite; the vitamin C or its derivatives include one or more of vitamin C and D-isoascorbic acid; the sulfur compounds include one or more of thiopropanetriol, thiourea, thioethylene glycol, dimercaptopropanol, thioacetic acid, and thiosalicylic acid; the amino acids include one or more of L-cysteine hydrochloride, L-methionine, L-lysine, L-arginine, L-valine, L-leucine, L-tryptophan, and L-glutathione; the organic acids include one or more of fumaric acid, maleic acid, tartaric acid, and pyrogallic acid; the phenols include one or more of hydroquinone, p-aminophenol, and 8-hydroxyquinoline; the amines include pyridoxamine hydrochloride; and the oil-soluble antioxidants include one or more of ascorbyl palmitate, tert-butylhydroxyanisole, ditert-butylhydroxytoluene, propyl gallate, and vitamin E.

[0105] Further, the antioxidant includes one or more of sodium bisulfite, sodium sulfite, sodium metabisulfite, vitamin E, ascorbyl palmitate, tert-butylhydroxyanisole, vitamin C, and D-isoascorbic acid.

[0106] In some of these examples, the bacteriostatic agent includes one or more of phenol, cresol, parabens, phenoxyethanol, chlorobutanol, benzyl alcohol, and benzalkonium chloride. By way of example, the parabens include one or more of methyl paraben, ethyl paraben, and propyl paraben.

[0107] Further, the bacteriostatic agent includes one or more of parabens, phenoxyethanol, and benzalkonium chloride.

[0108] In some of these examples, the transdermal drug delivery system of the polymer-based adhesive film preparation includes the following components by mass percentage:

[0109]

[0110] Specifically, the mass percentage of the penetration enhancer includes, but is not limited to: 0.05%, 0.5%, 1%, 2%, 4%, 5%, 8%, 14%, 15%, 17%, 20%, 23%, 25%, 27%, 30%, or the range between any two of the foregoing.

[0111] Specifically, the mass percentage of the antioxidant includes but is not limited to: 0.05%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 1%, 1.5%, 3%, 5%, 10%, 15%, 20%, 25%, 30%, or the range between any two of the foregoing.

[0112] Specifically, the mass percentage of the bacteriostatic agent includes but is not limited to: 0%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or the range between any two of the foregoing.

[0113] Some other examples of the present application provide a polymer-based adhesive film preparation, including a transdermal drug delivery system of the polymer-based adhesive film preparation as described above, and a pharmaceutically active ingredient. Without limitation, the pharmaceutically active ingredient includes an active ingredient for treating mental and emotional diseases, such as donepezil, asenapine, rivastigmine, memantine, agomelatine, rotigotine, fluoxetine, selegiline, risperidone, or their free bases or salt forms. In some of these examples, the pharmaceutically active ingredient includes one or more of rivastigmine, agomelatine, asenapine, rotigotine, and donepezil.

[0114] Tests have proven that the transdermal drug delivery system of the polymer-based adhesive film preparation of the present application can increase the drug loading of the preparation. Especially for treating mental and emotional diseases, it is usually necessary to load the drug amount for 1 to 7 days to design a long-acting preparation to achieve better patient compliance.

[0115] In some of these examples, in the polymer-based adhesive film preparation, the mass percentage of the pharmaceutically active ingredient is 0.1% - 95%. Specifically, in the polymer-based adhesive film preparation, the mass percentage of the pharmaceutically active ingredient includes but is not limited to: 0.1%, 1%, 5%, 8%, 10%, 12%, 15%, 16%, 18%, 20%, 22%, 25%, 28%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 95%, or the range between any two of the foregoing. Further, in the polymer-based adhesive film preparation, the mass percentage of the pharmaceutically active ingredient is 0.1% - 60%. Still further, in the polymer-based adhesive film preparation, the mass percentage of the pharmaceutically active ingredient is 0.1% - 30%.

[0116] The above-mentioned polymer-based adhesive film preparation can be prepared by traditional methods, for example, a closed-type or open-type preparation can be obtained.

