Compound traditional Chinese medicine patch for conditioning hyperplasia of mammary glands and preparation method thereof

Abstract

The invention discloses a compound traditional Chinese medicine patch for conditioning hyperplasia of mammary glands and a preparation method thereof, and relates to the technical field of traditional Chinese medicine preparations. The compound traditional Chinese medicine patch for conditioning hyperplasia of mammary glands is prepared from an iron-based metal organic framework composite drug carrying system, dopamine hydrochloride, a blank gel matrix, ethyl oleate, menthol, a solubilizer, a wetting agent and water, the iron-based metal organic framework composite drug loading system is composed of traditional Chinese medicine dihydric alcohol plastid, iron-based metal organic framework nanoparticles and cinnamomum camphora essential oil. The traditional Chinese medicine dihydric alcohol plastid and the cinnamomum camphora essential oil are loaded in the iron-based metal organic framework nano particles, so that the transdermal absorption of the medicine is improved, the pH response release property is realized, the dosage of active ingredients permeating into a focus part and the lasting action time are effectively increased, and then a coating layer is formed by polydopamine, so that the anti-inflammatory effect is improved. The dispersibility and compatibility of the drug loading system in vivo are further enhanced, the drug effect can be fully exerted, and the treatment effect on the hyperplasia of mammary glands is remarkably improved.

Description

Technical Field

[0001] The invention belongs to the technical field of Chinese medicine preparations, and specifically refers to a compound Chinese medicine patch for regulating breast hyperplasia and a preparation method thereof. Background Art

[0002] Breast hyperplasia is a common benign breast disease in women, accounting for 75% of all breast diseases. Breast hyperplasia is mostly caused by endocrine dysfunction in women, which stimulates breast tissue, causing excessive proliferation and incomplete restoration. The main manifestations are breast lumps or nodules, breast pain, often accompanied by chest tightness, emotional distress, and even mental tension, irritability, anxiety and depression, which aggravate the patient's pain. The disease has a long course and has a certain tendency to cancer. Relevant data surveys show that about 1.17% of patients with breast hyperplasia develop It is breast cancer and needs to be diagnosed and treated as early as possible. At present, estrogen receptor antagonists are the first choice for Western medicine treatment of breast hyperplasia. Although they can play a certain therapeutic role, long-term use of the drug has many adverse reactions and is prone to relapse after discontinuation of the drug. How to further optimize the treatment effect of breast hyperplasia is a hot spot in clinical research. Traditional Chinese medicine can exert pharmacological effects at multiple levels, multiple targets, and multiple pathways. The syndrome differentiation and treatment of breast hyperplasia has significant effects. Traditional Chinese medicine believes that liver depression and qi stagnation, Chong and Ren disorders, and phlegm and blood stasis blocking the meridians are related to the onset of breast hyperplasia, and it should be treated with soothing the liver and relieving depression, and regulating Chong and Ren.

[0003] As a type of transdermal drug delivery system, Babu patch has a wide range of applications, overcomes the shortcomings of oral administration, avoids the first-pass effect of the liver, increases the absorption rate of the drug, and is used for the treatment of breast hyperplasia. It has the advantages of easy use and stable effects.

[0004] The existing technology currently has the following problems:

[0005] The amount of active ingredients in Chinese medicine patches that penetrate through the skin to the lesion site is small, limiting the therapeutic effect on breast hyperplasia. Summary of the invention

[0006] In view of the above situation, in order to overcome the defects of the prior art, the present invention proposes a compound Chinese medicine patch for regulating breast hyperplasia, comprising the following components in parts by weight: 30-40 parts of an iron-based metal-organic framework composite drug delivery system, 8-12 parts of dopamine hydrochloride, 25-30 parts of a blank gel matrix, 20-30 parts of ethyl oleate, 6-10 parts of menthol, 10-15 parts of a solubilizer, 10-20 parts of a wetting agent, and 80-90 parts of water.

[0007] The iron-based metal organic framework composite drug delivery system comprises the following components in parts by weight: 15-25 parts of traditional Chinese medicine diol plastids, 30-50 parts of iron-based metal organic framework nanoparticles, and 10-20 parts of camphor essential oil.

[0008] The Chinese medicine diol matrix comprises the following components in parts by weight: 10-20 parts of Chinese medicine granules, 40-50 parts of anhydrous ethanol, 10-20 parts of propylene glycol, 0.1-0.2 parts of octadecylamine, and 1-2 parts of soybean lecithin.

[0009] The raw materials of the Chinese medicine granules include the following components in parts by weight: 3-5 parts of bupleurum, 3-5 parts of white peony root, 3-5 parts of cyperus, 3-5 parts of costusroot, 3-5 parts of green peel, 3-5 parts of fructus aurantii, 3-5 parts of angelica, 3-5 parts of safflower, 3-5 parts of peach kernel, 3-5 parts of ligusticum, and 3-5 parts of liquorice.

[0010] The preparation method of the iron-based metal organic framework composite drug delivery system specifically comprises the following steps:

[0011] (1) Add 10-12 times the amount of water to bupleurum, white peony root, cyperus, costusroot, green peel, fructus aurantii, angelica, safflower, peach kernel, ligusticum chuanxiong and liquorice, soak in a decoction machine for 2-3 hours, decoct 1-2 times, extract with slight boiling for 2-3 hours, combine the decoctions, concentrate the collected filtrate to 1 / 6 to 1 / 5 of the original volume, and then freeze-dry. The main medicine is to soothe the liver and relieve depression, regulate the Chong and Ren meridians, and auxiliary medicines such as phlegm-resolving, dispersing nodules, and promoting blood circulation and removing blood stasis are used in combination. The whole prescription has clear main and secondary functions, warms and clears at the same time, and uses tonifying and purging together. It is bidirectionally regulated, and both the symptoms and the root causes are taken into consideration. It can achieve the functions of soothing the liver and relieving depression, promoting blood circulation and removing blood stasis, and dispersing nodules and relieving pain, and effectively regulate various symptoms of breast hyperplasia to obtain Chinese medicine granules.

[0012] (2) 10.0 g of camphor leaves were added to 200 mL of a 3% sodium chloride solution, and the leaves were first subjected to microwave treatment in a microwave light wave ultrasonic extractor, and then to ultrasonic treatment. The leaves were then subjected to reflux extraction in a water distillation extraction device for 3-4 h, and the extraction device was washed with 5 mL of ethyl acetate, and dried with anhydrous sodium sulfate. The extract was concentrated under reduced pressure at room temperature. The camphor essential oil extracted by this process has a higher extraction rate and can also inhibit breast hyperplasia by regulating hormone levels. Therefore, the anti-inflammatory, antioxidant and immunomodulatory effects of camphor essential oil also play an important role in the treatment of breast hyperplasia, and camphor essential oil was obtained.

[0013] (3) 2-3 mL of anhydrous ethanol, 1-2 mL of propylene glycol and 5-7 mL of deionized water are prepared into a 10 mL solution for later use. 0.1-0.2 g of soybean lecithin and octadecylamine are weighed and added to 4 mL of anhydrous ethanol, and slowly stirred until dissolved. The solution is transferred to a round-bottom flask. Under vacuum conditions, the solution is heated to 30-40° C. in a water bath, and the ethanol is completely removed by rotary evaporation. The solution and the Chinese medicine particles described in step (1) are then added to the solution. The solution is placed on a heated magnetic stirrer and magnetically stirred for 30-40 min at a temperature of 3 5-40°C, rotation speed 300-400rpm, then ultrasound further assists dissolution, ultrasound power 80-100W, working time 5s, interval time 3s, 10 cycles, the bilayer structure of the diol plasmid wraps the Chinese medicine particles in the closed vesicles, improves the encapsulation rate and drug loading, and also has biomembrane function, strong deformation ability, better flexibility, easier to pass through the cell gap, can promote the transdermal absorption of the active ingredients in the Chinese medicine particles and the aggregation in the skin, and obtain the Chinese medicine diol plasmid;

[0014] (4) 360.0 mg of 2-aminoterephthalic acid powder and 1.0 g of ferric chloride hexahydrate were dissolved in 40 mL of DMF, stirred at 100-120°C for 10-20 h, centrifuged, and the precipitate was washed three times with DMF and 80% ethanol solution by mass. The iron-based MIL-101 was used as a drug carrier, which could responsively release the drug at the lesion site and simultaneously trigger the release of iron ions, thereby catalyzing the Fenton reaction and inducing ferroptosis, which was beneficial to inhibit the carcinogenesis of breast hyperplasia, and obtain iron-based metal organic framework nanoparticles;

