Medicinal preparation for treating hyperplasia of mammary glands and preparation method thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical preparation for treating hyperplasia of mammary glands and a preparation method thereof, and the pharmaceutical preparation for treating hyperplasia of mammary glands comprises a drug-loaded microneedle layer, a backing layer connected with the drug-loaded microneedle layer and a medical blank adhesive plaster adhered to the backing layer. The prepared medicine preparation is a traditional Chinese medicine compound microneedle patch, the designed traditional Chinese medicine compound has the effects of soothing liver-qi stagnation, promoting blood circulation to remove blood stasis, reducing swelling and removing stasis and the like, a micro-emulsion system formed through the synergistic effect of the traditional Chinese medicine compound and a soluble microneedle matrix has the effects of moisturizing, diminishing inflammation, resisting bacteria and resisting oxidation, the skin permeability of the medicine is improved, and meanwhile, the effect of improving the skin quality is achieved. The drug sustained release and skin protection effects are realized, the effective concentration of the drug at the hyperplasia part of mammary glands can be maintained, and the treatment effect is enhanced.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and particularly relates to a pharmaceutical preparation for treating breast hyperplasia and a preparation method thereof. Background Art

[0002] Fibrocystic breast disease is a common breast disease characterized by abnormal proliferation of non-cancerous cells in breast tissue, which may cause symptoms such as breast swelling, pain and breast lumps, and in severe cases, there is a risk of cancer. In recent years, the incidence of the disease has been increasing year by year. Existing treatments include drug therapy, surgical resection and physical therapy, but all have certain limitations and side effects. Among them, drug therapy can relieve symptoms, but long-term use may cause liver and kidney damage; although surgical treatment can effectively remove diseased tissue, it is more traumatic and has a longer postoperative recovery period. Therefore, seeking an efficient, safe and non-invasive treatment method is the focus of current research.

[0003] With the development of modern drug delivery technology, Chinese medicine microneedle patches have become a new type of topical drug preparation. They penetrate the stratum corneum of the skin through microneedles and deliver drug ingredients directly to the subcutaneous tissue, avoiding the reduced efficacy of traditional oral and topical drugs due to poor gastrointestinal absorption or skin barrier effects. The characteristics of Chinese medicine microneedle patches are that they can improve the bioavailability of drugs, reduce systemic adverse reactions, and have good patient compliance and application prospects.

[0004] However, there is currently little research and application of traditional Chinese medicine microneedle patches for breast hyperplasia, and the existing technology urgently needs further optimization and innovation. Summary of the invention

[0005] In view of the above situation, the present invention provides a drug preparation for treating breast hyperplasia and a preparation method thereof. The dosage form is a traditional Chinese medicine compound microneedle patch, which uses a compound clear paste prepared from the crude drugs of Bupleurum chinense, Curcuma aromatica, Cyperus rotundus, White Peony Root, Frankincense, Pinellia ternata, Fritillaria thunbergii and Prunella vulgaris as the effective ingredients, uses a PDMS (polydimethylsiloxane) microneedle negative mold as the drug preparation mold, uses a composite gel material to prepare a soluble drug-loaded microneedle layer, and uses a polymer with certain flexibility and tensile strength to prepare a microneedle backing layer. The prepared microneedles are strong and not easy to collapse, and have strong skin puncture ability. Under the synergistic effect of multiple components, it can achieve an effective combination of improved drug penetration rate and skin repair and regeneration, thereby enhancing the therapeutic effect.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is as follows: The invention provides a drug preparation for treating breast hyperplasia, which comprises a drug-loaded microneedle layer, a backing layer connected to the drug-loaded microneedle layer, and a medical blank adhesive tape adhered to the backing layer.

[0007] Furthermore, the drug-loaded microneedle layer is prepared from the following raw materials: a traditional Chinese medicine compound paste, a microneedle matrix and purified water.

[0008] Furthermore, the Chinese medicine compound clear paste is prepared from the following raw materials: northern bupleurum, yellow turmeric, cyperus, white peony, frankincense, pinellia, thunbergia bulb, selfheal, camphor essential oil, turpentine and 70% (v / v) ethanol solution, and the weight ratio of the northern bupleurum, yellow turmeric, cyperus, white peony, frankincense, pinellia, thunbergia bulb, selfheal, camphor essential oil and turpentine is 3:2:1.5:1:1:0.5:0.5:0.5:1:1.

[0009] Furthermore, the microneedle matrix is ​​selected from one or more of CMC-Na (sodium carboxymethyl cellulose), CS (chondroitin sulfate), silk fibroin, PVP K90 (polyvinyl pyrrolidone K90), and Gantrez AN-139 (methyl vinyl ether-maleic anhydride copolymer AN-139).

[0010] Furthermore, the backing layer is prepared from the following raw materials: a backing layer matrix and purified water, and the backing layer matrix is ​​selected from one of HA (hyaluronic acid), HPMC (hydroxypropyl methylcellulose) and PVA (polyvinyl alcohol).

[0011] Preferably, the backing layer matrix is ​​HA, and the molecular weight of HA is 10-300 kDa.

[0012] Furthermore, the drug preparation is cast using a PDMS microneedle negative mold as a mold, and the parameters of the PDMS microneedle negative mold are as follows: the needle shape is a cone, the needle height is 600 μm, the cone bottom diameter is 300 μm, the needle tip diameter is 15-20 μm, the array number is 40×40, the overall size is 25 mm×25 mm, and the overall groove depth is 1.5 mm.

[0013] Furthermore, the weight ratio of the traditional Chinese medicine compound ointment, the microneedle matrix and the backing layer matrix is ​​1:0.4-1.5:0.2-0.6.

