Colchicine patch as well as preparation method and application thereof

Abstract

The embodiment of the invention discloses a colchicine patch as well as a preparation method and application thereof. The colchicine patch is prepared from the following raw materials in percentage by weight: 0.4 to 3 percent of colchicine, 40 to 80 percent of solvent type pressure-sensitive adhesive, 0 to 10 percent of crystallization inhibitor, 0 to 5 percent of penetration enhancer and the balance of solvent. According to the invention, colchicine directly acts on local focuses through a transdermal administration mode, the core efficacy of inhibiting inflammatory cell infiltration of colchicine is retained, and the efficacy of oral tablets is maintained; meanwhile, adverse drug reaction is relieved, the application limitation that a traditional oral preparation is only suitable for the acute attack period is broken through, and the technical effect of long-term maintenance treatment in the non-acute attack period is achieved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparation, in particular to a colchicine patch, a preparation method and application thereof. BACKGROUND

[0002] Colchicine (Col) is also known as colchicine, which can effectively treat gouty arthritis (GA). However, its therapeutic window is narrow, the therapeutic dose is very close to the toxic dose, and it is easy to cause serious adverse reactions. For example, intravenous injection of Col has potential serious adverse reactions such as tissue necrosis, cytopenia, and disseminated intravascular coagulation. Oral therapeutic dose of Col (3-5 mg / d) will cause gastrointestinal side effects such as nausea, diarrhea, vomiting, and abdominal discomfort in 80% of patients, and oral administration cannot be continued for more than 1 week. The accumulation of Col in the body will lead to the risk of bone marrow suppression. Therefore, although Col has significant therapeutic effect on gouty arthritis, the risk of drug use is also high. Therefore, there is an urgent need for a drug that can reduce the adverse reactions of colchicine in clinical practice.

[0003] The patch can be used for local administration, so that the blood drug concentration is stable, and there is no serious peak-valley phenomenon of oral preparations. The patch can be directly used for lesions, and the advantage of targeted drug delivery has become the focus of research in the industry.

[0004] Preparation of colchicine ethosome patch and in vitro transdermal drug release (Song San Kong et al.) discloses the preparation of colchicine ethosome patch: colchicine is made into ethosome, and then the preparation is made by using amin glue. The amin glue is made of acrylic resin, triethyl citrate, and succinic acid pressure-sensitive adhesive material. On the one hand, the application of succinic acid makes the free colchicine into ionic state, which slows down the absorption rate of the drug through the skin in this ionic form. On the other hand, the transdermal effect of the ethosome and the actual therapeutic effect are greatly deviated. After the transdermal effect of the ethosome, most of them are still in the form of ethosome, which cannot be effectively released, so that colchicine cannot fully play the pharmacological role of blocking inflammatory response.

[0005] CN97104330A discloses a colchicine patch composed of colchicine and a transdermal enhancer. The patch is prepared according to the following weight ratio: colchicine 0.5-1.5, laurazepam 2.5-3.0, and polyacrylic acid pressure-sensitive adhesive 950.0-1050.0. The results of animal in vivo transdermal absorption test and human transdermal absorption test are as follows: the cumulative amount of mouse skin in vitro transdermal absorption test is 61.8% of the applied dose within 24 hours; the cumulative amount of rat in vivo transdermal absorption is 26.7% of the applied dose; and the cumulative amount of human transdermal absorption is 25.4% of the applied dose.

[0006] ​CN200710057506.6 discloses a colchicine transdermal absorption patch for treating acute gout and its preparation method. The Chinese medicinal material tulipa edulis is subjected to supercritical carbon dioxide extraction and then dispersed and refined to the nanoscale, with the particle size controlled below 500 nm. After mixing colchicine with a microemulsifier and heating to obtain a liquid oil phase, high-shear stirring is carried out at 1500 revolutions per minute, followed by microemulsification treatment for 5 - 15 minutes to prepare a microemulsion dispersion. Then, it is included with β-cyclodextrin to form a dispersion, and finally, it is made into a patch together with a transdermal absorption enhancer and a pressure-sensitive adhesive. This technology refines the raw materials to the nanoscale, improving the skin permeability, thereby increasing the blood concentration and bioavailability.

[0007] CN202010061254.X discloses a colchicine soluble microneedle patch and its preparation method, including microneedle bodies and a substrate, and optionally a medical adhesive tape. The microneedle bodies are made of a polymer material that can be dissolved in the body containing colchicine, and the substrate is made of a biocompatible material. The polymer material that can be dissolved in the body for the needle bodies is selected from hyaluronic acid or its salts. The molecular weight range of the polymer material in the needle bodies is 200 - 400 kDa, and the concentration is 0.02 - 0.1 g / ml. The mass ratio of hyaluronic acid or its salts to colchicine in the needle bodies of the microneedles is 1 - 2:1. The height of the needle bodies is 25 - 1000 μm, the radius of the bottom of the needle bodies is 100 - 600 μm, the radius of the tip is less than 15 μm, the interval between adjacent microneedles is 0 - 1000 μm, and the substrate is perpendicular to the microneedle array.