[0117] In some of these examples, the preparation method of the polymer-based adhesive film preparation is as follows:

[0118] (1) Dissolve or disperse the ionic liquid in a dispersant, and ultrasonically dissolve or disperse for 0.5 to 1 hour, or dissolve or disperse in a water bath at 50°C to 60°C for 0.5 to 1 hour to obtain A;

[0119] (2) Dissolve or disperse the drug active ingredient in a solvent to obtain the drug system B;

[0120] (3) Add a penetration enhancer, an antioxidant, and an antibacterial agent to the polymer matrix material, and stir at a speed of 2000 to 10000 rpm for 0.5 to 2 hours to obtain C;

[0121] (4) Add the product C of step (3) to the product B of step (2), stir at a speed of 500 to 1000 rpm for 10 to 30 min, then add the product A of step (1), and stir at a speed of 500 to 1000 rpm for 10 to 30 min to obtain D, and then the polymer-based adhesive film preparation with ionic liquid as an adjuvant can be obtained.

[0122] Without limitation, the solvent in step (2) can be one or more of ethanol, methanol, DMSO, NMP, ether, ethyl acetate, PEG200, PEG400, propylene glycol, and glycerol.

[0123] Furthermore, the product D of step (4) can be applied to the skin, and the spreading area is 1 to 50 cm 2 , and it can quickly form a film, which is an open-type polymer-based adhesive film preparation plastically modified by an ionic liquid.

[0124] Furthermore, the product D of step (4) can be coated on a release liner, the coating thickness is 0.1 to 5.0 mm, dried at 60 to 80°C for 0.5 to 2 hours, and then covered with a backing layer to obtain a closed-type polymer-based adhesive film preparation plastically modified by an ionic liquid.

[0125] Without limitation, the release liner can be a fluorine-treated polyester film or a silicone-treated polyester film.

[0126] Without limitation, the backing layer can be a polyester-polyethylene composite film, a polypropylene non-woven fabric, or a polyurethane film.

[0127] Without limitation, when using the polymer-based adhesive film preparation, it can be attached to the human skin, one patch each time, and the area of 1 to 50 cm 2 is appropriate.

[0128] Some other examples of the present application provide a transdermal drug delivery system of the polymer-based adhesive film preparation as described above or the application of the polymer-based adhesive film preparation as described above in the preparation of a drug for treating mental and emotional diseases.

[0129] Some other examples of the present application provide the use of ionic liquids as plasticizers, toughening agents or tackifiers in the preparation of transdermal drug delivery film preparations. Further, the transdermal drug delivery film is a polymer-based adhesive film preparation.

[0130] It can be understood that the ionic liquid scheme is the same as the ionic liquid in the aforementioned transdermal drug delivery system of the polymer-based adhesive film preparation, and will not be elaborated here.

[0131] For the experimental parameters not specified in the following specific examples, preference is given to the guidelines given in the present application document. It is also possible to refer to the experimental manuals in the art or other experimental methods known in the art, or to the experimental conditions recommended by the manufacturers.

[0132] The raw materials and reagents involved in the following specific examples can be obtained commercially, or can be prepared by those skilled in the art according to known means.

[0133] Examples 1 to 15 provide systems containing ionic liquids, and their compositions are shown in Table 1 below:

[0134] Table 1

[0135]

[0136]

[0137] Examples 16 to 30 provide polymer-based adhesive film preparations, and their compositions are shown in Table 2 below:

[0138] Table 2

[0139]

[0140]

[0141] Note: All polyacrylate pressure-sensitive adhesives are from Henkel and are polyacrylate copolymers prepared by polymerizing acrylate, acrylic acid and / or other functional monomers. Different models indicate different monomer compositions copolymerized with acrylate; all silicone pressure-sensitive adhesives are from Dow Corning. Specifically, silicone copolymers are obtained by crosslinking and curing silicone resin and polydimethylsiloxane elastomer. Different models indicate different types of silicone resin; polyisoprene pressure-sensitive adhesive is from Shanghai Modern Pharmaceutical Preparation Engineering Research Center Co., Ltd., and its main components include polyisoprene rubber; rubber pressure-sensitive adhesive is from Baling Petrochemical, and its main components include polyisoprene and styrene-isoprene-styrene triblock copolymer.

[0142] The preparation method of the above polymer-based adhesive film preparation is as follows:

[0143] (1) Dissolve or disperse the ionic liquid in a dispersant and sonicate for 1 hour to prepare a system A containing the ionic liquid;

[0144] (2) Dissolve the drug in glycerol to obtain drug system B;

[0145] (3) Add a penetration enhancer, an antioxidant, and an antibacterial agent to the polymer drug-loaded skeleton system, and stir at a speed of 5000 rpm for 1 hour to obtain C;

[0146] (4) Add the product C of step (3) to the drug system B of step (2), stir at a speed of 800 rpm for 20 min, and then add the ionic liquid-containing system A of step (1), and stir at a speed of 800 rpm for 2 min to obtain D, thus obtaining a polymer-based adhesive film preparation with an ionic liquid as an adjuvant.