[0014] The preparation method of the Chinese medicine compound clear paste comprises the following steps: Step A1: Weigh bupleurum root, yellow turmeric, cyperus rotundus, white peony root, frankincense, pinellia tuber, thunbergia thunbergii, selfheal, camphor essential oil and turpentine in a weight ratio of 3:2:1.5:1:1:0.5:0.5:0.5:1:1, use a grinder to grind bupleurum root, yellow turmeric, cyperus rotundus, white peony root, frankincense, pinellia tuber, thunbergia thunbergii and selfheal, and then pass through a 40-mesh sieve to obtain crude drug powder; Step A2: add 70% ethanol solution to the crude drug powder obtained in step A1 at a mass volume ratio of 1 g: 8 mL, and extract by heating reflux method at a temperature of 80°C for 2 h. After completion, filter the extract and the residue with filter cloth to separate them, add the same volume of 70% ethanol solution as that used in the first extraction to the residue for further extraction, repeat the extraction and filtration 3 times, and combine the 3 extracts to obtain a combined extract; Step A3: using a rotary evaporator to concentrate the combined extract obtained in step A2, the rotation speed is 50 r / min, the heating temperature is 30°C, the rotary evaporator is connected to an ethanol coolant circulation pump, the temperature of the ethanol coolant circulation pump is set to -10°C, and the combined extract is concentrated to each milliliter of concentrated solution equivalent to 3.5-4 g of crude drug powder, to obtain a Chinese medicine compound extract concentrate; Step A4: Add the camphor essential oil and turpentine weighed in step A1 to the Chinese medicine compound extract concentrate obtained in step A3, and stir and mix for 20 min under a constant temperature magnetic stirrer at a stirring speed of 100 r / min to obtain a Chinese medicine compound clear paste.

[0015] The present invention also provides a method for preparing a pharmaceutical preparation for treating breast hyperplasia, which specifically comprises the following steps: (1): Weigh the microneedle matrix and purified water in a weight ratio of 0.4-1.5:2, add the weighed microneedle matrix into the purified water, and stir for 20 min to dissolve under a constant temperature magnetic stirrer at a stirring speed of 80 r / min and a temperature of 45°C to obtain a microneedle matrix solution; (2): Weigh 1 portion of the traditional Chinese medicine compound paste and add it to the microneedle matrix solution obtained in step (1), stir in a constant temperature magnetic stirrer at 45°C for 10 min to mix well, and stir at a speed of 150 r / min to obtain a drug-loaded microneedle matrix solution; (3): Pour the drug-loaded microneedle matrix solution obtained in step (2) into the PDMS microneedle negative mold while it is hot, centrifuge it in a centrifuge at 4000 r / min for 20 min to remove bubbles, scrape the drug-loaded microneedle matrix solution flat with a plastic scraper, and cure it in a vacuum desiccator at room temperature for 6 h to obtain a drug-loaded microneedle layer; (4): Weigh the backing layer matrix and purified water in a weight ratio of 0.2-0.6:2, add the weighed backing layer matrix into the purified water, stir in a constant temperature magnetic stirrer at 45°C for 20 min to dissolve, and stir at a speed of 80 r / min to obtain a backing layer matrix solution; (5): Pour the backing layer matrix solution obtained in step (4) into the PDMS microneedle negative mold containing the drug-loaded microneedle layer in step (3) while it is still hot, centrifuge again at 4000 r / min for 20 min, scrape off the excess backing layer matrix solution, and cure in a vacuum dryer at room temperature for 12 h to obtain a backing layer connected to the drug-loaded microneedle layer. After drying, carefully demold the backing layer with tweezers to obtain a Chinese medicine compound microneedle; (6): Adhere one side of the Chinese medicine compound microneedle backing layer obtained in step (5) to the adhesive surface of a blank medical adhesive tape to obtain a Chinese medicine compound microneedle patch, i.e., a drug preparation for treating breast hyperplasia.

[0016] The beneficial effects achieved by the present invention are as follows: The pharmaceutical preparation for treating breast hyperplasia prepared by the present invention has positive significance in improving drug penetration and absorption, promoting skin repair and regeneration, and the used Bupleurum chinense, Curcuma chinensis and Cyperus rotundus have the effects of soothing the liver and relieving depression, and Fritillaria thunbergii and Pinellia tuber have the effects of clearing heat and resolving phlegm, dispersing nodules and reducing swelling, assisting in dredging stasis and softening hyperplastic tissue, complementing the heat-clearing and detoxifying effect of Prunella vulgaris, neutralizing the warm nature of other medicinal materials, and avoiding excessive stimulation to the skin; White Peony Root and Pinellia tuber in the compound can improve drug penetration, and components such as paeoniflorin and gingerol interact with each other to effectively reduce the irritation caused by other components. The designed Chinese medicine compound focuses on overall conditioning, and can achieve multiple effects such as regulating endocrine, soothing the liver and regulating qi, promoting blood circulation and removing blood stasis, reducing swelling and dispersing nodules, and anti-inflammatory and analgesic. The drug-loaded microneedle layer prepared by the soluble microneedle matrix and the Chinese herbal compound clear paste has sufficient mechanical strength and can effectively pierce the stratum corneum and epidermis without touching the pain nerves. The selected microneedle matrix can also maintain a gel network structure under the skin, and slowly release and efficiently deliver the active ingredients such as saponins, flavonoids and alkaloids in the Chinese herbal compound clear paste to the breast hyperplasia lesions, maintaining effective concentrations for a long time and exerting a sustained therapeutic effect; in addition, the essential oils and volatile oils in the Chinese herbal compound clear paste not only promote the fat-soluble components to enter the deep layer of the skin, but also easily form a microemulsified system in the hydrophilic environment of the microneedle matrix. This system helps to maintain the hydration state of the skin, plays a moisturizing, anti-inflammatory, antibacterial and antioxidant role, and provides a good microenvironment for the repair of skin cells. The presence of the backing layer can form a barrier to effectively prevent the drug in the microneedle from diffusing to the adhesive patch and reduce losses. Compared with traditional oral or injection treatments, microneedle patches are non-traumatic and easy to operate. At the same time, microneedle patches can avoid adverse reactions caused by drug metabolism through the gastrointestinal tract, increase blood drug concentrations, have high safety, and are suitable for patients with breast hyperplasia.