[0015] (5) adding the iron-based metal organic framework nanoparticles described in step (4) to the Chinese medicine diol plastids described in step (3), and then adding the camphor essential oil described in step (2), stirring continuously for 24 hours. After the reaction is completed, centrifuging, washing the precipitate with ultrapure water for 3-5 times, and removing the unloaded Chinese medicine diol plastids and camphor essential oil adsorbed on the surface. The encapsulation effect of the iron-based metal organic framework nanoparticles avoids the leakage problem of the Chinese medicine diol plastids during transdermal and storage. The porous structure of the iron-based metal organic framework can effectively load the Chinese medicine diol plastids and camphor essential oil, and control the release through its pore structure. It also has pH responsiveness, which not only increases the drug loading amount, but also enables the drug to be continuously released during transdermal absorption and enhances the effective release at the lesion site, thereby prolonging the drug action time and enhancing the therapeutic effect, thereby obtaining an iron-based metal organic framework composite drug delivery system;

[0016] Preferably, in step (2), during the microwave treatment, the microwave power is 400-500 W, the microwave time is 2-3 min, and during the ultrasonic treatment, the ultrasonic power is 200-300 W, the ultrasonic time is 10-20 min. Microwave and ultrasonic assisted extraction is beneficial to increase the content of active substances such as volatile oils, flavonoids, lignin compounds, coumarin, borneol, camphor, etc. in the essential oil, and has better anti-inflammatory, antioxidant and antibacterial activities;

[0017] Preferably, in step (3), the amount of octadecylamine added is 0.01-0.02 g. Octadecylamine can reduce the surface tension of the liquid, increase the wettability of the liquid and the solid surface, and help form a stable alcohol body structure.

[0018] The present invention also provides a method for preparing a compound Chinese medicine patch for regulating breast hyperplasia, which specifically comprises the following steps:

[0019] S1. Pour 0.6-1.0g of carbomer evenly into 10mL of purified water to fully swell, add 4% sodium hydroxide solution by mass to adjust the pH to 6.8 to form a gel, add 4mL of glycerol and 0.1-0.2g of Tween 80, stir and dissolve to form solution A, then stir solution A at 35°C and add 4mL of purified water to form a gel matrix with carbomer, which can fit more closely on the Babu backing and reduce irritation to the skin, to obtain a blank gel matrix;

[0020] S2. Dissolve the iron-based metal-organic framework composite drug delivery system in 100 mL of water, add 2 mL of 25% ammonia solution and dopamine hydrochloride solid, continue stirring for 12 hours, collect the precipitate by centrifugation, and then wash it with ultrapure water for 3 times. Polydopamine can be used as a hydrophilic protective layer to improve the dispersibility, biocompatibility and stability of the iron-based metal-organic framework in the skin, thereby facilitating the stability and release of the drug, improving the therapeutic effect of breast hyperplasia, and obtaining a coated iron-based metal-organic framework composite drug delivery system;

[0021] S3, the coated iron-based metal organic framework composite drug delivery system described in step S2 is mixed evenly with the blank gel matrix described in step S1, and then added to the oil phase of 2.0-3.0g ethyl oleate and 0.6-1.0g menthol, followed by adding 1.0-1.5g solubilizer polyethylene glycol 400 and 1.0-2.0g wetting agent Tween 80, and then adding 8.0-9.0g purified water under magnetic stirring, mixing evenly, coating on the Babu backing, and drying. The blank gel matrix not only protects the stability of the coated iron-based metal organic framework composite drug delivery system, but also increases the close fit with the Babu backing and the skin, promotes the penetration of drugs, improves the therapeutic effect, and obtains a compound Chinese medicine patch for regulating breast hyperplasia;

[0022] Preferably, in step S2, the amount of dopamine hydrochloride added is 0.8-1.2 g, and dopamine hydrochloride will self-polymerize in aqueous ammonia to form polydopamine.

[0023] The beneficial effects achieved by the present invention are as follows:

[0024] The invention forms an iron-based metal-organic framework composite drug-carrying system by loading Chinese medicine diol plastids and camphor essential oil into iron-based metal-organic framework nanoparticles, improves the transdermal absorption of drugs, has pH-responsive release, effectively increases the amount of active ingredients that penetrate into the lesion site and the duration of sustained action, and then forms a coating layer with polydopamine to further enhance the dispersibility and compatibility of the drug-carrying system in the body, which is conducive to the full play of the drug efficacy and significantly improves the therapeutic effect of breast hyperplasia; in the iron-based metal-organic framework composite drug-carrying system, the Chinese medicine diol plastids and camphor essential oil loaded by the iron-based metal-organic framework nanoparticles not only avoid leakage of the Chinese medicine diol plastids, but also impart pH responsiveness to the lesion site, and its porous structure increases the loading amount of the drug, and also enables the drug to be continuously released during the transdermal absorption process. and effective release, effectively prolonging the drug's action time and therapeutic effectiveness, wherein camphor essential oil can inhibit breast hyperplasia by regulating hormone levels, and also synergistically promotes the transdermal absorption and aggregation of Chinese medicine diol plastids in the skin, thereby enhancing the therapeutic effect of breast hyperplasia; polydopamine forms a hydrophilic protective layer on the surface of the iron-based metal organic framework composite drug delivery system, improves its dispersibility and biocompatibility in the skin, thereby helping the iron-based metal organic framework composite drug delivery system to better exert its therapeutic effect; the present invention uses an iron-based metal organic framework composite drug delivery system, dopamine hydrochloride, a blank gel matrix, ethyl oleate, menthol, a solubilizer, a wetting agent and water to prepare a compound Chinese medicine patch for regulating breast hyperplasia, which increases the amount of active ingredients that penetrate into the lesion site and the duration of sustained action, and significantly improves the therapeutic effect on breast hyperplasia. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is a scanning electron microscope image of the iron-based metal organic framework nanoparticles prepared in Example 1 of the present invention;

[0026] Figure 2 This is a perspective electron micrograph of the coated iron-based metal organic framework composite drug delivery system prepared in Example 1 of the present invention;

[0027] Figure 3 This is a graph showing the cumulative permeation results of Examples 1-4 of the present invention, Comparative Examples 1-3 and a normal group;

[0028] Figure 4 The graph shows the therapeutic efficacy results of Examples 1-4 and Comparative Examples 1-3 of the present invention. DETAILED DESCRIPTION

[0029] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments; based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0030] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein may be applied to the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only and are not intended to limit the content of this application.

[0031] The experimental methods in the following examples are conventional methods unless otherwise specified; the experimental materials used in the following examples are purchased from commercial channels unless otherwise specified.

[0032] The sources of the reagents used in the examples are as follows:

[0033] Dopamine hydrochloride CAS No: 335081-04-4, brand Trc, product number D533787;

[0034] Ethyl oleate CAS No: 111-62-6, brand Aladdin, product number E485366-1kg;

[0035] Menthol CAS No: 2216-51-5, brand Innochem, product number A46602;

[0036] Polyethylene glycol 400 CAS No: 25322-68-3, brand Innochem, product number A32939;

[0037] Tween 80 CAS No: 9005-65-6, brand Innochem, product number A43489;

[0038] Propylene glycol CAS No: 26264-14-2, brand Macklin, product number P967315-500g;

[0039] Octadecanamine CAS No: 124-30-1, brand Innochem, product number A50085;

[0040] Soybean lecithin CAS No: 55128-59-1, brand Sinopharm, item number 69014981;

[0041] Sodium chloride CAS No: 7647-14-5, brand Innochem, product number A02400;

[0042] 2-Aminoterephthalic acid CAS No: 10312-55-7, brand Innochem, product number A12557;

[0043] Ferric chloride hexahydrate CAS No: 10025-77-1, brand Innochem, product number A10004;

[0044] DMFCASNo:68-12-2, Brand: Innochem, Product No.: A04779;

[0045] Carbomer CAS No: 54182-57-9, brand Macklin, product number C965549-5g;

[0046] Glycerol CAS No: 26545-74-4, brand Sigma-aldrich, product number G0400006;

[0047] Ammonia CAS No: 1336-21-6, brand Innochem, product number A78689;

[0048] Ethyl acetate CAS No: 141-78-6, brand Innochem, product number G00003;

[0049] Sodium hydroxide CAS No: 1310-73-2, brand Innochem, product number A36865;

[0050] Anhydrous ethanol CAS No: 64-17-5, brand Innochem, product number G00004.