[0147] Comparative Examples 1 to 15 are the same as Examples 16 to 30 respectively, and the main difference is that the addition amount of the ionic liquid is 0%, and the rest is the same as Examples 16 to 30.

[0148] Test Example:

[0149] Perform performance tests on the polymer-based adhesive film preparations of the examples and comparative examples:

[0150] (1) Drug loading and crystallinity test:

[0151] Through high-temperature and low-temperature cross tests to accelerate the promotion of drug crystallization, investigate the crystallization of the drug in the film preparations of Examples 16 to 30. The results are shown in Table 3-1. The drug in the prescription preparation has good stability, no crystal precipitation, the film has good elasticity and does not draw.

[0152] For the film preparations of Comparative Examples 1 to 15, since no ionic liquid was added, different degrees of liquid crystals and solid crystals appeared, and the rubber film showed drawing. The results are shown in Table 3-2.

[0153] Table 3-1. Investigation results of drug crystallization test for Examples 16 to 30

[0154]

[0155] Table 3-2. Investigation results of drug crystallization test for Comparative Examples 1 to 15

[0156]

[0157]

[0158] (2) Plasticization and toughening modification test:

[0159] The mechanical and mechanical properties of the film preparation are manifested as wear resistance and flexibility, and can be characterized by measuring the tensile strength and elongation at break of the film.

[0160] Tensile strength = F / A;

[0161] Elongation at break = (L s - L o ) / L o × 100%.

[0162] Wherein, F is the breaking load force / N, A is the cross-sectional area of the cut film / mm 2 ; L s and L o are the initial and breaking lengths of the film / mm. A high elongation at break and a low tensile strength indicate that the film is softer but not tough; a low elongation at break and a medium tensile strength indicate that the film is more brittle; a medium elongation at break and a high tensile strength indicate that the film is soft and tough.

[0163] It can be seen from the test that the film preparations of Examples 16 - 30 have good elasticity, do not draw filaments, are soft and tough, and have very excellent elongation performance. The results are shown in Table 4-1.

[0164] For the film preparations of Comparative Examples 1 - 15, due to the absence of ionic liquid addition, the elongation rate decreases, the elasticity of the film is poor, and it is easy to break. The results are shown in Table 4-2.

[0165] Table 4-1. Mechanical property tests of film plasticization and toughening for Examples 16 - 30

[0166] Example Tensile strength (MPa) Elongation at break (%) Example 16 5.64 800.0 Example 17 4.78 600.2 Example 18 3.29 560.8 Example 19 3.56 467.9 Example 20 4.03 631.0 Example 21 6.07 723.4 Example 22 4.33 520.6 Example 23 5.21 625.0 Example 24 3.96 400.7 Example 25 4.90 490.2 Example 26 5.11 550.0 Example 27 6.27 690.0 Example 28 3.89 500.1 Example 29 4.32 357.3 Example 30 4.01 470.8

[0167] Table 4-2. Mechanical property tests of film plasticization and toughening for Comparative Examples 1 - 15

[0168] Example Tensile strength (MPa) Elongation at break (%) Example 31 4.79 235.87 Example 32 3.89 156.97 Example 33 3.01 125.06 Example 34 3.10 115.40 Example 35 3.70 155.37 Example 36 5.10 185.11 Example 37 3.10 152.23 Example 38 4.14 165.77 Example 39 2.12 115.00 Example 40 3.24 125.53 Example 41 4.09 135.05 Example 42 5.35 255.02 Example 43 3.10 145.89 Example 44 3.13 135.77 Example 45 4.32 120.30

[0169] (3) Tackifying modification test:

[0170] For the investigation of adhesion performance, the larger the ball number adhered by the preparation, the better the initial tack performance; the results of the holding tack force test show that when the patch hangs a heavy object and adheres to the steel plate for a longer time, the holding tack force of the preparation is better.

[0171] The results show that the film preparations of Examples 16 - 30 can significantly improve the physical adhesion performance of the preparation and meet the need for long-term transdermal drug administration. The results are shown in Table 5-1.

[0172] For the preparations of Comparative Examples 1 - 15, due to the absence of ionic liquid addition, the cohesive force of the adhesive decreases and the holding tackiness drops. The results are shown in Table 5-2.

