Transdermal absorption preparation

Abstract

The invention discloses a percutaneous absorption preparation which comprises a release film, a medicine storage layer and a backing layer, the medicine storage layer at least comprises an active ingredient, a penetration enhancer and a pressure-sensitive adhesive; the active ingredients are tandospirone and pharmaceutically acceptable salts thereof. According to the invention, the specific active components are matched with the combined penetration enhancer, so that the permeation amount per unit area can be effectively increased, the problem of crystallization of the active components in the patch can be solved, the preparation process is simple, and the quality is stable and reliable; the medicine storage layer is in a semi-solid gel shape with good transdermal absorption, active ingredients are completely dissolved and dispersed in the medicine storage layer, the preparation process is simple, the preparation quality is stable and reliable, the limitation of medicine taking times and time is reduced through local external administration treatment, and a new administration approach is provided.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a percutaneous absorption preparation and application thereof. Background Art

[0002] Anxiety disorder is an emotional disorder characterized by anxiety, including generalized anxiety disorder, panic disorder, etc. Among them, generalized anxiety disorder is the most common and seriously affects the patient's quality of life and social function.

[0003] Tandospirone citrate is a 5-HT1A receptor agonist that can bind to the 5-HT1A receptor with high selectivity to exert an anti-anxiety effect. It is mainly metabolized by CYP3A4 and partially metabolized by CYP2D6, and has low bioavailability. The current marketed dosage forms of tandospirone are tablets and capsules, with specifications of 5mg or 10mg. The recommended oral dose is 30mg / d, three times a day, and the number of medications is large. However, in clinical practice, tandospirone often needs to be taken for a long time, and patient compliance is poor.

[0004] Transdermal drug delivery system is a drug delivery route that delivers drugs through the skin surface to achieve local or systemic therapeutic effects. Modern transdermal drug delivery systems generally refer to patches. Patches can be absorbed through the skin and into the systemic circulation through capillaries. They can avoid the first-pass effect of the liver and the interference of gastrointestinal factors, maintain a constant blood drug concentration for a long time, avoid peak and valley phenomena, are easy to administer, and patients can take the drugs themselves. They have become the third largest drug delivery method after oral and injection.

[0005] Patent document CN112494465A discloses a transdermal patch of tandospirone citrate and a preparation method thereof. The transdermal patch comprises a drug storage layer, a backing layer and an anti-adhesive layer, wherein the drug storage layer is composed of tandospirone citrate, a penetration enhancer and a pressure-sensitive adhesive matrix; the weight percentage content of tandospirone citrate in the drug storage layer is 1% to 3%; the weight percentage content of the penetration enhancer in the drug storage layer is 2% to 4%, the penetration enhancer is monolaurin, lauric acid and laurocapram in a weight ratio of 1:0.5 to 1.5:0.1 to 0.2, and the pressure-sensitive adhesive matrix is ​​a polyisobutylene pressure-sensitive adhesive matrix; in this scheme, the API content of the drug storage layer is low, and the cumulative permeation amount still needs to be further improved. Summary of the invention

[0006] In view of the deficiencies of the prior art, the object of the present invention is to provide a percutaneous absorption preparation and application, so that tandospirone can continuously and effectively penetrate the skin and be rapidly absorbed to achieve better therapeutic effects, thereby improving the bioavailability of the drug, reducing the number of daily dosing to once, avoiding excessive fluctuations in blood drug concentrations, and improving the safety, effectiveness and compliance of medication.

[0007] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0008] According to a first embodiment of the present invention, a percutaneous absorption preparation is provided.

[0009] A percutaneous absorption preparation comprises a release film, a drug storage layer and a backing layer.

[0010] Preferably, the drug storage layer contains at least active ingredients, a penetration enhancer and a pressure-sensitive adhesive. The drug storage layer can maintain good drug release for a long time, which is beneficial to the long-term administration of antianxiety drugs.

[0011] Preferably, the active ingredient is tandospirone and a pharmaceutically acceptable salt thereof.

[0012] Preferably, the pharmaceutically acceptable salts include tandospirone hydrochloride, tandospirone sulfate, tandospirone hydrobromide, tandospirone hydroiodide, tandospirone nitrate, tandospirone hydrogen sulfate, tandospirone phosphate, tandospirone acid phosphate, tandospirone citrate, tandospirone acetate, tandospirone oxalate, tandospirone isonicotinate, tandospirone lactate, tandospirone salicylate, tandospirone citrate, tandospirone tartaric acid, tandospirone oleate, tandospirone tannic acid, tandospirone pantothenate, tandospirone hydrogen tartrate , tandospirone ascorbate, tandospirone succinate, tandospirone maleate, tandospirone gentisate, tandospirone fumarate, tandospirone gluconate, tandospirone glucuronide, tandospirone formate, tandospirone benzoate, tandospirone glutamate, tandospirone mesylate, tandospirone ethanesulfonate, tandospirone benzenesulfonate, tandospirone p-toluenesulfonate, tandospirone tetrafluoroborate, tandospirone trifluoroacetate, tandospirone hexafluorophosphate, tandospirone monomethyl sulfate, tandospirone acetate or tandospirone docusate, etc.

[0013] Preferably, the penetration enhancer is selected from sulfoxides: such as DMSO, dimethyl sulfoxide, deoxymethyl sulfoxide, pyrrochromene: 2-pyrrochromene, 5-methyl-2-pyrrochromene, 1,5-dimethyl-2-pyrrochromene, azone and its analogs: laurocapram, fatty acids and fats: oleic acid, isopropyl myristate, propylene glycol dipelargonate, isooctyl salicylate, isotridecyl myristate, ethyl laurate, octyl palmitate, alcohols: propylene glycol, isopropanol, ethanol, glycerol, isobutanol, n-octanol, etc., ionic liquid penetration enhancer: a combination of choline and acid (acids include organic acids, amino acids, geranic acid, oleic acid, citric acid, phenylalanine, taurine, etc.), etc. In the ionic liquid penetration enhancer of the present invention, the ionic liquid generally refers to a salt with a melting point below 100°C, which is composed of certain anions and cations.