[0017] Compared with the existing technology, the present invention provides a safe, effective and convenient treatment plan for breast hyperplasia through the combination of effective ingredients and the application of microneedle technology, which has significant clinical application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 The present invention is a flow chart of the preparation of a pharmaceutical preparation for treating breast hyperplasia; Figure 2 A schematic diagram of the structural composition of a pharmaceutical preparation for treating breast hyperplasia according to the present invention; Figure 3 for Figure 2 A magnified image of a single microneedle in part A; Figure 4 A force-displacement curve diagram of a pharmaceutical preparation for treating breast hyperplasia prepared in Example 1-6; Figure 5 This is a scanning electron microscope image of a pharmaceutical preparation for treating breast hyperplasia prepared in Example 6; Figure 6 The H&E tissue section staining results of pig skin using a pharmaceutical preparation for treating breast hyperplasia prepared in Examples 2-4 and 6.

[0019] Among them, 1. Chinese medicine compound microneedle patch, 2. drug-loaded microneedle layer, 201. Chinese medicine compound clear paste, 202. microneedle matrix solution, 3. backing layer, 4. medical blank adhesive patch, a, b, c and d are H&E tissue section staining images of pig skin after applying the Chinese medicine compound microneedle patches prepared in Examples 2-4 and Example 6, respectively.

[0020] The accompanying drawings are used to provide further understanding of the present invention and constitute a part of the specification. They are used to explain the present invention together with the embodiments of the present invention and do not constitute a limitation of the present invention. DETAILED DESCRIPTION

[0021] 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.

[0022] 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.

[0023] The preparation process in the following examples is referred to Figure 1 The structure of the prepared drug preparation for treating breast hyperplasia is as follows Figure 2 As shown, a single microneedle is composed of Figure 3As shown, unless otherwise specified, all methods are conventional; the materials used in the following embodiments, unless otherwise specified, are new materials purchased from the market.

[0024] The invention provides a drug preparation for treating breast hyperplasia, which comprises a drug-loaded microneedle layer, a backing layer connected to the drug-loaded microneedle layer, and a medical blank adhesive tape adhered to the backing layer.

[0025] The drug-loaded microneedle layer is prepared from the following raw materials: traditional Chinese medicine compound ointment, microneedle matrix and purified water.

[0026] The traditional Chinese medicine compound clear paste is prepared from the following raw materials: northern bupleurum, yellow silk curcuma, cyperus rotundus, white peony root, frankincense, pinellia, thunbergia thunbergii, selfheal, camphor essential oil, turpentine and 70% ethanol solution.

[0027] The backing layer is prepared from the following raw materials: a backing layer matrix and purified water.

[0028] The preparation method of the Chinese medicine compound clear paste comprises the following steps: Step A1: Weigh bupleurum root, yellow turmeric, cyperus rotundus, white peony root, frankincense, pinellia tuber, thunbergia thunbergii, selfheal, camphor essential oil and turpentine in a weight ratio of 3:2:1.5:1:1:0.5:0.5:0.5:1:1, use a grinder to grind bupleurum root, yellow turmeric, cyperus rotundus, white peony root, frankincense, pinellia tuber, thunbergia thunbergii and selfheal, and then pass through a 40-mesh sieve to obtain crude drug powder; Step A2: add 70% ethanol solution to the crude drug powder obtained in step A1 at a mass volume ratio of 1 g: 8 mL, and extract by heating reflux method at a temperature of 80°C for 2 h. After completion, filter the extract and the residue with filter cloth to separate them, add the same volume of 70% ethanol solution as that used in the first extraction to the residue for further extraction, repeat the extraction and filtration 3 times, and combine the 3 extracts to obtain a combined extract; Step A3: using a rotary evaporator to concentrate the combined extract obtained in step A2, the rotation speed is 50 r / min, the heating temperature is 30°C, the rotary evaporator is connected to an ethanol coolant circulation pump, the temperature of the ethanol coolant circulation pump is set to -10°C, and the combined extract is concentrated to each milliliter of concentrated solution equivalent to 3.5-4 g of crude drug powder, to obtain a Chinese medicine compound extract concentrate; Step A4: Add the camphor essential oil and turpentine weighed in step A1 to the Chinese medicine compound extract concentrate obtained in step A3, and stir and mix for 20 min under a constant temperature magnetic stirrer at a stirring speed of 100 r / min to obtain a Chinese medicine compound clear paste.