[0051] Example 1

[0052] This embodiment proposes a compound Chinese medicine patch for regulating breast hyperplasia, comprising the following components in parts by weight: 40 parts of an iron-based metal-organic framework composite drug delivery system, 12 parts of dopamine hydrochloride, 30 parts of a blank gel matrix, 30 parts of ethyl oleate, 10 parts of menthol, 15 parts of a solubilizer, 20 parts of a wetting agent, and 90 parts of water.

[0053] The iron-based metal organic framework composite drug delivery system comprises the following components in parts by weight: 25 parts of traditional Chinese medicine diol plastids, 50 parts of iron-based metal organic framework nanoparticles, and 20 parts of camphor essential oil.

[0054] The Chinese medicine diol matrix comprises the following components in parts by weight: 20 parts of Chinese medicine granules, 50 parts of anhydrous ethanol, 20 parts of propylene glycol, 0.2 parts of octadecylamine and 2 parts of soybean lecithin.

[0055] The Chinese medicine granules, whose raw materials include the following components in parts by weight: 5 parts of bupleurum, 5 parts of white peony root, 5 parts of cyperus, 5 parts of costusroot, 5 parts of green peel, 5 parts of fructus aurantii, 5 parts of angelica, 5 parts of safflower, 5 parts of peach kernel, 5 parts of ligusticum, and 5 parts of liquorice.

[0056] The preparation method of the iron-based metal organic framework composite drug delivery system specifically comprises the following steps:

[0057] (1) Add 12 times the amount of water to bupleurum, white peony root, cyperus, costusroot, green peel, fructus aurantii, angelica, safflower, peach kernel, ligusticum chuanxiong and liquorice, soak in a decoction machine for 3 hours, decoct twice, extract with slight boiling for 3 hours, combine the decoctions, concentrate the collected filtrate to 1 / 5 of the original volume, and then freeze-dry. The main medicine is to soothe the liver and relieve depression, regulate the Chong and Ren meridians, and auxiliary medicines such as phlegm-resolving and stagnation-dissolving, and blood circulation-activating and blood stasis-removing are used in combination. The whole prescription has clear main and secondary functions, warms and clears at the same time, and uses tonifying and purging together. It is a two-way regulation, taking both the symptoms and the root into consideration, and plays the role of soothing the liver and relieving depression, promoting blood circulation and removing blood stasis, and dispersing stagnation and relieving pain, effectively regulating various symptoms of breast hyperplasia, and obtaining Chinese medicine granules;

[0058] (2) 10.0 g of camphor leaves were added to 200 mL of 3% sodium chloride solution. In a microwave light wave ultrasonic extractor, microwave treatment was first performed and then ultrasonic treatment was performed. During the microwave treatment, the microwave power was 500 W and the microwave time was 3 min. During the ultrasonic treatment, the ultrasonic power was 300 W and the ultrasonic time was 20 min. Microwave and ultrasonic assisted extraction was beneficial to increase the content of active substances such as volatile oils, flavonoids, lignin compounds, coumarins, borneol, camphor, etc. in the essential oil, and had better anti-inflammatory, antioxidant and antibacterial activities. Then, reflux extraction was performed in a water distillation extraction device for 4 h, the extraction device was washed with 5 mL of ethyl acetate, and dried with anhydrous sodium sulfate. The extract was concentrated under reduced pressure at room temperature. The camphor essential oil extracted by this process had a higher extraction rate and could also inhibit breast hyperplasia by regulating hormone levels. Therefore, the anti-inflammatory, antioxidant and immunomodulatory effects of camphor essential oil also play an important role in the treatment of breast hyperplasia. Camphor essential oil was obtained.

[0059] (3) 3 mL of anhydrous ethanol, 2 mL of propylene glycol and 7 mL of deionized water are prepared into a 10 mL solution for later use. 0.2 g of soybean lecithin and octadecylamine are weighed and added to 4 mL of anhydrous ethanol and slowly stirred until dissolved. The amount of octadecylamine added is 0.02 g. Octadecylamine can reduce the surface tension of the liquid, increase the wettability of the liquid and the solid surface, and help form a stable alcohol body structure. The solution is transferred to a round-bottom flask, heated to 40° C. in a water bath under vacuum, and rotary evaporated until the ethanol is completely removed. The solution and the Chinese medicine granules described in step (1) are then added thereto. The particles were placed on a heated magnetic stirrer, magnetically stirred for 40 minutes, at a temperature of 40°C and a speed of 400 rpm, and then ultrasound was used to further assist dissolution, with an ultrasound power of 100 W, a working time of 5 seconds, an interval time of 3 seconds, and 10 cycles. The bilayer structure of the diol plasmid encapsulates the Chinese medicine particles in closed vesicles, thereby increasing the encapsulation rate and drug loading. It also has a biomembrane function, strong deformation ability, better flexibility, and is easier to pass through the intercellular space, which can promote the transdermal absorption of the active ingredients in the Chinese medicine particles and the aggregation in the skin, thereby obtaining the Chinese medicine diol plasmid;

[0060] (4) 360.0 mg of 2-aminoterephthalic acid powder and 1.0 g of ferric chloride hexahydrate were dissolved in 40 mL of DMF, stirred at 120 °C for 20 h, centrifuged, and the precipitate was washed three times with DMF and 80% ethanol solution. Iron-based MIL-101 was used as a drug carrier, which could responsively release drugs at the lesion site and simultaneously trigger the release of iron ions, thereby catalyzing the Fenton reaction and inducing ferroptosis, which was beneficial to inhibit the carcinogenesis of breast hyperplasia, and obtain iron-based metal organic framework nanoparticles;

[0061] (5) Add the iron-based metal organic framework nanoparticles described in step (4) to the Chinese medicine diol plastids described in step (3), and then add the camphor essential oil described in step (2), and continue stirring for 24 hours. After the reaction is completed, centrifuge and wash the precipitate with ultrapure water for 5 times to remove the unloaded Chinese medicine diol plastids and camphor essential oil adsorbed on the surface. The encapsulation effect of the iron-based metal organic framework nanoparticles avoids the leakage problem of the Chinese medicine diol plastids during transdermal and storage. The porous structure of the iron-based metal organic framework can effectively load the Chinese medicine diol plastids and camphor essential oil, and control the release through its pore structure. It also has pH responsiveness, which not only increases the drug loading amount, but also enables the drug to be continuously released during transdermal absorption and enhances the effective release at the lesion site, thereby prolonging the drug action time and enhancing the therapeutic effect. An iron-based metal organic framework composite drug delivery system is obtained.

[0062] This embodiment provides a method for preparing a compound Chinese medicine patch for regulating breast hyperplasia, which specifically comprises the following steps:

[0063] S1. Pour 1.0 g of carbomer evenly into 10 mL of purified water to fully swell, add 4% sodium hydroxide solution by mass to adjust the pH to 6.8 to form a gel, add 4 mL of glycerol and 0.2 g of Tween 80, stir and dissolve to form solution A, then stir solution A at 35 °C and add 4 mL of purified water to form a gel matrix with carbomer, which can fit more closely on the Babu backing and reduce irritation to the skin, to obtain a blank gel matrix;

[0064] S2. Dissolve the iron-based metal organic framework composite drug delivery system in 100 mL of water, add 2 mL of 25% ammonia solution and dopamine hydrochloride solid, continue stirring for 12 hours, collect the precipitate by centrifugation, and then wash it with ultrapure water 3 times. The amount of dopamine hydrochloride added is 1.2 g. Dopamine hydrochloride will self-polymerize in ammonia water to form polydopamine. Polydopamine, as a hydrophilic protective layer, can improve the dispersibility, biocompatibility and stability of the iron-based metal organic framework in the skin, thereby facilitating the stability and release of the drug, improving the therapeutic effect of breast hyperplasia, and obtaining a coated iron-based metal organic framework composite drug delivery system;

[0065] S3. Mix the coated iron-based metal-organic framework composite drug delivery system described in step S2 and the blank gel matrix described in step S1 evenly, then add to the oil phase of 3.0g ethyl oleate and 1.0g menthol, followed by adding 1.5g solubilizer polyethylene glycol 400 and 2.0g wetting agent Tween 80, and then add 9.0g purified water under magnetic stirring, mix evenly, apply it on the Babu backing, and dry it. The blank gel matrix not only protects the stability of the coated iron-based metal-organic framework composite drug delivery system, but also increases the close fit with the Babu backing and the skin, promotes the penetration of drugs, and improves the therapeutic effect, so as to obtain a compound Chinese medicine patch for regulating breast hyperplasia.