[0014] Preferably, the penetration enhancer is selected from at least one of DMSO, dimethyl sulfoxide, dew methyl sulfoxide, 2-pyrrochromene, 5-methyl-2-pyrrochromene, 1,5-dimethyl-2-pyrrochromene, laurocaprol, fatty acid, oleic acid, isopropyl myristate (IPM), propylene glycol dipelargonate, isooctyl salicylate, isotridecyl myristate, ethyl laurate, octyl palmitate, propylene glycol (PG), isopropanol, ethanol, glycerol, isobutanol, n-octanol, choline, choline geranic acid (CAGE), choline oleic acid ([Cho][Ole]), and choline citric acid. Preferably, the penetration enhancer is selected from at least one of isopropyl myristate, choline geranic acid, choline oleic acid, propylene glycol, a combination of isopropyl myristate and choline oleic acid, a combination of isopropyl myristate and propylene glycol, and a combination of propylene glycol and choline oleic acid. Among them, the mass ratio of isopropyl myristate and choline oleic acid in the combination is 1-9:1-9, for example, 1:1, 1:2, 2:1, 1:3, 3:1, etc.; the mass ratio of isopropyl myristate and propylene glycol in the combination is 1-9:1-9, for example, 1:1, 1:2, 2:1, 1:3, 3:1, etc.; the mass ratio of propylene glycol and choline oleic acid in the combination is 1-9:1-9, for example, 1:1, 1:2, 2:1, 1:3, 3:1, etc.

[0015] Preferably, the pressure-sensitive adhesive can be selected from but not limited to one of polyacrylate pressure-sensitive adhesive, silicone pressure-sensitive adhesive, hot-melt pressure-sensitive adhesive and hydrogel pressure-sensitive adhesive, preferably, the following types of pressure-sensitive adhesive: DURO-TAK 387-2516, DURO-TAK 87-235A, DURO-TAK 387-2353, DURO-TAK 387-2287, DURO-TAK 387-2852, DURO-TAK 387-2051, DURO-TAK 387-2052, DURO-TAK 387-2054, DURO-TAK 87-4287, DURO-TAK87-6908, DURO-TAK 87-2677, Duro-Tak 87-900A, Duro-Tak 87-9301, Gelva GMS 3083, Gelva GMS 3253, Duro-TAK 87-4098, Duro-TAK 87-2516, Duro-TAK 87-2052 or SRS7-4502 etc.The monomer of acrylic pressure-sensitive adhesive comprises acrylate, for example comprises unsubstituted acrylate, methyl substituted acrylate.Specifically, the monomer that can be used for preparing the acrylic pressure-sensitive adhesive without functional group comprises methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, pentyl acrylate, hexyl acrylate, heptyl acrylate, octyl acrylate, nonyl acrylate, decyl acrylate, lauryl acrylate, myristyl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate, pentyl methacrylate, hexyl methacrylate, heptyl methacrylate, octyl methacrylate, nonyl methacrylate, decyl methacrylate, lauryl methacrylate, myristyl methacrylate etc.

[0016] Preferably, in the drug storage layer, by weight percentage, the active ingredient is 1-40wt%, the penetration enhancer is 1-40wt% and the pressure-sensitive adhesive is 30-95wt%. Further, the active ingredient is 5-30wt%, the penetration enhancer is 1-25wt% and the pressure-sensitive adhesive is 50-90wt%.

[0017] Preferably, the active ingredient is 1wt%, 2wt%, 3wt%, 4wt%, 5wt%, 6wt%, 7wt%, 8wt%, 9wt%, 10wt%, 11wt%, 12wt%, 12.5wt%, 13wt%, 14wt%, 15wt%, 18wt%, 20wt%, 21wt%, 22wt%, 23wt%, 24wt%, 25wt%, 26wt%, 27wt%, 28wt%, 29wt%, 30wt%, 31wt%, 32wt%, 33wt%, 34wt%, 35wt%, 36wt%, 37wt%, 38wt%, 39wt% or 40wt%. More preferably, it is 1-15%, 2-15% or 5-35wt%.

[0018] Preferably, the penetration enhancer is 1wt%, 2wt%, 3wt%, 4wt%, 5wt%, 6wt%, 7wt%, 8wt%, 9wt%, 10wt%, 11wt%, 12wt%, 12.5wt%, 13wt%, 14wt%, 15wt%, 18wt%, 20wt%, 21wt%, 22wt%, 23wt%, 24wt%, 25wt%, 26wt%, 27wt%, 28wt%, 29wt% or 30wt%. More preferably, it is 5-25wt%.

[0019] Preferably, the pressure-sensitive adhesive is 50wt%, 55wt%, 60wt%, 65wt%, 68wt%, 70wt%, 70.5wt%, 73wt%, 75wt%, 78wt%, 80wt%, 85wt%, 90wt% or 95wt%, more preferably 70-85wt% or 60-80wt%.

[0020] Preferably, the drug storage layer at least comprises:

[0021] Active ingredient: tandospirone; penetration enhancer: at least one selected from isopropyl myristate, choline geranic acid, choline oleic acid, propylene glycol, a combination of isopropyl myristate and choline oleic acid, a combination of isopropyl myristate and propylene glycol, and a combination of propylene glycol and choline oleic acid; pressure-sensitive adhesive: polyacrylate pressure-sensitive adhesive Duro-TAK 87-4098.

[0022] Preferably, the drug storage layer at least comprises:

[0023] 5 to 15 wt% active ingredient, wherein the active ingredient is tandospirone;

[0024] 10-25wt% penetration enhancer, wherein the penetration enhancer is selected from at least one of isopropyl myristate, choline geranic acid, choline oleic acid, propylene glycol, a combination of isopropyl myristate and choline oleic acid, a combination of isopropyl myristate and propylene glycol, and a combination of propylene glycol and choline oleic acid;

[0025] 68-80wt% pressure-sensitive adhesive: polyacrylate pressure-sensitive adhesive Duro-TAK 87-4098.