[0008] CN202211267044.1 discloses a transdermal patch of colchicine and its use, including a backing layer and a drug reservoir layer. The drug reservoir layer contains colchicine, an adhesive, and 1,2 - propanediol.

[0009] CN202311272846.6 discloses a patch containing colchicine, its preparation method and application, including a polymer matrix layer. In the polymer matrix layer, by weight percentage, it contains the following components: colchicine 0.1% - 5.0%, a penetration enhancer 0.005% - 15% (alcohols, alkanolamines, alcohol ethers with a boiling point greater than or equal to 150°C), and a pressure-sensitive adhesive 80% - 99%.

[0010] CN202410069036.9 discloses a transdermal patch containing colchicine, its preparation method, and its uses. The patch comprises a matrix layer containing the active ingredient colchicine, a hot-melt pressure-sensitive adhesive, and optional other pharmaceutically acceptable excipients. The colchicine content is 0.1%–5% by weight of the matrix layer, the hot-melt pressure-sensitive adhesive content is 1.9%–99.9%, and the content of other pharmaceutically acceptable excipients is 0%–98%. The penetration enhancer is selected from one or more of alcohols, alkanolamines, and alcohol ethers. Gout commonly affects the finger (toe) joints of the hands and feet, where hot-melt adhesive patches offer limited freedom of movement. Summary of the Invention

[0011] Therefore, embodiments of the present invention provide a colchicine patch, its preparation method, and its application.

[0012] To achieve the above objectives, the embodiments of the present invention provide the following technical solutions:

[0013] According to a first aspect of the present invention, the present invention provides a colchicine patch comprising the following raw materials in weight percentages: 0.4%-3% colchicine, 40%-80% solvent-based pressure-sensitive adhesive, 0-10% crystallization inhibitor, 0-5% penetration enhancer, and the balance being solvent.

[0014] Furthermore, the solvent-based pressure-sensitive adhesive is an acrylate pressure-sensitive adhesive and / or an organosilicon pressure-sensitive adhesive.

[0015] Furthermore, the crystallization inhibitor is povidone.

[0016] Furthermore, the solvent is selected from one or more of ethyl acetate, ethanol, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0017] Furthermore, the penetration enhancer is selected from one or more of isopropyl myristate, sulfoxides, pyrrolidones, and menthol.

[0018] Furthermore, it includes the following raw materials in weight percentages: colchicine 0.4%-3%, solvent-based pressure-sensitive adhesive 50%-80%, isopropyl myristate 0.1%-10%, N,N-dimethylacetamide 0.5%-10%, ethyl acetate 10%-40%, and polyvinylpyrrolidone 0-10%.

[0019] According to a second aspect of the present invention, the present invention provides a method for preparing colchicine patches as described in any of the preceding claims, the method comprising: weighing a prescribed amount of colchicine, sequentially adding N,N-dimethylacetamide, ethyl acetate, isopropyl myristate and povidone, and stirring to dissolve; adding a prescribed amount of solvent-based pressure-sensitive adhesive, and stirring to mix evenly; coating on a substrate, drying at 60-85°C, and cutting and packaging.

[0020] According to a third aspect of the present invention, the present invention provides the use of the colchicine patch as described in any of the preceding claims in the preparation of a medicament for treating gouty arthritis.

[0021] The embodiments of the present invention have the following advantages:

[0022] 1. The patch of the present invention has excellent flexibility and deformation ability, and can closely fit the skin of active parts such as joints and waist, and can maintain effective adhesion even when the limb is in motion.

[0023] 2. The adhesive layer of the patch of the present invention has good water resistance and can maintain stable application performance under conditions of sweat immersion and washing, ensuring the consistency of the drug release environment.

[0024] 3. This invention delivers colchicine directly to the local lesion via transdermal administration, preserving its core efficacy in inhibiting inflammatory cell infiltration and maintaining the efficacy of oral tablets. At the same time, it reduces adverse drug reactions, breaking through the limitation of traditional oral preparations that are only applicable to the acute phase, and achieving the technical effect of long-term maintenance therapy in non-acute phases. Detailed Implementation

[0025] The following specific embodiments illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0026] Example 1

[0027] This embodiment provides a colchicine patch, the raw materials of which are 1.5% colchicine, 65% acrylate pressure-sensitive adhesive, 2% N,N-dimethylacetamide, and 31.5% ethyl acetate.

[0028] The preparation method of the above colchicine patch is as follows:

[0029] Weigh out the prescribed amount of colchicine, add N,N-dimethylacetamide and ethyl acetate in sequence, and stir to dissolve; add the prescribed amount of acrylic pressure-sensitive adhesive, and stir to mix evenly; coat it on the substrate, dry it at 65°C, and cut and package it.

[0030] Example 2

[0031] This embodiment provides a colchicine patch, the raw materials of which are: 1.5% colchicine, 60% acrylate pressure-sensitive adhesive, 0.8% isopropyl myristate, 2% N,N-dimethylacetamide, and 35.7% ethyl acetate.