[0066] In this example, the prepared iron-based metal organic framework nanoparticles were subjected to scanning electron microscopy, and the coated iron-based metal organic framework composite drug delivery system was subjected to transmission electron microscopy to observe its microscopic morphology. Figure 1 This is a SEM image of the iron-based metal organic framework nanoparticles prepared in Example 1, magnified 100,000 times. Figure 2 This is a TEM image of the coated iron-based metal organic framework composite drug delivery system prepared in Example 1, magnified 40,000 times. Figure 1 The iron-based metal organic framework nanoparticles prepared in this embodiment present an octahedral structure, such as Figure 2 The coated iron-based metal organic framework composite drug-carrying system prepared in this embodiment has a spherical structure due to the drug loading and coating.

[0067] Example 2

[0068] This embodiment proposes a compound Chinese medicine patch for regulating breast hyperplasia, comprising the following components in parts by weight: 30 parts of an iron-based metal-organic framework composite drug delivery system, 8 parts of dopamine hydrochloride, 25 parts of a blank gel matrix, 20 parts of ethyl oleate, 6 parts of menthol, 10 parts of a solubilizer, 10 parts of a wetting agent, and 80 parts of water.

[0069] The iron-based metal organic framework composite drug delivery system comprises the following components in parts by weight: 15 parts of Chinese medicine diol plastids, 30 parts of iron-based metal organic framework nanoparticles, and 10 parts of camphor essential oil.

[0070] The Chinese medicine diol matrix comprises the following components in parts by weight: 10 parts of Chinese medicine granules, 40 parts of anhydrous ethanol, 10 parts of propylene glycol, 0.1 parts of octadecylamine and 1 part of soybean lecithin.

[0071] The Chinese medicine granules, whose raw materials include the following components in parts by weight: 3 parts of bupleurum, 3 parts of white peony root, 3 parts of cyperus, 3 parts of costus root, 3 parts of green peel, 3 parts of aurantium, 3 parts of angelica, 3 parts of safflower, 3 parts of peach kernel, 3 parts of ligusticum, and 3 parts of liquorice.

[0072] The preparation method of the iron-based metal organic framework composite drug delivery system specifically comprises the following steps:

[0073] (1) Add 10 times the amount of water to bupleurum, white peony root, cyperus, costusroot, green peel, fructus aurantii, angelica, safflower, peach kernel, ligusticum chuanxiong and liquorice, soak in a decoction machine for 2 hours, decoct once, extract with slight boiling for 2 hours, combine the decoctions, concentrate the collected filtrate to 1 / 6 of the original volume, and then freeze-dry. The main medicine is to soothe the liver and relieve depression, regulate the Chong and Ren meridians, and auxiliary medicines such as phlegm-resolving and stagnation-dissolving, and blood circulation-activating and blood stasis-removing are used in combination. The whole prescription has clear main and secondary functions, warms and clears at the same time, and uses tonifying and purging together. It is a two-way regulation, taking both the symptoms and the root into consideration, and plays the role of soothing the liver and relieving depression, promoting blood circulation and removing blood stasis, and dispersing stagnation and relieving pain, effectively regulating various symptoms of breast hyperplasia, and obtaining Chinese medicine granules;

[0074] (2) 10.0 g of camphor leaves were added to 200 mL of 3% sodium chloride solution. In a microwave light wave ultrasonic extractor, microwave treatment was first performed and then ultrasonic treatment was performed. During the microwave treatment, the microwave power was 400 W and the microwave time was 2 min. During the ultrasonic treatment, the ultrasonic power was 200 W and the ultrasonic time was 10 min. Microwave and ultrasonic assisted extraction is beneficial to increase the content of active substances such as volatile oils, flavonoids, lignin compounds, coumarins, borneol, camphor, etc. in the essential oil, and has better anti-inflammatory, antioxidant and antibacterial activities. Then, reflux extraction was performed in a water distillation extraction device for 3 h, the extraction device was washed with 5 mL of ethyl acetate, and dried with anhydrous sodium sulfate. The extract was concentrated under reduced pressure at room temperature. The camphor essential oil extracted by this process has a higher extraction rate and can also inhibit breast hyperplasia by regulating hormone levels. Therefore, the anti-inflammatory, antioxidant and immunomodulatory effects of camphor essential oil also play an important role in the treatment of breast hyperplasia, and camphor essential oil was obtained.

[0075] (3) 2 mL of anhydrous ethanol, 1 mL of propylene glycol and 5 mL of deionized water are prepared into a 10 mL solution for later use. 0.1 g of soybean lecithin and octadecylamine are weighed and added to 4 mL of anhydrous ethanol and slowly stirred until dissolved. The amount of octadecylamine added is 0.01 g. Octadecylamine can reduce the surface tension of the liquid, increase the wettability of the liquid and the solid surface, and help form a stable alcohol body structure. The solution is transferred to a round-bottom flask, heated to 30° C. in a water bath under vacuum, and rotary evaporated until the ethanol is completely removed. The solution and the Chinese medicine granules described in step (1) are then added thereto. The particles were placed on a heated magnetic stirrer, magnetically stirred for 30 minutes, at a temperature of 35°C and a speed of 300 rpm, and then further assisted in dissolution by ultrasound, with an ultrasonic power of 80 W, a working time of 5 seconds, and an interval time of 3 seconds, for 10 cycles. The bilayer structure of the diol plasmid encapsulates the Chinese medicine particles in closed vesicles, thereby increasing the encapsulation rate and drug loading. It also has a biomembrane function, strong deformation ability, better flexibility, and is easier to pass through the intercellular space, which can promote the transdermal absorption of the active ingredients in the Chinese medicine particles and the aggregation in the skin, thereby obtaining the Chinese medicine diol plasmid;

[0076] (4) 360.0 mg of 2-aminoterephthalic acid powder and 1.0 g of ferric chloride hexahydrate were dissolved in 40 mL of DMF, stirred at 100 °C for 10 h, centrifuged, and the precipitate was washed three times with DMF and 80% ethanol solution. Iron-based MIL-101 was used as a drug carrier, which could responsively release drugs at the lesion site and simultaneously trigger the release of iron ions, thereby catalyzing the Fenton reaction and inducing ferroptosis, which was beneficial to inhibit the carcinogenesis of breast hyperplasia, and obtain iron-based metal organic framework nanoparticles;

[0077] (5) Add the iron-based metal organic framework nanoparticles described in step (4) to the Chinese medicine diol plastids described in step (3), and then add the camphor essential oil described in step (2), and continue stirring for 24 hours. After the reaction is completed, centrifuge and wash the precipitate with ultrapure water for 3 times to remove the unloaded Chinese medicine diol plastids and camphor essential oil adsorbed on the surface. The encapsulation effect of the iron-based metal organic framework nanoparticles avoids the leakage problem of the Chinese medicine diol plastids during transdermal and storage. The porous structure of the iron-based metal organic framework can effectively load the Chinese medicine diol plastids and camphor essential oil, and control the release through its pore structure. It also has pH responsiveness, which not only increases the drug loading amount, but also enables the drug to be continuously released during transdermal absorption and enhances the effective release at the lesion site, thereby prolonging the drug action time and enhancing the therapeutic effect. An iron-based metal organic framework composite drug delivery system is obtained.

[0078] This embodiment provides a method for preparing a compound Chinese medicine patch for regulating breast hyperplasia, which specifically comprises the following steps:

[0079] S1. Pour 0.6 g of carbomer evenly into 10 mL of purified water to fully swell, add 4% sodium hydroxide solution by mass to adjust the pH to 6.8 to form a gel, add 4 mL of glycerol and 0.1 g of Tween 80, stir and dissolve to form solution A, then stir solution A at 35 °C and add 4 mL of purified water to form a gel matrix with carbomer, which can fit more closely on the Babu backing and reduce irritation to the skin, to obtain a blank gel matrix;

[0080] S2. Dissolve the iron-based metal-organic framework composite drug delivery system in 100 mL of water, add 2 mL of 25% ammonia solution and dopamine hydrochloride solid, continue stirring for 12 hours, collect the precipitate by centrifugation, and then wash it with ultrapure water 3 times. The amount of dopamine hydrochloride added is 0.8 g. Dopamine hydrochloride will self-polymerize in ammonia water to form polydopamine. Polydopamine, as a hydrophilic protective layer, can improve the dispersibility, biocompatibility and stability of the iron-based metal-organic framework in the skin, thereby facilitating the stability and release of the drug, improving the therapeutic effect of breast hyperplasia, and obtaining a coated iron-based metal-organic framework composite drug delivery system;

[0081] S3. Mix the coated iron-based metal-organic framework composite drug delivery system described in step S2 and the blank gel matrix described in step S1 evenly, then add them to the oil phase of 2.0g ethyl oleate and 0.6g menthol, followed by adding 1.0g solubilizer polyethylene glycol 400 and 1.0g wetting agent Tween 80, and then add 8.0g purified water under magnetic stirring, mix evenly, apply it on the Babu backing, and dry it. The blank gel matrix not only protects the stability of the coated iron-based metal-organic framework composite drug delivery system, but also increases the close fit with the Babu backing and the skin, promotes the penetration of drugs, and improves the therapeutic effect, so as to obtain a compound Chinese medicine patch for regulating breast hyperplasia.