[0026] Preferably, the drug storage layer at least comprises:

[0027] 10wt% active ingredient, wherein the active ingredient is tandospirone;

[0028] 15wt% penetration enhancer, wherein the penetration enhancer is selected from at least one of isopropyl myristate, a combination of isopropyl myristate and choline oleic acid, a combination of isopropyl myristate and propylene glycol, and a combination of propylene glycol and choline oleic acid;

[0029] 75wt% pressure-sensitive adhesive: polyacrylate pressure-sensitive adhesive Duro-TAK 87-4098.

[0030] Preferably, the drug storage layer at least comprises:

[0031] Active ingredient: docusate tandospirone salt; penetration enhancer: at least one selected from isopropyl myristate, choline geranic acid, choline oleic acid, propylene glycol, a combination of isopropyl myristate and choline oleic acid, a combination of isopropyl myristate and propylene glycol, and a combination of propylene glycol and choline oleic acid; pressure-sensitive adhesive: polyacrylate pressure-sensitive adhesive Duro-TAK 87-4098.

[0032] Preferably, the drug storage layer at least comprises:

[0033] 10-30wt% active ingredient, wherein the active ingredient is docusate tandospirone salt;

[0034] 1-15wt% penetration enhancer, wherein the penetration enhancer is selected from at least one of isopropyl myristate, choline geranic acid, choline oleic acid, propylene glycol, a combination of isopropyl myristate and choline oleic acid, a combination of isopropyl myristate and propylene glycol, and a combination of propylene glycol and choline oleic acid;

[0035] 60-80wt% pressure-sensitive adhesive: polyacrylate pressure-sensitive adhesive Duro-TAK 87-4098.

[0036] Preferably, the drug storage layer at least comprises:

[0037] 20-25wt% active ingredient, wherein the active ingredient is docusate tandospirone salt;

[0038] 10-15wt% penetration enhancer, wherein the penetration enhancer is selected from at least one of isopropyl myristate, choline geranic acid, choline oleic acid, propylene glycol, a combination of isopropyl myristate and choline oleic acid, a combination of isopropyl myristate and propylene glycol, and a combination of propylene glycol and choline oleic acid;

[0039] 60-80wt% pressure-sensitive adhesive: polyacrylate pressure-sensitive adhesive Duro-TAK 87-4098.

[0040] Preferably, the mass ratio of isopropyl myristate and choline oleic acid in the combination is 1-3:1-3, for example, 1:1, 1:2, 2:1, 1:3, 3:1, etc.

[0041] Preferably, the mass ratio of isopropyl myristate and propylene glycol in the combination is 1-3:1-3, for example, 1:1, 1:2, 2:1, 1:3, 3:1, etc.

[0042] Preferably, the mass ratio of propylene glycol and choline oleic acid in the combination is 1-3:1-3, for example, 1:1, 1:2, 2:1, 1:3, 3:1, etc.

[0043] Preferably, the backing layer is a woven or nonwoven breathable film selected from paper, fabric, nonwoven fabric (e.g., polyester (e.g., polyethylene terephthalate (PET) etc.) nonwoven fabric, etc.), film (e.g., polyester, nylon, Saran, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, cellulose nitrate, polyvinyl chloride, ethylene-ethyl acrylate copolymer, polytetrafluoroethylene, metal foil, polyethylene terephthalate etc. single layer film, and laminated film obtained by laminating one or more of the above films, etc.), etc. It can be selected from, but not limited to, one or more of aluminum-polyester film, polyester-polyethylene composite film, polyethylene-aluminum-polyester / ethylene-vinyl acetate composite film, multilayer polyester film and polyester-ethylene-vinyl acetate composite film.

[0044] Preferably, the release film comprises a substrate and a release agent, wherein the substrate can be a composite film of one or more materials selected from polypropylene film, polyethylene film, polystyrene film, polyester film and silicon paper, and the release agent can be silicone oil, which can easily separate the release film from the drug-carrying layer during use. The release agent can be selected from, but not limited to, one or more selected from siliconized polyester film, fluoropolymer-coated polyester film, aluminum foil-silicone grease composite, siliconized aluminum foil and silicon paper.

[0045] According to one embodiment of the present invention, a method for preparing a percutaneous absorption preparation is provided, wherein the specific steps are: after the active ingredient, the penetration enhancer and the pressure-sensitive adhesive are uniformly mixed with the organic solvent in proportion, the mixture is coated on a release film, and after drying, a backing layer is laminated to obtain the percutaneous absorption preparation. Furthermore, the drying temperature is 60 to 70° C. Furthermore, the organic solvent is ethyl acetate, ethanol, propylene glycol, methanol, etc.

[0046] According to one embodiment of the present invention, there is provided a use of a percutaneous absorption preparation: the percutaneous absorption preparation is used to prepare a pharmaceutical preparation for treating anxiety.

[0047] Compared with the prior art, the beneficial technical effects of the present invention are as follows:

[0048] 1: The present invention selects specific raw materials and prepares a percutaneous absorption preparation in a specific ratio. The percutaneous absorption preparation uses a penetration enhancer to dissolve the active ingredient, and a pressure-sensitive adhesive to disperse the active ingredient, so that the active ingredient can be uniformly distributed in the colloid and can evenly penetrate the skin, greatly improving the absorption rate of the active ingredient through the skin, thereby significantly promoting absorption and improving the bioavailability of the drug.

[0049] 2: The present invention adopts specific active ingredients in combination with a penetration enhancer, which can effectively increase the permeation per unit area and solve the problem of crystallization of active components in the patch. The manufacturing process is simple and the quality is stable and reliable. The drug storage layer is a semi-solid colloid with good transdermal absorption, and the active ingredients are completely dissolved and dispersed in the drug storage layer. The manufacturing process is simple, the preparation quality is stable and reliable, and local external administration treatment reduces the number of medication times and time restrictions, providing a new route of administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 This is the in vitro release diagram for screening pressure-sensitive adhesives.

[0051]

[0052]

[0053] The linear equation and R obtained based on the average release process 2 The in vitro release rates were obtained.

[0054] Figure 2 It is a graph of prescription screening and changes in cumulative permeability per unit area.