[0029] The present invention also provides a method for preparing a pharmaceutical preparation for treating breast hyperplasia, which specifically comprises the following steps: (1): Weigh the microneedle matrix and purified water in a weight ratio of 0.4-1.5:2, add the weighed microneedle matrix into the purified water, and stir for 20 min to dissolve under a constant temperature magnetic stirrer at a stirring speed of 80 r / min and a temperature of 45°C to obtain a microneedle matrix solution; (2): Weigh 1 portion of the traditional Chinese medicine compound paste and add it to the microneedle matrix solution obtained in step (1), stir in a constant temperature magnetic stirrer at 45°C for 10 min to mix well, and stir at a speed of 150 r / min to obtain a drug-loaded microneedle matrix solution; (3): Pour the drug-loaded microneedle matrix solution obtained in step (2) into the PDMS microneedle negative mold while it is hot, centrifuge it in a centrifuge at 4000 r / min for 20 min to remove bubbles, scrape the drug-loaded microneedle matrix solution flat with a plastic scraper, and cure it in a vacuum desiccator at room temperature for 6 h to obtain a drug-loaded microneedle layer; (4): Weigh the backing layer matrix and purified water in a weight ratio of 0.2-0.6:2, add the weighed backing layer matrix into the purified water, stir in a constant temperature magnetic stirrer at 45°C for 20 min to dissolve, and stir at a speed of 80 r / min to obtain a backing layer matrix solution; (5): Pour the backing layer matrix solution obtained in step (4) into the PDMS microneedle negative mold containing the drug-loaded microneedle layer in step (3) while it is still hot, centrifuge again at 4000 r / min for 20 min, scrape off the excess backing layer matrix solution, and cure in a vacuum dryer at room temperature for 12 h to obtain a backing layer connected to the drug-loaded microneedle layer. After drying, carefully demold the backing layer with tweezers to obtain a Chinese medicine compound microneedle; (6): Adhere one side of the Chinese medicine compound microneedle backing layer obtained in step (5) to the adhesive surface of a blank medical adhesive tape to obtain a Chinese medicine compound microneedle patch, i.e., a drug preparation for treating breast hyperplasia.

[0030] By selecting a single microneedle matrix or a combination of multiple microneedle matrices to load the Chinese herbal compound ointment, soluble drug-loaded microneedle layers with different appearance, mechanical properties and hygroscopicity are prepared, thereby obtaining Chinese herbal compound microneedle patches with different drug loading capacities and skin puncture capacities. The prescription formula is shown in Table 1.

[0031] Table 1 Prescription composition of Chinese medicine compound microneedle patch

[0032] Example 1: This example adopts the raw material composition ratio of Group 1 in Table 1 to provide a pharmaceutical preparation for treating breast hyperplasia, including a drug-loaded microneedle layer, a backing layer connected to the drug-loaded microneedle layer, and a medical blank adhesive patch adhered to the backing layer. The components are 1 part by weight of Chinese medicine compound clear paste, 0.4 part by weight of PVP K90, and 0.2 part by weight of HA.

[0033] This embodiment also provides a method for preparing a pharmaceutical preparation for treating breast hyperplasia, which specifically comprises the following steps: (1): Weigh 0.4 parts of PVP K90 and add it to 2 parts of purified water. Stir for 20 min under a constant temperature magnetic stirrer at a speed of 80 r / min and a temperature of 45°C to dissolve the microneedle matrix solution. (2): Weigh 1 portion of the traditional Chinese medicine compound paste and add it to the microneedle matrix solution obtained in step (1), stir in a constant temperature magnetic stirrer at 45°C for 10 min to mix well, and stir at a speed of 150 r / min to obtain a drug-loaded microneedle matrix solution; (3): Pour the drug-loaded microneedle matrix solution obtained in step (2) into the PDMS microneedle negative mold while it is hot, centrifuge it in a centrifuge at 4000 r / min for 20 min to remove bubbles, scrape the drug-loaded microneedle matrix solution flat with a plastic scraper, and cure it in a vacuum desiccator at room temperature for 6 h to obtain a drug-loaded microneedle layer; (4): Weigh 0.2 parts of HA, add it to 2 parts of purified water, stir it in a constant temperature magnetic stirrer at 45°C for 20 min to dissolve it, and stir it at a speed of 80 r / min to obtain a backing layer matrix solution; (5): Pour the backing layer matrix solution obtained in step (4) into the PDMS microneedle negative mold containing the drug-loaded microneedle layer in step (3) while it is still hot, centrifuge again at 4000 r / min for 20 min, scrape off the excess backing layer matrix solution, and cure in a vacuum dryer at room temperature for 12 h to obtain a backing layer connected to the drug-loaded microneedle layer. After drying, carefully demold the backing layer with tweezers to obtain a Chinese medicine compound microneedle; (6): Adhere one side of the Chinese medicine compound microneedle backing layer obtained in step (5) to the adhesive surface of a blank medical adhesive tape to obtain a Chinese medicine compound microneedle patch, i.e., a drug preparation for treating breast hyperplasia.

[0034] Example 2: This example adopts the raw material composition ratio of Group 2 in Table 1 to provide a pharmaceutical preparation for treating breast hyperplasia, including a drug-loaded microneedle layer, a backing layer connected to the drug-loaded microneedle layer, and a medical blank adhesive patch adhered to the backing layer. The components are 1 part by weight of Chinese medicine compound clear paste, 1 part by weight of PVP K90, and 0.4 part by weight of HA.