[0082] Example 3

[0083] This embodiment proposes a compound Chinese medicine patch for regulating breast hyperplasia, comprising the following components in parts by weight: 35 parts of an iron-based metal-organic framework composite drug delivery system, 10 parts of dopamine hydrochloride, 27.5 parts of a blank gel matrix, 25 parts of ethyl oleate, 8 parts of menthol, 12.5 parts of a solubilizer, 15 parts of a wetting agent, and 85 parts of water.

[0084] The iron-based metal organic framework composite drug delivery system comprises the following components in parts by weight: 20 parts of traditional Chinese medicine diol plastids, 40 parts of iron-based metal organic framework nanoparticles, and 15 parts of camphor essential oil.

[0085] The Chinese medicine diol matrix comprises the following components in parts by weight: 15 parts of Chinese medicine granules, 45 parts of anhydrous ethanol, 15 parts of propylene glycol, 0.15 parts of octadecylamine and 1.5 parts of soybean lecithin.

[0086] The Chinese medicine granules, whose raw materials include the following components in parts by weight: 4 parts of bupleurum, 4 parts of white peony root, 4 parts of cyperus, 4 parts of costusroot, 4 parts of green peel, 4 parts of fructus aurantii, 4 parts of angelica, 4 parts of safflower, 4 parts of peach kernel, 4 parts of ligusticum, and 4 parts of liquorice.

[0087] The preparation method of the iron-based metal organic framework composite drug delivery system specifically comprises the following steps:

[0088] (1) Add 11 times the amount of water to bupleurum, white peony root, cyperus, costusroot, green peel, fructus aurantii, angelica, safflower, peach kernel, ligusticum chuanxiong and liquorice, soak in a decoction machine for 2.5 hours, decoct once, extract with slight boiling for 2.5 hours, combine the decoctions, concentrate the collected filtrate to 1 / 5 of the original volume, and then freeze-dry. The main medicine is to soothe the liver and relieve depression, regulate the Chong and Ren meridians, and auxiliary medicines such as phlegm-resolving and stagnation-dissolving, and blood circulation-activating and blood stasis-removing are used in combination. The whole prescription has clear priorities, warms and clears at the same time, and uses tonifying and purging together. It is a two-way regulation, taking both the symptoms and the root into consideration, and plays the role of soothing the liver and relieving depression, promoting blood circulation and removing blood stasis, and dispersing stagnation and relieving pain, effectively regulating various symptoms of breast hyperplasia, and obtaining Chinese medicine granules;

[0089] (2) 10.0 g of camphor leaves were added to 200 mL of 3% sodium chloride solution. In a microwave light wave ultrasonic extractor, microwave treatment was first performed and then ultrasonic treatment was performed. During the microwave treatment, the microwave power was 450 W and the microwave time was 2.5 min. During the ultrasonic treatment, the ultrasonic power was 250 W and the ultrasonic time was 15 min. Microwave and ultrasonic assisted extraction was beneficial to increase the content of active substances such as volatile oils, flavonoids, lignin compounds, coumarins, borneol, camphor, etc. in the essential oil, and it has better anti-inflammatory, antioxidant and antibacterial activities. Then, reflux extraction was performed in a water distillation extraction device for 3.5 h, the extraction device was washed with 5 mL of ethyl acetate, and dried with anhydrous sodium sulfate. The extract was concentrated under reduced pressure at room temperature. The camphor essential oil extracted by this process has a higher extraction rate and can also inhibit breast hyperplasia by regulating hormone levels. Therefore, the anti-inflammatory, antioxidant and immunomodulatory effects of camphor essential oil also play an important role in the treatment of breast hyperplasia. Camphor essential oil was obtained.

[0090] (3) 2.5 mL of anhydrous ethanol, 1.5 mL of propylene glycol and 6 mL of deionized water were prepared into a 10 mL solution for later use. 0.15 g of soybean lecithin and octadecylamine were weighed and added to 4 mL of anhydrous ethanol and slowly stirred until dissolved. The amount of octadecylamine added was 0.015 g. Octadecylamine can reduce the surface tension of the liquid, increase the wettability of the liquid and the solid surface, and help form a stable alcohol body structure. The solution was transferred to a round-bottom flask and heated to 35°C in a water bath under vacuum. The ethanol was completely removed by rotary evaporation. The solution and the medium described in step (1) were then added. The drug particles were placed on a heated magnetic stirrer and magnetically stirred for 35 minutes at a temperature of 37.5°C and a speed of 350 rpm. Ultrasound was then used to further assist in dissolution. The ultrasonic power was 90 W, the working time was 5 seconds, the interval time was 3 seconds, and 10 cycles were performed. The bilayer structure of the diol plasmid encapsulated the Chinese medicine particles in the closed vesicles, which improved the encapsulation rate and drug loading. It also had a biomembrane function, strong deformation ability, better flexibility, and was easier to pass through the intercellular space, which could promote the transdermal absorption of the active ingredients in the Chinese medicine particles and the aggregation in the skin, and obtain the Chinese medicine diol plasmid.

[0091] (4) 360.0 mg of 2-aminoterephthalic acid powder and 1.0 g of ferric chloride hexahydrate were dissolved in 40 mL of DMF, stirred at 110 °C for 15 h, centrifuged, and the precipitate was washed three times with DMF and 80% ethanol solution by mass. Iron-based MIL-101 was used as a drug carrier, which could responsively release drugs at the lesion site and simultaneously trigger the release of iron ions, thereby catalyzing the Fenton reaction and inducing ferroptosis, which was beneficial to inhibit the carcinogenesis of breast hyperplasia, and obtain iron-based metal organic framework nanoparticles;

[0092] (5) Add the iron-based metal organic framework nanoparticles described in step (4) to the Chinese medicine diol plastids described in step (3), and then add the camphor essential oil described in step (2), and continue stirring for 24 hours. After the reaction is completed, centrifuge and wash the precipitate with ultrapure water for 4 times to remove the unloaded Chinese medicine diol plastids and camphor essential oil adsorbed on the surface. The encapsulation effect of the iron-based metal organic framework nanoparticles avoids the leakage problem of the Chinese medicine diol plastids during transdermal and storage. The porous structure of the iron-based metal organic framework can effectively load the Chinese medicine diol plastids and camphor essential oil, and control the release through its pore structure. It also has pH responsiveness, which not only increases the drug loading amount, but also enables the drug to be continuously released during transdermal absorption and enhances the effective release at the lesion site, thereby prolonging the drug action time and enhancing the therapeutic effect. An iron-based metal organic framework composite drug delivery system is obtained.

[0093] This embodiment provides a method for preparing a compound Chinese medicine patch for regulating breast hyperplasia, which specifically comprises the following steps:

[0094] S1. Pour 0.8g of carbomer evenly into 10mL of purified water to fully swell, add 4% sodium hydroxide solution by mass to adjust the pH to 6.8 to form a gel, add 4mL of glycerol and 0.15g of Tween 80, stir and dissolve to form solution A, then stir solution A at 35°C and add 4mL of purified water to form a gel matrix with carbomer, which can fit more closely on the Babu backing and reduce irritation to the skin, to obtain a blank gel matrix;

[0095] S2. Dissolve the iron-based metal-organic framework composite drug delivery system in 100 mL of water, add 2 mL of 25% ammonia solution and dopamine hydrochloride solid, continue stirring for 12 hours, collect the precipitate by centrifugation, and then wash it with ultrapure water 3 times. The amount of dopamine hydrochloride added is 1.0 g. Dopamine hydrochloride will self-polymerize in ammonia water to form polydopamine. Polydopamine, as a hydrophilic protective layer, can improve the dispersibility, biocompatibility and stability of the iron-based metal-organic framework in the skin, thereby facilitating the stability and release of the drug, improving the therapeutic effect of breast hyperplasia, and obtaining a coated iron-based metal-organic framework composite drug delivery system;

[0096] S3. Mix the coated iron-based metal-organic framework composite drug delivery system described in step S2 and the blank gel matrix described in step S1 evenly, then add them to the oil phase of 2.5g ethyl oleate and 0.8g menthol, followed by adding 1.25g solubilizer polyethylene glycol 400 and 1.5g wetting agent Tween 80, and then add 8.5g purified water under magnetic stirring, mix evenly, apply it on the Babu backing, and dry it. The blank gel matrix not only protects the stability of the coated iron-based metal-organic framework composite drug delivery system, but also increases the close fit with the Babu backing and the skin, promotes the penetration of drugs, and improves the therapeutic effect, so as to obtain a compound Chinese medicine patch for regulating breast hyperplasia.