[0055] Figure 3 It is the in vitro release diagram of the comparative example. DETAILED DESCRIPTION

[0056] The technical solution of the present invention is illustrated below by way of example, and the scope of protection requested by the present invention includes but is not limited to the following embodiments.

[0057] The English abbreviations used correspond to the full Chinese names:

[0058] IPM-Isopropyl myristate; CAGE-Choline geranate / Choline geranate / [Choline][Geranic acid]; [Cho][Ole]-Choline oleate / Choline oleate / [Choline][Oleic acid]; PG-Propylene glycol

[0059] Synthesis of [Choline][Oleic Acid] Ionic Liquid: Weigh an appropriate amount of oleic acid into a conical flask, add an appropriate amount of anhydrous ethanol to dissolve, then add choline hydroxide aqueous solution, choline: oleic acid = 1:2 (molar ratio), and stir overnight. Add anhydrous Na2SO4 to remove water, filter, and remove ethyl acetate by rotary evaporation. Dry under vacuum at 60℃ for 48h to obtain. (For the specific preparation process, please refer to the literature: LiwenMu, Yijun Shi, Tuo Ji, Long Chen, Ruixia Yuan, Huaiyuan Wang, and Jiahua Zhu. IonicGrease Lubricants: Protic[Triethanolamine][Oleic Acid] and Aprotic[Choline][Oleic Acid]. ACS Applied Materials&Interfaces 2016, 8(7), 4977-4984.)

[0060] Choline Oleate: 1 H NMR (400MHz, DMSO) δ5.40–5.23(m,4H),3.87(d,J=3.9Hz,2H),3.49–3.44(m,2H),3.16(s,9H) ,2.10–1.91(m,12H),1.50–1.40(m,4H),1.28(d,J=19.9Hz,40H),0.87(dd,J=8.1,4.9Hz,6H).

[0061] Synthesis of docusate tandospirone salt: Weigh tandospirone into a conical flask, add ethyl acetate to dissolve, then add water, ethyl acetate: water (volume ratio of about 3:1) = 21 ml: 7 ml solvent to dissolve, add equimolar dilute hydrochloric acid dropwise, then add equimolar amount of docusate sodium, stir at 450 rpm overnight. Wash the water layer twice with ethyl acetate, collect the ethyl acetate layer, and wash it once with purified water. Take the ethyl acetate layer, add anhydrous sodium sulfate to remove water, filter, and remove ethyl acetate by rotary evaporation. Dry under vacuum at 60°C for 48 hours.

[0062] Tandospirone docusate: 1H NMR (400MHz, CDCl3) δ8.30(d,J=4.7Hz,2H),6.58(t,J=4.7Hz,1H),4.10(dt,J=14.2,7 .1Hz,2H),4.02–3.89(m,4H),3.46(t,J=6.5Hz,2H),3.11(qd,J=17.2,9.2Hz,7H),2.6 3(s,4H),1.85–1.73(m,2H),1.62(d,J=6.5Hz,4H),1.59–1.45(m,2H),1.34(ddd,J=22 .9,14.4,7.2Hz,7H),1.28–1.14(m,16H),1.01(d,J=11.0Hz,1H),0.89–0.79(m,12H).

[0063] Synthesis of choline geranyl acid (CAGE) ionic liquid: Weigh geranyl acid into a round-bottom flask, then add choline hydroxide solution, the molar ratio of geranyl acid to choline = 2:1. Add a magnetic stirrer and stir overnight, and remove ethyl acetate by rotary evaporation. Dry under vacuum at 60°C for 48 hours. (For the specific preparation process, please refer to the literature: Tanner EEL, Curreri AM, Balkaran JPR, et al. Design Principles of Ionic Liquids for Transdermal Drug Delivery [J]. Adv Mater, 2019, 1901103)

[0064] Test 1: Preparation of percutaneous absorption preparations

[0065] After the active ingredient, penetration enhancer and pressure-sensitive adhesive are uniformly mixed with an organic solvent according to a weight ratio, they are coated on a release film, dried at 60-70°C, and then laminated with a backing layer to obtain a transdermal absorption preparation. The mixing process, coating process, lamination, etc. can all be conventionally set, and the coating process can be: install the release film and the backing layer on a coating machine, set the oven drying temperature to 60-70 degrees, adjust the coating speed to 0.1-1m / s, the coating thickness to 180-240μm, the pump speed to 0.5-4%, and then start the coating machine for coating.

[0066] Test 2: Screening of pressure-sensitive adhesives

[0067] Step 1) Preparation of patch: A patch was prepared by combining pressure-sensitive adhesive (95% by mass) + tandospirone (5% by mass) in the manner of Experiment 1. The drug release performance and drug loading of different pressure-sensitive adhesives (models as recorded in Table 1) were compared to screen the pressure-sensitive adhesive. Patches containing different pressure-sensitive adhesives (without penetration enhancer) were prepared, and the best pressure-sensitive adhesive was selected by comprehensive consideration of in vitro release experiments and appearance shape.

[0068] Step 2) In vitro release experiment: Use a Franz diffusion cell, temperature 32°C, stirring speed 600 rpm, pH 7.4 phosphate buffer as medium. Take the tandospirone patch prepared in step 1) and cut it into 1.766 cm 2 After that, the samples were attached to nitrocellulose membranes for experiments. Samples were taken at 60, 120, 240, 360, and 480 minutes, and the high performance liquid chromatography was used to draw a curve and calculate the in vitro release rate per unit time.

[0069] In vitro release calculation method: Transmittance calculation method:

[0070] Where Qt is the cumulative release per unit area (μg / cm 2 ), Cn is the drug concentration of the nth sampling (μg / ml); V is the volume of the receiving solution (ml); Vn is the sampling volume (ml); A is the effective drug diffusion area (cm 2 ); Rt is the cumulative release rate per unit area (%); M0 is the drug content per unit area of ​​the patch (μg / cm 2 ). Regardless of whether the drug is in a dissolved or dispersed state in the patch, its release rate depends on the square root of time. Therefore, we can simplify it into the relationship between the cumulative release amount M and time t:

[0071] kt1 / 2

[0072] Where k is the release rate constant.