[0035] This embodiment also provides a method for preparing a pharmaceutical preparation for treating breast hyperplasia, which specifically comprises the following steps: (1): Weigh 1 part of PVP K90 and add it to 2 parts of purified water. Stir for 20 min under a constant temperature magnetic stirrer at a speed of 80 r / min and a temperature of 45°C to obtain a microneedle matrix solution; (2): Weigh 1 portion of the traditional Chinese medicine compound paste and add it to the microneedle matrix solution obtained in step (1), stir in a constant temperature magnetic stirrer at 45°C for 10 min to mix well, and stir at a speed of 150 r / min to obtain a drug-loaded microneedle matrix solution; (3): Pour the drug-loaded microneedle matrix solution obtained in step (2) into the PDMS microneedle negative mold while it is hot, centrifuge it in a centrifuge at 4000 r / min for 20 min to remove bubbles, scrape the drug-loaded microneedle matrix solution flat with a plastic scraper, and cure it in a vacuum desiccator at room temperature for 6 h to obtain a drug-loaded microneedle layer; (4): Weigh 0.4 parts of HA, add it to 2 parts of purified water, stir it in a constant temperature magnetic stirrer at 45°C for 20 min to dissolve it, and stir it at a speed of 80 r / min to obtain a backing layer matrix solution; (5): Pour the backing layer matrix solution obtained in step (4) into the PDMS microneedle negative mold containing the drug-loaded microneedle layer in step (3) while it is still hot, centrifuge again at 4000 r / min for 20 min, scrape off the excess backing layer matrix solution, and cure in a vacuum dryer at room temperature for 12 h to obtain a backing layer connected to the drug-loaded microneedle layer. After drying, carefully demold the backing layer with tweezers to obtain a Chinese medicine compound microneedle; (6): Adhere one side of the Chinese medicine compound microneedle backing layer obtained in step (5) to the adhesive surface of a blank medical adhesive tape to obtain a Chinese medicine compound microneedle patch, i.e., a drug preparation for treating breast hyperplasia.

[0036] Example 3: This example adopts the raw material composition ratio of Group 3 in Table 1 to provide a pharmaceutical preparation for treating breast hyperplasia, including a drug-loaded microneedle layer, a backing layer connected to the drug-loaded microneedle layer, and a medical blank adhesive patch adhered to the backing layer. The components are 1 part by weight of Chinese medicine compound clear paste, 0.5 part by weight of PVP K90, 0.5 part by weight of CMC-Na, and 0.4 part by weight of HA.

[0037] This embodiment also provides a method for preparing a pharmaceutical preparation for treating breast hyperplasia, which specifically comprises the following steps: (1): Weigh 0.5 parts of PVP K90 and 0.5 parts of CMC-Na, add them to 2 parts of purified water, and stir for 20 min under a constant temperature magnetic stirrer at a speed of 80 r / min and a temperature of 45°C to obtain a microneedle matrix solution; (2): Weigh 1 portion of the traditional Chinese medicine compound paste and add it to the microneedle matrix solution obtained in step (1), stir in a constant temperature magnetic stirrer at 45°C for 10 min to mix well, and stir at a speed of 150 r / min to obtain a drug-loaded microneedle matrix solution; (3): Pour the drug-loaded microneedle matrix solution obtained in step (2) into the PDMS microneedle negative mold while it is hot, centrifuge it in a centrifuge at 4000 r / min for 20 min to remove bubbles, scrape the drug-loaded microneedle matrix solution flat with a plastic scraper, and cure it in a vacuum desiccator at room temperature for 6 h to obtain a drug-loaded microneedle layer; (4): Weigh 0.4 parts of HA, add it to 2 parts of purified water, stir it in a constant temperature magnetic stirrer at 45°C for 20 min to dissolve, and stir at a speed of 80 r / min to obtain a backing layer matrix solution; (5): Pour the backing layer matrix solution obtained in step (4) into the PDMS microneedle negative mold containing the drug-loaded microneedle layer in step (3) while it is still hot, centrifuge again at 4000 r / min for 20 min, scrape off the excess backing layer matrix solution, and cure in a vacuum dryer at room temperature for 12 h to obtain a backing layer connected to the drug-loaded microneedle layer. After drying, carefully demold the backing layer with tweezers to obtain a Chinese medicine compound microneedle; (6): Adhere one side of the Chinese medicine compound microneedle backing layer obtained in step (5) to the adhesive surface of a blank medical adhesive tape to obtain a Chinese medicine compound microneedle patch, i.e., a drug preparation for treating breast hyperplasia.

[0038] Example 4: This example adopts the raw material composition ratio of group 4 in Table 1 to provide a pharmaceutical preparation for treating breast hyperplasia, including a drug-loaded microneedle layer, a backing layer connected to the drug-loaded microneedle layer, and a medical blank adhesive patch adhered to the backing layer. The components are 1 part by weight of traditional Chinese medicine compound clear paste, 0.5 part by weight of PVP K90, 0.5 part by weight of CS, and 0.4 part by weight of HA.

[0039] This embodiment also provides a method for preparing a pharmaceutical preparation for treating breast hyperplasia, which specifically comprises the following steps: (1): Weigh 0.5 parts of PVP K90 and 0.5 parts of CS, add them to 2 parts of purified water, and stir them for 20 min under a constant temperature magnetic stirrer at a speed of 80 r / min and a temperature of 45°C to obtain a microneedle matrix solution; (2): Weigh 1 portion of the traditional Chinese medicine compound paste and add it to the microneedle matrix solution obtained in step (1), stir in a constant temperature magnetic stirrer at 45°C for 10 min to mix well, and stir at a speed of 150 r / min to obtain a drug-loaded microneedle matrix solution; (3): Pour the drug-loaded microneedle matrix solution obtained in step (2) into the PDMS microneedle negative mold while it is hot, centrifuge it in a centrifuge at 4000 r / min for 20 min to remove bubbles, scrape the drug-loaded microneedle matrix solution flat with a plastic scraper, and cure it in a vacuum desiccator at room temperature for 6 h to obtain a drug-loaded microneedle layer; (4): Weigh 0.4 parts of HA, add it to 2 parts of purified water, stir it in a constant temperature magnetic stirrer at 45°C for 20 min to dissolve, and stir at a speed of 80 r / min to obtain a backing layer matrix solution; (5): Pour the backing layer matrix solution obtained in step (4) into the PDMS microneedle negative mold containing the drug-loaded microneedle layer in step (3) while it is still hot, centrifuge again at 4000 r / min for 20 min, scrape off the excess backing layer matrix solution, and cure in a vacuum dryer at room temperature for 12 h to obtain a backing layer connected to the drug-loaded microneedle layer. After drying, carefully demold the backing layer with tweezers to obtain a Chinese medicine compound microneedle; (6): Adhere one side of the Chinese medicine compound microneedle backing layer obtained in step (5) to the adhesive surface of a blank medical adhesive tape to obtain a Chinese medicine compound microneedle patch, i.e., a drug preparation for treating breast hyperplasia.