[0097] Example 4

[0098] This embodiment proposes a compound Chinese medicine patch for regulating breast hyperplasia, comprising the following components in parts by weight: 40 parts of an iron-based metal-organic framework composite drug delivery system, 8 parts of dopamine hydrochloride, 25 parts of a blank gel matrix, 30 parts of ethyl oleate, 10 parts of menthol, 15 parts of a solubilizer, 20 parts of a wetting agent, and 90 parts of water.

[0099] The iron-based metal organic framework composite drug delivery system comprises the following components in parts by weight: 25 parts of traditional Chinese medicine diol plastids, 50 parts of iron-based metal organic framework nanoparticles, and 10 parts of camphor essential oil.

[0100] The Chinese medicine diol matrix comprises the following components in parts by weight: 20 parts of Chinese medicine granules, 50 parts of anhydrous ethanol, 20 parts of propylene glycol, 0.1 parts of octadecylamine and 2 parts of soybean lecithin.

[0101] The Chinese medicine granules, whose raw materials include the following components in parts by weight: 5 parts of bupleurum, 5 parts of white peony root, 5 parts of cyperus, 5 parts of costusroot, 5 parts of green peel, 5 parts of fructus aurantii, 5 parts of angelica, 5 parts of safflower, 5 parts of peach kernel, 5 parts of ligusticum, and 5 parts of liquorice.

[0102] The preparation method of the iron-based metal organic framework composite drug delivery system specifically comprises the following steps:

[0103] (1) Add 12 times the amount of water to bupleurum, white peony root, cyperus, costusroot, green peel, fructus aurantii, angelica, safflower, peach kernel, ligusticum chuanxiong and liquorice, soak in a decoction machine for 2 hours, decoct twice, extract with slight boiling for 2 hours, combine the decoctions, concentrate the collected filtrate to 1 / 6 of the original volume, and then freeze-dry. The main medicine is to soothe the liver and relieve depression, regulate the Chong and Ren meridians, and auxiliary medicines such as phlegm-resolving and stagnation-dissolving, and blood circulation-activating and blood stasis-removing are used in combination. The whole prescription has clear main and secondary functions, warms and clears at the same time, and uses tonifying and purging together. It is a two-way regulation, taking both the symptoms and the root into consideration, and plays the role of soothing the liver and relieving depression, promoting blood circulation and removing blood stasis, and dispersing stagnation and relieving pain, effectively regulating various symptoms of breast hyperplasia, and obtaining Chinese medicine granules;

[0104] (2) 10.0 g of camphor leaves were added to 200 mL of 3% sodium chloride solution. In a microwave light wave ultrasonic extractor, microwave treatment was first performed and then ultrasonic treatment was performed. During the microwave treatment, the microwave power was 500 W and the microwave time was 2 min. During the ultrasonic treatment, the ultrasonic power was 300 W and the ultrasonic time was 10 min. Microwave and ultrasonic assisted extraction is beneficial to increase the content of active substances such as volatile oils, flavonoids, lignin compounds, coumarins, borneol, camphor, etc. in the essential oil, and has better anti-inflammatory, antioxidant and antibacterial activities. Then, reflux extraction was performed in a water distillation extraction device for 3 h, the extraction device was washed with 5 mL of ethyl acetate, and dried with anhydrous sodium sulfate. The extract was concentrated under reduced pressure at room temperature. The camphor essential oil extracted by this process has a higher extraction rate and can also inhibit breast hyperplasia by regulating hormone levels. Therefore, the anti-inflammatory, antioxidant and immunomodulatory effects of camphor essential oil also play an important role in the treatment of breast hyperplasia, and camphor essential oil was obtained.

[0105] (3) 3 mL of anhydrous ethanol, 2 mL of propylene glycol and 7 mL of deionized water are prepared into a 10 mL solution for later use. 0.2 g of soybean lecithin and octadecylamine are weighed and added to 4 mL of anhydrous ethanol and slowly stirred until dissolved. The amount of octadecylamine added is 0.01 g. Octadecylamine can reduce the surface tension of the liquid, increase the wettability of the liquid and the solid surface, and help form a stable alcohol body structure. The solution is transferred to a round-bottom flask, heated to 40° C. in a water bath under vacuum, and rotary evaporated until the ethanol is completely removed. The solution and the Chinese medicine granules described in step (1) are then added thereto. The particles were placed on a heated magnetic stirrer, magnetically stirred for 30 minutes, at a temperature of 40°C and a speed of 400 rpm, and then ultrasound was used to further assist dissolution, with an ultrasound power of 100 W, a working time of 5 seconds, an interval time of 3 seconds, and 10 cycles. The bilayer structure of the diol plasmid encapsulates the Chinese medicine particles in closed vesicles, thereby improving the encapsulation rate and drug loading. It also has a biomembrane function, strong deformation ability, better flexibility, and is easier to pass through the intercellular space, which can promote the transdermal absorption of the active ingredients in the Chinese medicine particles and the aggregation in the skin, thereby obtaining the Chinese medicine diol plasmid;

[0106] (4) 360.0 mg of 2-aminoterephthalic acid powder and 1.0 g of ferric chloride hexahydrate were dissolved in 40 mL of DMF, stirred at 120 °C for 10 h, centrifuged, and the precipitate was washed three times with DMF and 80% ethanol solution. Iron-based MIL-101 was used as a drug carrier, which could responsively release drugs at the lesion site and simultaneously trigger the release of iron ions, thereby catalyzing the Fenton reaction and inducing ferroptosis, which was beneficial to inhibit the carcinogenesis of breast hyperplasia, and obtain iron-based metal organic framework nanoparticles;

[0107] (5) Add the iron-based metal organic framework nanoparticles described in step (4) to the Chinese medicine diol plastids described in step (3), and then add the camphor essential oil described in step (2), and continue stirring for 24 hours. After the reaction is completed, centrifuge and wash the precipitate with ultrapure water for 5 times to remove the unloaded Chinese medicine diol plastids and camphor essential oil adsorbed on the surface. The encapsulation effect of the iron-based metal organic framework nanoparticles avoids the leakage problem of the Chinese medicine diol plastids during transdermal and storage. The porous structure of the iron-based metal organic framework can effectively load the Chinese medicine diol plastids and camphor essential oil, and control the release through its pore structure. It also has pH responsiveness, which not only increases the drug loading amount, but also enables the drug to be continuously released during transdermal absorption and enhances the effective release at the lesion site, thereby prolonging the drug action time and enhancing the therapeutic effect. An iron-based metal organic framework composite drug delivery system is obtained.

[0108] This embodiment provides a method for preparing a compound Chinese medicine patch for regulating breast hyperplasia, which specifically comprises the following steps:

[0109] S1. Pour 0.6 g of carbomer evenly into 10 mL of purified water to fully swell, add 4% sodium hydroxide solution by mass to adjust the pH to 6.8 to form a gel, add 4 mL of glycerol and 0.2 g of Tween 80, stir and dissolve to form solution A, then stir solution A at 35 °C and add 4 mL of purified water to form a gel matrix with carbomer, which can fit more closely on the Babu backing and reduce irritation to the skin, to obtain a blank gel matrix;

[0110] S2. Dissolve the iron-based metal organic framework composite drug delivery system in 100 mL of water, add 2 mL of 25% ammonia solution and dopamine hydrochloride solid, continue stirring for 12 hours, collect the precipitate by centrifugation, and then wash it with ultrapure water 3 times. The amount of dopamine hydrochloride added is 0.8 g. Dopamine hydrochloride will self-polymerize in ammonia water to form polydopamine. Polydopamine, as a hydrophilic protective layer, can improve the dispersibility, biocompatibility and stability of the iron-based metal organic framework in the skin, thereby facilitating the stability and release of the drug, improving the therapeutic effect of breast hyperplasia, and obtaining a coated iron-based metal organic framework composite drug delivery system;

[0111] S3. Mix the coated iron-based metal-organic framework composite drug delivery system described in step S2 and the blank gel matrix described in step S1 evenly, then add to the oil phase of 3.0g ethyl oleate and 1.0g menthol, followed by adding 1.5g solubilizer polyethylene glycol 400 and 2.0g wetting agent Tween 80, and then add 9.0g purified water under magnetic stirring, mix evenly, apply it on the Babu backing, and dry it. The blank gel matrix not only protects the stability of the coated iron-based metal-organic framework composite drug delivery system, but also increases the close fit with the Babu backing and the skin, promotes the penetration of drugs, and improves the therapeutic effect, so as to obtain a compound Chinese medicine patch for regulating breast hyperplasia.