[0073] The specific results are shown in Table 1 below:

[0074] Pressure sensitive adhesive model <![CDATA[In vitro release rate (μg·cm -2 ·h -1 / 2 )]]> Drug loading (%) Drug release rate SRS7-4502 48.67±7.84 5 15.45％ Duro-TAK 87-2052 20.17±0.62 5 6.45％ Duro-TAK 87-4098 30.47±1.08 5 8.72％ Duro-TAK 87-2516 / <5 /

[0075] During the preparation of the patch, it was found that when Duro-TAK 87-2516 pressure-sensitive adhesive was mixed with tandospirone, obvious precipitation occurred when the dosage of tandospirone reached 5%. The drug loading was extremely low, making it difficult to achieve the development purpose. Duro-TAK 87-2516 pressure-sensitive adhesive was not considered.

[0076] From the data in Table 1, we can see that the release rates of products with different pressure-sensitive adhesives are: SRS7-4502>Duro-TAK 87-4098>Duro-TAK 87-2052>Duro-TAK 87-2516. When pasting, the SRS7-4502 pressure-sensitive adhesive has poor adhesion and is difficult to adhere. Therefore, after comprehensive consideration, Duro-TAK 87-4098 pressure-sensitive adhesive is used as the matrix to obtain excellent adhesion and less skin irritation when peeling, and no adhesive residue caused by cohesive failure.

[0077] Experiment 3: Screening of penetration enhancers

[0078] Step 1) Preparation of patch: Using pressure-sensitive adhesive + penetration enhancer + tandospirone as a combination, the effects of different penetration enhancers are compared. The pressure-sensitive adhesive is Duro-TAK 87-4098, the active ingredient is tandospirone, the active ingredient content of the drug storage layer is 5%, and the penetration enhancer is selected from isopropyl myristate (IPM), [choline] [geranic acid] (CAGE), [choline] [oleic acid] ([Cho] [Ole]), propylene glycol (PG). Prepare the patch by the method of experiment 1 and cut it into 1.766 cm 2 Afterwards, the Q of the patches prepared with different penetration enhancers was evaluated according to the in vitro permeation test process. 24h size.

[0079] Step 2) In vitro transdermal test: Use Franz diffusion cell, temperature 32°C, stirring speed 600 rpm, pH 7.4 phosphate buffer as medium. Cut the tandospirone patch into 1.766 cm 2 Afterwards, the samples were attached to pig skin (stratum corneum facing upward) for the experiment. Samples were taken at 1, 2, 4, 6, 8, 12, and 24 hours, filtered, and analyzed by high performance liquid chromatography to draw a curve.

[0080] In vitro transdermal Q 24h Calculation method:

[0081] Transmittance calculation method:

[0082] Among them, Q t is the cumulative permeation per unit area (μg / cm 2 ), C n is the drug concentration of the nth sampling (μg / ml); V is the volume of the receiving solution (ml); V n is the sampling volume (ml); A is the effective diffusion area of ​​the drug (cm 2 );R t is the cumulative transmittance per unit area (%); M0 is the drug content per unit area of ​​the patch (μg / cm 2 ).

[0083] The specific results are shown in Table 2 below:

[0084]

[0085] The results in Table 2 show that compared with prescription 5 (without penetration enhancer), the other prescriptions all have a penetration enhancing effect on the drug, and the penetration enhancing strength is: prescription 1> prescription 6> prescription 2≈ prescription 3> prescription 4. It can be seen that using IPM as a single penetration enhancer significantly improves the permeability of the drug. 24h 156.75 μg cm-2 The penetration enhancement strength of prescription 1 is 1.9 times that of the group without penetration enhancer - prescription 5.

[0086] Experiment 4: Drug loading investigation

[0087] Step 1) Preparation of patch: Duro-TAK 87-4098 is used as the pressure-sensitive adhesive. The active ingredient is tandospirone or docusate tandospirone salt. Different penetration enhancers and drugs with varying contents are selected to prepare the patch in the manner of Experiment 1.

[0088] Step 2) In vitro transdermal test: Cut the prepared patch into 1.766 cm 2 Afterwards, attached to Piglet skin Experiments were performed to evaluate the Q of patches prepared with different drug contents. 24h size.

[0089] The specific results are shown in Table 3 below:

[0090]

[0091]

[0092] Figure 2 The results in Table 3 show that when the proportion of penetration enhancer remains unchanged, the higher the drug loading, the higher the cumulative permeation per unit area.

[0093] The experiment showed that the drug loading of 15% in prescription 10 was turbid after stirring and turbid after coating and drying, indicating that the drug was precipitated and the drug loading of 15% exceeded the drug loading capacity of the unit matrix. When the drug loading of prescription 7-8 was increased from 5% to 10%, Q 24h The permeation rate increased by about 35%, while the drug loading of formulations 8-9 increased from 10% to 12.5%, Q 24h There was almost no improvement. Based on cost considerations, a drug loading of 10% was selected for subsequent experiments.

[0094] During the preparation of the prescription 11 patch using the preferred permeation enhancer IPM in Experiment 3 and the preferred drug loading in Experiment 4, drug precipitation was found, indicating that the drug loading could not reach 10% using a single permeation enhancer IPM, which may be due to insufficient crystal inhibition effect.

[0095] In order to enhance the penetration-enhancing effect and reduce the crystal-inhibiting effect, the present application prepares the drug into docusate salt to increase the lipid solubility, or combines IPM with PG, or IPM with [Cho][Ole] to enhance the penetration-enhancing effect.

[0096] The difference between prescription 14 and 11 is that tandospirone-docusate salt is used as the active ingredient. Obviously, tandospirone-docusate salt can greatly increase the lipid solubility of the drug and increase the solubility of the active ingredient in the prescription, so that drug precipitation will not occur. And compared with prescriptions 7-9, Q 24h The content of the active ingredient tandospirone-docusate salt was reduced, and the Q 24h It is obviously reduced, indicating that the drug loading is reduced, which is not conducive to the improvement of permeability.