[0040] Example 5: This example adopts the raw material composition ratio of Group 5 in Table 1 to provide a pharmaceutical preparation for treating breast hyperplasia, including a drug-loaded microneedle layer, a backing layer connected to the drug-loaded microneedle layer, and a medical blank adhesive patch adhered to the backing layer. The components are 1 part by weight of Chinese medicine compound clear paste, 0.2 part by weight of PVP K90, 0.2 part by weight of Gantrez AN-139, and 0.2 part by weight of HA.

[0041] This embodiment also provides a method for preparing a pharmaceutical preparation for treating breast hyperplasia, which specifically comprises the following steps: (1): Weigh 0.2 parts of PVP K90 and 0.2 parts of Gantrez AN-139, add them to 2 parts of purified water, and stir for 20 min under a constant temperature magnetic stirrer at a speed of 80 r / min and a temperature of 45°C to obtain a microneedle matrix solution; (2): Weigh 1 portion of the traditional Chinese medicine compound paste and add it to the microneedle matrix solution obtained in step (1), stir in a constant temperature magnetic stirrer at 45°C for 10 min to mix well, and stir at a speed of 150 r / min to obtain a drug-loaded microneedle matrix solution; (3): Pour the drug-loaded microneedle matrix solution obtained in step (2) into the PDMS microneedle negative mold while it is hot, centrifuge it in a centrifuge at 4000 r / min for 20 min to remove bubbles, scrape the drug-loaded microneedle matrix solution flat with a plastic scraper, and cure it in a vacuum desiccator at room temperature for 6 h to obtain a drug-loaded microneedle layer; (4): Weigh 0.2 parts of HA, add it to 2 parts of purified water, stir it in a constant temperature magnetic stirrer at 45°C for 20 min to dissolve it, and stir it at a speed of 80 r / min to obtain a backing layer matrix solution; (5): Pour the backing layer matrix solution obtained in step (4) into the PDMS microneedle negative mold containing the drug-loaded microneedle layer in step (3) while it is still hot, centrifuge again at 4000 r / min for 20 min, scrape off the excess backing layer matrix solution, and cure in a vacuum dryer at room temperature for 12 h to obtain a backing layer connected to the drug-loaded microneedle layer. After drying, carefully demold the backing layer with tweezers to obtain a Chinese medicine compound microneedle; (6): Adhere one side of the Chinese medicine compound microneedle backing layer obtained in step (5) to the adhesive surface of a blank medical adhesive tape to obtain a Chinese medicine compound microneedle patch, i.e., a drug preparation for treating breast hyperplasia.

[0042] Example 6: This example adopts the raw material composition ratio of Group 6 in Table 1 to provide a pharmaceutical preparation for treating breast hyperplasia, including a drug-loaded microneedle layer, a backing layer connected to the drug-loaded microneedle layer, and a medical blank adhesive patch adhered to the backing layer. The components are 1 part by weight of Chinese medicine compound clear paste, 0.5 part by weight of PVP K90, 0.5 part by weight of Gantrez AN-139, and 0.4 part by weight of HA.

[0043] This embodiment also provides a method for preparing a pharmaceutical preparation for treating breast hyperplasia, which specifically comprises the following steps: (1): Weigh 0.5 parts of PVP K90 and 0.5 parts of Gantrez AN-139, add them to 2 parts of purified water, and stir for 20 min under a constant temperature magnetic stirrer at a speed of 80 r / min and a temperature of 45°C to obtain a microneedle matrix solution; (2): Weigh 1 portion of the traditional Chinese medicine compound paste and add it to the microneedle matrix solution obtained in step (1), stir in a constant temperature magnetic stirrer at 45°C for 10 min to mix well, and stir at a speed of 150 r / min to obtain a drug-loaded microneedle matrix solution; (3): Pour the drug-loaded microneedle matrix solution obtained in step (2) into the PDMS microneedle negative mold while it is hot, centrifuge it in a centrifuge at 4000 r / min for 20 min to remove bubbles, scrape the drug-loaded microneedle matrix solution flat with a plastic scraper, and cure it in a vacuum desiccator at room temperature for 6 h to obtain a drug-loaded microneedle layer; (4): Weigh 0.4 parts of HA, add it to 2 parts of purified water, stir it in a constant temperature magnetic stirrer at 45°C for 20 min to dissolve, and stir at a speed of 80 r / min to obtain a backing layer matrix solution; (5): Pour the backing layer matrix solution obtained in step (4) into the PDMS microneedle negative mold containing the drug-loaded microneedle layer in step (3) while it is still hot, centrifuge again at 4000 r / min for 20 min, scrape off the excess backing layer matrix solution, and cure in a vacuum dryer at room temperature for 12 h to obtain a backing layer connected to the drug-loaded microneedle layer. After drying, carefully demold the backing layer with tweezers to obtain a Chinese medicine compound microneedle; (6): Adhere one side of the Chinese medicine compound microneedle backing layer obtained in step (5) to the adhesive surface of a blank medical adhesive tape to obtain a Chinese medicine compound microneedle patch, i.e., a drug preparation for treating breast hyperplasia.