[0112] Comparative Example 1

[0113] This comparative example provides a compound Chinese medicine patch for regulating breast hyperplasia, which differs from Example 1 in that the iron-based metal-organic framework composite drug delivery system does not contain iron-based metal-organic framework nanoparticles; the preparation method of the iron-based metal-organic framework composite drug delivery system does not include step (4); and the preparation method of the compound Chinese medicine patch for regulating breast hyperplasia is the same as that of Example 1.

[0114] Comparative Example 2

[0115] This comparative example provides a compound Chinese medicine patch for regulating breast hyperplasia, which differs from Example 1 in that the iron-based metal-organic framework composite drug delivery system does not contain camphor essential oil; the preparation method of the iron-based metal-organic framework composite drug delivery system does not include step (2); and the preparation method of the compound Chinese medicine patch for regulating breast hyperplasia is the same as that of Example 1.

[0116] Comparative Example 3

[0117] This comparative example provides a compound Chinese medicine patch for regulating breast hyperplasia, which differs from Example 1 in that the compound Chinese medicine patch for regulating breast hyperplasia does not contain dopamine hydrochloride; the preparation method of the iron-based metal organic framework composite drug carrier system is the same as that of Example 1; the preparation method of the compound Chinese medicine patch for regulating breast hyperplasia does not include step S2.

[0118] Experimental Example 1

[0119] Transdermal absorption test

[0120] Test sample: the compound Chinese medicine patch for regulating breast hyperplasia prepared in Examples 1-4 and Comparative Examples 1-3.

[0121] Test method: (1) Accurately weigh 1g / mL of Chinese medicine diol plasmid and dilute it to 20mg / mL. Use distilled water as blank and use UV spectrophotometer to scan in the wavelength range of 300-500nm. The maximum absorption is at 350nm. Then dilute the Chinese medicine component into a drug solution of 0-20mg / mL, measure the absorbance A at 350nm, and get the standard curve equation A=0.1078C+0.0225 after regression. 2 =0.9945, the best linear range is 2-8 mg / mL;

[0122] (2) Six-week-old male SD rats (200±20g) were selected for this study and divided into 8 groups, with 5 rats in each group. Under laboratory conditions, the SD rats were adaptively fed with normal drinking water and diet for one week. One group continued to be fed normally as the normal group, and the remaining 7 groups were intramuscularly injected with 0.5mg / (kg / d) of estradiol benzoate for 20 consecutive days, and then intramuscularly injected with 4mg / (kg / d) of progesterone for 5 consecutive days to induce breast hyperplasia, as the experimental group. Then, the SD rats were killed by cervical dislocation, and the breasts of the SD rat control group and the experimental group were depilated with sodium sulfate. The skin of the breasts was removed, and the subcutaneous fat and connective tissue were removed. The skin integrity was cleaned and checked, and stored at 4°C for later use.

[0123] (3) Frans diffusion cell was used to conduct drug skin permeability test. The skin sample was sandwiched between the supply chamber and the receiving chamber of the Frans diffusion cell. The stratum corneum faced the supply chamber. The circular effective diffusion diameter of the bottom of the supply chamber was 1.5 cm. The dermis faced the receiving chamber. The volume of the receiving chamber was 7 mL. The receiving chamber contained 20 mL of PBS buffer and was stirred at 100 rpm with magnetic beads. The test samples were placed in the supply chamber and evenly applied on the ex vivo mouse skin. The normal group used the test sample of Example 1. The receiving chamber simulated the subcutaneous physiological temperature of 37°C. 1 mL of the receptor solution was taken out at 3 h, 6 h, 9 h, and 12 h after administration. 1 mL of PBS buffer was supplemented at the same time to ensure that the volume of PBS remained unchanged. The supernatant was filtered through a microporous membrane. The drug content in the taken receptor solution was determined by ultraviolet method. The cumulative permeation amount (mg / cm 2 ):

[0124] Cumulative penetration =

[0125] Among them, C n is the drug concentration measured at the nth sampling point, V is the volume of the receiving chamber, and S is the effective diffusion area.

[0126] Figure 3The cumulative permeation results of Examples 1-4, Comparative Examples 1-3 and the normal group are shown in the figure. As shown in the figure, the cumulative permeation of Examples 1-4 at 3h, 6h, 9h and 12h is 3.5-5.0 mg / cm 2 , 5.1-6.5mg / cm 2 , 6.3-7.6mg / cm 2 , 7.0-8.2mg / cm 2 , indicating that the cumulative penetration under the skin of the lesion site is high; the cumulative penetration of the normal group at 3h, 6h, 9h, and 12h was 1.9mg / cm 2 , 2.9mg / cm 2 、3.6mg / cm 2 , 4.3mg / cm 2 , indicating that the cumulative penetration under normal skin is less than that under the skin of the lesion site; the cumulative penetration of 3h, 6h, 9h, and 12h in Comparative Examples 1-3 were 0.8-1.6 mg / cm 2 1.9-2.5mg / cm 2 , 2.5-3.3mg / cm 2 3.1-3.9mg / cm 2 , indicating that the cumulative penetration amount under the skin of the lesion site is small; the iron-based metal-organic framework composite drug delivery system of comparative example 1 does not contain iron-based metal-organic framework nanoparticles, has no pH responsiveness, and cannot be continuously released through the porous structure, resulting in a small cumulative penetration amount under the skin of the lesion site; the iron-based metal-organic framework composite drug delivery system of comparative example 2 does not contain camphor essential oil, which is not conducive to its own penetration, nor is it conducive to promoting the transdermal absorption and aggregation of Chinese medicine diol plasmids in the skin, resulting in a small cumulative penetration amount under the skin of the lesion site; the compound Chinese medicine patch for regulating breast hyperplasia in comparative example 3 does not contain dopamine hydrochloride, which is not conducive to improving the dispersion and compatibility of the iron-based metal-organic framework composite drug delivery system in the skin, limits the effect, and results in a small cumulative penetration amount under the skin of the lesion site.

[0127] Experimental Example 2

[0128] Treatment efficacy experiment

[0129] Test sample: the compound Chinese medicine patch for regulating breast hyperplasia prepared in Examples 1-4 and Comparative Examples 1-3.

[0130] Test method: 140 patients with different degrees of breast hyperplasia were selected, with specific manifestations of breast lumps or nodules, often accompanied by chest and flank distension, emotional distress, and even mental tension, irritability, anxiety and depression. The age distribution was 30-60 years old. According to the order of the patients' admission time, the random number table method was used to determine the patients' inclusion in the group. They were divided into 7 groups, 20 in each group, and each group used the corresponding test sample. The method of taking the test sample was to apply the test sample to the affected part, one patch a day, and apply it again after one day. The effect was observed after 30 days. At the same time, the treatment effect was determined according to the following standards, and the treatment efficiency (%) was calculated, specifically:

[0131] Effective: The symptoms of breast hyperplasia completely disappeared, and the symptoms of breast hyperplasia changed from severe to moderate, from moderate to mild, and from mild to normal;

[0132] Ineffective: There was no significant improvement in the symptoms of breast hyperplasia.

[0133] The formula for calculating the treatment effectiveness is as follows:

[0134] Treatment effectiveness (%) = effective number of people / 20×100%

[0135] Figure 4 The results of the therapeutic efficacy of Examples 1-4 and Comparative Examples 1-3 are shown in the figure; as shown in the figure, the therapeutic efficacy of Examples 1-4 is 80-95%, indicating that the therapeutic effect of breast hyperplasia is better; the therapeutic efficacy of Comparative Examples 1-3 is 55-65%, indicating that the therapeutic effect of breast hyperplasia is not good; the iron-based metal organic framework composite drug delivery system of Comparative Example 1 does not contain iron-based metal organic framework nanoparticles, which increases the risk of leakage of the Chinese medicine diol plasmid, and cannot respond to release and sustained release at the lesion site, resulting in breast hyperplasia. The therapeutic effect is poor; the iron-based metal-organic framework composite drug delivery system of comparative example 2 does not contain camphor essential oil, which can neither exert the therapeutic effect of camphor essential oil on breast hyperplasia nor synergistically promote the transdermal absorption of Chinese medicine diol plasmids, resulting in poor therapeutic effect on breast hyperplasia; the compound Chinese medicine patch for regulating breast hyperplasia of comparative example 3 does not contain dopamine hydrochloride, which is not conducive to the dispersibility and compatibility of the iron-based metal-organic framework composite drug delivery system in the skin, thereby limiting its therapeutic effect, resulting in poor therapeutic effect on breast hyperplasia.