[0097] The difference between prescription 12 and 11 is that the combination of propylene glycol and IPM is used as a penetration enhancer, Q 24h The obvious increase indicates that propylene glycol in the combined penetration enhancer is an excellent solvent and has solubilizing and penetration-enhancing effects; the combined penetration enhancer of the two has a better effect.

[0098] The difference between prescription 13 and 11 is that it uses a combination of choline oleic acid and IPM as a penetration enhancer, Q 24h This indicates that the combined penetration enhancer choline oleic acid itself has the function of inhibiting crystal precipitation.

[0099] Based on the search results of Experiment 3, prescriptions 15-17 combined choline oleic acid and propylene glycol, which have good volume expansion and penetration enhancement effects, and explored the ratio. It was found that the combination of different ratios of the two resulted in Q 24h The difference is not big, and the composite penetration enhancer in prescription 15 has the best effect.

[0100] It can be seen from prescriptions 18-21 that when the content of the active ingredient is reduced and IPM is used as the sole permeation enhancer, or when the content of the active ingredient is maintained and [Cho][Ole] is used as the sole permeation enhancer, the Q of prescription 21 in the form of docusate tandospirone salt is 24h Much lower than the prescription 20 of the prototype form of tandospirone.

[0101] Prescription 22-23 uses a combined penetration enhancer to increase solubility. Tandospirone-docusate salt can significantly increase the lipid solubility of the drug. The Q 24h Also got promoted.

[0102] According to the results of the transdermal experiment, prescriptions 12, 13, 15-16 were used in combination with penetration enhancers. 24h The maximum penetration enhancement effect is the best, the prepared patch is stable and not easy to precipitate drug crystals. Compared with the best embodiment 3 disclosed in CN112494465A, the cumulative penetration amount of the patch prepared in this application is at least increased by 27 times, with excellent effect.

[0103] Based on the above prescriptions, the content of each component in each prescription was explored in more detail, and the specific preparation examples are as follows:

[0104] Example 1

[0105] A percutaneous absorption preparation, which is prepared using the following components:

[0106] Tandospirone 200 mg (accounting for about 10% of the total mass of the drug storage layer)

[0107] Isopropyl myristate 150 mg (accounting for about 7.5% of the total mass of the drug storage layer)

[0108] Acrylic pressure-sensitive adhesive Duro-TAK 87-4098 1500 mg (accounting for about 75% of the total mass of the drug storage layer)

[0109] [Choline] [Oleic acid] 150 mg (accounting for about 7.5% of the total mass of the drug storage layer)

[0110] Ethyl acetate 1200mg / /

[0111] The preparation process is as follows: Prepare according to the process of Experiment 1.

[0112] Example 2

[0113] A percutaneous absorption preparation, which is prepared using the following components:

[0114] Tandospirone 200 mg (accounting for about 10% of the total mass of the drug storage layer)

[0115] Isopropyl myristate 150 mg (accounting for about 7.5% of the total mass of the drug storage layer)

[0116] Acrylic pressure-sensitive adhesive Duro-TAK 87-4098 1500 mg (accounting for about 75% of the total mass of the drug storage layer)

[0117] Propylene glycol 150 mg (accounting for about 7.5% of the total mass of the drug storage layer)

[0118] Ethyl acetate 1200mg / /

[0119] The preparation process is as follows: Prepare according to the process of Experiment 1.

[0120] Example 3

[0121] A percutaneous absorption preparation, which is prepared using the following components:

[0122] Tandospirone 200 mg (accounting for about 10% of the total mass of the drug storage layer)

[0123] [Choline] [Oleic acid] 150 mg (accounting for about 7.5% of the total mass of the drug storage layer)

[0124] Acrylic pressure-sensitive adhesive Duro-TAK 87-4098 1500 mg (accounting for about 75% of the total mass of the drug storage layer) Propylene glycol 150 mg (accounting for about 7.5% of the total mass of the drug storage layer)

[0125] Ethyl acetate 1200mg / /

[0126] The preparation process is as follows: Prepare according to the process of Experiment 1.

[0127] Example 4

[0128] A percutaneous absorption preparation, which is prepared using the following components:

[0129] Tandospirone 200 mg (accounting for about 10% of the total mass of the drug storage layer)

[0130] [Choline] [Oleic acid] 100 mg (accounting for about 5% of the total mass of the drug storage layer)

[0131] Acrylic pressure-sensitive adhesive Duro-TAK 87-4098 1500mg (accounting for about 75% of the total mass of the drug storage layer) Propylene glycol 200mg (accounting for about 10% of the total mass of the drug storage layer)

[0132] Ethyl acetate 1200mg / /

[0133] The preparation process is as follows: Prepare according to the process of Experiment 1.

[0134] Example 5

[0135] A percutaneous absorption preparation, which is prepared using the following components:

[0136] Tandospirone 200 mg (accounting for about 10% of the total mass of the drug storage layer)

[0137] [Choline] [Oleic acid] 200 mg (accounting for about 10% of the total mass of the drug storage layer)

[0138] Acrylic pressure-sensitive adhesive Duro-TAK 87-4098 1500 mg (accounting for about 75% of the total mass of the drug storage layer) Propylene glycol 100 mg (accounting for about 5% of the total mass of the drug storage layer)

[0139] Ethyl acetate 1200mg / /

[0140] The preparation process is as follows: Prepare according to the process of Experiment 1.

[0141] Example 6

[0142] A percutaneous absorption preparation, which is prepared using the following components:

[0143] Docusate tandospirone salt 431.87 mg (accounting for about 21.6% of the total mass of the drug storage layer)

[0144] Propylene glycol 134 mg (accounting for about 6.7% of the total mass of the drug storage layer)

[0145] Acrylic pressure-sensitive adhesive Duro-TAK 87-4098 1300 mg (accounting for about 65% of the total mass of the drug storage layer) [Choline] [Oleic acid] 134 mg (accounting for about 6.7% of the total mass of the drug storage layer)

[0146] Ethyl acetate 1200mg / /

[0147] The preparation process is as follows: Prepare according to the process of Experiment 1.