[0173] Table 5-1 Adhesion performance results of Examples 16 - 30

[0174] Example Initial tack Holding power (time for patch to adhere to steel plate) Example 16 Ball No. 18 72 hours 45 minutes 03 seconds Example 17 Ball No. 16 70 hours 55 minutes 20 seconds Example 18 Ball No. 17 75 hours 05 minutes 07 seconds Example 19 Ball No. 18 78 hours 10 minutes 03 seconds Example 20 Ball No. 20 72 hours 12 minutes 21 seconds Example 21 Ball No. 17 85 hours 01 minutes 05 seconds Example 22 Ball No. 15 68 hours 45 minutes 08 seconds Example 23 Ball No. 21 70 hours 14 minutes 56 seconds Example 24 Ball No. 19 77 hours 52 minutes 00 seconds Example 25 Ball No. 18 59 hours 23 minutes 27 seconds Example 26 Ball No. 17 85 hours 24 minutes 55 seconds Example 27 Ball No. 16 78 hours 01 minutes 04 seconds Example 28 Ball No. 6 48 hours 33 minutes 33 seconds Example 29 Ball No. 5 58 hours 41 minutes 08 seconds Example 30 Ball No. 5 52 hours 13 minutes 08 seconds

[0175] Table 5-2 Adhesion performance results of Comparative Examples 1 - 15

[0176]

[0177]

[0178] The above results show that the skin route drug delivery system of the polymer-based adhesive film preparation plasticized and modified by ionic liquids fully improves the physical and mechanical properties, enhances the stability, and improves the adhesion function of the polymer-based adhesive film material in aspects such as plasticization modification, toughening modification, viscosity increase modification, and mechanical modification. At the same time, it can also accommodate liquid and oily substances, increase the drug loading capacity, inhibit drug crystallization, and effectively improve or solve problems in traditional methods such as low drug loading capacity, easy precipitation of drugs to form crystals, which affects the transdermal absorption efficiency, the addition of liquid or oily substances (drugs, excipients, etc.) to the polymer-based adhesive film preparation system results in less than ideal adhesion performance, the viscosity of the system decreases when exposed to water, the system is prone to aging, and the drug stability is poor.

[0179] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope described in this specification.

[0180] The above-described embodiments only represent several implementation manners of the present application, which are convenient for understanding the technical solutions of the present application specifically and in detail, but should not be construed as limiting the scope of patent protection of the application. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present application, several modifications and improvements can be made, and these all belong to the protection scope of the present application. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning, or limited experiments based on the technical solutions provided in the present application are all within the protection scope of the appended claims of the present application. Therefore, the protection scope of the patent of the present application should be subject to the content of the appended claims, and the specification can be used to explain the content of the claims.

Claims

1. A transdermal drug delivery system of a polymer-based adhesive film preparation, characterized in that, Comprising the following components by mass percentage: The ionic liquid-containing system is 0.1% to 70%, and The polymer matrix material is 30% to 99.9%.

2. The transdermal drug delivery system of the polymer-based adhesive film preparation according to claim 1, characterized in that, By mass percentage, the ionic liquid-containing system in the transdermal drug delivery system is 0.1% to 30%; and / or The polymer matrix material is 30% to 90%.

3. The transdermal drug delivery system of the polymer-based adhesive film preparation according to claim 1, characterized in that, By mass percentage, the ionic liquid-containing system comprises the following components: Ionic liquid is 0.1% to 99.9%, and Dispersant is 0.1% to 99.9%; Optionally, by mass percentage, the ionic liquid-containing system comprises the following components: Ionic liquid is 2% to 80%, and Dispersant is 20% to 98%; Further optionally, the dispersant includes one or more of water, methanol, acetone, ethyl acetate, chloroform, isopropanol, ethanol, propylene glycol, glycerol, n-octanol, n-dodecanol, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, dimethyl sulfoxide, dimethylformamide, dichloromethane, and tetrahydrofuran.

4. The transdermal drug delivery system of the polymer-based adhesive film preparation according to any one of claims 1 to 3, characterized in that, The ionic liquid includes a hydrogen bond acceptor anion and a hydrogen bond donor cation; Optionally, the hydrogen bond acceptor anion includes one or more of betaine, choline, basic amino acids, imidazole or its derivatives, and pyridine or its derivatives; further optionally, the basic amino acids include one or more of lysine, arginine, and histidine; Optionally, the hydrogen bond donor cation includes one or more of citric acid, geranic acid, maleic acid, tartaric acid, capric acid, phosphoric acid, boric acid, acetic acid, hydrochloric acid, and sulfonic acid; Further optionally, the ionic liquid includes one or more of betaine citrate, betaine geranate, betaine maleate, betaine caprate, choline geranate, choline citrate, choline maleate, lysine citrate, arginine citrate, histidine citrate, 1-ethyl-3-methylimidazolium acetate, 1-butyl-3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium hexafluorophosphate, 1-ethylpyridinium hydrochloride, and 1-butylpyridinium trifluoromethanesulfonate.