[0044] Example 7: This example adopts the raw material composition ratio of Group 7 in Table 1 to provide a pharmaceutical preparation for treating breast hyperplasia, including a drug-loaded microneedle layer, a backing layer connected to the drug-loaded microneedle layer, and a medical blank adhesive patch adhered to the backing layer. The components are 1 part by weight of traditional Chinese medicine compound clear paste, 1 part by weight of PVP K90, 0.5 part by weight of Gantrez AN-139, and 0.6 part by weight of HA.

[0045] This embodiment also provides a method for preparing a pharmaceutical preparation for treating breast hyperplasia, which specifically comprises the following steps: (1): Weigh 1 part of PVP K90 and 0.5 part of Gantrez AN-139, add them to 2 parts of purified water, and stir for 20 min under a constant temperature magnetic stirrer at a speed of 80 r / min and a temperature of 45°C to obtain a microneedle matrix solution; (2): Weigh 1 portion of the traditional Chinese medicine compound paste and add it to the microneedle matrix solution obtained in step (1), stir in a constant temperature magnetic stirrer at 45°C for 10 min to mix well, and stir at a speed of 150 r / min to obtain a drug-loaded microneedle matrix solution; (3): Pour the drug-loaded microneedle matrix solution obtained in step (2) into the PDMS microneedle negative mold while it is hot, centrifuge it in a centrifuge at 4000 r / min for 20 min to remove bubbles, scrape the drug-loaded microneedle matrix solution flat with a plastic scraper, and cure it in a vacuum desiccator at room temperature for 6 h to obtain a drug-loaded microneedle layer; (4): Weigh 0.6 parts of HA, add it to 2 parts of purified water, stir it in a constant temperature magnetic stirrer at 45°C for 20 min to dissolve, and stir at a speed of 80 r / min to obtain a backing layer matrix solution; (5): Pour the backing layer matrix solution obtained in step (4) into the PDMS microneedle negative mold containing the drug-loaded microneedle layer in step (3) while it is still hot, centrifuge again at 4000 r / min for 20 min, scrape off the excess backing layer matrix solution, and cure in a vacuum dryer at room temperature for 12 h to obtain a backing layer connected to the drug-loaded microneedle layer. After drying, carefully demold the backing layer with tweezers to obtain a Chinese medicine compound microneedle; (6): Adhere one side of the Chinese medicine compound microneedle backing layer obtained in step (5) to the adhesive surface of a blank medical adhesive tape to obtain a Chinese medicine compound microneedle patch, i.e., a drug preparation for treating breast hyperplasia.

[0046] Microneedle properties investigation The pharmaceutical preparations for treating breast hyperplasia prepared in Examples 1-6 were used to observe the microneedle arrays prepared with different microneedle matrix compositions, the integrity of the needle shape, and the ease of demolding using the naked eye and a microscope. The results are shown in Table 2.

[0047] Mechanical properties test A texture analyzer was used to evaluate the mechanical strength of the microneedles in the pharmaceutical preparations for treating breast hyperplasia prepared in Examples 1-6. Each group of dried microneedles was cut into 5×5 microneedle arrays with a scalpel for measurement. The program was set to single extrusion, and the sensor was moved from top to bottom to contact the needle tip. When the bottom of the sensor contacted the top of the microneedle, the sensor stroke and the force applied to the microneedle were recorded. The parameters were set to a maximum force of 100 N, an initial force of 0.15% of the maximum force (0.15 N), a deformation fraction of 80% (ie, 480 μm), and a downward speed of the probe of 0.04 mm / s. The instrument recorded the microneedle fracture force, from which a force-displacement curve was drawn to compare the mechanical strength differences of microneedles prepared with different microneedle matrix compositions. Results are shown in Figure 4 .

[0048] Microscopic morphology observation The drug preparation for treating breast hyperplasia prepared in Example 6 was fixed on a sample plate using conductive glue, gold was plated using a sputtering coating machine, and the morphology of the microneedles was examined using a scanning electron microscope. Figure 5 shown.

[0049] Skin puncture ability test The H&E tissue section method was used to investigate the skin puncture ability of the drug preparations for treating breast hyperplasia prepared in Examples 2-4 and Example 6. Take a piece of pig skin, shave the hair on the surface and cut it into 4 pieces. Apply the Chinese medicine compound microneedle patch prepared in Examples 2-4 and Example 6 for 3 minutes respectively. Cut the skin where the microneedles are located, soak it in 4% paraformaldehyde solution for fixation, embed the cut skin with liquid paraffin and slice it, stain the slices with hematoxylin and eosin, and observe the degree of microneedle penetration under a microscope. The tissue section staining results are shown in Figure 6 .

[0050] Table 2 Microneedle properties

[0051] The results in Table 2 show that the pharmaceutical preparations for treating breast hyperplasia prepared in Examples 5-7 have good molding effects and are easy to demould. Figure 4 The force-displacement curve results show that the composite microneedle matrix has higher mechanical strength than the single matrix and is not easy to remain on the mold.

[0052] Figure 5The results showed that the microneedles in the drug preparation for treating breast hyperplasia prepared in Example 6 were conical in shape, straight in shape, without collapse or defects, and the morphology of each microneedle was uniform.

[0053] Figure 6 The H&E tissue section staining results showed that the drug preparations for treating breast hyperplasia prepared in Examples 2-4 and Example 6 can effectively penetrate the stratum corneum and epidermis of the skin without touching the nerve endings in the dermis, and can achieve the effect of painless drug administration.

[0054] In summary, it can be seen from the test results of the examples that the drug preparation for treating breast hyperplasia prepared by the present invention delivers the effective active ingredients in the Chinese medicine compound to the hyperplasia lesions in the form of a microneedle patch, thereby increasing the local drug concentration and avoiding the first-pass effect of the drug after oral administration, and can play a role in rapid treatment. At the same time, compared with intravenous injection, the patient has good compliance and no pain, and the soluble microneedle matrix used has good biocompatibility, dissolves and releases the drug after piercing the skin, and will not remain in the body.