[0148] Example 7

[0149] A percutaneous absorption preparation, which is prepared using the following components:

[0150] Docusate tandospirone salt 431.87 mg (accounting for about 21.6% of the total mass of the drug storage layer)

[0151] IPM 134mg (accounting for about 6.7% of the total mass of the drug storage layer)

[0152] Acrylic pressure-sensitive adhesive Duro-TAK 87-4098 1300 mg (accounting for about 65% of the total mass of the drug storage layer) [Choline] [Oleic acid] 134 mg (accounting for about 6.7% of the total mass of the drug storage layer)

[0153] Ethyl acetate 1200mg / /

[0154] The preparation process is as follows: Prepare according to the process of Experiment 1.

[0155] Example 8

[0156] A percutaneous absorption preparation, which is prepared using the following components:

[0157] Tandospirone 5mg (accounting for about 5% of the total mass of the drug storage layer)

[0158] Isopropyl myristate 7.5 mg (accounting for about 7.5% of the total mass of the drug storage layer)

[0159] Acrylic pressure-sensitive adhesive Duro-TAK 87-4098 80 mg (accounting for about 80% of the total mass of the drug storage layer) Propylene glycol 7.5 mg (accounting for about 7.5% of the total mass of the drug storage layer)

[0160] Ethyl acetate 12mg / /

[0161] The preparation process is as follows: Prepare according to the process of Experiment 1.

[0162] Example 9

[0163] A percutaneous absorption preparation, which is prepared using the following components:

[0164] Tandospirone 4mg (accounting for about 4% of the total mass of the drug storage layer)

[0165] Isopropyl myristate 7.5 mg (accounting for about 7.5% of the total mass of the drug storage layer)

[0166] Acrylic pressure-sensitive adhesive Duro-TAK 87-4098 81 mg (accounting for about 81% of the total mass of the drug storage layer) Propylene glycol 7.5 mg (accounting for about 7.5% of the total mass of the drug storage layer)

[0167] Ethyl acetate 12mg / /

[0168] The preparation process is as follows: Prepare according to the process of Experiment 1.

[0169] Example 10

[0170] A percutaneous absorption preparation, which is prepared using the following components:

[0171] Tandospirone 2.7 mg (accounting for about 4.5% of the total mass of the drug storage layer)

[0172] Isopropyl myristate 2.25 mg (about 3.75% of the total mass of the drug storage layer)

[0173] Acrylic pressure-sensitive adhesive Duro-TAK 87-4098 52.8 mg (accounting for about 88% of the total mass of the drug storage layer) Propylene glycol 2.25 mg (accounting for about 3.75% of the total mass of the drug storage layer)

[0174] Ethyl acetate 6mg / /

[0175] The preparation process is as follows: Prepare according to the process of Experiment 1.

[0176] Embodiment 11

[0177] A percutaneous absorption preparation, which is prepared using the following components:

[0178] Tandospirone 27 mg (accounting for about 2.14% of the total mass of the drug storage layer)

[0179] Isopropyl myristate 45 mg (accounting for about 3.55% of the total mass of the drug storage layer)

[0180] Acrylic pressure-sensitive adhesive Duro-TAK 87-4098 114.87 mg (accounting for about 90.76% of the total mass of the drug storage layer)

[0181] Propylene glycol 45 mg (accounting for about 3.55% of the total mass of the drug storage layer)

[0182] Ethyl acetate 600mg / /

[0183] The preparation process is as follows: Prepare according to the process of Experiment 1.

[0184] Comparative Example: Investigate the effect of levulinic acid on the patch.

[0185] Step 1) Preparation of patch: Prepare the patch according to the formulation described in Table 4 in the manner of Experiment 1.

[0186] Step 2) In vitro release experiment: Use a Franz diffusion cell, temperature 32°C, stirring speed 600 rpm, pH 7.4 phosphate buffer as medium. Take the tandospirone patch prepared in step 1) and cut it into 1.766 cm 2 After that, the samples were attached to nitrocellulose membranes and the experiment was carried out. Samples were taken at 1, 2, 4, 6, 8, 10, and 12 hours, and the high performance liquid phase analysis was used to draw a curve graph to calculate the in vitro release rate per unit time. The specific calculation is shown in Experiment 2.

[0187] The specific results are shown in Table 4 below:

[0188]

[0189] from Figure 3 As shown in the data of Table 4, after adding levulinic acid, the patch prepared by using the pressure-sensitive adhesive and penetration enhancer selected by the present invention has a poor drug release rate and a poor release effect.

[0190] Through human trials, it was found that the tandospirone patch prepared in the present application has high patient compliance, is administered once a day, has high bioavailability, and has good preparation stability.

[0191] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A percutaneous absorption preparation, characterized in that: It includes a release film, a drug storage layer and a backing layer; The drug storage layer at least contains active ingredients, penetration enhancers and pressure-sensitive adhesives; The active ingredient is tandospirone and its pharmaceutically acceptable salts; the pharmaceutically acceptable salts include tandospirone hydrochloride, tandospirone sulfate, tandospirone hydrobromide, tandospirone hydroiodide, tandospirone nitrate, tandospirone hydrogen sulfate, tandospirone phosphate, tandospirone acid phosphate, tandospirone citrate, tandospirone acetate, tandospirone oxalate, tandospirone isonicotinate, tandospirone lactate, tandospirone salicylate, tandospirone citrate, tandospirone tartaric acid, tandospirone oleate, tandospirone tannic acid, tandospirone pantothenate, Tandospirone hydrogen tartrate, tandospirone ascorbate, tandospirone succinate, tandospirone maleate, tandospirone gentisate, tandospirone fumarate, tandospirone gluconate, tandospirone glucuronide, tandospirone formate, tandospirone benzoate, tandospirone glutamate, tandospirone mesylate, tandospirone ethanesulfonate, tandospirone benzenesulfonate, tandospirone p-toluenesulfonate, tandospirone tetrafluoroborate, tandospirone trifluoroacetate, tandospirone hexafluorophosphate, tandospirone monomethyl sulfate, tandospirone acetate or docusate tandospirone salt.