[0032] The preparation method of the above colchicine patch is as follows:

[0033] Weigh out the prescribed amount of colchicine, add N,N-dimethylacetamide, ethyl acetate and isopropyl myristate in sequence, and stir to dissolve; add the prescribed amount of acrylic pressure-sensitive adhesive, stir to mix evenly; coat onto the substrate, dry at 60-85℃, and cut and package.

[0034] Example 3

[0035] This embodiment provides a colchicine patch, the raw materials of which are 1.5% colchicine, 60% acrylate pressure-sensitive adhesive, 0.6% isopropyl myristate, 1.5% N,N-dimethylacetamide, and 36.4% ethyl acetate.

[0036] The preparation method of the above colchicine patch is the same as in Example 2.

[0037] Example 4

[0038] This embodiment provides a colchicine patch, the raw materials of which are 1.2% colchicine, 60% acrylate pressure-sensitive adhesive, 0.6% isopropyl myristate, 1.5% N,N-dimethylacetamide, and 36.7% ethyl acetate.

[0039] The preparation method of the above colchicine patch is the same as in Example 2.

[0040] Test Example 1

[0041] Safety test

[0042] The fur on both sides of the spine on the back of the rabbit was shaved, and the colchicine patches of Examples 1-6 were applied to the shaved areas. The patches were removed after 48 hours, and skin reactions were observed at 1, 24, 48, and 72 hours after removal. No irritation symptoms such as erythema or edema were found, indicating that the patches provided by this invention are well tolerated and non-irritating within 48 hours.

[0043] Test Example 2

[0044] One hundred and twenty patients clinically diagnosed with acute gouty arthritis were selected, including 82 males and 38 females, aged 28–62 years, with a mean age of 48.6 ± 8.2 years. They were randomly divided into treatment groups 1–4, with 30 patients in each group. There were no significant differences in general characteristics among the groups, making them comparable.

[0045] Treatment method: Patients in treatment groups 1-4 were given colchicine patches according to Examples 1-4, and were followed up after 48 hours.

[0046] Criteria for evaluating therapeutic efficacy:

[0047] Effective: Symptoms completely disappear, joint function returns to normal, and major physical and chemical test indicators are normal; or, major symptoms basically disappear, and major joint function and major physical and chemical indicators improve.

[0048] Ineffective: No improvement in any aspect compared to before treatment.

[0049] The clinical efficacy results are shown in Table 1 below.

[0050] Table 1

[0051] Group Valid Invalid Efficiency Treatment 1 group 25 5 83.3％ Treatment 2 group 27 3 90.0％ Treatment 3 group 29 1 96.7％ Treatment 4 group 26 4 86.7％

[0052] The results showed that the colchicine patch provided in this embodiment of the invention can improve the symptoms of gouty arthritis, restore joint function to normal, and has a good therapeutic effect on gouty arthritis.

[0053] During the treatment, no abnormalities were observed in routine blood, urine, or stool tests, occult blood tests, or liver and kidney function tests in patients in treatment groups 1-4. No aggravation of local inflammation at the application site or systemic adverse reactions were observed.

[0054] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A colchicine patch, characterized in that, The raw materials include the following weight percentages: colchicine 0.4%-3%, solvent-based pressure-sensitive adhesive 40%-80%, crystallization inhibitor 0-10%, penetration enhancer 0-5%, and the balance being solvent.

2. The colchicine patch according to claim 1, characterized in that, The solvent-based pressure-sensitive adhesive is an acrylic pressure-sensitive adhesive and / or an organosilicon pressure-sensitive adhesive.

3. The colchicine patch according to claim 1, characterized in that, The crystallization inhibitor is povidone.

4. The colchicine patch according to claim 1, characterized in that, The solvent is selected from one or more of ethyl acetate, ethanol, N,N-dimethylformamide, and N,N-dimethylacetamide.

5. The colchicine patch according to claim 1, characterized in that, The penetration enhancer is selected from one or more of isopropyl myristate, sulfoxides, pyrrolidones, and menthol.

6. The colchicine patch according to claim 1, characterized in that, The raw materials include the following weight percentages: colchicine 0.4%-3%, solvent-based pressure-sensitive adhesive 50%-80%, isopropyl myristate 0.1%-10%, N,N-dimethylacetamide 0.5%-10%, ethyl acetate 10%-40%, and polyvinyl acetate 0-10%.

7. The method for preparing the colchicine patch according to any one of claims 1-6, characterized in that, The method includes: weighing the prescribed amount of colchicine, adding N,N-dimethylacetamide, ethyl acetate, isopropyl myristate and povidone in sequence, and stirring to dissolve; adding the prescribed amount of solvent-based pressure-sensitive adhesive, stirring to mix evenly; coating on a substrate, drying at 60-85℃, and cutting and packaging.

8. The use of the colchicine patch according to any one of claims 1-6 in the preparation of a medicament for treating gouty arthritis.