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CN-121971412-A - Tuo Luo Te Luo Tou skin patch with gradient medicine release structure and preparation method thereof

CN121971412ACN 121971412 ACN121971412 ACN 121971412ACN-121971412-A

Abstract

The invention discloses a tolterodine transdermal patch with a gradient drug release structure and a preparation method thereof, belongs to the technical field of transdermal drug delivery systems, and aims to solve the problems of slow effect and insufficient drug release power in the later period of the existing single-layer tolterodine patch. The transdermal patch sequentially comprises a back lining layer, a gradient medicine-containing matrix layer and an anti-sticking release layer from top to bottom, wherein the gradient medicine-containing matrix layer sequentially comprises a high-concentration top-layer long-acting medicine release layer containing tulobuterol-mesoporous silica nanoparticles and silicone adhesive, a middle-concentration middle stable medicine release layer containing SIS hot melt adhesive and a low-concentration bottom-layer quick-acting contact layer containing specific permeation enhancer composition and acrylate adhesive from top to bottom. The invention breaks through the traditional concentration barrier through the synergistic effect of 'bottom permeation promotion driving + middle layer stable transition + top layer nano reservoir relay', and perfectly combines the rapid onset within 1-2 hours and the steady-state long-acting drug release over 24 hours.

Inventors

  • ZHENG KAI
  • Shen mengyuan
  • Gao Binying

Assignees

  • 浙江海阁堂医药有限公司

Dates

Publication Date
20260505
Application Date
20260323

Claims (8)

  1. 1. The tolterodine transdermal patch with the gradient drug release structure is characterized by comprising a backing layer (1), a gradient drug-containing matrix layer (2) and an anti-sticking release layer (3) which are sequentially arranged from top to bottom; Wherein, the gradient medicine-containing matrix layer (2) sequentially comprises from top to bottom: a top layer long-acting drug release layer (21) comprising a silicone-based pressure-sensitive adhesive and tulobuterol-mesoporous silica nanoparticles dispersed in the silicone-based pressure-sensitive adhesive; the middle stable drug release layer (22) comprises a styrene-isoprene-styrene segmented copolymer hot melt pressure sensitive adhesive, tackifying resin and free tolterone; a bottom quick-acting contact layer (23) comprising an acrylic pressure-sensitive adhesive, a permeation enhancer composition and tolterodine in free form; Wherein: the mass fraction of the tulobuterol in the top layer long-acting drug release layer (21) is 5.0% -8.0%; The mass fraction of the tulobuterol in the middle stable drug release layer (22) is 2.0% -4.0%; The mass fraction of the tulobuterol in the bottom quick-acting contact layer (23) is 0.5% -1.5%; the tulobuterol-mesoporous silica nanoparticle is an aminated mesoporous silica nanoparticle loaded with tulobuterol, the particle size of the tulobuterol-mesoporous silica nanoparticle is 50-200 nm, the pore diameter of the mesoporous silica nanoparticle is 5-8 nm, and the specific surface area of the mesoporous silica nanoparticle is 800-1000 m 2 /g.
  2. 2. The transdermal patch of claim 1, wherein the thickness ratio of the top layer long-acting drug release layer (21), the middle stable drug release layer (22) and the bottom layer quick-acting contact layer (23) is 1 (1.5-2): 0.5-1.
  3. 3. A transdermal patch according to claim 1, wherein the transdermal enhancer composition in the bottom quick-acting contact layer (23) consists of laurocapram, isopropyl myristate and propylene glycol in a mass ratio of 1:2:1, and the transdermal enhancer composition accounts for 3% -5% of the total mass of the bottom quick-acting contact layer (23).
  4. 4. The transdermal patch of claim 1, wherein the tackifying resin in the intermediate stable drug release layer (22) is one or more selected from the group consisting of hydrogenated rosin glyceride, terpene resin and petroleum resin, the acrylic pressure-sensitive adhesive is an acrylic copolymerization pressure-sensitive adhesive containing 2-ethylhexyl acrylate monomer, and the silicone pressure-sensitive adhesive is an amine compatible medical silicone pressure-sensitive adhesive.
  5. 5. The transdermal patch of claim 1, wherein the backing layer (1) is a polyester and polyurethane composite microporous breathable film with a thickness of 15-30 μm, and the release preventing layer (3) is a polyester film with one side coated with a fluorine release agent.
  6. 6. The transdermal patch of claim 1, wherein the patch area of the transdermal patch is 5-20 cm 2 and the total drug loading of tulobuterol is 1-5 mg/tablet.
  7. 7. The transdermal patch of claim 1, which has in vitro release characteristics of: The accumulated release amount of the adhesive is 10% -20% of the total drug loading amount after the adhesive is applied for 2 hours; The accumulated release amount of the adhesive is 40% -60% of the total drug loading amount after 12 hours of application; the accumulated release amount of the adhesive tape applied for 24 hours is 70% -90% of the total drug loading amount.
  8. 8. A method of preparing a transdermal patch according to any one of claims 1 to 7, comprising the steps of: S1, coating a bottom quick-acting contact layer coating liquid on an anti-sticking release layer (3), and drying at 50-60 ℃ to form a bottom layer assembly with a release film; S2, coating an intermediate stable drug release layer coating liquid on the first process protection film, and drying at 60-70 ℃ to form an intermediate layer component, and then carrying out hot-pressing compounding on the intermediate layer component and the coating surface of the bottom layer component obtained in the step S1 under the conditions of 60-80 ℃ and 0.3-0.6 MPa of pressure, and stripping the first process protection film to obtain a bottom-intermediate layer composite component; S3, coating a top layer long-acting drug release layer coating liquid on the backing layer (1), and drying at 60-70 ℃ to form a top layer assembly; S4, carrying out hot-pressing compounding on the coating surface of the top layer assembly obtained in the step S3 and the coating surface of the bottom-middle layer composite assembly obtained in the step S2 under the conditions that the temperature is 60-80 ℃ and the pressure is 0.3-0.6 MPa, and cutting the materials into the required size.