2. The percutaneous absorption preparation according to claim 1, characterized in that: The penetration enhancer is selected from at least one of DMSO, dimethyl sulfoxide, deoxymethyl sulfoxide, 2-pyrrolidone, 5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, laurocaprol, fatty acids, oleic acid, isopropyl myristate, propylene glycol dipelargonate, isooctyl salicylate, isotridecyl myristate, ethyl laurate, octyl palmitate, propylene glycol, isopropanol, ethanol, glycerol, isobutyl alcohol, n-octanol and ionic liquid penetration enhancers.

3. The percutaneous absorption preparation according to claim 2, characterized in that: The ionic liquid penetration enhancer is selected from at least one of choline, choline geranic acid, choline oleic acid and choline citric acid.

4. The percutaneous absorption preparation according to claim 3, characterized in that: The penetration enhancer is selected from at least one of isopropyl myristate, choline geranic acid, choline oleic acid, propylene glycol, a combination of isopropyl myristate and choline oleic acid, a combination of isopropyl myristate and propylene glycol, and a combination of propylene glycol and choline oleic acid.

5. The percutaneous absorption preparation according to claim 1, characterized in that: In the drug storage layer, the active ingredient is 1-40 wt%, the penetration enhancer is 1-40 wt% and the pressure-sensitive adhesive is 30-95 wt%.

6. The percutaneous absorption preparation according to claim 1, characterized in that: In the drug storage layer, the active ingredient is 1-35wt%, the penetration enhancer is 1-25wt% and the pressure-sensitive adhesive is 50-90wt%.

7. The percutaneous absorption preparation according to claim 1, characterized in that: The drug storage layer at least comprises: Active ingredient: Tandospirone or docusate tandospirone salt; Penetration enhancer: at least one selected from the group consisting of isopropyl myristate, choline geranic acid, choline oleic acid, propylene glycol, a combination of isopropyl myristate and choline oleic acid, a combination of isopropyl myristate and propylene glycol, and a combination of propylene glycol and choline oleic acid; Pressure-sensitive adhesive: polyacrylate pressure-sensitive adhesive, model selected from DURO-TAK 387-2516, DURO-TAK 87-235A, DURO-TAK 387-2353, DURO-TAK 387-2287, DURO-TAK 387-2852, DURO-TAK 387-2051, DURO-TAK387-2052, DURO-TAK 387-2054, DURO-TAK 87-4287, DURO-TAK 87-6908, DURO-TAK 87-2677, Duro-Tak 87-900A, Duro-Tak 87-9301, Gelva GMS 3083, Gelva GMS 3253, Duro-TAK87-4098, Duro-TAK 87-2516, Duro-TAK 87-2052, or SRS7-4502.

8. The percutaneous absorption preparation according to claim 1, characterized in that: The drug storage layer at least comprises: 1 to 30 wt% of an active ingredient, wherein the active ingredient is docusate tandospirone salt; 1-15wt% penetration enhancer, wherein the penetration enhancer is selected from at least one of isopropyl myristate, choline geranic acid, choline oleic acid, propylene glycol, a combination of isopropyl myristate and choline oleic acid, a combination of isopropyl myristate and propylene glycol, and a combination of propylene glycol and choline oleic acid; 60-90wt% pressure-sensitive adhesive: polyacrylate pressure-sensitive adhesive Duro-TAK 87-4098; or, 1 to 15 wt% active ingredient, wherein the active ingredient is tandospirone; 5-25wt% penetration enhancer, wherein the penetration enhancer is selected from at least one of isopropyl myristate, choline geranic acid, choline oleic acid, propylene glycol, a combination of isopropyl myristate and choline oleic acid, a combination of isopropyl myristate and propylene glycol, and a combination of propylene glycol and choline oleic acid; 68-92wt% pressure-sensitive adhesive: polyacrylate pressure-sensitive adhesive Duro-TAK 87-4098; or, 10 to 30 wt% of an active ingredient, wherein the active ingredient is docusate tandospirone salt; 1-15wt% penetration enhancer, wherein the penetration enhancer is selected from at least one of isopropyl myristate, choline geranic acid, choline oleic acid, propylene glycol, a combination of isopropyl myristate and choline oleic acid, a combination of isopropyl myristate and propylene glycol, and a combination of propylene glycol and choline oleic acid; 60-80wt% pressure-sensitive adhesive: polyacrylate pressure-sensitive adhesive Duro-TAK 87-4098. or, 20-25 wt% active ingredient, wherein the active ingredient is docusate tandospirone salt; 10-15wt% penetration enhancer, wherein the penetration enhancer is selected from at least one of isopropyl myristate, choline geranic acid, choline oleic acid, propylene glycol, a combination of isopropyl myristate and choline oleic acid, a combination of isopropyl myristate and propylene glycol, and a combination of propylene glycol and choline oleic acid; 60-80wt% pressure-sensitive adhesive: polyacrylate pressure-sensitive adhesive Duro-TAK 87-4098; Among them, the mass ratio of isopropyl myristate and choline oleic acid in the combination is 1-9:1-9; the mass ratio of isopropyl myristate and propylene glycol in the combination is 1-9:1-9; the mass ratio of propylene glycol and choline oleic acid in the combination is 1-9:1-9.

9. The percutaneous absorption preparation according to claim 1, characterized in that: The pressure-sensitive adhesive is selected from one of polyacrylate pressure-sensitive adhesive, silicone pressure-sensitive adhesive, hot-melt pressure-sensitive adhesive and hydrogel pressure-sensitive adhesive; The backing layer is a woven or nonwoven breathable film selected from paper, fabric, nonwoven fabric or film; The release film comprises a substrate and a release agent, and the substrate is a composite film of one or more materials selected from polypropylene film, polyethylene film, polystyrene film, polyester film and silicon paper.

10. A method for preparing the percutaneous absorption preparation according to any one of claims 1 to 9, the specific steps comprising: uniformly mixing the active ingredient, the penetration enhancer and the pressure-sensitive adhesive with an organic solvent in proportion, coating the mixture on a release film, drying the mixture and laminating a backing layer to obtain the percutaneous absorption preparation.

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