5. The transdermal drug delivery system of the polymer-based adhesive film preparation according to any one of claims 1 to 3, characterized in that, The polymer matrix material includes one or two of a gel matrix material and a pressure-sensitive adhesive: Optionally, by weight, the gel matrix material includes: 1 part of a gel material, and 0 to 50 parts of an adhesive; Further optionally, the gel material includes one or more of polyacrylate copolymers, povidone, and cellulose-based materials; still further optionally, the cellulose-based materials include one or more of methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and cellulose acetate; Further optionally, the adhesive includes one or more of hydrophobic polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / acrylic ester copolymer, ethylene / vinyl acetate copolymer, polyisobutylene, butyl rubber, polyisoprene, polyacrylate, silicone copolymer, styrene-isoprene-styrene triblock copolymer, ethylene-butadiene-styrene triblock copolymer, hydrogenated styrene-butadiene-styrene block copolymer, and polyurethane. Optionally, the pressure-sensitive adhesive includes one or more of polyacrylic acid pressure-sensitive adhesives, silicone pressure-sensitive adhesives, polyisoprene pressure-sensitive adhesives, and rubber pressure-sensitive adhesives.

6. The transdermal drug delivery system of the polymer-based adhesive film preparation according to any one of claims 1 to 3, characterized in that, It also includes one or more of a penetration enhancer, an antioxidant, and an antibacterial agent; Optionally, the penetration enhancer includes one or more of terpenes, amines, phospholipids, laurocapram, poloxamer, sodium lauryl sulfate, fatty acids, and fatty acid esters; Optionally, the antioxidant includes one or more of sulfites, vitamin C or its derivatives, sulfur compounds, amino acids, organic acids, phenols, amines, oil-soluble antioxidants, and chelating agents; Optionally, the antibacterial agent includes one or more of phenol, cresol, parabens, phenoxyethanol, chlorobutanol, benzyl alcohol, and benzalkonium chloride.

7. The transdermal drug delivery system of the polymer-based adhesive film preparation according to claim 6, characterized in that, By mass percentage, it includes the following components:

8. A polymer-based adhesive film preparation, characterized in that, A transdermal drug delivery system including the polymer-based adhesive film preparation according to any one of claims 1 to 7, and a drug active ingredient; Optionally, the drug active ingredient includes an active ingredient for treating mental and emotional diseases; Optionally, in the polymer-based adhesive film preparation, the mass percentage of the drug active ingredient is 0.1% to 95%; Further optionally, in the polymer-based adhesive film preparation, the mass percentage of the drug active ingredient is 0.1% to 60%.

9. Use of the transdermal drug delivery system of the polymer-based adhesive film preparation according to any one of claims 1 to 7 or the polymer-based adhesive film preparation according to any one of claims 10 to 11 in the preparation of a drug for treating mental and emotional diseases.

10. Application of an ionic liquid as a plasticizer, toughening agent, or tackifier in the preparation of a transdermal drug delivery film preparation; Optionally, the transdermal drug delivery film is a polymer-based adhesive film preparation; Optionally, the ionic liquid includes a hydrogen bond acceptor anion and a hydrogen bond donor cation; Further optionally, the hydrogen bond acceptor anion includes one or more of betaine, choline, basic amino acids, imidazole or its derivatives, and pyridine or its derivatives; further optionally, the basic amino acids include one or more of lysine, arginine, and histidine; Further optionally, the hydrogen bond donor cation includes one or more of citric acid, geranic acid, maleic acid, tartaric acid, capric acid, phosphoric acid, boric acid, acetic acid, hydrochloric acid, and sulfonic acid; Even more optionally, the ionic liquid includes one or more of betaine citrate, betaine geranate, betaine maleate, betaine caprate, choline geranate, choline citrate, choline maleate, lysine citrate, arginine citrate, histidine citrate, 1-ethyl-3-methylimidazolium acetate, 1-butyl-3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium hexafluorophosphate, 1-ethylpyridinium hydrochloride, and 1-butylpyridinium trifluoromethanesulfonate.

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