[0055] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

[0056] 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 pharmaceutical preparation for treating breast hyperplasia, characterized in that: It includes a drug-loaded microneedle layer, a backing layer connected to the drug-loaded microneedle layer, and a medical blank adhesive patch adhered to the backing layer; The drug-loaded microneedle layer is prepared from the following raw materials: a traditional Chinese medicine compound ointment, a microneedle matrix and purified water; The Chinese medicine compound clear paste is prepared from the following raw materials: northern bupleurum, yellow silk curcuma, cyperus, white peony root, frankincense, pinellia, thunbergia thunbergii, selfheal, camphor essential oil, turpentine and 70% ethanol solution; The backing layer is prepared from the following raw materials: a backing layer matrix and purified water; The weight ratio of the traditional Chinese medicine compound ointment, the microneedle matrix and the backing layer matrix is ​​1:0.4-1.5:0.2-0.

6.

2. A pharmaceutical preparation for treating breast hyperplasia according to claim 1, characterized in that: The preparation method of the Chinese medicine compound clear paste comprises the following steps: Step A1: weigh Bupleurum chinense, Curcuma aromatica, Cyperus rotundus, White Peony Root, Olibanum, Pinellia ternata, Fritillaria thunbergii and Prunella vulgaris, and grind and sieve to obtain crude drug powder; Step A2: adding 70% ethanol solution to the crude drug powder obtained in step A1, heating for extraction, separating the extract and the filter residue, adding 70% ethanol solution to the filter residue for repeated extraction, and combining the extracts to obtain a combined extract; Step A3: concentrating the combined extract obtained in step A2 to obtain a concentrated extract of the Chinese herbal compound; Step A4: Weigh camphor essential oil and turpentine oil, add them to the Chinese medicine compound extract concentrate obtained in step A3, stir and mix well to obtain the Chinese medicine compound clear paste.

3. A pharmaceutical preparation for treating breast hyperplasia according to claim 2, characterized in that: The weight ratio of the bupleurum root, yellow silk curcuma, cyperus rotundus, white peony root, frankincense, pinellia tuber, thunbergia thunbergii, selfheal, camphor essential oil and turpentine oil is 3:2:1.5:1:1:0.5:0.5:0.5:1:1; In step A1, the crushing process uses a crusher, and the sieving screen is 40 mesh; In step A2, the mass volume ratio of the crude drug powder and the 70% ethanol solution is 1 g: 8 mL, the extraction adopts the heating reflux method, the temperature is 80°C, the extraction time is 2 h, the separation process uses a filter cloth, the extraction is repeated 3 times, and the volume of the 70% ethanol solution added each time is the same; In step A3, the concentration process uses a rotary evaporator with a rotation speed of 50 r / min and a heating temperature of 30° C. The rotary evaporator is connected to an ethanol coolant circulation pump and the temperature is set to -10° C.; In step A4, the stirring process is carried out under a constant temperature magnetic stirrer, with a stirring time of 20 min and a rotation speed of 100 r / min.

4. A method for preparing a pharmaceutical preparation for treating breast hyperplasia according to any one of claims 1 to 3, characterized in that: The steps include: (1): Weigh the microneedle matrix and dissolve it in purified water to obtain a microneedle matrix solution; (2): Weigh the Chinese medicine compound paste, add it to the microneedle matrix solution obtained in step (1), stir and mix well to obtain a drug-loaded microneedle matrix solution; (3): Pour the drug-loaded microneedle matrix solution obtained in step (2) into the mold while it is hot, centrifuge to remove bubbles, scrape and solidify, and obtain a drug-loaded microneedle layer; (4): Weigh the backing layer matrix and dissolve it in purified water to obtain a backing layer matrix solution; (5): pouring the backing layer matrix solution obtained in step (4) into the mold containing the drug-loaded microneedle layer in step (3) while it is still hot, and solidifying it after centrifugal scraping to obtain a backing layer connected to the drug-loaded microneedle layer, and removing it from the mold to obtain a Chinese medicine compound microneedle; (6): Adhere one side of the Chinese medicine compound microneedle backing layer obtained in step (5) to the adhesive surface of a blank medical adhesive tape to obtain a Chinese medicine compound microneedle patch, i.e., a drug preparation for treating breast hyperplasia.

5. A method for preparing a pharmaceutical preparation for treating breast hyperplasia according to claim 4, characterized in that: In step (1) and step (4), the weight ratio of the microneedle matrix to purified water is 0.4-1.5:2, and the weight ratio of the backing layer matrix to purified water is 0.2-0.6:

2. The dissolution process is carried out under a constant temperature magnetic stirrer, with a stirring time of 20 min, a rotation speed of 80 r / min, and a temperature of 45°C; In step (2), the stirring process is carried out under a constant temperature magnetic stirrer, with a stirring time of 10 min, a rotation speed of 150 r / min, and a temperature of 45°C; In step (3) and step (5), the centrifugation process uses a centrifuge, the centrifugation time is 20 min, and the centrifugation speed is 4000 r / min. The curing process is carried out in a vacuum dryer at room temperature. The curing time in step (3) is 6 h, and the curing time in step (5) is 12 h.

6. The method for preparing a pharmaceutical preparation for treating breast hyperplasia according to claim 5, characterized in that: The mold is a PDMS microneedle negative mold.

7. A method for preparing a pharmaceutical preparation for treating breast hyperplasia according to claim 6, characterized in that: The microneedle matrix is ​​selected from one or more of CMC-Na, CS, silk fibroin, PVP K90, and Gantrez AN-139, and the backing layer matrix is ​​selected from one of HA, HPMC, and PVA.

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