[0136] The above experimental results show that the transdermal absorbability and therapeutic effect of Examples 1-4 of the present invention are significantly better than those of Comparative Examples 1-3. Among them, the cumulative permeation amount under the skin of the lesion site of Example 1 using the iron-based metal-organic framework composite drug delivery system and dopamine hydrochloride is greater, and the therapeutic effect of breast hyperplasia is better. The Chinese medicine diol plastids and camphor essential oil loaded with iron-based metal-organic framework nanoparticles not only avoid the leakage of the Chinese medicine diol plastids, but also give pH responsiveness to the lesion site. Its porous structure increases the drug loading amount, and also enables the drug to be continuously and effectively released during the transdermal absorption process, effectively prolonging the drug's action time and therapeutic effectiveness. Among them, camphor essential oil can inhibit breast hyperplasia by regulating hormone levels, and also synergistically promotes the transdermal absorption and aggregation of Chinese medicine diol plastids in the skin. Polydopamine forms a hydrophilic protective layer on the surface of the iron-based metal-organic framework composite drug delivery system, improves its dispersibility and biocompatibility in the skin, thereby helping the iron-based metal-organic framework composite drug delivery system to better exert its therapeutic effect.

[0137] While the embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that many changes, modifications, substitutions and variations can be made to the embodiments without departing from the principles and spirit of the invention.

[0138] The present invention and its implementation methods are described above, which is not restrictive. The drawings are only one of the implementation methods of the present invention, and the actual application is not limited thereto. In short, if ordinary technicians in the field are inspired by it and design methods and embodiments similar to the technical solution without creativity without departing from the purpose of the invention, they should all fall within the protection scope of the present invention.

Claims

1. A compound Chinese medicine patch for regulating breast hyperplasia, characterized in that: The compound Chinese medicine patch for regulating breast hyperplasia comprises the following components in parts by weight: 30-40 parts of an iron-based metal organic framework composite drug delivery system, 8-12 parts of dopamine hydrochloride, 25-30 parts of a blank gel matrix, 20-30 parts of ethyl oleate, 6-10 parts of menthol, 10-15 parts of a solubilizer, 10-20 parts of a wetting agent, and 80-90 parts of water; the iron-based metal organic framework composite drug delivery system comprises the following components in parts by weight: 15-25 parts of a Chinese medicine diol plastid, 30-50 parts of an iron-based metal organic framework nanoparticles, and 10-20 parts of a camphor tree. 10-20 parts of essential oil; the Chinese medicine diol matrix comprises the following components in parts by weight: 10-20 parts of Chinese medicine granules, 40-50 parts of anhydrous ethanol, 10-20 parts of propylene glycol, 0.1-0.2 parts of octadecylamine, and 1-2 parts of soybean lecithin; the raw materials of the Chinese medicine granules include the following components in parts by weight: 3-5 parts of bupleurum, 3-5 parts of white peony root, 3-5 parts of cyperus, 3-5 parts of costusroot, 3-5 parts of green peel, 3-5 parts of fructus aurantii, 3-5 parts of angelica, 3-5 parts of safflower, 3-5 parts of peach kernel, 3-5 parts of ligusticum, and 3-5 parts of liquorice.

2. A method for preparing the compound Chinese medicine patch for regulating breast hyperplasia according to claim 1, characterized in that: The specific steps include: S1. Pour 0.6-1.0g of carbomer evenly into 10mL of purified water to fully swell, add 4% sodium hydroxide solution to adjust the pH to 6.8 to form a gel, add 4mL of glycerol and 0.1-0.2g of Tween 80, stir and dissolve to form solution A, then stir solution A at 35°C and add 4mL of purified water to obtain a blank gel matrix; S2. Dissolve the iron-based metal-organic framework composite drug delivery system in 100 mL of water, add 2 mL of 25% ammonia solution and dopamine hydrochloride solid, continue stirring for 12 hours, collect the precipitate by centrifugation, and then wash it with ultrapure water for 3 times to obtain a coated iron-based metal-organic framework composite drug delivery system; S3. Mix the coated iron-based metal-organic framework composite drug delivery system described in step S2 and the blank gel matrix described in step S1 evenly, then add to the oil phase of 2.0-3.0g ethyl oleate and 0.6-1.0g menthol, followed by adding 1.0-1.5g solubilizer polyethylene glycol 400 and 1.0-2.0g wetting agent Tween 80, and then add 8.0-9.0g purified water under magnetic stirring, mix evenly, apply on the Babu backing, and dry to obtain a compound Chinese medicine patch for regulating breast hyperplasia.

3. The method for preparing the compound Chinese medicine patch for regulating breast hyperplasia according to claim 2, characterized in that: In step S2, the amount of dopamine hydrochloride added is 0.8-1.2 g.

4. The method for preparing the compound Chinese medicine patch for regulating breast hyperplasia according to claim 3, characterized in that: The preparation method of the iron-based metal organic framework composite drug delivery system specifically comprises the following steps: (1) Add 10-12 times the amount of water to bupleurum, white peony root, cyperus rotundus, costusroot, green peel, fructus aurantii, angelica, safflower, peach kernel, ligusticum chuanxiong and liquorice in a decoction machine and soak for 2-3 hours, decoct 1-2 times, extract at a low boiling temperature for 2-3 hours, combine the decoctions, concentrate the collected filtrate to 1 / 6 to 1 / 5 of the original volume, and then freeze-dry to obtain Chinese medicine granules; (2) 10.0 g of camphor leaves were added to 200 mL of a 3% sodium chloride solution, and the leaves were first subjected to microwave treatment in a microwave light wave ultrasonic extractor, and then to ultrasonic treatment. The leaves were then subjected to reflux extraction in a water distillation extraction device for 3-4 h, the extraction device was washed with 5 mL of ethyl acetate, and dried with anhydrous sodium sulfate. The extract was concentrated under reduced pressure at room temperature to obtain camphor essential oil. (3) 2-3 mL of anhydrous ethanol, 1-2 mL of propylene glycol and 5-7 mL of deionized water are prepared into a 10 mL solution for standby use, 0.1-0.2 g of soybean lecithin and octadecylamine are weighed and added to 4 mL of anhydrous ethanol, and slowly stirred until dissolved, and then transferred to a round-bottom flask. Under vacuum conditions, the mixture is heated to 30-40° C. in a water bath, and rotary evaporated until the ethanol is completely removed. Then, the solution and the Chinese medicine particles described in step (1) are added thereto, and the mixture is placed on a heated magnetic stirrer, and magnetically stirred for 30-40 min at a temperature of 35-40° C. and a rotation speed of 300-400 rpm. Then, ultrasound is used to further assist dissolution, with an ultrasonic power of 80-100 W, a working time of 5 s, and an interval time of 3 s. Ten cycles are performed to obtain a Chinese medicine diol plasmid; (4) dissolving 360.0 mg of 2-aminoterephthalic acid powder and 1.0 g of ferric chloride hexahydrate in 40 mL of DMF, reacting and stirring at 100-120° C. for 10-20 h, centrifuging, and washing the precipitate with DMF and 80% by mass ethanol solution three times to obtain iron-based metal organic framework nanoparticles; (5) Adding the iron-based metal organic framework nanoparticles described in step (4) to the Chinese medicine diol plasmids described in step (3), and then adding the camphor essential oil described in step (2), stirring is continued for 24 hours. After the reaction is completed, centrifugation is performed, and the precipitate is washed with ultrapure water for 3-5 times to remove the unloaded Chinese medicine diol plasmids and camphor essential oil adsorbed on the surface, thereby obtaining an iron-based metal organic framework composite drug delivery system.

5. The method for preparing the compound Chinese medicine patch for regulating breast hyperplasia according to claim 4, characterized in that: In step (2), during the microwave treatment, the microwave power is 400-500 W, and the microwave time is 2-3 min. During the ultrasonic treatment, the ultrasonic power is 200-300 W, and the ultrasonic time is 10-20 min.

6. The method for preparing the compound Chinese medicine patch for regulating breast hyperplasia according to claim 5, characterized in that: In step (3), the amount of octadecylamine added is 0.01-0.02 g.

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