Description

Tuo Luo Te Luo Tou skin patch with gradient medicine release structure and preparation method thereof Technical Field The invention relates to the technical field of transdermal drug delivery systems and pharmaceutical preparations, in particular to a tolote Luo Tou transdermal patch with a gradient drug release structure and a preparation method thereof. Background Tulobuterol (Tulobuterol) is a long-acting beta 2 receptor agonist, and can produce remarkable bronchodilatory effect by highly selectively exciting beta 2 receptors of respiratory smooth muscle, and is widely used for treating respiratory diseases such as bronchial asthma, acute and chronic bronchitis, emphysema and the like clinically. Clinical medicine studies have shown that the onset of asthma symptoms has a pronounced circadian rhythm, with patient airway resistance peaking at night to early morning (about 2 to 6 am, the "morning drop" phenomenon). Therefore, the tulobuterol is developed into a transdermal patch (such as pre-sleep application) so that the peak of the blood concentration coincides with the peak of asthma attack, and has extremely high clinical value. However, the existing single-layer matrix tolote Luo Tou patch has the defects that firstly, the effect has hysteresis, the drug release rate is low in the initial stage of the patch (within 1-2 hours), and the slight wheezing of a patient before sleeping is difficult to quickly relieve, and secondly, after the patch is applied for 16-24 hours, the diffusion driving force decays exponentially along with the decrease of the concentration of the drug in the matrix, so that the blood concentration cannot maintain the effective treatment level in the later stage of the drug administration. Disclosure of Invention The invention discloses a tolterodine transdermal patch with a gradient drug release structure, belongs to the technical field of transdermal drug delivery systems, and aims to solve the problems of slow onset of action and insufficient drug release power in the later period of the existing single-layer tolterodine patch. The transdermal patch sequentially comprises a back lining layer, a gradient medicine-containing matrix layer and an anti-sticking release layer from top to bottom, wherein the gradient medicine-containing matrix layer sequentially comprises a high-concentration top-layer long-acting medicine release layer containing tulobuterol-mesoporous silica nanoparticles and silicone adhesive, a middle-concentration middle stable medicine release layer containing SIS hot melt adhesive and a low-concentration bottom-layer quick-acting contact layer containing specific permeation enhancer composition and acrylate adhesive from top to bottom. The invention breaks through the traditional concentration barrier through the synergistic effect of 'bottom permeation promotion driving + middle layer stable transition + top layer nano reservoir relay', and perfectly combines the rapid onset within 1-2 hours and the steady-state long-acting drug release over 24 hours. In order to achieve the above purpose, the invention adopts the following technical scheme: a tolterodine transdermal patch with a gradient drug release structure comprises a back lining layer, a gradient drug-containing matrix layer and an anti-sticking release layer which are sequentially arranged from top to bottom; Wherein, the gradient medicine-containing matrix layer comprises from top to bottom in sequence: the top layer long-acting drug release layer comprises a silicone pressure sensitive adhesive and tulobuterol-mesoporous silica nano particles dispersed in the silicone pressure sensitive adhesive; The middle stable drug release layer comprises a styrene-isoprene-styrene segmented copolymer hot-melt pressure-sensitive adhesive, tackifying resin and free tulobuterol; the bottom quick-acting contact layer comprises an acrylic pressure-sensitive adhesive, a transdermal enhancer composition and free tolterone; Wherein: the mass fraction of the tulobuterol in the top layer long-acting drug release layer is 5.0% -8.0%; the mass fraction of the tulobuterol in the middle stable drug release layer is 2.0% -4.0%; the mass fraction of the tulobuterol in the bottom quick-acting contact layer is 0.5% -1.5%; the tulobuterol-mesoporous silica nanoparticle is an aminated mesoporous silica nanoparticle loaded with tulobuterol, the particle size of the tulobuterol-mesoporous silica nanoparticle is 50-200 nm, the pore diameter of the mesoporous silica nanoparticle is 5-8 nm, and the specific surface area of the mesoporous silica nanoparticle is 800-1000 m 2/g. The thickness ratio of the top layer long-acting drug release layer, the middle stable drug release layer and the bottom quick-acting contact layer is 1 (1.5-2) (0.5-1). The quick-acting contact layer is characterized in that the quick-acting contact layer comprises a bottom quick-acting contact layer and a bottom quick-acting contact layer, wherein the bottom quick-